Wednesday, 30 March 2016

Loss of Dorsolateral Nigral Hyperintensity on 3.0 Tesla Susceptibility-Weighted Imaging in Idiopathic Rapid Eye Movement Sleep Behavior Disorder

Very interesting... I feel strongly that MRI will give us appropriate markers for PD and related disorders with time...

Ann Neurol. 2016 Mar 26. doi: 10.1002/ana.24646. [Epub ahead of print]
De Marzi R, Seppi K, Högl B, Müller C, Scherfler C, Stefani A, Iranzo A, Tolosa E, Santamarìa J, Gizewski E, Schocke M, Skalla E, Kremser C, Poewe W.

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel MRI marker for Parkinson's Disease (PD), in 15 subjects with idiopathic REM sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HC) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate seen in PD and is in contrast to findings in HC. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD.

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder

This is a good use of PPMI and fits with what one would expect clinically...these patients do tend to be at the more severe end of the spectrum and so it is little surprise that the cognitive features are more prominent...

Parkinsonism Relat Disord. 2016 Mar 12. pii: S1353-8020(16)30060-8. doi: 10.1016/j.parkreldis.2016.03.006. [Epub ahead of print]
Chahine LM, Xie SX, Simuni T, Tran B, Postuma R, Amara A, Oertel WH, Iranzo A, Scordia C, Fullard M, Linder C, Purri R, Darin A, Rennert L, Videnovic A, Del Riva P, Weintraub D.

Cognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains.

Parkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ≥6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates.

The baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (β = -0.34, 95%CI -0.54, -0.13, p < 0.001), Symbol Digit Modalities Test (β = -0.69, 95%CI -1.3, -0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (β = -0.21, 95%CI -0.41, -0.013, p = 0.037).


Possible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.

Tuesday, 29 March 2016

Pathological alpha-synuclein in gastrointestinal tissues from prodromal parkinson's disease patients

Important result this... I haven't seen the paper in full yet but conformation of staining in the past appeared just as important as whether there is any staining or not... previous studies have found a high proportion of controls also stain positive. Particularly interesting here is that a significant proportion of patients had alpha synuclein prior to diagnosis!!

Ann Neurol. 2016 Mar 26. doi: 10.1002/ana.24648. [Epub ahead of print]
Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P.

It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson's disease patients. This study investigates whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson's disease patients in the prodromal phase.

We used the Danish National Pathology Registry, to identify archived paraffin embedded tissue blocks from 57 Parkinson's disease patients (98 blocks) and 90 control subjects (98 blocks). We employed two different immunohistochemistry techniques visualizing aggregated α -synuclein and phosphorylated α -synuclein.

Thirty-nine Parkinson's disease patients contributed tissues obtained in the prodromal disease phase, whilst 18 Parkinson's disease patients contributed tissues obtained solely after Parkinson's diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range: 20 years - 4 months), and post-diagnosis tissue on average 2.8 years after diagnosis (range: 2 days - 18 years). Phosphorylated- α -synuclein positivity was seen in 22/39 (56%) prodromal Parkinson's disease subjects and 30/67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p=0.0001 and p=0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson's disease patients and controls when using the aggregated α -synuclein immunohistochemistry technique.


We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson's disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10-20 years. 

Monday, 28 March 2016

Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data

This is a very interesting story and unveils another genetic risk factor for PD... these patients tend to have younger-onset PD, with prominent neuro-psychiatric features in some. The patient I have been involved with has had a pretty tough time, with multiple attempts at commencing advanced therapy, all of which have run into problems. It is important to suspect this in young patients with features of the 22q.11 deletion syndrome (aka Di George syndrome, aka CATCH-22, aka velocardiofacial syndrome). These include characteristic facial features (including cleft palate and ear pits), immune dysfunction, endrocrine dysfunction and cardiac abnormalities...

Lancet Neurol. 2016 Mar 23. pii: S1474-4422(16)00071-5. doi: 10.1016/S1474-4422(16)00071-5. [Epub ahead of print]

Mok KY, Sheerin U, Simón-Sánchez J, Salaka A, Chester L, Escott-Price V, Mantripragada K, Doherty KM, Noyce AJ, Mencacci NE, Lubbe SJ; International Parkinson's Disease Genomics Consortium (IPDGC), Williams-Gray CH, Barker RA, van Dijk KD, Berendse HW, Heutink P, Corvol JC, Cormier F, Lesage S, Brice A, Brockmann K, Schulte C, Gasser T, Foltynie T, Limousin P, Morrison KE, Clarke CE, Sawcer S, Warner TT, Lees AJ, Morris HR, Nalls MA, Singleton AB, Hardy J, Abramov AY, Plagnol V, Williams NM, Wood NW.

Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2.

We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients.

We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005).

Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both.

UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

Copyright © 2016 Mok et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Sunday, 27 March 2016

Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms

There is fascinating momentum in this area right now... let's hope it leads to some breakthroughs in our understanding about Parkinson's disease...

