tag:theconversation.com,2011:/fr/topics/neurodegenerative-disease-391/articlesNeurodegenerative disease – The Conversation2024-02-16T21:54:28Ztag:theconversation.com,2011:article/2228122024-02-16T21:54:28Z2024-02-16T21:54:28ZChronic wasting disease has been detected in British Columbia deer, and we need to act now<p>Since 1996, <a href="https://doi.org/10.20506/rst.21.2.1340">a deadly neurodegenerative disease</a> of cervids (deer, elk, moose, caribou, reindeer) has been spreading across Canada. </p>
<p>On Jan. 31, 2024, chronic wasting disease (CWD) was detected for the <a href="https://news.gov.bc.ca/releases/2024WLRS0005-000125">first time in British Columbia</a> in two deer. In just over half a century from its <a href="https://inspection.canada.ca/animal-health/terrestrial-animals/diseases/reportable/cwd/eng/1330143462380/1330143991594">first detection in the United States</a>, it has since been reported in <a href="https://www.usgs.gov/media/images/distribution-chronic-wasting-disease-north-america-0">32 states, five provinces (Alberta, Saskatchewan, Québec, Manitoba and British Columbia)</a>, as well as in Norway, Sweden, Finland and South Korea.</p>
<h2>Disease-causing proteins</h2>
<p>CWD differs from other diseases, as it is caused by a <a href="https://doi.org/10.1212/CON.0000000000000251">protein called a prion</a>. The protein is similar to other normal proteins in the body, except it’s abnormally shaped. The abnormal folding of these disease-causing prion proteins — which are found most abundantly in the brain — leads to brain damage that makes the brain appear like a sponge. </p>
<p>Diseases caused by prions in this manner are called <a href="https://www.cdc.gov/prions/index.html">transmissible spongiform encephalopathies (TSEs)</a>. Other TSEs include <a href="https://www.cdc.gov/prions/cjd/index.html">Creutzfeldt-Jakob disease</a> in people, <a href="https://www.cdc.gov/prions/bse/index.html">bovine-spongiform encephalopathy</a> (“mad cow disease”) in cows, and <a href="https://inspection.canada.ca/animal-health/terrestrial-animals/diseases/reportable/scrapie/eng/1329723409732/1329723572482">scrapie</a> in sheep and goats. </p>
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<a href="https://theconversation.com/what-is-chronic-wasting-disease-a-wildlife-scientist-explains-the-fatal-prion-infection-killing-deer-and-elk-across-north-america-181753">What is chronic wasting disease? A wildlife scientist explains the fatal prion infection killing deer and elk across North America</a>
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<p>And while there is no evidence at the moment that CWD can be transmitted to people, the <a href="http://www.bccdc.ca/health-info/diseases-conditions/chronic-wasting-disease">B.C. Centre for Disease Control</a> and <a href="https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/food-related-illnesses/chronic-wasting-disease.html">Health Canada</a> recommend that people not consume meat or other parts of an infected animal. </p>
<p>The impacts of CWD extend beyond concerns over disease in people. CWD threatens our confidence in the health of wild animals, intersecting with broader issues of food safety and sovereignty. The impacts can be especially severe for individuals and communities for whom cervids are a part of traditional foods and livelihoods, such as Indigenous communities, hunters, harvesters, butchers and cervid farmers. </p>
<p>Unlike many other infectious agents, <a href="https://www.cdc.gov/prions/cwd/cwd-animals.html">animals infected with CWD do not recover and there is no current vaccine</a> to prevent infection. This means that early detection and management is critical for reducing the impact of this disease. </p>
<h2>British Columbia’s preparations</h2>
<p>Since 2002, the province of B.C. has <a href="https://www2.gov.bc.ca/gov/content/environment/plants-animals-ecosystems/wildlife/wildlife-conservation/wildlife-health/chronic-wasting-disease/cwd-surveillance-and-testing#aboutcwd">established a surveillance program</a> to detect CWD as soon as possible. </p>
<p>Now that CWD has been detected in the province, the next step will be to chart a path forward for an effective, efficient and sustainable management program. </p>
<p><div data-react-class="InstagramEmbed" data-react-props="{"url":"https://www.instagram.com/p/ClFbGiWhFLn","accessToken":"127105130696839|b4b75090c9688d81dfd245afe6052f20"}"></div></p>
<p>The good news is that we have options. Our research team has been reviewing management approaches that have been used throughout North America. Although there aren’t many examples of successful CWD eradication — New York is one exception, as <a href="https://dec.ny.gov/nature/animals-fish-plants/wildlife-health/animal-diseases/chronic-wasting-disease">the only U.S. state to have stopped a CWD outbreak</a> through an intensive and comprehensive testing and culling program — there have been tremendous efforts to reduce CWD prevalence. </p>
<p>Our research suggests that a robust approach to such a difficult disease will require rapid, collective and collaborative action across sectors. This approach must involve wildlife managers, hunters, local communities, First Nations and researchers to integrate a number of approaches.</p>
<h2>Surveillance and management</h2>
<p>Many CWD management programs rely on <a href="https://doi.org/10.1016/j.prevetmed.2013.09.011">removing infected animals from the landscape</a>. This might involve population reduction through hunting, intensive culling and by increasing harvesting permits. Targeted removal both reduces the number of infected animals in the environment and provides us with necessary samples to identify which animals are infected and where they are. </p>
<p>This is because there are currently no ways to test living animals for CWD. We require specific tissues of the head (lymph nodes and tonsils) for testing. While it is mandatory to submit the heads from hunted cervids in select management units in B.C., in most regions, submission is voluntary. Hunters can participate in CWD management and surveillance by removing the head of the animal and <a href="https://www2.gov.bc.ca/gov/content/environment/plants-animals-ecosystems/wildlife/wildlife-conservation/wildlife-health/chronic-wasting-disease/cwd-surveillance-and-testing">submitting it to a local testing station or freezer for CWD testing</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4435%2C2954&q=45&auto=format&w=1000&fit=clip"><img alt="two large elk feed on trees on the side of the road" src="https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4435%2C2954&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/576175/original/file-20240216-20-11xp2f.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Cervids, like these large elk, are at risk of chronic wasting disease in British Columbia.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
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<p>The public can also participate in <a href="https://www2.gov.bc.ca/gov/content/environment/plants-animals-ecosystems/wildlife/wildlife-conservation/wildlife-health/chronic-wasting-disease/cwd-bc">CWD surveillance and management</a> by reporting signs of sick animals and vehicle collisions with cervids.</p>
<p>While CWD is sometimes portrayed as a “<a href="https://www.theguardian.com/world/2024/feb/14/british-columbia-chronic-wasting-disease-deer">zombie deer</a>” disease, with <a href="https://inspection.canada.ca/animal-health/terrestrial-animals/diseases/reportable/cwd/what-cervid-producers-should-know/eng/1330189947852/1330190096558">staggering footsteps, weight loss and a drooping head</a>, in truth, most infected animals appear healthy. </p>
<p>An infected cervid <a href="https://doi.org/10.2147/VMRR.S197404">may not show signs of illness for 18 months to two years</a>, and by then they may have been removed from the landscape by other animals, hunters or vehicles. This is why testing cervids that have been killed by vehicles is also a critical component of CWD surveillance and management.</p>
<h2>Curbing the spread</h2>
<p>Removing and testing animals is just one part of management. CWD can <a href="https://www.cdc.gov/prions/cwd/transmission.html">spread between animals</a> through contact with bodily fluids. And although it’s not possible to manage when and where an animal dies or defecates, it is possible to restrict the movement of infected carcasses and animal fluids across and within provincial borders. Legal restrictions on <a href="https://www2.gov.bc.ca/gov/content/sports-culture/recreation/fishing-hunting/hunting/regulations-synopsis">carcass transport and the use of urine-based scents in hunting</a> can also reduce the unintentional spread of CWD. </p>
<p>Since CWD prions can remain in the environment for years, it is important to regulate the use of scents and other deer attractants and ensure carcasses are removed to prevent prions from persisting in soil and water. </p>
<p>CWD management is complex. What works in one location might not work in another. Developing a robust management program in B.C. will require community engagement to ensure management approaches are rooted in local contexts, perspectives and priorities. Research has shown that <a href="https://doi.org/10.1080/10871209.2022.2075492">community-focused communication</a> <a href="http://doi.org/10.1080/10871209.2020.1808915">and engagement are essential</a> for the success of CWD management efforts. </p>
<p>In the days ahead, fostering open dialogue and collaboration will be paramount towards an effective and sustainable effort against CWD. We’re in this together. And together we can work to protect wildlife and the people and economies that depend on them. </p>
<p><em>Erica Dong, undergraduate research assistant on the project, supported the development of this article.</em></p><img src="https://counter.theconversation.com/content/222812/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kaylee Byers is the Regional Deputy Director of the British Columbia Node of the Canadian Wildlife Health Cooperative and collaborates with the Wildlife Health Program, which leads Chronic Wasting Disease surveillance in British Columbia.</span></em></p><p class="fine-print"><em><span>Sarah Robinson does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>B.C. has operated a surveillance program for over 20 years to detect chronic wasting disease, a fatal condition with no cure or vaccine. The disease has now been detected in deer in the province.Kaylee Byers, Assistant Professor, Faculty of Health Sciences, Simon Fraser University; Senior Scientist, Pacific Institute on Pathogens, Pandemics and Society; Regional Deputy Director, BC Node of the Canadian Wildlife Health Cooperative, Simon Fraser UniversitySarah Robinson, Postdoctoral Fellow, Pacific Institute on Pathogens, Pandemics and Society, Simon Fraser UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2214032024-01-31T13:36:42Z2024-01-31T13:36:42ZSleep can give athletes an edge over competitors − but few recognize how fundamental sleep is to performance<figure><img src="https://images.theconversation.com/files/571989/original/file-20240129-15-rvkoy3.jpg?ixlib=rb-1.1.0&rect=8%2C0%2C2663%2C1778&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Sleep has been an underappreciated strategy for gaining an edge over an opponent at any level of athletic competition.</span> <span class="attribution"><a class="source" href="https://newsroom.ap.org/detail/ChiefsRavensFootball/47d36cdc32f2464d8b6aaed9cba32412/photo?Query=football%20playoffs&mediaType=photo,video,graphic,audio&sortBy=&dateRange=now-24h&totalCount=54&currentItemNo=44">AP Photo/Alex Brandon</a></span></figcaption></figure><p>In the adrenaline-packed world of professional sports, the power of sleep rarely gets adequate attention.</p>
<p>A healthy sleep pattern can be a stealthy game plan for athletes to gain an edge over their opponents. Only a <a href="https://www.cnbc.com/2018/12/21/lebron-james-reveals-the-nighttime-routine-that-sets-him-up-for-success.html">few top elite athletes</a> know the secret of early bedtimes for optimal performance.</p>
<p>Sleep is vital not only for keeping the mind sharp and body healthy but also for excelling in all fields in life – whether <a href="https://theconversation.com/school-start-times-and-screen-time-late-in-the-evening-exacerbate-sleep-deprivation-in-us-teenagers-179178">in the classroom</a>, on the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158299/">battlefield</a> or in <a href="https://doi.org/10.1093/sleep/zsab051">other professional arenas</a>. </p>
<p>As a <a href="https://www.neurology.pitt.edu/people/joanna-fong-isariyawongse-md-faes-faan">neurologist specializing in sleep medicine</a> at the University of Pittsburgh, I have devoted my career to understanding and advocating for the importance of sleep health. </p>
<p>Here are some key facts to understand why sleep matters.</p>
<h2>The critical role of sleep in performance</h2>
<p>Sleep is a complex, <a href="https://www.sleepfoundation.org/stages-of-sleep#">cyclical process</a> that progresses through several stages, each with distinct characteristics and functions. Initially, it begins with light sleep, <a href="https://www.ncbi.nlm.nih.gov/books/NBK526132/#">encompassing stages 1 and 2</a>, where the body starts to relax and brain wave activity begins to slow down. </p>
<p>These stages are followed by deep sleep, also known as <a href="https://www.sleepfoundation.org/stages-of-sleep/slow-wave-sleep#:">slow-wave sleep</a>, where the body undergoes significant restorative processes. The final stage is <a href="https://my.clevelandclinic.org/health/body/12148-sleep-basics">rapid eye movement</a>, or REM sleep, characterized by vivid dreams and increased brain activity. Typically, a person cycles through these stages four to six times each night, with each cycle lasting approximately 90 minutes. </p>
<p>Sleep is when our bodies heal. Deep sleep helps repair muscles and bones through several key mechanisms, including the release of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824213/">human growth hormone</a> – a protein produced in the pituitary gland – and various <a href="https://doi.org/10.1038/npp.2016.148">anti-inflammatory agents</a>. </p>
<p><a href="https://www.health.harvard.edu/diseases-and-conditions/growth-hormone-athletic-performance-and-aging">Human growth hormone is a key player</a> in <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824213/">muscle development, tissue repair</a> and <a href="https://doi.org/10.1210/er.2008-0027">metabolism</a>, and is it vital for maintaining physical health. It significantly enhances the body’s capacity for self-repair, be it following an intense sports event or recovering from a sports-related injury. </p>
<p>In addition, sleep helps your brain to recalibrate through the waste-clearing <a href="https://doi.org/10.1016/j.sleep.2022.11.012">glymphatic system</a>, which is part of the central nervous system. Think of it as a dishwasher in your brain, flushing out waste products, including neurotoxic proteins such as <a href="https://doi.org/10.3389/fphar.2015.00221">amyloid-beta</a>, <a href="https://doi.org/10.1111%2Fj.1755-5949.2010.00177.x">abnormal tangles of a protein called tau</a> and <a href="https://doi.org/10.1101%2Fcshperspect.a009399">alpha-synuclein proteins</a>. </p>
<p>All three of those proteins have direct association with neurodegenerative diseases such as <a href="https://doi.org/10.1001/jamaneurol.2023.3889">Alzheimer’s dementia</a> and <a href="https://doi.org/10.1016/j.neubiorev.2017.08.016">chronic traumatic encephalopathy</a>, a disorder thought to be caused by repeated head injuries. For athletes, maintaining proper brain health and cognitive function is paramount.</p>
<p>In addition, deep sleep <a href="https://doi.org/10.1007/s00424-011-1044-0">strengthens the immune system</a> to help keep us healthy and free of illnesses.</p>
<p>REM sleep is the most active stage of sleep, the one in which we experience dreams. This contrasts with deep sleep, where the brain enters a state of synchronized slow waves, indicative of restorative rest. REM sleep is <a href="https://doi.org/10.1007/s11910-013-0430-8">essential for memory</a> and <a href="https://doi.org/10.3389/fpsyg.2019.00459">emotion processing</a>, which help with recall and reducing anxiety. </p>
<p>Athleticism by its purest definition and overall body control can often be linked to the benefits of Stage 2 sleep, which has been shown to play an instrumental role in the <a href="https://doi.org/10.1371/journal.pbio.1002429">consolidating of motor sequence memories</a> and physical skills learned during practice.</p>
<p>To fully benefit from these sleep cycles, adults need <a href="https://www.sciencedirect.com/science/article/abs/pii/S2352721815000157?via%3Dihub">seven to nine hours</a> of sleep per night. This duration ensures that they complete the necessary four to six sleep cycles, allowing their bodies and minds to fully experience the restorative effects of each sleep stage, which is essential for optimal health and performance.</p>
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<figcaption><span class="caption">Sleep is a performance enhancer, if you do it right.</span></figcaption>
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<h2>How sleep helps prevent injuries</h2>
<p>In professional sports, more training and higher pressure increase the chances of getting hurt. Research shows that collegiate athletes who sleep less than seven hours per night are <a href="https://doi.org/10.1249/JSR.0000000000000849">nearly twice as likely to get injured</a> when compared with those who sleep more than eight hours. In a game like football, where split-second decisions can lead to a touchdown or interception, a well-rested brain is the best tool for quick thinking and staying free of injury. </p>
<p>Good sleep also cuts down on the <a href="https://doi.org/10.1016/j.sleep.2019.03.008">risk of concussions</a>, which, sadly, are pretty common in sports. Up to <a href="https://doi.org/10.1097/00001199-200609000-00001">3.8 million cases</a> of concussions occur annually in the U.S. during competitive sports. Studies have shown that <a href="https://doi.org/10.1016/j.sleep.2019.03.008">sleepy athletes</a> are nearly three times more likely to suffer a concussion.</p>
<p>Sleep deficits have been linked to decreased performance in every cognitive measure, including <a href="https://doi.org/10.1093/sleep/zsab051">vigilant attention, spatial cognition</a> and tasks involving <a href="https://doi.org/10.1016/j.jadohealth.2013.12.034">inhibitory control</a>. On the sports field, this translates to sleepy athletes making more impulsive and risky decisions. </p>
<h2>Enhancing athletic performance through ample sleep</h2>
<p>Athletes of any level, even at the highest levels of competition, could gain a competitive edge by giving more attention to the value of sleep. Studies focusing on <a href="https://doi.org/10.1249/MSS.0b013e31820abc5a">sprinters</a>, <a href="https://doi.org/10.1016/j.physbeh.2013.07.002">tennis players</a> and <a href="https://doi.org/10.1249/MSS.0b013e31820abc5a">endurance athletes</a> have found that sleep can enhance the following four key abilities: </p>
<ul>
<li><p><a href="https://doi.org/10.1249/MSS.0b013e31820abc5a">Speed, strength and endurance</a>: More sleep can lead to faster sprint times, greater strength and <a href="https://doi.org/10.1007/s00421-009-1103-9">higher endurance</a>, which are crucial in sports where every second counts. Adequate sleep enhances muscle recovery and energy restoration, which are crucial for the strength and power needed in sprinting. </p></li>
<li><p>Accuracy and reaction time: One study found that tennis players who got more sleep showed better <a href="https://doi.org/10.1016/j.physbeh.2013.07.002">accuracy and faster reaction times</a>. Increased sleep enhances brain function by boosting cognitive processes such as focus, <a href="https://doi.org/10.1093/sleep/zsab051">decision-making</a> and sensory perception. Well-rested individuals also experience <a href="https://doi.org/10.1371/journal.pbio.1002429">better neuromuscular coordination</a>, essential for precise movements and quick responses. </p></li>
</ul>
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<figcaption><span class="caption">Sleep can make a critical difference when it comes to split-second decision-making.</span></figcaption>
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<ul>
<li><p>Cognitive skills and inhibitory control: Good sleep helps with <a href="https://doi.org/10.1093/sleep/zsab051">strategizing and decision-making</a> through improved recall and a clearer mind, thanks to the cleansing action of the glymphatic system. Sleep deprivation, on the other hand, can impair cognitive abilities, as evidenced in <a href="https://doi.org/10.1093/sleep/zsab051">research involving NASA recruits</a>. </p></li>
<li><p>Pain tolerance: More sleep can lead to <a href="https://doi.org/10.5665/sleep.1830">increased pain tolerance</a>, playing a vital role in the quality of life and recovery process following injuries or intense physical exertion. While the exact mechanisms are complex and involve a two-way relationship between sleep and pain, this benefit is particularly important in physically demanding sports. Improved pain tolerance can aid athletes not only in recovery but also in maintaining mental well-being, allowing them to focus on rehabilitation and training without being overly hindered by discomfort. </p></li>
</ul>
<h2>Essential sleep tips for peak performance</h2>
<p>Here are some practical and effective sleep tips tailored for athletes, designed to help them harness the power of sleep for top-notch performance in their respective sports: </p>
<ul>
<li><p>Consistency and quantity: A regular sleep schedule is crucial for peak performance. Athletes should make sure they’re getting eight to 10 hours of sleep, not just the day before a big game but every day throughout the competitive season. </p></li>
<li><p>Environment: A sleep-conducive environment – dark, quiet and cool – is essential to getting a restful night’s sleep.</p></li>
<li><p>Pre-sleep routines: Relaxing activities such as reading, stretching and meditation before bed can enhance sleep quality.</p></li>
<li><p>Screen limits: <a href="https://theconversation.com/school-start-times-and-screen-time-late-in-the-evening-exacerbate-sleep-deprivation-in-us-teenagers-179178">Reducing screen time</a> before bed helps maintain natural sleep rhythms and the production of melatonin.</p></li>
<li><p><a href="https://theconversation.com/whats-the-best-diet-for-healthy-sleep-a-nutritional-epidemiologist-explains-what-food-choices-will-help-you-get-more-restful-zs-219955">Dietary considerations</a>: Avoiding caffeine, alcohol and heavy meals before sleep aids in restfulness.</p></li>
<li><p><a href="https://theconversation.com/short-naps-can-improve-memory-increase-productivity-reduce-stress-and-promote-a-healthier-heart-210449">Strategic napping</a>: Short, well-timed naps can be a valuable tool for recovery and achieving peak performance. </p></li>
<li><p>Sleep banking: To prepare for travel when you anticipate reduced sleep, consider sleeping longer beforehand. This can be achieved either through extra napping or by extending your regular nightly sleep. </p></li>
</ul>
<p>It’s important for any athlete to remember that sleep isn’t a weakness. Success as an athlete is about more than just physical training and tactical preparedness; it’s also about harnessing the power of sleep for optimal performance.</p><img src="https://counter.theconversation.com/content/221403/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joanna Fong-Isariyawongse does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Studies show college athletes sleeping less than 7 hours per night are almost twice as likely to be injured when compared with athletes sleeping more than 8 hours.Joanna Fong-Isariyawongse, Associate Professor of Neurology, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2169802023-12-21T21:37:49Z2023-12-21T21:37:49ZThe Douglas-Bell Canada Brain Bank: a goldmine for research on brain diseases<figure><img src="https://images.theconversation.com/files/557356/original/file-20231005-26-rmh9lm.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4000%2C1508&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The experimental methods available today allow us to break the brain down into its elementary components in order to understand its functions and dysfunctions.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>Human beings have always been fascinated by the brain. </p>
<p>Although scientific knowledge about this 1.3 kg of fragile substance embedded in our cranium has long been incomplete, dazzling technical breakthroughs made in recent years are now ushering in a Golden Age of molecular neuroscience. </p>
<p>These breakthroughs have been made possible partly thanks to brain banks, which preserve human brains in the best possible conditions for scientific research. Here in Montréal, we have one of the world’s largest such banks, the Douglas-Bell Canada Brain Bank (DBCBB), <a href="https://douglasbrainbank.ca">founded in 1980 at the Douglas Hospital</a>. </p>
<p>The DBCBB, which receives several brains each month, has collected over 3,600 specimens to date. Every year, its team processes dozens of tissue requests from scientists in Québec, Canada and abroad, preparing some 2,000 samples for research. </p>
<p>Over the past 40 years, these efforts have led to a considerable number of discoveries about different neurological and psychiatric diseases. </p>
<p>As a full professor in the department of psychiatry at McGill University, researcher at the Douglas Research Centre and director of the DBCBB since 2007, I work in close collaboration with <a href="https://www.mcgill.ca/psychiatry/gustavo-turecki">Dr. Gustavo Turecki</a>, co-director of the DBCBB and responsible for the component devoted to psychiatric illnesses and suicide.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&rect=14%2C2%2C1535%2C1231&q=45&auto=format&w=1000&fit=clip"><img alt="cerebral hemisphere" src="https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&rect=14%2C2%2C1535%2C1231&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=475&fit=crop&dpr=1 600w, https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=475&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=475&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=596&fit=crop&dpr=1 754w, https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=596&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/552153/original/file-20231004-17-mdh992.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=596&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Douglas-Bell Canada Brain Bank, which receives several brains each month, has collected over 3,600 specimens to date.</span>
<span class="attribution"><span class="source">(Naguib Mechawar)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<h2>A brief history of research on the human brain</h2>
<p>Scientists only began to identify the microscopic elements that make up the human brain in the second half of the 19th century. </p>
<p>That was when brains were preserved for the first time in formalin, a solution that preserves biological tissue so that it can be handled more easily and stored over a longer term.</p>
<p>At the same time, precision instruments and protocols were being developed that made it possible to examine the microscopic characteristics of nervous tissue.</p>
<p>Until the middle of the 20th century, researchers were mainly satisfied with preserving the brains of patients, taken during autopsies, so they could use them to identify possible macroscopic or microscopic changes linked to either neurological or psychiatric symptoms.</p>
<p>This is in fact what the German neurologist Alois Alzheimer did when he analyzed the brain of one of his patients suffering from dementia. In 1906, he described, for the first time, the microscopic lesions which characterize the disease that now bears his name.</p>
<p>Until the end of the 1970s, numerous collections of brain specimens preserved in formalin were built in hospital environments, a bit like the cabinets of curiosities of olden days.</p>
<p>Towards the end of the 20th century, new experimental approaches were developed allowing the high-resolution analysis of cells and molecules within biological tissues.</p>
<p>It then became necessary to collect and preserve human brains, obtained with the consent of the individual or his or her family, in conditions compatible with modern scientific techniques.</p>
<p>Researchers began freezing one of the cerebral hemispheres in order to measure its various molecular components. The other hemisphere was preserved in formalin to be used for macroscopic and microscopic anatomical studies.</p>
<p>This was the context in which the Douglas-Bell Canada Brain Bank was created.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="The DBCBB premises" src="https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/552154/original/file-20231004-25-z5k7jp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Montréal is home to one of the world’s largest brain banks, the Douglas-Bell Canada Brain Bank, which was founded in 1980 at the Douglas Hospital.</span>
