Tag Archives: Brain

Two Hundred and Two Ex-(American) Footballers’ Brains Analysed After Death – This You Must Read

Who would have thought that American football could be so damaging to the brain? Boxing yes. Here force is targeted at the container for the brain. However, it turns out that other contact sports may also damage the brain according to a recent study of 202 ex-footballers who donated their brains before death.[1] The clinical condition of the patients was recorded and correlated with histopathological finding. The mean age at death is rather young at 66. Hold on to your seat and read on to learn that fully 87% of football players’ brains fulfilled the histopathological criteria for chronic traumatic encephalopathy (a progressive neurodegenerative disorder associated with repetitive head trauma). In fact it was present in 110 of the subsample of 111 footballers who were lucky (unlucky) enough to make the National Football League (NFL). Further, 86% of these NFL players had severe pathology. Yes, brains may be more willingly donated when cognitive deterioration is present than when it is not, leading to inclusion bias. A prospective study is needed. But should we wait the 20-40 years needed for the results? Even if this study has overestimated the effect, the bias could not create so large an association if there were none. Would you encourage your grandchildren to play? If your heart packs up, your lungs fail or your pancreas turns cancerous, you die as yourself. But if your cerebral cortex is damaged you live as someone else.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Mez J, Daneshvar DH, Kiernan PT, et al. Clinopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football. JAMA. 2017; 318(4): 360-70.
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Alcohol and its Effects

News blog readers may be familiar with the famous ‘J curve’ relating alcohol consumption to health outcomes, including brain health.[1] The J curve shows a negative correlation between alcohol consumption and cognitive functioning at a low level of alcohol consumption (< 7 units/week), turning to a positive association in quantities exceeding about 28 units/week. One large glass of wine per day should be safe according to this finding. However, the data from which these findings are derived is cross-sectional. The BMJ has recently published a longitudinal study of alcohol and its effect on both cognition and brain structure (as measured by functional MRI).[2] The news is bad I am afraid. In the words of the editor, Fiona Godlee, ‘better’ research flattens the J curve.[3] The study seems to show a linear increase in risk with increasing intake of alcohol. The result was statistically significant for people drinking more than about two small glasses of wine per day. Why was a harmful effect at low dose detected in this longitudinal study but not the cross-sectional studies? So here is the thing – people with higher cognitive functioning tend to have higher alcohol consumption at baseline. In fact, the ‘cleverer’ the person, the more they tend to drink. The result is a difference in the findings of cross-sectional and longitudinal studies. While cross-sectional studies show no difference in cognition with moderate alcohol intake, the longitudinal studies show that cognition and brain structure decline at relatively low levels of alcohol consumption. To put this another way, moderate alcohol intake abolishes the cognitive advantage that moderate alcohol consumers have at baseline. Interestingly, not all parts of the brain are equally affected on MRI. Likewise the effect on cognition is not global; it affects lexical more than semantic fluency, for example. This is an extremely well-written, detailed and interesting study. The cohort of people who participated in the study were civil servants followed up for 30 years. The results are of immense public health importance. Human happiness, wealth and prosperity all relate to brain function. A person’s intellectual endowment is a precious gift and should not be lightly squandered.  I will take these findings too heart, both in my personal life and as a public health practitioner. It is really a question of long-term loss vs. short-term gain – alcohol is a pleasant social lubricant, much beloved of myself, and a small glass of wine has even been shown to improve creative problem-solving![4]

— Richard Lilford, CLAHRC WM Director

References:

  1. Di Castelnuovo A, Costanzo  S, Bagnardi  V, Donati  MB, Iacoviello  L, de Gaetano    Alcohol dosing and total mortality in men and womenArch Intern Med. 2006; 166(22): 2437-45.
  2. Topiwala A, Allan C, Valkanova V, et al. Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. BMJ. 2017; 357:j2353.
  3. Godlee F. Better research flattens the J shaped curve. 2017; 357: j2755.
  4. Benedek M, Panzierer L, Jauk E, Neubauer AC. Creativity on tap? Effects of alcohol intoxication on creative cognition. Consciousness Cognition. 2017. [ePub].

Brain Activity and Heart Disease – a New Mechanism

The amygdala is a key component in the ‘salience network’ of the brain. This network is activated in conditions of fear and stress. A recent elegant paper in Lancet [1] examined the relationship, first, between amygdala activation (measured by PET scanning) and cardiovascular outcomes, and second, between activation of the amygdala and certain mediators of cardiovascular disease concerned with stimulation of bone marrow to produce inflammatory cells and with arterial inflammation. They showed positive correlations in all cases. I am interested in causal modelling,[2] [3] and I was therefore provoked by the authors’ ‘mediation model’, which I take to be a form of structural equation modelling. This suggested that only half of the amygdala’s ‘effect’ on cardiovascular disease could be explained by the two mechanisms proposed above (production of inflammatory cells and arterial inflammation). This paper represents a potential step change in understanding brain-body interactions, but I await replication with interest.