Parkinsonism Relat Disord. 2016 Mar 16. pii: S1353-8020(16)30066-9. doi: 10.1016/j.parkreldis.2016.03.012. [Epub ahead of print]
Felice VD, Quigley EM, Sullivan AM, O'Keeffe GW, O'Mahony SM.

Parkinson's disease is the second most common neurodegenerative disorder, affecting 1-2% of the population over 65 years of age. The primary neuropathology is the loss of midbrain dopaminergic neurons, resulting in characteristic motor deficits, upon which the clinical diagnosis is based. However, a number of significant non-motor symptoms (NMS) are also evident that appear to have a greater impact on the quality of life of these patients. In recent years, it has become increasingly apparent that neurobiological processes can be modified by the bi-directional communication that occurs along the brain-gut axis. The microbiota plays a key role in this communication throughout different routes in both physiological and pathological conditions. Thus, there has been an increasing interest in investigating how microbiota changes within the gastrointestinal tract may be implicated in health and disease including PD. Interestingly α-synuclein-aggregates, the cardinal neuropathological feature in PD, are present in both the submucosal and myenteric plexuses of the enteric nervous system, prior to their appearance in the brain, indicating a possible gut to brain route of "prion-like" spread. In this review we highlight the potential importance of gut to brain signalling in PD with particular focus on the role of the microbiota as major player in this communication.

Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson’s Disease

Saliva is a promising fluid for biomarker discovery in PD and alpha-synuclein an obvious choice in terms of potential markers to investigate, because (1) we know it is a protein involved in the disease process, (2) we know synuclein inclusions occur in the salivary glands and (3) because it has shown potential as a biomarker in other fluids such as CSF.

It is really interesting that this group have chosen to look separately at a-syn monomers and oligomers (and not just total a-syn). Their finding of an increase in a-syn oligomers but a decrease in total a-syn reflects similar findings (an increase in oligomers but decrease in total a-syn) in CSF.

Personally, I also wonder whether their assays for a-synuclein might not be particularly accurate - I had difficulty detecting a-synuclein in saliva myself! They measure concentrations of oligomeric a-syn which are orders of magnitude higher than the total a-syn (which doesn't make sense) and also orders of magnitude different from the values for salivary a-syn reported in other studies.

PLoS One. 2016 Mar 24;11(3):e0151156. doi: 10.1371/journal.pone.0151156. eCollection 2016.
Giorgio Vivacqua , Anna Latorre , Antonio Suppa , Michela Nardi , Sara Pietracupa , Romina Mancinelli , Giovanni Fabbrini , Carlo Colosimo , Eugenio Gaudio , Alfredo Berardelli

In Parkinson’s disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syntotal) concentration in saliva of PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig) concentrations or assessed the correlation between salivary a-syntotal, a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients’ clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD.

Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD).

This study demonstrates an inflammatory 'signature' present in the blood of patients with PD. Particularly interesting is that some of the immune-related biomarkers identified here might be able to predict slower progression of PD.

Mov Disord. 2016 Mar 21. doi: 10.1002/mds.26563. [Epub ahead of print]
Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, Cummins GA, Duncan GW, Khoo TK, Burn DJ, Barker RA; ICICLE-PD study group.

The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune-related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD.

Serum samples were collected in incident PD cases and age-matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C-reactive protein were measured, with data reduction using principal-component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale - part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated.

TNF-α, IL1-β, IL-2, and IL-10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal-component analysis of log-transformed data resulted in a 3-component solution explaining 51% of the variance. Higher "proinflammatory" and lower "anti-inflammatory" component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher "proinflammatory" component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed "anti-inflammatory" component score was the strongest predictor of slower motor progression (β = -0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = -0.175, P = 0.007).

Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes causally contribute to the progression of PD.

Thursday, 24 March 2016

Variation in Recent Onset Parkinson's Disease: Implications for Prodromal Detection

Most of these frequencies in this early clinical cohort soon after diagnosis... as seen elsewhere the RBDSQ tends to overestimate presence of true RBD (it lack specificity) and hyposmia is not present in all. The frequency of constipation appears low to me and the screening tool (bowel motions) per day is inadequate on its own to truly detect constipation...This is a really important study (the Tracking Parkinson's Study) and it is great to see results starting to emerge...

J Parkinsons Dis. 2016 Mar 19. [Epub ahead of print]
Swallow DM, Lawton MA, Grosset KA, Malek N, Smith CR, Bajaj NP, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams N, Wood NW, Grosset DG; PRoBaND Clinical Consortium.

The detection of prodromal Parkinson's disease (PD) is desirable to test drugs with neuroprotective potential, but will be affected by known disease variations.

To assess the prevalence of four key non-motor prodromal PD markers, and evaluate the sensitivity of case detection when non-motor screening tools for prodromal PD are implemented in an early clinical PD cohort.

Hyposmia (University of Pennsylvania smell identification test ≤15th centile or Sniffin' Sticks at or ≤10th centile corrected for age and sex), rapid-eye movement sleep behaviour disorder (RBD questionnaire >4), constipation (<1 daily spontaneous bowel motion) and depression (Leeds >6) were recorded in recent onset PD cases, and proposed non-motor screening criteria applied.

