tag:theconversation.com,2011:/fr/topics/what-we-know-dont-know-and-suspect-41387/articleswhat we know, don't know and suspect – The Conversation2018-10-24T04:55:08Ztag:theconversation.com,2011:article/1054912018-10-24T04:55:08Z2018-10-24T04:55:08ZWhat causes multiple sclerosis? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/241779/original/file-20181023-169810-p1hxbm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">People exposed to low levels of sunlight are more likely to have MS than those who live in warm climates.</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/TSgwbumanuE">chuttersnap</a></span></figcaption></figure><p>US actress Selma Blair announced on the weekend she has been diagnosed with multiple sclerosis. “I have probably had this incurable disease for 15 years at least,” she wrote. “And I am relieved to at least know.”</p>
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<img alt="" src="https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=502&fit=crop&dpr=1 600w, https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=502&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=502&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=631&fit=crop&dpr=1 754w, https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=631&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/241767/original/file-20181023-169816-1pypqt2.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=631&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">Selma Blair shared the news on Instagram.</span>
<span class="attribution"><a class="source" href="https://www.instagram.com/p/BpKjP_7FnWQ/?utm_source=ig_web_copy_link">Instagram</a></span>
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<p>Multiple sclerosis is an autoimmune disease, where the body mistakenly attacks the brain and spinal cord. It does this by damaging myelin – the protective coating around the nerves. When myelin is damaged, messages can no longer be clearly transmitted from the brain and spinal cord to other parts of the body.</p>
<p>The resulting symptoms include extreme tiredness, loss of concentration and memory, numbness, sensitivity to heat and cold, difficulties walking and balancing, spasms, dizziness and low mood.</p>
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Read more:
<a href="https://theconversation.com/explainer-multiple-sclerosis-32662">Explainer: multiple sclerosis</a>
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<p>Blair, aged 46, is one of <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4799713/">400,000 people in the United States</a> with MS. The <a href="http://apps.who.int/iris/bitstream/handle/10665/42394/924156203X_en.pdf?sequence=1&isAllowed=y">prevalence is similar to that in Australia</a>, where <a href="https://www.msaustralia.org.au/what-ms">around 25,000</a> people live with the disease. The <a href="https://www.ncbi.nlm.nih.gov/pubmed/19782378">average age of onset</a> for MS is 30, and around three-quarters of those affected are women.</p>
<p>There’s still a lot we don’t know about the causes, but so far the research indicates our genes and environment each have a role in driving susceptibility to MS.</p>
<h2>Genetics</h2>
<p>Genetics plays an important role in the development of MS, with more than 200 genetic markers implicated in the disease. Collectively, the identified genes may <a href="https://www.ncbi.nlm.nih.gov/pubmed/24852507">account for up to 25%</a> of the genetic component of MS risk, but each gene in isolation carries only a small risk. </p>
<p>Because of this, it’s not possible to generate a “genetic risk score” that accurately conveys the risk any given person has of developing MS. So we cannot single out the individuals who are at greater risk, even if we know how many of them might exist in the community.</p>
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<a href="https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=571&fit=crop&dpr=1 600w, https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=571&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=571&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=717&fit=crop&dpr=1 754w, https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=717&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/241960/original/file-20181024-169807-gk9t1v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=717&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">When myelin is damaged, messages can no longer be clearly transmitted from the brain and spinal cord to other parts of the body.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>Researchers are now trying to adopt a more sophisticated genetic approach to help identify individuals at risk by focusing on families who have more than one relative with the disease. We know, in some instances, family members who don’t have symptoms could still harbour asymptomatic disease. This could mean the MS is either at an earlier stage, less severe or “blocked” before it has become clinically overt. </p>
<p>Identifying mutations common to affected family members could help understand the genes likely to be directly relevant to the cause of MS. The unanswered question is whether findings in families can be extrapolated to the general population.</p>
<h2>Viruses</h2>
<p>There is a strong association between the <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/glandular-fever">Epstein-Barr virus</a>, which often results in glandular fever in young adults, and development of MS. If you <a href="https://www.ncbi.nlm.nih.gov/pubmed/10908883">have not been exposed</a> to the virus, you will likely not get the disease.</p>
<p>There are many theories for how the virus may be implicated in MS. The virus infects a <a href="http://www.bloodjournal.org/content/112/5/1570?sso-checked=true">type of white blood cell</a> important for the immune system. Infection of the cell could then cause corruption of the immune response, which could lead to the autoimmunity of MS.</p>
<p>But the Epstein-Barr virus is not <a href="http://n.neurology.org/content/55/2/164">sufficient on its own</a> to trigger MS, as more than 90% of people who aren’t affected by MS have been exposed to the virus.</p>
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Read more:
<a href="https://theconversation.com/humans-are-to-blame-for-the-rise-in-dangerous-viral-infections-94747">Humans are to blame for the rise in dangerous viral infections</a>
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<h2>Sunlight</h2>
<p>Sunlight, or more specifically exposure to ultraviolet (UV) radiation, decreases with increasing distance from the equator.</p>
<p>The further away from the equator you live the greater your risk of developing MS. In Australia, those living in <a href="https://www.ncbi.nlm.nih.gov/pubmed/3368080">northern Queensland</a> are <a href="https://www.ncbi.nlm.nih.gov/pubmed/3681330">seven times less likely</a> to develop MS <a href="https://www.ncbi.nlm.nih.gov/pubmed/3365543">than those in Tasmania</a>.</p>
<p>Ultraviolet light is known to have many effects on the immune system and our synthesis of vitamin D. In particular, UV appears to have an <a href="https://www.ncbi.nlm.nih.gov/pubmed/2687907">impact on immune activity</a>, making immune cells more tolerant and in some instances suppressing immune activity. </p>
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<img alt="" src="https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=397&fit=crop&dpr=1 600w, https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=397&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=397&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=499&fit=crop&dpr=1 754w, https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=499&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/241961/original/file-20181024-169831-1i0uer3.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=499&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">Smoking significantly increases a person’s chances of developing MS.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/lzcKZlVPYaU">Mathew MacQuarrie/Unsplash</a></span>
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<h2>Hormones</h2>
<p>The fact women are more likely to develop MS than men may be related to hormonal changes. </p>
<p>We know <a href="https://www.ncbi.nlm.nih.gov/pubmed/27145331">disease activity drops</a> during pregnancy. We also know women who have multiple children are on average less likely to get the disease and, if they do, it is likely to be less severe. </p>
<h2>Lifestyle</h2>
<p>Smoking significantly <a href="http://journals.sagepub.com/doi/abs/10.1177/1352458515609794?journalCode=msja">increases a person’s chances</a> of developing MS. Smokers, and people exposed to second-hand smoke, are <a href="https://www.ncbi.nlm.nih.gov/pubmed/19365595">almost twice as likely</a> to develop MS. In particular, they are more likely to develop progressive forms of MS.</p>
<p>For people who already have MS, there is <a href="https://www.ncbi.nlm.nih.gov/pubmed/28402456">good evidence</a> that stopping smoking reduces the severity of disease progression.</p>
<p>Although the subject of ongoing research, it would appear smoking influences the production of certain proteins in the lungs that may trigger immune cells to become more alert. At the extreme, this could set off the immune response.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-inflammation-and-how-does-it-cause-disease-84997">Explainer: what is inflammation and how does it cause disease?</a>
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<h2>What we suspect</h2>
<p>There is a great deal of interest in the role nutrition and diet could play in the development and management of MS. These studies are complex due to the many potential nutritional components found in our diets. </p>
<p>It is possible that <a href="https://www.ncbi.nlm.nih.gov/pubmed/27645350">keeping cholesterol and fats</a> in a healthy range could help MS symptoms, such as reducing levels of fatigue. However, this is an ongoing area of research.</p>
<p>There is stronger evidence when it comes to body weight and obesity and the risk of MS. Studies <a href="https://www.karger.com/Article/Abstract/450854">have shown</a> that being overweight or obese, particularly during adolescence, is associated with an increased risk of developing MS. It is also associated with worse outcomes in people who have MS. Not much is known about the mechanisms that may be responsible for this.</p>
<p>The results of <a href="https://www.ncbi.nlm.nih.gov/pubmed/29414293">physical therapy</a> for people with MS are varied but have been associated, at least in the short term, with some benefit, such as improved balance and coordination.</p><img src="https://counter.theconversation.com/content/105491/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Trevor Kilpatrick receives funding from the NHMRC, ARC, MSRA and the NMSS</span></em></p>Young women are disproportionately affected by multiple sclerosis, a disease where the body attacks the brain, scrambling communication to the rest of the body. Here’s what we know about the causes.Trevor Kilpatrick, Professor of neurologist and clinical director, Florey Institute of Neuroscience and Mental HealthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1026512018-09-25T19:59:05Z2018-09-25T19:59:05ZWhat causes schizophrenia? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/237840/original/file-20180925-85767-1dhlufw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The causes of schizophrenia are largely unknown.</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/Ilo2O4eukB4">Nicola Fioravanti/Unsplash</a></span></figcaption></figure><p>Schizophrenia is one of the world’s <a href="https://www.ncbi.nlm.nih.gov/pubmed/15207959">top ten causes of disability</a>. It develops between the ages of 16 and 30 and often persists for life. It affects between <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/schizophrenia">100,000 and 200,000 Australians</a>.</p>
<p>Symptoms include delusions and hallucinations (“psychotic” symptoms), diminished emotional expression, poverty of speech and lack of purposeful action (known as “negative” symptoms), and incoherent speech and disorganised behaviour (“disorganised” symptoms). A <a href="https://www.psychiatry.org/psychiatrists/practice/dsm/educational-resources/dsm-5-fact-sheets">diagnosis</a> of schizophrenia requires at least two symptoms, including one psychotic or disorganised, to be present for at least six months. These must result in significant social or occupational dysfunction. </p>
<p>It is thought <a href="https://www.bmj.com/content/295/6600/681">disruptions in brain development</a> early in life may underlie the emergence of schizophrenia in later years. While the causes of these disruptions aren’t exactly clear, research points to several possible reasons.</p>
<h2>Genes</h2>
<p><a href="http://www.szgene.org/">Hundreds of genes</a> have been linked to schizophrenia, but do not appear to follow typical patterns of inheritance across generations, where disorders can be predicted with confidence. Like diabetes and coronary heart disease, schizophrenia cannot be predicted from family history alone. This is because no one gene, or set of genes, has definitively been identified as causing the disorder. </p>
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Read more:
<a href="https://theconversation.com/schizophrenia-bipolar-disorder-and-depression-share-genetic-roots-study-16955">Schizophrenia, bipolar disorder and depression share genetic roots: study</a>
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<p>Family studies do provide robust evidence of a genetic contribution. For instance, across the population, a <a href="https://www.ncbi.nlm.nih.gov/pubmed/11479071">person’s risk</a> of developing schizophrenia is 1%. If one of their parents has the disorder, the risk increases to 15%. </p>
<p>Twin studies have found a 50% increase in the risk of schizophrenia in the identical twin of a person with schizophrenia. Because identical twins share 100% of their DNA, this means environmental risk factors must also be involved. We do not currently know exactly which genes interact with which environmental factors, nor the extent of these interactions. </p>
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<a href="https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=600&fit=crop&dpr=1 600w, https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=600&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=600&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=754&fit=crop&dpr=1 754w, https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=754&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/237845/original/file-20180925-85773-br4sxn.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>
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<span class="caption">Hundreds of genes have been implicated in schizophrenia.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>There is also an <a href="https://www.ncbi.nlm.nih.gov/pubmed/19683417">association between the age of the father</a> at the time the child is born and an increased risk of schizophrenia in the child. If the father is over the age of 55, the child’s risk of schizophrenia increases by 50%. This may be due to rare mutations in paternal sperm that could lead to abnormal development, or to family factors associated with having an older father. </p>
<h2>Obstetric complications</h2>
<p>Various <a href="https://www.ncbi.nlm.nih.gov/pubmed/12091183">obstetric complications</a> in utero and at birth have also been identified as risk factors for schizophrenia in the offspring. Complications during pregnancy include maternal bleeding, diabetes, rhesus incompatibility (when the mother has Rh-negative blood and the fetus Rh-positive, or vice versa), pre-eclampsia and abnormal fetal growth and development. </p>
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<a href="https://theconversation.com/blood-groups-beyond-a-b-and-o-what-are-they-and-do-they-matter-75063">Blood groups beyond A, B and O: what are they and do they matter?</a>
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<p>Maternal exposure to <a href="https://www.ncbi.nlm.nih.gov/pubmed/28338900">famine</a> during pregnancy has been linked to schizophrenia in the offspring. Complications at delivery include uterine atony (failure of the uterus to contract after delivery), lack of oxygen to the fetus and emergency caesarean. </p>
<p>Most of these obstetric associations are small, and other potential influencing factors weren’t controlled for. For example, exposure to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3479084/">maternal infections</a>, such as upper respiratory tract and genital or reproductive infections, has been linked to schizophrenia in the offspring. If exposed to these infections, these could be the real culprits rather than the obstetric complications described above.</p>
<p>Exposure to infections in childhood, such as <a href="https://www.ncbi.nlm.nih.gov/pubmed/25877655"><em>Toxoplasma gondii</em></a> (a parasitic organism carried by domestic cats) and <a href="https://www.ncbi.nlm.nih.gov/pubmed/22704639">viral central nervous system infections</a> (such as meningitis), have also been linked to schizophrenia in adulthood. Again, if exposed, these could have led to the mental illness as opposed to complications in delivery.</p>
<h2>Immune markers</h2>
<p>Markers of <a href="https://www.ncbi.nlm.nih.gov/pubmed/22104141">infection</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/23428789">inflammation</a> are often increased in adults with schizophrenia. This means immune system dysfunction may be involved in the development of the disorder.</p>
<h2>Drug use</h2>
<p>Studies following people from birth to adulthood have identified <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140673607611623/abstract">cannabis use</a> in childhood or adolescence as a likely risk factor. </p>
<p>These studies have adjusted for other risk factors and taken into account intoxication effects and reverse causation (that schizophrenia may cause cannabis use). They found a dose-response effect, which means the risk of psychosis increased as the frequency of cannabis use increased. Such dose-response effects provide the most robust evidence of causation.</p>
<p>The neurological and biological mechanisms of cannabis use are similar to those in schizophrenia, with the same neurons showing activity.</p>
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<a href="https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/237842/original/file-20180925-85767-18iybpp.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">There is strong evidence for the association between cannabis use in early life and schizophrenia.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/22193527">Methamphetamines</a>, particularly ice or crystal methamphetamine, have been linked to increased risk of persistent psychosis, and not just substance-induced psychosis. Controlled amphetamine administration that triggers temporary psychosis in healthy individuals can also be <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3554477/">blocked by antipsychotics</a>. This further strengthens the evidence of association. </p>
<h2>Social factors</h2>
<p>There is solid evidence supporting the link between having experienced <a href="https://www.ncbi.nlm.nih.gov/pubmed/22716913">child abuse</a>, or any type of abuse that includes <a href="https://www.tandfonline.com/doi/abs/10.1080/17522439.2015.1053969">bullying</a>, and schizophrenia. Stressful <a href="https://www.ncbi.nlm.nih.gov/pubmed/23671196">life events in adulthood</a> have been associated with schizophrenia too.</p>
