Mild Parkinsonian Signs in a Community Population

One question that many of the PREDICT-PD participants ask me is “I am slower than I used to be, does it mean that I am getting Parkinson’s?”

I am interested in the early motor phases of Parkinson’s disease. They are subtle in appearance and usually start before the classical symptoms of Parkinson’s arise, which are slowness of movement, stiffness and tremor. 

When studying subtle abnormalities it is important to know the full range of normal amongst older people. It can be difficult to establish the boundaries between what is normal and abnormal, especially at very early stages of Parkinson’s and in older people.

What it is known is that mild parkinsonian signs or subtle motor symptoms are quite common in the elderly population (ranging from 15% to 50%). The question of whether their presence occurs as part of normal aging or as the result of neurodegeneration has not been clearly answered. 

Here I share a paper that tries to address the issue mentioned above. 

https://www.ncbi.nlm.nih.gov/pubmed/32310187?dopt=Abstract

Abstract.

Background: Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance.

Objective: To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson’s disease (PD) and cognition.

Methods: This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson’s Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment.

Results: Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8 +/- 6.9 years and without MPS was 66.1 +/- 5.9 years (p < 0.001). Multivariate analysis revealed that MoCA scores were significantly lower in the MPS group (b= –0.152, 95% CI = –0.009, –0.138, p < 0.05). A significant correlation between the presence of REM sleep behavior disorder (RBD) and total MPS scores (b= 0.107, 95% CI = 0.053, 1.490, p < 0.05) was also found. Neither vascular risk factors nor other premotor symptoms were significantly associated with MPS.

Conclusion: MPS is common and closely related to cognitive impairment and increasing age. Presence of RBD is predictive of higher MPS scores. This study highlights the necessity of other investigations or sensitive risk markers to identify subjects at future risk of PD.

The main purpose was to know how frequent subtle motor symptoms were in an elderly community without Parkinson´s and evaluate if these features were associated with a loss of cognitive abilities or other features known to be part of the early phase of Parkinson’s including reduced sense of smell, constipation, depression and sleep disturbances. 

To do that, participants were evaluated with motor and memory tasks as well as answering a self-reported questionnaire about the other symptoms mentioned. 

The authors found that one quarter of the group had subtle movement symptoms and this proportion increased with age, with 3 out of 10 people older than 75 having some kind of movement abnormalities. It is important to note that none of these symptoms were strong enough to make the diagnosis of Parkinson’s. They also found that cognitive and motor symptoms were highly associated.

We can extract several conclusions from these results. It is undeniable that once we get older our movement becomes slower and clumsier. The point here is when these motor symptoms occur together with mild memory problems it could mean that some neurodegenerative condition apart from simple aging is occurring.  

In order to these findings be more convincing, we would need to know how many of these people ended up having Parkinson’s or other conditions like Alzheimer’s over time. This was not reported in the study and so further studies are needed.

Cristina Simonet

NEW Research - Motor complications in Parkinson's disease: 13‐year follow‐up of the CamPaIGN cohort

Back on the blog for the first time in a long time...

This marks another NY resolution to speak and flag more about the research that I/we think is interesting or important in the early identification or prediction of PD. In addition, we like to mention good quality clinical and genetic studies that tell us more about PD in general (not just prediction and early identification). 

First off, the latest from the CAMPAIGN study. CAMPAIGN is one of the most rigorous and thorough long term studies of PD. The team have managed to follow up the people that they recruited with PD for a long, long time in order to help us learn more about the features that emerge over time.

In the present study, they show that eventually motor complications may be inevitable and that current drugs become less effective/predictable over time. Importantly they provide further support for the notion that levodopa replacement itself is not a cause of motor fluctuations and that thoughts about saving levodopa for the future (i.e. not starting after diagnosis) are probably outdated ideas.

Ultimately, whilst the available treatment options are good for most patients, the results here support our ongoing desire to find drugs that delay progression rather than just manage the symptoms...