<span class="attribution"><span class="source">(Naguib Mechawar)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<h2>New experimental approaches are yielding results</h2>
<p>Leading researchers from many universities around the world now use DBCBB samples to advance their research. This, of course, includes a number of teams in Québec.</p>
<p>For example, with his team from the Douglas Research Centre, which is affiliated with McGill University, <a href="https://douglas.research.mcgill.ca/judes-poirier/">Judes Poirier</a> discovered that the APOE4 gene is a <a href="https://doi.org/10.1016/0140-6736(93)91705-Q">risk factor for Alzheimer’s disease</a>. More recently, the team of <a href="https://crhmr.ciusss-estmtl.gouv.qc.ca/en/researcher/gilbert-bernier">Gilbert Bernier</a>, professor in the department of neuroscience at Université de Montréal, discovered that the lesions characteristic of this disease are associated with <a href="https://doi.org/10.1038/s41598-018-37444-3">abnormal expression of the BMI1 gene</a>.</p>
<p>With regard to psychiatric illnesses, and more specifically depression, major progress has been made recently by the <a href="https://douglas.research.mcgill.ca/mcgill-group-suicide-studies-mgss/">McGill Group for Suicide Studies</a>. </p>
<p>Using cutting-edge methods to isolate and analyze human brain cells, Turecki’s team has succeeded in precisely identifying the cell types whose function is affected in men <a href="https://doi.org/10.1038/s41593-020-0621-y">who have suffered from major depression</a>, and then discovering that the cell types involved in this illness differ <a href="https://doi.org/10.1038/s41467-023-38530-5">between men and women</a>. </p>
<p>These experimental approaches generate huge data sets that can be examined in subsequent studies. This is the case, for example, of work carried out in my laboratory, which identified signs of persistent changes in neuroplasticity within the prefrontal cortex of people with a history of <a href="https://doi.org/10.1038/s41380-021-01372-y">child abuse</a>. In fact, the studies mentioned above enabled us to discover at least one of the cell types involved in this phenomenon. </p>
<p>In short, the experimental methods we have today allow us to break the brain down into its elementary components in order to understand its functions and dysfunctions.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Cerebral hemispheres preserved in formalin" src="https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/552155/original/file-20231004-27-62uc6y.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=504&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Leading researchers from many universities around the world benefit from Douglas-Bell Canada Brain Bank samples to advance their research.</span>
<span class="attribution"><span class="source">(Naguib Mechawar)</span>, <span class="license">Fourni par l'auteur</span></span>
</figcaption>
</figure>
<h2>Identify, prevent, screen and treat</h2>
<p>Thanks to the hard work and dedication of the entire DBCBB team, as well as the unfailing support of all its partners, patrons (often anonymous) and funding bodies — particularly the FRQS research fund and Québec’s suicide research network, the <a href="https://reseausuicide.qc.ca">Réseau québécois sur le suicide, les troubles de l'humeur et les troubles associés</a> — this invaluable resource has not only managed to survive, but to grow and become one of the largest brain banks in the world. </p>
<p>There is every reason to believe that, in the years to come, the DBCBB will play an important role in the increasingly precise identification of the biological causes of brain diseases, and, as a result, will contribute to the identification of new targets for better approaches to prevention, screening and treatment.</p><img src="https://counter.theconversation.com/content/216980/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Naguib Mechawar has received funding from CIHR, NSERC, HBHL (CFREF) and FQRS (NEURON ERA-NET and RQSHA).</span></em></p>Montréal is home to one of the world’s largest brain banks, the Douglas-Bell Canada Brain Bank, where discoveries about different neurological and psychiatric diseases are made.Naguib Mechawar, Neurobiologiste, Institut Douglas; Professeur titulaire, Département de psychiatrie, McGill UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2181882023-11-29T16:28:10Z2023-11-29T16:28:10ZNanoplastics linked to Parkinson’s and some types of dementia – new study<figure><img src="https://images.theconversation.com/files/562164/original/file-20231128-19-g1z53w.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C4608%2C3456&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-hands-senior-woman-trying-hold-2197824919">meeboonstudio/Shutterstock</a></span></figcaption></figure><p>Since it was <a href="https://www.sciencemuseum.org.uk/objects-and-stories/chemistry/age-plastic-parkesine-pollution">first produced</a> at the start of the 20th century, synthetic plastic – and especially plastic packaging – has been an ever-present fixture in everyday life. Yet all the convenience plastic has given us comes at a price. </p>
<p>When plastic breaks down slowly over time, it produces ever smaller parts called microplastics and nanoplastics – depending on their size. These tiny bits of plastic contaminate water and food sources and can enter humans and other living organisms. Indeed, researchers found that tiny plastic particles can be found in the blood of <a href="https://doi.org/10.1016/j.envint.2022.107199">most adults tested</a>.</p>
<p>We are only beginning to discover the harms these plastics can cause. It is of particular concern that nanoplastics are so tiny they can cross the protective blood-brain barrier and even enter individual neurons (a type of brain cell).</p>
<p>A <a href="https://doi.org/10.1126/sciadv.adi8716">new study</a> has shown that nanoplastics can induce changes within the brain that are seen in Parkinson’s disease. Parkinson’s disease is one of the fastest-growing and most devastating neurological disorders. It is characterised by the death of a specialist population of nerve cells that control movement. </p>
<p>The researchers showed that nanoplastics found in the environment can interact with a protein called alpha-synuclein. This protein occurs naturally in every brain where it plays a role in nerve cell communication. However, in diseases such as Parkinson’s and some forms of dementia, alpha-synuclein changes. </p>
<p>The proteins clump together, forming so-called alpha-synuclein fibrils. These fibrils can then be found accumulating in nerve cells in people with Parkinson’s disease and some forms of dementia. Normally, alpha-synuclein is recycled within the nerve cells, but when the protein starts to clump together, the machinery in the cells cannot keep up with the waste. </p>
<p>The researchers used a wide variety of laboratory techniques to investigate the effect of nanoplastics on cells and live mice. The team used nanoparticles of polystyrene, a material commonly used to produce single-use items such as drinking cups.</p>
<p>They found that the nanoplastics bound tightly to alpha-synuclein and caused it to form toxic clumps similar to what is seen in Parkinson’s disease. Importantly, the interaction between alpha-synuclein and the nanoplastics was seen across three models tested. These were test tubes, cultured nerve cells and live mice.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/cRLB7WqX0fU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Parkinson’s disease explained.</span></figcaption>
</figure>
<p>The researchers made four important observations. First, nanoplastics rapidly and tightly bind alpha-synuclein. Second, nanoplastics promote alpha-synuclein accumulation and fibril formation. Third, nanoplastics and alpha-synuclein can enter cultured neurons and impair protein breakdown (the naturally occurring disposal of protein clumps, such as alpha-synuclein fibrils). </p>
<p>Fourth, when nanoplastics and alpha-synuclein were injected into healthy mouse brains, alpha-synuclein fibrils formed and were found in nerve cells across the brain. This is one of the hallmarks of Parkinson’s disease and associated types of dementia. </p>
<p>In a few animals, the researchers saw that the injection of nanoplastics alone (without alpha-synuclein) caused alpha-synuclein fibrils to form and accumulate in nerve cells. This last point is the most concerning because it shows that nanoplastics can promote alpha-synuclein fibril formation by themselves in the nerve cells that specifically die in Parkinson’s disease in a living organism. </p>
<h2>Far-reaching implications</h2>
<p>These results highlight the need for further monitoring of plastic waste and environmental pollution. The effect of microplastics in promoting cancer and immune diseases is actively being researched, but this study further supports the notion that microplastics have far-reaching implications on human health. </p>
<p>The question of how and whether the interaction between the nanoplastics and alpha-synuclein occurs in the human brain remains unanswered and further research is needed. More research is also needed to understand whether different types of plastic have different effects. </p>
<p>Still, the results shine a light on potential environmental factors that promote Parkinson’s disease development. This in turn could lead to monitoring specific at-risk groups who have been exposed to large quantities of nanoplastics and whether these people suffer an increased number of neurological diseases.</p><img src="https://counter.theconversation.com/content/218188/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Janosch Heller receives funding from Irish Research Council. </span></em></p>Microscopic flakes of polystyrene can enter brain cells and cause harm, a new study in mice has shown.Janosch Heller, Assistant Professor in Biomedical Sciences, Dublin City UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2163762023-10-27T15:36:56Z2023-10-27T15:36:56ZParkinson’s disease: tai chi may help manage symptoms – new research<figure><img src="https://images.theconversation.com/files/556317/original/file-20231027-24-jjk33a.jpg?ixlib=rb-1.1.0&rect=53%2C8%2C6000%2C3979&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Tai chi has been practised for centuries.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-couple-enjoying-tai-chi-exercise-1450198265">Mladen Mitrinovic/ Shutterstock</a></span></figcaption></figure><p>The centuries-old martial art of tai chi is shown to have many health benefits – including <a href="https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004963.pub3/full?highlightAbstract=withdrawn%257Cexercise%257Cexercis%257Cbalance%257Cbalanc">improving balance</a>, reducing <a href="https://www.frontiersin.org/articles/10.3389/fpsyg.2021.746975/full">anxiety</a> and preventing <a href="https://www.cochrane.org/CD010366/VASC_tai-chi-to-prevent-cardiovascular-disease">cardiovascular disease</a>.</p>
<p>But these aren’t the only benefits this exercise may have. A <a href="https://jnnp.bmj.com/content/early/2023/09/27/jnnp-2022-330967">recently published study</a> has demonstrated for the first time that tai chi can reduce the severity of Parkinson’s symptoms in the long-term.</p>
<p>To conduct their study, the researchers recruited patients who had sporadic Parkinson’s disease. This is a type of Parkinson’s disease that’s not inherited from a family member. They focused on sporadic Parkinson’s disease so that they could examine the benefits of tai chi exclusively on Parkinson’s symptoms. The researchers excluded people with other health conditions (such as other neurodegenerative diseases) which may have prevented them from taking part in tai chi classes. </p>
<p>Participants were then divided into two groups – a control group of 187 people who did not exercise, and a group of 143 people who completed tai chi classes. Participants had an average age of 66 years. There were an equal number of male and female participants. All participants were at an early stage of Parkinson’s disease and had only been diagnosed for four years on average. This meant that any changes in symptoms observed between the two groups could be attributed to tai chi. </p>
<p>Participants in the tai chi group were given five classes over the duration of the study which started in 2016 and ended in 2018. They were also instructed to train twice a week for one hour. All participants were then followed up over a three-year period between 2019 and 2021 to track their symptoms.</p>
<p>The participants in the tai chi group had better motor function at the end of the study. The control group, on the other hand, experienced a faster decline of their motor functions – including their walking ability and balance. The control group also on average took more Parkinson’s drugs to manage symptoms over the course of the study compared to the tai chi group. This either means that the disease was more severe and progressed faster in the control group, or that tai chi had a protective effect on disease progression. </p>
<p>The positive effects of tai chi were also apparent in non-motor symptoms, with the tai chi group reporting better quality of life and wellbeing, sleep, as well as memory and thinking benefits.</p>
<p>Given that current medications used to treat and manage Parkinson’s don’t delay disease progression or prevent symptoms worsening, having an accessible yet effective supplement therapy such as tai chi could be beneficial for patients.</p>
<figure class="align-center ">
<img alt="An elderly couple perform tai chi in their home." src="https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/556318/original/file-20231027-23-8qrorf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Tai chi had benefits for both motor and non-motor symptoms.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/asian-old-senior-workout-exercise-doing-1752624563">Nattakorn_Maneerat/ Shutterstock</a></span>
</figcaption>
</figure>
<p>But as promising as these results are, the study had a few limitations of note. The first is that the groups were not randomised. The gold standard in clinical trials is to randomise participants into groups to prevent bias being introduced into the study.</p>
<p>So because the groups weren’t randomised, participants may have been recruited to a group because of motivation to exercise or other lifestyle factors. Another reason some participants were recruited to the control group was for practical reasons – such as the participant’s location, or work conflicts. </p>
<p>The researchers recommend that larger follow-up studies in the future use randomisation to prevent bias. </p>
<h2>Exercise and Parkinson’s</h2>
<p>This isn’t the first trial to show tai chi may have benefits for people with Parkinson’s disease. But previous trials only found benefits in the short-term, over a <a href="https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013856.pub2/epdf/full">periods of six months</a>. This study is the first of its kind to show long-term benefits.</p>
<p>Other types of exercise have also been investigated to see whether they benefit patients with Parkinson’s disease – including <a href="https://pubmed.ncbi.nlm.nih.gov/29228079">high-intensity interval training</a> and <a href="https://content.iospress.com/download/journal-of-parkinsons-disease/jpd229006?id=journal-of-parkinsons-disease%2Fjpd229006">aerobic exercise</a> such as walking or swimming. These have been shown to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632855/">benefit motor symptoms</a> and slow the disease’s progression over a short period of time. </p>
<p>It’s not entirely certain why exercise – and specifically tai chi – is so beneficial to people with Parkinson’s. But we do know from other research that a lack of exercise can <a href="https://pubmed.ncbi.nlm.nih.gov/20561356/">promote inflammation</a>, which is detected in the blood of people with Parkinson’s disease. Chronic inflammation can lead to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951017/">loss of neurons</a> (nerve cells that send messages all over the body) in the brain. </p>
<p>People who do tai chi are shown to have <a href="https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-022-00280-7">anti-inflammatory markers</a> in their blood. This may perhaps explain why it’s beneficial for people with Parkinson’s as it decreases inflammation.</p>
<p>Although more research will be needed – especially to understand if tai chi also benefits people with later stages of Parkinson’s disease – the findings of this latest study show tai chi could be used as a complement to treatment plans. It addresses both the physical and mental aspects of the condition, providing benefits such as improved balance, flexibility and wellbeing. Just be sure to consult with your GP or neurologist before trying it.</p><img src="https://counter.theconversation.com/content/216376/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>This centuries old martial art was shown to reduce the severity of symptoms in the long-term.Lucy Collins-Stack, Senior Post-Doctoral Researcher, University College CorkAideen Sullivan, Professor and Head of Department of Anatomy & Neuroscience, University College CorkLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2126442023-09-27T13:40:03Z2023-09-27T13:40:03ZThe tantalising scent of rain or freshly baked bread: why can certain smells transport us back in time?<figure><img src="https://images.theconversation.com/files/545770/original/file-20230817-27-s2icj0.jpg?ixlib=rb-1.1.0&rect=0%2C22%2C7348%2C4880&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/es/image-photo/selective-focus-cheerful-asian-woman-smiling-1460132408">LightField Studios / Shutterstock</a></span></figcaption></figure><p>My father was a carpenter, meaning I have spent a great deal of my life surrounded by wood, saws, planes and chisels. Simply by living among sawdust and woodchips, you learn to distinguish the different smells of wood.</p>
<p>Years after my father retired, I was walking through the underbelly of a hospital when, completely by chance, I stumbled upon the maintenance room. The smell of that room enveloped me, travelling instantaneously through my olfactory mucosa, to the olfactory nerve and then the olfactory bulb which, after a swift analysis, directed it to my limbic system. </p>
<p>Suddenly and unexpectedly, I was transported back to my native Toledo (in Spain), to my father’s carpentry workshop. It had been closed for years and I had never given it much thought, but for a second I felt I could see him in front of me, sanding block in hand, beckoning me over to help. And as if by magic, all the stress of my day began to evaporate, giving way to a serene sense of calm and happiness.</p>
<p>The noise of a nearby elevator snapped me back to reality.</p>
<h2>Smells that revive past emotions</h2>
<p>Is it possible that the mere smell of freshly cut wood had transported me back 20 years, and that my hippocampus was dredging up memories that I did not even know were there?</p>
<p>These kinds of occurrences are very common, as, undoubtedly, you can confirm. The scent of freshly baked cakes or bread, the chlorine of a swimming pool in summer, a salty sea breeze, coffee, and rain are smells that cause our minds to recover memories and emotions that we thought long forgotten.</p>
<p>Memory is the brain’s ability to compile, store and recover information based on past experiences. But what kinds of experiences are most easily stored? It is those connected to <a href="https://theconversation.com/tiene-nuestro-cerebro-un-boton-para-borrar-los-malos-recuerdos-194854">emotion</a>, whether positive or negative.</p>
<p>Our memories are like a bottomless drawer. The amount of information they can store is infinite, but it is not always easy to access. This is because our brains tuck away things that they consider to be less important at any given moment. The more hidden a piece of information is, the more difficult it is to retrieve.</p>
<p>Numerous scientific studies have tried to discover how we can recover memories and sensations from the past through a particular smell. This is known as <a href="https://www.sciencedirect.com/topics/neuroscience/olfactory-memory">olfactory memory</a>.</p>
<h2>A direct line to emotional memory</h2>
<p>The sense of smell is strongly connected to different areas of the brain, such as the limbic system and the orbitofrontal cortex. The former is essential in creating emotional responses to smells, while the latter helps to identify and distinguish them, as well as linking them to specific experiences and memories.</p>
<p>Before it reaches the cerebral cortex, information from the other senses must first pass through a control system, the thalamus. The sense of smell, however, has a VIP pass, and it bypasses the thalamus to connect directly to the brain’s memory circuits, located in the hippocampus.</p>
<p>For this reason, a familiar smell activates the same areas of the brain as those related to emotional memory. In fact, scent induced memories tend to be connected to past experiences with a greater emotional significance than other senses.</p>
<h2>The loss of smell, a sign of neurological illness</h2>
<p>Much like other senses, our sense of smell seems to diminish as we get older, but it can also be linked to various disorders. Many of us experienced this first hand <a href="https://pubmed.ncbi.nlm.nih.gov/32563019/">during the covid-19 pandemic</a>, when millions of people lost their sense of smell. For most this was temporary, but for some it was permanent.</p>
<p>Intriguingly, many disorders linked to a loss of smell are neurodegenerative, where one of the associated symptoms is memory loss.</p>
<p>It is significant that this deterioration of smell may precede other problems, as it can therefore be used to predict almost 70 <a href="https://pubmed.ncbi.nlm.nih.gov/30083097/">psychiatric and neurological conditions</a>. Continued decline in the ability to detect odours heralds the loss of grey matter – mostly made up of neurons – in the hippocampus as <a href="https://pubmed.ncbi.nlm.nih.gov/34893841">mild cognitive impairment (MCI)</a> sets in, and then subsequently progresses to <a href="https://pubmed.ncbi.nlm.nih.gov/26696886/">Alzheimer’s disease</a>.</p>
<p>In fact, a declining sense of smell can <a href="https://academic.oup.com/acn/article/28/5/391/5707?login=false">predict</a> whether individuals with MCI will develop Alzheimer’s in the future. But this does not just help to detect dementia: it can also be a sign of <a href="https://pubmed.ncbi.nlm.nih.gov/29360225/">cognitive dysfunction</a> and precedes or develops alongside a wide range of conditions such as <a href="https://pubmed.ncbi.nlm.nih.gov/20858529/">Parkinson’s disease</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/16991138/">Lewy body dementia</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/14755736/">Creutzfeldt-Jakob disease</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/12658108/">alcoholism</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/20825265/">schizophrenia</a>. </p>
<h2>Olfactory gymnastics to rehabilitate your memory?</h2>
<p>In the case of people suffering from neurological conditions such as Alzheimer’s or Parkinson’s, the absence of olfactory stimulation in the brain can actually cause other symptoms to worsen. In fact, <a href="https://www.frontiersin.org/articles/10.3389/fnins.2020.00140/full">several studies</a> have drawn a connection between a strong sense of smell and a lower overall risk of mortality.</p>
<p>Consequently, in recent years there has been interest in determining the therapeutic potential of scents to stimulate and rehabilitate memory in patients with neurological disorders.</p>
<p>Information available to date suggests that there is a connection. Olfactory enrichment –smelling a range of different scents– can reverse loss of smell caused by an <a href="https://pubmed.ncbi.nlm.nih.gov/27017331/">infection</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/33486898/">craneal trauma</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/23613901/">Parkinson’s</a> and <a href="https://pubmed.ncbi.nlm.nih.gov/34867284/">aging</a>. This improvement is associated with an increase in cognitive and memory capacity.</p>
<p>The method for this form of therapy could not be simpler: results are achieved by exposing people daily to various scents. A recent study supports the idea that two hours per night, over six months, is enough to improve memory function.</p>
<p>Obviously, more research is needed to definitively conclude that regular olfactory stimulation helps to protect the brain and prevent cognitive decline or impairment.</p>
<p>Until this happens, I will return to my father’s carpentry shop, thinking of these words by Marcel Proust: “Perfume is that last and best reserve of the past, the one which when all out tears have run dry, can make us cry again.”</p><img src="https://counter.theconversation.com/content/212644/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>José A. Morales García no recibe salario, ni ejerce labores de consultoría, ni posee acciones, ni recibe financiación de ninguna compañía u organización que pueda obtener beneficio de este artículo, y ha declarado carecer de vínculos relevantes más allá del cargo académico citado.</span></em></p>The sense of smell is directly connected to areas of the brain linked to memory and emotions. That is why some smells bring to light memories and feelings we thought we had forgotten.José A. Morales García, Investigador científico en enfermedades neurodegenerativas y Profesor de la Facultad de Medicina, Universidad Complutense de MadridLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2059142023-09-15T12:36:15Z2023-09-15T12:36:15ZAlzheimer’s disease is partly genetic − studying the genes that delay decline in some may lead to treatments for all<figure><img src="https://images.theconversation.com/files/548111/original/file-20230913-29-y9h0zu.jpg?ixlib=rb-1.1.0&rect=8%2C8%2C5483%2C4108&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Researchers are zeroing in on understanding what goes awry in the brains of people with Alzheimer's disease.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/alzheimers-and-dementia-research-conceptual-image-royalty-free-image/1414387544?phrase=alzheimer%27s+disease&adppopup=true">Tek Image/Science Photo Library via Getty Images</a></span></figcaption></figure><p>Diseases that run in families usually have genetic causes. Some are <a href="https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders">genetic mutations</a> that directly cause the disease if inherited. Others are <a href="https://theconversation.com/explainer-what-is-genetic-risk-25969">risk genes</a> that affect the body in a way that increases the chance someone will develop the disease. In <a href="https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet">Alzheimer’s disease</a>, genetic mutations in any of three specific genes can cause the disease, and other risk genes either increase or decrease the risk of developing Alzheimer’s. </p>
<p>Some genetic mutations or variants interact with other genetic alterations that lead to Alzheimer’s disease. In some cases, gene alterations can interact with Alzheimer’s-causing genetic variants in a way that proves beneficial; they actually suppress the pathological brain changes the other mutations would normally lead to. These protective gene variants can drastically slow or prevent cognitive decline. In <a href="https://doi.org/10.1038/s41591-019-0611-3">two recent</a> <a href="https://doi.org/10.1038/s41591-023-02318-3">case reports</a> on familial Alzheimer’s disease, mutations delayed Alzheimer’s symptoms for decades.</p>
<p>I am a <a href="https://scholar.google.com/citations?user=Jbl0lnsAAAAJ&hl=en">neurologist and neuroscientist</a> who has spent my career studying Alzheimer’s disease and dementia both in the laboratory and in the clinic. Determining how genes affect brain chemistry is vital to understanding how Alzheimer’s disease progresses and devising interventions to prevent or delay cognitive decline.</p>
<h2>The amyloid hypothesis</h2>
<p>In the early 1990s, scientists proposed the <a href="https://doi.org/10.1111/j.1750-3639.1991.tb00667.x">amyloid hypothesis</a> to explain how Alzheimer’s disease develops. The first neuropathological changes detected in the brain of Alzheimer’s disease patients were the formation of <a href="https://doi.org/10.1016/0165-6147(91)90609-v">amyloid plaques</a> – clumps of protein pieces called beta-amyloid. Other changes in the Alzheimer’s brain, such as the accumulation of another type of abnormal protein called neurofibrillary tangles, were thought to develop later in the course of the disease.</p>
<p>Beta-amyloid begins to accumulate in the brain <a href="https://doi.org/10.1038/s41582-018-0116-6">up to 15 years</a> before symptoms emerge. Symptoms correlate with the <a href="https://doi.org/10.1007%2Fs00401-019-02036-6">number of neurofibrillary tangles</a> in the brain – the more tangles, the worse the cognition. Researchers have tried to determine whether preventing or removing amyloid plaques from the brain would be an effective treatment. </p>
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<figcaption><span class="caption">Alzheimer’s disease results from the accumulation of abnormal proteins in the brain.</span></figcaption>