<p>People living in <a href="https://www.ncbi.nlm.nih.gov/pubmed/23015685">urban areas</a>, particularly areas with <a href="https://www.ncbi.nlm.nih.gov/pubmed/23594564">high income inequality</a>, also show increased risk, which may be associated with <a href="https://www.ncbi.nlm.nih.gov/pubmed/24114240">social fragmentation</a>. Both first- and second-generation <a href="https://www.ncbi.nlm.nih.gov/pubmed/15625195">immigrants</a> show increased risk, with surprisingly greater risk seen in the second generation.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/extreme-stress-in-childhood-is-toxic-to-your-dna-99009">Extreme stress in childhood is toxic to your DNA</a>
</strong>
</em>
</p>
<hr>
<p>Studies have also found a greater risk of schizophrenia in ethnic minority groups living in areas of low ethnic density than those living in high ethnic density areas. These finding indicate that sustained social marginalisation, particularly from early childhood, may have greater adverse effects than migration itself. </p>
<h2>Stress</h2>
<p>Social stressors can lead to <a href="https://www.ncbi.nlm.nih.gov/pubmed/26346639">biological disruptions</a>. For instance, stress <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127444/">increases the release of dopamine</a>. And evidence shows people with schizophrenia have increased <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730746/">dopamine production and release</a>. </p>
<p>Stress is also associated with dysregulation of a brain network known as the hypothalamic-pituitary-adrenal (HPA) axis, which is <a href="https://www.ncbi.nlm.nih.gov/pubmed/25108162">sensitised in people with schizophrenia</a>. </p>
<p>Stress associated with being raised in a harsh environment has been linked to the emergence of an <a href="https://www.ncbi.nlm.nih.gov/pubmed/20431047">inflammatory gene expression</a> in adolescents. And people with schizophrenia show immune system dysfunction in both the <a href="https://www.ncbi.nlm.nih.gov/pubmed/23062357">early</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/21641581">late</a> stages of the disorder. </p>
<p>Disruption to these biological systems can cause paranoid ideas, social withdrawal and other behavioural problems. These in turn cause additional stress and further biological disruption. In time, paranoid ideas can become <a href="https://www.ncbi.nlm.nih.gov/pubmed/20624329">delusional and fixed</a>, signalling schizophrenia, particularly in the presence of other symptoms.</p>
<p>While much progress has been made in identifying the potential causes of schizophrenia, most of the evidence comes from population-level studies that may or may not be applicable to a particular individual. More research is required to determine the various individual pathways to schizophrenia.</p><img src="https://counter.theconversation.com/content/102651/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Sandy Matheson 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>Genes, drugs in early life, and stress have been linked to the development of schizophrenia.Sandy Matheson, Scientist and Digital Librarian, Neuroscience Research AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/964092018-08-23T20:04:33Z2018-08-23T20:04:33ZWhat causes asthma? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/232811/original/file-20180821-30602-1en6nh0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Asthma usually develops in childhood, so why does it happen to these unlucky kids?</span> <span class="attribution"><span class="source">from www.shutterstock.com</span></span></figcaption></figure><p>Asthma is a chronic inflammatory disease of the lungs where the airways become so obstructed the sufferer struggles to breathe. It’s vastly more prevalent in Western societies, and usually develops in childhood. But what do we know about what causes it?</p>
<p>Given asthma is about <a href="https://www.ncbi.nlm.nih.gov/pubmed/9643741">five times more common</a> in Western societies, this suggests lifestyle plays a major role. And as it usually develops in childhood, <a href="https://www.ncbi.nlm.nih.gov/pubmed/22561836">many studies</a> have attempted to look at the events that transpired in infants who did or did not develop asthma by school age.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/do-kids-grow-out-of-childhood-asthma-61277">Do kids grow out of childhood asthma?</a>
</strong>
</em>
</p>
<hr>
<h2>The immune system</h2>
<p>A <a href="https://www.ncbi.nlm.nih.gov/pubmed/23419541">common finding</a> in those who developed asthma is that they had experienced a severe respiratory viral infection or “viral bronchiolitis” in early life. <a href="https://www.ncbi.nlm.nih.gov/pubmed/7767192">Other studies have shown</a> respiratory viruses trigger asthma exacerbations or “attacks” in those who already have asthma. So in already susceptible individuals, respiratory virus infections contribute to the onset, progression, and exacerbations of asthma.</p>
<p>Our immune system has a number of mechanisms to fight viruses. One of these is the production of proteins called interferons – so called because they interfere with viral replication. In <a href="https://www.ncbi.nlm.nih.gov/pubmed/15781584">some</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/28947081">studies</a>, cells from patients with asthma produced lower levels of interferons, suggesting this may make someone more susceptible to a respiratory virus, and then asthma.</p>
<p>It’s also important to recognise not all asthma is the same. We now know there are different sub-types of the disease, which may have different causes. </p>
<p>The dominant subtype, which affects around 50% of asthmatics is referred to as “eosinophilic asthma”. Research in the past two decades has led to the identification of a number of proteins found in abundance in people with eosinophilic asthma. </p>
<p>Several new therapies involving antibodies that neutralise or absorb these proteins are now entering the market. Some are available now, including one called “<a href="https://www.ncbi.nlm.nih.gov/pubmed/21971335">anti-interleukin-5</a>”.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=401&fit=crop&dpr=1 600w, https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=401&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=401&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=504&fit=crop&dpr=1 754w, https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=504&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/232813/original/file-20180821-30611-1jx6y9.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">A number of proteins are found in abundance in people with eosinophilic asthma.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<p>Importantly, some of these new drugs are effective in patients with severe asthma. Severe asthma is poorly controlled by mainstay treatments such as steroids, which work by reducing the inflammation of the airways. </p>
<p>Our saliva, breath and blood contain biomarkers (such as interleukin-5 and exhaled nitric oxide) that can tell a doctor which drugs may work best for us. But this remains imperfect, and we’ll hopefully find better biomarkers in the future. </p>
<p>We don’t know quite as much about the less dominant forms of asthma, but inroads are being made in this area too. One <a href="https://www.ncbi.nlm.nih.gov/pubmed/28687413">recent landmark study</a>, for example, reported that including azithromycin (an antibiotic) as an add-on therapy reduced the number of exacerbations in patients with eosinophilic asthma, but also those with non-eosinophilic asthma. </p>
<p>It’s doubtful the beneficial effects of azithromycin relate solely to its antibiotic activity, but these findings highlight the importance of the microbiota – the bugs that reside on our skin and in our lungs and gut.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/gut-instinct-how-the-way-youre-born-and-fed-affect-your-immune-system-65104">Gut instinct: how the way you're born and fed affect your immune system</a>
</strong>
</em>
</p>
<hr>
<h2>The microbiota</h2>
<p>The majority of known risk factors for asthma onset – for example, poor diet (low fibre/high sugar), urban living, smaller family size, Caesarean births, formula feeding and greater antibiotic use – affect the diversity of our microbiota.</p>
<p>In the late 80s an observation was put forward that younger siblings in large families have a lower risk of developing allergies, and this could be because they were exposed to more germs. This was known as the “<a href="https://www.ncbi.nlm.nih.gov/pubmed/2513902">hygiene hypothesis</a>”. </p>
<p>The hygeine hypothesis is now thought to be more of a “microbiota hypothesis” as the microbiota assembles and matures in early life. <a href="https://www.ncbi.nlm.nih.gov/pubmed/26424567">Recent</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/27618652">studies</a> show infants who are at high risk of developing asthma have an imbalanced gut microbiota at one month of age. </p>
<p>Because the prevalence of asthma has increased so rapidly over the past 50 years, this means our genetic make-up alone cannot be responsible. </p>
<p>The composition of the microbiota can change rapidly (within days), contains 150 times more genes than our genome, and is heavily influenced by our mother’s microbiota, particularly in early-life. This is now placing the spotlight on <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894525/">Western lifestyle choices</a>, and how these influence the metagenome (which is our genome together with the multitude of microbial genomes). </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/YB-8JEo_0bI?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">What actually is the gut microbiota?</span></figcaption>
</figure>
<p>We now need to find out how the microbiota affects our immune system to confer protection or susceptibility to respiratory virus infections, and later asthma.</p>
<p>A number of <a href="https://www.ncbi.nlm.nih.gov/pubmed/24950203">elegant studies</a>, largely performed in animal models, have demonstrated that diet affects the composition of the gut microbiota, which in turn, affects gut health but also all other organs and tissues. </p>
<p>This is because the feeding microbiota generates break-down products or “metabolites” that enter our blood stream. So these microbial byproducts can influence the development and maturation of our immune system, as well as non-immune cells, and thereby affect our immunity upon encounter with external exposures, such as a respiratory virus infection. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/22705104">A study found</a> treatment of mice with antibiotics (which disturb the microbiota) diminishes their ability to produce interferon proteins in response to influenza virus infection.</p>
<p>And a <a href="https://www.ncbi.nlm.nih.gov/pubmed/23449690">recent study showed</a> poor maternal diet in the third trimester of pregnancy increases the severity of viral bronchiolitis in the offspring. The investigators of this large study didn’t explore whether this effect was associated with alterations to the microbiota, which is the likely explanation, and this is something we need to find out. </p>
<p>Once we know more about the link between asthma and the bugs that reside within and on us, we’ll be better able to treat and hopefully prevent asthma.</p><img src="https://counter.theconversation.com/content/96409/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Simon Phipps receives funding from NHMRC of Australia. </span></em></p><p class="fine-print"><em><span>Md. Al Amin Sikder 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>More kids these days have asthma, and more people in the Western world, so do we know what causes it in the first place?Simon Phipps, Associate Professor, Respiratory Immunology, QIMR Berghofer Medical Research InstituteMd. Al Amin Sikder, PhD candidate in Medicine and Biomedical Sciences, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/943952018-05-24T04:38:34Z2018-05-24T04:38:34ZWhat causes chronic fatigue? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/218719/original/file-20180514-178757-43c6w8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The term chronic fatigue underemphasises the full scope of symptoms sufferers face. </span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/CwIU33KGToc">vladislav muslakov unsplash</a></span></figcaption></figure><p>Around <a href="http://www.ncbi.nlm.nih.gov/pubmed/23576883">200,000 people in Australia</a> suffer from a debilitating illness often branded with the unfortunate name of chronic fatigue syndrome (CFS). I say “unfortunate” because this implies patients are simply tired, run-down, burnt-out or overly stressed.</p>
<p>But myalgic encephalomyelitis, or ME/CFS as it is now more commonly called, is a serious and incapacitating disease that can have a devastating impact on a patient’s life. <a href="http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf">Symptoms</a> include:</p>
<ul>
<li><p>profound and unexplained fatigue for more than six months</p></li>
<li><p>memory or concentration difficulties</p></li>
<li><p>muscle pain (myalgia) and weakness</p></li>
<li><p>joint pain</p></li>
<li><p>sleep disturbances</p></li>
<li><p>flu-like symptoms</p></li>
<li><p>light headedness, palpitations, breathlessness</p></li>
<li><p>headaches</p></li>
<li><p>heightened sensitivity to light and sound</p></li>
<li><p>tender lymph nodes, sore throats</p></li>
<li><p>new sensitivities to food, medicines or chemicals.</p></li>
</ul>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-chronic-fatigue-syndrome-17204">Explainer: what is chronic fatigue syndrome?</a>
</strong>
</em>
</p>
<hr>
<p>Initially bewildered by their incapacitating fatigue, many ME/CFS patients continue trying to go about their daily lives. But such efforts come at a severe cost. Even small amounts of activity can trigger “crashes” called <a href="http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf">post-exertional malaise</a> that worsen symptoms, sometimes for many days.</p>
<p>Simple activities such as showering, grocery shopping or meeting a friend for coffee become difficult, if not impossible. Sadly, for around <a href="http://www.ncbi.nlm.nih.gov/pubmed/27127189">25% of patients</a>, symptoms are so severe they remain bed-bound or house-bound, and <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)01223-4/fulltext">suicide</a> risk is elevated.</p>
<p>Most patients face a <a href="https://www.tandfonline.com/doi/abs/10.1300/J092v07n04_02">major challenge</a> getting a diagnosis. One UK study found <a href="http://www.ncbi.nlm.nih.gov/pubmed/15805128">less than half of doctors</a> were confident with the diagnosis or treatment of ME/CFS and <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=15534161">more than 85%</a> of patients go from doctor to doctor for over two years without a diagnosis.</p>
<h2>What we know</h2>
<p>The underlying causes of ME/CFS have proved difficult to pinpoint. For many patients, blood and pathology testing are entirely normal.</p>
<p>This has led some to suggest ME/CFS is a psychological condition. In 2011, the findings of a <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960096-2/abstract">clinical trial</a> suggested patients <a href="http://www.ncbi.nlm.nih.gov/pubmed/23363640">could recover</a> through psychological therapy (cognitive behavioural therapy or CBT) and graded exercise therapy. These findings have fuelled debate as to whether ME/CFS might be a <a href="http://www.ncbi.nlm.nih.gov/pubmed/21793823">disease of the mind</a>.</p>
<p>But a <a href="https://www.ncbi.nlm.nih.gov/pubmed/25695122">landmark US study</a> examining nearly 10,000 research publications suggested otherwise, concluding that ME/CFS is a serious, chronic, complex and systemic disease.</p>
<p>Criticisms of psychological and exercise therapy for ME/CFS have been widespread, with over 50 published letters in leading scientific journals (<a href="http://www.ncbi.nlm.nih.gov/pubmed/27686885">BMJ</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/28805520">Journal of Health Psychology</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/29542715">Nature</a>, <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960689-2/fulltext">Lancet</a>) raising serious concerns about the <a href="https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3">robustness of the claims</a>.</p>
<p><a href="https://www.racgp.org.au/your-practice/guidelines/handi/interventions/other/graded-exercise-therapy-for-chronic-fatigue-syndrome/">Australian guidelines</a> continue to recommend exercise and CBT therapies despite the US <a href="https://www.cdc.gov/me-cfs/index.html">Centers for Disease Control and Prevention</a> discontinuing these recommendations.</p>
<p>While exercise can clearly benefit patients with a wide range of illnesses, physical activity can cause a rapid <a href="http://www.ncbi.nlm.nih.gov/pubmed/28216087">deterioration of symptoms</a> in patients with ME/CFS.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/research-check-can-lightning-process-coaching-program-help-youths-with-chronic-fatigue-84769">Research Check: can ‘Lightning Process’ coaching program help youths with chronic fatigue?</a>
</strong>
</em>
</p>
<hr>
<h2>What we don’t know</h2>
<p>There are no laboratory tests available to categorically diagnose someone with ME/CFS. But Australian research is playing a leading role in the discovery of possible diagnostic markers. For example, inflammatory blood proteins such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/28302133">activin B</a> and <a href="http://www.ncbi.nlm.nih.gov/pubmed/21619669">interferon</a> are increased in ME/CFS. Other studies have shown <a href="https://www.ncbi.nlm.nih.gov/pubmed/19567398">metabolic waste products</a> from some gut bacteria accumulate in ME/CFS patients and so may also provide diagnostic information in the future.</p>
<p>Women are <a href="http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf">four times</a> more likely to be diagnosed with ME/CFS than men, but the reason for this is unclear. Also, having a first-degree relative with ME/CFS <a href="http://www.ncbi.nlm.nih.gov/pubmed/21619629">more than doubles the risk</a> of developing the disease, but the role of genetics is not known. </p>
<p>For some, the onset of symptoms is slow. In others, ME/CFS begins with <a href="http://www.ncbi.nlm.nih.gov/pubmed/21756995">infections</a> causing <a href="https://www.ncbi.nlm.nih.gov/pubmed/16950834">glandular fever</a> (infectious mononucleosis), <a href="https://www.ncbi.nlm.nih.gov/pubmed/27279748">respiratory or gastrointestinal illnesses</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=402&fit=crop&dpr=1 600w, https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=402&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=402&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=506&fit=crop&dpr=1 754w, https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=506&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/218720/original/file-20180514-178743-1fzdmob.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=506&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">For some, chronic fatigue is preceded by infections such as glandular fever.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<p>While ME/CFS patients have <a href="https://www.ncbi.nlm.nih.gov/pubmed/21756995">immune disruptions</a> and <a href="https://www.ncbi.nlm.nih.gov/pubmed/28760971">abnormal inflammatory responses</a>, the underlying causes remain elusive. The vicious cycles of tissue damage typical of autoimmune diseases such as multiple sclerosis or lupus don’t seem to occur in ME/CFS.</p>