The link to the study is here and it is open access (👌). The abstract is copied below.
https://onlinelibrary.wiley.com/doi/full/10.1002/mds.27882

Alastair Noyce

Cognitive decline in Parkinson's disease: the impact of the motor phenotype on cognition

This is a nice large study looking at the relationship between different motor features of Parkinson's and having more severe cognitive features.

We already know that patients with a mainly shaky (tremulous) form of Parkinson's tend a run a milder course compared to those patients that have a very slow & stiff (akinetic rigid) form of Parkinson's. For example, patients with the tremulous form of Parkinson's also seem to live for longer than those with the akinetic rigid form. Of course these categories overlap substantially but they are generally well recognised.

Here the researchers show that in patients who tended to be more slow and stiff, scores on a variety of cognitive tests were worse than in the patients that had predominant tremor.

The study design was cross-sectional, which means that movement and cognition were measured at the same time. This means that strict conclusions cannot be drawn about the progression of movement or cognitive abnormalities either separately or together. The explanation for the association between akinetic-rigidity and worse cognition is likely due to involvement of common structures brain (more so than the structures that are involved in tremor), the overall burden of disease (likely to be less in those with predominant tremor), and shared risk factors (including genetic determinants).

- Alastair Noyce

J Neurol Neurosurg Psychiatry. 2018 Oct 8. pii: jnnp-2018-319008. doi: 10.1136/jnnp-2018-319008.

Wojtala J, Heber IA, Neuser P, Heller J, Kalbe E, Rehberg SP, Storch A, Linse K, Schneider C, Gräber S, Berg D, Dams J, Balzer-Geldsetzer M, Hilker-Roggendorf R, Oberschmidt C, Baudrexel S, Witt K, Schmidt N, Deuschl G, Mollenhauer B, Trenkwalder C, Liepelt-Scarfone I, Spottke A, Roeske S, Wüllner U, Wittchen HU, Riedel O, Dodel R, Schulz JB, Reetz K.

https://jnnp.bmj.com/content/early/2018/10/07/jnnp-2018-319008.long

OBJECTIVES: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function.

METHODS: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration.

RESULTS: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314).

CONCLUSION: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.

Parkinson's ex machina

Last week Anna talked about the need to ensure the 'human' is kept at the centre of drug design for Parkinson's treatments - "focussing on human cells, tissues and subjects". Today I also want to discuss the role of humans in Parkinson's and the role of machines.

Neurology (and neurologists) take pride from being a bastion of clinical medicine - the heart and soul of our practice is listening to our patient and observing their every movement. In some ways neurology has not moved on much (in spirit) from the historic view of 'physicians' portrayed so poignantly by Sir Luke Fields. Movement disorders, and the diagnosis and management of Parkinson's are perfect examples of this human approach, with no equipment other than a tendon hammer necessary to make the diagnosis.

taken from https://www.tate.org.uk/art/artworks/fildes-the-doctor-n01522 with thanks

However, today's world has moved on leaps and bounds, and medicine and neurology are desperately trying to keep pace. In the 130 years since this scene was painted, our world has changed almost unrecognisably (although a Google image search of 'doctor' would make anyone believe that it is still delivered primarily by middle aged white men - which thankfully is less true now than ever).

It is old hat to say that technology continues at a blistering pace. Miniaturisation  has made yesterday's science fiction into the everyday. 'The Fantastic Voyage' described a vessel that was shrunk and inserted into a person's body to save them - well thrombectomy for stroke, stunting for heart attacks, and a video camera so small you can swallow it to get diagnostic pictures throughout the gut are all in routine clinical practice in the NHS today.

The Fantastic Voyage (1966) - picture from https://www.britannica.com/topic/Fantastic-Voyage

High street technology has revolutionised our lives. There is more processing power in my 4 year old iPhone than Armstrong, Aldrin and Collins had on Apollo 11. There is now an enormous market in wearable technology that will give you a beat-by-beat analysis of your heart rate, count your steps in a day, your calorie output, measure your power in watts on a bike, feet climbed on the stairs and just about any other metric you can imagine.

