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.

http://link.springer.com/article/10.1007%2Fs12021-015-9293-2

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.

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.

http://www.ajnr.org/content/early/2016/01/28/ajnr.A4645.long

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.

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.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26432/abstract

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.

Lewy- and alzheimer-type pathologies in midbrain and cerebellum across the Lewy body disorders spectrum

...and on that note... here is another relevant recent publication...

Neuropathol Appl Neurobiol. 2016 Jan 26. doi: 10.1111/nan.12308. [Epub ahead of print]

Sierra M, Gelpi E, Martí MJ, Compta Y.

http://onlinelibrary.wiley.com/doi/10.1111/nan.12308/abstract

AIMS:

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are pathologically characterized by intraneuronal α-synuclein aggregates and thus labelled as Lewy body disorders (LBD). Conjoint cortical α-synuclein, tau and amyloid-β (Aβ), and striatal Aβ aggregates, have been related to dementia in LBD. Interpretation of current and emerging in vivo molecular imaging of these pathologies will need of precise knowledge of their topographic distribution. We aimed to assess these pathologies further down the encephalon across the LBD-spectrum.

METHODS:

Semi-quantitative rating of α-synuclein, Aβ and hyperphosphorylated tau aggregates in midbrain (and cerebellum in the case of Aβ as it represents the last β-amyloidosis stage) sections from cases representative of the LBD-spectrum (PD non-dementia, PD-dementia, DLB; n=10 each) compared to controls (n=10) and Alzheimer's disease (AD; n=10).

RESULTS:

α-synuclein midbrain scores rose from controls to AD and then LBD irrespective of dementia. Aβ and tau were more prominent in the tectum/tegmentum, increasing from controls to LBD (mostly in dementia cases in the case of Aβ), and then peaking in AD. By contrast, cerebellar Aβ scores were marginal across the LBD-spectrum, as opposed to AD, only showing a trend towards greater involvement in LBD cases with dementia.

CONCLUSIONS:

Frequency and severity of Aβ and tau pathologies in the midbrain across the LBD-spectrum were midway between controls and AD, with Aβ in the tectum/tegmentum being associated with dementia. These findings might have potential implications in the eventual interpretation of regional uptake of in vivo molecular imaging of these pathologies. This article is protected by copyright. All rights reserved.

An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia.

Probably reflects not only shared mechanisms but also dual pathology in some of these patients, which happens not infrequently...

PLoS One. 2016 Jan 26;11(1):e0147319. doi: 10.1371/journal.pone.0147319. eCollection 2016.

Berlyand Y, Weintraub D, Xie SX, Mellis IA, Doshi J, Rick J, McBride J, Davatzikos C, Shaw LM, Hurtig H, Trojanowski JQ, Chen-Plotkin AS.

http://www.ncbi.nlm.nih.gov/pubmed/26812251

Biomarkers from multiple modalities have been shown to correlate with cognition in Parkinson's disease (PD) and in Alzheimer's disease (AD). However, the relationships of these markers with each other, and the use of multiple markers in concert to predict an outcome of interest, are areas that are much less explored. Our objectives in this study were (1) to evaluate relationships among 17 biomarkers previously reported to associate with cognition in PD or AD and (2) to test performance of a five-biomarker classifier trained to recognize AD in identifying PD with dementia (PDD). To do this, we evaluated a cross-sectional cohort of PD patients (n = 75) across a spectrum of cognitive abilities. All PD participants had 17 baseline biomarkers from clinical, genetic, biochemical, and imaging modalities measured, and correlations among biomarkers were assessed by Spearman's rho and by hierarchical clustering. We found that internal correlation among all 17 candidate biomarkers was modest, showing a maximum pairwise correlation coefficient of 0.51. However, a five-marker subset panel derived from AD (CSF total tau, CSF phosphorylated tau, CSF amyloid beta 42, APOE genotype, and SPARE-AD imaging score) discriminated cognitively normal PD patients vs. PDD patients with 80% accuracy, when employed in a classifier originally trained to recognize AD. Thus, an AD-derived biomarker signature may identify PDD patients with moderately high accuracy, suggesting mechanisms shared with AD in some PDD patients. Based on five measures readily obtained during life, this AD-derived signature may prove useful in identifying PDD patients most likely to respond to AD-based crossover therapies.

