Friday, 22 September 2017

Such stuff as dreams are made?

Sleep seems to play an interesting role in neurodegenerative disease.  Sleep is important in many metabolic functions and there is some evidence to suggest that disruptions in sleep affect brain protein metabolism. As an example, amyloid beta is released at higher levels during wakefulness - so those who sleep less will be exposed to higher levels of the protein. Another aspect of interest is whether sleep disruption acts as a marker for early neurodegenerative disease, giving an early indication of the build up of abnormal proteins that characterise neurodegenerative disease.

So, disrupted sleep may be a cause or effect of neurodegenerative disease (and it's almost certainly a bidirectional relationship). But wouldn't it be nice if, rather than an expensive immunological treatment, we could prescribe sleep for our patients?

To tease out this relationship, investigators in the US have utilised the large community-based Framingham Heart Study. A sub-group of these participants had extensive sleep investigations and were followed up for dementia for up to 19 years afterwards. They were able to look at different stages of sleep and they found that less REM sleep, which tends to occur in the later stages of the night and is associated with dreaming, was associated with development of all types of dementia.  

As ever, there are difficulties with implying causality with this kind of observational study - whilst the authors controlled for multiple factors known to be associated with dementia risk there are likely to be other confounders - for example anxiety levels were not controlled for in this analysis. It will also be important to understand the role played by sleep disorders such as obstructive sleep apnoea and REM sleep behaviour disorder, which we are exploring in PREDICT.

Having said that, I for one will be using this as an excuse to get my full 8 hours..

Sleep architecture and the risk of incident dementia in the community.

Neurology. 2017 Sep 19;89(12):1244-1250. doi: 10.1212/WNL.0000000000004373. Epub 2017 Aug 23.

Pase MP, Himali JJ, Grima NA, Beiser AS, Satizabal CL, Aparicio HJ, Thomas RJ, Gottlieb DJ, Auerbach SH, Seshadri S

Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS).

Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years).

We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk.

Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia.

Tuesday, 19 September 2017


An article published in the journal Neurology last week confirms that James Parkinson’s legacy has been well and truly digitised.

Researchers in the USA completed a randomised controlled trial of tele-medicine for Parkinson’s disease. Tele-medicine is where the patient and physician are not face to face in a consulting room, but using technology similar to Skype or Facetime to have a consultation at the mutual convenience of both parties. The study showed that it is possible for physicians not only to listen to the patient’s problems, but also to examine them (using internationally recognised Parkinson’s specific examinations), and recommend medication changes that are then prescribed by the local GP.

Although quality of life for the patient and care giver was not better in the tele-medicine group compared to the face-to-face group, it did not get worse either. The telemedicine group felt they had excellent rapport with their ‘eDoc’, and it saved them a huge amount of time (and therefore money) by not having to travel to a regional neuroscience centre.

Although the UK and US are geographically very different, we do have some equivalent problems on this side of the pond. The Neurological Alliance has reported that the lack of neurologists is a major problem for people in the UK with neurological problems. Movement disorder specialists tend to be found only in regional referral hospitals. People with Parkinson’s in both countries have much greater difficulty than most patients in getting to appointments, particularly as the condition progresses.

This paper is also of particular relevance to the PREDICT-PD team. It shows that there is a very large desire and abillity of people with Parkinson’s to engage with online research. We will be recruiting 10,000 people from 60-80 to take part in PREDICT-PD. The researchers in this study were overwealmed by potential participants and even head to turn away almost 1 in 5 participants.

Important things for these researchers, and us too though, is that there is a potential bias due to the “digital divide” – the participants in this study were mainly white, well educated and willing and able to work online. We mustn’t leave behind people that don’t fit this mould.

National randomized controlled trial of virtual house calls for Parkinson disease

Objective: To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.
Methods: In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire–39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.
Results: A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] −2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70–120; p < 0.0001) and 38 miles per visit (95% CI 36–56; p < 0.0001).
Conclusions: Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience. identifier: NCT02038959.
Classification of evidence: This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.

Friday, 15 September 2017

How risky is risk scoring?

Here at PREDICT we are proponents of using evidence-based risk scoring to screen populations in an attempt to find those at the earliest stages of neurodegenerative disease. As my previous blog post shows, we are not the only team devising sensitive methods for risk statification. The drive to identify people at the early stages across the spectrum of neurodegenerative disease has become a major preoccupation of contemporary neuroscience. In keeping with this theme, earlier this year, the Movement Disorder Society (MDS) published research criteria to diagnose "probable prodromal" parkinson's disease.

