Monday, 29 February 2016

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.


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.

Sunday, 28 February 2016

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.

Saturday, 27 February 2016

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.


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.

Wednesday, 24 February 2016

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.


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.

Tuesday, 23 February 2016

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.



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.

Monday, 22 February 2016

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.


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.

Wednesday, 17 February 2016

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.

Tuesday, 16 February 2016

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.


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.

Monday, 15 February 2016

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.



The genetic background of Parkinson's disease: current progress and future prospects

Current update on the state of knowledge of PD genetics...

Acta Neurol Scand. 2016 Feb 12. doi: 10.1111/ane.12563. [Epub ahead of print]
Kalinderi K, Bostantjopoulou S, Fidani L.



Almost two decades of genetic research in Parkinson's disease (PD) have remarkably increased our knowledge regarding the genetic basis of PD with numerous genes and genetic loci having been found to cause familial PD or affect the risk for PD. Approximately 5-10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors. Nowadays, six genes, alpha synuclein, LRRK2, VPS35, Parkin, PINK1 and DJ-1, have definitely been associated with an autosomal dominant or recessive PD mode of inheritance. The advent of genome-wide association studies (GWAS) and the implementation of new technologies, like next generation sequencing (NGS) and exome sequencing has undoubtedly greatly aided the identification on novel risk variants for sporadic PD. In this review, we will summarize the current progress and future prospects in the field of PD genetics.

Thursday, 11 February 2016

A cumulative genetic risk score predicts progression in Parkinson's disease

Starting to see more of these initiatives... genetic variability clearly underlies at least some, if not a large proportion, of disease heterogeneity. This is not limited to simply getting PD alone but also contributes to the disease course....

Mov Disord. 2016 Feb 8. doi: 10.1002/mds.26505. [Epub ahead of print]
Pihlstrøm L, Morset KR, Grimstad E, Vitelli V, Toft M.


BACKGROUND:
The contribution of genetic variability to clinical heterogeneity in Parkinson's disease is insufficiently understood. We aimed to investigate the effect of cumulative genetic risk on clinical outcomes.

METHODS:
In a single-center study of 336 patients we genotyped 19 independent susceptibility variants identified in genome-wide association studies of Parkinson's disease. We tested for association between a cumulative genetic risk score and 3 outcome measures: survival, time until progression to Hoehn and Yahr stage 3, and Unified Parkinson's Disease Rating Scale motor score severity.

RESULTS:
Genetic risk score was significantly associated with time from diagnosis to Hoehn and Yahr stage 3 in a Cox regression model (P = 0.010). We observed no clear association for the other outcomes.

CONCLUSIONS:

We present results linking cumulative genetic risk to a motor outcome in Parkinson's disease. Our findings provide a valuable starting point for future large-scale efforts to map the genetic determinants of phenotypic variability.

Wednesday, 10 February 2016

Migraine is related to an increased risk of Parkinson's disease: A population-based, propensity score-matched, longitudinal follow-up study

I have not seen much on migraine and PD in the past... I wonder if the authors adjusted for smoking, coffee and alcohol, which are negatively associated with PD and can trigger headaches in those with migraine...

Cephalalgia. 2016 Feb 6. pii: 0333102416630577. [Epub ahead of print]
Wang HI, Ho YC, Huang YP, Pan SL.


BACKGROUND:
The association between migraine and Parkinson's disease (PD) remains controversial. The purpose of the present population-based, propensity score-matched follow-up study was to investigate whether migraineurs are at a higher risk of developing PD.

METHODS:
A total of 41,019 subjects aged between 40 and 90 years with at least two ambulatory visits with a diagnosis of migraine in 2001 were enrolled in the migraine group. A logistic regression model that included age, sex, pre-existing comorbidities and socioeconomic status as covariates was used to compute the propensity score. The non-migraine group consisted of 41,019 propensity score-matched, randomly sampled subjects without migraine. The PD-free survival rate were estimated using the Kaplan-Meier method. Stratified Cox proportional hazard regression was used to estimate the effect of migraine on the risk of developing PD.