Just a small number of the dizzying array of activity tracking watches available on the high street (picture from  Groupon.co.uk)

All this brings me onto a review I have read, "Optimizing clinical assessments in Parkinson's disease through the use of wearable sensors and data driven modelling"

The article offers a review on some of the hardware software and statistical approaches to understanding the data. At its heart is the understanding that a neurologist sees their patient for perhaps 3 or 4 15-20 appointments in a year. That clearly leaves 8,759 hours per year where the neurologist has no ability to observe their patient move. Wearable technology brings us a (relatively) non-intrusive window into the 'real lives' of our patients. With the vast amounts of data that this can bring, we need very sophisticated algorithms to understand it, and we need to understand the computer science and mathematical constructs that underlie those algorithms.

Going further than mere observation is prediction - the holy grail in healthcare, and our clearly stated aim in PREDICT-PD. This article concludes by cautioning us about the variation in quality and output of this technology, but offering us the hope that these devices and underlying data analysis will improve clinical decision making, provide more personalised care, and better understand and highlight the differences in the manifestations of what we currently call 'Parkinson's disease', leading to better trials, treatments and one day - cure.

RNR

Remedies from the natural world

An article caught my eye this week as several comments received on this blog and in clinic relate to ‘natural’ remedies for Parkinson’s. To provide some background, my therapeutic philosophy is a common one: I will only prescribe or endorse treatments that have gone through robust, unbiased, reproducible testing, and where the benefits outweight the risks. I also believe that there are undoubtedly treatments that have the power to radically alter diseases that are under our noses in the natural world, and once they are identified, purified and tested, will revolutionise medicine. Exenatide is a perfect example: originally derived from the saliva of the Gila monster, this is now a powerful drug against diabetes and may even have the ability to halt or slow Parkinson’s. 

This article looks at whether blackberry juice can reduce levodopa-induced dyskinesia. The first thing to point out was that they didn’t test it in humans with Parkinson’s disease, this experiment involved the MPTP mouse model of Parkinson’s. Mice were given the same amount of levodopa and then different groups were given increasing doses of blackberry juice. The good news is that there was some benefit on the extra movements associated with ‘dopamine overdose’. However, this was mainly seen in the 15mL/kg group. To put this into a human context (assuming that it works as well in humans with Parkinson’s as mice with MPTP induced parkinsonism, which is a very  big assumption, a human would have to drink over a litre of pure blackberry juice per day to have less dyskinesia. 

Science is a journey of increments. These positive results may yield a useful weapon for people with Parkinson’s, but plenty of work needs to be done. I highly recommend blackberries, especially ones forraged on a nice walk in the woods, but I wouldn’t suggest they’re going to make your Parkinson’s better just yet.

RNR

Effects of blackberry (Morus nigra) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson's disease.

Fahimi Z¹, Jahromy MH¹.

J Exp Pharmacol. 2018 Jul 4;10:29-35. doi: 10.2147/JEP.S161782. eCollection 2018.

Abstract

BACKGROUND AND OBJECTIVE: 

Levodopa-induced dyskinesia (LID) is a movement disorder that occurs due to levodopa consumption for a long period to attenuate Parkinsonism. Plants have been the basis for medical treatments in human history and still widely practiced. Blackberry (Morus nigra) is one of the fruits rich in anthocyanin. The present study examined the effect of blackberry fruit juice on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice.

MATERIALS AND METHODS: 

In this study, 42 male mice were used, which were divided into six groups equally: one control group and five groups receiving MPTP injection. After confirmation of Parkinsonism in MPTP groups, one group was preserved without treatment and four other groups were treated with levodopa (50 mg/kg ip). After the onset of LID (2 weeks), one group was kept without additional treatment and three other groups were treated with three different doses of blackberry fruit juice (5, 10, and 15 mL/kg) with levodopa orally for 7 days. Abnormal involuntary movement scale (AIMS) and cylinder behavioral test were carried out according to the schedule. The collected data were analyzed using the SPSS software with the significant level of P<0.05.

