Sunday, 15 October 2017

Smoking and age-at-onset of both motor and non-motor symptoms in Parkinson's disease

This is an interesting study that sets out to look at whether smoking history is associated with the age of onset of motor and non-motor symptoms in patients with PD.... lots of observational study data links smoking to a protective effect on PD.... it follows that in those that do get PD, smoking may delay the manifestation of certain signs. It is interesting that perhaps the features most indicative of synucleinopathies (motor signs and RBD) show the strongest associations with smoking status. Depression and constipation (although common in PD) are not PD specific and for constipation the prevalence appears low overall in this group. Ansomia here was ascertained using a questionnaire, which is in adequate because the correlation between objective and subjective anosmia is poor.

Parkinsonism Relat Disord. 2017 Sep 29. pii: S1353-8020(17)30354-1. doi: 10.1016/j.parkreldis.2017.09.022. [Epub ahead of print]
Gigante AF, Martino T, Iliceto G, Defazio G.

http://www.prd-journal.com/article/S1353-8020(17)30354-1/fulltext

INTRODUCTION: Several evidence suggest that smoking may decrease the risk of Parkinson's disease and is associated with an older age-at-onset of motor signs. The relation between smoking and age-at-onset of non-motor symptoms has never been analyzed. Objective of the study is to evaluate whether smoking habit and pack-years of smoking are associated with a delay of age-at-onset of motor signs, and of some non-motor symptoms.

METHODS: The study population consisted of 262 consecutive parkinsonian patients. Information on relevant demographic/clinical data focused on motor signs, REM sleep behavior disorder, constipation, depression, and hyposmia. Patients were stratified according to smoking habit (ever-versus never-smoker) and number of pack-years of smoking was computed. Repeatability of data on age-at-onset was checked 6 months after the initial interview in a randomly recruited subsample.

RESULTS: Smoking habit and number of pack-years smoked were associated with an older in age-at-onset of motor signs, REM sleep behavior disorder and depression. By contrast, smoking did not affect age-at-onset of hyposmia and constipation.

CONCLUSION: information from this study confirms that smoking may be associated with an older age-at-onset of motor signs, and that a similar effect can be observed on some non-motor symptoms like REM sleep behavior and depression.

Friday, 13 October 2017

200 years of Parkinson's Disease

2017 is an important year for Parkinson's research, as it marks 200 years since the seminal publication "An Essay on the Shaking Palsy" was published by James Parkinson. Based on careful observation (even from afar - a number of the 6 patients he described he "casually met with in the street"), it reads even today as a fantastic example of accurate clinical phenotyping and clear exposition.

The definition of the 'shaking paralysis' is very specific and recognisable:

"Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured"

and I think many patients would empathise with the description of the beginning of the disease 

"So slight and nearly imperceptible are the first inroads of this malady, and so extremely slow its progress, that it rarely happens, that the patient can form any recollection of the precise period of its commencement. The first symptoms perceived are, a slight sense of weakness, with a proneness to trembling in some particular part; sometimes in the head, but most commonly in one of the hands and arms".

It is instructive, looking back at the history of the disease, in what ways our concepts have changed. This special essay by a number of eminent Parkinson's specialists sheds some light on the very accurate descriptions of a number of features - the emphasis on specific characteristics of the tremor, the gait difficulties which lead to balance problems and risk of falls. The assumption that the intellect is uninjured is less accurate and there is a wealth of understanding now of the significance of non-motor features and clinical heterogeneity that is less well brought out in the original text. In the context of Parkinson's 200 year history, the authors underline the urgency of neuroprotective treatments, and the promising advances in neuroimaging and genetics.