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<p>Imagine the excitement of the scientific community in the 1990s when researchers identified three different genes causing familial Alzheimer’s disease – and all three were involved with beta-amyloid.</p>
<p>The first was the <a href="https://doi.org/10.1038/349704a0">amyloid precursor protein</a> gene. This gene directs cells to produce the amyloid precursor protein, which breaks down into smaller fragments, including the beta-amyloid that forms amyloid plaques in the brain.</p>
<p>The second gene was termed <a href="https://doi.org/10.1038/349704a0">presenilin 1, or PSEN-1</a>, a protein needed to cut the precursor protein into beta-amyloid. </p>
<p>The third gene, <a href="https://doi.org/10.1038/376775a0">presenilin 2, or PSEN-2</a>, is closely related to PSEN-1 but found in a smaller number of families with familial Alzheimer’s disease.</p>
<p>These findings added strength to the amyloid hypothesis explanation of the disease. However, <a href="https://doi.org/10.15252/emmm.201606210">uncertainty and opposition to the amyloid hypothesis</a> have developed over the past several decades. This was in part tied to a recognition that several other processes – neurofibrillary tangles, inflammation and immune system activation – are also involved in the neurodegeneration seen in Alzheimer’s. </p>
<p><a href="http://dx.doi.org/10.2174/1570159X15666170116143743">The hypothesis also</a> <a href="https://mitpress.mit.edu/9780262546010/how-not-to-study-a-disease/">got significant pushback</a> after <a href="https://doi.org/10.14283/jpad.2019.23">many clinical trials</a> attempting to block the effects of amyloid or remove it from the brain <a href="https://www.theatlantic.com/health/archive/2017/02/alzheimers-amyloid-hypothesis/517185/">were unsuccessful</a>. In some cases, treatments had significant side effects. Some researchers have <a href="https://doi.org/10.15252/emmm.201606210">come up with strong defenses</a> of the hypothesis. But until a clinical trial based on the amyloid hypothesis could show definitive results, uncertainty would remain. </p>
<h2>Genetic discoveries with treatment implications</h2>
<p>The vast majority – <a href="https://doi.org/10.1016/j.jalz.2016.01.012">more than 90%</a> – of Alzheimer’s cases occur in late life, with disease prevalence increasing progressively from age 65 and up. Such cases are mostly sporadic, with no clear family history of Alzheimer’s.</p>
<p>However, a relatively small number of families have one of the three known genetic mutations that cause the disease to be passed down. In <a href="http://dx.doi.org/10.1016/j.jalz.2016.01.012">familial Alzheimer’s</a>, 50% of each generation will inherit the mutated gene and develop the disease much earlier, usually from their 30s to early 50s.</p>
<p>In 2019 and 2023, researchers identified changes in at least two other genes that markedly delayed the onset of disease symptoms in people with familial Alzheimer’s disease mutations. These mutated genes were found in a very large family in Colombia whose members tended to develop Alzheimer’s symptoms by their 40s.</p>
<p>A <a href="https://doi.org/10.1038/s41591-019-0611-3">woman in the family</a> carrying a mutated PSEN-1 gene <a href="https://www.sciencenews.org/article/colombia-family-genetic-mutation-alzheimers-dementia-treatment">did not have any cognitive symptoms</a> until she was in her 70s. A genetic analysis showed that she had an additional mutation in a variant of the gene that codes for a <a href="https://doi.org/10.1126/science.aba0964">protein called apolipoprotein E</a>, or ApoE. Researchers believe the mutation, called the <a href="https://www.alz.org/news/2022/unlocking-the-christchurch-variant">Christchurch variant</a> – named after the city in New Zealand where the mutation was first discovered – is responsible for interfering with and slowing down her disease. </p>
<p>Importantly, her brain had a great deal of amyloid plaque but very few neurofibrillary tangles. This suggests that the link between the two was broken and that the suppressed number of neurofibrillary tangles also slowed down cognitive loss.</p>
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<figcaption><span class="caption">Researchers have studied certain families in Colombia with rare genetic variants that slow the progression of Alzheimer’s disease.</span></figcaption>
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<p>In May 2023, researchers reported that <a href="https://doi.org/10.1038/s41591-023-02318-3">two siblings in the same large family</a> also did not develop memory problems until their 60s or late 70s and were found to carry a mutation in a gene that codes for a protein called reelin. Studies in mice suggest that reelin has <a href="https://doi.org/10.1038/ncomms4443">protective effects against amyloid plaque deposition</a> in the brain. In these patients’ brains, as with the patient who had the Christchurch variant, there were extensive amyloid plaques but very few neurofibrillary tangles. This observation confirmed that the tangles are responsible for the cognitive loss and that there are several ways to “disconnect” amyloid and neurofibrillary tangle accumulation.</p>
<p>Finding medicines that might mimic the protective effects of the Christchurch variant or the reelin mutation could help delay Alzheimer’s disease symptoms for all patients. Since the vast majority of nonfamilial Alzheimer’s manifests after age 70 or 75, a 10-year delay in the emergence of first symptoms of Alzheimer’s could have a massive effect in <a href="https://doi.org/10.1016/s1474-4422(14)70136-x">decreasing the prevalence of the disease</a>.</p>
<p>These findings demonstrate that Alzheimer’s can be slowed and will hopefully lead to additional new therapies that can someday not only treat the disease but prevent it as well.</p>
<h2>Starts and stops</h2>
<p>Despite over 20 years of doubts and therapy failures, the past several years have seen positive results from three different treatments – aducanumab, lecanemab and donanemab – that remove amyloid plaques and slow loss of cognitive function to some extent. Although there is still discussion of how much slowing of decline is clinically significant, these successes provide support for the amyloid hypothesis. They also suggest that other strategies will be needed for optimal treatment.</p>
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<figcaption><span class="caption">The FDA approved the Alzheimer’s drug aducanumab (Aduhelm) in June 2021, to much controversy.</span></figcaption>
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<p>The U.S. Food and Drug Administration’s 2021 approval of the first antibody treatment for Alzheimer’s, <a href="https://theconversation.com/the-fdas-big-gamble-on-the-new-alzheimers-drug-162396">aducanumab, sold under the brand name Aduhelm</a>, was controversial. Only one of the two clinical trials testing its safety and effectiveness in people yielded positive results. The FDA approved the drug on the basis of that single study through an <a href="https://theconversation.com/the-fda-approved-a-new-drug-to-treat-alzheimers-but-medicare-wont-always-pay-for-it-a-doctor-explains-what-researchers-know-about-biogens-aduhelm-179177">accelerated approval process</a> in which treatments meeting an unmet clinical need can receive expedited approval.</p>
<p>The second antibody, <a href="https://theconversation.com/what-the-fdas-accelerated-approval-of-a-new-alzheimers-drug-could-mean-for-those-with-the-disease-5-questions-answered-about-lecanemab-197460">lecanemab, sold as Leqembi</a>, was approved in January 2023 via the same accelerated approval pathway. It was then <a href="https://www.fda.gov/news-events/press-announcements/fda-converts-novel-alzheimers-disease-treatment-traditional-approval">fully approved</a> in July 2023.</p>
<p>The third antibody, donanemab, completed a successful <a href="https://doi.org/10.1001/jama.2023.13239">phase three clinical trial</a> and is awaiting more safety data. When that is submitted to the FDA, the agency will consider the drug for approval.</p><img src="https://counter.theconversation.com/content/205914/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Steven T. DeKosky consults for Brainstorm Cell Therapeutics and Novo Nordisk Pharmaceuticals; is the Editor for Dementia for Up-To-Date, a point of care electronic textbook of medicine and is Associate Editor of Neurotherapeutics-The Journal of the American Society for Experimental Therapeutics (ASENT); chairs Drug Monitoring Safety Boards for Biogen, Prevail Pharmaceuticals, and Vaccinex Pharmaceuticals; and chairs Scientific Advisory Boards for Acumen Pharmaceuticals and Cognition Therapeutics.</span></em></p>Despite decades of starts and stops, new treatments and key genetic discoveries are giving researchers great hope for slowing or eventually preventing Alzheimer’s disease.Steven DeKosky, Professor of Neurology and Neuroscience, University of FloridaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2123692023-08-29T01:36:06Z2023-08-29T01:36:06ZNew study highlights the brain trauma risks for young athletes<figure><img src="https://images.theconversation.com/files/544981/original/file-20230828-245330-4v4rcf.jpg?ixlib=rb-1.1.0&rect=4%2C0%2C3197%2C2136&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/australian-rules-youths-leaping-take-mark-4816717">Shutterstock</a></span></figcaption></figure><p>The <a href="https://www.bu.edu/articles/2023/young-amateur-athletes-at-risk-of-cte-study-finds/">Boston University CTE Center</a> today reported the results of the largest-ever study of chronic traumatic encephalopathy (CTE) in young athletes. </p>
<p>The <a href="https://jamanetwork.com/journals/jamaneurology/fullarticle/2808952?resultClick=1">study</a>, examining autopsied tissue, found signs of CTE in 63 out of 152 young athlete brains. The subjects of the study competed in youth, high school and college competitions, and all died before the age of 30. </p>
<p>This case series includes the first American woman athlete diagnosed with the disease, just months after the Australian Sports Brain Bank reported the <a href="https://theconversation.com/australian-researchers-confirm-worlds-first-case-of-dementia-linked-to-repetitive-brain-trauma-in-a-female-athlete-208929">world’s first</a> case of CTE in a female athlete.</p>
<p>The results of this study have major implications for sporting leagues around the globe. Like other dementias, CTE is often assumed to be a disease that develops later in life, but as neuropathologist and Boston University CTE Centre Professor Ann McKee says, “this study clearly shows that the pathology of CTE starts early”. </p>
<p>These latest findings come as Australia’s Senate is due to <a href="https://www.aph.gov.au/Parliamentary_Business/Committees/Senate/Community_Affairs/Headtraumainsport">report</a> the findings of its inquiry into concussions and repeated head trauma in contact sport. </p>
<p>This should push sporting organisations to do more to protect the brains of all athletes, especially in junior and recreational competitions.</p>
<h2>CTE and young athletes</h2>
<p><a href="https://www.mayoclinic.org/diseases-conditions/chronic-traumatic-encephalopathy/symptoms-causes/syc-20370921">CTE</a> is a devastating and currently incurable form of dementia which causes <a href="https://www.frontiersin.org/articles/10.3389/fneur.2022.938163/full">neurodegeneration of the brain</a>. The disease has <a href="https://www.frontiersin.org/articles/10.3389/fspor.2021.676463/full">long</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987576/">been</a> associated with contact sport participation. </p>
<p>Dementias like CTE are often thought of as diseases of the elderly. However, some high-profile cases of CTE have been identified among younger athletes. </p>
<p>In Australia, much-loved NRL player and coach <a href="https://www.abc.net.au/news/2022-10-22/qld-paul-green-brain-scans-reveal-brain-disease-cte-diagnosis/101566032">Paul Green</a> was 49 when he died and was later found to have CTE. Former AFL star <a href="https://www.theguardian.com/sport/2023/mar/01/nrl-and-football-australia-accept-link-between-head-trauma-and-cte">Shane Tuck</a> was 38 when he died with the disease. Former AFLW player <a href="https://www.abc.net.au/news/2023-07-04/cte-diagnosis-in-female-athlete-heather-anderson-aflw-730/102555944">Heather Anderson</a> was only 28. A <a href="https://www.bu.edu/cte/our-research/case-studies/18-year-old/">recent study</a> in the United States also found CTE in the brain of an 18-year-old athlete. </p>
<p>The disease is <a href="https://www.mayoclinic.org/diseases-conditions/chronic-traumatic-encephalopathy/symptoms-causes/syc-20370921">known</a> to cause mood disorders and behaviour changes. People with CTE may be at higher risk of suicide. </p>
<p>These cases and the latest Boston University study indicate the risk of developing CTE is not restricted to those in their middle or older years. Although there is some evidence <a href="https://pubmed.ncbi.nlm.nih.gov/27552147/">developing brains are more vulnerable to trauma</a> – it creates a chronic inflammatory response affecting brain development – the pathology of CTE is still being studied.</p>
<p>The <a href="https://www.nejm.org/doi/full/10.1056/NEJMclde2302021">risk factors for young athletes</a> are complex and multifaceted but it is likely that playing junior contact sport heightens an athlete’s risk of developing neurodegenerative diseases as an adult.</p>
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<p>The strongest <a href="https://www.nature.com/articles/s41467-023-39183-0">predictor</a> for developing CTE is cumulative exposure to repeated brain trauma, rather than the number of diagnosable concussions. Prolonged exposure to repeated low-level impacts appears to produce a greater lifetime volume of brain trauma when compared with athletes who sustain a small number of more forceful injuries.</p>
<p>Again, the reasons for this dynamic require further study. One potential explanation is that low-level impacts, which often do not reach the <a href="https://www.concussioninsport.gov.au/medical_practitioners#assessment_of_concussion">clinical threshold</a> for a concussion diagnosis, are easier to ignore and play through. </p>
<p>For the athletes in the Boston University study to develop CTE before the age of 30, it is likely they were exposed to repeated brain trauma from an early age through youth sport.</p>
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Read more:
<a href="https://theconversation.com/australian-researchers-confirm-worlds-first-case-of-dementia-linked-to-repetitive-brain-trauma-in-a-female-athlete-208929">Australian researchers confirm world’s first case of dementia linked to repetitive brain trauma in a female athlete</a>
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<h2>Are contact sports safe for kids?</h2>
<p>Public health advocates in <a href="https://www.cambridge.org/core/journals/journal-of-law-medicine-and-ethics/article/abs/youth-sports-public-health-framing-risks-of-mild-traumatic-brain-injury-in-american-football-and-ice-hockey/1529848D096AD28A080B3EE828E7E553">North America</a>, <a href="https://www.frontiersin.org/articles/10.3389/fneur.2022.880905/full">Australia</a>, <a href="https://www.stuff.co.nz/sport/129063074/new-zealands-teenage-concussion-issue-rugby-pushes-for-national-guidelines-to-erase-blurred-lines">New Zealand Aotearoa</a> and the <a href="https://pubmed.ncbi.nlm.nih.gov/25586912/">United Kingdom</a> have long expressed concerns about the risks of contact sport for children. </p>
<p>Improved oversight would go some way toward reducing the serious health risks of mild traumatic brain injury (concussion). These include <a href="https://concussionfoundation.org/PCS-resources/what-is-PCS#:%7E:text=Post%2DConcussion%20Syndrome%2C%20or%20PCS,may%20diagnose%20Post%2DConcussion%20Syndrome">post-concussion syndrome</a> (where symptoms do not resolve within the expected time period of about one month) and <a href="https://www.ncbi.nlm.nih.gov/books/NBK448119/">second impact syndrome</a> (where a young athlete who has previously been concussed receives a second impact either on the same day or up to a week later, resulting in catastrophic outcomes).</p>
<p>Although professional athletes are increasingly subject to monitoring for brain injuries, these practices are not consistently in place for participants in <a href="https://theconversation.com/repeated-head-injury-may-cause-degenerative-brain-disease-for-people-who-play-sport-juniors-and-amateurs-included-196042">semi-professional, club or junior competitions</a>. It is essential that sports bodies implement the same reporting, monitoring and exclusion protocols all the way through their competitions, especially in junior sport.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&rect=40%2C0%2C6669%2C3098&q=45&auto=format&w=1000&fit=clip"><img alt="young players huddle on sporting field" src="https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&rect=40%2C0%2C6669%2C3098&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=282&fit=crop&dpr=1 600w, https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=282&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=282&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=354&fit=crop&dpr=1 754w, https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=354&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/544979/original/file-20230828-189469-cedpkj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=354&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Some codes have introduced restrictions to protect young players.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/kids-sport-team-gathering-rising-hands-1682342155">Shutterstock</a></span>
</figcaption>
</figure>
<h2>First steps</h2>
<p>Existing concussion guidelines are not designed to account for the types of sub-concussive injuries (where an impact does not result in observable symptoms) most strongly associated with CTE. To protect them from the disease, contact sporting bodies must reduce young athletes’ lifetime exposure to brain trauma. One way to do this would be to restrict contact in training and games for juniors. </p>
<p>Some sporting bodies have already taken the initial steps. <a href="https://www.play.afl/play/junior-football-rules">Australian Rules football players</a> are restricted to modified tackling until the age of 12. The <a href="https://www.playrugbyleague.com/framework/tackleready/">National Rugby League</a> will soon implement a ban on tackling until midway through under-7s competitions. </p>
<p>The US Soccer Federation <a href="https://www.nytimes.com/2015/11/10/sports/soccer/us-soccer-resolving-lawsuit-will-limit-headers-for-youth-players.html">prohibits</a> children under 11 from heading the ball. The UK Football Association will trial <a href="https://www.thefa.com/news/2022/jul/18/statement-heading-trial-u12-games-20221807#:%7E:text=The%20FA%20has%20been%20granted,of%20the%202022%2D23%20season.">a ban on deliberate heading</a> before age 12 – a clear acknowledgement of the dangers of repetitive low-grade brain trauma. </p>
<p>The prevalence of CTE in this study from the US, where athletes routinely wear helmets to play football and ice hockey, is further evidence helmets do not protect young players from concussions or the risk of CTE. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/do-women-soccer-players-have-more-concussions-this-world-cup-and-beyond-heres-how-to-keep-our-players-safe-208292">Do women soccer players have more concussions? This world cup and beyond, here's how to keep our players safe</a>
</strong>
</em>
</p>
<hr>
<p>Changes to tackling rules were met with resistance by those who <a href="https://www.dailymail.co.uk/sport/rugbyleague/article-11746861/Is-rugby-league-going-soft-Controversial-changes-NRL-leave-parents-fuming.html">fear</a> they would “soften” the games. Further measures to protect athletes will require courage from contact sports administrators.</p>
<p>This new study shows CTE can develop in young brains and builds off previous research suggesting the origins of this pathology may lie in junior contact sport. To protect players from neurodegenerative diseases like CTE, sports must <a href="https://concussionfoundation.org/sites/default/files/2023-06/CTE%20prevention%20protocol%20062023.pdf">reduce cumulative exposure to brain trauma</a> for all athletes, beginning with the junior leagues. In Australia, where children have at least four football codes to choose from, this message must be received with particular urgency.</p>
<hr>
<p><em>If this article has raised issues for you, or if you’re concerned about someone you know, call <a href="https://www.lifeline.org.au/">Lifeline</a> on 13 11 14. The National Dementia Helpline number is 1800 100 500.</em></p><img src="https://counter.theconversation.com/content/212369/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alan Pearce is currently unfunded. Alan is a non-executive unpaid director for the Concussion Legacy Foundation. He has previously received funding from Erasmus+ strategic partnerships program (2019-1-IE01-KA202-051555), Sports Health Check Charity (Australia), Australian Football League, Impact Technologies Inc., and Samsung Corporation, and is remunerated for expert advice to medico-legal practices.</span></em></p><p class="fine-print"><em><span>Kathleen Bachynski is a member of the Pink Concussions professional advisory board.
</span></em></p><p class="fine-print"><em><span>Stephen Townsend does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Chronic traumatic encephalopathy is often assumed to be a disease which develops later in life, but a new study clearly shows it can start early in the brains of young athletes.Stephen Townsend, Lecturer, School of Human Movement and Nutrition Sciences, The University of QueenslandAlan Pearce, Professor, College of Science, Health, Engineering, La Trobe UniversityKathleen Bachynski, Assistant Professor, Public Health, Muhlenberg CollegeLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2058572023-06-09T15:53:37Z2023-06-09T15:53:37ZWhy understanding how spiders spin silk may hold clues for treating Alzheimer’s disease<figure><img src="https://images.theconversation.com/files/528214/original/file-20230525-29-sg2yw.jpg?ixlib=rb-1.1.0&rect=0%2C6%2C4512%2C2996&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-macro-shot-european-garden-spider-1495428323">novama/Shutterstock</a></span></figcaption></figure><p>Really, we should envy spiders. Imagine being able to make silk like they do, flinging it around to get from place to place, always having a <a href="https://pubs.acs.org/doi/10.1021/acsmacrolett.8b00678">strong-as-steel safety line</a> or spinning a comfy hammock whenever they need a rest. </p>
<p>The fascinating properties of spider silk make it no wonder that scientists have been trying to unravel its secrets for decades.</p>
<p>If we could understand and recreate the spinning process, we could produce artificial spider silk for a <a href="https://www.sciencedirect.com/science/article/abs/pii/S0141813021021292">range of medical applications</a>. For example, artificial silk can help <a href="https://doi.org/10.1016/j.biomaterials.2021.120692">regenerate the nerves that connect our brain and limbs</a>, and can shuttle <a href="https://doi.org/10.1021/acs.biomac.0c01138">drug molecules directly into the cells where they are needed</a>. </p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/zNtSAQHNONo?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
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<p>Spider silk is made of <a href="https://www.sciencedirect.com/topics/engineering/spidroins">proteins called spidroins</a>, which the spider stores in a silk gland in its abdomen. There are several types of spidroin for spinning different sorts of silk. Spiders <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673682/">store them as a liquid</a> that resembles oil droplets.</p>
<p>But one of the questions that has eluded scientists so far is how spiders turn these liquid droplets into silk. We decided to investigate why the spidroins form droplets, to get us closer to replicating a spider’s spinning process. </p>
<h2>Weaving a web</h2>
<p>The trick that spiders use to speed up their spinning process can be used to spin better artificial silk, or even develop new spinning processes. </p>
<p>In 2017, we learned to <a href="https://www.nature.com/articles/ncomms15504">make synthetic silk fibres</a> by emulating the silk gland, but we did not know how things work inside the spider. Now we know that forming droplets first <a href="https://pubmed.ncbi.nlm.nih.gov/37084706/">speeds up the conversion to these fibres</a>. </p>
<p>An important clue to how the droplets and fibres are related came from an unexpected area of our research – on <a href="https://pubmed.ncbi.nlm.nih.gov/23013511/">Alzheimer’s and Parkinson’s diseases</a>. Proteins that are involved in these diseases, called <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/alpha-synuclein#:%7E:text=%CE%B1%2DSynuclein%20is%20a%20highly,linked%20to%20familial%20Parkinson%20disease.">alpha-synuclein</a> and <a href="https://www.alz.org/media/Documents/alzheimers-dementia-tau-ts.pdf">tau</a>, can assemble into tiny, oil-like droplets in human cells. </p>
<p>Tau is a protein that helps stabilise the internal skeleton of nerve cells (neurons) in the brain. This internal skeleton has a tube-like shape through which nutrients and other essential substances travel to reach different parts of the neuron. </p>
<p>In Alzheimer’s disease, an abnormal form of tau builds up and clings to the normal tau proteins, creating “tau tangles”. </p>
<p>Alpha-synuclein is found in large quantities in <a href="https://www.webmd.com/mental-health/what-is-dopamine">dopamine-producing nerve cells</a>. Abnormal forms of this protein are linked to Parkinson’s disease. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Beautiful spider web with water drops close-up" src="https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/528217/original/file-20230525-25-p40y48.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The trick spiders use to speed up their spinning process can be used to spin better artificial silk.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/beautiful-spider-web-water-drops-close-155560781">Aastels/Shutterstock</a></span>
</figcaption>
</figure>
<p>Oil droplets of either one of these proteins form in humans when they become entangled, like boiled spaghetti on a plate. At first, the proteins are flexible and elastic, much like spidroin oil droplets. </p>
<p>But if the proteins remain entangled, they get stuck together which alters their shape, changing them into rigid fibres. These can be toxic to human cells – for example, in neurodegenerative conditions such as Alzheimer’s. </p>
<p>However, <a href="https://pubmed.ncbi.nlm.nih.gov/33148640/">spidroins can form droplets</a> too. This left us wondering if the same mechanism that causes neurodegeneration in humans could help the spider to convert liquid spidroins into rigid silk fibres.</p>
<p>To find out, we used a <a href="https://www.nature.com/articles/nchembio.2269">synthetic spidroin called NT2RepCT</a>, which can be produced by bacteria. Under the microscope, we could see that this synthetic spidroin formed liquid droplets when it was dissolved in phosphate buffer, a type of salt found in the spider’s silk gland. This allowed us to replicate spider silk spinning conditions in the lab.</p>
<h2>Silky science</h2>
<p>Next, we studied how the spidroin proteins act when they form droplets. To answer this question, we turned to an analysis technique <a href="https://www.britannica.com/science/mass-spectrometry">called mass spectrometry</a>, to measure how the weight of the proteins changed when they formed droplets. To our surprise, we saw that the spidroin proteins, which normally form pairs, instead split into single molecules. </p>
<p>We needed to do more work to find out how these protein droplets help spiders spin silk. Previous research has shown spidroins have different parts, called domains, with separate functions. </p>
<p>The end part of the spidroin, called c-terminal domain, makes it form pairs. The c-terminal also starts <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1001921">fibre formation when it comes into contact with acid</a>. </p>
<p>So, we made a spidroin which contained only the c-terminal domain and tested its ability to form fibres. </p>
<p>When we used phosphate buffer to entangle the proteins into droplets, they turned into rigid fibre instantly. When we added acid without first making droplets, fibre formation took much longer. </p>
<p>This makes sense since the spidroin molecules must find each other when forming a fibre. Entangling the spidroins like spaghetti helps them rapidly assemble into silk. </p>
<p>This finding tells us how the spider can instantly convert its spidroins into a solid thread. It also uncovered how nature uses the same mechanism that can make brain proteins toxic to create some of its most amazing structures. </p>
<p>The surprising parallel between spider silk spinning and fibres toxic to humans could one day lead to new clues about how to fight neurodegenerative disorders. </p>