<p>One theory is that ME/CFS patients have a “chink” in their immunological armour, possibly leading to <a href="http://www.ncbi.nlm.nih.gov/pubmed/21756995">persistent “smouldering” infections</a> and chronic inflammation.</p>
<p>But it’s remarkably difficult to find direct evidence for such ongoing infections in <a href="http://www.ncbi.nlm.nih.gov/pubmed/21756995">most ME/CFS patients</a>. And <a href="http://www.ncbi.nlm.nih.gov/pubmed/23959519">antiviral drugs</a> or <a href="http://www.ncbi.nlm.nih.gov/pubmed/16911783">antibiotics</a> seem to have very modest activity in ME/CFS despite their life-saving activities in many other infectious diseases.</p>
<p>ME/CFS patients also have metabolic defects in the way <a href="https://www.ncbi.nlm.nih.gov/pubmed/28018972">energy</a> is generated in their bodies - pointing to one reason why they rapidly succumb to muscle fatigue during exercise. But whether this metabolic defect is due to immune attack, chronic infection or some other cause is unknown.</p>
<p>With no approved treatments or cures for ME/CFS, more research is urgently needed. So far, clinical trials examining the effects of <a href="https://www.ncbi.nlm.nih.gov/pubmed/9757853">immunosuppressive drugs</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/2146875">antibody therapies</a>, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23959519">anti-viral drugs</a>, <a href="http://www.ijcem.com/files/ijcem0065685.pdf">attention deficit hyperactivity disorder therapies</a> and <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)91345-8/fulltext">anti-depressants</a> have not led to major improvements. </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/28111818">Diets and nutritional supplements</a> also seem to provide little help. While some dietary supplements involved in generating <a href="https://www.ncbi.nlm.nih.gov/pubmed/26212172">metabolic energy</a> seem to improve some ME/CFS symptoms, larger and better studies are required.</p>
<p>A <a href="https://www.nature.com/articles/d41586-017-08965-0">reboot of ME/CFS research</a> is now underway. Sufferers are hopeful the recent establishment of a <a href="https://www.nhmrc.gov.au/health-topics/myalgic-encephalomyelitis-and-chronic-fatigue-syndrome">National Health and Medical Research Council ME/CFS Advisory Committee</a> will reinvigorate Australian biomedical ME/CFS research to find new treatments and possibly a cure.</p>
<hr>
<p><em>ME/CFS patients should always consult their medical doctor before taking any medication. More information can be found at <a href="https://emerge.org.au/">Emerge Australia</a>. Anyone seeking support and information about suicide can contact <a href="https://www.lifeline.org.au/?gclid=EAIaIQobChMIyKDF2cPo2gIVkTUrCh2M-gDgEAAYASAAEgIXE_D_BwE">Lifeline</a> on 131 114.</em></p><img src="https://counter.theconversation.com/content/94395/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mark Guthridge 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>Spoiler: there’s a lot more that we don’t know about what causes chronic fatigue.Mark Guthridge, Senior Research Fellow, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/863142017-11-12T18:57:41Z2017-11-12T18:57:41ZWhat causes breast cancer in women? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/192943/original/file-20171102-26472-1dzy4u3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Different people have very different chances of being diagnosed with breast cancer.</span> <span class="attribution"><a class="source" href="https://unsplash.com/photos/f3H7honxsXI">Pablo Heimplatz/Unsplash</a></span></figcaption></figure><p><em>This is a long read. Enjoy!</em></p>
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<p>Breast cancer is the <a href="http://www.who.int/cancer/detection/breastcancer/en/index1.html">most common cancer in women</a> worldwide and the second-most-common cause of death from cancer. Although the chances of curing breast cancer have risen recently, efforts to prevent occurrence in the first place have been less successful. Around <a href="http://www.breastcancer.org.au/about-breast-cancer/statistics.aspx?gclid=EAIaIQobChMI3PHIlpKW1wIVWAUqCh0IbQz5EAAYASAAEgLbJPD_BwE">one in eight women</a> in Australia are expected to be diagnosed before the age of 85.</p>
<p>Despite the disease being common, different people have very different chances of being diagnosed with breast cancer. Working out this chance for each person guides who will benefit most from ways to reduce risk. These can involve changes in diet and exercise, preventive medications, or even surgery in high-risk cases.</p>
<p>We’re aware of many things about a person’s lifestyle or genes that increase the chances of getting breast cancer, but we don’t always understand how these might cause the disease. This is partly because much of our research is based on “association studies”. </p>
<p>Here, a researcher notices something more common in people with the illness and compares people with and without the illness to confirm this link. While this provides us with an association between the common element and breast cancer, it does not prove that thing directly caused the illness.</p>
<p>Also, for breast cancer, usually no single risk is particularly large. There may be a few risks in any one person. So it’s often difficult to say absolutely what caused breast cancer in that person. </p>
<p>It’s likely a combination of the effects of a person’s risks combined with an element of bad luck. This is different, for example, to lung cancer where smoking is the clear cause in many cases.</p>
<hr>
<p><strong><em>More information – <a href="https://theconversation.com/interactive-body-map-what-really-gives-you-cancer-52427">Interactive body map: what really gives you cancer?</a></em></strong></p>
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<h2>Hormones</h2>
<p>Oestrogen, the predominant female hormone mainly produced by the ovaries, plays a well-known role in breast cancer development and protection. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193509/original/file-20171107-1027-13vt1kn.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 contraceptive pill contains oestrogen and so increases the risk of breast cancer for the period it is taken.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>A range of factors that are known to affect a woman’s <a href="https://www.theguardian.com/science/2008/oct/06/cancer.women">breast cancer risk</a> (like how many children she has) also affect how much oestrogen she is exposed to throughout life. Oestrogen causes breast development in puberty and during pregnancy helps the breasts develop for breastfeeding. Unfortunately, increased oestrogen over a long time can also cause damage to normal breast cell DNA and cause these <a href="https://www.ncbi.nlm.nih.gov/pubmed/25159108">damaged cells to multiply</a>, which can start a cancer.</p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/explainer-what-is-cancer-1673">Explainer: what is cancer?</a>
</strong>
</em>
</p>
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<p>Factors that increase <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC314432/">lifetime oestrogen exposure</a> and, with that, breast cancer risk, include having no or few children and starting your family at an older age. Oestrogen production is interrupted while women are not menstruating during pregnancy and breastfeeding, which decreases the overall lifetime exposure to oestrogen. Going through puberty earlier or menopause later, which both increase a woman’s total number of menstrual cycles, is also linked to higher risk. </p>
<p>Combined hormone replacement therapy (HRT) or the oral contraceptive pill, both of which contain oestrogen, <a href="https://ww5.komen.org/uploadedFiles/_Komen/Content/About_Breast_Cancer/Tools_and_Resources/Fact_Sheets_and_Breast_Self_Awareness_Cards/How%20Hormones%20Affect%20Breast%20Cancer.pdf">increase risk</a> for the period they are taken. However, for the contraceptive pill the risk is small, as breast cancer is rare at the age it is used. <a href="https://www.ncbi.nlm.nih.gov/pubmed/18513172">Reduced prescriptions for HRT</a> has recently been shown to have <a href="https://thebms.org.uk/2016/08/breast-cancer-now-study-finds-effect-combined-hrt-breast-cancer-risk-likely-underestimated/">led to a reduction</a> in breast cancer cases.</p>
<p>Women who have more children earlier and breastfeed are at <a href="https://ww5.komen.org/uploadedFiles/_Komen/Content/About_Breast_Cancer/Tools_and_Resources/Fact_Sheets_and_Breast_Self_Awareness_Cards/How%20Hormones%20Affect%20Breast%20Cancer.pdf">lower risk</a> of breast cancer. Both cause an increase of oestrogen around the pregnancy but then lower levels than normal for many years after. </p>
<h2>Dairy, meat and vegetables</h2>
<p>There is a widespread concern that <a href="http://www.dailymail.co.uk/health/article-1322661/Why-modern-life-DOES-cause-cancer.html">elements of the modern diet</a> add to breast cancer risk. But the belief that preservatives and pesticides are major contributors has <a href="https://academic.oup.com/jnci/article/89/23/1743/2526542/Pesticides-and-Breast-Cancer-Fact-or-Fad">never been confirmed</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/192944/original/file-20171102-26448-xgvk45.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Research shows vegetables can protect from cancer.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/WOxddhzhC1w">Alexandr Podvalny/Unsplash</a></span>
</figcaption>
</figure>
<p>Similarly, <a href="http://www.maurerfoundation.org/do-dairy-products-increase-risk-for-breast-cancer/">no risk increase</a> has been found for people consuming dairy products. Eating meat appears to cause <a href="http://wiki.cancer.org.au/policy/Position_statement_-_Meat_and_cancer_prevention#Breast_cancer">little or no risk</a>. But the fifth of the population eating the highest levels of red or processed meats (bacon, sausage, ham) have <a href="https://www.ncbi.nlm.nih.gov/pubmed/27869663">a 25% higher risk</a> of breast cancer than the fifth who eat the least – and appear to have increased rates of other cancers. This is probably because processing causes small amounts of cancer-causing toxins to form in the meat. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/not-everything-gives-you-cancer-but-eating-too-much-processed-meat-certainly-can-49812">Not everything gives you cancer, but eating too much processed meat certainly can</a>
</strong>
</em>
</p>
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<p>There is some limited evidence that eating more fish <a href="http://wiki.cancer.org.au/policy/Position_statement_-_Meat_and_cancer_prevention#Breast_cancer">reduces breast cancer risk</a>. This may be due to the protective effect of omega-3 fats. And there is relatively strong proof that vegetable consumption <a href="https://ww5.komen.org/BreastCancer/Table14Fruitandvegetableintakeandbreastcancerrisk.html">lessens risk</a>, although how this works is not known. </p>
<p>Despite much being said about the protective powers of “<a href="https://www.webmd.com/cancer/features/seven-easy-to-find-foods-that-may-help-fight-cancer#2">super veggies</a>”, such as kale, broccoli, tomatoes and strawberries, there is <a href="https://www.ncbi.nlm.nih.gov/pubmed/22215387">so far no evidence</a> they are really better than others. Similarly, organically grown vegetables <a href="https://www.ncbi.nlm.nih.gov/pubmed/24675385">do not give</a> greater protection than those grown in the usual way. </p>
<p>Studies exploring the benefits of vitamin supplements show <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805144/">no conclusive evidence</a> these affect breast cancer risk, although vitamin D may <a href="http://www.breastcancer.org/risk/factors/low_vit_d">provide modest protection</a> if at healthy levels compared to low levels.</p>
<h2>Lifestyle, obesity and stress</h2>
<p>Alcohol increases <a href="https://cris.maastrichtuniversity.nl/portal/files/1585303/guid-58ee3c46-e93f-4138-9d11-7148ee63180d-ASSET1.0">lifetime breast cancer risk</a> by around a tenth per drink per day for the period during which drinking occurs. Active smoking, but not <a href="https://www.ncbi.nlm.nih.gov/pubmed/18544575">passive smoking</a>, also <a href="https://www.ncbi.nlm.nih.gov/pubmed/25307527">increases risk</a> by about a fifth – especially in younger women. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/192941/original/file-20171102-26444-190a0kg.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">Exercise lessens the chance of breast cancer.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/yaA1X2sPvz4">Jacob Postuma/Unsplash</a></span>
</figcaption>
</figure>
<p>Caffeine may be <a href="https://ww5.komen.org/BreastCancer/FactorsThatDoNotIncreaseRisk.html">mildly protective</a> and chocolate appears <a href="http://foodforbreastcancer.com/foods/chocolate">safe in moderation</a>. This is provided consumption does not lead to substantial weight gain, as obesity has repeatedly been shown to <a href="https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet">increase breast cancer</a> occurrence by about a fifth, especially in post-menopausal women. </p>
<p>This may be because <a href="https://www.ncbi.nlm.nih.gov/pubmed/11511861">fatty tissues produce oestrogen</a>. Also, obese women have higher insulin levels, another hormone that can lead to breast cancer. Those developing full diabetes in later life, when insulin levels are usually very high, are at an <a href="http://www.diabetes.co.uk/diabetes-complications/breast-cancer.html">even higher risk</a> – a two-fifths increase.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/how-obesity-causes-cancer-and-may-make-screening-and-treatment-harder-73596">How obesity causes cancer, and may make screening and treatment harder</a>
</strong>
</em>
</p>
<hr>
<p>Contrary to popular belief, sugar itself does not appear to <a href="https://www.cancer.gov/about-cancer/causes-prevention/risk/myths">directly affect risk</a> in moderation. However, too much sugar may increase risk indirectly through obesity, which can then cause diabetes.</p>
<p>Exercise substantially <a href="https://ww5.komen.org/BreastCancer/LackofExercise.html">reduces the chance</a> of a breast cancer diagnosis, although how this works is not yet understood. The duration rather than intensity appears important, with three hours of moderate aerobic exercise weekly <a href="https://www.ncbi.nlm.nih.gov/pubmed/23274845">reducing breast cancer risk</a> by about a fifth. Exercise also <a href="http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.10067">improves survival</a> after breast cancer. </p>
<p>High stress levels are widely believed by the general public to cause cancer, likely because both are common. However, <a href="http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.10067">large studies</a> comparing people exposed to very high stress situations such as bereavement, bankruptcy or divorce have not found any difference. </p>
<p>Many researchers have also looked at whether sleep patterns might affect breast cancer, especially from <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241898/">nightshift work</a>, but have not confirmed a risk.</p>
<h2>Genetic factors</h2>
<p>It is well known women who inherit faults in particular genes which repair damaged DNA, particularly the BRCA 1 and 2 genes, have a high risk of both <a href="https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet">breast and ovarian cancer</a> – up to an 80% lifelong risk for breast cancer and 40% for ovarian cancer. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193510/original/file-20171107-1017-aefrnh.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">Having a mutation in the BRCA 1 and 2 genes may lead some women, like Angelina Jolie, to have preventive surgery.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/dgcomsoc/7103919579/in/photolist-bPKrN4-51z3py-95J34r-bgctCX-6tham9-88K1E4-5FGd2S-BbQ6F-cEJ6zY-dUiU8Z-7fk7jx-6wMSAM-9t3UrD-8Wfj7z-au4Fti-72v1Y7-eah9Mo-c5AHt5-dE3aNz-dFE5kh-r21Mi-6JiFvN-gaEbCC-6K1kuh-9JhHra-5d1qcr-eauJKx-eaAoPf-9Wm1F3-3X6yi8-zHfjD-8nFErg-d8dPKC-d8dPNm-d8dPGw-TKJ3K3-4fCohx-nVfwMi-oejxCU-e5TUJk-e6gCu9-e6gCw1-e6gCuL-e6gD6u-4SRxrg-9wq5f6-31WjW3-8nGrDQ-8nDiuc-4J2XXL">Cancillería del Ecuador/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>This high predictable risk leads some women to opt for preventive medication or even surgery, which includes removing both breasts and ovaries. Such solutions, although radical, give affected women the <a href="http://ascopubs.org/doi/abs/10.1200/jco.2004.04.188">same life expectancy</a> as women in the general population. </p>
<p>Even in the absence of such gene faults, a family history of breast cancer does <a href="https://canceraustralia.gov.au/clinical-best-practice/gynaecological-cancers/familial-risk-assessment-fra-boc">increase personal risk</a>. Those with a single first-degree relative (mother, sister or daughter) have approximately double the risk (http://www.breastcancer.org/risk/factors/family_history) of those with no family history or about 24% lifelong risk in Australia.</p>
<p>This may be due to a host of other genes that have more minor impacts on breast cancer risk. New candidates <a href="https://www.nature.com/nature/journal/vaop/ncurrent/full/nature24284.html">are regularly added</a> as research continues. Unsurprisingly, many of these genes are involved in processes in the body such as oestrogen and insulin action or DNA repair, although the way some work remains unknown. </p>
<p>Collections of these genetic markers can be tested together <a href="http://www.nejm.org/doi/pdf/10.1056/NEJMsr1501341">in a person’s blood</a> to better predict their breast cancer risk.</p>
<p>Breast density, which is the “whiteness” seen on a mammogram, is also very useful in <a href="https://www.ncbi.nlm.nih.gov/pubmed/26627479">predicting the chances</a> of breast cancer. More dense (white) tissue predicts higher risk. Given the strength of mammographic density as a risk factor and its prevalence in the population, it is likely to <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757943/">influence breast cancer</a> in a large number of women.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/women-should-be-told-about-their-breast-density-when-they-have-a-mammogram-66125">Women should be told about their breast density when they have a mammogram</a>
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</em>
</p>
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<p>Mammographic density is strongly related to oestrogen exposure and is also modified by <a href="https://www.ncbi.nlm.nih.gov/pubmed/26627479">menopause and HRT</a>.</p>
<h2>Calculating your risk</h2>