In 1,719 PD cases, mean age 68.6 years (SD 8.1), 65.5% male, mean disease duration 1.3 years (SD 0.9), 72.2% were hyposmic, 43.3% had RBD, 22.1% depression, and 21.5% constipation. 11.6% of cases had no key non-motor features, 38.8% one, 32.1% two, 15.5% three, and 2.0% all four. Increasing numbers of non-motor features were associated with younger age (p = 0.019), higher motor scores (p <  0.001), more postural instability gait difficulty (PIGD) (p <  0.001), greater cognitive impairment (p <  0.001) and higher total non-motor burden (p <  0.001). Cases with hyposmia alone were younger (p <  0.001), had less severe cognitive (p = 0.006) and other non-motor features (p <  0.001). All screening criteria selected younger patients (p = 0.001, p <  0.001), three of four greater overall non-motor burden (p = 0.005, p <  0.001), and inclusion of RBD more cognitive impairment (p = 0.003, p = 0.001) and PIGD (p = 0.004, p = 0.001).

Varying sensitivity levels, and age and phenotype selectivity, are found when different non-motor screening methods to detect prodromal PD are applied to an early clinical PD cohort.


Parkinson disease; anosmia; constipation; depression; rapid eye movement sleep behavior disorder

A Viewpoint on Wearable Technology-Enabled Measurement of Wellbeing and Health-Related Quality of Life in Parkinson's Disease

More on wearable tech for PD...

J Parkinsons Dis. 2016 Mar 10. [Epub ahead of print]
van Uem J, Isaacs T, Lewin A, Bresolin E, Salkovic D, Espay AJ, Matthews H, Maetzler W.


In this viewpoint, we discuss how several aspects of Parkinson's disease (PD) - known to be correlated with wellbeing and health-related quality of life-could be measured using wearable devices ('wearables'). Moreover, three people with PD (PwP) having exhaustive experience with using such devices write about their personal understanding of wellbeing and health-related quality of life, building a bridge between the true needs defined by PwP and the available methods of data collection. Rapidly evolving new technologies develop wearables that probe function and behaviour in domestic environments of people with chronic conditions such as PD and have the potential to serve their needs. Gathered data can serve to inform patient-driven management changes, enabling greater control by PwP and enhancing likelihood of improvements in wellbeing and health-related quality of life. Data can also be used to quantify wellbeing and health-related quality of life. Additionally these techniques can uncover novel more sensitive and more ecologically valid disease-related endpoints. Active involvement of PwP in data collection and interpretation stands to provide personally and clinically meaningful endpoints and milestones to inform advances in research and relevance of translational efforts in PD.

Monday, 21 March 2016

Challenges of modifying disease progression in prediagnostic Parkinson's disease

Delighted to see this one published now... encourage you to have a read...

Lancet Neurol. 2016 Mar 15. pii: S1474-4422(16)00060-0. doi: 10.1016/S1474-4422(16)00060-0. [Epub ahead of print]
Salat D, Noyce AJ, Schrag A, Tolosa E.

Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials.

Friday, 18 March 2016

Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions

New review article on RBD... this is an important model for prodromal PD particularly when it comes to considering therapeutics... but it is non-specific!! 

Lancet Neurol. 2016 Apr;15(4):405-19. doi: 10.1016/S1474-4422(16)00057-0.
Iranzo A, Santamaria J, Tolosa E.


Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) manifests as unpleasant dreams and vigorous behaviours during REM sleep that can result in injuries. Patients with IRBD have no known neurological diseases or motor or cognitive complaints; however, this sleep disorder is not harmless. In most cases, IRBD is the prelude of the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or, less frequently, multiple system atrophy. Patients can show abnormalities that are characteristic of the synucleinopathies, and longitudinal follow-up shows that most patients develop parkinsonism and cognitive impairments with time. Thus, diagnosis of IRBD needs to be accurate and involves informing the patient of the risk of developing a neurodegenerative disease. It is extraordinary for a sleep disorder to precede the full expression of a neurodegenerative disease, which renders IRBD of particular interest in studies of the prodromal stage of the synucleinopathies, and in the development of neuroprotective interventions to stop or slow neurodegenerative deterioration before motor and cognitive symptomatology emerges. Such therapeutics do not currently exist, and thus represent an unmet need in IRBD.

Thursday, 17 March 2016

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease

Systematic review of tech for PD... an ever more congested field... lots currently lacking replication and detailed validation...

J Neuroeng Rehabil. 2016 Mar 12;13(1):24.
Godinho C, Domingos J, Cunha G, Santos AT, Fernandes RM, Abreu D, Gonçalves N, Matthews H, Isaacs T, Duffen J, Al-Jawad A, Larsen F, Serrano A, Weber P, Thoms A, Sollinger S, Graessner H, Maetzler W, Ferreira JJ.

