Preventive Neurology Unit Showcase

Yesterday alongside the launch of the second phase of PREDICT-PD (a new drive to recruit 10'000 participants to the study!) was the showcase of the Preventive Neurology Unit. The Preventive Neurology Unit is a new and exciting unit that is part of the Wolfson Institute at Queen Mary University London. The Wolfson Institute of Preventive Medicine has a proud history of leading the way in terms of cancer prevention and epidemiology with many high impact publications. Now, thanks to Barts Charity, we are trying to replicate some of the successful preventive techniques used in cancer and apply them to neurological diseases.

The showcase yesterday gave the three senior clinical lecturers the opportunity to explain some of their work and objectives as well as hearing from Professor Jack Cuzick and Professor Gavin Giovannoni about their hopes for this new unit.

The showcase began by Dr Charles Marshall explaining his work regarding the benefits and difficulties of diagnosing Alzheimer's disease as early as possible. Current research suggests that amyloid deposits can begin accumulating in patient's brains up to 20 years before they have any symptoms of dementia. This period before symptoms begin would be the ideal time to intervene with medications to prevent the onset of dementia but unfortunately there is no way to easily identify these people. Dr Marshall explained how the use of 'Brain Stress tests' could help to identify patients before they develop any symptoms of dementia and how his work will use these tests to see if people who will go onto develop Alzheimer's dementia can be identified earlier and therefore start treatments sooner.

Next up was Dr Alastair Noyce who explained the PREDICT-PD project which I am sure most readers of this blog are familiar with. Dr Noyce explained how the project evolved from a keyboard tapping test called the BRAIN test and now has 1000 participants who have been taking part over 5 years and will soon have 10'000 participants! The benefits of this research could be huge if we can begin to identify patients who are highly likely to develop Parkinson's before they suffer from any symptoms then we can begin to start trying to prevent Parkinson's in the first place. Dr Noyce also explained some fascinating results about Exenatide (a diabetes medication) which has recently been shown to potentially have some neuroprotective effect in Parkinson's and could be the first disease modifying medication for Parkinson's disease. Medications such as this would be ideal to use in further studies if PREDICT-PD can successfully identify those at high risk of Parkinson's.

The final talk about preventive approaches to Multiple Sclerosis was delivered by Dr Ruth Dobson. The complex links between EBV, childhood obesity and vitamin D levels were examined. Dr Dobson explained some of the intriguing results regarding EBV infection and Multiple Sclerosis and some of the difficulties of interpreting this relationship. The audience was also fascinated to hear about the links between foetal and neonatal vitamin D levels and MS. The main point that Dr Dobson emphasised is that a preventive approach to MS has to happen much earlier than the couple of years prior to diagnosis; the most important potential modifiable risk factors are all in early childhood or potentially in-utero!

Overall the showcase was very successful and the audience provided lots of insightful questions and interesting discussion. It is an exciting time to be working on preventive approaches to neurological disease and yesterday definitely highlighted that.

Flying the flag, and raising support

At PREDICT-PD nothing we do would be possible without our funding from Parkinson's UK. In clinic, we know how invaluable the support they give to people with Parkinson's all over the UK.

I have just received a wonderful phone call from Parkinson's UK, offering me one of their places in the London Marathon 2019. 

Please help me make groundbreaking research a reality, bring us closer to a cure, and provide life changing support to people with Parkinson's, by sponsoring me at here 

I'm aiming for a Good For Age time of under 3 hours, smashing over 20 minutes from my previous record. Every donation will spur me on through training in the long winter months between now and April. Follow my progress on Strava. Last weekend was my first 20 miler since the 2015 London marathon, and this Sunday I'm running in the Wimbledon Half marathon.

Wish me luck!

