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.