<p>Scientists may use spider silk research, including what we have learned about the spider silk domains, to keep human proteins from sticking together – to stop them from becoming toxic. If spiders can learn how to keep their sticky proteins in check, perhaps so can we.</p><img src="https://counter.theconversation.com/content/205857/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Michael Landreh receives funding from the Swedish Research Council (VR), the Swedish Cancer Research Foundation (Cancerfonden), the Knut and Alice Wallenberg-Foundation (KAW), The Olle Engkvist Foundation, and Karolinska Institutet.</span></em></p><p class="fine-print"><em><span>Anna Rising receives funding from European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 815357), the Center for Innovative Medicine (CIMED) at Karolinska Institutet and Stockholm City Council, Karolinska Institutet SFO Regen (FOR 4-1364/2019), FORMAS (2019-00427), Olle Engkvist stiftelse (207-0375) and the Swedish Research Council (2019-01257).</span></em></p>The surprising parallel between spider silk spinning and fibres toxic to humans could lead to new clues about how to fight neurodegenerative disorders.Michael Landreh, Researcher, Department of Microbiology, Tumor and Cell Biology, Karolinska InstitutetAnna Rising, Researcher in Veterinary medicine biochemistry, Karolinska InstitutetLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2052212023-05-09T20:06:06Z2023-05-09T20:06:06ZHere’s how a new AI tool may predict early signs of Parkinson’s disease<figure><img src="https://images.theconversation.com/files/525006/original/file-20230509-15-3u2atx.jpg?ixlib=rb-1.1.0&rect=13%2C13%2C2982%2C1706&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://photos.aap.com.au/search/michael%20j%20fox">AP Photo/George Walker IV</a></span></figcaption></figure><p>In 1991, the world was shocked to learn actor <a href="https://www.theguardian.com/film/2023/jan/31/still-a-michael-j-fox-movie-parkinsons-back-to-the-future">Michael J. Fox</a> had been diagnosed with Parkinson’s disease. </p>
<p>He was just 29 years old and at the height of Hollywood fame, a year after the release of the blockbuster Back to the Future III. This week, documentary <a href="https://www.imdb.com/title/tt19853258/">Still: A Michael J. Fox Movie</a> will be released. It features interviews with Fox, his friends, family and experts. </p>
<p>Parkinson’s is a debilitating neurological disease characterised by <a href="https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055">motor symptoms</a> including slow movement, body tremors, muscle stiffness, and reduced balance. Fox has already <a href="https://www.cbsnews.com/video/michael-j-fox-on-parkinsons-and-maintaining-optimism">broken</a> his arms, elbows, face and hand from multiple falls. </p>
<p>It is not genetic, has no specific test and cannot be accurately diagnosed before motor symptoms appear. Its cause is still <a href="https://www.apdaparkinson.org/what-is-parkinsons/causes/">unknown</a>, although Fox is among those who thinks <a href="https://www.cbsnews.com/video/michael-j-fox-on-parkinsons-and-maintaining-optimism">chemical exposure may play a central role</a>, speculating that “genetics loads the gun and environment pulls the trigger”.</p>
<p>In research published today in <a href="https://pubs.acs.org/doi/10.1021/acscentsci.2c01468">ACS Central Science</a>, we built an artificial intelligence (AI) tool that can predict Parkinson’s disease with up to 96% accuracy and up to 15 years before a clinical diagnosis based on the analysis of chemicals in blood. </p>
<p>While this AI tool showed promise for accurate early diagnosis, it also revealed chemicals that were strongly linked to a correct prediction. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/lBrwkqlg1jA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Fox woke up one morning to notice his pinky finger was ‘auto-animated’.</span></figcaption>
</figure>
<h2>More common than ever</h2>
<p>Parkinson’s is the world’s <a href="https://www.who.int/news-room/fact-sheets/detail/parkinson-disease">fastest growing neurological disease</a> with <a href="https://shakeitup.org.au/understanding-parkinsons/">38 Australians</a> diagnosed every day.</p>
<p>For people over 50, the chance of developing Parkinson’s is <a href="https://www.parkinsonsact.org.au/statistics-about-parkinsons/">higher than many cancers</a> including breast, colorectal, ovarian and pancreatic cancer.</p>
<p>Symptoms such as <a href="https://www.apdaparkinson.org/what-is-parkinsons/symptoms/#nonmotor">depression, loss of smell and sleep problems</a> can predate clinical movement or cognitive symptoms by decades. </p>
<p>However, the prevalence of such symptoms in many other medical conditions means early signs of Parkinson’s disease can be overlooked and the condition may be mismanaged, contributing to increased hospitalisation rates and ineffective treatment strategies.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/drooling-is-a-common-symptom-of-parkinsons-could-a-workout-for-the-swallowing-muscles-help-158954">Drooling is a common symptom of Parkinson's. Could a workout for the swallowing muscles help?</a>
</strong>
</em>
</p>
<hr>
<h2>Our research</h2>
<p>At UNSW we collaborated with experts from Boston University to build an AI tool that can analyse mass spectrometry datasets (a <a href="https://www.sciencedirect.com/topics/neuroscience/mass-spectrometry">technique</a> that detects chemicals) from blood samples.</p>
<p>For this study, we looked at the Spanish <a href="https://epic.iarc.fr/">European Prospective Investigation into Cancer and Nutrition</a> (EPIC) study which involved over 41,000 participants. About 90 of them developed Parkinson’s within 15 years. </p>
<p>To train the AI model we used a <a href="https://www.nature.com/articles/s41531-021-00216-4">subset of data</a> consisting of a random selection of 39 participants who later developed Parkinson’s. They were matched to 39 control participants who did not. The AI tool was given blood data from participants, all of whom were healthy at the time of blood donation. This meant the blood could provide early signs of the disease. </p>
<p>Drawing on blood data from the EPIC study, the AI tool was then used to conduct 100 “experiments” and we assessed the accuracy of 100 different models for predicting Parkinson’s. </p>
<p>Overall, AI could detect Parkinson’s disease with up to 96% accuracy. The AI tool was also used to help us identify which chemicals or metabolites were likely linked to those who later developed the disease.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/does-methamphetamine-use-cause-parkinsons-and-what-do-pizza-boxes-have-to-do-with-it-192635">Does methamphetamine use cause Parkinson's? And what do pizza boxes have to do with it?</a>
</strong>
</em>
</p>
<hr>
<h2>Key metabolites</h2>
<p>Metabolites are chemicals produced or used as the body digests and breaks down things like food, drugs, and other substances from environmental exposure. </p>
<p>Our bodies can contain thousands of metabolites and their concentrations can differ significantly between healthy people and those affected by disease.</p>
<p>Our research identified a chemical, likely a triterpenoid, as a key metabolite that could prevent Parkinson’s disease. It was found the abundance of triterpenoid was lower in the blood of those who developed Parkinson’s compared to those who did not.</p>
<p>Triterpenoids are known <a href="https://www.sciencedirect.com/topics/neuroscience/neuroprotection">neuroprotectants</a> that can regulate <a href="https://onlinelibrary.wiley.com/doi/10.1002/ana.10483">oxidative stress</a> – a leading factor implicated in Parkinson’s disease – and prevent cell death in the brain. Many foods such as <a href="https://link.springer.com/article/10.1007/s11101-012-9241-9#Sec3">apples and tomatoes</a> are rich sources of triterpenoids.</p>
<p>A synthetic chemical (a <a href="https://www.cdc.gov/biomonitoring/PFAS_FactSheet.html">polyfluorinated alkyl substance</a>) was also linked as something that might increase the risk of the disease. This chemical was found in higher abundances in those who later developed Parkinson’s. </p>
<p>More research using different methods and looking at larger populations is needed to further validate these results. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="man holds water but hand is shaking so it spills out" src="https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/525016/original/file-20230509-22-5qvg2s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">AI could be used to detect Parkinson’s Disease years before symptoms develop.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/man-holds-glass-water-shaking-hand-2176542139">Shutterstock</a></span>
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Read more:
<a href="https://theconversation.com/bad-dreams-in-children-linked-to-a-higher-risk-of-dementia-and-parkinsons-disease-in-adulthood-new-study-199822">Bad dreams in children linked to a higher risk of dementia and Parkinson's disease in adulthood – new study</a>
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<h2>A high financial and personal burden</h2>
<p>Every year in Australia, the average person with Parkinson’s spends over <a href="https://www.hindawi.com/journals/pd/2017/5932675/">A$14,000</a> in out-of-pocket medical costs.</p>
<p>The burden of living with the disease can be intolerable.</p>
<p>Fox acknowledges the disease can be a “nightmare” and a “living hell”, but he has also found that “<a href="https://www.cbsnews.com/video/michael-j-fox-on-parkinsons-and-maintaining-optimism">with gratitude, optimism is sustainable</a>”. </p>
<p>As researchers, we find hope in the potential use of AI technologies to improve patient quality of life and reduce health-care costs by accurately detecting diseases early.</p>
<p>We are excited for the research community to try our AI tool, which is <a href="https://github.com/CRANK-MS/CRANK-MS">publicly available</a>. </p>
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<p><em>This research was performed with Mr Chonghua Xue and A/Prof Vijaya Kolachalama (Boston University).</em></p><img src="https://counter.theconversation.com/content/205221/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Diana Zhang completed this research while undertaking a Fulbright Future Scholarship funded by the Kinghorn Foundation. She is supported by a Scientia PhD and RTP scholarship from the University of New South Wales.</span></em></p><p class="fine-print"><em><span>William Alexander Donald receives funding from the Australian Research Council (FT200100798).</span></em></p>This AI tool showed promise for early diagnosis. It also pointed to chemicals that may reduce or increase the risk of Parkinson’s.Diana Zhang, Fulbright and Scientia PhD Scholar, UNSW SydneyWilliam Alexander Donald, Associate Professor, ARC Future Fellow & UNSW Scientia Fellow, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2016022023-03-20T16:19:01Z2023-03-20T16:19:01ZAlzheimer’s disease: problems with the brain’s energy supply could be a cause<figure><img src="https://images.theconversation.com/files/516357/original/file-20230320-1425-yqlsjf.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C8000%2C4491&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Mitochondria help ensure our cells have the energy they need to function.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/mitochondria-cross-section-view-mitochondrion-3d-2017459415">ART-ur/ Shutterstock</a></span></figcaption></figure><p>Scientists have been working to understand the root causes of dementia and Alzheimer’s disease for decades now. But one of the reasons we don’t yet have a cure for this disease is because of the complexity of the human brain – alongside the complexity of the disease itself. </p>
<p>One of the leading theories in the field suggests that Alzheimer’s disease is caused by the abnormal accumulation of two proteins called <a href="https://pubmed.ncbi.nlm.nih.gov/24493463/">amyloid beta and tau</a> in the brain, resulting in plaques and tangles. Amyloid plaques are clumps that form between neurons, which can damage surrounding cells, while tau tangles block communication between nerve cells.</p>
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Read more:
<a href="https://theconversation.com/alzheimers-disease-surprising-new-theory-about-what-might-cause-it-192143">Alzheimer's disease: surprising new theory about what might cause it</a>
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<p>For years now, scientists have been trying to understand how the accumulation of these proteins begins and how this affects brain health, leading to memory loss. Despite the huge amount of research that’s happened to date, there’s not been much success in <a href="https://pubmed.ncbi.nlm.nih.gov/31706733">treating and preventing</a> Alzheimer’s disease.</p>
<p>This has led many experts in the field to wonder whether there’s something else we should also be looking at in the brain when it comes to understanding and curing Alzheimer’s disease. </p>
<p>A recent article in <a href="https://www.newscientist.com/article/mg25734290-100-restoring-the-brains-mitochondria-could-slow-ageing-and-end-dementia/">New Scientist</a> describes an idea which could be important in the field of brain health. This article highlights an alternative theory: that damage to mitochondria (the energy-producing structures within cells) could actually be the cause of Alzheimer’s.</p>
<h2>Energy deficit</h2>
<p>Mitochondria are found in virtually all the body’s cells. They use both oxygen and breakdown products from food to make a high energy molecule known as adenosine triphosphate (ATP). ATP is like your cells’ energy currency – kind of like a rechargeable battery. Our cells use ATP for the energy needed to carry out everyday functions and maintain their own health. Once used up, mitochondria can reload it with energy.</p>
<p>Mitochondria also have a host of other functions important for cellular health, such as telling the cell’s nucleus (the cell’s hub of genetic information) to carry out important functions, and sending signals to other cells. They’re also packed full of antioxidants – molecules that protect cells from damage. </p>
<p>Mitochondria are particularly important for the brain. The human brain only accounts for around 2% of our total body weight, yet even at rest, the brain uses <a href="https://www.nature.com/articles/s41598-019-47783-4.pdf">around 20%</a> of the body’s total energy expenditure. As the control centre of the body, the brain needs this energy in order to carry out its many important functions which make virtually everything we do possible – whether that’s blinking, smiling or memorising a poem. </p>
<p>So, our brain cells – particularly our neurons, the brain cells that send and receive signals from our brain to the rest of the body – have high energy needs. This is why each neuron can contain <a href="https://www.nature.com/articles/s41598-019-47783-4.pdf">thousands of mitochondria</a>. </p>
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<img alt="A digital drawing of our brain's neurons sending signals throughout the body." src="https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=343&fit=crop&dpr=1 600w, https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=343&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=343&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=431&fit=crop&dpr=1 754w, https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=431&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/516358/original/file-20230320-24-6hgbkd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=431&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Our neurons need a lot of energy to make virtually everything we do possible.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/neuronal-network-electrical-activity-neuron-cells-1691666992">MattLphotography/ Shutterstock</a></span>
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<p>It’s thought that neurons are formed at birth and do not get regenerated at any point in a person’s life. Instead, their mitochondria and cellular parts are constantly turning over and being renewed. This ensures that their mitochondria remain healthy – which in turns ensures the neuron can function properly. Essentially, this means that as long as the mitochondria are healthy, the neuron is too. </p>
<p>But what would happen if the mitochondria stopped being able to <a href="https://pubmed.ncbi.nlm.nih.gov/16285865/">produce enough energy</a> for our cells to carry out their functions and repair damage? This would mean the cells may start to accumulate damage. In neurons, this could result in damage – and even death. </p>
<p>This is the foundation of the mitochondrial cascade hypothesis. </p>
<h2>Mitochondrial loss</h2>
<p>The <a href="https://pubmed.ncbi.nlm.nih.gov/15193340">mitochondrial cascade hypothesis</a> was actually first published by scientist and clinician professor Russell Swerdlow in 2004. This landmark article reviewed numerous studies which had previously found evidence of mitochondrial damage in Alzheimer’s disease. In the paper, Swerdlow proposed a new theory suggesting that problems with mitochondria and their function could provide an alternative explanation for why Alzheimer’s disease develops. </p>
<p>However, despite <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684616">increasing evidence</a> showing mitochondrial loss in the neurons of <a href="https://pubmed.ncbi.nlm.nih.gov/27154981/">patients with Alzheimer’s</a>, the idea that <a href="https://pubmed.ncbi.nlm.nih.gov/30026371">mitochondrial dysfunction</a> could be a cause has remained on the fringes of dementia research. There are many reasons why this is the case. </p>
<p>First, a large proportion of the limited funding given to dementia research in the past few decades has gone to scientists studying amyloid beta and tau. This was thanks to promising studies in the field which suggested that removing or reducing the amount of <a href="https://pubmed.ncbi.nlm.nih.gov/25753046/">amyloid beta and tau</a> in the brain could have an effect on cognitive function. </p>
<p>Second, until relatively recently the methods used to study mitochondria in humans have been limited – meaning that we’ve also been limited in our ability to detect, prevent or cure mitochondrial dysfunction. But <a href="https://pubmed.ncbi.nlm.nih.gov/35623561/">developments in the field</a> may soon make it possible to transfer healthy mitochondria into cells. This could therefore allow us to study what would happen if we replaced damaged mitochondria in the neurons of patients with Alzheimer’s disease.</p>
<p>But while it’s clear that problems with the brain’s mitochondria are linked to neurodegenerative diseases, there are still many questions we need to answer before we can start developing treatments. For example, we need to understand what damages the brain’s mitochondria, and how to prevent this damage. </p>
<p>Dementia is a complex disease. This may mean there isn’t a one-size-fits-all cure for it. It could be the case that we may need to target multiple different mechanisms in order to treat the disease.</p><img src="https://counter.theconversation.com/content/201602/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Afshan Malik receives funding from the charity Alzheimer's Research UK</span></em></p>Mitochondria, which are found in every cell in the body, play an important role in brain function.Afshan Malik, Reader in Diabetes and Mitochondrial Research, King's College LondonLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/2002102023-02-22T12:54:03Z2023-02-22T12:54:03ZHow frontotemporal dementia, the syndrome affecting Wendy Williams, changes the brain – research is untangling its genetic causes<figure><img src="https://images.theconversation.com/files/511473/original/file-20230221-16-3xvr3l.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some of the same genetic mutations can lead to FTD, ALS or symptoms of both.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/brain-lp-pr-royalty-free-illustration/1164761753">antoniokhr/iStock via Getty Images Plus</a></span></figcaption></figure><p>Around <a href="https://www.who.int/news-room/fact-sheets/detail/dementia">55 million people worldwide</a> suffer from dementia such as Alzheimer’s disease. On Feb. 22, 2024, it was revealed that former talk show host <a href="https://www.npr.org/2024/02/22/1233172648/wendy-williams-aphasia-frontotemporal-dementia-diagnosis">Wendy Williams</a> had been diagnosed with <a href="https://www.theaftd.org/what-is-ftd/disease-overview/">frontotemporal dementia, or FTD</a>, a rare type of dementia that typically affects people <a href="https://www.alzheimers.gov/alzheimers-dementias/frontotemporal-dementia">ages 45 to 64</a>. <a href="https://apnews.com/article/what-is-frontotemporal-dementia-bruce-willis-fbfdbfca4793bb65ef3f38f31e31bd68">Bruce Willis</a> is another celebrity who was diagnosed with the syndrome, according to his family. In contrast to Alzheimer’s, in which the major initial symptom is memory loss, FTD typically involves changes in behavior.</p>
<p>The <a href="https://www.nia.nih.gov/health/what-are-frontotemporal-disorders">initial symptoms of FTD</a> may include changes in personality, behavior and language production. For instance, some FTD patients exhibit inappropriate social behavior, impulsivity and loss of empathy. Others struggle to find words and to express themselves. This insidious disease can be especially hard for families and loved ones to deal with. There is no cure for FTD, and there are no effective treatments.</p>
<p><a href="https://www.theaftd.org/genetics-of-ftd/">Up to 40% of FTD cases</a> have some family history, which means a genetic cause may run in the family. Since researchers identified the first genetic mutations that cause FTD in 1998, <a href="https://doi.org/10.15252%2Fembj.201797568">more than a dozen genes</a> have been linked to the disease. These discoveries provide an entry point to determine the mechanisms that underlie the dysfunction of neurons and neural circuits in the brain and to use that knowledge to explore potential approaches to treatment.</p>
<p><a href="https://profiles.umassmed.edu/display/130139">I am a researcher</a> who studies the development of FTD and related disorders, including the motor neuron disease <a href="https://www.als.org">amyotrophic lateral sclerosis, or ALS</a>. ALS, also known as Lou Gehrig’s disease, results in progressive muscle weakness and death. Uncovering the similarities in pathology and genetics between FTD and ALS could lead to new ways to treat both diseases.</p>
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<figcaption><span class="caption">Wendy Williams’ care team announced her diagnosis of frontotemporal dementia on Feb. 22, 2024.</span></figcaption>
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<h2>Genetic causes of FTD</h2>
<p>Genes contain the instructions cells use to make the proteins that carry out functions essential to life. Mutated genes can result in mutated proteins that lose their normal function or become toxic. </p>
<p>How mutated proteins contribute to FTD has been under intense investigation for decades. For instance, one of the key proteins in FTD, called <a href="https://doi.org/10.1016%2Fj.neuron.2011.04.009">tau</a>, helps stabilize certain structures in neurons and can form clumps in diseased brains. Another key protein, <a href="https://doi.org/10.1038%2Fnrn.2017.36">progranulin</a>, regulates cell growth and a part of the cell called the lysosome that breaks down cellular waste products.</p>
<p>Remarkably, the most common genetic mutation in FTD – in a gene called C9orf72 – <a href="https://doi.org/10.15252%2Fembj.201797568">also causes ALS</a>. In fact, apart from the mutations in genes that encode for tau and progranulin, most genetic mutations that cause FTD <a href="https://doi.org/10.15252%2Fembj.201797568">also cause ALS</a>. Another protein, <a href="https://doi.org/10.15252/embj.201797568">TDP-43</a>, forms clumps in the brains of over 95% of ALS cases and almost half of FTD cases. Thus, these disorders share close links in genetics and pathology.</p>
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<figcaption><span class="caption">Frontotemporal dementia typically affects people under 60.</span></figcaption>
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<h2>Modifier genes</h2>
<p>The same genetic mutation can cause FTD in one patient, ALS in another or symptoms of both FTD and ALS at the same time. Remarkably, some people who carry these genetic mutations may have no obvious symptoms for decades.</p>
<p>One reason the same mutation can cause both FTD and ALS is that, in addition to <a href="https://theconversation.com/als-is-only-50-genetic-identifying-dna-regions-affected-by-lifestyle-and-environmental-risk-factors-could-help-pinpoint-avenues-for-treatment-179169">lifestyle and environmental factors</a>, other genes may also influence whether mutated genes lead to disease. Identifying these <a href="https://doi.org/10.1016%2Fj.neuron.2020.08.022">modifier genes</a> in FTD, ALS and other neurodegenerative diseases could lead to new treatment approaches by boosting the activity of those that protect against disease or suppressing the activity of those that promote disease. </p>
<p>Modifier genes have long been a focus of research in <a href="https://www.umassmed.edu/fen-biaogaolab/">my laboratory</a> at the University of Massachusetts Chan Medical School. When my laboratory was still in San Francisco, we collaborated with neurologist <a href="https://profiles.ucsf.edu/bruce.miller">Bruce Miller</a> and generated the first stem cell lines from FTD patients with mutations in <a href="https://doi.org/10.1016%2Fj.celrep.2012.09.007">progranulin</a> and <a href="https://doi.org/10.1007%2Fs00401-013-1149-y">C9orf72</a>. These stem cells can be turned into neurons for researchers to study in a petri dish. My team also uses fruit flies to identify modifier genes and then test how they influence disease in neurons from patients with FTD or ALS.</p>
<p>For instance, in close collaboration with cell biologist <a href="https://www.stjude.org/directory/t/j-paul-taylor.html">J. Paul Taylor</a>, my laboratory was among the first to discover a small <a href="https://doi.org/10.1038%2Fnature14974">subset of modifier genes</a> that help transport molecules into or out of the nucleus of a neuron. We also <a href="https://doi.org/10.1016%2Fj.neuron.2016.09.015">discovered</a> <a href="https://doi.org/10.1073%2Fpnas.1901313116">modifier genes</a> that encode for some proteins that help repair damaged DNA. Targeting these modifier genes using <a href="https://doi.org/10.1089%2Fnat.2018.0725">gene-silencing techniques</a> developed by Nobel laureate <a href="https://www.nobelprize.org/prizes/medicine/2006/mello/facts/">Craig Mello</a> and other researchers at UMass Chan could offer potential treatments.</p>
<h2>Treating behavioral changes in FTD</h2>
<p>Because the brain is an extremely complex organ, it can be very difficult to understand what causes personality and behavioral changes in FTD patients. </p>
<p>Over the years, my team has used mice to study the causes of these changes. For instance, we found that the reduced social interaction we observed in mice engineered to have FTD is linked to <a href="https://doi.org/10.1038%2Fnm.3717">two different</a> <a href="https://doi.org/10.1038%2Fs41593-019-0397-0">disease proteins</a> in the same part of the brain, suggesting that this symptom may be caused by defects in the same neural circuit. These deficits could be reversed by injecting a molecule called <a href="https://doi.org/10.1038%2Fnm.3717">microRNA-124</a> into the prefrontal cortex, the part of the brain that controls social behaviors.</p>
<p>Moreover, with my longtime collaborator neuroscientist <a href="https://www.upstate.edu/psych/faculty.php?empID=yaow">Wei-Dong Yao</a>, our labs found that mice with FTD have <a href="https://doi.org/10.1038%2Fnm.3717">defects at</a> <a href="https://doi.org/10.1038%2Fs41593-019-0397-0">the synapses</a> in this part of the brain. Synapses are areas where neurons are in contact with each other and play an important role in transporting information in the nervous system. Recently, he found that <a href="https://doi.org/10.1016/j.neuron.2022.12.027">lack of empathy</a> in another mouse model of FTD could be reversed by increasing activity in the prefrontal cortex. </p>
<p>Further research to understand the molecular mechanisms and brain circuitry behind FTD offer hope that its devastating symptoms, including behavioral and personality changes, will be treatable in the future.</p>
<p><em>This is an updated version of an article originally published on Feb. 22, 2023.</em></p><img src="https://counter.theconversation.com/content/200210/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Fen-Biao Gao receives and has previously received funding from the NIH, The Muscular Dystrophy Association, The Association for FTD, Target ALS Foundation, The ALS Association, The Tau Consortium, The Consortium for Frontotemporal Dementia Research, The Ricico Fund, The Cellucci Fund, Merck, and Stealth BioTherapeutics.
