Friday, 30 June 2017

Association of Autonomic Dysfunction With Disease Progression and Survival in Parkinson Disease

These post mortem studies have high value given the certainty in diagnosis and there still being an appreciable misdiagnosis rate in patients still living... for example, Multiple System Atrophy is a parkinsonian disorder associated with autonomic dysfunction and reduced survival. If there were a few MSA patients in amongst people with Parkinson's in a living cohort, then their presence could induce an association between autonomic dysfunction and reduced survival, and be attributed to an effect of AutD and survival in people Parkinson's... this would be an example of bias. By using post mortem diagnosis as the standard, the authors navigate around that potential source of misclassification.

People have intuitively associated AutD with more severe forms of Parkinson's or being at a more advanced stage clinically. This study reaffirms this suspicions. It is interesting however to see that pathological staging was not associated...

 2017 Jun 26. doi: 10.1001/jamaneurol.2017.1125. [Epub ahead of print]

IMPORTANCE: 

Evidence suggests that development of autonomic dysfunction (AutD) may negatively affect disease course and survival in patients with synucleinopathies. However, the few available studies on Parkinson disease (PD) have conflicting results, comprise a small number of patients, have short follow-up periods, and lack pathologic confirmation of the diagnosis.

OBJECTIVE: 

To examine the association of time of onset of AutD with disease progression and survival in PD.

DESIGN, SETTING, AND PARTICIPANTS: 

This retrospective review of clinical data from 100 consecutive patients with an autopsy-confirmed diagnosis of PD from the archives of the Queen Square Brain Bank in London, United Kingdom, from January 1, 2006, to June 3, 2016, included patients with PD regularly seen by hospital specialists (neurologists or geriatricians) in the United Kingdom throughout their disease until death. Patients with dementia before or within 1 year after onset of motor symptoms, monogenic forms of PD, comorbidities that affect autonomic function, a coexisting neuropathologic diagnosis, or insufficient clinical information were excluded.

MAIN OUTCOMES AND MEASURES: 

Survival and time from diagnosis to specific disease milestones were calculated to assess disease progression. Autonomic dysfunction was defined as autonomic failure at autonomic function testing or 2 of the following symptoms: urinary symptoms, constipation, upper gastrointestinal tract dysfunction, orthostatic hypotension, sweating abnormalities, or erectile dysfunction. Multivariable Cox proportional hazards regression models on the risk of a disease milestone and death were used.

RESULTS: 

A total of 100 patients (60 [60.0%] male; mean [SD] age at diagnosis, 63.9 [10.3] years; mean [SD] disease duration, 14.6 [7.7] years) were studied. Autonomic dysfunction developed in 85 patients (mean [SD] time from diagnosis, 6.7 [7.7] years) and was associated with older age at diagnosis, male sex, poor initial levodopa treatment response, and postural instability and gait difficulty motor PD subtype in linear regression analysis, but staging of α-synuclein pathologic changes was unrelated. Earlier AutD increased the risk of reaching the first milestone (hazard ratio, 0.86; 95% CI, 0.83-0.89; P < .001) and shortened survival (hazard ratio, 0.92; 95% CI, 0.88-0.96; P < .001). Older age at diagnosis and poorer levodopa treatment response were the other factors associated with shorter survival in adjusted multivariate analysis.

CONCLUSIONS AND RELEVANCE: 

Earlier AutD is associated with a more rapid development of disease milestones and shorter survival in patients with PD.

Association between Parkinson's disease and diabetes: Data from NEDICES study.

There is increasing evidence of a link between diabetes and Parkinson's... I had always assumed that any association between vascular risk factors and parkinsonism was driven by vascular disease mimicking PD or mixed pathology, rather than being associated with PD per se. But it is time to consider the alternative now that increasing data are available and drugs used to treat diabetes are being trialled for Parkinson's...

 2017 Jun 26. doi: 10.1111/ane.12793. [Epub ahead of print]

BACKGROUND: 

Despite growing evidence showing an association between Parkinson's disease (PD) and diabetes, epidemiological studies have shown conflicting results.

AIMS OF THE STUDY: 

To evaluate the association between PD and diabetes and the impact of diabetes duration in this association in an elderly (≥65 years) Spanish population.

METHODS: 

Data for this cross-sectional population-based analysis were obtained from NEDICES study. Subjects were identified from census list. Diagnosis of PD was confirmed by neurological examination. Diabetes was defined by self-report, being on antidiabetic medication or diagnosis on medical records. Logistic regression analysis adjusted by potential confounders was performed to estimate the association between both conditions and also after dividing patients into short-duration (<10 years) and long-duration (≥10 years) diabetes.

RESULTS: 

A total of 4998 subjects were included (79 PD and 4919 controls). Univariate analysis did not show any association between prevalence of PD and diabetes (OR 1.89, 95% CI 0.90-3.98, P=.09), although subgroup analysis showed a positive association in those with long-duration diabetes (3.27, 95% CI 1.21-8.85, P=.02).

CONCLUSIONS: 

Diabetes duration might be an important factor in the association between PD and diabetes, and the risk might be limited to those with longer disease duration.

Monday, 26 June 2017

Intake of dairy foods and risk of Parkinson disease

There has been some previous literature on consumption of diary products and risk of Parkinson's... the problem is that dietary questionnaires tend to be inaccurate. It is hard to know whether this could be a true causal association... the seems to be potential of misclassification of the exposure (i.e. people not reporting diary intake accurately) and there may also be residual confounding. That said dietary exposures may be particularly relevant these days given the increasing recognition of the role of the gut in PD...



Neurology. 2017 Jun 8. pii: 10.1212/WNL.0000000000004057. doi: 10.1212/WNL.0000000000004057. [Epub ahead of print]
Hughes KC, Gao X, Kim IY, Wang M, Weisskopf MG, Schwarzschild MA, Ascherio A.

http://www.neurology.org/content/early/2017/06/08/WNL.0000000000004057

OBJECTIVE: To prospectively examine the association between commonly consumed dairy products and the risk of Parkinson disease (PD) in women and men. METHODS: Analyses were based on data from 2 large prospective cohort studies, the Nurses' Health Study (n = 80,736) and the Health Professionals Follow-up Study (n = 48,610), with a total of 26 and 24 years of follow-up, respectively. Both US-based studies were conducted via mailed biennial questionnaires. Dietary intake was assessed with food frequency questionnaires administered repeatedly over the follow-up period. Incident cases of PD (n = 1,036) were identified via questionnaires and subsequently confirmed by reviewing medical records. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on total milk intake and PD risk and 1 study on total dairy intake and PD risk. RESULTS: While total dairy intake was not significantly associated with PD risk in our cohorts, intake of low-fat dairy foods was associated with PD risk. The pooled, multivariable-adjusted hazard ratio (HR) comparing people who consumed at least 3 servings of low-fat dairy per day to those who consumed none was 1.34 (95% confidence interval [CI] 1.01-1.79, p trend = 0.04). This association appeared to be driven by an increased risk of PD associated with skim and low-fat milk (HR 1.39, 95% CI 1.12-1.73, p trend <0 .01="" and="" for="" heterogeneity="" in="" men="" p="" results="" similar="" were="" women="">0.05). In the meta-analysis, the pooled relative risk comparing extreme categories of total milk intake was 1.56 (95% CI 1.30-1.88), and the association between total dairy and PD became significant (HR 1.27, 95% CI 1.04-1.55). CONCLUSIONS: Frequent consumption of dairy products appears to be associated with a modest increased risk of PD in women and men.