The impact of non-motor symptoms on the quality of life of Parkinson's disease patients: a longitudinal study

Reflective of what one sees in the clinic to an extent... although I am surprised that motor symptoms did not have an impact on QoL... there has been a big pendulum swing in recent years (which was probably necessary to increase awareness of non-motor symptoms)... but both motor and non-motor symptoms can negatively affect patients and both need addressing in the clinic....

Eur J Neurol. 2016 Jan 25. doi: 10.1111/ene.12950. [Epub ahead of print]

Prakash KM, Nadkarni NV, Lye WK, Yong MH, Tan EK.

http://www.ncbi.nlm.nih.gov/pubmed/26806538

BACKGROUND AND PURPOSE:

Non-motor symptoms (NMSs) are common amongst patients with Parkinson's disease (PD); however, little is known about their influence on the health-related quality of life (QoL) over a defined follow-up period. The study was aimed to establish the impact of NMSs on the QoL of patients with PD over a 2-year follow-up period.

METHOD:

A total of 227 newly referred PD patients were prospectively recruited between 2013 and 2014. The Non-Motor Symptoms Scale was used to evaluate NMSs burden whilst QoL was assessed with the Parkinson's Disease Questionnaire-39 items. Motor disabilities were assessed using the Part III (motor) Unified Parkinson's Disease Rating Scale (UPDRSm).

RESULTS:

The mean age was 64.37 (10.18) years; 59.9% were males and a majority (89.0%) were ethnic Chinese. Almost 65% were unemployed and 84.6% had attained no more than secondary level of education. In the univariate analysis, total NMSs burden, age, gender, subsequent visit, Hoehn and Yahr staging, disease duration and UPDRSm score were individually predictive of change in the Parkinson's Disease Questionnaire Summary Index score from baseline to follow-up visit. However, in the multivariate analysis, total NMSs burden significantly predicted the QoL scores whilst motor scores did not. Specifically, NMS domains 2 (sleep/fatigue), 3 (mood/apathy) and 5 (attention/memory) were most significantly predictive of QoL change.

CONCLUSION:

Unlike motor disabilities, NMSs burden, in particular sleep, mood and attention, have a significant impact on the QoL of PD patients over a 2-year follow-up period.

Autophagy and Alpha-Synuclein: Relevance to Parkinson's Disease and Related Synucleopathies

Are we starting to get closer to the truth... autophagy and lysosomal dysfunction giving rise to a synuclein predominant form of PD and all that goes with that (heavy non-motor and cognitive burden)... and a form characterised by mainly mitochondrial dysfunction with motor features as the main manifestation... significant overlap still probable and prion-like mechanisms remain a real possibility... who has looked at mitochondrial versus lysosomal function in RBD???

Mov Disord. 2016 Jan 27. doi: 10.1002/mds.26477. [Epub ahead of print]

Xilouri M, Brekk OR, Stefanis L.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26477/abstract

Evidence from human postmortem material, transgenic mice, and cellular/animal models of PD link alpha-synuclein accumulation to alterations in the autophagy lysosomal pathway. Conversely, alpha-synuclein mutations related to PD pathogenesis, as well as post-translational modifications of the wild-type protein, result in the generation of aberrant species that may impair further the function of the autophagy lysosomal pathway, thus generating a vicious cycle leading to neuronal death. Moreover, PD-linked mutations in lysosomal-related genes, such as glucocerebrosidase, have been also shown to contribute to alpha-synuclein accumulation and related toxicity, indicating that lysosomal dysfunction may, in part, account for the neurodegeneration observed in synucleinopathies. In the current review, we summarize findings related to the inter-relationship between alpha-synuclein and lysosomal proteolytic pathways, focusing especially on recent experimental strategies based on the manipulation of the autophagy lysosomal pathway to counteract alpha-synuclein-mediated neurotoxicity in vivo. Pinpointing the factors that regulate alpha-synuclein association to the lysosome may represent potential targets for therapeutic interventions in PD and related synucleinopathies. © 2016 International Parkinson and Movement Disorder Society.