He works for the NIH as a member of its CMND study section, for The Muscular Dystrophy Association as a member of its Research Advisory Council and for The Association for FTD as a member of its Scientific Review Panel. </span></em></p>FTD leads to changes in personality and behavior. Understanding its genetic and molecular causes could lead to new ways to treat neurodegenerative diseases.Fen-Biao Gao, Professor of RNA Therapeutics, Governor Paul Cellucci Chair in Neuroscience Research, Founding Director of Frontotempral Dementia Research Center, UMass Chan Medical SchoolLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1991482023-02-08T13:42:23Z2023-02-08T13:42:23ZCells routinely self-cannibalize to take out their trash, aiding in survival and disease prevention<figure><img src="https://images.theconversation.com/files/508693/original/file-20230207-23-r0tkni.png?ixlib=rb-1.1.0&rect=0%2C0%2C907%2C679&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Illustration of an autophagosome (light blue double-membrane to the right) engulfing cellular material.</span> <span class="attribution"><a class="source" href="https://doi.org/10.2210/rcsb_pdb/goodsell-gallery-012">David S. Goodsell and Daniel Klionsky/RCSB PDB-101</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Don’t let the textbook diagram of a simplified two-dimensional cell fool you – within this tiny structure of life is a complex universe of molecular machinery that is continually being built, put into motion and eventually broken down. </p>
<p>Cells use the thousands of different proteins within them as tools to shape their internal environment. In this environment are specialized compartments known as <a href="https://www.genome.gov/genetics-glossary/Organelle">organelles</a> that carry out the cell’s functions. Two important organelles within cells are mitochondria and the endoplasmic reticulum, which <a href="https://bio.libretexts.org/Bookshelves/Microbiology/Microbiology_(Boundless)/04%3A_Cell_Structure_of_Bacteria_Archaea_and_Eukaryotes/4.07%3A_Internal_Structures_of_Eukaryotic_Cells/4.7B%3A_Mitochondria">produce energy</a> and <a href="https://bio.libretexts.org/Bookshelves/Cell_and_Molecular_Biology/Book%3A_Cells_-_Molecules_and_Mechanisms_(Wong)/11%3A_Protein_Modification_and_Trafficking/11.03%3A_Protein_Folding_in_the_Endoplasmic_Reticulum">assemble proteins</a>, respectively. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of endoplasmic reticulum surrounded by an autophagosome" src="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=749&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=749&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=749&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=942&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=942&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508697/original/file-20230207-17-cb1m6k.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=942&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This microscopy image shows an endoplasmic reticulum engulfed by an autophagosome.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1371/journal.pbio.0040442.g001">Liza Gross/PLoS Biology</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>Since routine cellular activity generates toxic byproducts that can damage the cell, a disposal system is needed to degrade and recycle these molecules within cells. One of these processes is <a href="https://doi.org/10.1038/sj.cdd.4401765">autophagy</a>, a form of self-consumption cells use to eliminate and recycle abnormal or excess components, including proteins and organelles. Derived from Greek, the term literally translates to “self-eating.” In 2016, cell biologist Yoshinori Ohsumi won the <a href="https://www.nobelprize.org/prizes/medicine/2016/press-release/">Nobel Prize in Physiology or Medicine</a> for his work on autophagy. Autophagy is essential for cellular health and longevity. When this process is not working well, it’s <a href="https://doi.org/10.1056/nejmra2022774">linked to several human diseases</a>, including neurodegenerative and cardiovascular diseases and cancer. </p>
<p><a href="https://gustafssonlabucsd.org/team/">We are researchers</a> studying how autophagy is activated in cells. In our <a href="http://dx.doi.org/10.1126/scisignal.abo4457">recently published research</a>, we examined two key regulators of this process and identified a unique role one of them plays in degrading mitochondria that may serve as a potential target to treat certain diseases.</p>
<h2>Autophagy and human disease</h2>
<p>The connection between autophagy and disease is complex and not well understood. </p>
<p>For instance, autophagy appears to play a <a href="https://doi.org/10.1038/s41418-019-0474-7">paradoxical role in cancer</a>. On one hand, some studies have shown that because this process suppresses tumors by eliminating potentially harmful material, reduced or impaired autophagy can turn a cell cancerous. On the other hand, activating autophagy after a tumor has formed can promote cancer by helping it adapt and survive, potentially leading to treatment resistance.</p>
<p>These findings suggest that it is especially important to understand the precise steps and timing of autophagy when it comes to targeting this process as a cancer treatment strategy. Researchers are evaluating the anticancer effects of two malaria drugs, <a href="https://doi.org/10.3389/fphar.2020.00408">chloroquine and hydroxychloroquine</a>, that block the final steps of autophagy. So far, they have varying efficacy depending on cancer type and stage.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Ws0mOmfC9EU?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Yoshinori Ohsumi was awarded the 2016 Nobel Prize in Medicine for his discoveries of the mechanisms of autophagy.</span></figcaption>
</figure>
<p>Dysfunctional autophagy also plays an important role in <a href="https://doi.org/10.1111/bpa.12545">most neurodegenerative diseases</a>. The aggregation of abnormal proteins in brain cells are common features in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and ALS. Some scientists believe that the accumulation of these proteins is due at least in part to a decline in their degradation through autophagy.</p>
<p>Autophagy is also important for heart health. Researchers have found that autophagy in the heart <a href="https://doi.org/10.1161/CIRCRESAHA.118.312208">declines</a> <a href="https://doi.org/10.1111/acel.13187">with age</a> and contributes to cardiovascular disease. Decreased autophagy in cardiac muscle cells results in accumulating cellular garbage that can affect their ability to contract and even cause their death. With fewer cells and less contraction, the buildup of toxic material in cardiac muscle cells can ultimately lead to heart failure. </p>
<h2>Breaking down mitochondria with mitophagy</h2>
<p>For autophagy to be efficient, it needs to specifically get rid of only damaged proteins or organelles within the cell. Uncontrolled degradation would deprive a cell of its basic needs. </p>
<p>This is particularly true for mitochondria, as cells rely on them for much of their energy production. Our team has been very interested in how cells ensure that autophagy of mitochondria, also known as mitophagy, eliminates only dysfunctional mitochondria while sparing the healthy parts of the cell. Dysfunctional mitophagy has been linked to <a href="https://doi.org/10.1016/j.semcancer.2019.07.015">cancer</a>, <a href="https://doi.org/10.1111/cns.13140">neurodegeneration</a> and <a href="https://doi.org/10.1016/j.molmed.2022.06.007">cardiovascular disease</a>, among other diseases. </p>
<p>The process of autophagy starts when the cell begins to form a membrane near damaged proteins or organelles. This membrane will expand into a vesicle, or sac, known as an autophagosome, that engulfs the damaged material. It will then fuse with another internal cell structure full of acid called a lysosome that helps degrade its cargo. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Diagram depicting autophagy process" src="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/508689/original/file-20230207-31-jbph8w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Autophagy involves the formation of a membrane around the cellular material to be eliminated. This autophagosome eventually joins with another organelle called a lysosome (orange sphere, fifth step) which releases chemicals that break down its contents.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/stages-of-autophagy-illustration-royalty-free-illustration/713780595">Kateryna Kon/Science Photo Library via Getty Images</a></span>
</figcaption>
</figure>
<p>Beclin1 is a protein known to promote the formation of autophagosomes in cells. However, its role in mitophagy is controversial, in part because very little is known about its <a href="https://doi.org/10.1016/j.cell.2013.07.035">close relative Beclin2</a>. We wanted to <a href="http://dx.doi.org/10.1126/scisignal.abo4457">disentangle the functions</a> of these two proteins and determine their role in mitophagy. To do this, we used mouse and human cell models to examine how the presence or absence of these two proteins affected autophagy. </p>
<p>We discovered that activating a region unique to Beclin1 enables it to promote autophagosome formation next to dysfunctional mitochondria, facilitating their degradation in human cells. Because a similar region isn’t found in Beclin2, this meant that only Beclin1 may be essential for mitophagy.</p>
<p>Interestingly, we also observed Beclin1 at discrete points of contact between mitochondria and endoplasmic reticulum during mitophagy. This supports <a href="https://doi.org/10.1038/s41580-020-0241-0">emerging research</a> suggesting that physical interactions between these organelles facilitate the transfer of certain molecules needed to make autophagosomes. Our work indicates that only Beclin1 promotes engulfment of damaged mitochondria at these sites. Beclin2 may perform a different role in autophagy in other conditions.</p>
<h2>Targeting autophagy for treatments</h2>
<p>Autophagy represents a potential treatment target for many different diseases. Our team is currently studying how autophagy contributes to protein aggregation and mitochondrial dysfunction in the heart, and we are working to develop new tools to measure this process in cell and animal models.</p>
<p>However, therapeutic strategies to regulate autophagy is complicated by the fact that it is a complex multi-step process that involves many different proteins. Some diseases may require targeting the early steps of autophagsosome formation, while others may require focusing on when they fuse with lysosomes. Furthermore, different disease states may benefit from either autophagy activation or inhibition. More work needs to be done to identify all of the specific proteins that regulate each step of the autophagy pathway and how cells finetune this process in both health and disease. </p>
<p>We believe that helping cells better harness the power of autophagy in a complex molecular universe can train them to follow the three Rs – reduce, reuse, recycle – to promote health and longevity.</p><img src="https://counter.theconversation.com/content/199148/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Åsa Gustafsson receives funding from NIH. </span></em></p><p class="fine-print"><em><span>Justin Quiles receives funding from The American Heart Association. </span></em></p>Cells degrade and recycle damaged parts of themselves through a process called autophagy. When this “self-devouring” goes awry, it may promote cancer and neurodegenerative disease.Åsa Gustafsson, Professor of Pharmacy and Pharmaceutical Sciences, University of California, San DiegoJustin Quiles, Postdoctoral Scholar of Pharmacy and Pharmaceutical Science, University of California, San DiegoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1970092023-01-18T13:38:45Z2023-01-18T13:38:45ZVaccination to prevent dementia? New research suggests one way viral infections can accelerate neurodegeneration<figure><img src="https://images.theconversation.com/files/503691/original/file-20230109-7992-tpch1g.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2190%2C1369&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Many viruses interact with the olfactory system, and can damage other areas of the brain through it.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/brain-viral-infection-on-science-background-royalty-free-image/1352255856">Mohammed Haneefa Nizamudeen/iStock via Getty Images Plus</a></span></figcaption></figure><p>One in nine Americans ages 65 and over had <a href="https://www.alz.org/alzheimers-dementia/facts-figures">Alzheimer’s disease</a> in 2022, and countless others were indirectly affected as caregivers, health care providers and taxpayers. There is currently no cure – available treatments primarily focus on prevention by encouraging protective factors, such as exercise and healthy diet, and reducing <a href="https://doi.org/10.1186/s12929-019-0524-y">aggravating factors</a>, such as diabetes and high blood pressure.</p>
<p>One of these aggravating factors is viral infections. Researchers have identified that certain viruses such as <a href="https://doi.org/10.3389/fnagi.2018.00324">herpes simplex virus type 1</a> (HSV-1, which causes cold sores), <a href="https://doi.org/10.1371/journal.pone.0188490">varicella zoster virus</a> (VZV, which causes chickenpox and shingles) and <a href="https://doi.org/10.3233/JAD-220717">SARS-CoV-2</a> (which causes COVID-19) can lead to a higher risk of Alzheimer’s disease and dementia following infection.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/rTAOX4ahMK0?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">There is increasing evidence supporting the potential role viruses play in Alzheimer’s disease.</span></figcaption>
</figure>
<p>Figuring out how and when these viruses contribute to disease could help scientists develop new therapies to prevent dementia. However, researchers have been <a href="https://doi.org/10.1371/journal.ppat.1008575">unable to consistently detect</a> suspect viruses in brains of people who died of Alzheimer’s. Because the Alzheimer’s disease process can start decades before symptoms, some researchers have proposed that viruses act early in a “<a href="https://doi.org/10.1016/j.neurobiolaging.2003.12.021">hit-and-run</a>” manner; they trigger a cascade of events that lead to dementia but have already taken off. In other words, by the time researchers analyze patient brains, any detectable viral components are gone and causation is difficult to establish.</p>
<p>We are a <a href="https://scholar.google.com/citations?user=rH1ZZcwAAAAJ&hl=en">neurovirologist</a>, <a href="https://scholar.google.com/citations?user=hp81rCYAAAAJ&hl=en">neurologist</a> and <a href="https://scholar.google.com/citations?user=LEcQAR0AAAAJ&hl=en">neuroscientist</a> team interested in the role viruses play in neurodegenerative diseases. In our <a href="https://doi.org/10.1016/j.neurobiolaging.2022.12.004">recently published research</a>, we use new technology to search for the tire tracks of these viruses in Alzheimer’s patients. By focusing on the most vulnerable entry point to the brain, the nose, we discovered a genetic network that provides evidence of a robust viral response.</p>
<h2>Focusing on the olfactory system</h2>
<p>Many of the viruses implicated in dementia, including <a href="https://doi.org/10.1038/ncpneuro0401">herpesviruses</a> and the <a href="https://doi.org/10.1126/sciadv.abc5801">virus that causes COVID-19</a>, enter the nose and interact with the olfactory system.</p>
<p>The <a href="https://www.britannica.com/science/olfactory-system">olfactory system</a> is constantly bombarded with odors, pollutants and pathogens. Particles inhaled through the nostrils bind to specific olfactory receptor cells in the tissue lining the nasal cavity. These receptors send messages to other cells in what’s called the olfactory bulb, which acts like a relay station that transmits these messages down the long nerves of the olfactory tract. These messages are then transferred to the area of the brain responsible for learning and memory, the hippocampus.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/mFm3yA1nslE?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Sensory cells translate information from your environment into electrical signals your brain can interpret.</span></figcaption>
</figure>
<p>The hippocampus plays a critical role assigning contextual information to odors, such as danger from the foul smell of propane or comfort from the smell of lavender. This area of the brain is also dramatically damaged in Alzheimer’s disease, causing devastating learning and memory deficits. For as many as 85% to 90% of Alzheimer’s patients, <a href="https://doi.org/10.1016/B978-0-12-819973-2.00030-7">loss of smell</a> is an early sign of disease.</p>
<p>The mechanism leading to smell loss in Alzheimer’s disease is relatively unknown. Like muscles that atrophy from lack of use, <a href="https://doi.org/10.1002/cne.901780310">sensory deprivation</a> is thought to lead to atrophy of the brain regions that specialize in interpreting sensory information. Strong sensory input to these regions is critical to maintain general brain health.</p>
<h2>Olfactory inflammation and Alzheimer’s disease</h2>
<p>We hypothesize that viral infections throughout life are both contributors to and potential drug targets in Alzheimers’s disease. To test this idea, <a href="https://doi.org/10.1016/j.neurobiolaging.2022.12.004">we used emerging, state-of-the-art technology to investigate</a> the mRNA and protein networks of the olfactory system of Alzheimer’s disease patients. </p>
<p>The body uses <a href="https://theconversation.com/what-is-mrna-the-messenger-molecule-thats-been-in-every-living-cell-for-billions-of-years-is-the-key-ingredient-in-some-covid-19-vaccines-158511">mRNA</a>, which is transcribed from DNA, to translate genetic material into proteins. The body uses specific mRNA sequences to produce a network of proteins that are used to fight against certain viruses. In some cases, the body continues to <a href="https://doi.org/10.1038/sj.cr.7310019">activate these pathways</a> even after the the virus is cleared, leading to chronic inflammation and tissue damage. Identifying which mRNA sequences and protein networks are present can allow us to infer, to a degree, whether the body is or was responding to a viral pathogen at some point.</p>
<p>Previously, sequencing mRNA in tissue samples was difficult because the molecules degrade very quickly. However, <a href="https://doi.org/10.1371/journal.pone.0212031">new technology</a> specifically addresses that issue by measuring small subsections of mRNA at a time instead of trying to reconstruct the whole mRNA sequence at once.</p>
<p>We leveraged this technology to sequence the mRNA of olfactory bulb and olfactory tract samples from six people with familial Alzheimer’s, an inherited form of the disease, and six people without Alzheimer’s. We focused on familial Alzheimer’s because there is less variability in disease than in the sporadic, or nonfamilial, form of the disease, which can result from a number of different individual and environmental factors.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopy image of neurons in mouse olfactory bulb" src="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/503694/original/file-20230109-15603-tfjiny.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This image shows neurons in a small cross section of a mouse’s olfactory bulb.</span>
<span class="attribution"><a class="source" href="https://directorsblog.nih.gov/2017/11/16/snapshots-of-life-making-sense-of-smell/">Jeremy McIntyre/University of Florida College of Medicine via National Institutes of Health</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<p>In the familial Alzheimer’s samples, we found altered gene expression indicating signs of a past viral infection in the olfactory bulb, as well as inflammatory immune responses in the olfactory tract. We also found higher levels of proteins involved in demyelination in the olfactory tract of familial Alzheimer’s samples than in the controls. Myelin is a protective fatty layer around nerves that allows electrical impulses to move quickly and smoothly from one area of the brain to another. Damage to myelin stalls signal transduction, resulting in impaired neural communication and, by extension, neurodegeneration.</p>
<p>Based on these findings, we hypothesize that viral infections, and the resulting inflammation and demyelination within the olfactory system, may disrupt the function of the hippocampus by impairing communication from the olfactory bulb. This scenario could contribute to the accelerated neurodegeneration seen in Alzheimer’s disease.</p>
<h2>Implications for patient health</h2>
<p>Epidemiological data supports the role of viral infections in the development of Alzheimer’s disease. For example, the <a href="https://doi.org/10.1371/journal.pone.0188490">varicella zoster virus</a> is linked to a nearly threefold risk of developing dementia within five years of infection for patients with a shingles rash on their face. A recent report also found a <a href="https://doi.org/10.3233/JAD-220717">nearly 70% increased risk</a> of getting diagnosed with Alzheimer’s within a year of a COVID-19 diagnosis for people over 65.</p>
<p>These studies suggest that vaccination may be a potential measure to prevent dementia. For example, vaccination against the <a href="https://doi.org/10.1016/j.arr.2021.101534">seasonal flu virus</a> and <a href="https://doi.org/10.1371/journal.pone.0257405">herpes zoster</a> is associated with an up to 29% and 30% reduced risk of developing dementia, respectively.</p>
<p>Further research investigating how viral infections can trigger neurodegeneration could aid in the development of antiviral drugs and vaccines against the viruses implicated in Alzheimer’s disease.</p><img src="https://counter.theconversation.com/content/197009/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Bubak receives funding from the National Institute on Aging. </span></em></p><p class="fine-print"><em><span>Diego Restrepo receives funding from the National Institute of Health and the National Science Foundation </span></em></p><p class="fine-print"><em><span>Maria Nagel receives funding from the National Institutes of Health.</span></em></p>Inflammation and damage to the olfactory system from shingles, COVID-19 and herpes infections may contribute to Alzheimer’s disease.Andrew Bubak, Assistant Research Professor of Neurology, University of Colorado Anschutz Medical CampusDiego Restrepo, Professor of Cell and Developmental Biology, University of Colorado Anschutz Medical CampusMaria Nagel, Professor of Neurology and Ophthalmology, University of Colorado Anschutz Medical CampusLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1960162022-12-13T22:56:16Z2022-12-13T22:56:16ZWhy does the Alzheimer’s brain become insulin-resistant?<figure><img src="https://images.theconversation.com/files/499100/original/file-20221205-26-1etuem.jpg?ixlib=rb-1.1.0&rect=7%2C7%2C988%2C555&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Type 2 diabetes, characterised in its advanced stages by insulin resistance, is an important risk factor for Alzheimer's disease.</span> <span class="attribution"><span class="source">(Shutterstock)</span></span></figcaption></figure><p>As the population ages, the number of people with <a href="https://braininstitute.ca/research-data-sharing/neurodegenerative-disorders">neurodegenerative diseases</a>, such as <a href="https://alzheimer.ca/en/about-dementia/what-alzheimers-disease">Alzheimer’s disease</a>, increases. Approximately <a href="https://www.canada.ca/en/public-health/services/publications/diseases-conditions/dementia-highlights-canadian-chronic-disease-surveillance.html">75,000 Canadians</a> are diagnosed with Alzheimer’s disease each year and experience a decline in their cognitive abilities. The ordeal usually lasts for several years while their family members watch helplessly.</p>
<p>Neurodegenerative diseases are characterized by <a href="https://www.sciencedirect.com/science/article/abs/pii/S0924977X13001107">proteinopathies</a> — abnormal accumulations of proteins in the brain that impair the functioning of <a href="https://cancer.ca/en/cancer-information/resources/glossary/n/neuron">neurons</a>. The most widely studied therapeutic approach to developing drugs for Alzheimer’s is to try to reduce the aggregation of <a href="https://canjhealthtechnol.ca/index.php/cjht/article/view/eh0103/683">amyloid-beta peptide</a> and <a href="https://nouvelles.umontreal.ca/en/article/2022/10/20/unlocking-the-mysteries-of-tauopathies-a-protein-that-gives-hope/">tau protein</a> in neurons.</p>
<p>However, in order to reach their targets, the drugs must first cross the <a href="https://www.theglobeandmail.com/canada/article-toronto-researchers-look-at-new-approach-for-treating-alzheimers/">blood-brain barrier</a> (BBB) from the blood to the brain. This is because <a href="https://www.biorxiv.org/content/10.1101/2020.12.10.419598v1.full">endothelial cells</a>, cells that line the tiniest blood vessels in the brain, regulate the exchange between blood and the brain. They maintain a balance that allows access to essential molecules such as glucose, but restrict the passage of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494002/">most pharmaceuticals</a>, including the new and <a href="https://www.ft.com/content/32478dbf-7270-4eb6-a576-663a47a3603e">much-hyped</a> drug <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2212948">lecanemab</a>.</p>
<p>When these brain endothelial cells become diseased, the balance is upset. The brain struggles to get the substances it needs back into the circulation and rejects those that might harm it.</p>
<p>The brain and the other organs of the body are thus in constant communication, while in health or in disease.</p>
<p>As experts in neurodegenerative diseases and the BBB, we have conducted a study on insulin receptor dysfunction in Alzheimer’s disease.</p>
<h2>Insulin and the brain</h2>
<p><a href="https://www.healthlinkbc.ca/health-topics/types-insulin">Insulin</a> is an essential hormone for life. It is best known for its effect on the regulation of <a href="https://www.diabetescarecommunity.ca/living-well-with-diabetes-articles/blood-sugar-levels-in-canada/?gclid=Cj0KCQiAyracBhDoARIsACGFcS4fee8N8dfBJj9HKxpUiGlNO6RANNF9BiZN52dsd6oxqgLCW7Od_WsaArF9EALw_wcB">blood sugar</a> and remains an essential part of the pharmaceutical treatment of <a href="https://www.healthlinkbc.ca/health-topics/types-insulin">diabetes</a>. In recent decades, researchers have noted vascular and metabolic abnormalities <a href="https://pubmed.ncbi.nlm.nih.gov/30022099/">in a high proportion of patients with dementia</a>.</p>
<p>Indeed, Type 2 diabetes, characterized in the later stages by <a href="http://www.diabetesclinic.ca/en/diab/1basics/insulin_resistance.htm">insulin resistance</a>, is a major risk factor for Alzheimer’s disease. There is some evidence to suggest that the <a href="https://pubmed.ncbi.nlm.nih.gov/29377010/">Alzheimer’s brain is less responsive to insulin</a>. Conversely, studies have shown that insulin can <a href="https://pubmed.ncbi.nlm.nih.gov/32730766/">improve memory</a>, prompting the development of clinical trials on the effect of insulin on Alzheimer’s disease.</p>
<p>Yet we still don’t know what cell types and mechanisms are involved in the action — and loss of action — of insulin in the brain. The vast majority of insulin is produced by the <a href="https://pancreaticcancercanada.ca/the-pancreas/">pancreas</a> and secreted into the bloodstream. Therefore, to affect the brain, insulin must first interact with the BBB and its endothelial cells, which are in contact with the blood and can take up insulin through <a href="https://pubmed.ncbi.nlm.nih.gov/36280236/">receptors</a>.</p>
<h2>Alzheimer’s and the insulin receptor</h2>
<p>In order to measure the amount of these insulin receptors in the brain, <a href="https://doi.org/10.1093/brain/awac309">we performed analyses directly in human tissues</a>. These samples came from a <a href="https://www.rushu.rush.edu/research/departmental-research/religious-orders-study">cohort</a> of over a thousand people who agreed to donate their brains after death. We have access to them through a partnership with researchers at Rush University in Chicago.</p>
<p>We found that the <a href="https://healthenews.mcgill.ca/new-insights-into-how-insulin-interacts-with-its-receptor/">insulin-binding receptor</a> is predominantly located in the microvessels, so, within the BBB itself. Moreover, the abundance of this receptor is decreased in Alzheimer’s patients. This decrease could lead to the loss of insulin response in the Alzheimer brain.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="schematic" src="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=781&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=781&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=781&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=982&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=982&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499093/original/file-20221205-15238-9izujo.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=982&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The brain insulin receptor is located mainly at the BBB, and its ability to respond to blood insulin is diminished in Alzheimer’s disease.</span>
<span class="attribution"><span class="source">(Manon Leclerc)</span>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<h2>Insulin receptor dysfunction</h2>
<p>In order to better control the experimental variables and measure the response of the insulin receptor, we then tested our hypotheses in mice. The <em>in situ</em> cerebral perfusion technique consists of injecting insulin directly into the carotid artery (an artery located in the neck) so that it reaches the brain in its entirety. We have shown that circulating insulin mainly activates receptors located on the cerebral microvessels.</p>
<p>Although it was generally accepted that insulin crosses the BBB to reach cells such as neurons deeper in the brain tissue, our results show that the proportion of insulin that crosses the BBB is low.</p>
<p>These two observations thus confirm that the majority of insulin must interact with cells in the BBB before it can exert an action on the brain.</p>
<p>We then applied the same method to <a href="https://www.criver.com/products-services/research-models-services/genetically-engineered-model-services/transgenic-mouse-rat-model-creation/transgenic-mice?region=3601">transgenic mice</a>, which were genetically modified to model Alzheimer’s disease. We found that the response to insulin at the BBB was dysfunctional, with no activation of the insulin receptor in these diseased mice.</p>
<p>Thus, in both humans and rodents, the brain insulin receptor is located primarily at the BBB, and its ability to respond to blood insulin is impaired in Alzheimer’s disease.</p>
<h2>A significant breakthrough</h2>
<p>In sum, our results suggest that alterations in the number, structure and function of insulin receptors at the level of BBB endothelial cells may contribute to the cerebral insulin resistance observed in Alzheimer’s disease.</p>
<p>Alzheimer’s research efforts are currently focused on drugs that, in order to reach their therapeutic target, the neurons, must first cross the BBB, which severely restricts their passage. By targeting the metabolic dysfunction of the brain instead, we propose a research alternative that has two major advantages.</p>
<p>The first is that we can use treatments that do not have to cross the BBB barrier, since it is the endothelial cells themselves that become the therapeutic target. The second involves <a href="https://www.nature.com/articles/nrd.2018.168">“drug repurposing,”</a> which consists of taking advantage of the phenomenal therapeutic arsenal already approved to fight diabetes and obesity, but using this in the context of Alzheimer’s.</p>
<p>It should be remembered that the few drugs available to us provide only a modest improvement in symptoms. Combating insulin resistance in the brain would make it possible to break the vicious circle between neuropathology (disease that affects the brain) and diabetes, and in theory slow down the progression of the disease.</p>
<h2>The work is not finished</h2>
<p>On the basic research side, we will continue to study the mechanisms downstream from the microvessels to understand the action of insulin on the deep layers of the brain.</p>
<p>We hope that clinical research will follow suit with human studies to repurpose drugs that target certain metabolic diseases, such as diabetes, towards fighting Alzheimer’s.</p>
<p>In the meantime, while waiting for pharmaceutical solutions, each of us would do well to adopt the preventive cocktail that we all know well: a healthy diet combined with frequent physical and mental exercise.</p><img src="https://counter.theconversation.com/content/196016/count.gif" alt="La Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Frederic Calon has received funding from: Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC), Fonds de la recherche du Québec en santé (FRQS), Alzheimer Society of Canada.</span></em></p><p class="fine-print"><em><span>Manon Leclerc has received scholarships from the Fondation du CHU de Québec and the Fonds de Recherche du Québec - Santé (FRQS).</span></em></p><p class="fine-print"><em><span>Vincent Emond ne travaille pas, ne conseille pas, ne possède pas de parts, ne reçoit pas de fonds d'une organisation qui pourrait tirer profit de cet article, et n'a déclaré aucune autre affiliation que son organisme de recherche.</span></em></p>Impaired insulin receptors in the blood vessels between the blood and the brain may contribute to the insulin resistance observed in Alzheimer’s disease.Frederic Calon, Professeur, Université LavalManon Leclerc, PhD student, Université LavalVincent Emond, Professionnel de recherche, Université LavalLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1925702022-12-08T13:32:46Z2022-12-08T13:32:46ZPeople can have food sensitivities without noticeable symptoms – long-term consumption of food allergens may lead to behavior and mood changes<figure><img src="https://images.theconversation.com/files/499637/original/file-20221207-18-b6a7kw.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Asymptomatic sensitization may lead people to continue consuming food allergens, causing hidden neurological issues.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/young-woman-in-striped-shirt-from-back-choosing-royalty-free-image/1357286617">Garetsworkshop/iStock via Getty Images Plus</a></span></figcaption></figure><p>The prevalence of food allergies is increasing worldwide, <a href="https://doi.org/10.1111/j.1399-3038.2011.01145.x">approaching an epidemic level</a> in some regions. In the U.S. alone, <a href="https://www.foodallergy.org/resources/facts-and-statistics">approximately 10% of children and adults</a> suffer from food allergies, with allergies to cow’s milk, eggs, peanuts and tree nuts being the most common. Some patients have mild symptoms that might not need medical attention, leaving these cases unreported. </p>
<p>Food allergies, or food hypersensitivities, result from the overreaction of the immune system to typically harmless proteins in food. They can manifest as a <a href="https://acaai.org/allergies/allergic-conditions/food/">spectrum of symptoms</a>, ranging from itching, redness and swelling for milder reactions, to vomiting, diarrhea, difficulty breathing and other potentially life-threatening symptoms for severe reactions.</p>
<p>Besides self-reporting, food allergies can be <a href="https://acaai.org/allergies/testing-diagnosis/">diagnosed by exposing patients</a> to trace amounts of offending proteins, or allergens, via their mouth or skin and observing their immediate reactions. More commonly, doctors use blood tests to measure the levels of <a href="https://www.aaaai.org/tools-for-the-public/allergy,-asthma-immunology-glossary/immunoglobulin-e-(ige)-defined">immunoglobulin E, or IgE</a>, a specialized antibody that the immune system uses to identify allergens and trigger a response. Although healthy individuals may have low levels of IgE in the blood, patients with food allergies have much higher levels that increase their risk of having severe allergic reactions.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Patient undergoing skin-prick allergy test on arm" src="https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499636/original/file-20221207-16-gmhxjg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Skin-prick allergy tests involve exposing patients to trace amounts of an allergen and observing their reactions.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/immunologist-doing-skin-prick-allergy-test-on-a-royalty-free-image/1288998568">ronstik/iStock via Getty Images</a></span>
</figcaption>
</figure>
<p>But <a href="https://doi.org/10.1159%2F000517824">some people</a> who test positive on skin-prick allergy tests with moderate increases in IgE don’t notice any allergy-related symptoms when they eat the allergen. This condition is sometimes referred to as <a href="https://www.verywellhealth.com/what-is-sensitization-82988">asymptomatic sensitization</a>. In many cases, people with this condition may not even be aware that they have a food hypersensitivity. </p>
<p>Are they truly asymptomatic, though? Or are there effects within their body that they aren’t aware of?</p>