<p>Importantly, it is the sum of all the above factors that defines personal risk. Research suggests women often do not have an accurate idea of <a href="https://www.ncbi.nlm.nih.gov/pubmed/24372085">their own risk</a> of breast cancer, but there are several ways they can find out.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=365&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=365&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=365&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=458&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=458&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193511/original/file-20171107-1068-ucsoda.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=458&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Online calculators are available to estimate your risk of breast cancer.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/benderish/104135032/in/photolist-acHHA-mPvWQf-7JJV36-mPuode-Mzfv3-baBMS6-8BYA2n-TCxw6a-do1KNU-4rRFDR-865LyM-q1vuQG-dwGsT6-hZLGR-DQJMmU-81BJ2h-79ig27-7sBQg4-eCrs2r-2bn9d7-pvdLfb-6qSCmh-aDbmf5-xX4JU-bGZrqg-7fkhRJ-eGKHWw-5MQ6wu-aANukh-4Ge47a-q1vuHs-4rVJCL-78nn16-akJDDr-79t4Er-Bv28Hm-79wVoL-79t64c-79t4vP-bnZLkt-7o5hMj-kjqbm-Bq74-5fqivV-9xPKwX-9MrkL-6UrTxD-78nn9i-5H6tgv-4GDRD">Ben Jeffrey/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Online breast cancer risk calculators are available, although some are designed for researchers rather than patients. A good one for patients is <a href="https://www.mdcalc.com/gail-model-breast-cancer-risk">the Gail model</a>, which uses family and reproductive history, as well as the occurrence of benign breast conditions, and can be filled in online. Cancer Australia also provides a <a href="https://breastcancerrisk.canceraustralia.gov.au/">risk calculator</a>. Neither include mammographic density or the host of breast cancer genes that have been discovered, each with a small risk association. However, it can give an overall idea quite quickly.</p>
<p><a href="http://ccge.medschl.cam.ac.uk/boadicea/boadicea-model/">The BOADICEA calculator</a> is mainly used by researchers and works off a detailed family history. <a href="http://www.ems-trials.org/riskevaluator/">The Tyler-Cuzick calculator</a>, mainly designed for use by doctors, adds mammographic density to other risk factors with the aim of making even better breast cancer risk predictions. </p>
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Read more:
<a href="https://theconversation.com/its-all-relative-how-to-understand-cancer-risk-55494">It's all relative: how to understand cancer risk</a>
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<p>Clearly, predicting an individual’s risk of breast cancer without being able to reduce it would be of limited value. The above information does allow women to make a number of lifestyle choices, such adjustments being most valuable in women with higher risk.</p>
<p>Beyond this, drugs that limit oestrogen in the body can substantially lessen the chances of breast cancer. These include <a href="https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/tamoxifen-and-raloxifene-for-breast-cancer-prevention.html">tamoxifen</a>, which can reduce risk by about a third in all women, and <a href="https://www.cancer.org/cancer/breast-cancer/risk-and-prevention/aromatase-inhibitors-for-lowering-breast-cancer-risk.html">aromatase inhibitors</a>, which lessen risk by about two-thirds in post-menopausal women. </p>
<p>In practice, few women opt for such measures. This is likely due to concerns over relatively common “menopause-like” <a href="http://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/tamoxifen/side-effects">side effects</a> and more serious, although rare, <a href="https://www.drugs.com/sfx/tamoxifen-side-effects.html">side effects of tamoxifen</a>, including endometrial cancer and venous blood clots.</p>
<p>Good consumption of vegetables, limiting alcohol, avoiding being substantially overweight, especially after menopause, and getting regular moderate exercise will lower risk. Looking at mammographic density and considering genetic tests, especially in women with a family history, may be valuable and should be discussed with the family doctor. </p>
<p>Preventive medication or surgery can be used for those at high risk, usually in consultation with a breast cancer specialist.</p><img src="https://counter.theconversation.com/content/86314/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Redfern receives funding from the NHMRC, the Cancer Council of WA and the WA Department of Health</span></em></p><p class="fine-print"><em><span>Rik Thompson receives funding from National Breast Cancer Foundation and the Australia India Council. He is affiliated with Breast Cancer Trials as Director. </span></em></p>There is usually no one factor that causes breast cancer. It’s likely a combination of the effects of a person’s risks combined with an element of bad luck.Andrew Redfern, Senior Lecturer, The University of Western AustraliaRik Thompson, Professor of Breast Cancer Research, Institute of Health and Biomedical Innovation and School of Biomedical Sciences,, Queensland University of TechnologyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/865442017-11-08T19:14:00Z2017-11-08T19:14:00ZWhat causes SIDS? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/193337/original/file-20171106-1020-bgsa7y.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Discovering causes of SIDS is difficult, since diagnosis is one of exclusion.</span> <span class="attribution"><span class="source">from www.shutterstock.com</span></span></figcaption></figure><p>Sudden infant death syndrome (SIDS) is a devastating and unexpected event in which a seemingly healthy infant dies during sleep in the first year of life. There is <a href="https://www.ncbi.nlm.nih.gov/pubmed/19692691">no warning or prior indication</a> of <a href="http://pediatrics.aappublications.org/content/114/1/234?download=true">any underlying disease</a>. </p>
<p>It’s one of the most significant causes of infant death after birth in developed countries, profoundly affecting families and their communities. Despite the previous significant decline in SIDS deaths in the Western world, <a href="https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/1471-2393-15-S1-A12">recent</a> <a href="http://pedsinreview.aappublications.org/content/33/7/314">investigations</a> <a href="https://www.ncbi.nlm.nih.gov/pubmed/26634772">have reported a plateau</a> in rates. </p>
<h2>What we know</h2>
<p>SIDS is complex, and the diagnosis is one of exclusion, meaning a complete post mortem examination and investigation of the circumstances of death <a href="http://pediatrics.aappublications.org/content/114/1/234?download=true">aren’t able to explain</a> the cause of death.</p>
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<strong>
Read more:
<a href="https://theconversation.com/what-causes-autism-what-we-know-dont-know-and-suspect-53977">What causes autism? What we know, don’t know and suspect</a>
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<p>Many theories from both animal and human studies have attempted to understand what causes SIDS, with multiple abnormalities reported in a number of functions and systems in the body. This includes the brain, heart, lungs, gastrointestinal system, hormones, and immune system. As well as <a href="http://journals.lww.com/jpgn/Abstract/1991/04000/Gastroesophageal_Reflux_in_Infants_with_a_History.5.aspx">metabolic</a>, <a href="https://link.springer.com/content/pdf/10.1007/s00401-009-0490-7.pdf">infectious</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246416/">nutritional</a>, <a href="http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.31722/abstract">environmental and genetic</a> factors.</p>
<p>One of the most influential hypotheses is the <a href="https://www.karger.com/Article/Abstract/244052">triple risk model</a> which suggests an <a href="https://www.researchgate.net/publication/311955709_Evolution_and_significance_of_the_triple_risk_model_in_sudden_infant_death_syndrome_Triple_risk_model">increased risk</a> when an infant who is already at risk is exposed to certain stressors such as a lack of oxygen, at a particular age. </p>
<h2>What we suspect</h2>
<p>To date, the precise cause of death in SIDS has not been identified. But there is substantial evidence the syndrome results from a combination of circumstances where breathing and heart rate are compromised, in an infant who also has abnormalities in important brain function controlling these systems. These are in place at a specific period of postnatal development. </p>
<p>Many <a href="http://onlinelibrary.wiley.com/doi/10.1002/ppul.10287/abstract">studies</a> in SIDS victims have supported the concept that SIDS infants are not entirely <a href="http://europepmc.org/abstract/med/4065274">“normal” prior to death</a>. These infants have some form of <a href="https://link.springer.com/content/pdf/10.1007/s00401-009-0490-7.pdf">underlying vulnerability</a> exposing them to an <a href="https://www.ncbi.nlm.nih.gov/pubmed/19692691">increased risk</a> for sudden death. </p>
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Read more:
<a href="https://theconversation.com/what-causes-depression-what-we-know-dont-know-and-suspect-81483">What causes depression? What we know, don’t know and suspect</a>
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<p>It’s thought SIDS, or at least some SIDS cases, are caused by <a href="https://www.ncbi.nlm.nih.gov/pubmed/19692691">some form of underlying neural</a> (nerve) or systematic abnormality in the brainstem that impairs critical responses to life-threatening challenges. For example, a lack of oxygen during sleep. </p>
<p>This failure is thought to result from abnormalities in a network of neural pathways in the brainstem that control breathing, autonomic control (the regulation of our internal organs), and arousal. Abnormalities in various <a href="http://www.annualreviews.org/doi/abs/10.1146/annurev.pathol.4.110807.092322">brainstem chemicals</a> <a href="https://link.springer.com/content/pdf/10.1007/s00401-009-0490-7.pdf">have been reported</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193339/original/file-20171106-1008-be1j4c.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">Abnormalities in the brain stem have been discovered in SIDS infants.</span>
<span class="attribution"><a class="source" href="https://unsplash.com/photos/WCbCRXk7nmU">Carlo navarro/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Abnormalities in the expression of the brain chemical serotonin (the mood hormone) in the brainstem have been the most significantly and consistently observed in SIDS infants. </p>
<p>This system is a <a href="http://www.annualreviews.org/doi/abs/10.1146/annurev.pathol.4.110807.092322">key player in regulating</a> the <a href="https://www.ncbi.nlm.nih.gov/pubmed/10432487">brain’s control</a> of the upper airways (nose and respiratory tract), ventilation and gasping, keeping body temperature stable and ensuring the baby gets enough oxygen. </p>
<p>Abnormalities in this system have been reported in <a href="https://academic.oup.com/jnen/article/59/5/377/2609877/Decreased-Serotonergic-Receptor-Binding-in-Rhombic">many</a> <a href="https://jamanetwork.com/journals/jama/fullarticle/185314">studies of SIDS infants</a> from varying <a href="https://academic.oup.com/jnen/article/62/11/1178/2916478/Serotonergic-Brainstem-Abnormalities-in-Northern">ethnic</a>, social and <a href="https://academic.oup.com/jnen/article-abstract/76/10/864/4096520/Medullary-Serotonin-Neuron-Abnormalities-in-an">cultural</a> backgrounds. </p>
<p>Given the complex role of this system in the brainstem, associated abnormalities are <a href="http://onlinelibrary.wiley.com/doi/10.1002/dev.20367/abstract">probably responsible</a> for <a href="https://www.ncbi.nlm.nih.gov/pubmed/22792083">impaired defence mechanisms</a>. This includes head-lifting, crying, gasping for air and arousal from sleep, in response to a <a href="https://academic.oup.com/jnen/article/59/5/377/2609877/Decreased-Serotonergic-Receptor-Binding-in-Rhombic">lack of oxygen</a>. But it’s still not clear whether these abnormalities are the primary cause of SIDS, or a secondary symptom.</p>
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Read more:
<a href="https://theconversation.com/what-causes-alzheimers-disease-what-we-know-dont-know-and-suspect-75847">What causes Alzheimer’s disease? What we know, don’t know and suspect</a>
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<p>A <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184958">recent study has revealed</a> promising findings in the quest to find out the cause of these brain chemical abnormalities in SIDS. In this study, some of the SIDS infants were found to have a significant developmental abnormality of another important chemical messenger, “Substance P”, in multiple regions in the brainstem. These regions are intimately related to heart and breathing function and autonomic control. </p>
<p>This means <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184958">abnormal Substance P transmission</a> in the brainstem could result in dysfunction of critical responses to harmful situations, such as a lack of oxygen. So if an infant experiences a life threatening situation during sleep, they <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184958">might not be able</a> to execute the motor responses to protect themselves.</p>
<p>This abnormality could potentially explain why it’s more dangerous for infants to sleep on their front, given it’s been known for many years infants sleeping face down are at greater risk of SIDS. </p>
<p>It’s thought if an infant has this underlying vulnerability in brain chemistry, and breathing becomes compromised by sleeping face down, the infant is then at greater risk of death because they can’t respond in the normal way by lifting their head out of danger.</p>
<h2>What we’re yet to find out</h2>
<p>Unfortunately, there are to date no tests or markers in the body that can help prevent or diagnose SIDS. But researchers from around the world are working towards using what we already know about SIDS and further trying to understand why SIDS occurs in some infants. And if we can find out who is more at risk, we could prevent future deaths with genetic screening for these brain chemical abnormalities. </p>
<p>Identifying a cause might also provide some form of closure for families who are left to make sense of, not only the death of their child, but the heartache that comes with the uncertain diagnosis of SIDS.</p><img src="https://counter.theconversation.com/content/86544/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Fiona Bright receives funding from River's Gift SIDS charity Australia and Red Nose Australia. She is affiliated with River's Gift and Red Nose Australia. </span></em></p>SIDS is diagnosed when no other cause of death is found, but SIDS infants do have some characteristics in common.Fiona Bright, Lecturer, Faculty of Health and Medical Science, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/814832017-08-14T20:16:41Z2017-08-14T20:16:41ZWhat causes depression? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/180309/original/file-20170731-19115-1iwrdim.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">When thinking about what causes depression it's important to remember some depression is a normal mood state. </span> <span class="attribution"><a class="source" href="https://unsplash.com/collections/526331/depressed?photo=5L4XAgMSno0">Benjamin Combs/Unsplash</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>The term and even diagnosis of “depression” can have different meanings and consequences. Depression can be a normal mood state, a clinical disorder, and even a disease.</p>
<p>If your favourite soccer team loses, you might feel emotionally depressed for a few minutes. If you were a player on the team and you brought about the loss, your state of depression and self-criticism might last much longer. Both can be viewed as normal “depressed mood” states.</p>
<p>Such states are common, with <a href="http://journals.sagepub.com/doi/abs/10.3109/00048677909159109">a study of university students finding</a> that 95% of individuals had periods of feeling depressed, being self-critical and feeling hopeless every 6-8 weeks. So we should accept that a “depressed mood” is a universal and common experience. For most, the depressed mood is transient because the person will come to terms with the cause, or its cause will cease to exist over time, or be neutralised in some way. </p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-depression-11447">Explainer: what is depression?</a>
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<p>There’s no precise boundary between “depressed mood” states and “clinical depression”, but differences lie in impairment, symptoms and duration. Clinical depression is associated with distinct impairment (such as “absenteeism” with the individual unable to get to work, or “presenteeism” where the individual gets to work but the depression compromises their performance). Symptoms common in clinical depression include loss of appetite, sleep and libido changes, an inability to be cheered up, an inability to experience pleasure in life and a lack of energy. Clinical depression generally lasts months or years if untreated.</p>
<p>Current formal classification manuals tend to view clinical depression as a single condition simply varying by severity (major depression versus a set of minor depressions, regrettably including normal depressive moods). For the sake of discussing the causes of depression, I’ll look at two distinct types of depression: melancholia and the situational depressions. </p>
<h2>Biological and disease-like depression</h2>
<p>The key “biological” depressive disorder is melancholia. For some 2000 years, this was more viewed as a movement disorder rather than a mood disorder due to it showing “psychomotor disturbance”. This means the individual is slow to move or speak, lacking energy and unable to be cheered up, or agitated - wringing their hands, pacing up and down and repetitively uttering phrases. In addition, those with melancholia lose the capacity to find pleasure in life or be cheered up. They also lack energy and experience appetite and sleep changes.</p>
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Read more:
<a href="https://theconversation.com/back-to-black-why-melancholia-must-be-understood-as-distinct-from-depression-38025">Back to black: why melancholia must be understood as distinct from depression</a>
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<p>A small percentage of those with melancholic depression develop “psychotic depression”. This is where an individual experiences delusions or hallucinations, often of derogatory voices telling them they’re worthless and better off dead, or of pathological guilt. For those with a bipolar disorder, most depressed episodes are melancholic or psychotic depression in type.</p>
<p>Melancholia has a strong genetic contribution, <a href="https://www.ncbi.nlm.nih.gov/pubmed/6466042">with a study quantifying</a> a three times greater history of depression in family members of those with melancholia. If one parent has melancholia, their child has a 10% chance of developing the same; if both parents have melancholia, the chance is approximately 40%.</p>
<p>Once termed “endogenous depression” as it seemed to come from “within” rather than being caused by external stressors, episodes are generally more severe and persistent than would be expected from depression caused by environmental stressors. It doesn’t respond to counselling or psychotherapy and requires medication (most commonly an antidepressant drug but also perhaps other drug types). The psychotic form requires an antipsychotic drug in addition to an antidepressant. </p>
<p>There are a number of differing classes of antidepressants. The SSRIs (selective serotonin reuptake inhibitors) are viewed as <a href="http://www.cambridge.org/catalogue/catalogue.asp?isbn=0521671442">increasing levels of the neurotransmitter serotonin</a> in the brain and so correct the “chemical” disturbance underlying many depressive conditions. However, in melancholia it’s thought that there are also disturbances in other neurotransmitters such as noradrenaline and dopamine. Melancholia is therefore more likely to respond to the broader action antidepressant drugs such as the serotonergic and noradrenergic reuptake inhibitors (SNRIs) and tricyclics (TCAs), with the latter targeting all three implicated neurotransmitters. </p>
