Sunday, 19 June 2016

The Evolution of REM Sleep Behavior Disorder in Early Parkinson Disease

This is an interesting result but I think that the prevalence at 2 years of follow-up is near the maximum prevalence of RBD in PD (I can't imagine that it would be much more than 50%) in all PD patients. Video PSG makes the diagnosis more objective but only reduces bias, it does not get rid of it completely. I am also not sure about RBE (which is new to me)... and how reliable this is as prodromal RBD... only 18% developed RBD and longer follow is required...

Sleep. 2016 Jun 9. pii: sp-00086-16. [Epub ahead of print]
Sixel-Döring F, Zimmermann J, Wegener A, Mollenhauer B, Trenkwalder C.

To investigate the development of REM sleep behavior disorder (RBD) and REM sleep behavioral events (RBE) not yet fulfilling diagnostic criteria for RBD as markers for neurodegeneration in a cohort of Parkinson disease (PD) patients between their de novo baseline assessment and two-year follow-up in comparison to healthy controls (HC).

Clinically confirmed PD patients and HC with video-supported polysomnography (vPSG) data at baseline were re-investigated after two years. Diagnostic scoring for RBE and RBD was performed in both groups and related to baseline findings.

One hundred thirteen PD patients and 102 healthy controls (HC) were included in the study. Within two years, the overall occurrence of behaviors during REM sleep in PD patients increased from 50% to 63% (P = 0.02). RBD increased from 25% to 43% (P < 0.001). Eleven of 29 (38%) RBE positive PD patients and 10/56 (18%) patients with normal REM sleep at baseline converted to RBD. In HC, the occurrence of any REM behavior increased from 17% to 20% (n.s.). RBD increased from 2% to 4% (n.s.). One of 15 (7%) RBE positive HC and 1/85 (1%) HC with normal REM at baseline converted to RBD.


RBD increased significantly in PD patients from the de novo state to two-year follow-up. We propose RBE being named "prodromal RBD" as it may follow a continuous evolution in PD possibly similar to the spreading of Lewy bodies in PD patients. RBD itself was shown as a robust and stable marker of early PD.

Friday, 17 June 2016

Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson's disease

This is a fascinating study by the Oxford group and it is an exciting development... my worry is that SPECT may change too close to the point of diagnosis to be really useful as a prodromal marker... potentially here we have something that is abnormal whilst the SPECT scan is not yet abnormal... great stuff!

Brain. 2016 Jun 12. pii: aww124. [Epub ahead of print]
Rolinski M, Griffanti L, Piccini P, Roussakis AA, Szewczyk-Krolikowski K, Menke RA, Quinnell T, Zaiwalla Z, Klein JC, Mackay CE, Hu MT.

Resting state functional magnetic resonance imaging dysfunction within the basal ganglia network is a feature of early Parkinson's disease and may be a diagnostic biomarker of basal ganglia dysfunction. Currently, it is unclear whether these changes are present in so-called idiopathic rapid eye movement sleep behaviour disorder, a condition associated with a high rate of future conversion to Parkinson's disease. In this study, we explore the utility of resting state functional magnetic resonance imaging to detect basal ganglia network dysfunction in rapid eye movement sleep behaviour disorder. We compare these data to a set of healthy control subjects, and to a set of patients with established early Parkinson's disease. Furthermore, we explore the relationship between resting state functional magnetic resonance imaging basal ganglia network dysfunction and loss of dopaminergic neurons assessed with dopamine transporter single photon emission computerized tomography, and perform morphometric analyses to assess grey matter loss. Twenty-six patients with polysomnographically-established rapid eye movement sleep behaviour disorder, 48 patients with Parkinson's disease and 23 healthy control subjects were included in this study. Resting state networks were isolated from task-free functional magnetic resonance imaging data using dual regression with a template derived from a separate cohort of 80 elderly healthy control participants. Resting state functional magnetic resonance imaging parameter estimates were extracted from the study subjects in the basal ganglia network. In addition, eight patients with rapid eye movement sleep behaviour disorder, 10 with Parkinson's disease and 10 control subjects received 123I-ioflupane single photon emission computerized tomography. We tested for reduction of basal ganglia network connectivity, and for loss of tracer uptake in rapid eye movement sleep behaviour disorder and Parkinson's disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson's disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson's disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson's disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson's disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder.

