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

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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.

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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.

Changing Tack

In a very wide ranging and well written review, two leaders of the Parkinson’s field lay down set the terms of engagement and (to mix my combative metaphors), lay down the gauntlet in the quest to find disease modifying treatments.

After defining three kinds of ‘disease modification’ (neuroprotection: preventing the progression of PD; neurorescue: repairing damaged brain cells; neurorestoration: replacing what has been lost), they provide a brief but comprehensive overview of why every attempt so far has failed, from both a mechanistic perspective as well as a methodological perspective.

The key messages to take from this article are thus:

1.     We really need to stop thinking of Parkinson’s as a single condition. As well as many different ways that people experience their Parkinson’s (the different phenotypes), there are also many different molecular and cellular processes. Each person will likely have a different milieu of process that results in their particular phenotype.

2.     Once we can do this, we can start approaching disease modification in a more personalised way. This means recruiting the people with the right kind of Parkinson’s, at the right time, to the right study. We need to become much more sophisticated in the way we study new treatments, probably recruiting very specific groups of participants, for example people with particular genetic changes related to their Parkinson’s, and testing cocktails of treatments, rather than our current blunderbuss approach.

3.     Given that Parkinson’s is a complex, and slowly progressive condition, we must have better progression markers on which to design our studies.

This is going to require a lot of work, with the Parkinson’s population, scientists, clinicians, and industry. In order to get the highly effective treatments that our oncologists have avaiable to them, we need to change the terms of warfare.

What can we all do in the mean time? Pay attention to these three battles. Not necessarily throw the baby out with the bathwater if a particular study doesn’t prove miraculous (which it almost certainly won’t). And if you have Parkinson’s: exercise more!

At PREDICT-PD towers, we strongly believe that identifying the disease earlier, in the prodromal phase, will bring us closer to many of these objectives. Earlier disease is more likely to be simpler disease; it may be possible to identify early phenotypes that map onto particular pathological pathways; we have an opportunity to identify biomarkers that predict the development of established Parkinson’s, thus giving an ideal method of proving efficacy of new treatments.

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Disease modification in Parkinson's Disease: Current approaches, challenges, and future considerations.

Anthony E Lang and Alberto J Espay.

Mov Disord, 2018 vol. 386 p. 896.

http://doi.wiley.com/10.1002/mds.27360

The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

Using Smartphones and Machine Learning to Quantify Parkinson Disease Severity: The Mobile Parkinson Disease Score

Smart phone technology and app-based approaches for measuring PD symptoms and signs have been around for some time and there are seemingly innumerable companies and groups that all suggest that their approach is the best...

The results of this recent study published in JAMA Neurology do however look really impressive. I have always felt that given the heterogeneity of PD (motor and non-motor), a good measuring device will take account of multiple domains. This app measures voice, gait, balance, reaction time and finger tapping (which you might argue are exclusively motor)... but the results suggest that it does measure these really well. 

The hardest thing is to develop a tool that captures fluctuation well and objectively. Some purpose-built devices do (the PKG for example), but it is impressive to see these kind of results through utilisation of the standard hardware that comes with a smart phone. Furthermore the objective response to dopaminergic therapy is substantial and apparently clinically meaningful. 

Will we see this app used in clinical trials in the coming years... I expect we might!

- Alastair Noyce

JAMA Neurol. 2018 Mar 26. doi: 10.1001/jamaneurol.2018.0809. [Epub ahead of print]
Zhan A, Mohan S, Tarolli C, Schneider RB, Adams JL, Sharma S, Elson MJ, Spear KL, Glidden AM, Little MA, Terzis A, Dorsey ER, Saria S.

https://jamanetwork.com/journals/jamaneurology/fullarticle/2676504

IMPORTANCE: Current Parkinson disease (PD) measures are subjective, rater-dependent, and assessed in clinic. Smartphones can measure PD features, yet no smartphone-derived rating score exists to assess motor symptom severity in real-world settings.

OBJECTIVES: To develop an objective measure of PD severity and test construct validity by evaluating the ability of the measure to capture intraday symptom fluctuations, correlate with current standard PD outcome measures, and respond to dopaminergic therapy.