<p>In recent years, studies have not only implicated dysregulation in brain chemicals (“neurotransmitters”), but also in brain network circuits in those with melancholia. Disruptions in the circuits linking the basal ganglia (situated at the base of the forebrain and associated with emotion) and the pre-frontal cortex (the brain region implicated in personality expression and social behaviour) <a href="http://www.cambridge.org/catalogue/catalogue.asp?isbn=9781139243544">result in</a> depressed mood, impaired cognition and psychomotor disturbance. These are, in essence, the key features of melancholia. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pubmed/25692565">Brain imaging studies have also identified</a> disrupted function in circuits and networks linking the insula (a brain region associated with awareness of our emotions) to other regions in the frontal cortex. These indicative findings are being progressively advanced by highly technical brain imaging strategies, and so in future years should clarify the multiple functional and structural changes that occur in the brain for those with melancholia.</p>
<p>There’s no “test” to diagnose biological depression, with <a href="https://www.ncbi.nlm.nih.gov/pubmed/7093598">former methods falling out of fashion</a> due to inaccuracy, so diagnosis relies on the doctor identifying its characteristic features, excluding environmental factors and weighting a family history of depression.</p>
<h2>Psychological and social depression</h2>
<p>Non-melancholic depression is generally induced by a social stressor. A diagnosis of “reactive depression” captures a clinical, non-melancholic disorder caused by the individual experiencing a social stressor that impacts and compromises self-esteem. This could be a boyfriend or employer berating a young woman to the point where she feels worthless. </p>
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Read more:
<a href="https://theconversation.com/biology-is-partly-to-blame-for-high-rates-of-mental-illness-in-women-the-rest-is-social-75700">Biology is partly to blame for high rates of mental illness in women – the rest is social</a>
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<p>In many ways, such scenarios are similar to a “normal” depressed mood state, but more severe. Here we would expect the individual to come to terms with or neutralise the stressor, or even spontaneously improve across all clinical parameters after weeks. A chronic environmentally or socially driven non-melancholic depression generally reflects an ongoing stressor that the individual cannot escape. An example would be a wife who lives with a constantly abusive husband, but is unable to leave him due to having a number of young children and no money of her own.</p>
<p>Other non-melancholic disorders are principally driven by psychological or personality-based factors - with actual episodes generally triggered by social stressors. <a href="http://www.cambridge.org/catalogue/catalogue.asp?isbn=0521671442">Research has identified</a> a number of personality styles that put people at risk: </p>
<ol>
<li><p>those with high levels of general anxiety who are at risk of depression because of their worrying, catastrophising propensities, and their tendency to take things too personally</p></li>
<li><p>“shy” people who are often this way due to having been bullied or humiliated in their early years. They often view social interactions with others as threatening in comparison to the safety of their own company</p></li>
<li><p>those who are “hypersensitive” to judgement by others. This could be praise or
feeling (perhaps inappropriately) they are being rejected or abandoned. These people often respond by sleeping more and craving certain foods that may settle their emotional dysfunction</p></li>
<li><p>“self-focused” individuals who are hostile and volatile with others, blame others when things go wrong and prioritise their own needs. When depressed, they tend to show a “short fuse” and create collateral damage for those around them</p></li>
<li><p>those who were neglected or abused in their early years and who therefore have low basic self-worth. They often repeat such cycles of deprivation and abuse in their adult relationships, and so readily become depressed </p></li>
<li><p>perfectionists who are prone to self-criticism and a loss of pride. They may also have a limited range of adaptive strategies to stress.</p></li>
</ol>
<p>There are several brain regions implicated in these non-melancholic mood states and disorders. A key site is the amygdala (an almond-shaped region in the brain that processes emotional reactions) which shows a heightened response when an individual is depressed.</p>
<p>If there is “<a href="http://www.sciencedirect.com/science/article/pii/0091305795021353">chemical</a>” dysfunction in the non-melancholic disorders, <a href="http://jamanetwork.com/journals/jamapsychiatry/fullarticle/211231">serotonin is the most likely neurotransmitter</a> implicated. We suspect serotonin has a role to play but we can’t be sure yet and further studies are needed.</p>
<p>So, we should reject a “one size fits all” model for considering “depression” and instead favour a “horses for courses” model. There are multiple types of depression (normal and clinical), with the latter reflecting differing biological, psychological and social causes and therefore requiring treatments that address the primary causal factor.</p><img src="https://counter.theconversation.com/content/81483/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gordon Parker receives funding from the National Health and Medical Research Council. </span></em></p>Some depression is caused by environmental factors, and some is biological.Gordon Parker, Scientia Professor, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/794092017-06-19T20:00:25Z2017-06-19T20:00:25ZWhat we know, don’t know and suspect about what causes motor neuron disease<figure><img src="https://images.theconversation.com/files/173960/original/file-20170615-23574-lpx29a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some types of MND start with a loss of grip. But what causes this?</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p><em>This is a longer read.</em></p>
<hr>
<p>Since 2014, <a href="https://www.forbes.com/sites/dandiamond/2014/08/29/the-als-ice-bucket-challenge-has-raised-100m-but-its-finally-cooling-off/#4a044fbd5cfb">the ice bucket challenge</a>, which involves people pouring a bucket of icy water over their heads, has raised awareness and much-needed research funds for motor neuron disease. While <a href="http://www.alsa.org/research/research-we-fund/">research</a> for a cure is underway, first we need to know what causes it.</p>
<p>MND affects <a href="https://www.mndaust.asn.au/Documents/Information-resources/MND-Week-background-fact-sheet.aspx">two per every 100,000</a>, or approximately 420,000 people worldwide. It <a href="https://www.mndaust.asn.au/Documents/Information-resources/MND-Week-background-fact-sheet.aspx">occurs in all countries of the world</a>, and does not discriminate based on race, ethnicity or socioeconomic status.</p>
<p>MND is the <a href="https://www.alsmndalliance.org/what-is-alsmnd/">name</a> given to a group of diseases in which the motor neurons that control muscles progressively die. <a href="https://en.wikipedia.org/wiki/Motor_neuron">Motor neurons</a> are cells in the brain and spinal cord that allow us to move, speak, swallow and breathe by sending commands from the brain to the muscles that carry out these functions. </p>
<p>Motor neurons can be divided into either <a href="http://www.medicinenet.com/script/main/art.asp?articlekey=33871">upper motor neurons</a>, which live in the main brain region and project into the brainstem and spinal cord, or <a href="http://www.medicinenet.com/script/main/art.asp?articlekey=33870">lower motor neurons</a>, which reside in the brainstem or spinal cord and directly innervate muscles.</p>
<p>Normally, upper motor neurons transmit signals to lower motor neurons, directing them to make movements. The lower neurons then signal the muscles themselves, controlling normal movements. When the signal is disrupted at some point in the pathway, it affects the ability of muscles to contract and move.</p>
<p>MND is <a href="https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Motor-Neuron-Diseases-Fact-Sheet">classified</a>, in part, by whether the upper or lower neurons are the ones degenerating and dying. In amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease, the most common type of MND, both upper and lower motor neurons are affected. Other types of MND may just affect one or the other, and each condition has slightly different symptoms.</p>
<p>Disease of the <a href="https://www.ole.bris.ac.uk/bbcswebdav/institution/Faculty%20of%20Health%20Sciences/MB%20ChB%20Medicine/Year%203%20Medicine%20and%20Surgery%20-%20Hippocrates/Neurology%20-%20Presenting%20complaints/page_29.htm">upper motor neurons</a> causes stiffness of muscles (spasticity), muscle weakness and exaggerated tendon reflexes, such as knee jerks. But if the <a href="https://www.ole.bris.ac.uk/bbcswebdav/institution/Faculty%20of%20Health%20Sciences/MB%20ChB%20Medicine/Year%203%20Medicine%20and%20Surgery%20-%20Hippocrates/Neurology%20-%20Presenting%20complaints/page_29.htm">lower are primarily affected</a>, muscles no longer receive innervation, causing them to weaken and waste away (atrophy), while also developing uncontrollable twitches (fasciculations) and losing their reflex responses.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=770&fit=crop&dpr=1 600w, https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=770&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=770&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=968&fit=crop&dpr=1 754w, https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=968&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/174359/original/file-20170619-17336-12nlryl.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=968&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">US baseballer Lou Gehrig was diagnosed in his 30s, and his specific type of MND became known as Lou Gehrig’s disease.</span>
<span class="attribution"><span class="source">Wikimedia Commons</span></span>
</figcaption>
</figure>
<p>If both are affected, symptoms <a href="http://brainfoundation.org.au/disorders/motor-neurone-disease">usually start mildly</a> with a loss of grip, a slurred word or stumbling while walking. The disease then <a href="https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Motor-Neuron-Diseases-Fact-Sheet">spreads</a> as motor neurons continue to die, affecting all <a href="https://en.wikipedia.org/wiki/Skeletal_muscle">skeletal muscles</a>, which are under control by the central nervous system. This leads to muscle weakness and atrophy on both sides of the body. </p>
<p>Muscles become spastic, spasm and display uncontrollable twitches. In <a href="https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Motor-Neuron-Diseases-Fact-Sheet">75% of individuals</a>, muscles of the face and throat that control speech, swallowing and chewing also become weak and waste away, leading to slurred or nasal speech and difficulty eating. Over time, the disease spreads to muscles of the diaphragm and chest, leading to an inability to breathe without mechanical support, and eventually, death.</p>
<p>Symptoms of MND can vary from person to person, and the rate of progression can also differ widely between individuals. However, it does progress in all cases. For the majority of people, this period of disease progression is quite rapid, with most living <a href="https://www.alsmndalliance.org/what-is-alsmnd/">two to five years</a> after the onset of symptoms. Only <a href="http://www.alsa.org/about-als/facts-you-should-know.html">20% of patients live for five years</a>, 10% for ten years and 5% for 20 years or more. One famous <a href="https://www.scientificamerican.com/article/stephen-hawking-als/">notable exception</a> is the theoretical physicist Stephen Hawking, who was first diagnosed at age 21 and is now 75 years old, meaning he has lived with the condition for over 50 years.</p>
<p>The cause of most cases of MND is currently unknown, although multiple hypotheses have been put forward. This is currently an area of major research throughout the world.</p>
<h2>Genetic causes</h2>
<p>A small number of cases of MND (<a href="http://www.alsa.org/research/focus-areas/genetics/">5-10%)</a> are inherited from family and can be attributed to a specific <a href="https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation">genetic mutation</a>, or an alteration in the sequence of DNA. It’s estimated that, currently, about <a href="http://www.alsa.org/research/focus-areas/genetics/">60% of the genes</a> associated with familial MND have been identified. For most MND genes, an individual only needs to inherit one copy of the mutated gene to cause the disease.</p>
<p>The first gene mutation to be discovered in MND was one called “SOD1”, in 1993. <a href="http://www.alsa.org/research/focus-areas/genetics/sod1.html">SOD1 mutations</a> account for about 10-20% of cases of familial MND (and 1-2% of sporadic cases). While it’s unclear exactly how changes in this gene lead to MND, it’s thought that it takes on a toxic property, leading to damage in the brain cells and, eventually, death of motor neurons.</p>
<p>Another important gene implicated in familial MND is “C9orf72”, which was found in 2011 and is known to be the most common genetic cause of MND. <a href="http://www.alsa.org/research/focus-areas/genetics/">Mutations in this gene</a> account for 25-40% of familial MND (and 7% of sporadic cases). This gene has also been shown to account for 25% of cases of another neurodegenerative disease, a type of dementia called frontotemporal dementia. </p>
<p>This gene contains abnormal repetitions in the DNA code, called <a href="http://www.als.net/news/what-is-c9orf72-what-are-we-doing-about-it/">repeat expansions</a>. While healthy individuals have up to 30 of these repetitions, individuals with MND, frontotemporal dementia or both can have hundreds or even thousands of repeats. But it’s still a <a href="http://www.sciencedirect.com/science/article/pii/S0006899316301974">matter of debate</a> how this could lead to the development of the disease, with several potential mechanisms put forward, and further research needed.</p>
<p>In addition to these two major genetic discoveries, <a href="http://www.alsa.org/research/focus-areas/genetics/">several other genes</a> have been implicated (NEK1, TDP43, FUS and UBQLN2) that appear to play a smaller role in the number of cases of MND they cause. </p>
<p>It’s important to remember, though, that genetic mutations play a small role in most cases of MND. While 5-10% of cases are familial, with a clear genetic link, the other 90-95% of cases are sporadic and are likely to be due to a complex interaction of genetic risk factors and environmental variables.</p>
<h2>Age and gender</h2>
<p>Non-genetic factors that may contribute to the development of MND have been extensively studied over the years, with several potential causes emerging. One of the major risk factors for MND is advancing age. MND is rare before the age of 40, with an <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">average age of onset</a> of 58-63 years for sporadic MND and 40-60 years for familial MND. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">Males</a> are also more likely than females to have MND, but we don’t know why.</p>
<h2>Lifestyle causes</h2>
<p>A number of lifestyle risk factors for MND have also emerged. <a href="https://www.ncbi.nlm.nih.gov/m/pubmed/21320987/">Smoking</a> is known to increase the risk of MND, with one study indicating smokers were 42% more likely to be diagnosed with MND, while former smokers had a 44% higher risk. </p>
<p>Certain <a href="https://www.ncbi.nlm.nih.gov/pubmed/15529299">dietary factors</a>, such as higher intake of antioxidants and vitamin E, have been shown, at least in some studies, to decrease the risk of MND.</p>
<p>Interestingly, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">increased physical fitness and lower body mass index (BMI)</a> have been shown to be associated with a higher risk of MND. The diagnosis of baseballer Lou Gehrig led scientists to theorise that <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">strenuous physical activity and excessive use of muscles</a> could contribute to the development of MND. </p>
<p>While evidence for this has been inconsistent, an increased risk for MND has been demonstrated among professional soccer players, and MND patients have <a href="https://mndresearch.wordpress.com/2013/12/08/physical-activity-and-mnd-is-there-a-link/">higher levels of vigorous physical activity</a> compared to individuals without MND. Other factors, however, may account for this relationship, such as <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2239342/">repeated head injuries</a>, another purported cause of MND.</p>
<p>A <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">number of occupations</a> have also been found to be associated with increased risk of MND, including electrical workers, farmers, house painters and military personnel. Other individuals exposed to electromagnetic fields, certain chemicals, pesticides and heavy metals, such as lead, manganese, iron and selenium, during the course of their work are also at risk. </p>
<p>But it’s still unclear how <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">exposure to these toxins</a> may lead to the development of MND, and not all studies in this area have been consistent in demonstrating increased risk. Another issue with these toxin exposure studies is that many rely on self-reports, with individuals having to recall their past exposures. This can lead to <a href="http://www.alsa.org/research/focus-areas/environmental-factors/">recall bias</a>, where people with the disease are more likely to report a past exposure, leading to an over-inflation of risk.</p>
<h2>Other illnesses</h2>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">Exposure to viruses</a> has also been cited as a potential cause of MND. Polio virus, for example, can infect motor neurons, and may be linked to later weakening of these neurons. </p>
<p><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723705/">Retroviruses</a>, such as HIV, have also been shown to be potentially linked to the development of MND. </p>
<p>In addition to viruses, other medical conditions may also be linked to an increased risk of MND. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334292/">Type I diabetes</a> has been shown to be associated with a threefold increase in risk (although, interestingly, <a href="http://archneur.jamanetwork.com/article.aspx?articleid=2299316">Type II diabetes</a> was associated with a lower risk for MND). </p>
<p>Consistent with <a href="http://journal.frontiersin.org/article/10.3389/fphar.2014.00157/full">other neurodegenerative diseases</a>, such as Alzheimer’s and Parkinson’s disease, <a href="https://www.sciencedaily.com/releases/2012/06/120605121704.htm">increased inflammation</a> has also recently gained attention as a potential cause of MND. One study showed that, in MND, inflammatory cells called macrophages can ingest motor neurons.</p>
<h2>What makes treatment so complicated?</h2>