But we have to remember the pitfalls of the approach, and this paper from an international group which seeks to evaluate the MDS criteria illustrates some of the difficulties. Whilst we hope to see disease modifying treatment for Parkinson's in the future, currently being "at-risk" confers relatively little advantage and is likely to cause anxiety and distress. Compounding this is the fact that some of those identified as high risk will still not go on to get the disorder, depending how high the risk cut-off score is set. In this combined study of 1348 participants, 2/5 who were identified as "probable prodomal" Parkinson's Disease eventually developed Parkinson's Disease. When the bar was set lower i.e. "probable prodromal" Parkinson's Disease, only 7/24 who fulfilled criteria went on to develop the disease. The participants had been followed up for a maximum of 6 years by the end of the study and with further follow up we may see larger numbers being diagnosed but this should strike a note of caution, and shows the score lacks sensitivity.

Risk scores in Parkinson's are still very much a research tool and clearly there is a long way to go before we would want to introduce them to the clinic. But there are great opportunities; whilst we need to refine scoring systems by continuing to identify the most sensitive markers, the differences in outcome in the high risk groups will also be worth studying for possible protective factors.

Mov Disord. 2017 Jul;32(7):1025-1034. doi: 10.1002/mds.27035. Epub 2017 May 16.

Application of the movement disorder society prodromal Parkinson's disease research criteria in 2 independent prospective cohorts.

Pilotto A, Heinzel S, Suenkel U, Lerche S, Brockmann K, Roeben B, Schaeffer E, Wurster I, Yilmaz R, Liepelt-Scarfone I, von Thaler AK, Metzger FG, Eschweiler GW, Postuma RB, Maetzler W, Berg D

The research criteria for prodromal PD of the MDS propose a new approach for the assessment of the individual probability of prodromal PD. These criteria require a testing of their reliability in different prospective cohorts.
The objective was to evaluate the MDS prodromal PD criteria in 2 independent prospective studies.
Prodromal PD probabilities of the Tübingen Evaluation of Risk Factors for Early Detection of Neurodegeneration cohort (TREND study, n = 650, recruited by the presence of probable rapid eye movement sleep behavior disorder, depression, and/or hyposmia or none of these at baseline and 2-, 4-, and 6-year follow-up) and the population-based Prospective Evaluation of Risk Factors for Idiopathic Parkinson's Syndrome cohort (PRIPS Tübingen subsample; n = 715, baseline and 3- and 5-year follow-up) were calculated. Baseline posttest probabilities, time to PD diagnosis, marker constellations, and longitudinal changes of prodromal PD probabilities were analyzed.
Incident PD cases (TREND, n = 10; PRIPS = 7) showed significantly higher likelihood ratios of risk and prodromal markers at baseline when compared with nonconverters. Only 2 of 17 incident PD cases met the criteria for probable prodromal PD (ie, posttest probability > 80%) and 5 had possible prodromal PD (ie, > 50%) 1.4 to 3.8 years before diagnosis. The criteria showed high specificity and negative predictive values (>98%), but low sensitivity (TREND, 30%; PRIPS, 14%) and positive predictive values (TREND, 19%, PRIPS, 50%). The individual risk for prodromal PD in incident PD cases showed an inverse correlation with the time to conversion (Spearman rho = .80, P = .006) and unlike in nonconverters, increased during follow-up.
The MDS prodromal criteria provide a practical framework for the calculation of prodromal PD risk. Although specificity of the criteria is high, most patients will not meet the criteria before diagnosis unless testing is thoroughly performed with numerous and highly specific markers objectively assessed. © 2017 International Parkinson and Movement Disorder Society.

Wednesday, 13 September 2017

Predicting Cognition in Parkinson's - Another risk score

The development of tools to predict risk of neurological disease is an ever expanding field. In PREDICT the algorithm used to predict risk of Parkinson's disease was based on a meta-analysis of symptoms preceding a diagnosis of Parkinson's in both cohort and case-control studies. Here the authors take a slightly different approach to look at the development of dementia in patients with Parkinson's Disease and use only longitudinal cohort studies to both develop and test a risk prediction model.

