Wednesday, 15 November 2017

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!


J Alzheimers Dis. 2017;60(3):989-997. doi: 10.3233/JAD-170407.
Vitamin D and the Risk of Dementia: The Rotterdam Study.
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.
To determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.
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.
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).
Lower serum vitamin D concentrations are associated with a higher incidence of dementia.

Friday, 10 November 2017

Cognitive changes before Parkinsons: Requires ATTENTION to detail

There are a number of studies now, including PREDICT-PD which are profiling healthy people thought to be at risk of Parkinsons. PARS is one of the key studies in the field and has previously reported poorer cognition in their high risk group - people who have both smell loss and evidence of dopamine deficit on imaging.

The study has now published longitudinal data on cognition in the group of participants with smell loss. Of 10 participants who went on to develop Parkinsons there were poorer overall cognitive scores and executive function scores at baseline. An analysis of the association between dopamine deficit on imaging and cognition showed that reduction in dopamine predicted poorer attention and processing speed over time.

The results overall are borderline in terms of statistical significance but that's not necessarily surprising. We know that smell loss is non-specific and a risk factor for other neurological diseases so all the participants analysed here are likely to perform worse than the general population. The numbers are also probably too small to show statistically significant changes. I think the association between dopamine and poorer attention is interesting, suggesting that this domain of cognition (rather than executive function changes) may be particularly sensitive for tracking changes in Parkinsons risk over time.


Mov Disord. 2017 Oct 24. doi: 10.1002/mds.27189. [Epub ahead of print]

Cognition and the course of prodromal Parkinson's disease.

Weintraub D, Chahine LM, Hawkins KA, Siderowf A, Eberly S, Oakes D, Seibyl J, Stern MB, Marek K, Jennings D; PARS Investigators.

Prospective data on cognition in prodromal Parkinson's disease are limited. The objectives of this study were to assess in prodromal PD (1) if baseline cognition predicts conversion to clinical PD, (2) if baseline dopamine transporter binding predicts longitudinal changes in cognition, and (3) if impaired olfaction predicts future cognitive decline.

Prodromal participants were 136 hyposmic individuals enrolled in the Parkinson Associated Risk Study. We examined baseline neuropsychological test performance in PD converters versus nonconverters and the association between baseline dopamine transporter binding and change in cognition. An additional 73 normosmic individuals were included in analyses of the relationship between hyposmia and cognitive decline.

In prodromal participants, baseline cognitive scores did not significantly predict conversion, but converters performed numerically worse on 5 of the 6 cognitive domains assessed, with the greatest differences in executive function/working memory (0.68 standard deviation lower) and global cognition (0.64 standard deviation lower). Lower baseline dopamine transporter binding predicted greater future decline in processing speed/attention (P = 0.02). Hyposmia predicted greater future decline in language (P = 0.005) and memory (P = 0.01) abilities.

Given hyposmia in the general population predicts cognitive decline, the role of cognition in predicting conversion in prodromal PD needs to be assessed in large cohorts followed long-term. The dopamine system may be associated with changes in processing speed/attention in individuals at risk for PD. © 2017 International Parkinson and Movement Disorder Society.

Wednesday, 8 November 2017

Semiquantitative Analysis of Dopamine Transporter Scans in Patients With Parkinson Disease

There are a number of quantitative software packages for use with DAT-SPECT imaging... these ideally need to be compared head to head to determine which is the most useful... particularly in the prodromal phase the change in DAT-SPECT may be slight and hard to discern through visual reads. This is a good use of PPMI data which is now available for download and use...

There likely exists a floor effect of binding in established PD and the slope of change in binding is likely to be greatest in the early stages (pre- and immediately post- diagnosis)... interested in the correlation between SBR and motor severity here too... 

Clin Nucl Med. 2017 Nov 3. doi: 10.1097/RLU.0000000000001885. [Epub ahead of print]
Tinaz S, Chow C, Kuo PH, Krupinski EA, Blumenfeld H, Louis ED, Zubal G.

PURPOSE: Dopamine transporter (DaT) imaging is an adjunct diagnostic tool in parkinsonian disorders. Interpretation of DaT scans is based on visual reads. SBRquant is an automated method that measures the striatal binding ratio (SBR) in DaT scans, but has yet to be optimized. We aimed to (1) optimize SBRquant parameters to distinguish between patients with Parkinson disease (PD) and healthy controls using the Parkinson's Progression Markers Initiative (PPMI) database and (2) test the validity of these parameters in an outpatient cohort.