RESULTS:
During follow-up, 148 subjects in the migraine group and 101 in the non-migraine group developed PD. Compared to the non-migraine group, the hazard ratio of PD for the migraine group was 1.64 (95% confidence interval: 1.25-2.14, p = 0.0004). The PD-free survival rate for the migraine group was significantly lower than that for the non-migraine group (p = 0.0041).

CONCLUSIONS:

This study showed an increased risk of developing PD in patients with migraine.

The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: Mechanisms of action

Interesting review on GLP-1 agonists... the results of these clinical trials are eagerly awaited...

Drug Discov Today. 2016 Feb 3. pii: S1359-6446(16)30001-0. doi: 10.1016/j.drudis.2016.01.013. [Epub ahead of print]
Athauda D, Foltynie T.



Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD).

Tuesday, 9 February 2016

Course and risk factors for excessive daytime sleepiness in Parkinson's disease

Interesting to look at things associated with excessive daytime somnolence in PD... what is particular interesting to me is the finding that EDS is non-persistent. This has been a concern of mine for a while, particularly in the pre-diagnostic phase of PD. Strategies that aim to identifying those at risk may miss people with fluctuating or non-persistent symptoms at the early stage. This is one reason why strategies that involve repeat testing may be more effective...

Parkinsonism Relat Disord. 2016 Jan 22. pii: S1353-8020(16)30020-7. doi: 10.1016/j.parkreldis.2016.01.020. [Epub ahead of print]
Zhu K, van Hilten JJ, Marinus J.


INTRODUCTION:
Excessive daytime sleepiness (EDS) is a common feature of Parkinson's disease (PD) that contributes to the disease burden and increases risk of harm. The aim of this study was to examine persistency, cross-sectional and longitudinal associations, and risk factors for EDS in patients with PD.

METHODS:
Analyses were performed on data from the SCOPA-PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who were examined annually. Cross-sectional analyses were conducted to evaluate differences between patients with and without EDS at baseline, while linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in SCOPA-SLEEP-Daytime Sleepiness (SCOPA-SLEEP-DS) scores. A survival analysis was done using data of patients without EDS at baseline to identify risk factors for future EDS.

RESULTS:
EDS proved a non-persistent symptom, although persistency and the proportion of patients with EDS increased with longer follow-up. At baseline 43% of patients had EDS, while 46% of patients without EDS at baseline developed this symptom during follow-up. Male gender, poorer nighttime sleep, cognitive and autonomic dysfunction, hallucinations, less severe dyskinesias, dose of dopamine agonists and use of antihypertensives were associated with higher EDS scores over time, while use of benzodiazepines was associated with lower scores. Baseline SCOPA-SLEEP-DS score and PIGD phenotype were risk factors for future EDS.

CONCLUSION:

With longer disease duration a large proportion of patients develop EDS. Some risk factors are modifiable and patients should be monitored to improve quality of life and reduce risk of harm.

Monday, 8 February 2016

Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.


The authors of this study have developed a new technique for identifying oligomeric alpha-synuclein in CSF (the form of alpha-synuclein which is thought to be responsible for causing neuronal damage in PD). Although the ability of this new assay to classify patients and controls is only modest, and has yet to be validated in an independent cohort, the methodological advance this paper represents is in itself significant.


Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease.

Majbour NK, Vaikath NN, van Dijk KD, Ardah MT, Varghese S, Vesterager LB Montezinho et al.
Mol Neurodegener. 2016 Jan 19;11(1):7. doi: 10.1186/s13024-016-0072-9.

Abstract
BACKGROUND:
Despite decades of intensive research, to date, there is no accepted diagnosis for Parkinson's disease (PD) based on biochemical analysis of blood or CSF. However, neurodegeneration in the brains of PD patients begins several years before the manifestation of the clinical symptoms, pointing to serious flaw/limitations in this approach.

RESULTS:
To explore the potential use of alpha-synuclein (α-syn) species as candidate biomarkers for PD, we generated specific antibodies directed against wide array of α-syn species, namely total-, oligomeric- and phosphorylated-Ser129-α-syn (t-, o- and p-S129-α-syn). Next we sought to employ our antibodies to develop highly specific ELISA assays to quantify α-syn species in biological samples. Finally we verified the usefulness of our assays in CSF samples from 46 PD patients and 48 age-matched healthy controls. We also assessed the discriminating power of combining multiple CSF α-syn species with classical Alzheimer's disease biomarkers. The combination of CSF o-/t-α-syn, p-S129-α-syn and p-tau provided the best fitting predictive model for discriminating PD patients from controls. Moreover, CSF o-α-syn levels correlated significantly with the severity of PD motor symptoms (r = -0.37).