<p>I am a <a href="https://scholar.google.com/citations?user=kXRRwk4AAAAJ&hl=en">neuroscientist</a> studying how the brain is affected by food allergies. I became interested in this topic when I found that some of my family members had a hypersensitivity to cow’s milk. Some totally avoid dairy products because they have experienced severe, life-threatening symptoms. Those who don’t have typical allergic reactions occasionally eat dairy, but appear to develop seemingly unrelated illnesses a day or two later.</p>
<p>What I and other researchers have found is that food allergens can affect your brain and behavior if you’re hypersensitized, even if you don’t have typical food allergy symptoms.</p>
<h2>Food allergies linked to behavioral disorders</h2>
<p>Researchers have suspected food hypersensitivities to be a potential cause for behavioral disorders for decades.</p>
<p>A <a href="https://doi.org/10.1097/00007611-194908000-00017">1949 case report</a> described behavioral and mood disturbances in patients after they ate certain foods, such as milk and eggs. Their symptoms improved after removing the suspected foods from their diet, suggesting that a food hypersensitivity was the likely culprit. However, I was intrigued that the patients had been able to eat the offending foods up until they chose to avoid them. In other words, they were asymptomatically sensitized, or tolerant, to the allergens.</p>
<p>Several recent studies in people have supported the association between food allergies and various neuropsychiatric disorders, including <a href="https://doi.org/10.1111/all.12829">depression, anxiety</a>, <a href="https://doi.org/10.1016/j.aller.2016.03.001">attention-deficit/hyperactivity disorder</a> and <a href="https://doi.org/10.1002/aur.2106">autism</a>. They strengthen the possibility that some reactions to food allergens could involve the nervous system and manifest as behavioral disorders.</p>
<figure>
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<figcaption><span class="caption">The food you eat can affect your brain in many ways.</span></figcaption>
</figure>
<p>However, the idea of food hypersensitivity causing neuropsychiatric disorders is still controversial because of inconsistencies across studies. Differences in the types of allergies, ethnic backgrounds, dietary habits and other factors among the study participants can produce conflicting results. More importantly, some studies included those with self-reported food allergies, while others included only those with lab-confirmed food allergies. This limited investigations to only symptomatic individuals.</p>
<h2>Food hypersensitivity, brain and behavior</h2>
<p><a href="https://doi.org/10.1016/j.bbi.2021.03.002">My laboratory tested</a> whether food allergens could manifest as behavioral symptoms, particularly in asymptomatically sensitized individuals. We wanted to find out whether eating offending foods could lead to brain inflammation and behavioral changes after sensitization, even in the absence of other obvious severe reactions.</p>
<p>To minimize the individual differences found in human studies, we decided to work with mice. We sensitized mice of the same age and genetic background to the common milk allergen β-lactoglobulin, or BLG, and fed them the same diet in the same room. We found that while <a href="https://doi.org/10.1016/j.bbi.2021.03.002">BLG-sensitized mice</a> produced moderately but significantly elevated levels of IgE, they did not show immediate allergic reactions. They could even eat food containing the milk allergen for two weeks without showing any obvious symptoms, despite maintaining elevated levels of IgE. This indicated that they were asymptomatically sensitized.</p>
<p>We then observed whether they showed any changes in emotionally driven behavior. Because we could not ask mice how they felt, we deduced their “feelings” by noting changes from their normal, survival-oriented behavior. Mice instinctively explore their environment to search for food and shelter while avoiding potential danger. However, “anxious” mice tend to spend more time hiding to play it safe. We identified “depressed” mice by briefly holding them by the tail. Most mice will keep fighting to get out of the uncomfortable predicament, while depressed mice quickly give up.</p>
<p>Our experiments were designed to simulate situations where asymptomatically sensitized individuals would eat either a large amount of an offending food in one day or small amounts every day for a few weeks. We mimicked these situations by placing a large amount of the milk allergen directly into the stomach of sensitized mice with a feeding tube, or giving them an allergen-containing mouse chow to eat the allergen a little at a time.</p>
<p>Interestingly, BLG-sensitized mice showed <a href="https://doi.org/10.1016/j.bbi.2021.03.002">anxiety-like behavior</a> one day after receiving a large amount of the allergen. Another group of sensitized mice developed <a href="https://doi.org/10.3390/cells11040738">depression-like behavior</a> after eating small amounts of allergen for two weeks. In addition, BLG-sensitized mice showed signs of brain inflammation and neuronal damage, suggesting that changes in the brain may be responsible for their behavioral symptoms.</p>
<p>We also investigated the <a href="https://doi.org/10.3389/falgy.2022.870628">long-term effect</a> of allergen consumption by keeping BLG-sensitized mice on the allergen-containing diet for one month. We found that IgE levels declined in sensitized mice by the end of the month, indicating that continually eating small amounts of the allergen led to decreased immune responses, or “desensitization.” In contrast, signs of brain inflammation remained, suggesting that the harmful effect of allergens persisted in the brain.</p>
<h2>Chronic brain inflammation</h2>
<p>Researchers have yet to study prolonged brain inflammation, or neuroinflammation, in people who are asymptomatically sensitized. In general, though, <a href="https://doi.org/10.1172/JCI90609">chronic neuroinflammation</a> is a known contributor to neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease, although the exact causes of these diseases are unknown. A better understanding of the role allergens play in neuroinflammation can help researchers clarify whether food allergens trigger chronic inflammation that can lead to these diseases.</p>
<p>This knowledge could be especially important for patients undergoing <a href="https://www.aaaai.org/Tools-for-the-Public/Allergy,-Asthma-Immunology-Glossary/Oral-Immunotherapy-Defined">oral immunotherapy</a>, an approach to allergy treatment that involves incrementally ingesting small amounts of allergens over time. The goal is to desensitize the immune system and reduce the incidence of anaphylaxis, or life-threatening allergic reactions. In 2020, the U.S. Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treatment-peanut-allergy-children">approved a standardized form of peanut allergens</a> to prevent anaphylaxis in eligible pediatric patients. However, its possible long-term effect on the nervous system is unknown.</p>
<p>Food allergens can affect the brain and behavior of seemingly asymptomatic people, making them not so asymptomatic neurologically. Considering how your brain responds to the food you eat puts a whole new meaning to the phrase “you are what you eat.”</p><img src="https://counter.theconversation.com/content/192570/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kumi Nagamoto-Combs receives funding from the National Institute of Allergy and Infectious Disease and the National Institute on Aging. </span></em></p>Food allergies have been linked to behavioral and mood disorders, including depression, anxiety and ADHD.Kumi Nagamoto-Combs, Assistant Professor of Biomedical Sciences, University of North DakotaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1936062022-12-07T13:43:23Z2022-12-07T13:43:23ZHarnessing the brain’s immune cells to stave off Alzheimer’s and other neurodegenerative diseases<figure><img src="https://images.theconversation.com/files/499323/original/file-20221206-23-z5d85z.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1599%2C1200&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Microglia (colored green) play several essential roles in maintaining brain health and function. </span> <span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg">Gerry Shaw/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p><a href="https://www.fda.gov/news-events/congressional-testimony/path-forward-advancing-treatments-and-cures-neurodegenerative-diseases-07292021">Many neurodegenerative diseases</a>, or conditions that result from the loss of function or death of brain cells, remain largely untreatable. Most available treatments target <a href="https://doi.org/10.1038/d41586-018-05719-4">just one of the multiple processes</a> that can lead to neurodegeneration, which may not be effective in completely addressing disease symptoms or progress, if at all.</p>
<p>But what if researchers harnessed the brain’s inherent capabilities to cleanse and heal itself? My colleagues <a href="https://neurograd.virginia.edu/people/profile/kez9hf">and I</a> in the <a href="https://www.lukenslab.com">Lukens Lab</a> at the University of Virginia believe that the brain’s own immune system may hold the key to neurodegenerative disease treatment. In our <a href="https://doi.org/10.1016/j.cell.2022.09.030">research</a>, we found a protein that could possibly be leveraged to help the brain’s immune cells, or microglia, stave off Alzheimer’s disease.</p>
<h2>Challenges in treating neurodegeneration</h2>
<p>No available treatments for neurodegenerative diseases stop ongoing neurodegeneration while also helping affected areas in the body heal and recuperate.</p>
<p>In terms of failed treatments, Alzheimer’s disease is perhaps the most infamous of neurodegenerative diseases. Affecting <a href="https://www.alz.org/alzheimers-dementia/facts-figures">more than 1 in 9 U.S. adults 65 and older</a>, Alzheimer’s results from brain atrophy with the death of neurons and loss of the connections between them. These casualties contribute to memory and cognitive decline. <a href="https://doi.org/10.1002/alz.12450">Billions of dollars</a> have been funneled into researching treatments for Alzheimer’s, but <a href="https://doi.org/10.1002/trc2.12050">nearly every drug tested to date</a> has failed in clinical trials.</p>
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<figcaption><span class="caption">Alzheimer’s disease leads to loss of connections between neurons and cell death.</span></figcaption>
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<p>Another common neurodegenerative disease in need of improved treatment options is <a href="https://www.nationalmssociety.org/What-is-MS/Definition-of-MS">multiple sclerosis</a>. This autoimmune condition is caused by immune cells attacking the protective cover on neurons, known as myelin. Degrading myelin leads to communication difficulties between neurons and their connections with the rest of the body. <a href="https://doi.org/10.1016/j.amjmed.2020.05.049">Current treatments</a> suppress the immune system and can have potentially debilitating side effects. Many of these treatment options fail to address the toxic effects of the myelin debris that accumulate in the nervous system, which can kill cells.</p>
<h2>A new frontier in treating neurodegeneration</h2>
<p>Microglia are <a href="https://doi.org/10.1146/annurev-immunol-051116-052358">immune cells</a> masquerading as brain cells. <a href="https://doi.org/10.1146/annurev-immunol-032713-120240">In mice</a>, microglia originate in the yolk sac of an embryo and then infiltrate the brain early in development. The origins and migration of microglia <a href="https://doi.org/10.3389/fimmu.2018.01014">in people</a> are still under study.</p>
<p>Microglia play important roles in healthy brain function. Like other immune cells, microglia respond rapidly to pathogens and damage. They help to clear injuries and mend afflicted tissue, and can also take an active role in fighting pathogens. Microglia can also regulate brain inflammation, a normal part of the immune response that can cause swelling and damage if left unchecked.</p>
<p>Microglia also support the health of other brain cells. For instance, they can <a href="https://doi.org/10.3389/fncel.2018.00323">release molecules that promote resilience</a>, such as the protein BDNF, which is known to be beneficial for neuron survival and function.</p>
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<figcaption><span class="caption">Microglia are the often overlooked essential workers of the brain.</span></figcaption>
</figure>
<p>But the keystone feature of microglia are their astounding <a href="https://doi.org/10.3389/fimmu.2019.00790">janitorial skills</a>. Of all brain cell types, microglia possess an exquisite ability to clean up gunk in the brain, including the damaged myelin in multiple sclerosis, pieces of dead cells and amyloid beta, a toxic protein that is a hallmark of Alzheimer’s. They accomplish this by consuming and breaking down debris in their environment, effectively eating up the garbage surrounding them and their neighboring cells. </p>
<p>Given the many essential roles microglia serve to maintain brain function, these cells may possess the capacity to address multiple arms of neurodegeneration-related dysfunction. Moreover, as lifelong residents of the brain, microglia are already educated in the best practices of brain protection. These factors put microglia in the perfect position for researchers to leverage their inherent abilities to protect against neurodegeneration.</p>
<p><a href="https://doi.org/10.1038/s41593-018-0242-x">New data</a> in both animal models and human patients points to a previously underappreciated role microglia also play in the development of neurodegenerative disease. Many genetic risk factors for diseases like <a href="https://doi.org/10.1186/s13024-017-0184-x">Alzheimer’s</a> and <a href="https://doi.org/10.1126/science.aav7188">multiple sclerosis</a> are strongly linked to abnormal microglia function. These findings support an <a href="https://doi.org/10.1038/s41593-018-0242-x">accumulating number of animal studies</a> suggesting that disruptions to microglial function may contribute to neurologic disease onset and severity.</p>
<p>This raises the next logical question: How can researchers harness microglia to protect the nervous system against neurodegeneration? </p>
<h2>Engaging the magic of microglia</h2>
<p>In our lab’s <a href="https://doi.org/10.1016/j.cell.2022.09.030">recent study</a>, we keyed in on a crucial protein called SYK that microglia use to manipulate their response to neurodegeneration. </p>
<p>Our collaborators found that microglia <a href="https://doi.org/10.1016/j.cell.2022.09.033">dial up the activity of SYK</a> when they encounter debris in their environment, such as amyloid beta in Alzheimer’s or myelin debris in multiple sclerosis. When we inhibited SYK function in microglia, we found that twice as much amyloid beta accumulated in Alzheimer’s mouse models and six times as much myelin debris in multiple sclerosis mouse models.</p>
<p>Blocking SYK function in the microglia of Alzheimer’s mouse models also worsened neuronal health, indicated by increasing levels of toxic neuronal proteins and a surge in the number of dying neurons. This correlated with hastened cognitive decline, as the mice failed to learn a spatial memory test. Similarly, impairing SYK in multiple sclerosis mouse models exacerbated motor dysfunction and hindered myelin repair. These findings indicate that microglia use SYK to protect the brain from neurodegeneration. </p>
<p>But how does SYK protect the nervous system against damage and degeneration? We found that microglia use SYK to migrate toward debris in the brain. It also helps microglia remove and destroy this debris by stimulating other proteins involved in cleanup processes. These jobs support the idea that SYK helps microglia protect the brain by charging them to remove toxic materials.</p>
<p>Finally, we wanted to figure out if we could leverage SYK to create “super microglia” that could help clean up debris before it makes neurodegeneration worse. When we gave mice a drug that boosted SYK function, we found that Alzheimer’s mouse models had lower levels of plaque accumulation in their brains one week after receiving the drug. This finding points to the potential of increasing microglia activity to treat Alzheimer’s disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Light micrograph of microglia cells" src="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=480&fit=crop&dpr=1 600w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=480&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=480&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=603&fit=crop&dpr=1 754w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=603&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/499341/original/file-20221206-3886-rjau9u.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=603&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Of the many brain cells (shown in black), giving microglia a boost could help them more effectively clean up debris in the brain.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/microglia-silver-carbonate-royalty-free-image/1321565343">Jose Luis Calvo Martin & Jose Enrique Garcia-Mauriño Muzquiz/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<h2>The horizon of microglia treatments</h2>
<p>Future studies will be necessary to see whether creating a super microglia cleanup crew to treat neurodegenerative diseases is beneficial in people. But our results suggest that microglia already play a key role in preventing neurodegenerative diseases by helping to remove toxic waste in the nervous system and promoting the healing of damaged areas. </p>
<p>It’s possible to have too much of a good thing, though. <a href="https://doi.org/10.1038/s41593-018-0242-x">Excessive inflammation</a> driven by microglia could make neurologic disease worse. We believe that equipping microglia with the proper instructions to carry out their beneficial functions without causing further damage could one day help treat and prevent neurodegenerative disease.</p>
<figure class="align-right ">
<img alt="Uncharted Brain, podcast series" src="https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/494827/original/file-20221111-22-1t5f3l.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=754&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption"></span>
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<p><em>Listen to The Conversation’s podcast series <a href="https://theconversation.com/uk/topics/uncharted-brain-decoding-dementia-128903">Uncharted Brain: Decoding Dementia</a> to find out more about the latest research unlocking clues to the ongoing mystery of how dementia works in the brain. Find all episodes via <a href="https://podfollow.com/the-anthill/view">The Anthill podcast</a>.</em></p><img src="https://counter.theconversation.com/content/193606/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>This work was supported by funding from the NIH (1RF1AG071996-01, R01NS106383), The Alzheimer’s Association (ADSF-21-816651), the Cure Alzheimer’s Fund, The Owens Family Foundation, and a Wagner Scholarship</span></em></p>Microglia, immune cells disguised as brain cells, are known as the janitors of the brain. Dialing up their usual duties just enough could provide an avenue to treat neurodegenerative disease.Kristine Zengeler, Ph.D. Candidate in Neuroscience, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1921432022-10-14T14:23:53Z2022-10-14T14:23:53ZAlzheimer’s disease: surprising new theory about what might cause it<p>In 1906, Alois Alzheimer, a psychiatrist and neuroanatomist, <a href="https://www.alzint.org/about/dementia-facts-figures/types-of-dementia/alzheimers-disease/alois-alzheimer/">reported</a> “a peculiar severe disease process of the cerebral cortex” to a gathering of psychiatrists in Tübingen, Germany. The case was a 50-year-old woman who suffered from memory loss, delusions, hallucinations, aggression and confusion – all of which worsened until her untimely death five years later. </p>
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<p><em>You can listen to more articles from The Conversation, narrated by Noa, <a href="https://theconversation.com/us/topics/audio-narrated-99682">here</a>.</em></p>
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<p>In the autopsy, Alzheimer noticed distinctive plaques on her brain. These plaques – clumps of amyloid-beta protein – are still considered to be the cause of Alzheimer’s disease. </p>
<p>However, this theory has two major problems. First, it does not explain why many subjects (even old people) have plaques in their brains in the absence of any neurological symptoms, such as memory loss. Second, clinical trials for drugs that reduce these plaques have been unsuccessful – with <a href="https://theconversation.com/new-alzheimers-drug-slows-cognitive-decline-and-may-be-available-as-early-as-next-year-191627">one recent exception</a>, but more of that later.</p>
<p>When amyloid-beta protein accumulates in the form of plaques (insoluble clumps), the original soluble form of the protein, which performs important functions in the brain, is consumed and lost. Some studies have shown that reduced levels of soluble amyloid-beta – called amyloid-beta 42 – have led to patients having worse clinical outcomes.</p>
<p>In a <a href="https://pubmed.ncbi.nlm.nih.gov/36120786/">recent study</a>, published in the Journal of Alzheimer’s Disease, we investigated whether it’s the amount of plaques in the brain or the amount of amyloid-beta 42 remaining that is more important for Alzheimer’s disease progression. </p>
<p>To answer this question, we studied data on a group of people who have a rare inherited gene mutation that puts them at high risk of developing Alzheimer’s disease. The participants were from the <a href="https://dian.wustl.edu/about/what-is-diad/">Dominantly Inherited Alzheimer Network</a> cohort study.</p>
<p>We found that the depletion of amyloid-beta 42 (the functional version of amyloid-beta) is more harmful than the amount of plaques (the insoluble clumps of amyloid beta).</p>
<p>Participants had an average of three years follow-up and we found that those with high levels of amyloid-beta 42 in their cerebrospinal fluid (the liquid around the brain and spinal cord) were protected and their cognition was preserved over the study period. This chimes with many studies that showed important functions of amyloid-beta 42 in <a href="https://content.iospress.com/download/journal-of-alzheimers-disease/jad220808?id=journal-of-alzheimers-disease/jad220808&supplementaryFilename=jad--1-jad220808-s001.pdf">memory and cognition</a>.</p>
<p>It is also relevant because we studied people with the genetic mutation who develop Alzheimer’s disease, a group that is considered to provide the strongest evidence supporting the idea that amyloid-beta plaques are harmful. However, even in this group, those with higher cerebronspinal fluid (CSF) levels of amyloid-beta 42 remained cognitively normal regardless of the amount of plaques in their brains. </p>
<p>It is also worth mentioning that in some rare, inherited forms of Alzheimer’s disease – for example, in carriers of the so-called Osaka gene mutation or Arctic mutation – people can develop dementia having low levels of amyloid-beta 42 and no detectable plaques. This suggests that plaques aren’t the cause of their dementia, but low levels of amyloid-beta 42 might be. </p>
<h2>Lecanemab – the one recent exception</h2>
<p>How will our findings affect drug development and clinical trials for Alzheimer’s disease? Until the recent trial with <a href="https://theconversation.com/new-alzheimers-drug-slows-cognitive-decline-and-may-be-available-as-early-as-next-year-191627">lecanemab</a>, an antibody drug that reduces plaques, all the drug trials in Alzheimer’s disease have failed. </p>
<p>Some drugs were designed to reduce the levels of amyloid-beta 42, based on the rationale that if levels of the normal protein are reduced, patients will accumulate fewer plaques. Unfortunately, these drugs often made the patient’s condition <a href="https://www.alzforum.org/therapeutics/verubecestat">worse</a>.</p>
<p>Lecanemab was recently reported to have a small but significant effect in reducing cognitive decline. According to <a href="https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00813-8">previous studies</a>, this drug increases the levels of amyloid-beta 42 in the CSF. This is, again, in line with our hypothesis, namely that the increase of the normal amyloid protein can be beneficial. </p>
<p>We will know more when the results of the lecanemab trial are published. At the moment, all we have is a <a href="https://investors.biogen.com/news-releases/news-release-details/lecanemab-confirmatory-phase-3-clarity-ad-study-met-primary">press release</a> from the makers of the drug.</p>
<p>We think that it will be important for future trials to focus on the levels of amyloid-beta 42, and whether it is beneficial to increase and restore its levels to normal values instead of targeting it for removal. This could be achieved using proteins similar to amyloid-beta 42 – so-called “protein analogues” – but that clump together less than the natural ones. </p>
<p>This active protein replacement approach might become a promising new avenue of treatment for Alzheimer’s and other protein aggregation diseases, such as Parkinson’s and motor neuron disease.</p><img src="https://counter.theconversation.com/content/192143/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrea Sturchio is a cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies, that covers synthetic soluble non-aggregating peptide analogues as replacement treatment in proteinopathies.
Affiliations: Karolinska Institutet and the University of Cincinnati. The analysis of the data was done when affiliated only with the University of Cincinnati</span></em></p><p class="fine-print"><em><span>Kariem Ezzat is a cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies, that covers synthetic soluble non-aggregating peptide analogues as replacement treatment in proteinopathies. Affiliations: Karolinska Institutet .</span></em></p><p class="fine-print"><em><span>Samir EL Andaloussi is a cofounder of REGAIN Therapeutics, owner of a provisional patent on compositions and methods for treatment and/or prophylaxis of proteinopathies, that covers synthetic soluble non-aggregating peptide analogues as replacement treatment in proteinopathies. Affiliations: Karolinska Institutet .</span></em></p>Too much amyloid-beta in the brain has long been considered the cause of Alzheimer’s. New research suggests it might be the opposite.Andrea Sturchio, MD, PhD Student, Clinical Neuroscience, Karolinska InstitutetKariem Ezzat, Research Scientist, Laboratory Medicine, Karolinska InstitutetSamir EL Andaloussi, Professor, Laboratory Medicine, Karolinska InstitutetLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1882072022-08-31T12:27:02Z2022-08-31T12:27:02ZExpanding Alzheimer’s research with primates could overcome the problem with treatments that show promise in mice but don’t help humans<figure><img src="https://images.theconversation.com/files/481658/original/file-20220829-8371-fvt75z.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C2121%2C1412&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Rhesus macaques experience an aging process similar to people's.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/rhesus-macaque-royalty-free-image/993621062">Goddard Photography/E+ via Getty Images</a></span></figcaption></figure><p>As of 2022, an estimated <a href="https://doi.org/10.1002/alz.12638">6.5 million Americans</a> have Alzheimer’s disease, an illness that robs people of their memories, independence and personality, causing suffering to both patients and their families. That number may double by 2060. The U.S. has made <a href="https://doi.org/10.1126/science.361.6405.838">considerable investments</a> in Alzheimer’s research, having allocated <a href="https://www.alz.org/news/2022/increase-in-federal-alzheimers-and-dementia-resear">US$3.5 billion in federal funding</a> this year. </p>
<p>Why, then, are researchers no closer to a cure today than they were 30 years ago? </p>
<p>Back in 1995, researchers created the <a href="https://doi.org/10.1038/373523a0">first transgenic mouse model</a> of Alzheimer’s disease, which involved genetically modifying mice to carry a gene associated with early-onset Alzheimer’s. Myriad studies have since focused on mouse models that accumulate <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> in their brains, a hallmark of the disease. Although these studies made great strides in understanding specific mechanisms involved in the disease, they have <a href="https://doi.org/10.1002/trc2.12114">failed to translate</a> into effective treatments.</p>
<p>As <a href="https://scholar.google.com/citations?user=LWCllSsAAAAJ">research</a> <a href="https://scholar.google.com/citations?hl=en&user=0tW5idcAAAAJ">scientists</a> <a href="https://psych.wisc.edu/staff/bennett-allyson/">working</a> with nonhuman primates, we believe that part of the problem is that mice don’t reflect the full spectrum of Alzheimer’s disease. A more complementary animal model, however, could help researchers better translate the results from animal studies to humans. </p>
<h2>Why animal models?</h2>
<p>A critical aspect of understanding what goes awry in Alzheimer’s disease is the relationship between brain and behavior. Researchers rely heavily on animal models to do these types of studies because <a href="https://grants.nih.gov/grants/policy/air/why.htm">ethical and practical issues</a> make them impossible to conduct in people.</p>
<p>In recent years, researchers have developed <a href="https://doi.org/10.15252/embj.2021110002">alternative methods</a> to study Alzheimer’s, such as computer models and cell cultures. Although these options show promise for advancing Alzheimer’s research, they don’t supersede the need for animal models because of important limitations.</p>
<p>One is their inability to replicate the complexity of the human brain. The human brain has an estimated <a href="https://doi.org/10.1002/cne.21974">86 billion neurons</a> that perform highly complex computations. While computer models can simulate the workings of specific neural circuits, they are unable to fully capture these complex interactions and work best when used <a href="https://doi.org/10.1016/j.neuron.2021.07.015">in concert with animal models</a>.</p>
<p>Similarly, cell cultures and brain organoids – miniature brains derived from human stem cells – are <a href="https://doi.org/10.3389/fphar.2020.00396">unable to adequately mimic</a> the aging process and all the ways the components of the human body interact with one another.</p>
<p>As a result of these limitations, researchers turn to animal models that better reflect human biology and disease processes.</p>
<h2>The problem with mice</h2>
<p>According to the National Association for Biomedical Research, approximately <a href="https://www.science.org/content/article/how-many-mice-and-rats-are-used-us-labs-controversial-study-says-more-100-million">95% of lab research conducted in animals in the U.S.</a> is done in mice and rats. Alzheimer’s is no exception: For more than 25 years, research on Alzheimer’s has <a href="https://doi.org/10.1002/cpns.81">focused on using transgenic mice</a> to better understand the biological changes associated with the disease.</p>
<p>Because mice do not naturally get Alzheimer’s, they are genetically engineered to develop <a href="https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease">abnormal proteins</a> known as amyloid plaques and neurofibrillary tau tangles to mimic Alzheimer’s in their brains. These protein accumulations impair brain function and are associated with memory impairment. While studies on <a href="https://doi.org/10.1038/35050110">treatments that remove these proteins</a> have been able to improve cognition in mice, similar interventions have failed in people.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Four white mice in a cage" src="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481630/original/file-20220829-8838-qz7uav.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many Alzheimer’s studies have been conducted in transgenic mice.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/white-research-mice-royalty-free-image/170617385">filo/E+ via Getty Images</a></span>
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</figure>
<p>This highlights the challenge of <a href="https://doi.org/10.1002/trc2.12114">translating animal research</a> in the lab to people in the clinic. Mouse studies often mirror only a single aspect of the disease that may not be directly relevant to people. For example, most transgenic mouse models focus on amyloid protein buildup while <a href="https://mitpress.mit.edu/9780262546010/how-not-to-study-a-disease/">neglecting other crucial aspects</a> of the disease, such as overall neurodegeneration. Such limitations have led some scientists to <a href="https://doi.org/10.3390/ijms222313168">question the value of using mouse models for Alzheimer’s research</a>. </p>
<p>It is important to recognize, however, that scientific knowledge often advances in <a href="https://www.statnews.com/2015/12/02/science-groundbreaking/">incremental steps</a> through the collective results of many studies using different methods and models. Rodent studies provide the necessary foundation for animal models that better mimic the full scope of Alzheimer’s – such as nonhuman primates.</p>
<h2>Nonhuman primates offer a closer model</h2>
<p>The specific features of a species – including brain structure, cognitive ability, life span and the extent to which they show the hallmarks of Alzheimer’s – determine how suitable it is for specific research questions. Based on these factors, we believe that nonhuman primates are particularly well suited for Alzheimer’s research.</p>
<p><a href="https://primate.wisc.edu/primate-info-net/pin-factsheets/">Primates</a> are a diverse group of mammals that includes humans, apes, monkeys and prosimians. Nonhuman primates are particularly valuable for understanding <a href="https://doi.org/10.1002/ajp.23309">human aging</a> and <a href="https://doi.org/10.1073/pnas.1912954116">Alzheimer’s disease</a> because their genetic makeup, brain, behavior, physiology and aging process closely resemble those of people. Aging monkeys experience cognitive, physical and sensory decline as well as a variety of illnesses, such as cancer and cardiovascular disease, much like aging people. Perhaps most critical for Alzheimer’s research, nonhuman primates live much longer than rodents and can <a href="https://doi.org/10.1002/ajp.23299">naturally develop some of the hallmarks associated with Alzheimer’s</a> as they get older. </p>
<p>Using nonhuman primates in research <a href="https://www.nature.com/articles/d41586-021-01894-z">faces some challenges</a>. Compared to mice, nonhuman primates are more expensive to house and feed, and face a growing shortage in research facilities. Nonhuman primates are also prime targets for activists seeking to stop the use of animals in research. Yet, in light of ongoing failures with rodent models, nonhuman primates could significantly help scientists better understand and treat Alzheimer’s. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Scientist looking at brain MRIs on multiple computer screens" src="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/481632/original/file-20220829-8843-ucjkc0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Animal models pave the way for clinical research in humans.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/female-radiologist-analysing-the-mri-image-of-the-royalty-free-image/1326240246">simonkr/E+ via Getty Images</a></span>
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<p>Scientists study Alzheimer’s in nonhuman primates in a number of ways.</p>
<p>In one approach, researchers examine species with short life spans, such as <a href="https://doi.org/10.1002/ajp.23337">gray mouse lemurs</a> or <a href="https://doi.org/10.1002/ajp.23271">common marmosets</a>, to measure how brain and behavior naturally change with age and identify potential predictors of disease. Other researchers may instead accelerate the disease process by <a href="https://doi.org/10.1002/ajp.23289">inducing plaque</a> or <a href="https://doi.org/10.1002/alz.12318">tangle formation</a> in the brains of longer-lived species, like rhesus macaques. These approaches yield studies that are particularly promising for testing treatments in a short time frame.</p>
<p>A third approach takes advantage of recent advances in genomics to study marmosets <a href="https://doi.org/10.1002/alz.049952">born with genetic mutations</a> involved in Alzheimer’s. This method provides the opportunity to test preventive treatments during early life, well before any sign of the disease appears. </p>
<p>Lastly, <a href="https://doi.org/10.1002/ajp.23254">comparing Alzheimer-like patterns across primate species</a> may help reveal critical risk factors for developing the disease, which could be reduced to promote healthy aging.</p>
<p>We believe that research in nonhuman primates, when conducted with the highest <a href="https://doi.org/10.1016/j.neuroimage.2020.117700">ethical standards</a>, provides the best chance to understand how and why Alzheimer’s disease progresses, and to design treatments that are safe and effective in people.</p><img src="https://counter.theconversation.com/content/188207/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Agnès Lacreuse receives funding from NIH, serves on the American Psychological Association Committee for Animal Research and Ethics and volunteers for Speaking of Research</span></em></p><p class="fine-print"><em><span>Allyson Bennett serves on the Board of Directors for Public Responsibility for Medicine & Research and volunteers for Speaking of Research.
