ɑ-Synuclein strains and the variable pathologies of synucleinopathies

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

J Neurochem. 2016 Feb 29. doi: 10.1111/jnc.13595. [Epub ahead of print]

Peelaerts W, Baekelandt V.

http://onlinelibrary.wiley.com/doi/10.1111/jnc.13595/abstract;jsessionid=19B4DD4A84BB14BCAB704D2D7D9CAB0D.f03t03

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

Association Between Parkinson's Disease and Inflammatory Bowel Disease: a Nationwide Taiwanese Retrospective Cohort Study

There is some plausibility here... but not all studies point the same way. May be some biological similarities, genetic homogeneity, or inflammation in the gut per se as a risk factor. The strengthening of association with hypertension and CAD here is a bit strange. We previously published on Crohn's and PD genetic comorbidity (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888265/)

Inflamm Bowel Dis. 2016 Feb 24. [Epub ahead of print]

Lin JC, Lin CS, Hsu CW, Lin CL, Kao CH.

http://journals.lww.com/ibdjournal/pages/articleviewer.aspx?year=9000&issue=00000&article=98896&type=abstract

OBJECTIVES:

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder. Previous studies have suggested that chronic systemic inflammation increases the risk of Parkinson's disease (PD). This study examined the effects of IBD on the development of PD.

METHODS:

In a nationwide population-based cohort of 23.22 million insured residents of Taiwan aged ≥ 20 years, we compared people diagnosed with IBD during 2000 to 2011 (n = 8373) with IBD-free individuals. Patients with PD were identified in the National Health Insurance Research Database. Using univariable and multivariable Cox proportion hazard regression models, we estimated the adjusted hazard ratio (aHR) for PD with a 95% confidence interval (CI) with adjustment for age, sex, and comorbidities.

RESULTS:

In the cohort, IBD was associated with an increased incidence of PD (crude hazard ratio = 1.43, 95% CI = 1.15-1.79). The risk was highest among individuals with Crohn's disease (aHR = 1.40, 95% CI = 1.11-1.77). In the multivariable model, the risk of PD was increased for men (aHR = 1.28, 95% CI = 1.05-1.56) and higher for patients with hypertension (aHR = 1.72, 95% CI = 1.33-2.24), coronary artery disease (aHR = 1.31, 95% CI = 1.04-1.66), or depression (aHR = 2.51, 95% CI = 1.82-3.46).

CONCLUSIONS:

We suggest that IBD is associated with an increased risk of PD. Patients with IBD should be aware of the potential risk for PD development.

Electroencephalographic prodromal markers of dementia across conscious states in Parkinson's disease.

This study explores an exciting new potential PD biomarker: EEG recordings during sleep - something I certainly hadn't heard much about up until now.

 The same neural system implicated in PD dementia (the cholinergic system) is also known to be involved in regulating sleep. 

The EEG measures used in this study appear potentially useful as a marker for the development of dementia among patients with PD, but further studies will be needed for validation.

We know that sleep disorders (such as RBD) are associated with, and occasionally precede, Parkinson's, so perhaps sleep EEG might even be useful as a pre-motor biomarker as well.

J Rehabil Med. 2016 Feb 4. doi: 10.2340/16501977-2051. [Epub ahead of print]
Hokstad A, Indredavik B, Bernhardt J, Langhammer B, Gunnes M, Lundemo C, Bovim MR, Askim T.