<p>Despite decades of research, there is only one treatment currently approved for MND, a drug called <a href="http://alsworldwide.org/research-and-trials/article/rilutek-riluzole">riluzole (Rilutek)</a>, first approved by the US Food and Drug Administration in 1995. This aims to reduce the release of the neurotransmitter <a href="http://web.alsa.org/site/PageServer?pagename=ALSA_Glutamate">glutamate</a> from motor neurons, which was once thought to drive the death of these neurons. But the drug doesn’t reverse nerve damage or muscle weakness caused by the disease, and only prolongs life for about three months. </p>
<p>Aside from riluzole, most current treatments such as muscle relaxants or physical therapy attempt to maintain patient quality of life.</p>
<p>In May 2017, the US approved the first new treatment for MND in 22 years, a drug called <a href="http://www.alsa.org/news/media/press-releases/approval-of-new-als-drug-050417.html">Radicava</a> (edaravone), which is expected to be on the US market by August 2017. This drug, originally developed for the treatment of stroke in Japan, was approved in 2015 for the treatment of MND in Japan and South Korea. </p>
<p>The drug aims to prevent <a href="http://www.drugdevelopment-technology.com/projects/radicava-edaravone-for-the-treatment-of-amyotrophic-lateral-sclerosis-als">damage of neurons</a>, and the company that developed it reports it can slow the physical decline of MND patients by <a href="http://www.alsa.org/news/media/press-releases/approval-of-new-als-drug-050417.html">33%</a>. </p>
<p>The drug, which is not a cure and only slows disease progression, is stunningly expensive, <a href="http://www.alsa.org/research/radicava/radicava-frequently-asked-questions.html">costing nearly US$150,000</a> a year. And patients in the last stage of the clinical trial that led to approval in the US were only followed up to <a href="http://www.alsa.org/research/radicava/radicava-frequently-asked-questions.html">six months</a>, so the long-term benefits of the drug are unknown. The drug is not yet approved for use in Australia.</p>
<p>The causes of MND are many and complex. This is further complicated by the fact we don’t know what ultimately causes the death of motor neurons when someone has MND. If we could find this out, then we may well be on the way to developing more effective, and perhaps even curative, therapies for the disease.</p><img src="https://counter.theconversation.com/content/79409/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lyndsey Collins-Praino receives funding from the Neurosurgical Research Foundation and the University of Adelaide Commercial Accelerator Scheme.</span></em></p><p class="fine-print"><em><span>Viythia Katharesan 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>While research for a cure for MND is underway, first we need to know what causes it.Lyndsey Collins-Praino, Senior Lecturer in School of Medicine, University of AdelaideViythia Katharesan, Lecturer in the School of Medicine, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/758472017-06-01T20:13:50Z2017-06-01T20:13:50ZWhat causes Alzheimer’s disease? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/171067/original/file-20170525-23232-1rvtxjj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A hallmark of Alzheimer's disease is gradual deterioration of memory.</span> <span class="attribution"><a class="source" href="https://unsplash.com/search/memories?photo=7sPg5OLfExc">Roman Kraft/Unsplash</a></span></figcaption></figure><p><em>This is a long read.</em></p>
<hr>
<p>Alzheimer’s disease is the most common form of dementia, which is an <a href="https://www.fightdementia.org.au/about-dementia/what-is-dementia">umbrella term</a> used to describe general loss of memory, thinking skills and other day-to-day functions (such as cooking, paying bills, cleaning and even dressing). </p>
<p>A hallmark of <a href="https://www.fightdementia.org.au/about-dementia/types-of-dementia/alzheimers-disease">Alzheimer’s disease</a> is gradual deterioration of memory. But it is a biological disease, which means that, besides seeing outwards symptoms such as memory loss, we can also measure the breakdown that occurs in the brain as a consequence of disease progression.</p>
<p>Alzheimer’s is identified by the presence of two proteins in the brain, known as <a href="http://www.alz.org/braintour/plaques.asp">amyloid</a> and <a href="http://www.alz.org/braintour/tangles.asp">tau</a>. Amyloid proteins <a href="http://www.nature.com/nrm/journal/v15/n6/fig_tab/nrm3810_T1.html">aggregate into sticky clumps</a> called “plaques”. And tau proteins tend to form “tangles”. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=773&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=773&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=773&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=972&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=972&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171073/original/file-20170525-23234-2af3w.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=972&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Dementia is an umbrella term used to describe general loss of memory, thinking skills and other day-to-day functions.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>While it is still unclear how amyloid and tau interact to cause the disease, these plaques and tangles seem to <a href="https://www.nia.nih.gov/alzheimers/publication/2011-2012-alzheimers-disease-progress-report/primer-alzheimers-disease-and">play a role in blocking messages</a> between brain cells. They induce inflammation wherever they accumulate, and may gum up the transportation system that helps clear the brain of debris.</p>
<p>Ultimately, the disease causes the death of brain cells. This results in an overall <a href="http://www.alzforum.org/news/research-news/brain-changes-speak-volumes-about-normal-aging-and-dementia">shrinking of brains</a> of patients with Alzheimer’s disease. Currently, while people can be diagnosed with <em>probable</em> Alzheimer’s disease, a <a href="http://www.alz.org/professionals_and_researchers_diagnosing_alzheimers.asp">reliable diagnosis</a> can only be made postmortem by searching for the tau and amyloid proteins. </p>
<p>Brain imaging techniques mean we can determine levels of these proteins in people who are still alive. However, while abnormal levels of the proteins in a healthy brain can increase the chances of developing Alzheimer’s disease, <a href="https://www.theatlantic.com/health/archive/2017/02/alzheimers-amyloid-hypothesis/517185/">this outcome is not always guaranteed</a>.</p>
<h2>Amyloid and tau</h2>
<p>Knowing the biology and mechanisms behind the genesis of Alzheimer’s disease is <a href="https://www.scientificamerican.com/article/why-alzheimer-s-drugs-keep-failing/">critical for the success</a> of future <a href="https://www.fightdementia.org.au/research/trials">clinical trials</a>. </p>
<p>The accumulation of amyloid protein in the brain is mainly found in Alzheimer’s disease, along with the way it spreads. Around 30% of healthy adults aged over 60 have high amyloid concentrations in their brain. It <a href="https://www.ncbi.nlm.nih.gov/pubmed/23477989">takes about 20 years</a> before people in this group start to display dementia symptoms such as memory loss. </p>
<p><a href="http://www.sciencemag.org/news/2016/05/tau-protein-not-amyloid-may-be-key-driver-alzheimer-s-symptoms">Tau</a>, on the other hand, is found across a wide range of conditions. These include Alzheimer’s disease, <a href="http://www.alz.org/dementia/chronic-traumatic-encephalopathy-cte-symptoms.asp">chronic traumatic encephalopathy</a> (a neurodegenerative disease linked to repetitive concussions and brain trauma), <a href="https://ghr.nlm.nih.gov/condition/niemann-pick-disease">Niemann-Pick</a> disease (a heritable disease that affects fat metabolism in cells) and <a href="http://www.alz.org/dementia/down-syndrome-alzheimers-symptoms.asp">Down Syndrome</a>. </p>
<p>Animal studies suggest a range of <a href="http://www.alzforum.org/news/research-news/more-evidence-distinct-tau-strains-may-cause-different-tauopathies">tau “strains”</a> exist, like “<a href="http://www.iflscience.com/health-and-medicine/new-prion-disease-raises-questions-about-whether-alzheimer-s-and-parkinson-s/">prions</a>”. Prions are small, infectious and <a href="http://memory.ucsf.edu/cjd/overview/prions">abnormally twisted (or misfolded) proteins</a> that can affect the brain by causing normally-functioning proteins to turn into diseased copies. </p>
<p>This, and the fact tau proteins are present across a range of conditions, makes it hard to determine the tau strains specific to Alzheimer’s disease.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171070/original/file-20170525-23245-1nbxqkg.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>
<figcaption>
<span class="caption">The accumulation of amyloid protein in the brain is found in Alzheimer’s disease.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>We are <a href="http://www.alzforum.org/news/conference-coverage/next-generation-tau-pet-tracers-strut-their-stuff">still in the early stages</a> of studying tau in the brain. So far, <a href="https://www.newscientist.com/article/2082820-toxic-form-of-tau-protein-foils-memory-formation-in-alzheimers/">findings suggest</a> increased tau in memory-related areas of the brain is closely related to memory decline, even in healthy older adults.</p>
<p>But how amyloid plaques and tau tangles interact to influence the onset of Alzheimer’s disease remains a puzzle for researchers. Amyloid first begins to <a href="http://www.nationalacademies.org/hmd/%7E/media/353F303C759D406C8B893618DF9260F7.ashx">appear in the outer edges of the brain</a> (what we call the “cortex”), which is where higher-order cognitive functions are located. </p>
<p>Tau <a href="https://news.usc.edu/91957/researchers-pinpoint-brain-region-as-ground-zero-of-alzheimers-disease/">first appears deep in the brain</a>, very early in the areas of the brain stem related to sleep, arousal and vigilance, and subsequently in <a href="http://www.massgeneral.org/News/pressrelease.aspx?id=1861">memory centres</a> like the entorhinal cortex and hippocampus. </p>
<p>Interestingly, while high levels of amyloid plaques can be seen in healthy older adults, the plaques do not seem to affect cognitive function to the same degree as tau tangles. This has led some researchers to suggest that <a href="http://www.sciencemag.org/news/2016/05/tau-protein-not-amyloid-may-be-key-driver-alzheimer-s-symptoms">amyloid is necessary, but not sufficient by itself,</a> to result in dementia symptoms.</p>
<p>Another big question is which comes first, amyloid or tau? <a href="https://www.ncbi.nlm.nih.gov/pubmed/22002422">A seminal autopsy study</a> of 2,332 brains aged between ten and 90 years old showed tau appears as early as in people’s 20s and will keep accumulating across the lifespan, even in healthy people, until death. </p>
<p>One working hypothesis is that once amyloid appears on the scene, <a href="http://www.alzforum.org/news/research-news/brain-imaging-suggests-av-unleashes-deadly-side-tau">tau will accelerate its misfolding</a>, which will <a href="http://www.alzforum.org/news/conference-coverage/tau-pet-studies-agree-tangles-follow-amyloid-precede-atrophy">promote more amyloid and brain cell death</a>. A <a href="http://www.alzforum.org/news/conference-coverage/amyloid-and-neurodegeneration-have-different-underlying-genetics">commonly used analogy</a> is that tau represents the “gun” and amyloid the “bullet”.</p>
<h2>The role of genes</h2>
<p>So how does amyloid appear on the scene in the first place? <a href="http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers-genes/art-20046552">Genes</a> may play an important role. </p>
<p>If you inherit the Alzheimer’s disease gene from only one parent and still get the disease, it is known as <a href="http://www.dian-info.org/">dominantly inherited Alzheimer’s disease</a>, or familial or autosomal dominant Alzheimer’s disease. Here, <a href="http://www.alzforum.org/early-onset-familial-ad/overview/what-early-onset-familial-alzheimer-disease-efad">mutations in one of three genes</a> (amyloid precursor protein, presenilin 1 or presenilin 2) cause a rapid accumulation of amyloid in the brain. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=561&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=561&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=561&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=705&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=705&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171072/original/file-20170525-23232-1odlb05.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=705&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Familial Alzheimer’s disease results in severe loss of brain volume and memory at a devastatingly young age.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>This results in severe loss of brain volume and memory at a devastatingly young age (approximately 40 years old). Dominantly inherited Alzheimer’s disease is rare in the <a href="http://www.dian-info.org/institutions_Australia.htm">Australian population</a>, accounting for only 1% of all Alzheimer’s disease cases. </p>
<p>However, people who carry these mutations have a 99.9% chance of developing the disease, and a 50% chance of passing the mutations to their children.</p>
<p>Amyloid also accumulates with age. <a href="http://www.alz.org/alzheimers_disease_causes_risk_factors.asp">Age is the greatest risk factor</a> for sporadic Alzheimer’s disease (which accounts for 99% of Alzheimer’s disease cases). As the average age of onset for sporadic Alzheimer’s disease is 80, it is sometimes called late-onset Alzheimer’s disease. </p>
<p>The strongest genetic risk factor for sporadic Alzheimer’s disease is a gene called “<a href="https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-genetics-fact-sheet">apolipoprotein E (APOE) ε4</a>”, and emerging research suggests this increased risk may be due to inefficiencies in clearing amyloid from the brain. The ε4 gene is not itself predictive or diagnostic of Alzheimer’s disease. Only 40% of patients carry the ε4 gene, and many carriers do not develop the disease. </p>
<h2>Diet, diabetes and obesity</h2>
<p>Diet has long been seen as a <a href="https://www.thl.fi/fi/web/thlfi-en/research-and-expertwork/projects-and-programmes/finger-research-project">potential preventive factor</a> against dementia risk. However, the effects of dietary supplements (such as omega-III fatty acids) and adherence to specific diets (such as the <a href="http://www.alz.org/brain-health/adopt_healthy_diet.asp">Mediterranean diet</a>) <a href="http://www.cochrane.org/CD009002/DEMENTIA_omega-3-fatty-acids-treatment-dementia">have not been entirely convincing</a>. Evidence is yet to definitively show any particular diet or supplement has a substantial effect on reducing dementia risk or even memory decline.</p>
<p>Some evidence <a href="http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/diabetes-and-alzheimers/art-20046987">links type 2 diabetes</a> with risk of Alzheimer’s disease. But there is stronger support for an association between <a href="http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00033-9/abstract">weight</a> (body mass index, or BMI) and dementia. </p>
<p>Higher BMI (over 40) is linked with greater risk of premature death and increased risk of dementia compared with people of normal weight. Evidence also suggests people with lower BMI (under 18) in midlife and beyond have a significantly increased risk of dementia compared to those in healthy ranges (18.5 to 25). </p>
<p>A recent paper suggests <a href="http://www.alzforum.org/news/research-news/no-being-thin-does-not-lead-alzheimers-disease">low BMI does not cause Alzheimer’s disease</a> but that lower BMI may arise as a result of brain changes, such as appetite suppression, that occur early due to the disease.</p>
<p>Some studies have also suggested Alzheimer’s disease can be known as <a href="http://www.newyorker.com/magazine/2017/04/03/is-fat-killing-you-or-is-sugar">“type 3” diabetes</a>, as patients show poorer energy consumption in the brain. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769828/">Some researchers suggest this is driven by insulin resistance</a>. However, this a controversial area of research and study results to this effect need independent replication.</p>
<h2>Physical activity</h2>
<p>Studies now suggest exercise <a href="http://www.health.harvard.edu/mind-and-mood/can-you-grow-new-brain-cells">can increase neuroplasticity</a> in the brain. Neuroplasticity refers to the brain’s ability to form new connections between nerve networks, particularly in memory centres.</p>
<p>Breaking a sweat may <a href="http://www.sciencemag.org/news/2013/10/how-exercise-beefs-brain">increase levels of a protein</a> called the brain-derived neurotrophic factor, which induces the growth and survival of brain cells. Just as protein shakes may help muscles grow after exercise, this protein may <a href="http://www.huffingtonpost.com/paul-spector-md/your-brain-the-new-users-_b_9608948.html">strengthen the brain’s ability</a> to cope with injury or disease, not just Alzheimer’s. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171074/original/file-20170526-23230-6dwe6.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">Exercise can help the brain repair nerve connections.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<h2>Sleep</h2>
<p>Sleep <a href="http://www.npr.org/sections/health-shots/2016/01/04/460620606/lack-of-deep-sleep-may-set-the-stage-for-alzheimers">problems are common</a> in patients with Alzheimer’s disease. It is likely brain regions that regulate sleep-wake cycles deteriorate, resulting in sleep disruptions. </p>
<p><a href="http://www.alzforum.org/news/research-news/sleep-and-brain-cleansing-fresh-insights-regulation-and-disruption">Animal studies</a> suggest disrupted sleep may result in increased amyloid accumulation. This is because a waste-draining system (known as the glymphatic system proposed to be involved in clearing amyloid from the brain) is <a href="http://www.cell.com/neuron/abstract/S0896-6273(17)30088-0">significantly more active</a> when people are asleep, and less effective during sleep disruption. </p>
<p>While research into the mechanisms behind sleep and amyloid clearance is still in the early stages, mounting evidence supports the idea sleep disturbances, or <a href="https://www.bumc.bu.edu/busm/2017/02/23/prolonged-sleep-may-predict-dementia-risk/">abnormal sleeping patterns</a>, may be an early <a href="https://www.researchgate.net/profile/Bryce_Mander/publication/304191436_Sleep_A_Novel_Mechanistic_Pathway_Biomarker_and_Treatment_Target_in_the_Pathology_of_Alzheimer's_Disease/links/5775841b08ae4645d60bad5e.pdf">indicator of Alzheimer’s disease</a>. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=882&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=882&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=882&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1109&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1109&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171075/original/file-20170526-23230-id3l9a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1109&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Sleep disturbance may be an early indicator of Alzheimer’s disease.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<h2>Mood</h2>
<p>Earlier-life depression has been associated with <a href="https://newoldage.blogs.nytimes.com/2013/05/01/does-depression-contribute-to-dementia/?_r=0">a doubled risk of developing dementia</a>. Recent <a href="http://www.neurology.org/content/88/4/371.short">evidence also suggests</a> anxiety, stress and elevated cortisol (stress-hormone) levels may play a role. </p>