Sunday, 25 June 2017

Moist smokeless tobacco (Snus) use and risk of Parkinson's disease

I can't believe I didn't see this when it was first published... this study supports a (potentially causal) association between smoking and PD. It suggests again that smoking is protective and that nicotine itself may be the protective factor. Given that it is an observational study, it may well be affected by reverse causation, but it ties in nicely with what has been observed for cigarette smoking and supports the fact that there are clinical trials taking place using nicotine replacement therapy... this is a question that needs a definitive answer!

Int J Epidemiol. 2016 Dec 10. pii: dyw294. [Epub ahead of print]
Yang F, Pedersen NL, Ye W, Liu Z, Norberg M, Forsgren L, Trolle Lagerros Y, Bellocco R, Alfredsson L, Knutsson A, Jansson JH, Wennberg P, Galanti MR, Lager AC, Araghi M, Lundberg M, Magnusson C, Wirdefeldt K.

https://academic.oup.com/ije/article-abstract/doi/10.1093/ije/dyw294/2656164/Moist-smokeless-tobacco-Snus-use-and-risk-of?redirectedFrom=fulltext

BACKGROUND: Cigarette smoking is associated with a lower risk of Parkinson's disease. It is unclear what constituent of tobacco smoke may lower the risk. Use of Swedish moist smokeless tobacco (snus) can serve as a model to disentangle what constituent of tobacco smoke may lower the risk. The aim of this study was to determine whether snus use was associated with a lower risk of Parkinson's disease.

METHODS: Individual participant data were collected from seven prospective cohort studies, including 348 601 men. We used survival analysis with multivariable Cox regression to estimate study-specific relative risk of Parkinson's disease due to snus use, and random-effects models to pool estimates in a meta-analysis. The primary analyses were restricted to never-smokers to eliminate the potential confounding effect of tobacco smoking.

RESULTS: During a mean follow-up time of 16.1 years, 1199 incident Parkinson's disease cases were identified. Among men who never smoked, ever-snus users had about 60% lower Parkinson's disease risk compared with never-snus users [pooled hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.28-0.61]. The inverse association between snus use and Parkinson's disease risk was more pronounced in current (pooled HR 0.38, 95% CI 0.23-0.63), moderate-heavy amount (pooled HR 0.41, 95% CI 0.19-0.90) and long-term snus users (pooled HR 0.44, 95% CI 0.24-0.83).

CONCLUSIONS: Non-smoking men who used snus had a substantially lower risk of Parkinson's disease. Results also indicated an inverse dose-response relationship between snus use and Parkinson's disease risk. Our findings suggest that nicotine or other components of tobacco leaves may influence the development of Parkinson's disease.

Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter-Deficit Prodromal Cohort

This is an exciting study and one of the most eagerly anticipated in the field of prodromal/pre-diagnostic PD... the authors show that the two step screening process works in so far as they can predict a significant proportion of participants that will 'convert' to PD at 4 years of follow-up. However the true screening performance cannot be determined because of big differences in follow up at each stage - we don't know what happens in normosmic participants or those that refused DaTSCAN. 

I am very interested in the proportion at baseline that had subtle motor dysfunction. It seems to offer further support for dispelling the notion of 'pre-motor' and settling on more appropriate terms like pre-diagnostic and prodromal. Motor dysfunction is seen in the PREDICT-PD cohort (http://jnnp.bmj.com/content/88/3/212) and in individuals with iRBD (https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/aws093). Nonetheless it is a huge leap forward in the pre-diagnostic identification of PD...

JAMA Neurol. 2017 Jun 8. doi: 10.1001/jamaneurol.2017.0985. [Epub ahead of print]
Jennings D, Siderowf A, Stern M, Seibyl J, Eberly S, Oakes D, Marek K; PARS Investigators.

http://jamanetwork.com/journals/jamaneurology/article-abstract/2630495

IMPORTANCE: Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD.

OBJECTIVE: To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD.

DESIGN, SETTING, AND PARTICIPANTS: Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up.

MAIN OUTCOMES AND MEASURES: Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4-year follow-up.

RESULTS: Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit.

CONCLUSIONS AND RELEVANCE: The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD.

Monday, 19 June 2017

Estimating the causal influence of body mass index on risk of Parkinson disease: A Mendelian randomisation study

This is one of the first true causal studies in Parkinson's disease... it uses a method called Mendelian Randomisation to estimate the effect that body mass index has on Parkinson's. Many association studies are flawed because of reverse causation (Parkinson's affects BMI rather than the other way around) or confounding (there is another/other factor(s) associated with both BMI and Parkinson's that explain the observed association). Mendelian Randomisation ought to mitigate the risk of reverse causation and confounding, and therefore the association here should represent a true causal one... I am very proud of this work which represents a large collaborative effort by the International Parkinson's Disease Genomics Consortium and colleagues at Bristol University...

PLoS Med. 2017 Jun 13;14(6):e1002314. doi: 10.1371/journal.pmed.1002314. eCollection 2017 Jun. Noyce AJ, Kia DA, Hemani G, Nicolas A, Price TR, De Pablo-Fernandez E, Haycock PC, Lewis PA, Foltynie T, Davey Smith G; International Parkinson Disease Genomics Consortium, Schrag A, Lees AJ, Hardy J, Singleton A, Nalls MA, Pearce N, Lawlor DA, Wood NW.

http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002314

BACKGROUND: Both positive and negative associations between higher body mass index (BMI) and Parkinson disease (PD) have been reported in observational studies, but it has been difficult to establish causality because of the possibility of residual confounding or reverse causation. To our knowledge, Mendelian randomisation (MR)-the use of genetic instrumental variables (IVs) to explore causal effects-has not previously been used to test the effect of BMI on PD.

METHODS AND FINDINGS: Two-sample MR was undertaken using genome-wide association (GWA) study data. The associations between the genetic instruments and BMI were obtained from the GIANT consortium and consisted of the per-allele difference in mean BMI for 77 independent variants that reached genome-wide significance. The per-allele difference in log-odds of PD for each of these variants was estimated from a recent meta-analysis, which included 13,708 cases of PD and 95,282 controls. The inverse-variance weighted method was used to estimate a pooled odds ratio (OR) for the effect of a 5-kg/m2 higher BMI on PD. Evidence of directional pleiotropy averaged across all variants was sought using MR-Egger regression. Frailty simulations were used to assess whether causal associations were affected by mortality selection. A combined genetic IV expected to confer a lifetime exposure of 5-kg/m2 higher BMI was associated with a lower risk of PD (OR 0.82, 95% CI 0.69-0.98). MR-Egger regression gave similar results, suggesting that directional pleiotropy was unlikely to be biasing the result (intercept 0.002; p = 0.654). However, the apparent protective influence of higher BMI could be at least partially induced by survival bias in the PD GWA study, as demonstrated by frailty simulations. Other important limitations of this application of MR include the inability to analyse non-linear associations, to undertake subgroup analyses, and to gain mechanistic insights.

CONCLUSIONS: In this large study using two-sample MR, we found that variants known to influence BMI had effects on PD in a manner consistent with higher BMI leading to lower risk of PD. The mechanism underlying this apparent protective effect warrants further study.