Abstract:
In Parkinson's disease, electroencephalographic abnormalities during wakefulness and non-rapid eye movement sleep (spindles) were found to be predictive biomarkers of dementia. Because rapid eye movement sleep is regulated by the cholinergic system, which shows early degeneration in Parkinson's disease with cognitive impairment, anomalies during this sleep stage might mirror dementia development. In this prospective study, we examined baseline electroencephalographic absolute spectral power across three states of consciousness (non-rapid eye movement sleep, rapid eye movement sleep, and wakefulness) in 68 non-demented patients with Parkinson's disease and 44 healthy controls. All participants underwent baseline polysomnographic recordings and a comprehensive neuropsychological assessment. Power spectral analyses were performed on standard frequency bands. Dominant occipital frequency during wakefulness and ratios of slow-to-fast frequencies during rapid eye movement sleep and wakefulness were also computed. At follow-up (an average 4.5 years after baseline), 18 patients with Parkinson's disease had developed dementia and 50 patients remained dementia-free. In rapid eye movement sleep, patients with Parkinson's disease who later developed dementia showed, at baseline, higher absolute power in delta and theta bands and a higher slowing ratio, especially in temporal, parietal, and occipital regions, compared to patients who remained dementia-free and controls. In non-rapid eye movement sleep, lower baseline sigma power in parietal cortical regions also predicted development of dementia. During wakefulness, patients with Parkinson's disease who later developed dementia showed lower dominant occipital frequency as well as higher delta and slowing ratio compared to patients who remained dementia-free and controls. At baseline, higher slowing ratios in temporo-occipital regions during rapid eye movement sleep were associated with poor performance on visuospatial tests in patients with Parkinson's disease. Using receiver operating characteristic curves, we found that best predictors of dementia in Parkinson's disease were rapid eye movement sleep slowing ratios in posterior regions, wakefulness slowing ratios in temporal areas, and lower dominant occipital frequency. These results suggest that electroencephalographic slowing during sleep is a new promising predictive biomarker for Parkinson's disease dementia, perhaps as a marker of cholinergic denervation.

What a gastrointestinal biopsy can tell us about Parkinson's disease?

There's definitely mileage in continuing to explore gut for biomarkers... defining the appearances in healthy people is key since positive staining for alpha-synuclein is common in controls... but the conformation of this may dictate what is and what is not pathological...

Neurogastroenterol Motil. 2016 Feb 23. doi: 10.1111/nmo.12797. [Epub ahead of print]

Corbillé AG, Clairembault T, Coron E, Leclair-Visonneau L, Preterre C, Neunlist M, Derkinderen P.

BACKGROUND:

The intraneuronal inclusions called Lewy bodies and neurites, which represent the characteristic pathological changes in Parkinson's disease, are found in the enteric neurons in the great majority of parkinsonian patients. This observation led to a substantial amount of research over the last few years in order to develop a minimally invasive diagnostic procedure in living patients based on gastrointestinal (GI) biopsies.

PURPOSE:

In this review, we will begin by discussing the studies that focused on the detection of Lewy bodies and neurites in GI biopsies, then broaden the discussion to the pathological changes that also occur in the enteric glial cells and intestinal epithelial cells. We conclude by proposing that a GI biopsy could represent a unique window to assess the whole pathological process of the brain in Parkinson's disease.

© 2016 John Wiley & Sons Ltd.

Changes in Olfactory Bulb Volume in Parkinson's Disease: A Systematic Review and Meta-Analysis

Systematic review and meta-analysis of olfactory bulb volumes in PD patients...

PLoS One. 2016 Feb 22;11(2):e0149286. doi: 10.1371/journal.pone.0149286.

Li J, Gu CZ, Su JB, Zhu LH, Zhou Y, Huang HY, Liu CF.

http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0149286

OBJECTIVE:

The changes in olfactory bulb (OB) volume in Parkinson's disease (PD) patients have not yet been comprehensively evaluated. The purpose of this meta-analysis was to explore whether the OB volume was significantly different between PD patients and healthy controls.

METHODS:

PubMed and Embase were searched up to March 6, 2015 with no language restrictions. Two independent reviewers screened eligible studies and extracted data on study characteristics and OB volume. Additionally, a systematic review and meta-analysis using a random-effects model were conducted. Publication bias was determined by using funnel plots and Begg's and Egger's tests. Subgroup analyses were performed to assess possible sources of heterogeneity.

RESULTS:

Six original case-control studies of 216 PD patients and 175 healthy controls were analyzed. The pooled weighted mean difference (WMD) in the OB volume between the PD patients and the healthy participants was -8.071 for the right OB and -10.124 for the left OB; these values indicated a significant difference among PD patients compared with healthy controls. In addition, a significant difference in the lateralized OB volume was observed in PD patients, with a pooled WMD of 1.618; these results indicated a larger right OB volume than left OB volume in PD patients. In contrast, no difference in the lateralized OB volume was found in healthy controls. No statistical evidence of publication bias among studies was found based on Egger's or Begg's tests. Sensitivity analyses revealed that the results were consistent and robust.

CONCLUSIONS:

Overall, both the left and the right OB volume were significantly smaller in PD patients than in healthy controls. However, significant heterogeneity and an insufficient number of studies underscore the need for further observational research.