There is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson's disease using such devices. However, clinimetric properties and clinical validation vary among the different devices.

Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) 'recommended', (ii) 'suggested' or (iii) 'listed' based on the following criteria: (1) used in the assessment of Parkinson's disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no).


Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were 'recommended', 34 devices were 'suggested', and 30 devices were classified as 'listed'. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson's Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as 'recommended'. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as 'recommended'. Within the hybrid devices group only the Kinesia® system was classified as 'recommended'.

Wednesday, 16 March 2016

Age, Gender, Comorbidity, and the MDS-UPDRS: Results from a Population-Based Study

Interesting work on mild parkinsonian signs... action and postural tremor, and non-specific changes in gait can elevate scores... important to determine which domains indicate sub-clinical PD.

Neuroepidemiology. 2016 Mar 12;46(3):222-227. [Epub ahead of print]
Keezer MR, Wolfson C, Postuma RB.

Understanding sources of variation in International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores is essential for planning clinical trials in Parkinson's disease and interpreting studies of mild parkinsonian signs.

We describe the characteristics of the MDS-UPDRS in a population-based sample of individuals without parkinsonism. Multiple linear regression and Spearman's rank correlation coefficients were used to examine potential associations.

Among 194 consecutive individuals without parkinsonism, the mean total MDS-UPDRS score was 12.5 (SD 9.8). Sixty-nine percent (134/193) had motor examination (Part III) scores of 2 or more, 16% (30/194) had scores of 10 or more. Female sex, arthritis or spondylosis, diabetes mellitus, and essential tremor were found to be associated with statistically significant increases in MDS-UPDRS Part III scores. For every 10-year increase in age, the Part III score was greater on average by 2.2 (1.5-2.8).


Elevated MDS-UPDRS scores are common in the general population. The overall burden of motor signs of parkinsonism is especially high in older age groups, in women, and in those with particular comorbidities. Whether this represents evidence of a subclinical neurodegenerative process or the effect of comorbid conditions requires further examination.

Tuesday, 15 March 2016

Chronic constipation and co-morbidities: A prospective population-based nested case-control study

Another observational study reporting an association between constipation and PD... although the methods here looks largely cross-sectional looking at prevalent constipation. If so I am unsurprised by the results... we know patients with PD suffer from constipation. What has been interesting in recent years is the clear association of PD with preceding constipation... sometimes by as much as 10-20 years. We systematically reviewed and meta-analysed these studies last year...

United European Gastroenterol J. 2016 Feb;4(1):142-51. doi: 10.1177/2050640614558476. Epub 2015 Nov 11.
Choung RS, Rey E, Richard Locke G 3rd, Schleck CD, Baum C, Zinsmeister AR, Talley NJ.

Chronic constipation (CC) is common in the community but surprisingly little is known about relevant gastro-intestinal (GI) and non-GI co-morbidities.

The purpose of this study was to assess the epidemiology of CC and in particular provide new insights into the co-morbidities linked to this condition.

In a prospective, population-based nested case-control study, a cohort of randomly selected community residents (n = 8006) were mailed a validated self-report gastrointestinal symptom questionnaire. CC was defined according to Rome III criteria. Medical records of each case and control were abstracted to identify potential CC comorbidities.

Altogether 3831 (48%) subjects returned questionnaires; 307 met criteria for CC. Age-adjusted prevalence in females was 8.7 (95% confidence interval (CI) 7.1-10.3) and 5.1 (3.6-6.7) in males, per 100 persons. CC was not associated with most GI pathology, but the odds for constipation were increased in subjects with anal surgery relative to those without (odds ratio (OR) = 3.3, 95% CI 1.2-9.1). In those with constipation vs those without, neurological diseases including Parkinson's disease (OR = 6.5, 95% CI 2.9-14.4) and multiple sclerosis (OR = 5.5, 95% CI 1.9-15.8) showed significantly increased odds for chronic constipation, adjusting for age and gender. In addition, modestly increased odds for chronic constipation in those with angina (OR = 1.4, 95% CI 1.1-1.9) and myocardial infarction (OR = 1.5, 95% CI 1.0-2.4) were observed.


Neurological and cardiovascular diseases are linked to constipation but in the community constipation is unlikely to account for most lower GI pathology.

Sunday, 13 March 2016

Longitudinal course of mild parkinsonian signs in elderly people: A population-based study in Japan

Interesting and important to elucidate those mild parkinsonian signs in the elderly that progress to frank parkinsonism... 

J Neurol Sci. 2016 Mar 15;362:7-13. doi: 10.1016/j.jns.2016.01.016. Epub 2016 Jan 9.
Wada-Isoe K, Tanaka K, Uemura Y, Nakashita S, Tajiri Y, Tagashira S, Yamamoto M, Yamawaki M, Kishi M, Nakashima K.