Tuesday, 13 June 2017

Association between Parkinson's Disease and Cigarette Smoking, Rural Living, Well-Water Consumption, Farming and Pesticide Use: Systematic Review and Meta-Analysis

My personal opinion is that they are all causally related to PD... animal models strongly support the notion that pesticides and similar toxins increase risk of Parkinson's and much of the epidemiological literature points in that direction. As for smoking... the weight of evidence is pretty overwhelming... novel methods may answer this question once and for all...

PLoS One. 2016 Apr 7;11(4):e0151841. doi: 10.1371/journal.pone.0151841. eCollection 2016.
Breckenridge CB1, Berry C2, Chang ET3, Sielken RL Jr4, Mandel JS3. Author information Abstract

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151841

OBJECTIVE: Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson's disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a "positive control" because a strong inverse association has been described consistently in the literature.

METHODS: PubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson's disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat. Studies were categorized into two study quality groups (Tier 1 or Tier 2); data were abstracted and a forest plot of relative risks (RRs) was developed for each risk factor. In addition, when available, RRs were tabulated for more highly exposed individuals compared with the unexposed. Summary RRs for each risk factor were calculated by meta-analysis of Tier 1, Tier 2 and all studies combined, with sensitivity analyses stratified by other study characteristics. Indices of between-study heterogeneity and evidence of reporting bias were assessed. Bradford Hill's viewpoints were used to determine if a causal relationship between PD and each risk factor was supported by the weight of the evidence.

FINDINGS: There was a consistent inverse (negative) association between current cigarette smoking and PD risk. In contrast, associations between PD and rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat were less consistent when assessed quantitatively or qualitatively.

CONCLUSION: The weight of the evidence and meta-analysis support the conclusion that there is a causal relationship between PD risk and cigarette smoking, or some unknown factor correlated with cigarette smoking. There may be risk factors associated with rural living, farming, pesticide use or well-water consumption that are causally related to PD, but the studies to date have not identified such factors. To overcome the limitations of research in this area, future studies will have to better characterize the onset of PD and its relationship to rural living, farming and exposure to pesticides.

Saturday, 10 June 2017

A Life-Long Approach to Physical Activity for Brain Health

There is lots of observational data to support the notion of physical activity being protective against many diseases associated with ageing. Unfortunately even with cohort studies it is difficult to mitigate the effect of reverse causality (i.e. physical activity diminishing as a result of undiagnosed disease and therefore participation in physical activity appearing protective)... 
Randomised controlled trials have been done and are supportive but because the nature of the intervention makes it hard to blind participants... other causal approaches may end up being useful...

Front Aging Neurosci. 2017 May 23;9:147. doi: 10.3389/fnagi.2017.00147. eCollection 2017. Macpherson H, Teo WP, Schneider LA, Smith AE.

http://journal.frontiersin.org/article/10.3389/fnagi.2017.00147/full

It is well established that engaging in lifelong Physical activity (PA) can help delay the onset of many chronic lifestyle related and non-communicable diseases such as cardiovascular disease, type two diabetes, cancer and chronic respiratory diseases. Additionally, growing evidence also documents the importance of PA for brain health, with numerous studies indicating regular engagement in physical activities may be protective against cognitive decline and dementia in late life. Indeed, the link between PA and brain health may be different at each stage of life from childhood, mid-life and late life. Building on this emerging body of multidisciplinary research, this review aims to summarize the current body of evidence linking regular PA and brain health across the lifespan. Specifically, we will focus on the relationship between PA and brain health at three distinct stages of life: childhood and adolescence, mid-life, late life in cognitively healthy adults and later life in adults living with age-related neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD).

Wednesday, 7 June 2017

Death certificates data and causes of death in patients with parkinsonism

Perhaps no surprises here in terms of causes of death... the proportion of atypical parkinson's cases suggests some bias in the recruitment (perhaps not given that the setting was a tertiary movement disorder clinic). Even so that bias doesn't mitigate what are helpful results and I agree with the authors' conclusions about the need for better documentation on death certificates and the potential for such data to inform prognosis and counselling discussions...

Parkinsonism Relat Disord. 2017 May 26. pii: S1353-8020(17)30188-8. doi: 10.1016/j.parkreldis.2017.05.022. [Epub ahead of print]
Moscovich M, Boschetti G, Moro A, Teive HAG, Hassan A, Munhoz RP.

http://www.prd-journal.com/article/S1353-8020(17)30188-8/fulltext

INTRODUCTION: Assessment of variables related to mortality in Parkinson disease (PD) and other parkinsonian syndromes relies, among other sources, on accurate death certificate (DC) documentation. We assessed the documentation of the degenerative disorder on DCs and evaluated comorbidities and causes of death among parkinsonian patients.

METHODS: Demographic and clinical data were systematically and prospectively collected on deceased patients followed at a tertiary movement disorder clinic. DCs data included the documentation of parkinsonism, causes, and place of death.

RESULTS: Among 138 cases, 84 (60.9%) male, mean age 77.9 years, mean age of onset 66.7, and mean disease duration 10.9 years. Clinical diagnoses included PD (73.9%), progressive supranuclear palsy (10.9%), multiple system atrophy (7.2%), Lewy body dementia (7.2%) and corticobasal degeneration (0.7%). Psychosis occurred in 60.1% cases, dementia in 48.5%. Most PD patients died due to heterogeneous causes before reaching advanced stages. Non-PD parkinsonian patients died earlier due to causes linked to the advanced neurodegenerative process. PD was documented in 38.4% of DCs with different forms of inconsistencies. That improved, but remained significant when it was signed by a specialist.

CONCLUSIONS: More than half of PD cases died while still ambulatory and independent, after a longer disease course and due to causes commonly seen in that age group. Deaths among advanced PD patients occurred due to causes similar to what we found in non-PD cases. These findings can be useful for clinical, prognostic and counseling purposes. Underlying parkinsonian disorders are poorly documented in DCs, undermining its' use as sources of data collection.

Tuesday, 6 June 2017

Factor structure of the Montreal Cognitive Assessment items in a sample with early Parkinson's disease

Useful data from the PPMI study looking at the various components of the MoCA and how these change in the early stages of PD after diagnosis... this may have relevance for an even earlier stage of PD, prior to diagnosis, and this is a focus of some of the work we are doing at the moment.

Parkinsonism Relat Disord. 2017 May 25. pii: S1353-8020(17)30189-X. doi: 10.1016/j.parkreldis.2017.05.023. [Epub ahead of print]

Benge JF, Balsis S, Madeka T, Uhlman C, Lantrip C, Soileau MJ.

http://www.prd-journal.com/article/S1353-8020(17)30189-X/fulltext

INTRODUCTION: The Montreal Cognitive Assessment (MoCA) is a frequently utilized cognitive screening tool that has attractive clinical attributes when utilized in individuals with Parkinson's disease. However, the construct validity of this instrument has not been well-characterized in Parkinson's samples. The purpose of this study is to explore the underlying factor structure of the MoCA in individuals with early stage Parkinson's disease.

METHOD: Item responses from the MoCA in 357 individuals with Parkinson's disease from the Parkinson's Progression Markers Initiative were analyzed first for frequency of errors and polychoric inter item correlations. This correlation matrix was then analyzed with exploratory factor analysis.

RESULTS: Omitting items with ceiling effects, three factors emerged which explained the majority of the variance. These factors were reflective of executive dysfunction, memory, and verbal attention. Scores on the MoCA and all of its subscales were significantly different between individuals with Parkinson's disease-no cognitive impairment and those who met criteria for mild cognitive impairment.