CONCLUSION:
Our new ELISA assays can serve as research tools to address the unmet need for reliable CSF biomarkers for PD and related disorders.

Sunday, 7 February 2016

The prediagnostic phase of Parkinson's disease

This has been online for a couple of weeks but just indexed for Pubmed today... hope you enjoy!!

J Neurol Neurosurg Psychiatry. 2016 Jan 11. pii: jnnp-2015-311890. doi: 10.1136/jnnp-2015-311890. [Epub ahead of print]
Noyce AJ, Lees AJ, Schrag AE.


Abstract
The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those 'at risk'. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis. We discuss imaging markers across a range of modalities, and the emerging literature on fluid and peripheral tissue biomarkers. We then explore current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials, what we are learning from these initiatives, and how these studies will bring the field closer to realistically commencing primary or secondary preventive trials for PD. Further progress in this field hinges on greater clinical and biological description, and understanding of the prediagnostic, peridiagnostic and immediate postdiagnostic stages of PD. Identifying subjects 3-5 years before they are currently diagnosed may be an ideal group for neuroprotective trials. At the very least, these initiatives will help clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of disease.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

KEYWORDS:

EPIDEMIOLOGY; MOVEMENT DISORDERS; PARKINSON'S DISEASE

Saturday, 6 February 2016

α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models

This is important stuff... evidence that alpha-syn accumulation affecting lysosomal degradation... lysosomes are responsible for much of the clearance of abnormal proteins from cells... so impairing lysosomal function could start a cycle of events leading to further accumulation and dysfunction... what's particularly exciting here is that the investigators show it is modifiable. Human midbrain models sound like a good idea too... this is the most affected part of the brain in PD!!

Proc Natl Acad Sci U S A. 2016 Feb 2. pii: 201520335. [Epub ahead of print]
Mazzulli JR, Zunke F, Isacson O, Studer L, Krainc D.


Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

Friday, 5 February 2016

Substantia nigra echogenicity correlated with clinical features of Parkinson's disease

This is a large study looking at TCS in PD patients... the association with male gender has been reported before by some but not all investigators. However the association with markers of disease severity is unexpected and will require further replication....

Parkinsonism Relat Disord. 2016 Jan 26. pii: S1353-8020(16)30021-9. doi: 10.1016/j.parkreldis.2016.01.021. [Epub ahead of print]
Zhou HY, Sun Q, Tan YY, Hu YY, Zhan WW, Li DH, Wang Y, Xiao Q, Liu J, Chen SD.

BACKGROUND:
Transcranial sonography can display structural alterations in the substantia nigra (SN) of patients with Parkinson's disease (PD), and is considered to be a potential useful tool for the diagnosis of PD. The aim of this study was to assess the correlation between SN echogenicity and clinical features in Chinese patients with PD.

METHODS:
A total of 420 subjects including 290 patients with PD and 130 controls were recruited from the neurological clinic or the community. Transcranial sonographic evaluations of the SN were performed in all subjects, and motor and non-motor symptoms were thoroughly assessed by a series of rating scales in PD patients.

RESULTS:
Two hundred and one patients were successfully assessed by transcranial sonography. SN hyperechogenicity was found to be associated with male sex (p = 0.004), higher scores on the Unified Parkinson's Disease Rating Scale (UPDRS) part II (p = 0.001) and autonomic symptoms scores (p = 0.003). Moreover, regression analysis revealed that UPDRS part II scores (odds ratio = 1.141, p < 0.001) and gender (odds ratio = 2.409, p = 0.007) could be the independent predictors for SN hyperechogenicity; in addition, among all items of UPDRS part II, speech, dressing, hygiene, and turning in bed and adjusting bed clothes significantly correlated with SN hyperechogenicity.