I think field still has much to gain from employing Parkinson's transparent approach and humanity; his clarity when his thoughts are only "conjecture founded on analogy" and the hope that "the leading of the attention of those who humanely employ anatomical examination in detecting the causes and nature of diseases, particularly to this malady" will start to bear significant fruit before another 200 years passes.

http://onlinelibrary.wiley.com/doi/10.1002/mds.27115/full


Mov Disord. 2017 Sep;32(9):1264-1310. doi: 10.1002/mds.27115.
Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

Obeso JA, Stamelou M, Goetz CG, Poewe W, Lang AE, Weintraub D, Burn D, Halliday GM, Bezard E, Przedborski S, Lehericy S, Brooks DJ, Rothwell JC, Hallett M, DeLong MR, Marras C, Tanner CM, Ross GW, Langston JW, Klein C, Bonifati V, Jankovic J, Lozano AM, Deuschl G, Bergman H, Tolosa E, Rodriguez-Violante M, Fahn S, Postuma RB, Berg D, Marek K, Standaert DG, Surmeier DJ, Olanow CW, Kordower JH, Calabresi P, Schapira AHV, Stoessl AJ
This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.




Tuesday, 10 October 2017

Does Parkinson's change your personality?

Punctual, self-controlled, industrious, even-tempered. These are often traits that people aspire to in some way or another. They are also traits that seem to be overabundant in people with Parkinson’s disease.

At the heart of the disorder is a problem with neurotransmitters. Dopamine is the key player in the smooth movements controlled by the deep brain structures that are affected in PD, and loss of dopamine (by PD or something that mimics PD) results in the slow, stiff movements that are so characteristic of the disorder. PD is more than just a movement disorder though, and the same neurotransmitter is also responsible for decision making, thought process and reward seeking.

We understand that the underlying process that causes PD actually starts up to a decade before the person notices slowing, stiffness and tremor. We also know that there are some things that are well known to be harbingers of PD – for instance anxiety/depression, constipation, loss of sense of smell, particular sleep disorders.  There are also some things that seem to be ‘protective’ against the disease, for example smoking, high caffeine consumption and alcohol consumption.

Could all of these be linked by subtle changes to a person’s personality? For example, someone who is the ‘life and soul’ of the party (i.e. highly extrovert, with high novelty seeking behaviour) may be more likely to smoke and drink, and be less anxious and depressed.

When it comes to marrying these observations with Parkinson’s disease, I am left wondering, which is the chicken and which is the egg, and ultimately, can we ever work out which comes first?

This paper doesn’t answer the question, but it is a good place to start to understand where the current understanding comes from, from clinical, behavioural and biological perspectives.

As ever, please join the discussion below.

RNR


Personality in Parkinson's disease: Clinical, behavioural and cognitive correlates.
Gabriella Santangelo et al
J Neurol Sci, 2017 vol 374 pp17-25


Affective disorders and personality changes have long been considered pre-motor aspects of Parkinson's disease (PD). Many authors have used the term "premorbid personality" to define distinctive features of PD patients' personality characterized by reduced exploration of new environmental stimuli or potential reward sources ("novelty seeking") and avoidance behaviour ("harm avoidance") present before motor features. The functional correlates underlying the personality changes described in PD, implicate dysfunction of meso-cortico-limbic and striatal circuits. As disease progresses, the imbalance of neurotransmitter systems secondary to degenerative processes, along with dopamine replacement therapy, can produce a reversal of behaviours and an increase in reward seeking, laying the foundations for the emergence of the impulse control disorders. Personality disorders can be interpreted, therefore, as the result of individual susceptibility arising from intrinsic degenerative processes and individual personality features, in combination with extrinsic factors such as lifestyle, PD motor dysfunction and drug treatment. For a better understanding of personality disorders observed in PD and their relationship with the prodromal stage of the disease, prospective clinical studies are needed that correlate different personality profiles with other disease progression markers. Here, we review previous studies investigating the clinical, cognitive and behavioural correlates of personality traits in PD patients.

Friday, 6 October 2017

Same Same but Different: How many types of Parkinson's Disease are there?

To continue a theme from last week, it is vital that we continue to explore the role of neurotransmitters other than dopamine and structures other than the substantia nigra in the pathology of Parkinson's. I couldn't agree more with the first sentence from this paper, which itself offers a multi-disciplinary view of use of technology and smart analysis to unpick the heterogeneity we see in Parkinson's disease and understand what that means for the underlying disease process. 

"Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity"

Using existing datasets which have sought to characterise non-motor symptoms in Parkinson's, the authors utilise the statistical technique of cluster analysis to look for significant groupings of these symptoms. This is a great way of objectively validating what neurologists recognise in the clinic - that there are recognisable sub-types of Parkinson's disease, some more benign and some that progress quickly. 

They were able to identify 4 clusters - a mildly affected group, a predominantly non-motor symptom group, a tremor-dominant group with minimal non-motor symptoms and a group severely affected in all areas except tremor.  They also showed that there are clear groups of patients which are predominantly characterised by a specific symptom.

By further analysing these symptoms, interesting relationships were found - for example attention and memory problems were closely linked with drowsiness. Tremor was found to be the most isolated symptom - pointing to the likelihood of a quite different underlying disease process. 

From: Front Aging Neurosci. 2017 Sep 20;9:301. doi: 10.3389/fnagi.2017.00301.eCollection 2017

There seems to be a lot of promise with this approach in unpicking different aspects of the disease,  many of which can be picked up at a very early stage and will require different treatment approaches. 

-Anna


Front Aging Neurosci. 2017 Sep 20;9:301. doi: 10.3389/fnagi.2017.00301. eCollection 2017.
Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms

Mu J, Chaudhuri KR, Bielza C, de Pedro-Cuesta J, Larrañaga P, Martinez-Martin P

Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.

Available from: https://www.researchgate.net/publication/319933517_Parkinson%27s_Disease_Subtypes_Identified_from_Cluster_Analysis_of_Motor_and_Non-motor_Symptoms [accessed Oct 06 2017].

Thursday, 5 October 2017

High-dose transdermal nicotine in Parkinson's disease patients: a randomized, open-label, blinded-endpoint evaluation phase 2 study

This is a fairly small study to assess the effect of transdermal nicotine on PD motor symptoms. I really like the video UPDRS rating approach with raters that were blind to the treatment groups... we have used similar methods in the past. However, I am only aware of anecdotes, and perhaps some animal models of PD, that suggest motor improvements in established PD brought about by nicotine... the tantalising study is to see if nicotine affects risk of PD... i.e. not symptom benefit, but neuroprotection....

Eur J Neurol. 2017 Sep 28. doi: 10.1111/ene.13474. [Epub ahead of print]
Villafane G, Thiriez C, Audureau E, Straczek C, Kerschen P, Cormier-Dequaire F, Van Der Gucht A, Gurruchaga JM, Quéré-Carne M, Evangelista E, Paul M, Defer G, Damier P, Remy P, Itti E, Fénelon G.

http://onlinelibrary.wiley.com/doi/10.1111/ene.13474/abstract

BACKGROUND: Studies of the effects of nicotine on motor symptoms in Parkinson's disease (PD) brought out discordant results. The aim of the present study was to evaluate the efficacy and safety of high doses of transdermal nicotine on motor symptoms in PD.

METHODS: Forty PD patients were randomly assigned to a treated and untreated arm in an open-label study. Treated patients received increasing doses of nicotine to reach 90 mg/day by 11 weeks. This dosage was maintained for 28 weeks (W39), and then reduced over six weeks. Final evaluation was performed six weeks after washout. The main outcome measure was the off-dopa UPDRS motor score measured on video recordings by raters blinded to the medication status of the patients.

RESULTS: There was no significant difference in off-dopa UPDRS motor scores between the nicotine-treated and non-treated groups, neither at W39 (19.4±9.3 vs. 21.5±14.2), nor considering W39 differences from baseline (-1.5±12.1 vs. +0.9±12.1). PDQ-39 scores decreased in nicotine-treated patients and increased in non-treated patients, but the difference was not significant. Overall tolerability was acceptable, and 12/20 treated patients reached the maximal dosage.