— Richard Lilford, CLAHRC WM Director

References:

  1. Tawakol A, Ishai A, Takx RAP, et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet. 2017; 389: 834-45.
  2. Lilford RJ, Girling AJ, Sheikh, et al. Protocol for evaluation of the cost-effectiveness of ePrescribing systems and candidate prototype for other related health information technologies. BMC Health Serv Res. 2014; 14: 314.
  3. Watson SI & Lilford RJ. Essay 1: Integrating multiple sources of evidence: a Bayesian perspective. In: Challenges, solutions and future directions in the evaluation of service innovations in health care and public health. Southampton (UK): NIHR Journals Library, 2016.

Nodding Syndrome: Autoimmune Reaction to the Parasitic Worms That Cause River Blindness?

We have described the above enigmatic disorder of young children in East Africa before; a degenerative brain disease characterised by repetitive nodding movement, an inability to swallow, and eventually global brain failure.[1] Authors of a recent study hypothesised that the disease may be caused by an autoimmune response to the river blindness parasite.[2] They detected auto-antibodies to the parasite more often in cases than age-matched controls from the same village. The antibody attacks various cell markers in the mouse brain among neural networks that are affected in nodding syndrome. But only about half the patients with nodding syndrome exhibited the antibodies. The authors speculate that a number of yet to be identified antibodies may also be involved. I wonder why the disease does not map onto the geography of river blindness, which appears to be much broader than that of nodding syndrome.

So, here is my hypothesis. Remember, a few News Blogs ago,[3] I articulated a ‘three hits hypothesis’ as the cause of many diseases. One example was cytomegalovirus infection, which in the presence of the malaria parasite, and along with genetic predisposition, leads to Burkitt’s lymphoma. So I suspect that exposure to river blindness may be a sensitising event, and propose a search for a further exposure that is more specific to the ‘nodding syndrome belt’ extending from South Sudan, through Uganda to North Tanzania (see Figure).

Map of African countries showing where River Blindness is endemic and where outbreaks of Nodding Disease have occurred.

Data on River Blindness taken from the World Health Organization.

— Richard Lilford, CLAHRC WM Director

References:

  1. Chilton PJ. A Mysterious Disease with Unknown Cause. NIHR CLAHRC West Midlands News Blog. 27 June 2014.
  2. Johnson TP, Tyagi R, Lee PR, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med. 2017; 9.
  3. Lilford RJ. Three Hits Hypothesis. NIHR CLAHRC West Midlands News Blog. 7 April 2017.

Small Pollution Particles May Pass Directly into the Brain through the Snout

Yes, they appear to be able to follow the pathway used by smell neurons and thus pass directly from the olfactory membrane into the brain, i.e. not going via the lung and bloodstream. Experiments in rodents using radio-labelled nano-particles show that very small particles really can penetrate directly through the roof of the nose and pass into the brain along olfactory neurons.[1] Here these particles set in motion an inflammatory process, which activates micro-glia (brain type macrophages), which attack neurons and lead to amyloid deposits – the hall mark of dementia. People who are exposed to particles have a high risk of dementia,[2] and animals randomised to be exposed (or not) to pollution particles acquire brain amyloid and manifest cognitive decline. So there you have it – there is growing and quite compelling evidence that pollution particles are bad news for humans and other animals. It is time to act – phase out diesel cars, incentivise car manufacturers to clean up emissions, gradually increase tax on cars/lorries/fuels, incentivise cycling in cities (and make it safer), and build rail lines. But none of this will happen without public support so proselytise and increase susceptibility to the message by increasing science teaching in schools. In the end, lots of things come back to the intellectual sophistication of the average citizen. In the meantime I suspect that an increasing proportion of people will adopt face masks, although I do not know how effective they are in trapping particles.

— Richard Lilford, CLAHRC WM Director

References:

  1. Underwood E. The Polluted Brain. Science. 2017; 355(6323): 342-5.
  2. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. Lancet. 2017; 389(10070): 718-26.

More on Brain Health in Young Children and Effect on Life Course

Brain health in early childhood is a recurring theme of your News Blog. Peter Chilton referred me to an interesting article in Nature Human Behaviour published at the end of last year.[1] This study was based on a prospective study of children in the South Island of New Zealand. The investigators wanted to determine the prognosis for the 20% of the population with the worst brain health indicators at age three. These indicators include single parent family; low socioeconomic group; poor self-control; and low IQ. Outcome variables covered a range of important economically burdensome outcomes, such as obesity, cigarette smoking, and crime. These variables were harvested from various databases where health and crime statistics are recorded. A 20% ‘segment’ of this young population could be defined which predicted 80% of crime, and similar high rates on other outcomes. This 20:80 ratio, called the Pareto ratio, is often encountered in social science – for example, wealth distributes itself roughly in this proportion across many societies (about 20% of people control 80% of wealth). The authors say that their study shows plenty of ‘headroom’ for preventive interventions. That is to say, society could achieve massive gains if health and social outcomes among the highest risk segment could be improved to average levels. We have discussed interventions, such as early childhood education, before.[2-4] Many studies show statistically significant and economically worthwhile results for such interventions, but the gains come nowhere near the theoretical headroom defined here. Likely this is because brain health at age three is only partly the result of remediable factors.