CONCLUSIONS: In keeping with prior studies in Parkinson's disease, executive dysfunction seems to underpin performance of many items of the MoCA. Implications of this finding both in terms of optimizing the MoCA for use in this population and further steps to validate the constructs behind the MoCA are discussed.

Monday, 24 April 2017

Longitudinal whole-brain atrophy and ventricular enlargement in nondemented Parkinson's disease

Great example of how MRI can to used to supplement clinical trials in PD... I think it very helpful that the authors included the estimation of how use of an imaging biomarker could reduce a required sample size to 1/15th especially at a time when we are adding to our armoury of options for use in clinical trials of disease modifying therapy... MRI is widely available and reasonable in terms of cost too...

Neurobiol Aging. 2017 Mar 16;55:78-90. doi: 10.1016/j.neurobiolaging.2017.03.012. [Epub ahead of print]
Mak E, Su L, Williams GB, Firbank MJ, Lawson RA, Yarnall AJ, Duncan GW, Mollenhauer B, Owen AM, Khoo TK, Brooks DJ, Rowe JB, Barker RA, Burn DJ, O'Brien JT.

http://www.neurobiologyofaging.org/article/S0197-4580(17)30083-0/abstract

We investigated whole-brain atrophy and ventricular enlargement over 18 months in nondemented Parkinson's disease (PD) and examined their associations with clinical measures and baseline CSF markers. PD subjects (n = 100) were classified at baseline into those with mild cognitive impairment (MCI; PD-MCI, n = 36) and no cognitive impairment (PD-NC, n = 64). Percentage of whole-brain volume change (PBVC) and ventricular expansion over 18 months were assessed with FSL-SIENA and ventricular enlargement (VIENA) respectively. PD-MCI showed increased global atrophy (-1.1% ± 0.8%) and ventricular enlargement (6.9 % ± 5.2%) compared with both PD-NC (PBVC: -0.4 ± 0.5, p < 0.01; VIENA: 2.1% ± 4.3%, p < 0.01) and healthy controls. In a subset of 35 PD subjects, CSF levels of tau, and Aβ42/Aβ40 ratio were correlated with PBVC and ventricular enlargement respectively. The sample size required to demonstrate a 20% reduction in PBVC and VIENA was approximately 1/15th of that required to detect equivalent changes in cognitive decline. These findings suggest that longitudinal MRI measurements have potential to serve as surrogate markers to complement clinical assessments for future disease-modifying trials in PD.

Sunday, 23 April 2017

Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort

Important to seek validation of these criteria and existing prodromal cohorts are a good place to start... of course, as I have written here before, there are some issues with using RBD patients such as: 1) it is a precursor for synucleinopathy rather than PD specifically, and 2) the cases that develop PD tend to be at the more severe end of the spectrum with prominent cognitive impairment. However, aside from these things, RBD is a very important model for studying the pre-diagnostic phase of PD...

Mov Disord. 2017 Apr 21. doi: 10.1002/mds.26989. [Epub ahead of print]
Fereshtehnejad SM, Montplaisir JY, Pelletier A, Gagnon JF, Berg D, Postuma RB.

BACKGROUND: Recently, the International Parkinson and Movement Disorder Society introduced the prodromal criteria for PD. Objectives Our study aimed to examine diagnostic accuracy of the criteria as well as the independence of prodromal markers to predict conversion to PD or dementia with Lewy bodies.

METHODS: This prospective cohort study was performed on 121 individuals with rapid eye movement sleep behavior disorder who were followed annually for 1 to 12 years. Using data from a comprehensive panel of prodromal markers, likelihood ratio and post-test probability of the criteria were calculated at baseline and during each follow-up visit.

RESULTS: Forty-eight (39.7%) individuals with rapid eye movement sleep behavior disorder converted to PD/dementia with Lewy bodies. The prodromal criteria had 81.3% sensitivity and 67.9% specificity for conversion to PD/dementia with Lewy bodies at 4-year follow-up. One year before conversion, sensitivity was 100%. The criteria predicted dementia with Lewy bodies with even higher accuracy than PD without dementia at onset. Those who met the threshold of prodromal criteria at baseline had significantly more rapid conversion into a neurodegenerative state (4.8 vs. 9.1 years; P < 0.001). Pair-wise combinations of different prodromal markers showed that markers were independent of one another.

CONCLUSION: The prodromal criteria are a promising tool for predicting incidence of PD/dementia with Lewy bodies and conversion time in a rapid eye movement sleep behavior disorder cohort, with high sensitivity and high specificity with long follow-up. Prodromal markers influence the overall likelihood ratio independently, allowing them to be reliably multiplied. Defining additional markers with high likelihood ratio, further studies with longitudinal assessment and testing thresholds in different target populations will improve the criteria.

Monday, 10 April 2017

Prevalence of Prodromal Parkinson's Disease as Defined by MDS Research Criteria among Elderly Patients Undergoing Colonoscopy

J Parkinsons Dis. 2017 Apr 4. doi: 10.3233/JPD-161036. [Epub ahead of print]

This is very similar to an idea our group had a few years ago... here they are just describing the clinical features of the 100 screened participants and how they fit within the MDS Task Force framework... the interesting thing to know is whether the colonoscopies of those people that are higher risk are abnormal... the potential for colonoscopy to give us valid PD biomarkers has taken a bit of a knock in recent years but I still think it may hold some promise...

Matej S, Zuzana L, Vladimir H, Norbert L, Eva F, Dominika J, Barbora R, Peter S, Zuzana U, Adriana V, Laura G, Maria Z, Eduard V, Frantisek T, Eva M, Zuzana.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd161036

BACKGROUND: Gastrointestinal symptoms are a well-recognized and common premotor feature of Parkinson's disease (PD). Moreover, multiple studies have assessed the value of colonic α-synuclein as a potential marker of prodromal PD. Recently, the International Parkinson and Movement Disorders Society (MDS) defined research criteria for prodromal PD.

OBJECTIVE: The aim of our study was to test the MDS research criteria in patients undergoing diagnostic colonoscopies as potential candidates for inclusion in prospective trials evaluating colonic biopsies as a potential biomarker of prodromal PD.

METHODS: We evaluated elderly patients without manifest parkinsonism undergoing diagnostic colonoscopies. During the study we assessed all risks and prodromal markers of the MDS research criteria, excluding radiotracer imaging and genetic testing.

RESULTS: The mean age of the 100 enrolled patients was 61.6±9.7 years; 42 were men. The most common prodromal marker in our cohort was constipation (40%), followed by MDS-UPDRS part III scores of >6 points, excluding action tremor items (39%) and hyposmia (37%). Substantia nigra hyperechogenicity was identified in 9%, and polysomnography confirmed REM sleep behavior disorder in 2% of the patients. Five of the 100 enrolled patients (5%) fulfilled the criteria for probable prodromal PD, while another 3 patients met the 50% probability threshold.

CONCLUSIONS: Our findings suggest, that the prevalence of prodromal PD in patients undergoing diagnostic colonoscopies may be higher compared to the general elderly population, although this should be confirmed in further studies including also matched controls not undergoing colonoscopy. The real prevalence of prodromal PD in this cohort will have to be confirmed in longitudinal follow-up. Patients undergoing diagnostic colonoscopies may be good candidates for multistep screening and inclusion in prospective trials.