RESULTS: 

Parkinson's disease was confirmed with AIMS test on the fourth day after MPTP injection. The onset of LID was observed after 2 weeks of levodopa treatment using both behavioral tests. The result of administration of M. nigra fruit juice for 1 week showed that this addition is useful in hindering LID. These effects were more pronounced at doses 10 and 15 mL/kg with nearly the same results on attenuating AIMS. Low dose of the fruit juice does not seem to affect LID significantly.

CONCLUSION: 

M. nigra fruit juice is effective to attenuate LID in an MPTP-induced Parkinson mice model.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2), to patients with Parkinson's who do not carry this mutation. They found that on average patients with the mutation tended to have a milder form of Parkinson's (i.e. they had lower motor impairment scores and better scores on memory and other cognitive tests). 

Even though mutations in LRRK2 are the commonest genetic cause of Parkinson's, they are still pretty rare overall and affect about 1% of all patients with Parkinson's. This proportion is higher in North Africans (such as those in this study).

These findings in many ways match ones clinical impression as well. I would say on average patients with LRRK2 Parkinson's tend to have milder symptoms and a lower burden of non motor symptoms. These features may also be less prominent in the phase of the disease before diagnosis compared with Parkinson's that is not related to LRRK2. Of course, this is all 'on average'. On an individual basis it can be very tricky to choose between patients that do or don't have an underlying genetic cause, unless they are particular young when it starts or have a strong family history....

- Alastair Noyce

Acta Neurol Scand. 2018 Jul 10. doi: 10.1111/ane.12996. [Epub ahead of print]
Ben Romdhan S, Farhat N, Nasri A, Lesage S, Hdiji O, Ben Djebara M, Landoulsi Z, Stevanin G, Brice A, Damak M, Gouider R, Mhiri C.

https://onlinelibrary.wiley.com/doi/abs/10.1111/ane.12996

OBJECTIVES: The LRRK2-G2019S mutation is the most common cause of Parkinson's disease (PD) in North Africa. G2019S-PD has been described as similar to idiopathic with minor clinical differences. The aim of this study was to determine the G2019S-related phenotype and to investigate gender and gene dosage effects on clinical features of G2019S carriers.

PATIENTS AND METHODS: The G2019S mutation was screened in 250 Tunisian patients with PD. Twenty-four patients carrying mutations in other PD genes were excluded. Logistic regression models were used to compare clinical features between the studied groups.

RESULTS: G2019S carriers (107 cases) and non-carriers (119 cases) were similar in disease duration, levodopa doses, and gender and phenotype distributions. However, carriers had a younger age at examination, higher level of education, and were more likely to report family history of PD and to develop PD at earlier age (P = 0.017). Adjusted for age, sex, disease duration, levodopa-equivalent dose and educational level, MMSE scores remained significantly higher (adjust P = 0.019) and UPDRS-III scores were lower (adjust P = 0.012) in the G2019S carriers than non-carriers. Demographic characteristics of men and women with G2019S mutation were similar, but men had higher level of education, better cognition (adjust P-value for educational level = 0.042) and less tendency towards depression than females (adjust P = 0.046). Furthermore, PD phenotype did not differ between the homozygous and heterozygous G2019S carriers.

CONCLUSION: In this study, G2019S carriers had a more benign phenotype than non-carriers. Cognitive impairment and depression were less common in G2019S male carriers compared with females. In addition, we found that LRRK2 gene dosage does not influence the severity of PD.

Application of the Movement Disorder Society prodromal criteria in healthy G2019S-LRRK2 carriers

This is an interesting application of the MDS Task Force criteria for prodromal PD. Here the Ashkenazi Jewish consortium applied the MDS criteria to non-manifesting carriers and non-carriers of the G2019S-LRRK2 mutation. 

Despite relatively small numbers of participants being diagnosed with PD during the follow-up period, they report impressive specificity of the criteria for idenitfying those in the pre-diagnostic (prodromal) phase of PD. 8 of the 10 patients (80%) that were diagnosed during follow-up were in the highest probability group at baseline. Unfortunately I could not find the raw data in the manuscript to determine how they arrived at 91.8 % specificity but working backwards from the reported specificity and positive predictive value I think there must have 9 out of 110 (8.2%) who were in the high probability group  at baseline, but did not subsequently get diagnosed with PD during follow-up. It will be interesting to see what happens to those participants with more time.