Risk Factor Profile in Parkinson's Disease Subtype with REM Sleep Behavior Disorder

Agree that PD-RBD represents a certain variant of PD and it appears to run a more aggressive course. In that respect it is not surprising that there may be slight differences in risk factors for it and PD without RBD. However, RBD doesn't appear to be a static phenomenon... in some people it seems to come and go, or appear later, and after all, it is still indicative of a synucleinopathy. In our work, risk factors for PD are associated with RBD scores using the RBDSQ, although I think there are a number of issues with that questionnaire!

J Parkinsons Dis. 2016 Jan 29. [Epub ahead of print]

Jacobs ML, Dauvilliers Y, St Louis EK, McCarter SJ, Romenets SR, Pelletier A, Cherif M, Gagnon JF, Postuma RB.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150725

BACKGROUND:

Numerous large-scale studies have found diverse risk factors for Parkinson's disease (PD), including caffeine non-use, non-smoking, head injury, pesticide exposure, and family history. These studies assessed risk factors for PD overall; however, PD is a heterogeneous condition. One of the strongest identifiers of prognosis and disease subtype is the co-occurrence of rapid eye movement sleep behavior disorder (RBD).In previous studies, idiopathic RBD was associated with a different risk factor profile from PD and dementia with Lewy bodies, suggesting that the PD-RBD subtype may also have a different risk factor profile.

OBJECTIVE:

To define risk factors for PD in patients with or without associated RBD.

METHODS:

In a questionnaire, we assessed risk factors for PD, including demographic, medical, environmental, and lifestyle variables of 189 PD patients with or without associated polysomnography-confirmed RBD. The risk profile of patients with vs. without RBD was assessed with logistic regression, adjusting for age, sex, and disease duration.

RESULTS:

PD-RBD patients were more likely to have been a welder (OR = 3.11 (1.05-9.223), and to have been regular smokers (OR = 1.96 (1.04-3.68)). There were no differences in use of caffeine or alcohol, other occupations, pesticide exposure, rural living, or well water use. Patients with RBD had a higher prevalence of the combined family history of both dementia and parkinsonism (13.3% vs. 5.5% , OR = 3.28 (1.07-10.0).

CONCLUSION:

The RBD-specific subtype of PD may also have a different risk factor profile.

Abnormal Echogenicity of the Substantia Nigra, Raphe Nuclei, and Third-Ventricle Width as Markers of Cognitive Impairment in Parkinsonian Disorders: A Cross-Sectional Study

This fits with what one would expect given the patients examined and their clinical features... although some people are skeptical about TCS, I think it can be a useful adjunct to the clinical work up of patients with Parkinsonism, and I have little doubt that SN hyperechogenicity is a risk marker...

Parkinsons Dis. 2016;2016:4058580. doi: 10.1155/2016/4058580. Epub 2016 Jan 10.

Bouwmans AE, Leentjens AF, Mess WH, Weber WE.

http://www.hindawi.com/journals/pd/2016/4058580/

Background. Patients with Parkinson's disease (PD) have a high risk of cognitive problems. Objective. This study assesses whether abnormal echogenicity of the substantia nigra (SN) and raphe nuclei (RN) and the diameter of third ventricle are markers of cognitive impairment in patients with PD and other forms of parkinsonism. Methods. 126 outpatients with early signs of parkinsonism underwent transcranial sonography (TCS). The scales for the outcome of Parkinson's disease cognition (SCOPA-COG) were used as cognitive measure. Definite neurological diagnosis was established after two-year follow-up. Results. One-third of the patients with PD and half of those with APS had signs of cognitive impairment. The echogenicity of the SN was not related to cognitive impairment. The diameter of the third ventricle was significantly larger in PD patients with cognitive impairment compared to those without. In patients with APS we found a significantly higher frequency of hypoechogenic RN in patients with cognitive problems. Conclusions. Cognitive impairment is already present in a substantial proportion of patients with PD and APS at first referral. In patients with APS the frequency of hypoechogenic RN points to the direction of other pathophysiology with more emphasis on deficits in the serotonergic neurotransmitter system. The larger diameter of the third ventricle in PD patients with cognitive impairment may reflect Alzheimer like brain atrophy, as has been reported in earlier studies.