We aimed to clarify the longitudinal course of mild parkinsonian signs (MPS) and their association with dementia and functional disability by conducting a comprehensive epidemiological study, including brain MRI, and assessments of cognition, depression, and sleep, in people aged ≥65years living in Ama-cho. We diagnosed MPS and parkinsonism (PS) using a modified Unified Parkinson's Disease Rating Scale. The phase I study was conducted between 2008 and 2010 (n=729) and the phase II between 2011 and 2013 (n=436). By phase II, 8.5% of the phase I participants without PS had developed PS. In addition to older age, a lower Mini-Mental State Examination (MMSE) score, and lower body mass index, the MPS rigidity subtype was a significant independent predictor of PS onset. By phase II, 10.1% of the participants without dementia or PS at phase I had developed dementia. Older age, lower MMSE score, and the axial dysfunction and tremor MPS subtypes were significant independent predictors of dementia development. By phase II, 38.8% of participants with MPS at phase I showed no motor symptoms. Younger age and adequate sleep were significant predictors for this reversion. Periventricular and deep white matter hyperintensity Fazekas scores increased with the evolution of parkinsonian signs. MPS is therefore critically, although sometimes reversibly, associated with PS and dementia development in elderly people.

Saturday, 12 March 2016

Association Between Tuberculosis and Parkinson Disease: A Nationwide, Population-Based Cohort Study

Some interesting associations with PD being reported of late... particularly with chronic bacterial and viral infections...

Medicine (Baltimore). 2016 Feb;95(8):e2883. doi: 10.1097/MD.0000000000002883.
Shen CH, Chou CH, Liu FC, Lin TY, Huang WY, Wang YC, Kao CH.

Few studies have investigated the association between tuberculosis (TB) and Parkinson disease (PD). This nationwide, population-based, retrospective cohort study investigated the risk of PD in patients with TB.We selected patients newly diagnosed with TB (International Classification of Diseases, Ninth Revision, Clinical Modification: 011) from 2000 to 2009 in the Taiwan National Health Insurance Database as the TB cohort. The comparison cohort (the non-TB cohort) was frequency matched to the TB cohort at a ratio of 4:1 by sex, age, and the index date. We analyzed the risks of PD by using Cox proportional hazard regression models.A total of 121,951 patients with TB and 487,800 non-TB controls were enrolled in this study. The TB cohort had a 1.38-fold risk of PD compared with the non-TB cohort after adjustment for age, sex, and comorbidities (aHR, 95% CI: 1.30-1.46). The adjusted risk of PD in the TB and non-TB cohorts increased in subgroups regardless of age, sex, and comorbidities. Combined effect of TB and comorbidities on the risk of PD were significant in patients with TB who had diabetes (aHR: 2.26, 95% CI: 2.02-2.52), hypertension (aHR: 2.23, 95% CI: 2.04-2.44), head injury (aHR: 2.32, 95% CI: 1.95-2.77), chronic kidney disease (aHR: 2.02, 95% CI: 1.49-2.72), chronic obstructive pulmonary disease (aHR: 1.84, 95% CI: 1.66-2.05), depression (aHR: 4.66, 95% CI: 3.59-6.05), dementia (aHR: 3.70, 95% CI: 2.99-4.59), and stroke (aHR: 2.56, 95% CI: 2.28-2.87). The risk of PD was higher in a follow-up within 1 year (aHR: 1.78, 95% CI: 1.58-2.00) and decreased with the follow-up period in the TB cohort. Patients with TB have an independently 1.38-fold risk of PD. The risk of PD decreased with the follow-up period in the TB cohort. Physicians should be aware of the risk of PD in patients with TB when treating such patients.

Friday, 11 March 2016

Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease: A Preliminary Study

More research on this topic... it seems clear that those patients with RBD represent a more severe end of the PD spectrum... I am surprised that there is no association with impaired cognitive function but that might reflect the small sample size. At the risk the of sounding repetitive the RBDSQ is not the same as RBD diagnosed with polysomnography... compared to objective measurement it lacks specificity. Still in the right context and with bed partner corroboration, it can be a very useful tool...

J Mov Disord. 2016 Mar 2. doi: 10.14802/jmd.15039. [Epub ahead of print]
Kim CS, Sung YH, Kang MJ, Park KH.

Rapid eye movement sleep behavior disorder (RBD) is associated with α-synucleinopathies, such as Parkinson's disease (PD). We aimed to assess the differences in the clinical characteristics of PD with and without RBD.

Forty-two patients previously diagnosed with PD were evaluated for clinical history, motor and cognitive functioning using the Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE), autonomic symptoms, sleep characteristics using the Pittsburg Sleep Quality Index (PSQI), and the presence of RBD using the Korean version of the RBD screening questionnaire (RBDSQ). The prevalence of RBD and the patients' demographic features were evaluated. The patients were classified into two groups, PD with RBD and PD without RBD, based on the RBDSQ scores. The motor and cognitive functions, as well as other clinical features of the two groups were compared.

A total of 42 PD patients were enrolled. Eighteen patients were classified as PD with RBD. Compared to PD without RBD, PD with RBD showed higher scores of rigidity in the UPDRS subscale. Regarding sleep problems, PD with RBD revealed higher sleep disturbance, lower sleep efficiency, and lower overall sleep quality in the PSQI. There was no difference in cognitive dysfunction between the two groups according to the Korean version of the MMSE.