RNR

To D or not to D, that is the question

At medical school we learned about the role that vitamin D has in bone metabolism, including its transformation from a less active form made by the kidneys to the more active form, which requires adequate sunlight on the skin. Low levels would lead to rickets in children, and osteomalacia in adults. Northern climes were associated with fair skin to allow more of the active vitamin D to be made in the ‘weaker’ sunshine, and that between October and March, even the fairest skinned amongst us would be unable to get enough natural sunshine (I was at medical school in Sheffield).

Since then however, there seems to have been some “mission creep”. Vitamin D now has been associated with countless conditions that seem to have nothing to do with calcium and phosphate turnover. Low levels are associated with worse response to TB treatment; vitamin D supplements are given in the community to people with non-specific aches, pains and low levels of depression; low vitamin D increases your risk of stroke and heart attack.

The brain diseases are involved too. People with MS are exhorted to take on extra vitamin D; low vitamin D levels are associated with a higher incidence of dementia. There is clearly much we have to learn about this intruiging compound, and its functions are clearly much more complex than has previously been thought.

What about Parkinson’s disease? There are several ongoing studies of prodromal Parkinson’s disease – research identifying people who have the underlying process that causes PD, but haven’t yet developed the full motor manifestations that are necessary for the clinical diagnosis. PREDICT-PD is one (and although we are partial, we think it's the best one), but the PRIPS study in Europe and the PARS study in North America are also very well designed studies that are reporting key discoveries in the fight against Parkinson’s.

An article this week reported on the levels of vitamin D in participants of the PARS study. The authors compared those thought to be at high risk of PD based on poor smell and abnormal DaT scans (a kind of brain scan that looks at dopamine transporters) and found no differences between the two groups.

At the moment, therefore, there is no justification for recommending taking vitamin D supplements to reduce your risk of PD. On the other hand, as many of our blog posts have highlighted, getting out and about, and doing some exercise in the sunshine, or even taking a nice holiday to escape the brisk British November greyness, might well do you good!

RNR

https://www.ncbi.nlm.nih.gov/pubmed/28984598

J Alzheimers Dis. 2017;60(3):989-997. doi: 10.3233/JAD-170407.

Vitamin D and the Risk of Dementia: The Rotterdam Study.

Licher S^1,2, de Bruijn RFAG², Wolters FJ^1,2, Zillikens MC³, Ikram MA^1,2,4, Ikram MK^1,2.

Author information

Abstract

BACKGROUND:

Vitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results.

OBJECTIVE:

To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.

METHODS:

Within the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimer's disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership.

RESULTS:

At baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24).

CONCLUSION:

Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

Unrecognised vitamin D deficiency is common in Parkinson disease: a report from the Harvard Biomarker Study

The headline findings from this study are dramatic: patients with PD are nearly twice as likely as age matched controls to be deficient in vitamin D. Although this study does not reveal much regarding a possible causal role for vitamin D in PD, the results are clinically relevant.

An association between PD and low vitamin D levels has previously been reported in smaller observational studies (Sato et al., 1997; Evatt et al., 2008; Knekt et al., 2010) - although none of these found a correlation between vitamin D levels and disease severity. Further evidence for a causal role of vitamin D in PD come from genetic studies which have shown polymorphisms in the vitamin D receptor to be associated with increased risk of developing PD (Scherzner et al., 2007; Butler et al., 2011; Kim et al., 2005). Furthermore, in animal models of PD, vitamin D appears to have a neuroprotective effect (Wang et al., 2001). Taken together, this evidence points towards a link between vitamin D and Parkinson's disease, but up until now the studies have been small and subject to limitations.

This large case-control study provides new support for the existence of a relationship between PD and low vitamin D3 levels. Patients with PD were found to be nearly twice as likely as age matched controls to be deficient in vitamin D3 (17.6% vs 9.3%, p=0.002) and the degree of deficiency is correlated to the severity and duration of disease. However, after adjusting for age, sex, race and vitamin D3 supplementation the association between PD and vitD3 deficiency was only just statistically significant (p=0.047). As Raja Mahana points out in a response to the article, there was no adjusting for multiple statistical tests, which, if performed, may have tipped this value over the edge of the 95% cutoff for statistical significance (Mahana, 2013).

