Tag Archives: Brain

Neither Child Nor Adult: the Science, Sociology and Literature of Adolescence

Adolescents often get a bad press. The teenage years can be very troubled and, as a parent I can say, troubling. For a rich, tender and insightful view News Blog readers may have encountered ‘My Brilliant Friend’ by Elena Ferrante.

The period of adolescence seems to be widening: at one end, puberty is occurring ever earlier; at the other, the latest neurophysiology findings suggest that brain maturation continues to the age of 24.[1][2]

The topic of adolescence is heavily featured in the most recent edition of Nature.[3] The argument is made that the topic has been relatively under researched and that we, as a society, should adopt a more positive attitude to this crucial phase of life. While childhood sets many of the patterns for later life, adolescence  is also a crucial formative stage, especially as far as mental health is concerned.

This has been long recognized at CLAHRC WM, where we have a thriving scientific programme focusing on psychoprophylaxis, and increasing portion of our work is carried out in schools.

— Richard Lilford, CLAHRC WM Director

References:

  1. Patton GC, Olsson CA, Skirbekk V, et al. Adolescence and the next generation. 2018; 554: 458-66.
  2. Ledford H. Who exactly counts as an adolescent? 2018; 554: 429-31.
  3. Dahl RE, Allen NB, Wilbrecht L, Suleiman AB. Importance of investing in adolescence from a developmental science perspective. 2018; 554: 441-50.
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So Where Are We up to with Alcohol and Health?

First, let me come clean – I am a moderate drinker. No doubt about it. Five nights a week on a mean of two glasses, and two nights on a mean of three glasses. These are average sized glasses, so let’s say 24 units (1.5 x 16) per week. I love wine and seek good news…

The story so far:

  1. There is a ‘J-shaped’ curve of the association between alcohol and many diseases.[1]
    093 - Alcohol j curve
    * Cancer does not follow this pattern. Cancers of mouth, throat and gullet are almost certainly increased, and probably breast too.[2]
  2. But Mendelian randomisation (inheriting genes predisposing to alcohol consumption) does not show a J-shaped curve – risk rises incrementally.[3]
  3. Longitudinal studies show that, on one dimension of cognition, decline is faster in linear relationship to alcohol dose, and this finding ‘triangulates’ with a drop in right-sided hippocampal volume (detected by MRI) in relation to alcohol intake.[4]

Conclusion: the J-shaped curve is an artefact of selection bias.

So what’s new? First, a meta-analysis of longitudinal studies [5] shows a substantial protective effect against dementia for low to moderate alcohol intake (RR 0.63, 0.53-0.75) and also in Alzheimer’s disease (RR 0.57, 0.44-0.74). Second, there some evidence from these studies that chronic drinking is protective of cognitive decline, while episodic drinking is harmful at the same total intake. Third, a new longitudinal study suggests that chronic (i.e. non-binge) drinking is indeed protective against cognitive impairment in older people.[6]

This new study (the Rancho Bernardo study) is based on a cohort of 6,339 middle-class residents of a suburb in San Diego. Of the surviving residents, 2,479 attended a research clinic in 1985 where detailed alcohol histories were elicited. The participants were followed up every four years with cognitive tests. Co-variates were collected and added sequentially to a logistic regression model, starting with those (e.g. sex and age) least likely to be on the causal pathway linking alcohol to outcome. The APOE genotype was examined as an interaction term. Potential confounding effects of diet were also examined. Various sensitivity analyses were conducted. Drinking up to 3 units per day after age 65, and 4 units per day at a younger age significantly increased the chance of healthy survival, with an odds ratio exceeding 2. The J curve is there in the data, with the probability of healthy longevity increasing through no, low, moderate and even heavy drinking, only to decline again when drinking was ‘excessive’ (meaning over 4 drinks per day aged under 65 and over 3 per day for men over 65, and 3 or 2 drinks per day in younger or older women. And, yes, more frequent drinking is better than episodic drinking at a given intake – ORs of Cognitively Health Longevity increased three-fold with daily drinking vs. not drinking at all, but only two-fold if drinking was ‘infrequent’. Conclusions were robust to various sensitivity analyses.

What is the truth? No person knoweth it! But the idea that regular, moderate drinking offers some protective effects to trade-off against cancer risk has empirical support. I wonder if there are different genes predisposing to binge vs. steady drinking? I hypothesise that the genes are associated with poor impulse control leading to binge drinking. I hope that this hypothesis will now be put to an empirical test. Another question, of course, concerns the type of drink. The middle-class people in the Rancho Bernardo study may have favoured wine over other drinks – I hope so!

— 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 women: an updated meta-analysis of 34 prospective studies.  Arch Intern Med. 2006; 166(22): 2437-45.
  2. Lilford RJ. Oh Dear – Evidence Against Alcohol Accumulates. NIHR CLAHRC West Midlands News Blog. 7 December, 2017.
  3. Holmes MV, Dale CE, Zuccolo L, et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ. 2014; 349: g4164.
  4. Lilford RJ. Alcohol and its Effects. NIHR CLAHRC West Midlands News Blog. 18 August, 2017.
  5. Peters R, Peters J, Warner J, Beckett N, Bulpitt C. Alcohol, dementia and cognitive decline in the elderly: a systematic review. Age Ageing. 2008; 37(5): 505-12.
  6. Richard EL, Kritz-Silverstein D, Laughlin GA, Fung TT, Barrett-Connor E, McEvoy LK. Alcohol Intake and Cognitively Healthy Longevity in Community-Dwelling Adults: The Rancho Bernardo Study. J Alzheimer’s Dis. 2017; 59: 803-14.

Diagnosing CTE in Living Patients

Earlier this year our News Blog included a study looking at the brains of former American footballers, which found chronic traumatic encephalopathy (CTE) was present in 110 of 111 footballers who had played in the National Football League (NFL).[1] [2] However, this can only be seen during autopsy, and, at present, we are only able to make a presumptive diagnosis of CTE while the patient is alive. Now a study published in Neurosurgery [3] has found that it may be possible to diagnose CTE in living patients. PET imaging was conducted on the brain of a footballer 52 months prior to this death, and after autopsy, it was found that data from the PET scan (showing the level of binding of a molecular imaging probe) correlated significantly with deposition of tau proteins in the brain (P=0.02). Although this is only a single patient, further investigation is warranted, which could confirm whether PET scanning is a useful diagnostic tool in patients at high-risk of CTE – not only American footballers, but also military personnel.

— Peter Chilton, Research Fellow

References:

  1. Lilford RJ. Two Hundred and Two Ex-(American) Footballers’ Brains Analysed After Death – This You Must Read. NIHR CLAHRC West Midlands News Blog. 15 September 2017.
  2. 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.
  3. Omalu B, Small GW, Bailes J, et al. Postmortem Autopsy-Confirmation of Antemortem [F-18]FDDNP-PET Scans in a Football Player With Chronic Traumatic Encephalopathy. 2017.

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.

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.