We already know from smaller studies that, similar to alzheimer's, factors such as age and lower educational attainment are associated with development of cognitive impairment in Parkinson's but this study took a far more robust approach, using a huge data set, looking at the significance of 9 clinical and genetic biomarkers and then replicating their findings in a further large data set. They found that 7 markers were informative or valid for use in the model and of these, age at onset of Parkinson's disease was responsible for over half the variance, followed by cognitive score (MMSE) at baseline. The score generated was highly accurate for prediction of global cognitive decline and for dementia. As an example, of participants scoring in the highest quartile, 51.7% had developed dementia at 10 years compared to 1.1% in the lowest quartile.

Clearly this score captures many of the important factors predictive of dementia in Parkinson's and is likely to be helpful in risk stratifying; but it doesn't tell us everything. The focus on only 9 factors from the outset probably limits the predictive value of the model. Further exploratory work in such large cohorts will take us even further.

Prediction of cognition in Parkinson's disease with a clinical-genetic score: a longitudinal analysis of nine cohorts.

Liu G, Locascio JJ, Corvol JC, Boot B, Liao Z, Page K, Franco D, Burke K, Jansen IE, Trisini-Lipsanopoulos A, Winder-Rhodes S, Tanner CM, Lang AE, Eberly S, Elbaz A, Brice A, Mangone G, Ravina B, Shoulson I, Cormier-Dequaire F, Heutink P, van Hilten JJ, Barker RA, Williams-Gray CH, Marinus J, Scherzer CR; HBS; CamPaIGN; PICNICS; PROPARK; PSG; DIGPD; PDBP.
Cognitive decline is a debilitating manifestation of disease progression in Parkinson's disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease.

In this longitudinal analysis, we built a prediction algorithm for global cognitive impairment (defined as Mini Mental State Examination [MMSE] ≤25) using data from nine cohorts of patients with Parkinson's disease from North America and Europe assessed between 1986 and 2016. Candidate predictors of cognitive decline were selected through a backward eliminated Cox's proportional hazards analysis using the Akaike's information criterion. These were used to compute the multivariable predictor on the basis of data from six cohorts included in a discovery population. Independent replication was attained in patients from a further three independent longitudinal cohorts. The predictive score was rebuilt and retested in 10 000 training and test sets randomly generated from the entire study population.

3200 patients with Parkinson's disease who were longitudinally assessed with 27 022 study visits between 1986 and 2016 in nine cohorts from North America and Europe were assessed for eligibility. 235 patients with MMSE ≤25 at baseline and 135 whose first study visit occurred more than 12 years from disease onset were excluded. The discovery population comprised 1350 patients (after further exclusion of 334 with missing covariates) from six longitudinal cohorts with 5165 longitudinal visits over 12·8 years (median 2·8, IQR 1·6-4·6). Age at onset, baseline MMSE, years of education, motor exam score, sex, depression, and β-glucocerebrosidase (GBA) mutation status were included in the prediction model. The replication population comprised 1132 patients (further excluding 14 patients with missing covariates) from three longitudinal cohorts with 19 127 follow-up visits over 8·6 years (median 6·5, IQR 4·1-7·2). The cognitive risk score predicted cognitive impairment within 10 years of disease onset with an area under the curve (AUC) of more than 0·85 in both the discovery (95% CI 0·82-0·90) and replication (95% CI 0·78-0·91) populations. Patients scoring in the highest quartile for cognitive risk score had an increased hazard for global cognitive impairment compared with those in the lowest quartile (hazard ratio 18·4 [95% CI 9·4-36·1]). Dementia or disabling cognitive impairment was predicted with an AUC of 0·88 (95% CI 0·79-0·94) and a negative predictive value of 0·92 (95% 0·88-0·95) at the predefined cutoff of 0·196. Performance was stable in 10 000 randomly resampled subsets.

Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson's disease. This model could improve trials of cognitive interventions and inform on prognosis.

Tuesday, 12 September 2017

Fighting Fit

A systematic review and meta-analysis of Tai Chi or Qigong has been published in the Journal of Parkinsonism and Related disorders.
It is fair to say that there have been no game-changing therapeutic breakthroughs in Parkinson’s since the licensing of levodopa in 1967. Although both Tai Chi and Qigong predate this discovery by thousands of years, this paper is a timely reminder that benefit doesn’t always come in pill form.