</span></em></p><p class="fine-print"><em><span>Amanda M. Dettmer volunteers for Speaking of Research.</span></em></p>Nonhuman primates like rhesus monkeys share certain characteristics with people that may make them better study subjects than mice for research on neurodegenerative diseases.Agnès Lacreuse, Professor of Behavioral Neuroscience, UMass AmherstAllyson J. Bennett, Professor of Psychology, University of Wisconsin-MadisonAmanda M. Dettmer, Associate Research Scientist, Yale UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1876072022-08-04T12:22:28Z2022-08-04T12:22:28ZIlluminating the brain one neuron and synapse at a time – 5 essential reads about how researchers are using new tools to map its structure and function<figure><img src="https://images.theconversation.com/files/475765/original/file-20220725-30588-3lzyhd.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1960%2C1527&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The U.S. BRAIN Initiative seeks to elucidate the connection between brain structure and function.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/computer-artwork-of-human-brain-profile-royalty-free-illustration/85757401">Science Photo Library - PASIEKA/Brand X Pictures via Getty Images</a></span></figcaption></figure><p>Scientists know both a lot and very little about the brain. With <a href="https://doi.org/10.48550/arXiv.1906.01703">billions of neurons and trillions of connections</a> among them, and the experimental limitations of examining the seat of consciousness and bodily function, studying the human brain is a technical, theoretical and ethical challenge. And one of the biggest challenges is perhaps one of the most fundamental – seeing what it looks like in action.</p>
<p>The U.S. <a href="https://braininitiative.nih.gov">Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative</a> is a collaboration among the National Institutes of Health, Defense Advanced Research Projects Agency, National Science Foundation, Food and Drug Administration and Intelligence Advanced Research Projects Activity and others. Since its inception in 2013, <a href="https://braininitiative.nih.gov">its goal</a> has been to develop and use new technologies to examine how each neuron and neural circuit comes together to “record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought.”</p>
<p>Just as <a href="https://theconversation.com/genomic-sequencing-heres-how-researchers-identify-omicron-and-other-covid-19-variants-172935">genomic sequencing</a> enabled the creation of a <a href="https://theconversation.com/the-human-genome-project-pieced-together-only-92-of-the-dna-now-scientists-have-finally-filled-in-the-remaining-8-176138">comprehensive map of the human genome</a>, tools that elucidate the connection between brain structure and function could help researchers answer long-standing questions about how the brain works, both in sickness and in health.</p>
<p>These five stories from our archives cover research that has been funded by or advances the goals of the BRAIN Initiative, detailing a slice of what’s next in neuroscience.</p>
<h2>1. Mapping the brain</h2>
<p>Attempts to map the structure of the brain date back to <a href="https://web.stanford.edu/class/history13/earlysciencelab/body/brainpages/brain.html">antiquity</a>, when philosophers and scholars had only the unaided eye to map anatomy to function. New <a href="https://embryo.asu.edu/pages/golgi-staining-technique">visualization techniques</a> in the 20th century led to the discovery that, just like all the other organs of the body, the brain is composed of individual cells – <a href="https://doi.org/10.1016/j.cub.2006.02.053">neurons</a>.</p>
<p>Now, <a href="https://theconversation.com/mapping-how-the-100-billion-cells-in-the-brain-all-fit-together-is-the-brave-new-world-of-neuroscience-170182">further advances in microscopy</a> that make use of artificial intelligence and genomics have allowed scientists not just to see each individual neuron in the entire brain, but also to identify the connections among them and begin to ascertain their function. </p>
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<a href="https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Stitched high-resolution microscopy image of mouse brain." src="https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/432261/original/file-20211116-25-1vtphzf.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Zooming in on this high-resolution image of a mouse brain reveals rectangular lines where individual image tiles were stitched together, each colored dot representing a specific cell type.</span>
<span class="attribution"><a class="source" href="http://kimlab.io">Yongsoo Kim</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<p>Neuroscientist <a href="https://scholar.google.com/citations?user=WOQx1ksAAAAJ&hl=en">Yongsoo Kim</a> of Penn State likened this method to a photo mosaic, piecing together areas of the brain that haven’t been charted before. “It’s like building a Google map of the brain,” wrote Kim. “By combining millions of individual street photos, you can zoom in to see each street corner and zoom out to see an entire city.” Creating these high-resolution maps, he wrote, could help scientists develop new theories on how the brain works and lead to better treatments for brain disorders like dementia.</p>
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Read more:
<a href="https://theconversation.com/mapping-how-the-100-billion-cells-in-the-brain-all-fit-together-is-the-brave-new-world-of-neuroscience-170182">Mapping how the 100 billion cells in the brain all fit together is the brave new world of neuroscience</a>
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<h2>2. Brain folds and wrinkles</h2>
<p>Another fundamental question researchers have been puzzling over is how the brain develops the bumps and grooves that riddle its surface. Until roughly the <a href="https://doi.org/10.1093%2Fcercor%2Fbhr053">second trimester</a> of fetal development, the human brain is completely smooth.</p>
<p>Scientists have proposed a number of theories on the mechanics of brain folding. One of them, <a href="https://www.jstor.org/stable/1740783">differential tangential growth</a>, posits that folds form because of a mismatch in growth rates between the outer and inner layers of the brain. To ease the forces compressing the outer layer and restore structural stability, the layers buckle and fold.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/WBWJBFRnqwY?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Harvard researchers modeled how folding reduces instability caused by differential growth rates in the brain.</span></figcaption>
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<p>Biomechanical engineer <a href="https://scholar.google.com/citations?user=ukOZ0BAAAAAJ&hl=en">Mir Jalil Razavi</a> and computer scientist <a href="https://scholar.google.com/citations?user=r6DIjzUAAAAJ&hl=en">Weiying Dai</a> of Binghamton University <a href="https://theconversation.com/brain-wrinkles-and-folds-matter-researchers-are-studying-the-mechanics-of-how-they-form-170194">created models</a> to clarify this theory. They identified other factors that may also be at play, like the number of axons – the part of the neuron that transmits electrical signals – in a particular area. “Our brain models provide a potential explanation for why brains may form abnormally during development, highlighting the important role that the brain’s structure plays in its proper functioning,” they wrote.</p>
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Read more:
<a href="https://theconversation.com/brain-wrinkles-and-folds-matter-researchers-are-studying-the-mechanics-of-how-they-form-170194">Brain wrinkles and folds matter – researchers are studying the mechanics of how they form</a>
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<h2>3. Where memories are stored</h2>
<p>Just like the RAM in a computer, memories take up physical space in the brain. Researchers have hypothesized that memories may be stored by <a href="https://doi.org/10.1016/0166-2236(94)90101-5">rearranging the connections, or synapses</a>, among neurons. While this theory has largely been confirmed by observing <a href="https://doi.org/10.1038/37601">changes in the electrical signals</a> neurons produce after memory formation, what triggers these changes has been unclear.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Image of magenta-colored neurons in a live fish brain, with the synapses colored in green" src="https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=766&fit=crop&dpr=1 600w, https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=766&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=766&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=963&fit=crop&dpr=1 754w, https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=963&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/440053/original/file-20220110-27-14nulz7.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=963&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Neurons in a live fish brain, with synapses colored green.</span>
<span class="attribution"><span class="source">Zhuowei Du and Don B. Arnold</span>, <a class="license" href="http://creativecommons.org/licenses/by-nc-nd/4.0/">CC BY-NC-ND</a></span>
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<p>Biomedical engineer <a href="https://scholar.google.com/citations?user=z040dHgAAAAJ&hl=en">Don Arnold</a> of the University of Southern California and his colleagues took a mapping approach. They <a href="https://theconversation.com/where-are-memories-stored-in-the-brain-new-research-suggests-they-may-be-in-the-connections-between-your-brain-cells-174578">compared 3D maps of zebrafish synapses</a> before and after memory formation – namely, learning to associate a light with an unpleasant stimulus. They found that one brain region gained synapses while another’s were destroyed, indicating that associative memories may be a result of the formation and loss of connections among neurons.</p>
<p>These findings imply that it might one day be possible to treat conditions like PTSD by physically erasing the associative memory linking a harmless trigger with a traumatic experience. More research is needed, and there are obvious ethical considerations to address. “Nevertheless,” Arnold wrote, “it’s tempting to imagine a distant future in which synaptic surgery could remove bad memories.”</p>
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Read more:
<a href="https://theconversation.com/where-are-memories-stored-in-the-brain-new-research-suggests-they-may-be-in-the-connections-between-your-brain-cells-174578">Where are memories stored in the brain? New research suggests they may be in the connections between your brain cells</a>
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<h2>4. Seizures hijack memory pathways</h2>
<p><a href="https://www.epilepsy.com/what-is-epilepsy/understanding-seizures">Seizures</a> are sudden surges of electrical activity in the brain. People who experience temporal lobe seizures are sometimes unable to remember what happened immediately prior. This may be due to disruptions to the circuitry in the hippocampus, the part of the temporal lobe key to memory consolidation.</p>
<p>Neurology researchers <a href="https://scholar.google.com/citations?user=bjrXv58AAAAJ&hl=en&oi=ao">Anastasia Brodovskaya</a> and <a href="https://scholar.google.com/citations?user=nMb-pTcAAAAJ&hl=en">Jaideep Kapur</a> of the University of Virginia hypothesized that seizures can cause memory loss by <a href="https://theconversation.com/seizures-can-cause-memory-loss-and-brain-mapping-research-suggests-one-reason-why-172280">using the same pathways</a> the brain uses to process memories. They mapped the neurons of mice learning to navigate a maze and during induced seizures, finding that both cases activated the same brain circuits.</p>
<p>“Because they use the same brain pathways, seizures can disrupt the memory consolidation process by taking over the circuit,” they wrote. “This meant that seizures can hijack the memory pathways and cause amnesia.”</p>
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Read more:
<a href="https://theconversation.com/seizures-can-cause-memory-loss-and-brain-mapping-research-suggests-one-reason-why-172280">Seizures can cause memory loss, and brain-mapping research suggests one reason why</a>
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<h2>5. What the nose knows</h2>
<p>What the eye can’t see, the nose can for many organisms. From dogs to mosquitoes, many animals behave in ways that allow them to detect and pursue an odor long before its source comes into view.</p>
<p>Scientists <a href="https://scholar.google.com/citations?user=wn_f7y0AAAAJ&hl=en">John Crimaldi</a>, <a href="https://scholar.google.com/citations?user=JEi-fdoAAAAJ&hl=en">Brian Smith</a>, <a href="https://www.bbe.caltech.edu/people/elizabeth-j-hong">Elizabeth Hong</a> and <a href="https://scholar.google.com/citations?user=GpkJjVUAAAAJ&hl=en">Nathan Urban</a> of the <a href="https://www.odor2action.org/">Odor2Action</a> research network use technology to study olfaction, or sense of smell. They <a href="https://theconversation.com/from-odor-to-action-how-smells-are-processed-in-the-brain-and-influence-behavior-173811">trace how the shape of an odor plume</a> informs how it will be detected, how those odor molecules are translated into electrical signals in the brain, and how these electrical signals are reformatted into useful information that influence behavior.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/MyHR6a-zJM0?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">This video from the Wachowiak Lab at the University of Utah shows the activity of the olfactory bulb in a mouse brain. Each odor the mouse is exposed to makes different combinations of neurons light up.</span></figcaption>
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<p>A better understanding of the olfactory system, they wrote, can lead to the development of <a href="https://doi.org/10.1177%2F0278364908095118">electronic noses</a> that make searching for chemical weapons and disaster victims safer for people and animals. They also believe that examining the olfactory system can help advance study of the brain. “Its relative simplicity is what allows scientists like us to study it from end to end and learn how the brain works as a whole,” they wrote.</p>
<p>While a grand unified theory of the brain still remains elusive, new tools and techniques are helping researchers excavate its hidden depths. As Crimaldi and his team put it, “An exciting future in scientific and medical development, we believe, is right under our noses.”</p>
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Read more:
<a href="https://theconversation.com/from-odor-to-action-how-smells-are-processed-in-the-brain-and-influence-behavior-173811">From odor to action – how smells are processed in the brain and influence behavior</a>
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<p><em>Editor’s note: This story is a roundup of articles from The Conversation’s archives.</em></p><img src="https://counter.theconversation.com/content/187607/count.gif" alt="The Conversation" width="1" height="1" />
From figuring out where memories are stored to how sensory information translates to behavior, new technologies are helping neuroscientists better understand how the brain works.Vivian Lam, Associate Health and Biomedicine EditorLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1869752022-08-03T12:09:46Z2022-08-03T12:09:46ZMany drugs have mirror image chemical structures – while one may be helpful, the other may be harmful<figure><img src="https://images.theconversation.com/files/477203/original/file-20220802-11469-xcg7eb.jpeg?ixlib=rb-1.1.0&rect=0%2C0%2C1732%2C1732&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Drugs can convert between different isomers in the body, leading to unexpected effects.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/illustration/pill-bipolar-disorder-opposites-royalty-free-illustration/1370292588">Dmitrii Guzhanin/iStock via Getty Images</a></span></figcaption></figure><p>The effects a drug or chemical compound have on the body depend on how its atoms are arranged in space. Some compounds have a dark twin with the same molecular formula but different 3D structure – and this can have consequences for what they do or don’t do in the body.</p>
<p>Consider the tragic story of <a href="https://www.nytimes.com/2013/09/23/booming/the-death-and-afterlife-of-thalidomide.html">thalidomide</a>, a morning sickness drug that caused thousands of birth defects and miscarriages. While <a href="https://www.acs.org/content/acs/en/molecule-of-the-week/archive/t/thalidomide.html">one form</a>, or isomer, of thalidomide has a sedative effect, the other is thought to cause abnormal physiological development. Because the two versions can <a href="https://doi.org/10.1073/pnas.1417832112">convert back and forth in the body</a>, it’s dangerous to take either form of thalidomide while pregnant.</p>
<p><a href="https://scholar.google.com/citations?user=dChGtb0AAAAJ&hl=en">My research</a> has focused on one such compound found in red grapes and peanuts, resveratrol. It has been a scientific mystery why clinical trials on using resveratrol to treat Alzheimer’s disease have had inconsistent results. Turns out, it may be because <a href="https://doi.org/10.1038/s41467-022-30785-8">two different forms were used</a> – while one may help with cognition and memory, the other may be toxic to the nervous system.</p>
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<iframe width="440" height="260" src="https://www.youtube.com/embed/41n3mDoVbvk?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Thalidomide has since been repurposed to treat other conditions, including cancer.</span></figcaption>
</figure>
<h2>Isomers and amino acids</h2>
<p>Many drugs have the same atoms and bonds but are arranged differently in space. These drugs are called <a href="https://www.khanacademy.org/test-prep/mcat/chemical-processes/stereochemistry/a/chiral-drugs">chiral</a> compounds – meaning they exist as two nonsuperimposable mirror images. For example, your hands are also nonsuperimposable mirror images of each other. Although they look the same, they don’t overlap when you put one on top of the other. </p>
<p>Usually these mirror-image versions have very similar properties because they share the same elements and bonds. But the way they are arranged in space can drastically change the effects they have in the body. Just as you wouldn’t be able to fit a left-handed glove on your right hand, a left-handed version of a drug wouldn’t be able to fit into a target in the body shaped to fit a right-handed molecule.</p>
<p>Chiral molecules come in two versions, or isomers, defined by their <a href="https://www.khanacademy.org/test-prep/mcat/chemical-processes/stereochemistry/a/chiral-drugs">optical activity</a>. This means that if you shine polarized light on a chiral molecule, one will rotate the light to the left (indicated by the prefix L-, or levorotatory) while the other will rotate it to the right (indicated by the prefix D, or dextrorotatory).</p>
<p><a href="https://www.nature.com/scitable/topicpage/an-evolutionary-perspective-on-amino-acids-14568445/">Amino acids</a>, the building blocks of proteins, are chiral molecules. Living organisms primarily make proteins from <a href="https://atlasofscience.org/l-amino-acids-key-for-the-evolution-of-life-came-from-extraterrestrial-space/">amino acids with L configurations</a>. The D configuration, however, has many other functions in nature. <a href="https://doi.org/10.3389/fmicb.2018.00683">Bacteria</a>, for example, use D configuration amino acids to make their cell walls. <a href="https://doi.org/10.1007/s00726-020-02892-7">Mammals</a> use D configuration amino acids as messengers in their nervous and endocrine systems. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/Bw_cetheReo?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The structure of a compound matters just as much as its individual atoms and bonds.</span></figcaption>
</figure>
<p>The amino acid tyrosine is one important exception to the L configuration rule. Unlike other amino acids, both the L and D configurations of tyrosine can be activated for protein synthesis by an enzyme called <a href="https://doi.org/10.1016/0022-2836(67)90259-8">tyrosyl-tRNA synthetase (TyrRS)</a>. </p>
<p>The presence of D-tyrosine can make it difficult for cells to synthesize proteins that only use L-tyrosine. However, cells have evolved enzymes that can discriminate between both versions and ensure that only L-tyrosine is used. When tyrosine-consuming enzymes are absent, the resulting increased levels of tyrosine in the body can have <a href="https://medlineplus.gov/genetics/condition/tyrosinemia/">toxic effects</a>, including <a href="https://doi.org/10.1056/NEJM199002153220704">damage to the nervous system</a>. </p>
<p><a href="https://doi.org/10.1038/s41467-022-30785-8">Recently published work</a> from my lab suggests a potential reason why too much tyrosine can be neurotoxic. When we added increasing amounts of L-tyrosine to rat brain cells in a petri dish, we found that it decreased levels of TyrRS, the enzyme that activates tyrosine to make proteins without causing damage to the body. Surprisingly, adding D-tyrosine not only caused TyrRS levels to drop, but also killed the neurons.</p>
<p>When we looked at the brains of Alzheimer’s patients who show increased tyrosine levels, we also found that TyrRS enzyme levels are depleted. Our hypothesis is that as tyrosine levels in the brain increase, TyrRS enzyme levels drop and cause damaging effects on the brains of those with Alzheimer’s. These findings indicate the potentially important role TyrRS may play in the synthesis of proteins essential for cognition and memory.</p>
<h2>Grapes, peanuts and Alzheimer’s</h2>
<p>These findings have implications for studies on <a href="https://doi.org/10.3390%2Fbiomedicines6030091">resveratrol</a>, a compound found in red wine that researchers have been examining for potential health benefits. While <a href="https://doi.org/10.1016/j.trci.2018.09.009">some clinical trials</a> found that resveratrol can improve cognitive function in people with Alzheimer’s disease, <a href="https://doi.org/10.1212/WNL.0000000000002035">others found it had the opposite effect</a> and made the disease more severe. Why resveratrol can have such varying effects has remained a scientific enigma.</p>
<p>Resveratrol comes in two forms, cis-resveratrol and trans-resveratrol. The <a href="https://courses.lumenlearning.com/suny-mcc-organicchemistry/chapter/geometric-stereoisomers-cistrans/">“cis-” and “trans-” prefixes</a>, much like L- and D-, describe how the same atoms in two isomers are arranged differently in space. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Isomerization of trans- to cis-resveratrol" src="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=201&fit=crop&dpr=1 600w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=201&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=201&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=253&fit=crop&dpr=1 754w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=253&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/477022/original/file-20220801-24154-m6587b.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=253&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">At low concentrations, the trans form of resveratrol, left, can switch to the cis form, right.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Rasveratrol_isomerization.png">V8rik/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>My colleagues and I found that because the two forms of resveratrol <a href="https://doi.org/10.1007/s11357-020-00295-w">bind to TyrRS in different ways</a>, they can result in <a href="https://doi.org/10.1038/s41467-022-30785-8">opposite effects in neurons</a>. While cis-resveratrol was able to increase TyrRS levels in rat neurons in a petri dish, high concentrations of trans-resveratrol depleted TyrRS and caused neural damage. However, low concentrations of trans-resveratrol can <a href="https://doi.org/10.1038/nature14028">convert into cis-resveratrol</a> in the body. This result leads to an increase in TyrRS levels and its associated benefits.</p>
<p>We hypothesize that many clinical trials on resveratrol failed because none tested cis-resveratrol alone. We believe that this may also explain why trials that used high doses of trans-resveratrol saw harmful effects, while trials that used low doses of trans-resveratrol that were then converted into cis-resveratrol in the body saw beneficial effects.</p>
<p>Beyond the individual atoms and bonds of molecules, the body also cares about how they’re arranged in space. Paying attention to the different forms a drug takes could help lead to more effective treatments.</p><img src="https://counter.theconversation.com/content/186975/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sajish Mathew receives funding from NIH COBRE grant (P20GM109091). </span></em></p>From thalidomide to resveratrol, molecules with the exact same chemical properties can have drastically different effects in the body depending on how they’re arranged in space.Sajish Mathew, Assistant Professor of Drug Discovery and Biomedical Sciences, University of South CarolinaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1844952022-06-08T09:38:58Z2022-06-08T09:38:58ZParkinson’s disease: bad dreams could be an early warning sign – new study<figure><img src="https://images.theconversation.com/files/467443/original/file-20220607-15494-xj39l9.jpg?ixlib=rb-1.1.0&rect=10%2C0%2C6800%2C4400&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/scared-woman-hiding-under-blanket-afraid-1299304081">Tero Vesalainen/Shutterstock</a></span></figcaption></figure><p>Every night when we go to sleep, we spend a couple of hours in a virtual world created by our brains in which we are the main protagonist of an unfolding story we did not consciously create. In other words, we dream. </p>
<p>For most people, dreams are mainly pleasant, sometimes negative, often bizarre, but rarely terrifying. That is, if they are remembered at all. Yet for <a href="https://academic.oup.com/sleep/article/33/6/774/2454580">about 5%</a> of people, highly memorable and terrifying nightmares (bad dreams that make you wake up) happen on a weekly or even nightly basis.</p>
<p>Recent studies have shown that people with Parkinson’s disease have bad dreams and nightmares more often than people without the disease. Studies suggest that between <a href="https://www.sciencedirect.com/science/article/pii/S0022510X14005577">17%</a> and <a href="https://link.springer.com/article/10.1007/s10072-014-1870-x">78%</a> of people with Parkinson’s have nightmares weekly. </p>
<p>A study I conducted in 2021 found that people newly diagnosed with Parkinson’s who experience recurring dreams with “<a href="https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mdc3.13318">aggressive or action-packed</a>” content, have more rapid disease progression in the years following their diagnosis, compared with those without aggressive dreams. As such, my study, alongside <a href="https://onlinelibrary.wiley.com/doi/10.1111/jsr.13163">similar studies</a>, strongly suggests that the dreams of people with Parkinson’s can predict future health outcomes.</p>
<p>This made me wonder, might the dreams of people who don’t have Parkinson’s predict future health outcomes, too? My latest study, published in <a href="https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(22)00204-8/fulltext">The Lancet’s eClinicalMedicine journal</a>, shows that they can. Specifically, it showed that developing frequent bad dreams or nightmares in older age could be an early warning sign of imminent Parkinson’s disease in otherwise healthy people.</p>
<p>I analysed data from a large US study that contained data over 12 years from 3,818 older men living independently. At the beginning of the study, the men completed a range of questionnaires, one of which included a question about bad dreams.</p>
<p>The participants who reported bad dreams at least once a week were then followed at the end of the study for an average of seven years to see whether they were more likely to be diagnosed with Parkinson’s.</p>
<p>During this period, 91 people were diagnosed with Parkinson’s. Those who reported having frequent bad dreams at the beginning of the study were twice as likely to develop Parkinson’s compared with those who had them less than weekly. </p>
<p>Intriguingly, a significant proportion of the diagnoses happened during the first five years of the study. During this period, the participants with frequent bad dreams were more than three times as likely to develop Parkinson’s disease.</p>
<h2>Years before</h2>
<p>These results suggest that older adults who will one day be diagnosed with Parkinson’s disease may start to experience bad dreams and nightmares a few years before developing the <a href="https://www.nhs.uk/conditions/parkinsons-disease/symptoms/">characteristic symptoms of Parkinson’s</a>, including tremors, stiffness and slowness of movement.</p>
<figure class="align-center ">
<img alt="Woman holding her wrist to steady it so she can drink a glass of water." src="https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/467478/original/file-20220607-20-ujizr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Symptoms of Parkinson’s include tremors, stiffness and slowness of movement.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/senior-woman-holding-glass-waterhand-shaking-1685125852">CGN089/Shutterstock</a></span>
</figcaption>
</figure>
<p>The study also shows that our dreams can reveal important information about our brain structure and function and may prove to be an important target for neuroscience research.</p>
<p>However, it is important to highlight that only 16 of the 368 men with frequent bad dreams in this study developed Parkinson’s. Since Parkinson’s is a relatively rare condition, most people who have frequent bad dreams are unlikely to ever get the disease. </p>
