Raising a glass to Parkinson's?

Lifestyle factors have been studied at length in relation to Parkinson's Disease and there is good evidence that having ever smoked is associated with reduced risk of the disease. Alcohol drinking has also been linked to reduced risk of disease, and multiple studies have looked at the association. The difficulty with drawing robust conclusions in this area relates to the design of the studies - many of the studies are case control, taking people with and without the disease and asking them to report whether and how much they drink now and in the past. This kind of study suffers from problems with bias - if you have been diagnosed with the disease you are more likely to have attended hospital, to be the kind of person who worries about their health and so makes more health-conscious choices, you may recall things differently in light of your diagnosis and you are likely to have made different choices subsequent to diagnosis.

Longitudinal studies of populations who are healthy at baseline are less likely to suffer from these biases as reporting of alcohol consumption is made prior to subsequent diagnosis. This problem with investigating causation in medicine is illustrated nicely by a study published in the Journal of Neurology by a Spanish team. They looked at 31 studies in the field and broke down the analysis into different types of study as well as looking seperately at men and women and different ways of classifying alcohol consumption.

When looking at the case-control studies, as in previous studies, they found higher numbers of 'never-drinkers' in the group with Parkinson's. However, when looking at longitudinal studies, there was no difference in having ever drunk alcohol between people who went on to develop Parkinson's and people who didn't. However, there were far more case-control studies in the article, giving more power to detect these kind of effects, as  you can see in the diagram below.

Pooled odds ratios comparing "never drinking" to "ever drinking"alcohol in a)case control and b)prospective longitudinal studies, showing higher likelihood of Parkinson's disease in those who never drank in case control but not longitudinal studies. From https://link.springer.com/article/10.1007/s00415-018-9032-3 

All in all, alcohol consumption remains an interesting part of the puzzle of Parkinson's causation, especially given possible genetic links the authors discuss between variants of the alcohol dehydrogenase gene which cause adverse effects of alcohol and dopaminergic function. In the PREDICT-PD study we are collecting data on alcohol use in all of our participants and will continue to study these links.

-Anna

J Neurol. 2018 Aug 28. doi: 10.1007/s00415-018-9032-3. [Epub ahead of print]

Alcohol consumption and risk for Parkinson's disease: a systematic review and meta-analysis.

Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG

The possibility that alcohol consumption should be considered as a "protective factor" for Parkinson's disease (PD) has been suggested by several case-control studies. However, other case-control studies and data from prospective longitudinal cohort studies have been inconclusive. We carried out a systematic review which included all the eligible studies published on PD risk related with alcohol consumption, and conducted a meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The systematic review was performed using two databases, and the meta-analysis of the eligible studies with the software Meta-Disc1.1.1. Heterogeneity between studies was tested with the Q-statistic. The meta-analysis included 26 eligible retrospective case-control studies (8798 PD patients, 15,699 controls) and 5 prospective longitudinal cohort studies (2404 PD patients, 600,592 controls) on alcohol consumption and PD. In retrospective case-control studies the frequency of PD patients never drinkers was higher and the frequency of heavy + moderate drinkers was lower [diagnostic OR (95% CI) 1.33(1.20-1.48) and 0.74(0.64-0.85)], respectively, when compared to healthy controls. In contrast, in prospective studies, the differences were not significant with the exception of a trend towards a higher frequency of non-drinkers in PD women and a significantly lower frequency of moderate + heavy drinkers in PD men in those studies which stratified data by gender. The present meta-analysis suggests an inverse association between alcohol consumption and PD, which is supported by the results of case-control studies but not clearly by prospective ones.

Non-motor features of PD... new report from the HPFS

Here we see evidence to support the fact that it you have a combination of smell loss, probable REM sleep behaviour disorder and constipation, you are more likely to have Parkinson's... this is not surprising because we have seen this in lots of other studies but it is nice to see it all brought together in one study.

The comments are as follows... odds ratios (ORs) in this context are a little bit meaningless. How does one interpret an odds ratio of 160, let alone an OR of 1323 other than to say it looks like a lot?? By comparison, if you look at ORs between an established risk factor (such as smoking) and disease outcome (such as lung cancer), the ORs are between 20-40. It is not a criticism of the approach; in PREDICT-PD we too have traditionally modelled ORs. However, we rank an individual's OR against the ORs of everyone else in the cohort, meaning that, whilst not their literal risk, it is correct in relation to all other participants in the cohort.   

The combination of the three factors has a positive predictive value of 35% - meaning that if you have all three together there is a 35% chance of you having a diagnosis of PD. Long story short... these three non-motor features, in combination, still look like some of the most useful for recognising PD... either in those that have a diagnosis or who are in the prodromal phase...