METHODS: For optimization, 336 DaT scans (215 PD patients and 121 healthy controls) from the PPMI database were used. Striatal binding ratio was calculated varying the number of summed transverse slices (N) and positions of the striatal regions of interest (d). The resulting SBRs were evaluated using area under the receiver operating characteristic curve. The optimized parameters were then applied to 77 test patients (35 PD and 42 non-PD patients). Striatal binding ratios were also correlated with clinical measures in the PPMI-PD group.

RESULTS: The optimal parameters discriminated the training groups in the PPMI cohort with 95.8% sensitivity and 98.3% specificity (lowest putamen SBR threshold, 1.037). The same parameters discriminated the groups in the test cohort with 97.1% sensitivity and 100% specificity (lowest putamen SBR threshold, 0.875). A significant negative correlation (r = -0.24, P = 0.0004) was found between putamen SBRs and motor severity in the PPMI-PD group.

CONCLUSIONS: SBRquant discriminates DaT scans with high sensitivity and specificity. It has a high potential for use as a quantitative diagnostic aid in clinical and research settings.

Tuesday, 7 November 2017

Let them eat cake!

There has been some interesting work on weight and its link to Parkinsons coming out in the last few years including Alastair's paper, which suggested a protective effect of higher BMI for future development of Parkinsons disease. However, there have also been observational studies linking increased BMI in mid-life to future risk of Parkinson's disease.

This paper, from a group in Aberdeen, looks at a cohort of patients from initial diagnosis of Parkinsons disease or atypical parkinsonism with yearly follow up and includes an age and sex-matched control group who didn't develop the disease. It is illuminating from two points of view - firstly for the weight differences between people just diagnosed with Parkinson's and their healthy contemporaries and secondly for the impact of weight loss in Parkinsons and atypical Parkinsonism.

Even very early in the disease, at diagnosis, people with Parkinsons are likely to weigh significantly less than healthy controls, with an average weight of 72.5kg vs 77.3kg.  Weight loss after diagnosis is also important - it was associated with dementia, higher dependency and mortality. The only significant predictor of weight loss was older age.

These findings raise a lot of questions - given that lower weight is present at diagnosis and therefore presumably prior to diagnosis - is weight loss or low weight a risk factor for Parkinsons or is it part of the prodromal stage of the disease? If it is part of the prodrome, is it due to reduced appetite, increased energy demands or secondary to other prodromal features - is eating less pleasureable due to smell loss?

For patients already diagnosed with Parkinsons, monitoring weight and addressing factors that may affect appetite and eating are important, especially because of the prognostic implications. But while this paper identifies the link, it's not able to address causality directly - so the question of whether weight acts as a marker of disease risk and more severe disease once diagnosed or contributes directly to worse outcomes remains unanswered. Sadly it's still unclear if targeted intervention as suggested in the article i.e.eating more cake, has any effect on outcomes.


Neurology. 2017 Oct 27. pii: 10.1212/WNL.0000000000004691 doi:10.1212/WNL.0000000000004691. [Epub ahead of print]

Early weight loss in parkinsonism predicts poor outcomes: Evidence from an incident cohort study.

Cumming K, Macleod AD, Myint PK, Counsell CE

To compare weight change over time in patients with Parkinson disease (PD), those with atypical parkinsonism, and matched controls; to identify baseline factors that influence weight loss in parkinsonism; and to examine whether it predicts poor outcome.
We analyzed data from the Parkinsonism Incidence in North-East Scotland (PINE) study, an incident, population-based prospective cohort of parkinsonian patients and age- and sex-matched controls with annual follow-up. Mixed-model analysis described weight change in patients with PD, those with atypical parkinsonism, and controls. Baseline determinants of sustained clinically significant weight loss (>5% loss from baseline) and associations between early sustained weight loss and death, dementia, and dependency in parkinsonism were studied with Cox regression.
A total of 515 participants (240 controls, 187 with PD, 88 with atypical parkinsonism) were followed up for a median of 5 years. At diagnosis, atypical parkinsonian patients had lower body weights than patients with PD, who were lighter than controls. Patients with PD lost weight more rapidly than controls, and weight loss was most rapid in atypical parkinsonism. After multivariable adjustment for potential confounders, only age was independently associated with sustained clinically significant weight loss (hazard ratio [HR] for 10-year age increase 1.83, 95% confidence interval [CI] 1.44-2.32). Weight loss occurring within 1 year of diagnosis was independently associated with increased risk of dependency (HR 2.11, 95% CI 1.00-4.42), dementia (HR 3.23, 95% CI 1.40-7.44), and death (HR 2.23, 95% CI 1.46-3.41).
Weight loss occurs in early parkinsonism and is greater in atypical parkinsonism than in PD. Early weight loss in parkinsonism has prognostic significance, and targeted dietary interventions to prevent it may improve long-term outcomes.