Sunday, 2 April 2017

Viral hepatitis and Parkinson disease: A national record-linkage study

This is a study led by Julia Pakpoor in the HES database, a very large UK cohort study using routinely collected medical data. Two previous studies from Taiwan showed a link between hepatitis and future Parkinson's, but here we show it on a larger scale and in a Western population. It is not clear whether this a feature peculiar to the virus, the treatment or a common risk factor that predisposes to both...

Neurology. 2017 Mar 29. pii: 10.1212/WNL.0000000000003848. doi: 10.1212/WNL.0000000000003848. [Epub ahead of print]
Pakpoor J, Noyce A, Goldacre R, Selkihova M, Mullin S, Schrag A, Lees A, Goldacre M.

http://www.neurology.org/content/early/2017/03/29/WNL.0000000000003848.short

OBJECTIVE: To study associations between viral hepatitis and Parkinson disease (PD).

METHODS: A retrospective cohort study was done by analyzing linked English National Hospital Episode Statistics and mortality data (1999-2011). Cohorts of individuals with hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis, and HIV were constructed, and compared to a reference cohort for subsequent rates of PD.

RESULTS: The standardized rate ratio (RR) of PD following hepatitis B was 1.76 (95% confidence interval [CI] 1.28-2.37) (p < 0.001), based on 44 observed compared with 25 expected cases. The RR of PD following hepatitis C was 1.51 (95% CI, 1.18-1.9) (p < 0.001), based on 48.5 expected and 73 observed cases. There was no significant association between autoimmune hepatitis, chronic active hepatitis or HIV, and subsequent PD. When including only those episodes of care for PD that occurred first at least 1 year following each exposure condition, the RR for hepatitis B and hepatitis C were 1.82 (1.29-2.5) and 1.43 (1.09-1.84), respectively.

CONCLUSIONS: We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly.

Saturday, 25 March 2017

Excessive Daytime Sleepiness Predicts Neurodegeneration in Idiopathic REM Sleep Behavior Disorder

Interesting to see how excessive daytime somnolence (sleepiness) predicts which patients with RBD go on to get PD... and strange that it does not predict all neurodegenerative outcomes. I would have thought excessive daytime somnolence was influenced by many factors, but perhaps this suggest specific pathological involvement of a brain structure related to PD (the locus ceruleus?)

Sleep. 2017 Mar 16. doi: 10.1093/sleep/zsx041. [Epub ahead of print]
Zhou J, Zhang J, Lam SP, Chan JW, Mok V, Chan A, Li SX, Liu Y, Tang X, Yung WH, Wing YK.

https://academic.oup.com/sleep/article-abstract/doi/10.1093/sleep/zsx041/3072757/Excessive-Daytime-Sleepiness-Predicts?redirectedFrom=fulltext

STUDY OBJECTIVES: To determine the association of excessive daytime sleepiness (EDS) with the conversion of neurodegenerative diseases in patients with idiopathic REM sleep behavior disorder (iRBD).

METHODS: A total of 179 patients with iRBD (79.1% males, mean age = 66.3 ± 9.8 years) were consecutively recruited. Forty-five patients with Epworth Sleepiness Scale score ≥ 14 were defined as having EDS. Demographic, clinical and polysomnographic data were compared between iRBD patients with and without EDS. The risk of developing neurodegenerative diseases was examined using Cox proportional hazards model.

RESULTS: After a mean follow-up of 5.8 years (SD = 4.3 years), 50 patients (27.9%) developed neurodegenerative diseases. There was a significantly higher proportion of conversion in patients with EDS compared with those without EDS (42.2 % vs 23.1%, P = 0.01). EDS significantly predicted an increased risk of developing neurodegenerative diseases (adjusted hazard ratios [HR] = 2.56, 95% confidence interval [CI] 1.37-4.77) after adjusting for age, sex, body mass index, current depression, obstructive sleep apnea, and periodic limb movement during sleep. Further analyses demonstrated that EDS predicted the conversion of Parkinson's disease (PD) (adjusted HR = 3.55, 95% CI 1.59-7.89), but not dementia (adjusted HR = 1.48, 95% CI 0.44-4.97).

CONCLUSIONS: EDS is associated with an increased risk of developing neurodegenerative diseases, especially PD, in patients with iRBD. Our findings suggest that EDS is a potential clinical biomarker of α-synucleinopathies in iRBD.

Thursday, 23 March 2017

Predictive markers for early conversion of iRBD to neurodegenerative synucleinopathy diseases

Nice new paper on predictors for conversion to a 'degenerative synucleinopathy' in patients with iRBD... as expected DAT SPECT is one of those predictors... this field is shaping up nicely in terms of identifying a group to trial neuroprotective agents directed against abnormal and aggregated synuclein... a word of caution, as always, degenerative synucleinopathy describes PD, MSA and LBD, not simply PD... 

Yuanyuan Li, PhD, Wenyan Kang, PhD, Qiong Yang, MS, Lina Zhang, MS, Linyuan Zhang, PhD, Fangyi Dong, MS, Shengdi Chen, MD, PhD and Jun Liu, MD, PhD

Neurology
Published online before print March 22, 2017, doi: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0000000000003838 Neurology 10.1212/WNL.0000000000003838

http://www.neurology.org/content/early/2017/03/22/WNL.0000000000003838.short?rss=1&utm_source=dlvr.it&utm_medium=twitter

Objective: To determine the predictive value of clinical assessment and dopamine transporter (DAT) uptake for the early development of neurodegenerative synucleinopathy diseases from idiopathic REM sleep behavior disorder (iRBD) over 5 years in a Chinese population.

Methods: Forty-three patients with iRBD were administered clinical assessment tests, and 35 were examined by DAT-SPECT imaging during 2011. Cox proportional hazard and Kaplan-Meier analyses were used to evaluate the predictive value of the markers in a follow-up study over 5 years.

Results: Eighteen patients (41.9%) developed neurodegenerative synucleinopathy diseases after a median of 4.1 years of prospective follow-up (median interval of 10.5 years from the estimated onset of iRBD symptoms). Patients with higher scores on the Nonmotor Symptom Questionnaire (hazard ratio [HR] 3.11, 95% confidence interval [CI] 1.15–8.40, p = 0.026) and Scale for Outcomes in Parkinson Disease–Autonomic questionnaire (HR 4.46, 95% CI 1.64–12.10, p = 0.003) were more likely to develop neurodegenerative synucleinopathy diseases. Furthermore, the population with decreased 99mTc-TRODAT-1 binding in the left striatum (HR 2.7, 95% CI 1.02–7.14, p = 0.046) and putamen (HR 3.23, 95% CI 1.16–8.33, p = 0.024) had a relatively higher risk of developing neurodegenerative synucleinopathy diseases.

Conclusions: Our findings elucidate the predictive value of autonomic dysfunction and DAT uptake in identifying patients with iRBD at a high risk of progressing into neurodegenerative synucleinopathy diseases and could form a basis for future disease-prevention trials.

Sunday, 19 March 2017

Meta-analysis of dorsolateral nigral hyperintensity on magnetic resonance imaging as a marker for Parkinson's disease

Nice paper by friends in Austria... imaging markers for PD, beyond those we already have, are desperately needed. This nice meta-analysis shows that the MRI can be used differentiate patients from controls effectively. The results are shown for 3 Tesla MRI and 7 Tesla. Fortunately 3T MRI performs almost as well as 7T, because lots of hospitals may not have access to 7T imaging. Now it is important to try and work out far before diagnosis this change occurs, and whether it changes over time...