In addition, importantly, no significant association was found with total vitamin D levels, suggesting that vitamin D2 levels were not changed in patients with PD (they may even have been higher). The authors offer no explanation for these seemingly conflicting results - in fact, they do not mention this in their discussion at all.

This failure to discuss important negative findings, combined with the borderline statistical significance and the lack of correction for multiple comparisons mean this study should be treated with a degree of scepticism.

Further limitations include:

1. Confounding - some additional, unmeasured factors may account for the association
2. Generalisability - patients and controls were drawn entirely from two hospitals in a small area of Massachusetts and are therefore not representative of all patients with Parkinson's disease. Further studies in minority populations that may be at even higher risk of vitamin D deficiency are necessary.
3. Correlation does not imply causation - the association found in this study could be explained if vitamin D deficiency accelerates PD pathology or if PD predisposes to vitamin D deficiency, because of a reduced tendency to go outdoors (sunlight is needed for the body to synthesise vitamin D).

Therefore it is impossible to make any claims about whether vitamin D deficiency causes Parkinson's Disease or whether Parkinson's Disease results in vitamin D deficiency from the results of this study alone.

Nonetheless, this study does show that patients with PD are at a considerably increased risk of vitamin D deficiency, whether as a result of confounding/reverse causality or not. The issues of confounding and reverse causality are only really important for scientists trying to understand whether low vitamin D has a causal role in PD. From a clinical viewpoint, all that really matters is that patients with PD have an increased risk of being vitamin D deficient and this, combined with an increased risk of falls and fractures, makes patients with PD an important population in which to consider testing of vitamin D levels and supplementation (Dobson et al, 2013).

Ding H, Dhima K, Lockheart K et al. (2013). Unrecognized vitamin D3 deficiency is common in Parkinson disease Neurology DOI: 10.1212/WNL.0b013e3182a95818

Abstract: Unrecognized vitamin D3 deficiency is common in Parkinson disease

Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD).

Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 6 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study.

Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values 5 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6%of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up.

Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Additional references:

  

Butler MW, Burt A, Edwards TL, Zuchner S, Scott WK, Martin ER, Vance JM, Wang L (2011) Vitamin D receptor gene as a candidate gene for Parkinson disease. Ann Hum Genet 75: 201-210

Dobson R, Yarnall A, Noyce AJ, Giovannoni G (2013) Bone health in chronic neurological diseases: a focus on Multiple sclerosis and Parkinsonian syndromes. Pract Neurol 13: 70-79

Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V (2008) Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 65: 1348-1352

Kim JS, Kim YI, Song C, Yoon I, Park JW, Choi YB, Kim HT, Lee KS (2005) Association of vitamin D receptor gene polymorphism and Parkinson's disease in Koreans. J Korean Med Sci 20: 495-498

Knekt P, Kilkkinen A, Rissanen H, Marniemi J, Sääksjärvi K, Heliövaara M (2010) Serum vitamin D and the risk of Parkinson disease. Arch Neurol 67: 808-811

Mehanna R (2013) Is Parkinson's disease associated with deficit in Vitamin D? Neurology

Sato Y, Iwamoto J, Honda Y (2011) Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in Parkinson's disease. Parkinsonism Relat Disord 17: 22-26

Scherzer CR, Eklund AC, Morse LJ, Liao Z, Locascio JJ, Fefer D, Schwarzschild MA, Schlossmacher MG, Hauser MA, Vance JM, Sudarsky LR, Standaert DG, Growdon JH, Jensen RV, Gullans SR (2007) Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A 104: 955-960

Wang JY, Wu JN, Cherng TL, Hoffer BJ, Chen HH, Borlongan CV, Wang Y (2001) Vitamin D(3) attenuates 6-hydroxydopamine-induced neurotoxicity in rats. Brain Res 904: 67-75