CONCLUSIONS: High doses of transdermal nicotine were tolerated, but our study failed to demonstrate significant improvement in UPDRS motor scores. Improvement in unblinded secondary outcomes (UPDRS-II, UPDRS-IV, doses of L-dopa-equivalents) suggest a possible benefit for patients treated with nicotine, which should be confirmed in larger double blind, placebo-controlled studies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Wednesday, 4 October 2017

Caffeine as symptomatic treatment for Parkinson disease (Café-PD): A randomized trial

My comments on this paper for Medscape News:

The principal research question was whether caffeine could be a symptomatic treatment for PD. RCTs can be considered definitive when they are large enough and well conducted. Although this study seems to have been well conducted, the are some differences in the groups at baseline, such as smoking, gender and l-dopa doses, which may have relevance, and suggest that randomisation wasn’t perfect. The trial was halted early when an independent data monitoring committee agreed that it could not achieve its primary outcome. This was appropriate given what was seen in the interim analysis and the confidence intervals did not include the estimated treatment differences that they were expecting. The authors list a number of other limitations too.

Much of the epidemiological literature is undertaken with risk of PD as the outcome. First it is important to note that the factors that affect progression may not be the same as those affect risk and secondly whether we are talking about risk or progression, the current study was only really (at least at the first stage) designed to assess symptomatic benefit, not disease modification. For that reason, I think further work is required before one can rule out caffeine as a potential neuroprotective agent.

Neurology. 2017 Sep 27. pii: 10.1212/WNL.0000000000004568. doi: 10.1212/WNL.0000000000004568. [Epub ahead of print]

Postuma RB, Anang J, Pelletier A, Joseph L, Moscovich M, Grimes D, Furtado S, Munhoz RP, Appel-Cresswell S, Moro A, Borys A, Hobson D, Lang AE.

http://www.neurology.org/content/early/2017/09/27/WNL.0000000000004568.abstract

OBJECTIVE: To assess effects of caffeine on Parkinson disease (PD).

METHODS: In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life.

RESULTS: Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo).

CONCLUSION: Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects.

CLINICALTRIALSGOV IDENTIFIER: NCT01738178.

CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.

Tuesday, 3 October 2017

Neuro-protection - STAT

The last major breakthrough in Parkinson’s drugs was levodopa in 1967. That was 50 years ago and despite huge effort, no concrete progress has been made with a truly disease modifying or disease preventing drug in the meantime. Might the answer be staring us in the face?

Two truths are self evident: 1) Parkinson’s disease is more common as people age; 2) Vascular disease (such as heart disease and stroke) are also more common as people age.

Fortunately, there is much that can be done to reduce a person’s risk of having a stroke or heart attack. As well as exercise (yet another mention for the miracle cure), there is a wide selection of medicines that have excellent evidence of benefit.

In the UK, there have been two very large, very well conducted studies of people with early stage PD – the Tracking Parkinson’s study (PRoBaND) and the Oxford Discovery study. These studies give us an incredible opportunity to discover subtle findings that you need observations of thousands of people.

In the attached paper, many of the leaders of the British Parkinson’s disease field (including several professors from UCL) looked at the relationship between Parkinson’s and vascular treatment.

They found that in nearly 3000 people from across the UK with early stage PD, nearly 60% had increased risk of vascular disease, and yet only 1 in 4 of those people were having treatment for it.

Statins were designed as cholesterol lowering drugs. As they’ve been widely used, it seems there are lots more beneficial properties to statins. Such is the likelihood that they have a benefit to brain cells, there is a study of statins in MS and statins in Parkinson's underway currently. (For more information see this Queen Square MS centre page, and the PD STAT study site).

Whether or not statins work to protect the brain in humans remains to be seen (return here for the answer when the studies are published). What is clear is that if you have Parkinson’s, you should be asking your GP to assess your heart health!

Do you think Statins will be part of the answer? Do you think we're joining the dots enough, either individually between specialists, GPs and people with Parkinson's, or as a research community? Let us know your thoughts. Join the discussion below.

RNR


Statins are underused in recent-onset Parkinson's disease with increased vascular risk: findings from the UK Tracking Parkinson's and Oxford Parkinson's Disease Centre (OPDC) discovery cohorts.

BACKGROUND:Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately.

OBJECTIVES:To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype.

METHODS:Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment.

RESULTS:In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD.

CONCLUSIONS:Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment.


TRIAL REGISTRATION NUMBER:GN11NE062, NCT02881099.