<p>While the mechanisms explaining how mood might increase dementia risk remain unclear, <a href="http://www.nature.com/nrneurol/journal/v7/n6/abs/nrneurol.2011.60.html">studies suggest</a> symptoms of anxiety or depression may be associated with factors that increase your risk of vascular conditions such as heart disease and stroke. </p>
<p>They have also been associated with increasing levels of amyloid in the brain, and increased inflammation.</p>
<h2>Cognitive reserve or resilience</h2>
<p>Some people with high amyloid in their brains do not develop Alzheimer’s disease. It is suggested these people have “cognitive reserve”, which makes them able to <a href="https://academic.oup.com/brain/article/137/4/1167/371918/Compensatory-mechanisms-in-higher-educated">better compensate</a> for, or be more resilient to, increasing levels of disease in the brain. </p>
<p>This term “cognitive reserve” refers to any psychological and social factors (such as <a href="http://www.alzforum.org/news/research-news/cognitive-reserve-more-evidence-it-prevents-neurodegeneration">higher levels of education, occupational attainment or intelligence</a>) that could increase one’s chances of compensating for disease burden.</p>
<p>However, other research suggests individuals with cognitive reserve are also more likely to exhibit a <a href="http://www.neurology.org/content/75/11/990.short">sudden and precipitous drop</a> in memory performance at a later stage, unlike the “slow and steady” decline that is characteristic of most Alzheimer’s disease cases. As such, while cognitive reserve may be protective to a degree, it may simply delay disease onset.</p>
<h2>Preventing Alzheimer’s disease</h2>
<p>While a <a href="http://www.sciencemag.org/news/2017/02/another-alzheimers-drug-flops-pivotal-clinical-trial">cure continues to elude us</a>, many Alzheimer’s experts now realise <a href="http://news.harvard.edu/gazette/story/2017/04/harvard-researchers-plot-early-attack-against-alzheimers/">early diagnosis and intervention</a> is key to stopping the disease in its tracks. </p>
<p>If brain shrinkage has already begun, removing amyloid from the brain is unlikely to be effective. Recent <a href="http://www.sciencemag.org/news/2016/03/why-big-change-lilly-s-alzheimer-s-trial-not-evidence-its-drug-has-failed-again">clinical trials</a>, in which amyloid plaques were removed from the brains of Alzheimer’s disease patients, showed cognitive performance and clinical symptoms did not drastically improve over the course of the trial. </p>
<p>Clinical trials experts are <a href="http://www.tedmed.com/speakers/show?id=6607">turning their gaze</a> to earlier stages in the disease trajectory. For instance, <a href="https://www.florey.edu.au/alzheimers-disease">Australian researchers are recruiting participants</a> for a study that will test drugs that aim to remove amyloid in healthy older adults with high levels of amyloid plaques.</p>
<p>Additionally, we and other scientists are trying to understand factors that contribute to amyloid accumulation, so it can be stopped before it even starts. </p>
<p>This involves studying middle-aged adults, and following them over a long time to determine what combinations of genetic and environmental factors put people at risk of Alzheimer’s disease, or protect them against it. If you’d like to be a part of such a study in middle-aged Australians, you can head to the <a href="https://www.healthybrainproject.org.au/">Healthy Brain Project</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/171076/original/file-20170526-23260-6jor39.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">Engaging your brain can be helpful in reducing dementia risk.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>While the brain-training sector is worth millions of dollars annually, there is <a href="https://www.theatlantic.com/science/archive/2016/10/the-weak-evidence-behind-brain-training-games/502559/">no convincing evidence</a> that brain training (computerised programs aimed at improving your memory through games and puzzles) can <a href="https://www.scientificamerican.com/article/brain-training-doesn-t-make-you-smarter/">result in better cognitive abilities</a> in everyday life. </p>
<p>But maintaining physical, social and brain health is an <a href="https://www.theguardian.com/society/2015/mar/12/dancing-sudoku-fish-and-fruit-the-keys-to-a-mentally-alert-old-age">important component of reducing dementia risk</a>, which all Australians can implement in their daily lives. Learning a new language, picking up bridge, travelling and going back to study are ideal examples as they incorporate brain challenges and increase social engagement, which are both important for dynamically engaging the brain.</p><img src="https://counter.theconversation.com/content/75847/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Yen Ying Lim receives funding from the National Health and Medical Research Council, the Australian Research Council, and the Alzheimer's Association. </span></em></p><p class="fine-print"><em><span>Rachel Buckley receives funding from the National Health and Medical Research Council, the Australian Research Council and the Brain Foundation. </span></em></p>Alzheimer’s disease is the most common form of dementia, but treatments are still far from successful in clinical trials. Here is what we know about the disease, and what is yet to be uncovered.Yen Ying Lim, Research Fellow, Florey Institute of Neuroscience and Mental HealthRachel Buckley, Research Fellow, Harvard Medical School, Research Fellow, Florey Institute of Neuroscience and Mental HealthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/575792016-04-14T07:01:28Z2016-04-14T07:01:28ZWhat causes Parkinson’s disease? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/118639/original/image-20160414-22075-1cr08pm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Motor symptoms of Parkinson's include tremors, stiffness and slowness or loss of spontaneous movement.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/79519692@N00/231180076/in/photolist-mqRMo-7RyWYU-7LtkKX-6p5wTX-aoiRqJ-8hZWGu-D7RaZi-6GHET-DUjfpZ-Ba7N7x-AsJZR3-acQhgV-hsAvvp-68MVC-bnYakX-pALEDN-pDJRmJ-gKpdQk-p19gmW-pZLEbh-beS3gt-onnXYp-7gSTSt-eobJgL-pQUUdQ-oBXnDx-8vqXno-8k9ekD-cF4PXh-eg99jP-7pGmGk-8P3SwX-i1Tip-JVZFK-6tBJaX-7Z6yJz-afjNJ-doJdk-67j9Dg-5Epx4V-tL7a7G-4N7hvv-2dK3NE-5miJj1-aKtnk-bmAHW7-aDBUvk-6rPqC-h1GgW-sbnZCe">Lisa/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Parkinson’s disease is the second-most-prevalent neurodegenerative condition in Australia, with an estimated 70,000 Australians living with the disease. Because of its complex and debilitating nature, Parkinson’s is a great burden on its sufferers and a great <a href="http://www.aihw.gov.au/publication-detail/?id=6442467990">cost</a> to society.</p>
<p>Key motor symptoms include tremors, rigidity and stiffness, slowness or loss of spontaneous movement, and poor balance and co-ordination. Non-motor symptoms can be equally debilitating and include dementia, constipation, pain, sleep disturbance, dizziness when you stand up, and sexual dysfunction. Not all people with Parkinson’s will experience all of these symptoms; there is considerable variability in the severity of symptoms among patients, breadth of symptoms, speed of decline, and responsiveness to therapy. </p>
<p>Currently, there is no cure or drug to slow the underlying disease progression. However, there are now multiple surgical therapies and medicines that can be very effective in managing the motor symptoms of the disease. </p>
<p>There are some known causes of Parkinson’s disease, but these are the exception. The underlying causes of sporadic Parkinson’s are unknown and likely influenced by a number of risk factors – molecular, genetic, behavioural and environmental. </p>
<h2>Known risk factors</h2>
<p><strong>Ageing</strong></p>
<p>Advancing age is the biggest risk factor for Parkinson’s disease. However, not everyone who ages develops Parkinson’s (only around 1-2%) and not everyone who has Parkinson’s is of advanced age (approximately 20% of cases begin before age 60). </p>
<p>It is likely ageing increases the vulnerability of the brain to the degeneration seen with Parkinson’s. Fundamental processes of the cell, such as mitochondrial activity (energy production) and protein degradation, fatigue with age and have been identified as factors involved in cell death leading to the symptoms observed in Parkinson’s. </p>
<p>Iron also accumulates in the brain with age, and especially in people with Parkinson’s. Too much iron can cause cell death by <a href="http://www.ncbi.nlm.nih.gov/pubmed/12666096">oxidative stress</a> – a rusting-type chemical reaction. In fact, rare genetic causes of brain iron elevation often present as Parkinson’s. </p>
<p><strong>Genetics</strong></p>
<p>Approximately 15% of individuals with Parkinson’s have a family history of the disease, which is one of the greatest risk factors. For most cases, however, the genetic contribution is complex. Familial mutations can cause Parkinson’s and account for around 5% of cases. </p>
<p>There are 18 chromosomal gene locations that have been named “PARK” (PARK1-18) because of their link to Parkinson’s. However, mutations in only six genes have been unequivocally shown to cause the disease. Scientists are still trying to determine the functions of these genes and how they interact normally compared to in the diseased state.</p>
<p>Variants in other genes have been shown to increase the risk of Parkinson’s, yet not everyone with these variants develops Parkinson’s. This shows the complex genetic and environmental interactions that underlie the disease.</p>
<p><strong>Toxins</strong></p>
<p>In 1983, a group of injecting drug users injected drugs contaminated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine), <a href="http://content.time.com/time/magazine/article/0,9171,141542,00.html">resulting in the development of Parkinson’s symptoms</a>. MPTP is a synthetic chemical compound with a similar chemical structure to the herbicide paraquat.</p>
<p>Paraquat and especially MPTP are used routinely in laboratories to induce Parkinson’s in rodents. Rotenone is an organic pesticide that also causes Parkinsonian neurodegeneration in rodents. Historical exposure to pesticides, especially paraquat and rotenone, has been repeatedly associated with increased risk of Parkinson’s in studies throughout the world. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/118649/original/image-20160414-4676-8ierbz.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>
<figcaption>
<span class="caption">Pesticides are used to give lab rats Parkinson’s.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/jz909/1450513463/in/photolist-3dbg7P-aYJmUR-gdHXEr-4otNGD-nKk49a-o2wq88-bkaH9d-jZtpkk-71EWJx-6pxbhW-nKm11T-9ztKDr-7Zskpt-o2GzZo-FqB8c-pm4ZeY-bkaHgq-hKwMX1-boxv7T-dpuBXG-oVnd6P-bsD2eD-8aXcTA-8aXcP5-3v3yx-6dkuDb-ce7RZw-Nt5QP-6QKkBc-nKkc9E-52LCHk-NYaqJ-2AhCW9-8wQE8x-ds1MuW-ds1MwS-ds1MvU-3HRSHZ-nrqASz-jgp5ru-93nrci-5mEtvZ-pPtEg6-e6EQGQ-23666p-9BJi2j-p7wBdB-kkxxv-5wCTgg-7k9FWP">Jetsandzeppelins/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>A <a href="http://www.ncbi.nlm.nih.gov/pubmed/11022853">meta-analysis</a> reported pesticide exposure was associated with increased Parkinson’s risk with an odds ratio of 1.94. This means persistent exposure to pesticides is associated with almost doubling of the risk for Parkinson’s. It must be clarified that this would only increase the risk from 1-2% to 2-4% in those aged over 50. </p>
<p>Paraquat is a widely used herbicide, while the use of rotenone has declined significantly throughout the world. Farming practices have changed dramatically over many years. It is possible that the increased risk of Parkinson’s associated with pesticides reflects the use of these and other chemicals in a time when they were handled less safely. </p>
<p><strong>Metals</strong></p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/16325915">Manganism</a> is a condition with symptoms that resemble Parkinson’s and is caused by chronic exposure to the metal manganese. Animal experiments have shown that iron exposure in infancy is associated with Parkinsonian neurodegeneration later in life. <a href="https://www.researchgate.net/profile/Monique_Breteler/publication/7067653_Epidemiology_of_Parkinson's_disease/links/53f4adef0cf2888a74911323.pdf">Epidemiological evidence</a> of exposure to iron and heavy metals is inconclusive (although brain iron has been repeatedly observed in Parkinson’s independent of environmental exposure).</p>
<h2>Suspected risk factors</h2>
<p><strong>Head trauma</strong></p>
<p><a href="http://oem.bmj.com/content/70/12/839.long">Epidemiological studies</a> linking head injuries to the development of Parkinson’s have been inconsistent, with varying strengths of association reported. </p>
<p>The nature of the head trauma appears to have relevance in determining risk. <a href="http://archneur.jamanetwork.com/article.aspx?articleid=591102">Injuries causing concussion or loss of consciousness</a> have been more strongly related to Parkinson’s disease. </p>
<p>Many believe chronic brain damage from boxing led to Muhammad Ali developing Parkinson’s. It is not possible, however, to determine that <a href="https://patients.aan.com/resources/neurologynow/index.cfm?event=home.showArticle&id=ovid.com%3A%2Fbib%2Fovftdb%2F01222928-200602020-00005">boxing definitely</a> led to the development of Ali’s Parkinson’s.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=446&fit=crop&dpr=1 600w, https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=446&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=446&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=561&fit=crop&dpr=1 754w, https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=561&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/118654/original/image-20160414-4674-kdb0e3.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=561&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Most assume Muhammad Ali’s boxing career led to Parkinson’s disease.</span>
<span class="attribution"><span class="source">Youtube</span></span>
</figcaption>
</figure>
<h2>Protective factors</h2>
<p>Some studies have suggested <a href="https://www.researchgate.net/profile/Monique_Breteler/publication/7067653_Epidemiology_of_Parkinson's_disease/links/53f4adef0cf2888a74911323.pdf">antioxidants, vitamins and smoking</a> may have a small protective effect on the development of Parkinson’s. Caffeine intake has been consistently associated with decreased Parkinson’s risk, particularly for men, and lower Parkinson’s incidence is reported in people who have ever smoked cigarettes.</p>
<p>Most of the studies to date have been case control studies or cross-sectional surveys, which are prone to recall and selection bias. These studies cannot determine causation. More robust epidemiological studies, such as large cohort studies looking at large populations and incidences of the disease, are required to further investigate the causes of Parkinson’s.</p>
<p>The main research challenges are the lack of clear markers of the disease, lack of diagnostic tests, and the later age of onset of the disease. Parkinson’s research requires significant commitment on the part of community members, researchers, community-based stakeholders, the health sector, governments and other funding agencies.</p><img src="https://counter.theconversation.com/content/57579/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Darshini Ayton has received funding from Parkinson's Victoria. </span></em></p><p class="fine-print"><em><span>Narelle Warren receives funding from the National Health and Medical Research Council, the Australian Research Council, Limbs 4 Life, UCB Australia, and Parkinson's Victoria. This research was funded by Parkinson's Victoria. </span></em></p><p class="fine-print"><em><span>Scott Ayton receives funding from NHMRC, ARC, Bethlehem Griffiths Research Foundation, Alzheimer's Association, Alzheimers' Research UK, The Michael J. Fox Foundation, Weston Brain Institute, and Parkinson's Victoria. He is a member of the Liberal party. </span></em></p>Parkinson’s disease is the second-most-prevalent neurodegenerative condition in Australia, with an estimated 70,000 living with the disease. But what do we know about the causes and risk factors?Darshini Ayton, Research Fellow and Lecturer, Monash UniversityNarelle Warren, Lecturer in Anthropology, Monash UniversityScott Ayton, Research Fellow, Florey Institute of Neuroscience and Mental Health, Florey Institute of Neuroscience and Mental HealthLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/539772016-02-18T19:20:13Z2016-02-18T19:20:13ZWhat causes autism? What we know, don’t know and suspect<figure><img src="https://images.theconversation.com/files/110250/original/image-20160204-5853-11j9tr8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The revelation that autism didn't have one cause helped researchers change their thinking.</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p><em>This is a long read, enjoy. Andrew will be answering reader questions from 4pm-5pm AEDST on Friday, February 19.</em></p>
<hr>
<p>One of the great and enduring mysteries of autism is what causes the brain to develop so differently. The behavioural differences of many individuals with autism are so apparent that it seems intuitive that the causes would also be obvious. </p>
<p>But research over the past 70 years has indicated this isn’t so. Into this knowledge gap have come all sorts of weird and wacky ideas about the causes of autism: television, power lines, vaccines and sex position during conception. None have any credence, but have fuelled the mystery surrounding what may cause autism.</p>
<p>In the 1950s and 1960s, there was a <a href="http://archpsyc.jamanetwork.com/article.aspx?articleid=489479">widely held belief</a> that autism was caused by parental coldness towards the child. The term “refrigerator mother” was often directed towards the mothers of these children. </p>
<p>Leo Kanner, the man who <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1939-0025.1949.tb05441.x/abstract">first described the behaviours</a> that characterise autism, explored “a genuine lack of maternal warmth” as a possible explanation for autism. This inaccurate belief left a legacy of shame and guilt in the autism community for at least the following two decades.</p>
<p><a href="https://embryo.asu.edu/pages/infantile-autism-syndrome-and-its-implications-neural-theory-behavior-1964-bernard-rimland">Several eminent scientists</a> eventually extinguished the myth. Two of them were themselves parents of children with autism, and they highlighted a major flaw in the theory: parents who fitted the “refrigerator” stereotype also had children who did not have autism. </p>
<p>Since this time, research has focused on biological factors that may lead to autistic behaviours. This has found very clearly there is no one cause of autism. </p>
<p>A variety of genetic factors are likely to be the ultimate cause of most cases of autism. These may work by themselves, or in combination with environmental factors, to lead a child’s brain to develop differently and result in autistic behaviours.</p>
<h2>Genetics</h2>
<p>To examine the influences of nature (genetics) and nurture (environment) on a given human quality, scientists study twins. </p>