“Both [Tai Chi and Qigong] integrate balance, flexibility, and neuromuscular coordination training with a number of cognitive components, including heightened body awareness, focused mental attention, imagery, multi-tasking, and planned and goal-oriented training”

Meta-analyses can shine sunlight on an otherwise murky world of studies, trials and observations. By carefully taking all the published literature on a given topic, critically analysing the way the studies have been reported and conducted - looking in particular for risks of bias - and then putting all the small data sets together, the results are more than the sum of its parts.

This study confirms previously reported findings of better movement and balance, but was the first to undertake meta-analysis of the effects of these exercises by people with PD on depression and cognitive function.

The results are heartening. They found 15 studies from around the world (Italy, Germany, USA, Korea and China). Participants in their studies had on average mild-to-moderate PD, although there were participants with severe Parkinson’s. The average age is in keeping with what we see in the UK (mean 67.5 years). This reassures me that the findings reported are applicable to the majority of people with Parkinson’s in the UK.

Movement, balance and frequency of falls were generally robustly improved in those doing the exercises compared to those who had no treatment. The findings were not quite as marked in those who were given other forms of exercise (e.g. dance, aerobic or resistance training).

They also found that there was less depression vs controls (although this finding was quite weak when compared to people doing other forms of exercise) and a very robust finding of better quality of life, even when compared to other exercises. The effect on cognition wasn’t statistically significant but did suggest some improvement. The magnitude of the effect of Tai Chi/Qigong on quality of life is similar to that of Deep Brain Stimulation!

I am delighted with the results of this study, but I’m not surprised. This comes hot on the heels of the Lancet Commission on Dementia where physical and social exercise were key ways to protect the brain.

Effects of Tai Chi/Qigong on non-motor function. Data values indicate weight, effect size and confidence interval of LL (lower limit) to UL (upper limit).  
Plots to the left of zero indicate negative effect sizes for all outcomes in favor of Tai Chi (i.e. fewer symptoms). 
The last paragraph is interesting, and I reflected that had this been a study examining the effects of a drug, and the senior author was the CEO of a pharma company, my attitude would have been much more scathing!

"Conflict of interest
Financial disclosure
Peter Wayne is the founder and sole owner of the Tree of Life Tai Chi Center. Peter Wayne's interests were reviewed and managed by the Brigham and Women's Hospital and Partner's HealthCare in accordance with their conflict of interest policies."

Song R, Grabowska W, Park M, Osypiuk K, Vergara-Diaz GP, Bonato P, et al. The impact of Tai Chi and Qigong mind-body exercises on motor and non-motor function and quality of life in Parkinson's disease: A systematic review and meta-analysis. Parkinsonism Relat Disord. 2017 Aug;41:3–13. 

PURPOSE:To systematically evaluate and quantify the effects of Tai Chi/Qigong (TCQ) on motor (UPDRS III, balance, falls, Timed-Up-and-Go, and 6-Minute Walk) and non-motor (depression and cognition) function, and quality of life (QOL) in patients with Parkinson's disease (PD).

METHODS:A systematic search in 7 electronic databases targeted clinical studies evaluating TCQ for individuals with PD published through August 2016. Meta-analysis was used to estimate effect sizes (Hedges's g) and publication bias for randomized controlled trials (RCTs). Methodological bias in RCTs was assessed by two raters.

RESULTS:Our search identified 21 studies, 15 of which were RCTs with a total of 735 subjects. For RCTs, comparison groups included no treatment (n = 7, 47%) and active interventions (n = 8, 53%). Duration of TCQ ranged from 2 to 6 months. Methodological bias was low in 6 studies, moderate in 7, and high in 2. Fixed-effect models showed that TCQ was associated with significant improvement on most motor outcomes (UPDRS III [ES = -0.444, p < 0.001], balance [ES = 0.544, p < 0.001], Timed-Up-and-Go [ES = -0.341, p = 0.005], 6 MW [ES = -0.293, p = 0.06], falls [ES = -0.403, p = 0.004], as well as depression [ES = -0.457, p = 0.008] and QOL [ES = -0.393, p < 0.001], but not cognition [ES = -0.225, p = 0.477]). I(2) indicated limited heterogeneity. Funnel plots suggested some degree of publication bias.

CONCLUSION:Evidence to date supports a potential benefit of TCQ for improving motor function, depression and QOL for individuals with PD, and validates the need for additional large-scale trials.