CONCLUSIONS:

This is the first report suggesting the correlation between SN echogenicity and UPDRS part II, and we conclude that increased SN echogenicity might reflect more severe disease disability or poorer medical response.

Thursday, 4 February 2016

Circadian system - A novel diagnostic and therapeutic target in Parkinson's disease?

I first started wondering about circadian rhythm in PD about three years ago when I attended an excellent talk at Barts and the London School of Medicine and Dentistry and the idea came up. It seems may of the pre and post diagnosis symptoms of PD could be accounted for (at least in part) by altered circadian rhythm... I anticipate this will be an area of further focus in the coming years!

Mov Disord. 2016 Jan 30. doi: 10.1002/mds.26509. [Epub ahead of print]
Videnovic A, Willis GL.



The circadian system regulates biological rhythmicity in the human body. The role of the circadian system in neurological disorders is a theme that is attracting an increasing amount of interest from the scientific community. This has arisen, in part, from emerging evidence that disorders such as Parkinson's disease (PD) are multifactorial with many features exhibiting diurnal fluctuations, thereby suggestive of circadian involvement. Although the importance of fluctuating motor and nonmotor manifestations in PD have been well acknowledged, the role of the circadian system has received little attention until recently. It is proposed that intervening with circadian function provides a novel research avenue down which new strategies for improving symptomatic treatment and slowing of the progressive degenerative process can be approached to lessen the burden of PD. In this article we review the literature describing existing circadian research in PD and its experimental models. © 2016 International Parkinson and Movement Disorder Society.

Wednesday, 3 February 2016

Risk of Injurious Fall and Hip Fracture up to 26 y before the Diagnosis of Parkinson Disease: Nested Case-Control Studies in a Nationwide Cohort

Notwithstanding the issues around case ascertainment and differentiation from atypical Parkinson's this is really interesting. In fact even if atypical Parkinson's did explain some of the association, one would not expect the effect to be present up to 10 years before diagnosis. 

Certainly prominent falling should still raise the possibility of atypical Parkinson's in individual patients, but this study suggests the presence of motor features many years before eventual diagnosis. We have been saying this for some time... subtle motor dysfunction ought to be present if looked for and the notion of 'premotor' PD may not hold true. Only if you have looked at people with prodromal or pre-diagnostic disease (without bias) and can find no hint of motor problems, then waited to see motor dysfunction subsequently emerge can one be confident of a premotor phase.

Whether the association with fracture risk suggests common disease mechanisms between osteoporosis and PD, or whether subtle reduction in mobility increases fracture risk will remain unclear... but given the lag time between fracture and PD, l-dopa, undernutrition and lack of sunlight exposure should not be playing a role...

PLoS Med. 2016 Feb 2;13(2):e1001954. doi: 10.1371/journal.pmed.1001954. eCollection 2016.
Nyström H, Nordström A, Nordström P.

BACKGROUND:
Low muscle strength has been found in late adolescence in individuals diagnosed with Parkinson disease (PD) 30 y later. This study investigated whether this lower muscle strength also may translate into increased risks of falling and fracture before the diagnosis of PD.

METHODS AND FINDINGS:
Among all Swedish citizens aged ≥50 y in 2005, two nested case-control cohorts were compiled. In cohort I, individuals diagnosed with PD during 1988-2012 (n = 24,412) were matched with up to ten controls (n = 243,363), and the risk of fall-related injuries before diagnosis of PD was evaluated. In cohort II, individuals with an injurious fall in need of emergency care during 1988-2012 (n = 622,333) were matched with one control (n = 622,333), and the risk of PD after the injurious fall was evaluated. In cohort I, 18.0% of cases and 11.5% of controls had at least one injurious fall (p < 0.001) prior to PD diagnosis in the case. Assessed by conditional logistic regression analysis adjusted for comorbid diagnoses and education level, PD was associated with increased risks of injurious fall up to 10 y before diagnosis (odds ratio [OR] 1.19, 95% CI 1.08-1.31; 7 to <10 y before diagnosis) and hip fracture ≥15 y before diagnosis (OR 1.36, 95% CI 1.10-1.69; 15-26 y before diagnosis). In cohort II, 0.7% of individuals with an injurious fall and 0.5% of controls were diagnosed with PD during follow-up (p < 0.001). The risk of PD was increased for up to 10 y after an injurious fall (OR 1.18, 95% CI 1.02-1.37; 7 to <10 y after diagnosis). An important limitation is that the diagnoses were obtained from registers and could not be clinically confirmed for the study.