Statin Use and Its Association with Essential Tremor and Parkinson's Disease

The story of statins and PD (and ET) re-emerges... but this design would be prone to recall bias that may be differential... ET patients in particular seem to be an increasingly difficult group to diagnose with so many ending up as dystonic tremor...

Neuroepidemiology. 2016 Jun 16;47(1):11-17. [Epub ahead of print]
Shalaby SY, Louis ED.

Statins have potent anti-inflammatory and immunomodulating effects, and may have neuroprotective properties in patients with Parkinson's disease (PD). There are no studies about the use of statins in the related tremor disorder, essential tremor (ET). We determined whether statin use differed in ET cases vs. controls and PD cases vs. controls

One hundred and thirty nine ET cases, 108 PD cases, and 124 controls participated in a research study of the epidemiology of movement disorders. They were frequency matched based on age and gender. Statin use was assessed by self-report.

In adjusted logistic regression analyses, statin use (current or ever) was inversely associated with PD (ORs 0.56-0.63), with marginal values (p values = 0.07-0.187). In similar adjusted models, ET was not associated with statin use (p values = 0.45-0.50). However, ET was inversely associated with longer-term statin use (adjusted OR 0.27, p values = 0.04-0.048).


We observed a marginally significant inverse association between PD and statin use. Although in primary analyses we found no evidence that statin use was protective in ET, there was an inverse association in analyses that assessed longer term use of statins. Further observational studies are warranted.

Thursday, 16 June 2016

Motor features in Parkinson's disease with normal olfactory function

A thorn in the side of those that believe hyposmia should form part of the clinical criteria for PD... my feeling this that this proportion is about correct... of course tremor is only a little bit more common...

Mov Disord. 2016 Jun 9. doi: 10.1002/mds.26687. [Epub ahead of print]
Rossi M, Escobar AM, Bril A, Millar Vernetti P, De Palo JI, Cerquetti D, Merello M.

Normosmic Parkinson's disease (PD) might be a unique clinical phenotype with a more benign course when compared with hyposmic PD.

The objective of this study was to evaluate motor features and the acute levodopa response according to olfactory function.

A total of 169 de novo PD patients that underwent olfactory testing and acute levodopa challenge for clinical prediction of sustained long-term dopaminergic response were evaluated.

The overall frequency of normosmia was 33%. Normosmic PD patients scored nonsignificantly different to hyposmic/anosmic patients on motor scale and on degree of improvement with levodopa. Motor scores at follow-up were comparable among groups.


Normal olfactory function is common in early PD and was not associated with a different motor phenotype when compared with PD patients with olfactory dysfunction. 

Wednesday, 15 June 2016

A clinical view on the development of technology-based tools in managing Parkinson's disease

I agree in most part... but an important factor is the rapidity of uptake... currently the process of application, regulatory approval to test, validation, regulatory approval to implement, means that technology has already moved on... we need to get better at processing applications to use low-burden tech and validating it in-situ...

Mov Disord. 2016 Jun 7. doi: 10.1002/mds.26673. [Epub ahead of print]
Maetzler W, Klucken J, Horne M.

Recently, quantitative, objective, and easy-to-use technology-based tools that can assess PD features over long time periods have been developed and generate clinically relevant and comparable patient information. Herein, we present a clinician's view on technological developments that have the potential to revolutionize clinical management concepts in PD. According to prominent examples in clinical medicine (e.g., blood glycosylated hemoglobin and blood pressure), we argue that the consideration of technology-based assessment in the clinical management of PD must be based on specific assumptions: (1) It provides a valid and accurate parameter of a clinically relevant feature of the disease; (2) there is confirmed evidence that the parameter has an ecologically relevant effect on the specific clinical application; (3) a target range can be defined wherein the parameter reflects the adequate treatment response; and (4) implementation is simple to allow repetitive use. Currently, there are no technology-based tools available that fulfil all these assumptions; however, assessments of akinesia, dyskinesia, motor fluctuations, physical inactivity, gait impairment, and postural instability seem relatively close to the specifications described. An iterative process of integration is recommended to bring technology-based tools into clinical practice.