<p>To appreciate how these studies work, it’s first important to understand there are two types of twins. Identical twins share all of their DNA and, assuming they grow up in the same household, they will also share all of their environment. Fraternal twins also share all of their environment, but only around half of their DNA, just like non-twin siblings.</p>
<p>Twin studies start by defining a clear population, say the metropolitan area of a city, and finding as many sets of twins as possible in that area where one or both of the twins have the given trait of interest – in this case, autism. </p>
<p>Scientists then look at the “concordance” of that trait – that is, the percentage chance that if one twin has autism, the other twin will also have autism. If the concordance is higher for identical twins than fraternal twins, then we can say the difference is due to the increased amount of genetic material shared by the identical twins, and that autism is influenced by genetics.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=406&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=406&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=406&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=510&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=510&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111877/original/image-20160218-1264-107lv0c.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=510&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Twin studies provided the first evidence autism may be genetic.</span>
<span class="attribution"><span class="source">Choku/Flickr</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1469-7610.1977.tb00443.x/abstract">first twin study of autism</a> was conducted in 1977 on 11 identical and ten fraternal twins across Great Britain, where at least one of the twins had autism. Concordance for identical twins was 36%, compared to 0% for the fraternal twins. </p>
<p>While the study was only small in size, it provided the first evidence that autism may be genetic in origin. Since this pioneering study, more than a dozen <a href="http://link.springer.com/chapter/10.1007%2F978-1-4614-9509-3_2#page-1">further twin studies</a> have confirmed this original observation. </p>
<p>The best current estimate is that there is a 50-80% concordance for identical twins and a 5-20% concordance for fraternal twins. This indicates a strong genetic component to the condition. The figure for fraternal twins – 5-20% – also represents the chance of a couple who already have a child with autism having a second child with autism (referred to as the “recurrence risk”).</p>
<p>Once scientists have established that the cause of a disorder is influenced by genes, the next task is to identify the exact genes that might be involved. However, after several decades of intensive research, scientists could find no one genetic mutation that all individuals diagnosed with autism shared. </p>
<p>It was these <a href="https://www.mja.com.au/journal/2013/198/6/autism-one-or-multiple-disorders">findings</a> (or lack of findings) that led scientists to stop thinking of autism as one condition with one cause. They started viewing it as many different conditions which all have relatively similar behavioural symptoms.</p>
<p>This new view of autism has proved extremely fruitful in discovering subtypes of autism. For example, a <a href="http://www.ncbi.nlm.nih.gov/pubmed/24468882">number of conditions</a> have very clear genetic or chromosomal abnormalities that can lead to autistic behaviours. </p>
<p>These include disorders that have abnormalities of the chromosomes, such as Down syndrome. While no chromosomal condition itself accounts for any more than 1% of individuals with autism, when combined they account for approximately 10-15% of all individuals diagnosed with autism.</p>
<p>The exact genetic abnormalities that may lead to the remaining cases of autism are not completely clear. There are two reasons for this. </p>
<p>The first is that the genetic regions involved are likely to be very complex. Scientists have needed to develop new techniques to examine them. </p>
<p>The second is that it is probable the genetic mutations are very rare and complex. The DNA chain that forms our chromosomes contains more than 3 billion building blocks. To identify small pieces of DNA that may be linked to the development of autism among so many base pairs, scientists need to study a very large number of people with autism. </p>
<p>To date, no study has been able to examine the thousands of people necessary to identify with accuracy all of the small mutations that might lead to autism.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111879/original/image-20160218-1276-dzmm3p.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>
<figcaption>
<span class="caption">With more than 3 billion building blocks in the DNA chain that forms our chromosomes, it’s difficult for scientists to isolate genes that could cause autism.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/saynine/456229624/">James Gentry/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>However, with genetic technologies improving at an astronomical pace, as well as global scientific cooperation that will lead to large numbers of people being studied, major advances in the understanding of the causes of autism are likely in the very near future.</p>
<p>A likely prospect is that many cases of autism will be related to what is called “<a href="http://www.nature.com/ng/journal/v46/n8/full/ng.3039.html">common genetic variation</a>”. This refers to differences in genes that are also found in many individuals who do not have autism and which by themselves are not sufficient to lead to autism. However, when multiple genetic risk factors are found in the same person, they combine to have a major effect on how the brain develops. </p>
<p>A <a href="http://www.nature.com/nature/journal/v485/n7397/full/nature10945.html">small proportion</a> of autism cases are also likely to be caused by what are known as <em>de novo</em> (“new”) mutations. Most often, the egg and sperm that create a baby contain genetic material that is present in the mother and father, respectively. However, in rare cases, the egg and sperm may contain genetic material that is not found in either parent. There is now good evidence that some people with autism may have inherited <em>de novo</em> genetic mutations that have an effect on brain development.</p>
<h2>Environmental causes</h2>
<p>Recognition <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548163/">has grown</a> over the past decade that aspects of our environment may also contribute to autism. However, despite substantial research, no one environmental factor has yet been found to be a definite cause of autism. </p>
<p>The most widely used research technique to examine environmental risk factors for autism is epidemiology, which examines how often, and why, diseases occur in different groups of people.</p>
<p>Several environmental factors during prenatal life have been linked with autism. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20414802">Bacterial</a> or <a href="http://www.ncbi.nlm.nih.gov/pubmed/22562209">viral</a> infections in the mother during pregnancy have been found to slightly increase the risk of autism in the offspring. This could be due to the passage of harmful infectious organisms from the mother to the fetus through the placenta, or because the immune response of the mother may be detrimental to the developing brain of the fetus.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111880/original/image-20160218-1264-1mmuauz.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">Older fathers are said to increase the risk of autism.</span>
<span class="attribution"><span class="source">shutterstock</span></span>
</figcaption>
</figure>
<p>Other factors in the mother that may be related to offspring autism include a <a href="http://jama.jamanetwork.com/article.aspx?articleid=1570279">folic acid deficiency</a> at the time of conception, the presence of <a href="http://jama.jamanetwork.com/article.aspx?articleid=2247143">gestational diabetes</a> and the use of <a href="http://pediatrics.aappublications.org/content/early/2014/04/09/peds.2013-3406">certain antidepressants</a> during pregnancy, but no conclusive evidence exists for any of these links.</p>
<p>Being an older parent, particularly an older father, is also thought to increase the risk of having a child with autism. As males get older, the number of sperm that contain <em>de novo</em> genetic mutations increases. </p>
<p>Some of the <em>de novo</em> genetic mutations will have minimal or no effect on the resulting baby, but some mutations can lead to the brain developing differently. </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/25662027">Several studies</a> have found that fathers who are over 50 at the time of conception have a greater chance of passing on de novo mutations and also a greater risk of having a child with autism.</p>
<p>An obvious, but very important, observation is that not all people who are exposed to these factors are diagnosed with autism. One possible explanation for this is a phenomenon called gene-environment interaction, which is when the genetic make-up of two different people leads them to respond differently to an environmental factor.</p>
<h2>Brain development</h2>
<p>For a considerable time scientists were searching for one clear brain difference that may lead to autistic behaviours. However, this hope has yet to be fulfilled, with few studies identifying brain characteristics that are shared by different individuals diagnosed with autism. </p>
<p>This may be a further indication that autism has many different causes, but it may also be a reflection of the difficulties in studying the brain. </p>
<p>Currently, scientists use a variety of clever techniques to understand the structure and function of the brain, such as magnetic fields, X-rays and radioactive chemicals. As ingenious as these methods are, they are unable to provide a full measure of the tremendous complexity of how the brain operates.</p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=452&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=452&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=452&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=568&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=568&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111882/original/image-20160218-1252-1y5wivd.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=568&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Few studies have identified brain characteristics that are shared by different individuals diagnosed with autism.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
</figcaption>
</figure>
<p>It is also unlikely that autism affects just one area of the brain alone. The complex behaviours of individuals with autism, which include cognitive, language and sensory difficulties, make it difficult to pinpoint just one brain region that may be affected. Nevertheless, some promising leads have shown how different brain pathways may lead to autistic behaviours.</p>
<p>There is <a href="http://www.ncbi.nlm.nih.gov/pubmed/17555719">increasing evidence</a> that differences in brain development may begin prenatally in some individuals with autism. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20414801">Several studies</a> of prenatal ultrasound measurements have found evidence for differences in the growth patterns of the brain in foetuses later diagnosed with autism. Newborns later diagnosed with autism are often also reported to have large heads at birth (“macrocephaly”).</p>
<p>Another research technique has been to dissect the brains of individuals with autism who have prematurely died, so-called post-mortem studies. A <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1307491">recent study</a> that examined the brains of 11 autistic individuals at the microscopic level found changes in the structure and organisation of the brain cells that form during foetal life, indicating differences in brain development that begin very soon after conception.</p>
<p>Another well-studied area in autism is head circumference growth in the first years of life. This research dates back to 1943 and Leo Kanner’s <a href="http://simonsfoundation.s3.amazonaws.com/share/071207-leo-kanner-autistic-affective-contact.pdf">original study</a> that found five of the 11 children with autism he examined had large heads. </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/9031582">Several</a> small <a href="http://www.ncbi.nlm.nih.gov/pubmed/8894947">studies</a> throughout the 1990s and 2000s searched the medical records of relatively small groups of children with autism. These found that a key period was the first two years of life, in which a minority of children later diagnosed with autism had a marked increase in the rate of growth of their head. </p>
<p>During the first two years of life, the size of an infant’s head is a reasonable indicator of total brain size, and for many years “brain overgrowth” during very early development was seen as a risk factor for a later diagnosis of autism.</p>
<p>However, more recently, this view has been <a href="http://www.jaacap.com/article/S0890-8567(14)00529-2/abstract">challenged</a> by the release of the largest ever study in this area, which found no link between infant head circumference growth and autism.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=354&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=354&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=354&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=444&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=444&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111883/original/image-20160218-1236-1acrds.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=444&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Head size has nothing to do with autism.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/merwing/516164481/">Aimee Ray/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p><a href="http://www.sciencedirect.com/science/book/9780123919243">Studies</a> using brain imaging machines have <a href="http://www.ncbi.nlm.nih.gov/pubmed/25850620">examined</a> whether parts of the brains of individuals with autism may be different in size, shape or function. </p>
<p>However, the only consistent finding is just how much inconsistency there is. Not every individual with autism has differences in the size or pattern of growth of different brain regions. For those individuals who do, it is unclear how this may relate to their autistic behaviours.</p>
<p>A great deal of brain imaging research has examined the connections within the brain of individuals with autism. Connectivity is a measure of how well and how much two brain areas communicate with each other. In the study of autism, scientists distinguish between short-range connections (between neighbouring brain areas) and long-range connections (between brain areas further apart). </p>
<p>One <a href="http://www.ncbi.nlm.nih.gov/pubmed/22018722">prominent theory</a> that has emerged from brain imaging studies is that some individuals with autism may have under-connectivity in long-range connections, but over-connectivity in short-range connections. </p>
<p>If found to be accurate, these brain differences may be able to explain why some individuals with autism have difficulties with complex tasks that require the integration of information from multiple brain regions (such as cognitive and social abilities), but have no difficulties, or even enhanced abilities, for tasks that require less integration across brain areas (such as sensory processing).</p>
<h2>Other biological factors</h2>
<p>There is preliminary <a href="http://www.nature.com/mp/journal/v20/n3/full/mp201448a.html">evidence</a> some <a href="http://jneurodevdisorders.biomedcentral.com/articles/10.1186/1866-1955-4-25">but not all</a> individuals with autism are exposed to higher levels of testosterone in the womb. Excessively high testosterone concentrations in the bloodstream can be harmful and cause cells to die, particularly within the brain, which is highly sensitive to changes in hormone levels. </p>
<p>One thought is that the pattern of cell death caused by high testosterone levels may alter brain development in a way that leads to autistic behaviours in childhood. This theory is still to be proven. Again, it is certain that not all individuals with autism are exposed to excessive levels of testosterone in the womb.</p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=663&fit=crop&dpr=1 600w, https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=663&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=663&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=833&fit=crop&dpr=1 754w, https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=833&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/111884/original/image-20160218-1243-url3jz.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=833&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 scientists believe a disruption of good gut bacteria may be a potential cause for autism.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/wellcomeimages/15385435563/">Wellcome Images/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The link between gastrointestinal (“gut”) problems and autism is another scientific area that has received a great deal of attention. It is now well known that between <a href="http://pediatrics.aappublications.org/content/124/2/680">30% and 50%</a> of individuals with autism experience significant gastrointestinal problems, such as diarrhoea, constipation and an irritable bowel. </p>
<p>It has long been a mystery why, but there is now extremely good evidence that the complex community of microbes in the gut plays an important role in human development and is essential for healthy immune and endocrine systems, as well as the brain. </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564498/">Some scientists believe</a> a disruption in the natural balance of these “good” bacteria may be a potential cause of autism. Antibiotics, for example, are commonly used with infants in Western societies and are known to kill “good bacteria” along with the “bad” bacteria for which they were prescribed.</p>
<p>A difference in the community of microbes, which humans have evolved to rely upon, may disrupt brain development and lead to autism. At the present time, the evidence for this potential cause of autism is not strong, but there will be substantial research in this area in coming years.</p>
<p>Autism has no one single cause, both in terms of genes and the brain. In a minority of cases, there are very clear genetic abnormalities that cause autism. In other cases, the genetic differences are more complex and yet to be discovered.</p>
<p>While there is currently no evidence for any environmental causes, it is possible subtle influences of the environment may affect individuals differently depending on their genetic make-up, leading to autism in some children. These relationships are also yet to be discovered.</p>
<hr>
<p><em>Andrew will be on hand for an Author Q&A between 4 and 5pm AEDT on Friday, February 19, 2016. Post your questions in the comments section below.</em></p><img src="https://counter.theconversation.com/content/53977/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew Whitehouse receives funding from the NHMRC, ARC and Autism CRC. </span></em></p>One of the great and enduring mysteries of autism is what causes the brain to develop so differently.Andrew Whitehouse, Bennett Chair of Autism, Telethon Kids Institute, The University of Western AustraliaLicensed as Creative Commons – attribution, no derivatives.