Systematic reviews on neurodevelopmental and neurodegenerative disorders linked to pesticide exposure: Methodological features and impact on risk assessment

This is a systematic review of systematic reviews (yes you did read that correctly) on the link between pesticides and neurodegenerative/neuro-developmental disorders. The authors critically appraise existing systematic reviews in the field, which in itself is a useful endeavour. Too often we accept what systematic reviews say, when in fact their conclusions depend very much on the methodological rigour applied. Our 2012 systematic review/meta-analysis in Annals (http://onlinelibrary.wiley.com/doi/10.1002/ana.23687/abstract) comes under scrutiny. The issue is however that traditional observational studies, in epidemiological terms, do not give sufficient information about causation. Although I accept that in our study at least, lots of supporting evidence was found through farming occupation and rural living. There was high heterogeneity in the pesticide studies included in our meta, which brings into question whether the point estimates can be relied upon. Formal study quality assessment may have addressed this in part, but I have used these scales before and I am not convinced they are particularly helpful....

Environ Int. 2016 Feb 17. pii: S0160-4120(16)30020-4. doi: 10.1016/j.envint.2016.01.020. [Epub ahead of print]

Hernández AF, González-Alzaga B, López-Flores I, Lacasaña M.

http://www.sciencedirect.com/science/article/pii/S0160412016300204

BACKGROUND:

Epidemiological data are not currently used in the risk assessment of chemical substances in a systematic and consistent manner. However, systematic reviews (SRs) could be useful for risk assessment as they appraise and synthesize the best epidemiological knowledge available.

OBJECTIVES:

To conduct a comprehensive literature search of SRs pertaining to pesticide exposure and various neurological outcomes, namely neurodevelopmental abnormalities, Parkinson's disease (PD) and Alzheimer's disease (AD), and to assess the potential contribution of SRs to the risk assessment process.

SEARCH METHODS AND SELECTION CRITERIA:

Search was conducted in PubMed and Web of Science databases and articles were selected if the following inclusion criteria were met: being a SR, published until April 2015 and without language restrictions.

DATA COLLECTION AND ANALYSIS:

For each neurological outcome, two review authors independently screened the search results for included studies. Data were extracted and summarized in two tables according to 16 criteria. Disagreements were resolved by discussion.

MAIN RESULTS:

The total number of studies identified in the first search was 65, 304 and 108 for neurodevelopment, PD and AD, respectively. From them, 8, 10 and 2 met the defined inclusion criteria for those outcomes, respectively. Overall, results suggest that prenatal exposure to organophosphates is associated with neurodevelopmental disturbances in preschool and school children. In contrast, postnatal exposures failed to show a clear effect across cohort studies. Regarding PD, 6 SRs reported statistically significant combined effect size estimates, with OR/RR ranging between 1.28 and 1.94. As for AD, 2 out of the 8 original articles included in the SRs found significant associations, with OR of 2.39 and 4.35, although the quality of the data was rather low.

CONCLUSIONS:

The critical appraisal of the SRs identified allowed for discussing the implications of SRs for risk assessment, along with the identification of gaps and limitations of current epidemiological studies that hinder their use for risk assessment. Recommendations are proposed to improve studies for this purpose. In particular, harmonized quantitative data (expressed in standardized units) would allow a better interpretation of results and would facilitate direct comparison of data across studies. Outcomes should be also harmonized for an accurate and reproducible measurement of adverse effects. Appropriate SRs and quantitative synthesis of the evidence should be performed regularly for a continuous update of the risk factors on health outcomes and to determine, if possible, dose-response curves for risk assessment.

Evaluation of handwriting kinematics and pressure for differential diagnosis of Parkinson's disease

Nice to see handwriting get a thorough once over... it is an under utilised clue that may be relevant in the pre-diagnostic stage...

Artif Intell Med. 2016 Feb 4. pii: S0933-3657(16)00006-3. doi: 10.1016/j.artmed.2016.01.004. [Epub ahead of print]

Drotár P, Mekyska J, Rektorová I, Masarová L, Smékal Z, Faundez-Zanuy M.

OBJECTIVE:

We present the PaHaW Parkinson's disease handwriting database, consisting of handwriting samples from Parkinson's disease (PD) patients and healthy controls. Our goal is to show that kinematic features and pressure features in handwriting can be used for the differential diagnosis of PD.