PD with RBD was associated with poorer sleep and motor symptoms. Therefore, RBD symptoms in PD are possibly poor prognostic markers.

Thursday, 10 March 2016

The mPower study, Parkinson disease mobile data collected using ResearchKit

Really exciting to see these data being released... particularly after an uplifting set of talks at UCL Partners on Friday on Tech in Health Care... the aim of these tools is to guide clinical practice and provide real world, practical solutions to augment the subjective and 'snapshot' nature of clinical consultations... looking forward to having a look through (if authorised!)...

Sci Data. 2016 Mar 3;3:160011. doi: 10.1038/sdata.2016.11.
Bot BM, Suver C, Neto EC, Kellen M, Klein A, Bare C, Doerr M, Pratap A, Wilbanks J, Dorsey ER, Friend SH, Trister AD.

Current measures of health and disease are often insensitive, episodic, and subjective. Further, these measures generally are not designed to provide meaningful feedback to individuals. The impact of high-resolution activity data collected from mobile phones is only beginning to be explored. Here we present data from mPower, a clinical observational study about Parkinson disease conducted purely through an iPhone app interface. The study interrogated aspects of this movement disorder through surveys and frequent sensor-based recordings from participants with and without Parkinson disease. Benefitting from large enrollment and repeated measurements on many individuals, these data may help establish baseline variability of real-world activity measurement collected via mobile phones, and ultimately may lead to quantification of the ebbs-and-flows of Parkinson symptoms. App source code for these data collection modules are available through an open source license for use in studies of other conditions. We hope that releasing data contributed by engaged research participants will seed a new community of analysts working collaboratively on understanding mobile health data to advance human health.

Wednesday, 9 March 2016

Alpha-synuclein as a biomarker for Parkinson's disease

Review article on the potential utility for alpha-synuclein as a biomarker of PD...

Brain Pathol. 2016 Mar 3. doi: 10.1111/bpa.12370. [Epub ahead of print]
Atik A, Stewart T, Zhang J.

Parkinson's disease (PD) is a common neurodegenerative disorder, characterized pathologically by the presence of α-synuclein (α-syn)-rich Lewy bodies. As clinical diagnosis of PD is challenging, misdiagnosis is common, highlighting the need for disease-specific and early stage biomarkers. Both early diagnosis of PD and adequate tracking of disease progression could significantly improve outcomes for patients, particularly in regard to existing and future disease modifying treatments. Given its critical roles in PD pathogenesis, α-syn may be useful as a biomarker of PD. The aim of this review is, therefore, to summarize the efficacy of tissue and body fluid α-syn measurements in the detection of PD as well as monitoring disease progression. In comparison to solid tissue specimens and biopsies, biofluid α-syn levels may be the most promising candidates in PD diagnosis and progression based on specificity, sensitivity and availability. Although α-syn has been tested most extensively in cerebrospinal fluid (CSF), the relatively invasive procedure for collecting CSF is not suitable in most clinical settings, leading to investigation of plasma, blood and saliva as alternatives. The exploration of combined biomarkers, along with α-syn, to improve diagnostic accuracy is also likely required.

Restless legs syndrome associated with major diseases: A systematic review and new concept

Interesting update on RLS... clearly associated with iron deficiency anaemia and kidney disease, but other disease associations may be explained (at least in part) by bias and confounding. The spectrum of causal factors that underlie RLS is wide and current clinical categorisation may fail to capture that... and may have implications on treatment...

Neurology. 2016 Mar 4. pii: 10.1212/WNL.0000000000002542. [Epub ahead of print]
Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J.

Recent publications on both the genetics and environmental factors of restless legs syndrome (RLS) defined as a clinical disorder suggest that overlapping genetic risk factors may play a role in primary (idiopathic) and secondary (symptomatic) RLS. Following a systematic literature search of RLS associated with comorbidities, we identified an increased prevalence of RLS only in iron deficiency and kidney disease. In cardiovascular disease, arterial hypertension, diabetes, migraine, and Parkinson disease, the methodology of studies was poor, but an association might be possible. There is insufficient evidence for conditions such as anemia (without iron deficiency), chronic obstructive pulmonary disease, multiple sclerosis, headache, stroke, narcolepsy, and ataxias. Based on possible gene-microenvironmental interaction, the classifications primary and secondary RLS may suggest an inappropriate causal relation. We recognize that in some conditions, treatment of the underlying disease should be achieved as far as possible to reduce or eliminate RLS symptoms. RLS might be seen as a continuous spectrum with a major genetic contribution at one end and a major environmental or comorbid disease contribution at the other.

Sunday, 6 March 2016

The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder

This is amazing... it would be great to see this replicated in other RBD cohorts and in other groups thought to be at higher risk of PD... notable that alternate finger tapping also distinguished the cases from the controls!