Mov Disord. 2017 Feb 2. doi: 10.1002/mds.26932. [Epub ahead of print]
Mahlknecht P, Krismer F, Poewe W, Seppi K.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26932/abstract

BACKGROUND: Dorsolateral nigral hyperintensity on iron-sensitive magnetic resonance imaging (MRI) sequences seems to be a typical finding in Parkinson's disease (PD), but most studies have involved small samples and have had heterogeneous control populations.

OBJECTIVES: The objective of this study was to perform a meta-analysis on dorsolateral nigral hyperintensity as an imaging marker for PD.

METHODS: The methods included a systematic literature search and a hierarchical summary receiver operating characteristics curve approach.

RESULTS: Of the 16 identified studies, 10 were suitable for analysis, including 364 PD and 231 control cases. The meta-analysis showed an overall sensitivity and specificity of the absence of dorsolateral nigral hyperintensity for PD versus controls of 97.7% and 94.6% (3 and 7 Tesla) and of 94.6% and 94.4% (3 Tesla only). Descriptive analysis among the 4 studies including patients with non-PD parkinsonism showed that dorsolateral nigral hyperintensity was absent in 89.4% of cases with atypical parkinsonian disorders (n = 74), but only in 21.7% of cases with non-neurodegenerative parkinsonism (n = 69). Moreover, in 2 of these studies, the absence of dorsolateral nigral hyperintensity predicted ipsilateral dopamine-transporter deficiency with 87.5% sensitivity and 83.6% specificity.

CONCLUSIONS: Visual assessment of dorsolateral nigral hyperintensity on iron-sensitive MRI sequences provides excellent diagnostic accuracy for PD versus controls. Moreover, its loss appears to be a marker of nigral pathology and holds the potential for the differentiation of neurodegenerative from non-neurodegenerative parkinsonian disorders.

Thursday, 16 March 2017

Oral ambroxol increases brain glucocerebrosidase activity in a non-human primate

Generally speaking, I am not a big fan of animal studies... here we see that Ambroxol (found in cough syrups) can alter GCase activity. Important work no doubt, and I guess the rationale was to demonstrate that it crosses the blood brain barrier....

Synapse. 2017 Mar 12. doi: 10.1002/syn.21967. [Epub ahead of print]
Migdalska-Richards A, Ko WK, Li Q, Bezard E, Schapira AH

Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood-brain barrier, increase GCase activity and reduce alpha-synuclein protein levels. In this study we analyze the effect of ambroxol treatment on GCase activity in healthy non-human primates. We show that daily administration of ambroxol results in increased brain GCase activity. Our work further indicates that ambroxol should be investigated as a novel therapy for both PD and neuronopathic GD in humans.

Monday, 13 March 2017

Dopamine transporter imaging does not predict the number of nigral neurons in Parkinson disease

How important could this paper turn out to be?!! It addresses one of the key questions regarding DAT-SPECT imaging and PD - does DAT deficit indicate neuronal loss or dysfunction?? This is important because once cells have gone, they are not coming back, but with dysfunction comes the hope of being able to restore function.

The numbers are small I know, but this provides further support that the DAT-SPECT could be a good biomarker of prodromal PD... perhaps not just by showing a slowing of decline over time, but potentially even an improvement in appearances given the right neuro-protective agent...

Neurology. 2017 Mar 10. pii: 10.1212/WNL.0000000000003810. doi: 10.1212/WNL.0000000000003810. [Epub ahead of print]
Saari L, Kivinen K, Gardberg M, Joutsa J, Noponen T, Kaasinen V.

http://www.neurology.org/content/early/2017/03/10/WNL.0000000000003810.long

OBJECTIVE: To examine possible associations between in vivo brain dopamine transporter SPECT imaging and substantia nigra pars compacta (SNc) neuronal survival in Parkinson disease (PD).

METHODS: Nigral neuron numbers were calculated for 18 patients (11 patients with neuropathologically confirmed PD) who had been examined with dopamine transporter (DAT) SPECT before death. Correlation analyses between SNc tyrosine hydroxylase (TH)-positive and neuromelanin-containing neuron counts and DAT striatal specific binding ratios (SBRs) were performed with semiquantitative region of interest-based and voxel-based analyses.

RESULTS: Mean putamen SBR did not correlate with the number of substantia nigra TH-positive (r = -0.11, p = 0.66) or neuromelanin-containing (r = -0.07, p = 0.78) neurons. Correlations remained clearly nonsignificant when the time interval between SPECT and death was used as a covariate, when the voxel-based analysis was used, and when only patients with PD were included.

CONCLUSIONS: This cohort study demonstrates that postmortem SNc neuron counts are not associated with striatal DAT binding in PD. These results fit with the theory that there is no correlation between the number of substantia nigra neurons and striatal dopamine after a certain level of damage has occurred. Striatal DAT binding in PD may reflect axonal dysfunction or DAT expression rather than the number of viable neurons.

Saturday, 11 March 2017

Clinical manifestations of nonmotor symptoms in 1021 Japanese Parkinson's disease patients from 35 medical centers

Good paper showing the distribution of non motor features in Japanese patients with PD... unsurprising to see constipation and sleep disorders among the most frequent... interesting to see that a number of features vary according to gender... this fits with ones experience seeing patients in the clinic as well... 

Parkinsonism Relat Disord. 2017 Feb 21. pii: S1353-8020(17)30074-3. doi: 10.1016/j.parkreldis.2017.02.024. [Epub ahead of print] Maeda T, Shimo Y, Chiu SW, Yamaguchi T, Kashihara K, Tsuboi Y, Nomoto M, Hattori N, Watanabe H, Saiki H; J-FIRST group.


INTRODUCTION: We aimed to investigate the prevalence and severity of nonmotor symptoms (NMSs) and to identify factors affecting NMSs and the health-related quality of life of Japanese patients with Parkinson's disease (PD).

METHODS: A total of 1021 patients with PD who had one or more NMS and showed wearing-off under anti-parkinsonian treatment were enrolled from 35 medical centers in Japan for this observational study. The primary measurements were the Movement Disorder Society unified Parkinson's disease rating scale (MDS-UPDRS) part I and the Parkinson's Disease Questionnaire (PDQ-8). The relationships of MDS-UPDRS and PDQ-8 with the patient's clinical background and undertaken medical interventions were determined. Here, we report baseline data of our 52-week ongoing study.

RESULTS: The mean MDS-UPDRS part I and PDQ-8 scores were 10.9 and 7.3, respectively. The most common NMSs were constipation problems (85.4%), sleep problems (73.7%), pain and other sensations (72.7%) and daytime sleepiness (72.0%). Fatigue was an NMS that affected 79.6% of females but only 72.6% of males, whereas features of dopamine dysregulation syndrome affected only 5.6% of females and 10.8% of males. Positive correlations were found between the MDS-UPDRS part I and the PDQ-8 (p < 0.0001, r = 0.56) and between the number of NMSs and the PDQ-8 score (p < 0.0001, r = 0.47).

CONCLUSIONS: This study revealed distinctive patterns of NMSs in Japanese patients with PD and suggested that the prevalence and severity of NMSs vary between sexes, and that the NMSs are important factors affecting the long-term quality of life of PD patients. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Saturday, 25 February 2017

Technologies Assessing Limb Bradykinesia in Parkinson's Disease

Very pleased to see this online... the culmination of a lot of hard work from Hasan Hasan who tirelessly re-ran the literature search to keep it up to date. We have tried to be very balanced here and simply present the available tech to assess bradykinesia in PD. We will also aim to keep this up to date by including new technologies every few months to the Google drive version of the table... I hope people will find the resource useful...