Saturday, 11 June 2016

Prodromal Parkinson's disease as defined per MDS research criteria in the general elderly community

Great to see the application of these criteria to an incident PD cohort. The are some issues with the criteria in my opinion with over-emphasis in some places and some exposures that are missing, but overall it is a big step in the right direction... 

Mov Disord. 2016 Jun 6. doi: 10.1002/mds.26674. [Epub ahead of print]
Mahlknecht P, Gasperi A, Willeit P, Kiechl S, Stockner H, Willeit J, Rungger G, Sawires M, Nocker M, Rastner V, Mair KJ, Hotter A, Poewe W, Seppi K.

Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts.

We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable.

After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of "probable prodromal PD" status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%).


Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society.

Identification of TMEM230 mutations in familial Parkinson's disease

New PD gene... the function of the protein product appears to play a role in vesicle function... this is further evidence of the importance of such pathways in the mechanisms of PD and may provide opportunities for targeted therapy...

Nat Genet. 2016 Jun 6. doi: 10.1038/ng.3589. [Epub ahead of print]
Deng HX, Shi Y, Yang Y, Ahmeti KB, Miller N, Huang C, Cheng L, Zhai H, Deng S, Nuytemans K, Corbett NJ, Kim MJ, Deng H, Tang B, Yang Z, Xu Y, Chan P, Huang B, Gao XP, Song Z, Liu Z, Fecto F, Siddique N, Foroud T, Jankovic J, Ghetti B, Nicholson DA, Krainc D, Melen O, Vance JM, Pericak-Vance MA, Ma YC, Rajput AH, Siddique T.


Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.

Thursday, 9 June 2016

Potential Benefit of Singing for People with Parkinson's Disease: A Systematic Review

A fair few patients that I see in clinic have talked about the benefits they enjoy from singing... and that these extend beyond helping with speech difficulties. These types of research studies are tricky to do and when bringing them together because the differences in methods makes it difficult to interpret the data collectively... still singing is unlikely to do harm and has potential to do good.

J Parkinsons Dis. 2016 Jun 3. [Epub ahead of print]
Barnish J, Atkinson RA, Barran SM, Barnish MS.

There is evidence that participation in performing arts brings psychosocial benefits in the general population and in recent years there has been substantial interest in the potential therapeutic benefit of performing arts, including singing, for people with chronic medical conditions including those of neurological aetiology.

To systematically review the existing body of evidence regarding the potential benefit of singing on clinical outcomes of people with PD.

Seven online bibliographic databases were systematically searched in January 2016 and supplementary searches were conducted. Full-text original peer-reviewed scientific papers that investigated the potential benefit of singing on at least one of speech, functional communication, cognitive status, motor function and quality of life in human participants with PD were eligible for inclusion.

449 unique records were identified, 25 full-text articles were screened and seven studies included in the review. All seven studies assessed the impact of singing on speech, five found partial evidence of benefit and two found no evidence of benefit. One study assessed each of functional communication and quality of life and no significant benefit was found. No included study assessed the impact of singing on motor function or cognitive status.


Singing may benefit the speech of people with PD, although evidence is not unequivocal. Further research is required to assess wider benefits including on functional communication, cognitive status, motor function and quality of life. Substantial methodological limitations were identified in the existing literature. Recommendations are made for advancing the state of the literature

Wednesday, 8 June 2016

Retinal nerve fiber layer thinning: a window into rapid eye movement sleep behavior disorders in Parkinson's disease

I am not convinced by some of the analyses that were carried out here... there were some unusual groupings. Nonetheless there is further evidence that RNFL is about in PD and in RBD, and particularly in PD with RBD. These results align with those of others... OCT may yield a sensitive albeit non-specific biomarker for neurodegeneration...

Sleep Breath. 2016 Jun 3. [Epub ahead of print]
Yang ZJ, Wei J, Mao CJ, Zhang JR, Chen J, Ji XY, Liu JY, Shen Y, Xiong KP, Huang JY, Yang YP, Liu CF.