CONCLUSIONS:

The increased risks of falling and hip fracture prior to the diagnosis of PD may suggest the presence of clinically relevant neurodegenerative impairment many years before the diagnosis of this disease.

Using the Gene Ontology to Annotate Key Players in Parkinson's Disease.

I have seen Paul (Denny) speak about this a couple of times at meetings. This is a really important endeavour and one that will benefit the Parkinson's disease research community...

Neuroinformatics. 2016 Jan 29. [Epub ahead of print]
Foulger RE, Denny P, Hardy J, Martin MJ, Sawford T, Lovering RC.



The Gene Ontology (GO) is widely recognised as the gold standard bioinformatics resource for summarizing functional knowledge of gene products in a consistent and computable, information-rich language. GO describes cellular and organismal processes across all species, yet until now there has been a considerable gene annotation deficit within the neurological and immunological domains, both of which are relevant to Parkinson's disease. Here we introduce the Parkinson's disease GO Annotation Project, funded by Parkinson's UK and supported by the GO Consortium, which is addressing this deficit by providing GO annotation to Parkinson's-relevant human gene products, principally through expert literature curation. We discuss the steps taken to prioritise proteins, publications and cellular processes for annotation, examples of how GO annotations capture Parkinson's-relevant information, and the advantages that a topic-focused annotation approach offers to users. Building on the existing GO resource, this project collates a vast amount of Parkinson's-relevant literature into a set of high-quality annotations to be utilized by the research community.

Tuesday, 2 February 2016

Lateral Asymmetry and Spatial Difference of Iron Deposition in the Substantia Nigra of Patients with Parkinson Disease Measured with Quantitative Susceptibility Mapping

Evidence of iron loading in the nigra... as shown by other groups. Perhaps supports the finding of increased echogenic signal in the region of the nigra using transcranial sonography. This study shows laterality of deposition and was analysis by imaging experts blind to the clinical details...

AJNR Am J Neuroradiol. 2016 Jan 28. [Epub ahead of print]
Azuma M, Hirai T, Yamada K, Yamashita S, Ando Y, Tateishi M, Iryo Y, Yoneda T, Kitajima M, Wang Y, Yamashita Y.


BACKGROUND AND PURPOSE:
Quantitative susceptibility mapping is useful for assessing iron deposition in the substantia nigra of patients with Parkinson disease. We aimed to determine whether quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference in iron deposits in the substantia nigra of patients with Parkinson disease.

MATERIALS AND METHODS:
Our study population comprised 24 patients with Parkinson disease and 24 age- and sex-matched healthy controls. They underwent 3T MR imaging by using a 3D multiecho gradient-echo sequence. On reconstructed quantitative susceptibility mapping, we measured the susceptibility values in the anterior, middle, and posterior parts of the substantia nigra, the whole substantia nigra, and other deep gray matter structures in both hemibrains. To identify the more and less affected hemibrains in patients with Parkinson disease, we assessed the severity of movement symptoms for each hemibrain by using the Unified Parkinson's Disease Rating Scale.

RESULTS:
In the posterior substantia nigra of patients with Parkinson disease, the mean susceptibility value was significantly higher in the more than the less affected hemibrain substantia nigra (P < .05). This value was significantly higher in both the more and less affected hemibrains of patients with Parkinson disease than in controls (P < .05). Asymmetry of the mean susceptibility values was significantly greater for patients than controls (P < .05). Receiver operating characteristic analysis showed that quantitative susceptibility mapping of the posterior substantia nigra in the more affected hemibrain provided the highest power for discriminating patients with Parkinson disease from the controls.

CONCLUSIONS:

Quantitative susceptibility mapping is useful for assessing the lateral asymmetry and spatial difference of iron deposition in the substantia nigra of patients with Parkinson disease.