The positive predictive value (PPV) tells us about the probability of getting a diagnosis of PD over time if you are in the highest risk group at baseline. Based on the follow-up so far, 47% of people that screened positive at baseline have been diagnosed with PD. Whilst that's approximately 50:50 - if you imagine a scenario where a preventive treatment were available and the toxicity or side effects of that treatment were low then perhaps 50% PPV for a screening test is not widely inappropriate. Of course these data only apply to carriers of the G2019S LRRK2 mutation which in itself puts people at significantly higher risk of PD. The MDS Task Force criteria have been applied to other at risk cohorts, but we are in the final stages of applying them to the PREDICT-PD population-based cohort... watch this space.

- Alastair Noyce

Mov Disord. 2018 Mar 30. doi: 10.1002/mds.27342. [Epub ahead of print]
Mirelman A, Saunders-Pullman R, Alcalay RN, Shustak S, Thaler A, Gurevich T, Raymond D, Mejia-Santana H, Orbe Reilly M, Ozelius L, Clark L, Gana-Weisz M, Bar-Shira A, Orr-Utreger A, Bressman SB, Marder K, Giladi N; AJ LRRK2 Consortium.

https://onlinelibrary.wiley.com/doi/full/10.1002/mds.27342

BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD.

OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters.

METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point.

RESULTS: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers.

CONCLUSIONS: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.

 © 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.

Do subjects with minimal motor features have prodromal PD?

This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild parkinsonian signs (subtle bradykinesia, tremor, rigidity, gait disturbance) have Parkinson's disease pathology at post-mortem. The authors observed no PD pathology in participants without mild parkinsonian signs, moderate PD pathology in those with mild parkinsonian signs and frank PD pathology in those with a clinical diagnosis of PD. Some caution should be exercised that the group with mild parkinsonian signs was significantly older than the other two groups, but the pattern of pathology was not typically age-related.

Their observation add further weight the notion that there is a significant motor aspect to the phase of PD before diagnosis, as suggested by our group and others... (the citations in this paper relating to the previous literature on prodromal motor symptoms are a little light if you ask me ! 😀)... 

However this new study could turn out to be a landmark one. I (and some others) have long been asserting that the term 'premotor' may not be an appropriate one. Unless we have laid eyes on people with idiopathic anosmia, RBD or other non-motor prodromal features, then we can't be sure that there are no motor signs. The really important thing to work on now is characterising what specifically starts to change in terms of motor function in those that will eventually go on to get a diagnosis of PD? This is a major focus of the PREDICT-PD study over the next 3 years... and we are exploring this in a variety of ways...

Ann Neurol. 2018 Feb 8. doi: 10.1002/ana.25179. [Epub ahead of print]
Chu Y, Buchman AS, Olanow CW, Kordower JH.

http://onlinelibrary.wiley.com/doi/10.1002/ana.25179/full

BACKGROUND: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson's disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and α-synuclein pathology consistent with prodromal PD.

METHODS: Brain sections were obtained from older adults with a clinical diagnosis of PD (N=21) and without a clinical diagnosis of PD (N=27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n=9) or minimal motor features (n-18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and α-synuclein accumulation in the nigrostriatal system.

RESULTS: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that was intermediate between subjects with no motor deficit and PD. Phosphorylated α-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with α-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that was comparable in subjects with both minimal motor features and PD.

INTERPRETATION: Minimal motor features in older adults may represent prodromal PD and identify at risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression.

This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

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.

Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

Polygenic (or genetic) risk scores have become widely used in the study of common genetic variation and its role in disease... these risk scores are derived by combining the effects of the genetic variants identified in genome wide association (GWA) studies. GWA studies themselves are usually a comparison between the genetic variants that exist in a particular disease group (for example Parkinson's disease) compared with the variants seen in a healthy control group. Stringent levels of 'statistical significance' are applied to rule out false positive results and the regions that are identified are independent of one another. This independence means that the odds of the disease attributed to each variant/region can be multiplied together to give an overall genetic risk score for that disease. You can see how this might be useful for predicting who might get Parkinson's.