— Richard Lilford, CLAHRC WM Director

References:

  1. Caspi A, Houts RM, Belsky DW, Harrington H, Hogan S, Ramrakha S, Poulton R, Moffitt TE. Childhood forecasting of a small segment of the population with large economic burden. Nature Hum Behav. 2016; 1: 0005.
  2. Lilford RJ. Pregnancy before age 16 – dropping quite rapidly from a peak in 1997. NIHR CLAHRC West Midlands News Blog. February 10, 2017.
  3. Lilford RJ. If you want to reduce partner violence or teenage pregnancy, then teach algebra and history? NIHR CLAHRC West Midlands News Blog. December 9, 2016.
  4. Lilford RJ. Evidence-based education (or how wrong the CLAHRC WM Director was). NIHR CLAHRC West Midlands News Blog. July 15, 2016.

Legalisation of Marijuana

Having borne down heavily on tobacco, it seems like everyone is now campaigning to make marijuana legal – are they mad?

A libertarian would say that there is no case to ban tobacco (or effectively ban it by draconian taxes on consumption). All tobacco can do is kill you, and as long as you know this you may use it. Marijuana is a different case altogether. It appears that it does not just kill you, it maims you – and not just your body, but you – your personality, your memory, your intelligence, i.e. your essence. And it is particularly attractive to teenagers – those with the most precious and vulnerable brains. Use is increasing in the US and has increased in association with decriminalisation, even if cause and effect is hard to prove.[1] Meanwhile a recent longitudinal cohort study found that persistent cannabis dependence was linked to downward socioeconomic mobility, financial difficulties, workplace problems, and relationship conflict.[2] It gets worse, the concentration of psycogenic compounds is increasing in the plant due to selective breeding. The attitude and fashion among liberal metropolitans “tobacco is vulgar, but marijuana is cool.” Have we gone mad? If we could confine the need to people over 18, and campaign against it, then over time we could reduce use. But a chemical that actually alters the structure of the adolescent brain and is more ubiquitous than boxing? We urgently need more information on the effects legalising cannabis has on usage. Also, more research on its effects on the brain using functional MRI. I wonder if Mendelian randomisation could shed light on causality?

— Richard Lilford, CLAHRC WM Director

References:

  1. Azofeifa A, Mattson ME, Grant A. Monitoring Marijuana Use In the United States: Challenges in an Evolving Environment. JAMA. 2016; 316:1765-6.
  2. Cerdá M, Moffitt TE, Meier MH, et al. Persistent Cannabis Dependence and Alcohol Dependence Represent Risks for Midlife Economic and Social Problems: A Longitudinal Cohort Study. Clin Psychol Sci. 2016; 4(6): 1028-46.

 

Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain

This News Blog has frequently discussed synaptic pruning [1] [2] – a process that occurs in the foetus at mid-gestation, children at around the age of two, and in late adolescence. Abnormalities in neural synaptic pruning are associated with diseases, such as schizophrenia and autism.[3] It turns out that there is another period of synaptic pruning – during pregnancy. Functional MRI shows that many areas of grey matter shrink in pregnancy. Greater pruning is associated with higher scores on standard questionnaires measuring a mother’s attachment to her baby.[4] More brain does not necessarily mean better brain.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening Up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. van Spronsen M, Hoogenraad CC. Synapse Pathology in Psychiatric and Neurologic Disease. Curr Neurol Neurosci Rep. 2010; 10(3): 207-14.
  4. Hoekzema E, Barba-Müller E, Pozzobon C, et al. Pregnancy leads to long-lasting changes in human brain structure. Nature Neurosci. 2016.

A Fascinating Account of the Opening Up of an Area of Scientific Enquiry

News Blog readers may have seen previous posts on synaptic pruning.[1] Synaptic pruning involves the elimination of synapses with weak connections between brain neurons. Pruning is especially exuberant after periods of rapid neuronal multiplication (in mid-gestation, around the age of two years, and in late adolescence). Over-exuberant synaptic pruning is associated with schizophrenia. It may also play a crucial role in degenerative brain diseases, such as Alzheimer’s, and in people with memory loss after West Nile fever. The biochemical trigger arises from products of the complement cascade. Astrocytes induce neuronal cells to make the protein C1q, which triggers the complement cascade in neurons. Complement factors, such as C3 attach to weak synapses, and micro-glia (the macrophages of the brain) then ingest the tagged synapses. This process can be visualised by staining living brain cells – bits of synapse end up in the micro-glia. A genetic predisposition to over-express certain complement components increases the risk of schizophrenia markedly, as reported in a previous post.[2] As brains age C1q levels increase four-fold, and this likely predisposes to degenerative diseases, such as Alzheimer’s. Drugs to dampen down this cascade are entering clinical trials. For a lively account if the human story behind one of the leading scientists involved in unravelling this story, see an article by Emily Underwood.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands. 11 March 2016.
  2. Lilford RJ. Molecular Diagnostic Testing, Including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder. NIHR CLAHRC West Midlands. 23 October 2015.
  3. Underwood E. This woman may know a secret to saving the brain’s synapses. Aug 18 2016.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.