DESIGN, SETTING, AND PARTICIPANTS: This observational study assessed individuals with PD who remotely completed 5 tasks (voice, finger tapping, gait, balance, and reaction time) on the smartphone application. We used a novel machine-learning-based approach to generate a mobile Parkinson disease score (mPDS) that objectively weighs features derived from each smartphone activity (eg, stride length from the gait activity) and is scaled from 0 to 100 (where higher scores indicate greater severity). Individuals with and without PD additionally completed standard in-person assessments of PD with smartphone assessments during a period of 6 months.

MAIN OUTCOMES AND MEASURES: Ability of the mPDS to detect intraday symptom fluctuations, the correlation between the mPDS and standard measures, and the ability of the mPDS to respond to dopaminergic medication.

RESULTS: The mPDS was derived from 6148 smartphone activity assessments from 129 individuals (mean [SD] age, 58.7 [8.6] years; 56 [43.4%] women). Gait features contributed most to the total mPDS (33.4%). In addition, 23 individuals with PD (mean [SD] age, 64.6 [11.5] years; 11 [48%] women) and 17 without PD (mean [SD] age 54.2 [16.5] years; 12 [71%] women) completed in-clinic assessments. The mPDS detected symptom fluctuations with a mean (SD) intraday change of 13.9 (10.3) points on a scale of 0 to 100. The measure correlated well with the Movement Disorder Society Unified Parkinson Disease's Rating Scale total (r = 0.81; P < .001) and part III only (r = 0.88; P < .001), the Timed Up and Go assessment (r = 0.72; P = .002), and the Hoehn and Yahr stage (r = 0.91; P < .001). The mPDS improved by a mean (SD) of 16.3 (5.6) points in response to dopaminergic therapy.

CONCLUSIONS AND RELEVANCE: Using a novel machine-learning approach, we created and demonstrated construct validity of an objective PD severity score derived from smartphone assessments. This score complements standard PD measures by providing frequent, objective, real-world assessments that could enhance clinical care and evaluation of novel therapeutics.

Parkinson's in the community

This article, which comes from a large UK study of Parkinson's Disease (PRoBaND), is an important snapshot of the impact of Parkinson's across the country today. The authors focus particularly on the most common genetic risk factor for Parkinson's - the GBA mutation. This mutation is of particular interest as it is associated with a rarer syndrome - Gaucher's Disease. In this disease, which is a lysosomal storage disorder, lipids accumulate in cells and there is disruption of the normal lysosomal function which is to digest and dispose of unwanted materials. The implication from this association is that a similar process may be involved in Parkinson's Disease.

However, most people with Parkinson's do not have this mutation. Here, over 2000 patients were recruited from across the country and of these, 1893 patients underwent genetic testing. In total a minority, 142 of these patients had mutations in the GBA gene. Of these, the majority, around 2/3 had mutations not linked with Gaucher's Disease, while the other 1/3 has mutations exactly the same as those seen in Gaucher’s disease. There were differences between carriers of these two different types of mutation, with those who had the Gaucher's Disease mutations more likely to have a severe form of the disease - younger at onset, with faster progression and higher medication requirements. While previous studies have reported more cognitive impairment in GBA carriers, this was not bourne out by this study.

We still have a long way to go in connecting the dots in genetics - a number of patients had mutations whose significance is unknown and only 10% of patients had any mutations in this gene. It may be that GBA-related Parkinson's represents a slightly different disease which may have different underlying pathology and treatment options from other forms. However, the connection between lysosomal storage disorders and Parkinson's is increasingly strong and the hope is that these connections will allow us to unlock mechanisms and develop specific treatments.

http://jnnp.bmj.com/content/early/2018/01/28/jnnp-2017-317348

J Neurol Neurosurg Psychiatry. 2018 Jan 29. pii: jnnp-2017-317348. doi: 10.1136/jnnp-2017-317348.

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR; PRoBaND clinical consortium.

OBJECTIVES:

To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function.

METHODS:

We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia.

RESULTS:

We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage.

CONCLUSIONS:

Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.