<p>Still, for those who have other known Parkinson’s <a href="https://jamanetwork.com/journals/jamaneurology/article-abstract/2789505">risk factors</a>, such as excessive daytime sleepiness or constipation, the finding could be important. Being aware that frequent bad dreams and nightmares (particularly when they start suddenly in later life) may be an early indicator of Parkinson’s, could lead to earlier diagnoses and earlier treatment. One day, doctors may even be able to intervene to stop Parkinson’s disease from developing at all.</p>
<p>My team now plans to use electroencephalography (a technique to measure brainwaves) to look at the biological reasons for dream changes in people with Parkinson’s. This may help us identify treatments that could simultaneously treat bad dreams, and also slow down or prevent the onset of Parkinson’s in people at risk of developing the condition.</p><img src="https://counter.theconversation.com/content/184495/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Abidemi Otaiku does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>People reported having frequent bad dreams at the beginning of the study were twice as likely to develop Parkinson’s compared with those who had them less than once a week.Abidemi Otaiku, NIHR Academic Clinical Fellow in Neurology, University of BirminghamLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1819542022-05-27T03:07:52Z2022-05-27T03:07:52ZOn your back? Side? Face-down? Mice show how we sleep may trigger or protect our brain from diseases like ALS<figure><img src="https://images.theconversation.com/files/462143/original/file-20220510-18-s2q22z.jpg?ixlib=rb-1.1.0&rect=35%2C35%2C5955%2C3952&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://images.unsplash.com/photo-1531353826977-0941b4779a1c?ixlib=rb-1.2.1&ixid=MnwxMjA3fDB8MHxwaG90by1wYWdlfHx8fGVufDB8fHx8&auto=format&fit=crop&w=3270&q=80">Unsplash/Lux Graves</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the <a href="http://dx.doi.org/10.1136/jnnp.61.2.131">most common form</a> of motor neuron disease. People with ALS progressively lose the ability to initiate and control muscle movements, including the ability to speak, swallow and breathe. </p>
<p>There is no known cure. But recently, <a href="https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-022-00291-4">we studied mice</a> and identified a new target in the fight against this devastating disease: the brain’s waste clearance system. </p>
<p><a href="https://www.nature.com/articles/s41593-018-0235-9">Neurodegenerative diseases</a> – including Parkinson’s disease, Alzheimer’s and multiple sclerosis – share many similarities, even though their clinical symptoms and disease progression may look very different. The incidence of these diseases increase with age. They are progressive and relentless, and result in gradual loss of brain tissue. We also see waste proteins accumulate in the brain. </p>
<p>Our new research looked at how the glymphatic system, which removes waste from the brain, could prevent ALS.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/als-is-only-50-genetic-identifying-dna-regions-affected-by-lifestyle-and-environmental-risk-factors-could-help-pinpoint-avenues-for-treatment-179169">ALS is only 50% genetic – identifying DNA regions affected by lifestyle and environmental risk factors could help pinpoint avenues for treatment</a>
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</em>
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<hr>
<h2>Protein chains, folds and misfolds</h2>
<p>Inside our bodies, long protein chains fold to form functional shapes that allow them to perform <a href="https://medlineplus.gov/genetics/understanding/howgeneswork/protein/">specific tasks</a> like creating antibodies to fight off infection, supporting cells or transporting molecules. </p>
<p>Sometimes this process goes awry, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded protein can grow and fragment, creating seeds that spread throughout the brain to form new clusters.</p>
<p>The accumulation of waste proteins begins early in the neurodegenerative disease process – well before the onset of symptoms and brain loss. As researchers, we wanted to see if eliminating or slowing the spread of these waste proteins and their seeds could halt or slow the progression of disease.</p>
<h2>Targeting waste removal</h2>
<p>The <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636982/">glymphatic system</a> removes waste, including toxic proteins, from the brain. </p>
<p>This brain-wide network of fluid-filled spaces, known as <a href="https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-015-0010-1">Virchow-Robin spaces</a>, is mostly switched off while we’re awake. But it kicks into gear during sleep to distribute compounds essential to brain function and to get rid of toxic waste. </p>
<p>This may explain why <a href="https://theconversation.com/animals-sleep-but-little-is-known-about-how-sharks-do-it-180219">all creatures</a>, great and small (<a href="https://qbi.uq.edu.au/article/2013/08/flies-sleep-just-us">even flies</a>), need sleep to survive. (Interestingly, whales and dolphins alternate their sleep between brain hemispheres, keeping the other hemisphere awake to watch for predators and alerting them to breathe!)</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="pair of dolphins underwater" src="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Unlike us, dolphins sleep with one side of their brain at a time.</span>
<span class="attribution"><a class="source" href="https://images.unsplash.com/photo-1562742686-0b38a29473ab?ixlib=rb-1.2.1&ixid=MnwxMjA3fDB8MHxwaG90by1wYWdlfHx8fGVufDB8fHx8&auto=format&fit=crop&w=3273&q=80">Unsplash/NOAA</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>As we age, sleep quality <a href="https://doi.org/10.1111/j.1532-5415.2008.01755.x">declines</a> and the risk of neurodegenerative disease, including ALS, increases. </p>
<p>Sleep disturbances are also a common symptom of ALS and research has shown a single night without sleep can result in <a href="https://www.pnas.org/doi/10.1073/pnas.1721694115">increased accumulation</a> of toxic waste protein in the brain. As such, we thought glymphatic function might be impaired in ALS. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/longer-naps-in-the-day-may-be-an-early-sign-of-dementia-in-older-adults-179365">Longer naps in the day may be an early sign of dementia in older adults</a>
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</em>
</p>
<hr>
<h2>Ageing mice</h2>
<p>To investigate this, we looked to mice. The animals were genetically modified to express human TDP-43 – the protein implicated in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to turn the TDP-43 protein expression off and they aged normally. But when the mice are switched to normal food, TDP-43 expression is turned on and misfolded proteins begin to accumulate. </p>
<p>Over time, the mice display the classical signs of ALS including progressive muscle impairments and brain atrophy. </p>
<p>Using magnetic resonance imaging (MRI) to see brain structure, we investigated glymphatic function in these mice just three weeks after turning on TDP-43 expression.</p>
<p>As we watched the glymphatic system go to work, we saw the TDP-43 mice had worse glymphatic clearance than the control mice that had not been genetically modified. Importantly, these differences were seen very early in the disease process. </p>
<p>Our study provides the first evidence the glymphatic system might be a potential therapeutic target in the treatment of ALS.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1508474747537039367"}"></div></p>
<h2>How can we improve glymphatic function?</h2>
<p>Not all sleep is equal. Sleep includes both rapid eye movement (REM) and non-REM sleep. This latter stage includes slow wave sleep – <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309589/">when the glymphatic system is most active</a>. Sleep therapies that enhance this phase may prove to be particularly beneficial for preventing diseases like ALS. </p>
<p>Sleep position is also thought to affect glymphatic clearance. </p>
<p>Research conducted in rodents has <a href="https://pubmed.ncbi.nlm.nih.gov/26245965/">demonstrated</a> glymphatic clearance is most efficient in the lateral (or side-sleeping) position, compared to either supine (on the back) or prone (front-lying) positions. The reasons for this are not yet fully understood but possibly relates to the effects of gravity, compression and stretching of tissue.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/sleeping-on-it-helps-you-better-manage-your-emotions-and-mental-health-heres-why-179156">‘Sleeping on it’ helps you better manage your emotions and mental health – here’s why</a>
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</p>
<hr>
<p>Lifestyle choices may be helpful in improving glymphatic function too. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747747/">Omega-3</a>, found in marine-based fish, has long been considered to be beneficial to health and reduced risk of neurodegenerative diseases. New research shows these benefits may be partly due to the positive effect of <a href="https://pubmed.ncbi.nlm.nih.gov/27789520/">Omega-3 on glymphatic function</a>.</p>
<p>Moderate consumption of alcohol has been shown to improve waste clearance. In mouse studies, both short and long-term exposure to <a href="https://pubmed.ncbi.nlm.nih.gov/29396480/">small amounts of alcohol were shown to boost glymphatic function</a> while high doses had the opposite effect. </p>
<p><a href="https://pubmed.ncbi.nlm.nih.gov/28579942/">Exercise</a> has also been shown to be beneficial. </p>
<p>All these studies show small lifestyle changes can improve brain waste clearance to minimise the risk of neurodegenerative disease. Next, research needs to focus on therapies directly targeting the glymphatic system to help those already suffering from these debilitating diseases.</p><img src="https://counter.theconversation.com/content/181954/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Wright receives funding from the NHMRC and FightMND. He has previously received funding from the Bethlehem Griffiths Research Foundation to investigate glymphatic function in ALS.</span></em></p>Our new research with mice visualised how differently aged brains pump out toxic protein waste during sleep.David Wright, Associate Professor of Medical Imaging, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1804992022-04-04T20:43:37Z2022-04-04T20:43:37ZBruce Willis’s aphasia diagnosis draws attention to a common language disorder<figure><img src="https://images.theconversation.com/files/456211/original/file-20220404-13-kc2qvo.jpg?ixlib=rb-1.1.0&rect=230%2C15%2C3052%2C2302&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Aphasia is a language disorder that affects about 30 per cent of stroke patients.</span> <span class="attribution"><span class="source">(Denis Makarenko/Shutterstock.com)</span></span></figcaption></figure><p>Until the recent news that <a href="https://variety.com/2022/film/news/bruce-willis-retiring-acting-apashia-1235219017/">Bruce Willis</a> had been diagnosed with aphasia and was retiring from acting, many people were <a href="https://www.aphasia.org/2020-aphasia-awareness-survey/">unfamiliar with the condition</a>. Despite its low profile, aphasia is not uncommon. </p>
<p>Across <a href="https://www.sac-oac.ca/news-events/news/speech-hearing-month-2021-what-aphasia">Canada</a> and the <a href="https://www.aphasia.org/">United States</a>, it’s estimated that more than two million people are living with aphasia and its associated challenges in communication and in using and understanding language.</p>
<p><a href="https://www.aphasia.ca/">Aphasia</a> affects language abilities, including listening, speaking, reading and writing. Some common language symptoms that occur in individuals living with aphasia are:</p>
<ul>
<li><p>Difficulty coming up with the right word. An individual might use a related word (for example, they may say or write “daughter” when trying to find the word “niece”) or even use a made up word (for example, say or write “pitsy” when trying to find the word “niece”).</p></li>
<li><p>Making mistakes in grammar or syntax such as omitting word endings. Examples include leaving off the plural “s” or “ed” to indicate past tense, or putting words in the wrong order, such as: “The cat was his ran house out.”</p></li>
<li><p>Needing more time to process what is said to them and needing more time to formulate a response.</p></li>
<li><p>Difficulty understanding individual letters, speech sounds or words when listening or reading, even though prior to the onset of aphasia, these letters, sounds and words were automatically understood.</p></li>
</ul>
<p>For individuals with aphasia who use sign language, their ability to use and understand signs is also negatively affected. Some people with aphasia may also experience problems using and understanding nonverbal means of communication, such as gestures and facial expressions.</p>
<h2>Causes of aphasia</h2>
<figure class="align-center ">
<img alt="A silhouette of a head with a maze, and a red line going from through the maze from the braid to the mouth" src="https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=376&fit=crop&dpr=1 600w, https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=376&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=376&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=472&fit=crop&dpr=1 754w, https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=472&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/456217/original/file-20220404-15-yuez6j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=472&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Aphasia affects language abilities including listening, speaking, reading and writing.</span>
<span class="attribution"><span class="source">(Shutterstock)</span></span>
</figcaption>
</figure>
<p>Aphasia is not a disease, but rather a consequence of damage to the language-dominant regions of the brain. This brain damage is typically caused by a stroke (<a href="https://www.heartandstroke.ca/stroke/what-is-stroke">interruption of blood flow to or within the brain</a>), or sometimes by a traumatic brain injury, a brain tumour or an infection, such as meningitis. Stroke is the <a href="https://doi.org/10.3109/17549507.2010.520090">most common cause</a>, with aphasia affecting approximately <a href="https://doi.org/10.1016/j.apmr.2016.03.006">30 per cent of stroke patients</a>. </p>
<p>Aphasia is also <a href="https://doi.org/10.1002/ana.410110607">a key component</a> of a progressive neurodegenerative disease called <a href="https://www.aphasia.org/aphasia-resources/primary-progressive-aphasia/">primary progressive aphasia</a>, a type of <a href="https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/frontotemporal-dementia">frontotemporal dementia</a>.</p>
<p>Because the parts of the brain that support language also support other cognitive abilities, individuals living with aphasia may experience some difficulties in <a href="https://doi.org/10.1044/1058-0360(2012/11-0067)">attention, memory and thinking skills</a> like problem solving or planning. People living with aphasia may be challenged in these other cognitive functions because we often use and understand language in concert with these other functions. For example, rehearsing out loud or using your inner mind’s voice to repeat silently the items you have been asked to pick up at the store.</p>
<p>There is great <a href="https://doi.org/10.1093/brain/awab377">variability in the language symptoms</a> experienced by individuals living with aphasia. For example, one individual may experience significant difficulties equally across all language modalities. Another person may experience difficulties primarily in their verbal output and few difficulties with understanding what is said, written or gestured. </p>
<p>Likewise, there is a spectrum of aphasia severity. Some people with aphasia may only be able to understand short, common words. Others may only experience comprehension difficulties when reading books or following complex podcasts that include, for example, technical jargon or complex stories. </p>
<p>Variability also is common among those living with aphasia who are bilingual or multilingual. One individual with aphasia might experience similar difficulties in all of their languages while another might struggle more in one versus another of their languages.</p>
<h2>Living with aphasia</h2>
<figure class="align-right ">
<img alt="A bald man in a black suit with other people behind him" src="https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=852&fit=crop&dpr=1 600w, https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=852&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=852&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1071&fit=crop&dpr=1 754w, https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1071&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/456213/original/file-20220404-21-pldbem.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1071&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Like Bruce Willis, who has retired from acting, many people with aphasia are unable to remain in their vocation of choice.</span>
<span class="attribution"><span class="source">(THE CANADIAN PRESS/Frank Gunn)</span></span>
</figcaption>
</figure>
<p>Regardless of the breadth and severity of the language symptoms, aphasia is challenging for those living with the language disorder, as well as for their family and friends. Having aphasia can make it difficult to complete daily activities like reading prescription medication labels, booking an appointment or using a phone. </p>
<p>Like Willis, many individuals with aphasia will not be able to remain in their vocation of choice. Aphasia also can lead to negative consequences for social roles, relationships and activities. Consider how many components of parenting involve language (listening to your child’s day at school, reading with your child, reprimanding) and how essential communication is to maintaining close relationships with family and friends. </p>
<p>Most leisure activities similarly involve language, whether it is reading for pleasure, watching movies or travelling. Because of these daily struggles, many individuals with aphasia also experience <a href="https://doi.org/10.1186/s13063-016-1257-9">mental health issues such as depression</a>.</p>
<h2>Assessment and services for people with aphasia</h2>
<p>However, there is help and hope for those with aphasia. Decades of aphasia research indicate <a href="https://doi.org/10.1002/14651858.CD000425.pub4">there are many interventions</a> to improve individuals’ language abilities and help them compensate for their language impairments. An important first step for getting help is <a href="https://doi.org/10.1161/STR.0b013e3181e7512b">seeking an assessment from a speech-language pathologist</a>. </p>
<p>Given the various manifestations of aphasia, a comprehensive assessment is needed to determine its presence and an individual’s language and communication strengths and weaknesses. The assessment also will help the <a href="https://www.sac-oac.ca/">speech-language pathologist</a> identify <a href="https://www.heartandstroke.ca/services-and-resources/aphasia-services">interventions that can help individuals living with aphasia</a> and their family and friends achieve their language and communication goals.</p>
<p>In addition to assessment and intervention services, family and friends can <a href="https://www.sac-oac.ca/sac-resource-page-stroke-awareness">find other ways</a> to <a href="https://www.aphasia.ca/">support someone living with aphasia</a>. </p>
<p>By sharing his diagnosis of aphasia, Willis and his family are helping <a href="https://doi.org/10.1080/02687038.2019.1702847">increase awareness</a> of this complex and often debilitating language disorder. Increasing awareness among the public and health-care professionals is an important step in ensuring that individuals living with aphasia <a href="https://doi.org/10.1080/09638288.2020.1722264">can participate in their community and receive appropriate health-care services</a>.</p><img src="https://counter.theconversation.com/content/180499/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Across Canada and the United States, more than two million people are living with aphasia and its language and communication challenges.Laura Murray, Associate Dean of Graduate and Postdoctoral Studies, Faculty of Health Sciences, Western UniversityJ.B. Orange, Professor and Acting Director, School of Communication Sciences and Disorders; Scientific Director, Canadian Centre for Activity and Aging, Western UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1785302022-03-07T19:07:08Z2022-03-07T19:07:08ZEven mild COVID can cause brain shrinkage and affect mental function, new study shows<figure><img src="https://images.theconversation.com/files/450254/original/file-20220307-44826-okpuk3.jpg?ixlib=rb-1.1.0&rect=24%2C8%2C5515%2C3671&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/magnetic-resonance-scan-brain-mri-600w-1147345766.jpg">Shutterstock</a></span></figcaption></figure><p>Most of what we know about how COVID can affect the brain has come from studies of severe infection. In people with severe COVID, inflammatory cells from outside the brain can enter brain tissue and <a href="https://www.nature.com/articles/s41586-021-03710-0">spread inflammation</a>. There may be changes to <a href="https://journals.lww.com/jcat/Abstract/2021/07000/Neuroimaging_in_the_First_6_Weeks_of_the_COVID_19.14.aspx">blood vessels</a>. Brain cells can even have changes similar to those seen in people with <a href="https://www.sciencedirect.com/science/article/pii/S2211124719304383">Alzheimer’s disease</a>. </p>
<p>For the first time, a <a href="https://www.nature.com/articles/s41586-022-04569-5">new study</a> has investigated the effects of mild COVID (that is, infection that doesn’t lead to a hospital admission) on the brain. The findings may further explain some of the brain changes contributing to long COVID. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/we-calculated-the-impact-of-long-covid-as-australia-opens-up-even-without-omicron-were-worried-168662">We calculated the impact of 'long COVID' as Australia opens up. Even without Omicron, we're worried</a>
</strong>
</em>
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<hr>
<h2>Brain scans and tests show changes</h2>
<p>Many people who have had COVID report feelings of “brain fog”, fatigue and problems with concentration and memory long after their initial symptoms resolve. These problems, collectively referred to as “long COVID”, may last for months even after mild infection.</p>
<p>Long COVID is very common, and may affect <a href="https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1003773">more than half of the people</a> who catch COVID, even if they have a mild case. </p>
<p>Scientists collected data as part of the massive <a href="https://www.ukbiobank.ac.uk/">UK Biobank</a> database. They looked at brain magnetic resonance imaging (MRI) scans and tests of brain function in 785 volunteers who were assessed before the pandemic. They then compared this to the same data collected three years later, when about half of those participants had mild COVID infection, and the other half had not caught COVID. This allowed the scientists to determine the specific effects of mild COVID infection on brain structure and function. </p>
<p>The group who had mild COVID an average of five months beforehand had thinning of brain tissue in several brain regions, ranging from 0.2% to around 2% compared to their pre-COVID scan. This is equivalent to between one and six years of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871717/">normal brain ageing</a>. Affected brain regions included the parahippocampal gyrus (an area related to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3786097/">memory</a>) and the orbitofrontal cortex, which is located at the front of the brain and is important for <a href="https://www.sciencedirect.com/science/article/pii/S027826260300277X?via%3Dihub">smell and taste</a>. </p>
<p>The post-COVID group also showed a reduction in overall brain size between their MRI scans that wasn’t seen in the non-COVID group, and had altered connections between different brain regions in the olfactory cortex, an area related to smell. </p>
<p>They performed worse in a test for attention and mental flexibility, a finding that was associated with volume reductions within a part of the cerebellum related to smell and <a href="https://academic.oup.com/scan/article/15/9/905/5901876">social relationships</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Older woman looks concerned with supportive younger woman standing behind her" src="https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/450256/original/file-20220307-85122-1g86kvk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Further research is needed to see if COVID affects the brains of younger people in the same way.</span>
<span class="attribution"><a class="source" href="https://image.shutterstock.com/image-photo/serious-senior-woman-adult-daughter-600w-574538410.jpg">Shutterstock</a></span>
</figcaption>
</figure>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-does-covid-affect-the-brain-two-neuroscientists-explain-164857">How does COVID affect the brain? Two neuroscientists explain</a>
</strong>
</em>
</p>
<hr>
<h2>Comparing to other illnesses</h2>
<p>To show these changes were specific to COVID and not just related to having a respiratory illness, the scientists also looked at a group of people who had pneumonia. They did not see the same changes, confirming they are related to COVID.</p>
<p>Decreases in brain volume are common to many brain diseases and disorders associated with degeneration, and have been found in people with <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748802/">mild cognitive impairment</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/32350798/">Alzheimer’s disease</a>, <a href="https://www.frontiersin.org/articles/10.3389/fpsyt.2018.00651/full">depression</a> and <a href="https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482564">traumatic brain injury</a>, among others. </p>
<p>Problems with memory and attention are also frequent for people with these diseases and disorders, indicating mild COVID infection may accelerate brain degeneration. These changes could explain the reported symptoms of long COVID, such as brain fog.</p>
<p>The study did not look at the mechanisms of mild COVID in the brain. However, the authors suggest this could be due to inflammation, degeneration which spreads through the brain pathways associated with smell, or sensory deprivation due to loss of smell.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/isolated-confused-and-depressed-the-pandemics-toll-on-people-with-dementia-and-their-carers-176970">Isolated, confused and depressed: the pandemic's toll on people with dementia and their carers</a>
</strong>
</em>
</p>
<hr>
<h2>The same for everyone?</h2>
<p>So does this study prove all people who have had mild COVID infections will have these same brain changes and long-term brain degeneration? Not necessarily. </p>
<p>There are several important things we still do not know. This includes whether these brain changes will get worse over time, or whether they will go back to normal or previous levels of function. More research over a long time would help us understand the trajectory of brain changes. </p>
<p>This study also only included people aged 51–81, so we do not know whether these findings are relevant for younger people or children. </p>
<p>The brain changes found in this study were more pronounced in the older participants, so it could be that older people are more susceptible. Another study is needed to determine whether the same brain alterations would occur in younger people, or whether these findings are common only to older people. </p>
<p>There were some differences between the groups before COVID, with smaller volumes of areas deep within the brain. However, these were in different brain areas to those affected after COVID. </p>
<p>The scientists also found slightly reduced scores for brain functions of thinking and remembering in the group that went on to have COVID. This study did not specifically exclude people with degenerative brain conditions such as Alzheimer’s or Parkinson’s diseases, but the scientists do not think these would explain the changes they found.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1362537381358936070"}"></div></p>
<h2>Effects of different variants and vaccination unknown</h2>
<p>Because of the nature of the study, information about the strain of COVID people were infected with was not available. So we can’t assume the findings would be the same for people with the now more prevalent Omicron strain. </p>
<p>We also can’t determine the effect vaccination may have in lessening brain changes. Given the timing of the study, it is likely most of the people in the post-COVID group were infected in 2020, so may not have been vaccinated. </p>
<p>This study provides the first important information about brain changes in people with mild COVID infection. Until we have all the information, we should be alert but not alarmed at emerging findings.</p><img src="https://counter.theconversation.com/content/178530/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sarah Hellewell does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Brain changes including shrinkage, weakened connections and poorer performance on thinking and memory tests could explain ‘brain fog’ after COVID – even after ‘mild’ cases.Sarah Hellewell, Research Fellow, Faculty of Health Sciences, Curtin University, and The Perron Institute for Neurological and Translational Science, Curtin UniversityLicensed as Creative Commons – attribution, no derivatives.