Retinal nerve fiber layer (RNFL) thinning occurs in Parkinson's disease (PD) and other neurodegenerative diseases. Idiopathic RBD (iRBD) is a well-established prodromal hallmark of synucleinopathies and occurs secondary to many neurodegenerative diseases, including PD. The aim of this study is to determine whether or not retinal structures are altered with the onset of rapid eye movement (REM) sleep behavior disorders (RBD).

In all, a total of 63 patients with PD, 14 patients with idiopathic RBD, and 26 sex- and age-matched healthy controls were enrolled and underwent optical coherence tomography measurements (HD-OCT (Zeiss) ) for the average and every quadrant of RNFL thickness. The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was used to classify PD patients with clinically probable RBD (PD + pRBD) or without probable RBD (PD - pRBD). Patients with iRBD were identified by polysomnography.

For patients with RBD (idiopathic or secondary to PD), we found a significant decrease in RNFL thickness compared with groups without RBD (PD - pRBD and healthy controls) (all p < 0.05). Average RNFL thickness in patients with iRBD is significantly thinner than in healthy controls (p < 0.05). In PD, the average RNFL thickness was dramatically thinner in the PD + pRBD group than the PD - pRBD group (p < 0.005). Compared with healthy controls, RNFL thickness was slightly thinner in the drug-naive PD group but not the PD group with drug treatment. Multiple linear regression analysis showed that RBDSQ score was negatively associated with average and inferior RNFL variation in PD (all p < 0.005).


The findings show that RNFL was slightly but significantly thinner in idiopathic RBD. In PD, RNFL thickness may vary depending on the presence of RBD.

Monday, 6 June 2016

Cognitive functioning in individuals with Parkinson's disease and traumatic brain injury: A longitudinal study

TBI is already thought to be a risk factor for neurodegenerative disease and here is further evidence linking it... PD patients with TBI in the past run a more aggressive cognitive course than those without...

Parkinsonism Relat Disord. 2016 May 24. pii: S1353-8020(16)30185-7. doi: 10.1016/j.parkreldis.2016.05.024. [Epub ahead of print]
Schiehser DM, Filoteo JV, Litvan I, Pirogovsky-Turk E, Lessig SL, Song DS.

To examine longitudinal changes in cognition in individuals with Parkinson's disease (PD) with and without a history of traumatic brain injury (TBI).

Twenty-five PD participants with a history of mild-moderate post-acute (>9 months) TBI and 25 demographically-matched PD controls without a history of TBI were administered measures of cognition (Mattis Dementia Rating Scale), mood, and motor functioning at baseline and at a two-year follow-up evaluation.

Individuals with PD and a history of TBI evidenced significantly greater decrements in overall cognition over the two year follow-up period compared to those without a history of TBI. Secondary subscale analyses suggest cognitive decrements may be mainly in the area of executive function, while a trend for group differences on the memory subscale was also observed. Groups did not differ on demographic, motor function, disease severity, cognitive, and mood profiles at baseline and evidenced comparable changes in mood and motor symptoms from baseline to follow-up.


Findings suggest that a history of mild-moderate TBI is a risk factor for cognitive decline in individuals with PD.

Detection of Alzheimer's disease at mild cognitive impairment and disease progression using autoantibodies as blood-based biomarkers

Disease specific biomarkers are going to be vital in unpicking the spectrum of neurodegenerative diseases and clarifying who is entered into which clinical trials....

Alzheimers Dement (Amst). 2016 Apr 12;3:51-62. doi: 10.1016/j.dadm.2016.03.002. eCollection 2016.
DeMarshall CA, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, Kosciuk M, Thayasivam U, Han M, Belinka B, Nagele RG; Alzheimer's Disease Neuroimaging Initiative.

There is an urgent need to identify biomarkers that can accurately detect and diagnose Alzheimer's disease (AD). Autoantibodies are abundant and ubiquitous in human sera and have been previously demonstrated as disease-specific biomarkers capable of accurately diagnosing mild-moderate stages of AD and Parkinson's disease.