Brain. 2016 Feb 26. pii: aww006. [Epub ahead of print]
Ehrminger M, Latimier A, Pyatigorskaya N, Garcia-Lorenzo D, Leu-Semenescu S, Vidailhet M, Lehericy S, Arnulf I.

Idiopathic rapid eye movement sleep behaviour disorder is characterized by nocturnal violence, increased muscle tone during rapid eye movement sleep and the lack of any other neurological disease. However, idiopathic rapid eye movement sleep behaviour disorder can precede parkinsonism and dementia by several years. Using 3 T magnetic resonance imaging and neuromelanin-sensitive sequences, we previously found that the signal intensity was reduced in the locus coeruleus/subcoeruleus area of patients with Parkinson's disease and rapid eye movement sleep behaviour disorder. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex with neuromelanin-sensitive imaging in 21 patients with idiopathic rapid eye movement sleep behaviour disorder and compared the results with those from 21 age- and gender-matched healthy volunteers. All subjects underwent a clinical examination, motor, cognitive, autonomous, psychological, olfactory and colour vision tests, and rapid eye movement sleep characterization using video-polysomnography and 3 T magnetic resonance imaging. The patients more frequently had preclinical markers of alpha-synucleinopathies, including constipation, olfactory deficits, orthostatic hypotension, and subtle motor impairment. Using neuromelanin-sensitive imaging, reduced signal intensity was identified in the locus coeruleus/subcoeruleus complex of the patients with idiopathic rapid eye movement sleep behaviour. The mean sensitivity of the visual analyses of the signal performed by neuroradiologists who were blind to the clinical diagnoses was 82.5%, and the specificity was 81% for the identification of idiopathic rapid eye movement sleep behaviour. The results confirm that this complex is affected in idiopathic rapid eye movement sleep behaviour (to the same degree as it is affected in Parkinson's disease). Neuromelanin-sensitive imaging provides an early marker of non-dopaminergic alpha-synucleinopathy that can be detected on an individual basis.

Saturday, 5 March 2016

Olfactory impairment predicts cognitive decline in early Parkinson's disease

I think this is supportive of those with marked olfactory deficit having a more aggressive disease type... the proportion of PD patients with hyposmia (or worse) is as one would expect... ~90% in those that are recently diagnosed... (~35% were anosmic)

Parkinsonism Relat Disord. 2016 Feb 19. pii: S1353-8020(16)30041-4. doi: 10.1016/j.parkreldis.2016.02.013. [Epub ahead of print]
Fullard ME, Tran B, Xie SX, Toledo JB, Scordia C, Linder C, Purri R, Weintraub D, Duda JE, Chahine LM, Morley JF.

To evaluate the association between baseline olfaction and both cross-sectional and longitudinal cognitive assessments, motor symptoms, non-motor symptoms (NMS), and CSF biomarkers in early Parkinson's disease (PD).

Parkinson's Progression Marker's Initiative (PPMI) participants underwent baseline olfactory testing with the University of Pennsylvania Smell Identification Test (UPSIT). Serial assessments included measures of motor symptoms, NMS, neuropsychological assessment, and CSF biomarkers. Up to three years follow-up data were included.

At baseline, worse olfaction (lowest tertile) was associated with more severe NMS, including anxiety and autonomic symptoms. Those in the lowest olfactory tertile were more likely to report cognitive impairment (37.4%) compared to those in the middle (24.4%) and highest olfactory tertiles (14.2%, p < 0.001). Aβ1-42 was significantly lower, and tau/Aβ1-42 ratio was higher in those with worse olfaction. In longitudinal analyses, lower UPSIT score was associated with greater decline in MoCA score (β = 0.02 [0.01, 0.03], p = 0.001) over time, as were composite measures of UPSIT score and either Aβ1-42 or tau/Aβ1-42 ratio. In a Cox proportional hazards model, a composite measure of olfaction and Aβ1-42 was a significant predictor of conversion from normal cognition to mild cognitive impairment (MCI; i.e., MoCA < 26), with subjects most impaired on both measures being 87% more likely to develop incident MCI (HR = 1.87 [1.16, 3.01], p = 0.01).


Worse baseline olfaction is associated with long-term cognitive decline. The addition of AD CSF biomarkers to olfactory testing may increase the likelihood of identifying those at highest risk for cognitive decline and progression to MCI.

Friday, 4 March 2016

Lysosomal Dysfunction and α-Synuclein Aggregation in Parkinson's Disease: Diagnostic Links

Everybody is talking about lysosomal dysfunction these days... thats why I think investigating the link between GBA and PD is so important... may have very real relevance to sporadic PD...

Mov Disord. 2016 Feb 29. doi: 10.1002/mds.26562. [Epub ahead of print]
Moors T, Paciotti S, Chiasserini D, Calabresi P, Parnetti L, Beccari T, van de Berg WD.