METHODS AND MATERIAL:

The database contains records from 37 PD patients and 38 healthy controls performing eight different handwriting tasks. The tasks include drawing an Archimedean spiral, repetitively writing orthographically simple syllables and words, and writing of a sentence. In addition to the conventional kinematic features related to the dynamics of handwriting, we investigated new pressure features based on the pressure exerted on the writing surface. To discriminate between PD patients and healthy subjects, three different classifiers were compared: K-nearest neighbors (K-NN), ensemble AdaBoost classifier, and support vector machines (SVM).

RESULTS:

For predicting PD based on kinematic and pressure features of handwriting, the best performing model was SVM with classification accuracy of Pacc=81.3% (sensitivity Psen=87.4% and specificity of Pspe=80.9%). When evaluated separately, pressure features proved to be relevant for PD diagnosis, yielding Pacc=82.5% compared to Pacc=75.4% using kinematic features.

CONCLUSION:

Experimental results showed that an analysis of kinematic and pressure features during handwriting can help assess subtle characteristics of handwriting and discriminate between PD patients and healthy controls.

Copyright © 2016 Elsevier B.V. All rights reserved.

Age at onset and Parkinson disease phenotype

Really nice study using the PPMI dataset... what a rich source of data this will prove to be...!

Neurology. 2016 Feb 10. pii: 10.1212/WNL.0000000000002461. [Epub ahead of print]

Pagano G, Ferrara N, Brooks DJ, Pavese N.

http://www.neurology.org/content/early/2016/02/10/WNL.0000000000002461.long

OBJECTIVE:

To explore clinical phenotype and characteristics of Parkinson disease (PD) at different ages at onset in recently diagnosed patients with untreated PD.

METHODS:

We have analyzed baseline data from the Parkinson's Progression Markers Initiative database. Four hundred twenty-two patients with a diagnosis of PD confirmed by DaTSCAN imaging were divided into 4 groups according to age at onset (onset younger than 50 years, 50-59 years, 60-69 years, and 70 years or older) and investigated for differences in side, type and localization of symptoms, occurrence/severity of motor and nonmotor features, nigrostriatal function, and CSF biomarkers.

RESULTS:

Older age at onset was associated with a more severe motor and nonmotor phenotype, a greater dopaminergic dysfunction on DaTSCAN, and reduction of CSF α-synuclein and total tau. The most common presentation was the combination of 2 or 3 motor symptoms (bradykinesia, resting tremor, and rigidity) with rigidity being more common in the young-onset group. In about 80% of the patients with localized onset, the arm was the most affected part of the body, with no difference across subgroups.

CONCLUSIONS:

Although the presentation of PD symptoms is similar across age subgroups, the severity of motor and nonmotor features, the impairment of striatal binding, and the levels of CSF biomarkers increase with age at onset. The variability of imaging and nonimaging biomarkers in patients with PD at different ages could hamper the results of future clinical trials.

Mutations of glucocerebrosidase gene and susceptibility to Parkinson's disease: an updated meta-analysis in an European population

Interesting to see a meta of this... I would rather see the effect size estimates for the more controversial variants like T369M... E326K is pretty established now, and L444P and N370S well recognised...

Neuroscience. 2016 Feb 8. pii: S0306-4522(16)00130-5. doi: 10.1016/j.neuroscience.2016.02.007. [Epub ahead of print]

Zhao F, Bi L, Wang WJ, Wu XS, Li YF, Gong FF, Lu SS, Feng F, Qian ZZ, Hu CY, Wu YL, Sun YH.

http://www.sciencedirect.com/science/article/pii/S0306452216001305

This meta-analysis aims to investigate the association between mutations of glucocerebrosidase (GBA) gene and susceptibility to Parkinson's disease (PD) in an European population. Several electronic databases were extensively searched. Odds ratios and 95% confidence intervals were calculated to assess the association. In total, fourteen published papers screening L444P, N370S and other GBA variants were identified. The GBA mutations were significantly associated with PD in the European population. Subgroup analysis stratified by the age of onset (AAO) revealed that the association between GBA mutations and PD existed in the patients with age at onset ⩽ 50 years but did not exist in the patients with age at onset > 50 years. Furthermore, the associations between N370S, L444P with PD were also analyzed to explore the roles of the two most frequent GBA mutations in the development of PD. The results showed that significant associations between N370S, L444P with PD were observed, respectively. Overall, the study supported that GBA mutations were a risk factor for PD in the European population. Patients with early-onset were more likely to carry GBA mutations than those with late-onset. Moreover, both L444P and N370S were associated with increased PD risk.