J Parkinsons Dis. 2017;7(1):65-77. doi: 10.3233/JPD-160878.
Hasan H, Athauda DS, Foltynie T, Noyce AJ.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd160878

BACKGROUND: The MDS-UPDRS (Movement Disorders Society - Unified Parkinson's Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can be subject to rater variability. Novel technological tools can be used to overcome such issues.

OBJECTIVE: To systematically explore and describe the available technologies for measuring limb bradykinesia in PD that were published between 2006 and 2016.

METHODS: A systematic literature search using PubMed (MEDLINE), IEEE Xplore, Web of Science, Scopus and Engineering Village (Compendex and Inspec) databases was performed to identify relevant technologies published until 18 October 2016. RESULTS: 47 technologies assessing bradykinesia in PD were identified, 17 of which offered home and clinic-based assessment whilst 30 provided clinic-based assessment only. Of the eligible studies, 7 were validated in a PD patient population only, whilst 40 were tested in both PD and healthy control groups. 19 of the 47 technologies assessed bradykinesia only, whereas 28 assessed other parkinsonian features as well. 33 technologies have been described in additional PD-related studies, whereas 14 are not known to have been tested beyond the pilot phase.

CONCLUSION: Technology based tools offer advantages including objective motor assessment and home monitoring of symptoms, and can be used to assess response to intervention in clinical trials or routine care. This review provides an up-to-date repository and synthesis of the current literature regarding technology used for assessing limb bradykinesia in PD. The review also discusses the current trends with regards to technology and discusses future directions in development.

Wednesday, 22 February 2017

Identification of candidate cerebrospinal fluid biomarkers in parkinsonism using quantitative proteomics

Good work by Nadia... it was a huge amount of work to gather samples from so many patients... but of course this is really important. You need large numbers to capture the heterogeneity in the diseases. It's been said many times but biomarkers for all of these diseases are desperately needed. This work is definitely a positive step in that direction...

Parkinsonism Relat Disord. 2017 Jan 31. pii: S1353-8020(17)30030-5. doi: 10.1016/j.parkreldis.2017.01.016. [Epub ahead of print]
Magdalinou NK, Noyce AJ, Pinto R, Lindstrom E, Holmén-Larsson J, Holtta M, Blennow K, Morris HR, Skillbäck T, Warner TT, Lees AJ, Pike I, Ward M, Zetterberg H, Gobom J.

http://www.prd-journal.com/article/S1353-8020(17)30030-5/abstract

INTRODUCTION: Neurodegenerative parkinsonian syndromes have significant clinical and pathological overlap, making early diagnosis difficult. Cerebrospinal fluid (CSF) biomarkers may aid the differentiation of these disorders, but other than α-synuclein and neurofilament light chain protein, which have limited diagnostic power, specific protein biomarkers remain elusive.

OBJECTIVES: To study disease mechanisms and identify possible CSF diagnostic biomarkers through discovery proteomics, which discriminate parkinsonian syndromes from healthy controls.

METHODS: CSF was collected consecutively from 134 participants; Parkinson's disease (n = 26), atypical parkinsonian syndromes (n = 78, including progressive supranuclear palsy (n = 36), multiple system atrophy (n = 28), corticobasal syndrome (n = 14)), and elderly healthy controls (n = 30). Participants were divided into a discovery and a validation set for analysis. The samples were subjected to tryptic digestion, followed by liquid chromatography-mass spectrometry analysis for identification and relative quantification by isobaric labelling. Candidate protein biomarkers were identified based on the relative abundances of the identified tryptic peptides. Their predictive performance was evaluated by analysis of the validation set.

RESULTS: 79 tryptic peptides, derived from 26 proteins were found to differ significantly between atypical parkinsonism patients and controls. They included acute phase/inflammatory markers and neuronal/synaptic markers, which were respectively increased or decreased in atypical parkinsonism, while their levels in PD subjects were intermediate between controls and atypical parkinsonism.

CONCLUSION: Using an unbiased proteomic approach, proteins were identified that were able to differentiate atypical parkinsonian syndrome patients from healthy controls. Our study indicates that markers that may reflect neuronal function and/or plasticity, such as the amyloid precursor protein, and inflammatory markers may hold future promise as candidate biomarkers in parkinsonism.

Wednesday, 15 February 2017

Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players

Great paper by dear friend and colleague Helen Ling... this is one of the strongest indications yet that repetitive head trauma is a risk factor for neuro-degeneration... in this instance it has been suggested in professional footballers who have headed the ball repeatedly... Clearly this does not provide definitive evidence but it is nonetheless a very important paper and one that has great public health importance... However this topic clearly divides people, including doctors... there will be thousands of people that get dementia and parkinsonism that never played football and vice versa thousands of footballers that don't get these diseases during their lives... a selection of media links so that you can see different interpretations...

http://www.bbc.co.uk/news/health-38971750
http://news.sky.com/story/football-in-denial-over-link-between-heading-and-brain-injury-10768739
http://www.independent.co.uk/sport/football/news-and-comment/dementia-in-football-heading-fa-pfa-footballers-head-injury-a7580496.html
http://www.dailymail.co.uk/health/article-4225776/Heading-football-raises-risk-dementia.html

Acta Neuropathologica
Helen Ling, Huw R. Morris, James W. Neal, Andrew J. Lees, John Hardy, Janice L. Holton, Tamas Revesz, David D. R. Williams

http://link.springer.com/article/10.1007/s00401-017-1680-3/fulltext.html

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case–control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Monday, 13 February 2017

Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder

Great work by friends and colleagues on this paper the results within... however the most important question is whether NfL differentiates the really challenging cases from one another. For example, many neurologists would recognise 'text book' PD compared with one of the so-called Parkinson's plus disorder... a smaller number would recognise when there are atypical features in the patient with PD and would therefore try to characterise further or wait until time gave further clues... But there are some patients in which you just do not know. It could be PD or a mimic... it is for those patients that I would love to see a biomarker that really differentiates and I suspect the NfL is not specific enough and more than one marker may be required...

Neurology. 2017 Feb 8. pii: 10.1212/WNL.0000000000003680. doi: 10.1212/WNL.0000000000003680. [Epub ahead of print]
Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K; Swedish BioFINDER study.

OBJECTIVE: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders.

METHODS: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated.

RESULTS: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73-0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81).

CONCLUSIONS: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that blood NfL levels discriminate between PD and APD.

Evaluating the performance of the Montreal Cognitive Assessment in early stage Parkinson's disease

This may be true but I would argue that the PD patients in PPMI are perhaps not typical of PD patients in general... people participating in such studies tend to be from a higher socioeconomic background and perhaps be better educated. At said, in our PREDICT-PD experience, I do not think that 37% of the controls achieved full marks, which suggests something special about the PPMI patients. Although I would agree with the authors in other respects... I suspect that a number of items in the MoCA may be redundant in the earlier stages of PD...

Parkinsonism Relat Disord. 2017 Jan 28. pii: S1353-8020(17)30029-9. doi: 10.1016/j.parkreldis.2017.01.012. [Epub ahead of print]
Kletzel SL, Hernandez JM, Miskiel EF, Mallinson T, Pape TL.

