The prodromes of Parkinson's

Following on nicely from our last post, we are delighted to publicise our latest peer-reviewed publication.

This will come out in a special edition of the European Journal of Neuroscience, dedicated to the memory of Tom Isaacs. Tom was the founder and leader of the Cure Parkinson's Trust - a truly dynamic leader and a real disruptive presence (in all the right ways) within  Parkinson's research. We are honoured to have our names and our ideas as testimonial to him in this way.

It is clear that Parkinson's is more of an umbrella condition than one single entity. For instance, some people have significant tremor, while others have none. Some progress very slowly, and a decade from diagnosis have barely any more symptoms - others progress more quickly. For many Parkinson's affects mainly movement while others have many non-motor symptoms. It is likely (although not yet proven) that these different subtypes of Parkinson's have a different underlying process causing them.

It therefore stands to reason that the earliest phases are also different. In our article we lay out the evidence that Parkinson's that comes from people with a particular kind of sleep disorder (REM sleep behavioural disorder), smell loss, and genetic forms do all look different. The evidence is not bomb-proof, but in Predict-PD we will be able to shed light on both the sleep disorder, smell loss and try and pick apart differences in the general population.

To see the article, please see the journal website. Please also remember to talk to friends and family to read more about the study and sign up themselves: www.predictpd.com

RNR

Comparing apples and apples

Drug trials (or trials of any new treatment for that matter) are designed by comparing a group on the new treatment against a group on something else. That may be no treatment, the best available treatment, or placebo (or dummy treatment). In order to make a fair comparison, it is essential to compare like with like.

An extreme example of this would be to say that “men are faster than women”, having compared the Jamaican mens olympic sprint team, against a selection of girls from the local secondary school. This is obviously ridiculous in so many ways: adult men vs teenage girls, trained atheletes vs untrained and so on…

In studies of Parkinson’s, it is also important that we compare like with like. For the past 50 years, researchers have used the “Hoehn and Yahr Scale” to create standardised definitions. (The scale is named after Margaret Hoehn and Melvin Yahr who pioneered research into progression and epidemiology of Parkinson’s in the 1960s.) Designed to give researchers a simple and global assessment of disease severity, this is probably the most widely used Parkinson’s staging system in use. According to the latest version of this scale there are 6 stages from 0= Asymptomatic to 5 = wheelchair bound or bedridden unless unaided.

Despite its widespread use, until now there have been no systematic attempts to prove how useful and reproducible it is. The researchers in this study assessed the acceptability, reproducibility, content and validity of the scale. They compared how different raters scored people (known as inter-rater reliability), and how that compared with other scoring systems of stiffness, tremor and other features of Parkinson’s. They also looked at whether the same assessor gave the same patient the same score at different times (known as test-retest reliability).

The good news is that inter-rater reliability and test-retest reliability are incredibly high. In other words, if one clinician judges a person to have stage II, so will almost every other (trained) clinician. It also correlated quite well with other physical assessment scores.

As ever, it is not a perfect test. The difference between stages is not the same (in other words, going from I to II is not the same as going from III-IV). Nor does it correlate at all well with quality of life. It also does not take into account non-motor features of Parkinson’s. Furthermore, only 2.9% of more than 3000 participants were at the most advanced stage V, so may not be quite as reliable for these people.

In summary, we have a pretty good measure of giving a number to the amount that an individual is affected by Parkinson’s. Until we have a blood test/scan/marker of progression, this is the best we have, and we need to make sure we have ways of addressing its weaknesses. Using it we can compare like with like, and, hopefully, get ever closer to preventing people advancing through the scale.

RNR

http://onlinelibrary.wiley.com/doi/10.1002/mds.27242/abstract;jsessionid=A596451DCF79B33BF34C1802EFD6E2CF.f04t03

Martinez-Martin P, Skorvanek M, Rojo-Abuin JM, Gregova Z, Stebbins GT, Goetz CG, et al. Validation study of the hoehn and yahr scale included in the MDS-UPDRS. Mov Disord. 2018 Jan 11;17:427. 

Brain Training

If the first maxim of a doctor is “First do no harm”, a close runner up should be “Use only treatments that work”. The bookshops and app-stores are full of brain training methods. For the most part, these are not evidence based and while entertaining, are unlikely to be the reason why someone is awarded a Nobel prize.

Targeted cognitive training however is perhaps a different kettle of fish. This study assessed the effects of a multi-domain cognitive training regime over three months, and then the residual effects after 18 months. Participants underwent a series of cognitive and behavioural tasks at each assessment. Some of the participants then went on to have MRI imaging at the later time point to see the effects.

The authors report increased cognitive function in several (alhtough not all) domains that was preserved even after a delay despite there overall Parkinson’s condition getting worse.

The imaging findings they report are very hard to interpret. In an earlier report of this study, 44 participants were randomised to either the REHACOP cognitive training programme that formed the intervention, and 19 were randomised to occupational therapy as a control. There was a high drop out rate (7/22 in the intervention group, 4/19 in the control group) which creates a high risk of bias. In this paper, only the participants in the brain training group had repeat imaging at 18 months. Therefore, the findings do not compare the intervention and controls, but just the intervention group to themselves 15 months later. Furthermore, the two of the authors hold copyright for the training programme, and this could create a financial conflict of interest.

While I hope that there can be evidence based treatments that can improve the thinking and behaviour of people with Parkinson’s disease, I think this paper has some significant issues such that it doesn’t provide the evidence that would make me change my practice.  

The search continues

http://rdcu.be/wdRA/

DOI: 10.1111/ene.13472

Long-term effects of cognitive rehabilitation on brain, functional outcome and cognition in Parkinson's disease

Abstract

Background

Cognitive rehabilitation has demonstrated efficacy in producing short-term cognitive and brain changes in Parkinson's disease (PD) patients. To date, no study has assessed the long-term effects of cognitive rehabilitation using neuroimaging techniques in PD. The aim was to assess the longitudinal effects of a 3-month cognitive rehabilitation program evaluating the cognitive, behavioural and neuroimaging changes after 18 months.

Methods

Fifteen PD patients underwent a cognitive, behavioural and neuroimaging assessment at pre-treatment (T₀), post-treatment (T₁) and after 18-months (T₂). This study examined the long-term effects (from T₀ to T₂) and the maintenance of the changes (from T₁ to T₂). T1-weighted, diffusion-weighted, functional magnetic resonance imaging (fMRI) during both a resting-state and a memory paradigm were acquired. Voxel-based-morphometry and tract-based-spatial-statistics were used for grey and white matter analyses. A ROI-to-ROI approach was used for resting-state functional connectivity (FC), and model-based for brain activation during the memory paradigm.

Results

PD patients showed increased cognitive performance, decreased functional disability, increased brain FC and activation at T₂ compared with T₀ (p<.05-FDR). Moreover, patients showed the maintenance of the improvements in cognition and functionality and the maintenance of the increased brain FC and activation at T₂ compared with T₁. However, significant grey matter reduction and alterations of white matter integrity were found at T₂ (p<.05-FWE).

Conclusions

Findings suggest that the improved cognitive performance and the increased brain FC and activation after cognitive rehabilitation were significantly maintained after 18 months in PD patients, despite the structural brain changes, consistent with a progression of neurodegenerative processes.