- Alastair Noyce

https://jnnp.bmj.com/content/early/2018/08/03/jnnp-2018-318275.long

Heads Up: Head injuries and Parkinson's

There has been a lot of publicity over the last year about the links between neurodegenerative disease and multiple mild head injuries incurred in many common sports including football and rugby, for example Alan Shearer's BBC documentary on the links between dementia and football.  Chronic traumatic encephalopathy (CTE) is a term that has been coined to describe patients who develop behavioural, mood, cognitive and motor disturbances after prolonged exposure to mild head injuries and show abnormal protein folding in the brain.


Alan Shearer, footballer (from the BBC documentary Alan Shearer: Dementia, Football and Me) https://www.bbc.co.uk/programmes/b09g0gzk)

This disease process bears similarities to Parkinson's Disease in that normal proteins become misfolded and then aggregate into abnormal deposits which is then associated with brain cell death. We have also known for a long time that previous history of head injuries and concussion increases your risk of Parkinson's. The study below, of almost 700 individuals including a significant number of athletes who had died and agreed to have an autopsy looks in more detail at the links between these conditions.

Overall, they found that people who had repeated head injury during life were much more likely to have the abnormal protein found in Parkinson's, alpha-synuclein, as well as the tau protein, which has been described in CTE. More exposure to head injury - for example greater than 8 years of playing contact sport increased the likelihood of Parkinson's-type pathology. They go on to look at the relationships between the different forms of protein and show that the distribution of the Parkinson's protein alpha-synculein is similar whether or not there was evidence of CTE and likely accounts for the movement problems seen in CTE.

Descriptions of protein-related brain diseases are ever expanding and I believe will guide us in  understanding the causes of Parkinson's and how the disease progresses. By studying the processes by which mild head injury leads to protein misfolding and how the different proteins interact we are gaining new mechanistic insights which we hope will lead to promising new treatments. From a prevention point of view, the neurological dangers of repetitive mild head injury are increasingly clear - while the authors here showed that playing more than 8 years of competitive sport was significantly associated with more pathology, we still need more data before we can develop clear recommendations for both our patients and the wider public. 

-Anna 

https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nly065/5059623

Lewy Body Pathology and Chronic Traumatic Encephalopathy Associated With Contact Sports.

Adams JW, Alvarez VE, Mez J, Huber BR, Tripodis Y, Xia W, Meng G, Kubilus CA, Cormier K, Kiernan PT, Daneshvar DH, Chua AS, Svirsky S, Nicks R, Abdolmohammadi B, Evers L, Solomon TM, Cherry JD, Aytan N, Mahar I, Devine S, Auerbach S, Alosco ML, Nowinski CJ, Kowall NW, Goldstein LE, Dwyer B, Katz DI, Cantu RC, Stern RA, Au R, McKee AC, Stein TD

Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease(AD) Center (n = 261). Participants with CTE and LBD were more likely to have β-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE ɛ4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.

The Importance of being Picky

This week the UCL Institute of Neurology who ran the randomised trial of the diabetes drug, Exenatide as a disease modifying treatment for Parkinson’s, have published a paper looking at particular groups who may benefit more from the treatment. 

The tenet of clinical trials is that you specify who can enter the trial, and you give one group the intervention (in this case drug) of interest, and you give another group something else (in this case placebo), and see which does better against a pre-specified list of measures. This implies a ‘winner-takes-all’ outcome that is beyond reproach. Either the new drug did better than no drug, or it didn’t – end of discussion. 

This approach is important. New drugs are met with excitement, clinicians want it to work, scientists have often spent years suggesting that it will, and patients are desperate for it to work. Therefore rigid and robust tests with a categorical ‘winner’ help to provide an unbiased outcome.

However, the disadvantage is that the baby can get thrown out with the bathwater. The randomised clinical trial, when done well is a robust and unbiased tool for making a judgement. However, it is not ‘perfect’. No matter how good the design of the study, there will be flaws and biases that are both explicit and hidden, and there is always the issue of ‘generalisability’ – how well the recruited volunteers represent the patient in clinic.

The UCL team have continued to look at the data. For a future trial, are there some people that are likely to do better from this treatment, and are the some people that will never respond. This is key and at the heart of this endeavour is the understanding that a ‘One-size-fits-all’ approach in Parkinson’s will never work.

As Exenatide, and other compounds, are proven to be safe for people with Parkinson’s, great care will need to be taken to ensure that the right people are chosen for trials of effectiveness. This will entail careful analysis and subgroup analyses of early studies.

In this analysis, it seems that people with a shorter duration of disease and less impact of disease (in other words, milder disease) may get more benefit from Exenatide. This fits closely with the hypothesis that lies at the heart of PREDICT-PD: very early identification of Parkinson’s will allow effective disease modification that may be enough to proactively prevent the onset of motor symptoms.

RNR

onlinelibrary.wiley.com/doi/pdf/10.1111/ejn.14096

Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Aviles-Olmos I, et al. Post hoc analysis of the Exenatide-PD trial - factors that predict response. Eur J Neurosci. 2018 Aug 2.

Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson's disease in a randomised, placebo-controlled trial. Additionally, there were trends favouring the exenatide group in assessments of non-motor symptoms, cognition and quality of life. The aim of this exploratory post-hoc analysis was to generate new hypotheses regarding (1) whether candidate baseline factors might predict the magnitude of response to exenatide and (2) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, non-motor symptoms, cognition and quality of life after 48-weeks treatment with exenatide were evaluated among post-hoc subgroups defined by age, motor phenotype, disease duration, disease severity, BMI and insulin resistance. In the subgroup analyses, exenatide once-weekly was associated with broadly improved outcome measures assessing motor severity, non-motor symptoms, cognition and quality of life across all subgroups, however tremor-dominant phenotype and lower MDS-UPDRS Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of GLP-1 receptor agonists in PD. This article is protected by copyright. All rights reserved.

Professional occupation and the risk of Parkinson's disease

This research article investigates the link between occupation and risk of PD... it is not just another paper linking farming to Parkinson's (although I find that link interesting too)... instead it uses a classification model called RIASEC which divides occupations according to personality characteristics. 
This topic has always fascinated me... in part because it plays out in clinical practice and is apparent in the patients one sees in clinic... and in part because if dopaminergic deficit influences choice of occupation, then susceptibility really does begin decades before one gets the diagnosis.
Some of the former observation may be down to selection bias... after all the patients I saw in 5 years at Queen Square generally represent a different demographic to that of patients I see at the Royal London... but my overall clinical impression is still consistent with what the authors observe here.
The link between farming and Parkinson's has always been put down to cumulative  pesticide (or other similar toxin) exposure... but in this paper these are very broad occupational categories seemingly driven by personality traits. The authors attempt to explain the association by the notion that higher dopaminergic activity is associated with creative behaviour (and perhaps occupation) and also offers relative protection against Parkinson's. They present alternative possibilities that relate to smoking (and other substance abuse) potentially being protective against Parkinson's and more common in creative occupations OR that creative occupations generate higher dopaminergic reserve which in turn acts as a buffer against neurodegeneration. 
I would like to propose an alternative possibility... and that is circadian clock function has both a strong influence on our behaviour and also potentially on our choice of occupation, as well as having a strong influence on the regulation of normal cellular processes. 'Morning persons' are more likely to pursue conventional occupations than 'evening persons', who I am willing to bet are more likely to be creative... we have recently shown that a lifetime averaged tendency towards one extreme of chronotype (that is being a 'morning person') is causally linked with PD (preprint here). The role that circadian clock function might have in explaining the fascinating work reported in this paper warrants further exploration...

- Alastair Noyce

Eur J Neurol. 2018 Jul 14. doi: 10.1111/ene.13752. [Epub ahead of print]
Darweesh SKL, Ikram MK, Faber MJ, de Vries NM, Haaxma CA, Hofman A, Koudstaal PJ, Bloem BR, Ikram MA.

https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.13752

BACKGROUND AND PURPOSE: Creativity in Parkinson's disease (PD) is strongly related to dopaminergic activity and medication. We hypothesized that patients with PD, including those who are in the pre-diagnostic phase of PD, are prone to choose highly structured 'conventional' professional occupations and avoid highly creative 'artistic' occupations.

METHODS: At baseline of the population-based Rotterdam Study, we asked 12 147 individuals aged ≥45 years about their latest occupation and categorized occupations according to the RIASEC model. Participants underwent baseline and follow-up (median 11 years) examinations for PD. We determined associations of artistic (versus any other occupation) and conventional (versus any other occupation) occupations with PD. Additionally, we pooled our results with a recently published case-control study (Radboud Study).

RESULTS: At baseline, conventional occupations were common [n = 4356 (36%)], whereas artistic occupations were rare [n = 137 (1%)]. There were 217 patients with PD, including 91 with prevalent PD and 126 with incident PD. The risk of PD varied substantially across occupational categories (chi-square, 14.61; P = 0.01). The penalized odds ratio (OR) of artistic occupations for PD was 0.19 [95% confidence interval (CI), 0.00-1.31; P = 0.11], whereas the OR of conventional occupations for PD was 1.23 (95% CI, 0.95-1.66; P = 0.10). The direction and magnitude of ORs were similar in cross-sectional and longitudinal subsamples. Pooled ORs across the Rotterdam and Radboud Studies were 0.20 (95% CI, 0.08-0.52; P < 0.001) for artistic and 1.23 (95% CI, 0.92-1.67; P = 0.08) for conventional occupations.

CONCLUSIONS: The risk of PD varies substantially by choice of professional occupation. Our findings suggest that dopaminergic degeneration affects choice of occupation, which may start in the pre-diagnostic phase of PD.