One can also calculate how much of the disease that the genetic risk score explains (usually only a very small amount). The genetic risk score for the present study came from here. There is now a bigger GWA study for Parkinson's that has been published too.

In the present study, the authors set out to see if the original genetic risk score that predicted the odds of getting PD also predicted the rate of disease progression in those that already have the disease, using cognitive and motor scores. It is not always the case that risk factors that are associated with getting a disease are also associated with more aggressive disease, but here we see evidence that this might be the case. Whether this is a reflection of common mechanisms underpinning risk and progression, or whether the original GWAS study contained an excess of patients with more aggressive forms of PD remains to be determined...

- Alastair Noyce


JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4206. [Epub ahead of print]
Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR.

https://jamanetwork.com/journals/jamaneurology/article-abstract/2669922?redirect=true

IMPORTANCE: Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.

OBJECTIVE: To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.

DESIGN, SETTING, AND PARTICIPANTS: This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.

MAIN OUTCOMES MEASURES: The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.

RESULTS: Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).

CONCLUSIONS AND RELEVANCE: Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

Progression in the LRRK2-Asssociated Parkinson Disease Population.

I think this is a really important study.

We have long suspected that patients with LRRK2-associated PD manifest Parkinson's in a different way to those that don't carry LRRK2 mutations. Here the authors show differences in the rate of progression of motor features – those with LRRK2-associated PD progress at a slower rate. This fits somewhat with notion that LRRK2 patients run a more benign course than 'regular PD' but what is at odds with this is that more of them had the postural instability gait disorder (PIGD) type of PD which is usually associated with a poor prognosis. The authors don't mention it much in the discussion but what is interesting to me is that the increase in PIGD type cases is not the result of a reduction in tremor-dominant cases, so much as a reduction in the indeterminate type. To me these observations lead to interesting questions:

1) Do LRRK2 patients fit into these two subtypes of PD better than those without LRRK2 mutations?? This is plausible because one would expect the pathology of LRRK2 to perhaps be less heterogeneous (even though a range of pathologies have been reported). 

2) Is there an imaging correlate for these different types in LRRK2 cases?

3) Does this tells us about the outcome measures we should be selecting for clinical trials in LRRK2 patients? And indeed,

4) Does it give us increased confidence that as a result of less heterogeneity (whether clinical or pathological) we would be more likely to detect an effect of a disease modifying therapy?

I was interested in the cognitive progression too. It fell short of nominal statistical significance but the MoCA is a relatively blunt tool for testing cognition and I expect that there would be differences in favour of slower progression in LRRK2 carriers if domains were studied more fully.

Important to exclude the GBA carriers in this work because they could bias the results, but there are other genetic factors that can influence seemingly monogenic forms of PD and should be kept in mind in future work.

- Alastair Noyce

JAMA Neurol. 2018 Jan 8. doi: 10.1001/jamaneurol.2017.4019. [Epub ahead of print]

Saunders-Pullman R, Mirelman A, Alcalay RN, Wang C, Ortega RA, Raymond D, Mejia-Santana H, Orbe-Reilly M, Johannes BA, Thaler A, Ozelius L, Orr-Urtreger A, Marder KS, Giladi N, Bressman SB; LRRK2 Ashkenazi Jewish Consortium.

https://jamanetwork.com/journals/jamaneurology/article-abstract/2668463?redirect=true

IMPORTANCE: Few prospective longitudinal studies have evaluated the progression of Parkinson disease (PD) in patients with the leucine-rich repeat kinase 2 (LRRK2 [OMIM 609007]) mutation. Knowledge about such progression will aid clinical trials.

OBJECTIVE: To determine whether the longitudinal course of PD in patients with the LRRK2 mutation differs from the longitudinal course of PD in patients without the mutation.