INTRODUCTION: Mild cognitive impairment is common in Parkinson's disease, even in the early stages, and can be a risk for developing dementia. To properly track development and progression of cognitive impairment, reliable measurement tools are necessary. The Montreal Cognitive Assessment is currently used as a global cognitive screening tool and has been recommended as an abbreviated diagnostic tool to measure mild cognitive impairment in the context of global cognitive function. However psychometric properties of the Montreal Cognitive Assessment in PD have not been assessed in this context.

METHODS: Data were obtained from the Parkinson's Progression Markers Initiative (n = 395). We examine psychometric properties of the Montreal Cognitive Assessment among newly diagnosed Parkinson's disease patients using Rasch analysis.

RESULTS: Only one item misfit the measurement model and principle component analysis indicated the Montreal Cognitive Assessment was unidimensional. Distribution of items calibrations formed a logical hierarchy from least to most challenging. Test items were markedly off-target (i.e., too easy) for this sample; this was also reflected in low person separation reliability. While 37% of participants performed all items correctly indicating a large ceiling effect, 22% of participants obtained a raw score in the range of 21-25 indicating mild cognitive impairment. No meaningful differential item functioning was detected.

CONCLUSION: Results suggest that in the context of early stage Parkinson's disease, the Montreal Cognitive Assessment is a unidimensional measure of global cognitive function. Implications for the use of the Montreal Cognitive Assessment in early stage Parkinson's disease and potential improvements to the assessment are discussed.

Wednesday, 18 January 2017

Gender differences in Parkinson's disease depression

This is interesting and has potential relevance to mood changes in the prodromal phase of PD as well... the may be gender-specific features to depression and this may mean we need to reconsider how we measure depression in cohorts like PREDICT-PD...

Parkinsonism Relat Disord. 2016 Dec 29. pii: S1353-8020(16)30519-3. doi: 10.1016/j.parkreldis.2016.12.026. [Epub ahead of print]
Perrin AJ, Nosova E, Co K, Book A, Iu O, Silva V, Thompson C, McKeown MJ, Stoessl AJ, Farrer MJ, Appel-Cresswell S.

http://www.prd-journal.com/article/S1353-8020(16)30519-3/abstract

INTRODUCTION: 30-40% of patients with Parkinson's disease (PD) experience depression during their illness; identifying subtypes of depression and groups at risk remains a challenge in routine clinical care. One avenue that remains underexplored is the gender-specific profiles manifested in PD depression. We sought to explore this in a large sample of clinical PD patients.

METHODS: 307 patient records at a tertiary referral centre were reviewed for clinical and demographic factors. We used recursive partitioning to determine which items on the Beck Depression Inventory (BDI) were most useful in differentiating patients who scored in the depressed range (≥14) from those who scored in the non-depressed range (≤13). We also used recursive partitioning to identify those BDI items that were most effective in differentiating depressed from non-depressed patients in both genders.

RESULTS: We were able to identify a subset of items on the BDI that were most useful in partitioning depressed from non-depressed in the entire cohort. Partitioning of men and women with PD depression relied on different key BDI items, melancholy featuring prominently in women, while the more classical factors associated with depression in PD (apathy and loss of libido) featured more prominently in men.

CONCLUSION: Unique factors not previously identified as core features of depression in PD were found most useful in partitioning depressed women from non-depressed women. This raises the possibility that a female-specific depressive profile has been under-appreciated in past work. Additional studies are required to discern how this may impact future research, diagnosis and treatment.

Tuesday, 17 January 2017

PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson's disease

Here's the latest one from the PREDICT-PD team... this shows that intermediate markers (smell loss, subjective RBD and slowed finger tapping) persist in the higher risk group over three years of follow-up... but most interestingly higher baseline risk scores are associated with new diagnoses of PD at three years of follow-up. This is the strongest indicator yet that the PREDICT-PD algorithm is working...

Mov Disord. 2017 Jan 16. doi: 10.1002/mds.26898. [Epub ahead of print]
Noyce AJ, R'Bibo L, Peress L, Bestwick JP, Adams-Carr KL, Mencacci NE, Hawkes CH, Masters JM, Wood N, Hardy J, Giovannoni G, Lees AJ, Schrag A.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26898/abstract

BACKGROUND: A number of early features can precede the diagnosis of Parkinson's disease (PD).

OBJECTIVE: To test an online, evidence-based algorithm to identify risk indicators of PD in the UK population.

METHODS: Participants aged 60 to 80 years without PD completed an online survey and keyboard-tapping task annually over 3 years, and underwent smell tests and genotyping for glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) mutations. Risk scores were calculated based on the results of a systematic review of risk factors and early features of PD, and individuals were grouped into higher (above 15th centile), medium, and lower risk groups (below 85th centile). Previously defined indicators of increased risk of PD ("intermediate markers"), including smell loss, rapid eye movement-sleep behavior disorder, and finger-tapping speed, and incident PD were used as outcomes. The correlation of risk scores with intermediate markers and movement of individuals between risk groups was assessed each year and prospectively. Exploratory Cox regression analyses with incident PD as the dependent variable were performed.

RESULTS: A total of 1323 participants were recruited at baseline and >79% completed assessments each year. Annual risk scores were correlated with intermediate markers of PD each year and baseline scores were correlated with intermediate markers during follow-up (all P values < 0.001). Incident PD diagnoses during follow-up were significantly associated with baseline risk score (hazard ratio = 4.39, P = .045). GBA variants or G2019S LRRK2 mutations were found in 47 participants, and the predictive power for incident PD was improved by the addition of genetic variants to risk scores.

CONCLUSIONS: The online PREDICT-PD algorithm is a unique and simple method to identify indicators of PD risk.

Wednesday, 11 January 2017

The relevance of gender in Parkinson's disease: a review

The consistent and clear gender differences particularly in risk of being diagnosed with PD are intriguing... although I would not say one gets a clear flavour of gender-specific differences in the course of PD after diagnosis... of course when there are gender-specific differences for a disease, there is always focus on sex-hormones. At least in terms of the risk of being diagnosed with PD there is no clear evidence that HRT, contraceptive pills or surgical menopause can account for the observed gender difference...

J Neurol. 2017 Jan 4. doi: 10.1007/s00415-016-8384-9. [Epub ahead of print]
Picillo M, Nicoletti A, Fetoni V, Garavaglia B, Barone P, Pellecchia MT.

https://www.ncbi.nlm.nih.gov/pubmed/28054129

Since the official and systematic inclusion of sex and gender in biomedical research, gender differences have been acknowledged as important determinants of both the susceptibility to develop neurodegenerative diseases in general population and the clinical and therapeutic management of neurodegenerative patients. In this review, we gathered the available evidence on gender differences in Parkinson's disease (PD) regarding clinical phenotype (including motor and non-motor symptoms), biomarkers, genetics and therapeutic management (including pharmacological and surgical treatment). Finally, we will briefly discuss the role of estrogens in determining such differences. Several data demonstrate that PD in women starts with a more benign phenotype, likely due to the effect of estrogens. However, as the disease progresses, women are at higher risk of developing highly disabling treatment-related complications, such as motor and non-motor fluctuations as well as dyskinesia, compared with men. In addition, women have lower chances of receiving effective treatment for PD as deep brain stimulation. Taken together these findings challenge the definition of a more benign phenotype in women. Still, much work needs to be done to better understand the interaction between gender, genetics and environmental factors in determining the PD risk and clinical features. Improving our understanding in this field may result in implementation of strategies to identify prodromal PD and speed efforts to discern new directions for disease tailored treatment and management.