Sera from 236 subjects, including 50 mild cognitive impairment (MCI) subjects with confirmed low CSF Aβ42 levels, were screened with human protein microarrays to identify potential biomarkers for MCI. Autoantibody biomarker performance was evaluated using Random Forest and Receiver Operating Characteristic curves.

Autoantibody biomarkers can differentiate MCI patients from age-matched and gender-matched controls with an overall accuracy, sensitivity, and specificity of 100.0%. They were also capable of differentiating MCI patients from those with mild-moderate AD and other neurologic and non-neurologic controls with high accuracy.


Autoantibodies can be used as noninvasive and effective blood-based biomarkers for early diagnosis and staging of AD.

Wednesday, 1 June 2016

Parkinson's disease and colorectal cancer risk-A nested case control study

This is a very large matched case-control study showing a negative association between Parkinson's and colorectal cancer... the hypothesis came from gut bacteria that promote inflammation being common to both conditions... but this is a really complicated field and the gut microbiome studies in PD so far have thrown up contrasting results... plenty of studies in the past have documented negative associations between Parkinson's and cancer... the reason... nobody knows...

Cancer Epidemiol. 2016 May 24;43:9-14. doi: 10.1016/j.canep.2016.05.007. [Epub ahead of print]
Boursi B, Mamtani R, Haynes K, Yang YX.

A pro-inflammatory gut microbiota was described in both Parkinson's disease and colorectal cancer (CRC) and recently α-synuclein was demonstrated in the enteric nervous system. We sought to evaluate the association between Parkinson's disease and CRC.

We conducted a nested case-control study using a large primary-care database. Cases were defined as all individuals with CRC. Up to 4 controls were matched with each case based on age, sex, practice-site and duration of follow-up. The primary exposure of interest was diagnosis of Parkinson's disease prior to CRC as well as disease duration, and Parkinson's specific therapies. The primary analysis was a conditional logistic-regression to estimate odds ratios (ORs) and 95% confidence interval (95%CI).

The study included 22,093 CRC cases and 85,833 matched controls. Past medical history of Parkinson's disease >1 year before index-date was associated with lower CRC risk (OR 0.74, 95%CI 0.59-0.94). The inverse association was more prominent among females compared to males (0.64, 95%CI 0.42-0.96 and 0.8, 95%CI 0.60-1.07, respectively). While patients who received no therapy or therapy with dopamine agonists had a non-significant decrease in cancer risk, patients who were treated with dopamine had a non-significant elevated cancer risk.

Parkinson's disease is inversely associated with CRC risk.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Constipation and risk of Parkinson's disease: A Danish population-based cohort study

Further evidence that supports the results from our meta-analysis last year... constipation is robustly associated with a future diagnosis of Parkinson's... what is more it tends to occur a long time before the eventual diagnosis. I think it is the earliest non motor feature.... 

Parkinsonism Relat Disord. 2016 May 19. pii: S1353-8020(16)30168-7. doi: 10.1016/j.parkreldis.2016.05.016. [Epub ahead of print]
Svensson E, Henderson VW, Borghammer P, Horváth-Puhó E, Sørensen HT.

To examine long-term associations between constipation and Parkinson's disease (PD) in men and women, we conducted a population-based cohort study using prospectively collected registry data on hospital contacts for constipation and PD, stratified by follow-up time and sex.

We linked Danish registries to construct a cohort of all patients in Denmark with an outpatient hospital diagnosis of constipation 1995-2012 and a matched general population comparison cohort. Using Cox regression, we computed hazard ratios (HRs) for PD and corresponding 95% confidence intervals (CIs), adjusting for potential confounders, stratified by sex and follow-up time.

The 31,905 patients with constipation had a higher risk of PD than 159,092 comparison cohort members (adjusted (a) HR = 3.03, 95% CI 2.50-3.66), which was sustained to 11-15 years follow-up (aHR = 3.65, 95% CI 1.67-7.95). Increased risk was apparent in both sexes but stronger in men [aHR = 3.52 (2.67-4.64] than women [aHR = 2.64 (95% CI 2.02-3.44].

In this large population-based cohort study, constipation was associated with sustained increased risk of a PD diagnosis, and the relative risk was higher for men than for women.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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),...