Lysosomal impairment is increasingly recognized as a central event in the pathophysiology of PD. Genetic associations between lysosomal storage disorders, including Gaucher disease and PD, highlight common risk factors and pathological mechanisms. Because the autophagy-lysosomal system is involved in the intralysosomal hydrolysis of dysfunctional proteins, lysosomal impairment may contribute to α-synuclein aggregation in PD. The degradation of α-synuclein is a complex process involving different proteolytic mechanisms depending on protein burden, folding, posttranslational modifications, and yet unknown factors. In this review, evidence for lysosomal dysfunction in PD and its intimate relationship with α-synuclein aggregation are discussed, after which the question of whether lysosomal proteins may serve as diagnostic biomarkers for PD is addressed. Changes in lysosomal enzymes, such as reduced glucocerebrosidase and cathepsin levels, have been observed in affected brain regions in PD patients. The detection of lysosomal proteins in CSF may provide a read-out of lysosomal dysfunction in PD and holds promise for the development of diagnostic PD biomarkers. Initial PD biomarker studies demonstrated altered lysosomal enzyme activities in CSF of PD patients when compared with controls. However, CSF lysosomal enzyme activities alone could not discriminate between PD patients and controls. The combination of CSF lysosomal markers with α-synuclein species and indicators of mitochondrial dysfunction, inflammation, and other pathological proteins in PD may be able to facilitate a more accurate diagnosis of PD. Further CSF biomarker studies are needed to investigate the utility of CSF lysosomal proteins as measures of disease state and disease progression in PD. 

Thursday, 3 March 2016

Increased peripheral inflammation in asymptomatic leucine-rich repeat kinase 2 mutation carriers

There have been reports of changes in peripheral inflammatory markers in patients with PD, but I don't recall reports in non-manifesting carriers of strong genetic risk factors for PD...

Mov Disord. 2016 Feb 25. doi: 10.1002/mds.26529. [Epub ahead of print]
Dzamko N, Rowe DB, Halliday GM.

We aimed to determine if peripheral or central inflammatory cytokines are altered in healthy subjects carrying a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, and thus genetically at risk of Parkinson's disease (PD). We also aimed to identify differences in inflammatory cytokines between LRRK2 G2019S-associated and idiopathic PD once the disease manifests.

Participants were genetically screened and phenotyped, and biological samples were collected and stored by the Michael J. Fox Foundation LRRK2 Cohort Consortium. Serum samples and matching clinical data were obtained from 71 asymptomatic LRRK2 G2019S mutation carriers (CSF n = 25), 75 neurologically normal controls (CSF n = 22), 75 idiopathic PD patients (CSF n = 29), and 76 PD patients with a LRRK2 G2019S mutation (CSF n = 20). Inflammatory cytokines were measured using multiplex enzyme-linked immunosorbent assays.

Serum levels of interleukin 1 beta could discriminate asymptomatic LRRK2 G2019S mutation carriers from controls, with a high inflammatory subgroup of carriers identified. This subgroup was significantly higher in a number of PD-implicated pro-inflammatory cytokines. Once PD had manifest, LRRK2 G2019S patients were discriminated from idiopathic PD by higher serum platelet-derived growth factor, and higher CSF vascular endothelial growth factor and interleukin 8.


The results suggest that peripheral inflammation is higher in a percentage of subjects carrying the LRRK2 G2019S mutation. Replication and longitudinal follow-up is required to determine whether the increased peripheral cytokines can predict clinical PD. Importantly, these biological changes were observed prior to the clinical manifestations thought to herald PD.

Wednesday, 2 March 2016

ɑ-Synuclein strains and the variable pathologies of synucleinopathies

More on the prion hypothesis of Parkinson's disease and related conditions...

J Neurochem. 2016 Feb 29. doi: 10.1111/jnc.13595. [Epub ahead of print]
Peelaerts W, Baekelandt V.

Several decades ago, a mysterious transmissible agent was found responsible for a group of progressive and lethal encephalopathies affecting the nervous system of both animals and humans. This infectious agent showed a strain-encoded manner of inheritance even though it lacked nucleic acids. The identification of infectious proteins resolved this apparent conundrum. Misfolded infectious protein particles, or prions, were found to exist as conformational isomers with a unique fingerprint that can be faithfully passaged to next generations. Protein-based strain-encoded inheritance is characterized by strain-specific infectivity and symptomatology. It is found in diverse organisms, such as yeast, fungi and mammals. Now, this concept is revisited to examine the pathological role of amyloid proteins involved in neurodegenerative diseases where it might underlie certain types of dementia and motor-related neurodegenerative disorders. Given the discovery of the SNCA gene and the identification of its gene product, ɑ-synuclein (ɑ-SYN), as the main histopathological component of Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA), the scientific community was left puzzled by the fact that a single protein appeared to be involved in different diseases with diverging clinical phenotypes. Recent studies are now indicating that ɑ-SYN may act in a way similar to prions and that ɑ-SYN misfolded structural variants may behave as strains with distinct biochemical and functional properties inducing specific phenotypic traits, which might finally provide an explanation for the clinical heterogeneity observed between PD, MSA and DLB patients. These crucial new findings may pave the way for unexplored therapeutic avenues and identification of new potential biomarkers.