DESIGN, SETTING, AND PARTICIPANTS: A prospective comprehensive assessment of a large cohort of patients from 3 sites with LRRK2 PD or with nonmutation PD was conducted from July 21, 2009, to September 30, 2016. All patients of Ashkenazi Jewish ancestry with PD were approached at each site; approximately 80% agreed to an initial visit. A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. A total of 144 patients (26.4%) had the LRRK2 G2019S mutation. Patients with GBA (OMIM 606463) mutations were excluded from the analysis.

MAIN OUTCOMES AND MEASURES: Linear mixed-effects models for longitudinal motor scores were used to examine the association of LRRK2 mutation status with the rate of change in Unified Parkinson's Disease Rating Scale III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa-equivalent dose at baseline. Mixed-effects models were used to assess change in cognition, as measured by Montreal Cognitive Assessment scores.

RESULTS: Among the 545 participants, 233 were women, 312 were men, and the mean (SD) age was 68.2 (9.1) years for participants with the LRRK2 mutation and 67.8 (10.7) years for those without it. Seventy-two of 144 participants with the LRRK2 mutation and 161 of 401 participants with no mutation were women. The estimate (SE) of the rate of change in the Unified Parkinson's Disease Rating Scale III motor score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than among those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02). The estimate (SE) of the difference in the rate of change of the Montreal Cognitive Assessment score between those with the LRRK2 mutation (-0.096 [0.090] points per year) and those without the mutation (-0.192 [0.102] points per year) did not reach statistical significance (difference, 0.097 [0.055] points per year; P = .08).

CONCLUSIONS AND RELEVANCE: Prospective longitudinal follow-up of patients with PD with or without the LRRK2 G2019S mutation supports data from a cross-sectional study and demonstrates a slower decline in motor Unified Parkinson's Disease Rating Scale scores among those with LRRK2 G2019S-associated PD.

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis

Okay. Not strictly Parkinson's research but the BRAIN tap test comes from the PREDICT-PD team. Here we show that the BRAIN test can be used for detecting symptoms of Multiple Sclerosis (another disease of the nervous system). 

This gives support to the notion that the BRAIN test may be able to differentiate people with subtle signs of Parkinson's as opposed to those that have MS or stroke... the characteristics of alternate finger tapping may be different between these groups of patients.

The BRAIN test is already being used in a number of observational studies and a couple of clinical trials....

J Neurol. 2017 Dec 4. doi: 10.1007/s00415-017-8690-x. [Epub ahead of print]
Shribman S1, Hasan H2, Hadavi S3, Giovannoni G4, Noyce AJ5,6. Author information Abstract

https://link.springer.com/article/10.1007%2Fs00415-017-8690-x

BACKGROUND: The BRadykinesia Akinesia INcordination (BRAIN) test is an online keyboard-tapping test previously validated as a sensitive tool for detecting signs of Parkinson's disease.

OBJECTIVES: To determine whether the BRAIN test can measure disability in MS and identify the presence of pyramidal or cerebellar dysfunction.

METHODS: Kinesia scores (KS, number of key taps in 30 s), akinesia times (AT, mean dwell time on each key) and incoordination scores (IS, variance of travelling time between keys) were calculated in 39 MS patients. These were correlated against the Expanded Disability Status Scale (EDSS) scores, pyramidal and cerebellar functional system scores and 9-hole peg test scores.

RESULTS: EDSS correlated with KS (r = - 0.594, p < 0.001), AT (r = 0.464, p = 0.003) and IS (r = 0.423, p = 0.007). 9-HPT scores strongly correlated with KS (r = 0.926, p < 0.001). Pyramidal scores correlated with KS (r = - 0.517, p < 0.001). Cerebellar scores correlated with KS (r = - 0.665, p < 0.001), AT (r = 0.567, p < 0.001) and IS (r = 0.546, p = 0.007). Receiver operating characteristic curves demonstrate that KS can distinguish between the presence or absence of pyramidal and cerebellar dysfunction with area under curve 0.840 (p < 0.001) and 0.829 (p < 0.001), respectively.

CONCLUSIONS: The BRAIN test can remotely measure disability in MS. Specific scores differ according to the presence and severity of pyramidal or extrapyramidal dysfunction. It demonstrates huge potential in monitoring disease progression in clinical trials.