Monday, 1 February 2016

Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase

Minor hallucinations preceding diagnosis... some by a long time. If only there were a way of measuring this reliably...
However clinical experience (at least in my opinion) suggests the prevalence in PD ought to be lower (maybe ~20% but not nearly half of all patients!). Observer bias may play a role but overall the findings are very interesting... looking forward to seeing how this field progresses...
It will be interesting to know what happens to that 5% of controls too...

Mov Disord.
2016 Jan;31(1):45-52. doi: 10.1002/mds.26432. Epub 2015 Sep 26.
Pagonabarraga J, Martinez-Horta S, Fernández de Bobadilla R, Pérez J, Ribosa-Nogué R, Marín J, Pascual-Sedano B, García C, Gironell A, Kulisevsky J.


OBJECTIVES:
The description of minor hallucinatory phenomena (presence, passage hallucinations) has widened the spectrum of psychosis in Parkinson's disease (PD). Minor hallucinatory phenomena seem to antedate the development of more severe hallucinations. Early detection of minor hallucinations may be useful for screening patients with more severe endophenotypes. Motivated by the observation of "de novo," drug-naive PD patients reporting minor hallucinations, we aimed to prospectively identify "de novo" untreated PD patients experiencing hallucinatory phenomena, and to compare their clinico-demographic characteristics with those of untreated PD patients without hallucinations and healthy controls.

METHODS:
Screening and description of psychosis was assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-Part I and a structured interview covering all types of psychotic phenomena reported in PD. Clinical, neuropsychological, and demographic data of PD patients with and without psychotic phenomena were compared with those of age- and education-matched healthy controls.

RESULTS:
Fifty drug-naive, "de novo" PD patients and 100 controls were prospectively included. Minor hallucinations were experienced in 42% (21 of 50) PD patients and 5% controls (P < 0.0001). Coexistence of passage and presence hallucinations was the most common finding. Unexpectedly, 33.3% of patients with minor hallucinations manifested these as a pre-motor symptom, starting 7 months to 8 years before first parkinsonian motor symptoms. The presence of minor hallucinations was significantly associated with presence of rapid eye movement sleep behavior disorder.

CONCLUSIONS:

In this first study to prospectively analyze the frequency of minor hallucinatory phenomena in incident, untreated PD patients, hallucinations appeared as a frequent early non-motor symptom that may even predate the onset of parkinsonism.

Risk factors for probable REM sleep behavior disorder: A community-based study

Not familiar with the Chinese RBD questionnaire but prevalence of probable RBD appears high so may be some false positives in there....

Neurology. 2016 Jan 27. pii: 10.1212/WNL.0000000000002414. [Epub ahead of print]
Wong JC, Li J, Pavlova M, Chen S, Wu A, Wu S, Gao X.

OBJECTIVE:
To examine risk factors for REM sleep behavior disorder (RBD) in a large-scale community-based study.

METHODS:
This community-based study included 12,784 Chinese adults (10,556 men and 2,228 women, aged 24 years or older) who were free of Parkinson disease and dementia in 2012. Probable RBD (pRBD) status was determined by a validated questionnaire (Chinese RBD questionnaire-Hong Kong) in 2012. Potential risk factors-including age, sex, smoking, socioeconomic status, physical activity, obesity, consumption of tea (surrogate for caffeine intake) and alcohol, serum concentrations of lipids and glucose, and chronic disease status-were assessed in 2006. Logistic regression was used to calculate odds ratios and 95% confidence intervals and to test differences in prevalence of pRBD across exposures.

RESULTS:
Prevalence of pRBD was 5.9% in men and 4.1% in women. In the fully adjusted model, risk factors that were significantly associated with a higher risk of having pRBD included lower education level, coal mining and other blue collar occupation, lower physical activity level, diabetes or prediabetes, lower body mass index, head injury, higher low-density lipoprotein level, and chronic olfactory and taste dysfunction. In sensitivity analyses, restricting to pRBD cases with symptom onset within 1 year or excluding coal miners or those with history of head injury generated similar results.

CONCLUSION:

We found several potential risk factors for pRBD, including socioeconomic status, head injury, olfactory and taste dysfunction, and various cardiovascular risk factors. Future prospective studies to establish the temporal relationship between these potential risk factors and RBD are warranted.