Friday, 3 November 2017

Fast-track approvals and Hippocrates - an old problem revisited

The UK news today announced government plans to fast-track drugs through the approval process (see this article from the BBC).

It is true that the approvals process is arduous and hugely costly. In a 2014 report examining the approvals process through different divisions of the US regulator, the FDA, the difference between the slowest and fastest divisions for median approval time was 400 days, i.e. over a year. It comes as little surprise to neurologists and people suffering neurological problems that the slowest was neurology and the fastest was cancer and antiviral drugs.

A significant risk of rushing things through is that vital safety signals get lost. In cancer, where a last-ditch drug might extend survival by a few weeks or months in a rapidly progressing fatal condition, these risks may be outweighed by the benefit given. However, in neurological diseases such as Parkinson’s disease, where people live with the condition for decades, even small risks must be given much greater weight. The chances of complete cure are low, and the number of patients that may be treated with it are much higher.

The Hippocratic oath instructs the physician to “First do no harm”. While we all strive to find the silver bullet for conditions such as Parkinson’s disease, motor neurone disease and so many others that cause such distress and suffering, we must ensure that we do so safely and effectively. We depend on a rigorous regulatory system to protect the public, but also to examine their processes and ensure the costs (both financial and opportunity costs to patients) are kept to a minimum.


NB these opinions are my own. We're keen to hear yours - please comment below.

For a very eloquent summary of the dillemas facing the FDA and how the fast-track process relates to neurology I recommend this article from the Lancet Neurology

Does neurology need a faster FDA?
Adrian Burton

The Lancet Neurology, 2014 vol 13(8) pp760-761.

Monday, 30 October 2017

On Thinking and Feeling

Sarah Getz and Bonnie Levin have published a broad and wideranging review of cognitive and neuropsychiatric symptoms in early PD.

The bottom line of this article underscores the tennet that PD is not just a movement disorder!

Although a noticeable proportion of people with PD may develop dementia, a significant body of work has shown that even at the earliest stages (including the prodromal or pre-motor stages), there are detectable memory deficits. One particular aspect of difficulty is in ‘executive function’ – the thinking process that allows for planning, initiating and concentrating on a task as well as ‘thinking outside the box’. I think this has interesting significance when considering the daily function of people with Parkinson’s, such as driving (see an earlier blog post from the PREDICT-PD blog).

Depression, fatigue and apathy are all very common symptoms that have a major impact on the quality of life of people with PD, not to mention their family and caregivers. Fatigue has been reported to occur in up to 2 in every 3 people with PD and has been described as the most debilitating symptom. Apathy is a real danger – muscles, be they physical, cognitive or emotional, need use. Apathy robs the person of the drive to exercise those muscles and thereby jeopardises their future ability to move, think and feel as they once did. It goes hand in hand with depression and also with increasing disability do to PD.

As we learn more about these less visible aspects of PD, we now need to search for ways to treat them. This is particularly important as the bedrock of PD treatment may make some aspects of thinking and feeling worse.


Cognitive and Neuropsychiatric Features of Early Parkinson's Disease.
Getz SJ, Levin B.
Arch Clin Neuropsychol. 2017 Nov 1;32(7):769–85. 

The clinical definition of Parkinson's disease (PD) is based on cardinal motor features including bradykinesia as well as an additional symptom of tremor, postural instability, or rigidity. Evidence from neuropathological, imaging, and clinical research suggests a premotor, early phase of PD pathology. Further understanding of the earliest biomarkers of PD is crucial for the development of neuroprotective, disease modifying, cognitive, and psychiatric interventions. Recent research has explored early non-motor markers of PD pathology. This issue is especially timely as the International Parkinson and Movement Disorder Society has recently provided a research definition for prodromal PD which includes combinations of prodromal markers and risk factors aimed at identifying target populations for disease-prevention trials. In this review of early PD, we will outline early non-motor symptoms, early cognitive and neuropsychiatric features, neuropsychological assessment strategies, emerging evidence for early biomarkers, and treatment recommendations.

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 m...