Toward Monitoring Parkinson's through Analysis of Static Handwriting Samples: A Quantitative Analytical Framework

More on handwriting in PD... quantify (or qualifying) the range of changes is important...

IEEE J Biomed Health Inform. 2016 Jan 18. [Epub ahead of print]

Zhi N, Jaeger B, Gouldstone A, Sipahi R, Frank S.

http://ieeexplore.ieee.org/xpl/articleDetails.jsp?arnumber=7384677

Detection of changes in micrographia as a manifestation of symptomatic progression or therapeutic response in Parkinson's disease (PD) is challenging as such changes can be subtle. A computerized toolkit based on quantitative analysis of handwriting samples would be valuable as it could supplement and support clinical assessments, help monitor micrographia, and link it to PD. Such a toolkit would be especially useful if it could detect subtle yet relevant changes in handwriting morphology, thus enhancing resolution of the detection procedure. This would be made possible by developing a set of metrics sensitive enough to detect and discern micrographia with specificity. Several metrics that are sensitive to the characteristics of micrographia were developed, with minimal sensitivity to confounding handwriting artifacts. These metrics capture character size-reduction, ink utilization, and pixel density within a writing sample from left to right. They are used here to 'score' handwritten signatures of 12 different individuals corresponding to healthy and symptomatic PD conditions, and sample control signatures that had been artificially reduced in size for comparison purposes. Moreover, metric analyses of samples from ten of the twelve individuals for which clinical diagnosis time is known show considerable informative variations when applied to static signature samples obtained before and after diagnosis. In particular, a measure called pixel density variation showed statistically significant differences (p < 0.05) between two comparison groups of remote signature recordings: earlier versus recent, based on independent and paired t-test analyses on a total of 40 signature samples. The quantitative framework developed here has the potential to be used in future controlled experiments to study micrographia and links to PD from various aspects, including monitoring and assessment of applied interventions and treatments. The inherent value in this methodology is further enhanced by its reliance solely on static signatures, not requiring dynamic sampling with specialized equipment.

Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings

These latest reports of Lewy pathology being visible in the submandibular gland in early disease (<5 years) suggest the possibility of saliva gland biopsy being used as a confirmation of  diagnosis, but the sensitivity seems to be a little low for this to be a particularly useful test.
It would be interesting to see if any of the volunteers with false positive results go on to develop PD.

http://www.ncbi.nlm.nih.gov/pubmed/26799362

Mov Disord. 2016 Jan 22. doi: 10.1002/mds.26476. [Epub ahead of print]

Adler CH1, Dugger BN2, Hentz JG3, Hinni ML4, Lott DG4, Driver-Dunckley E1, Mehta S1, Serrano G2, Sue LI2, Duffy A1, Intorcia A2, Filon J2, Pullen J2, Walker DG2,5, Beach TG2.

Abstract

INTRODUCTION:

Finding a peripheral tissue biopsy site to diagnose early PD would be of value for clinical care, biomarker validation, and as research enrollment criteria. Whereas autopsy and advanced PD studies suggest that the submandibular gland is an important biopsy site, there are no studies in early PD. The aim of this study was to determine whether needle biopsy of the submandibular gland reveals Lewy type alpha-synucleinopathy in early PD.

METHODS:

Twenty-five early PD (duration < 5 years) and 10 controls underwent transcutaneous needle core biopsies of the submandibular gland. Tissue was stained for phosphorylated alpha-synuclein, reviewed blind to clinical diagnosis, and only nerve element staining was considered positive.

RESULTS:

Mean (standard deviation) age was 69.5 (8.3) for the PD group, 64.8 (8.0) years for controls, and disease duration 2.6 (1.1) years. Six PD and 1 control subject had inadequate glandular tissue. Positive staining was found in 14 of 19 (74%) PD and 2 of 9 (22%) control subjects. PD-positive and -negative cases did not differ clinically. Adverse events (mainly swelling and bruising) were common (77% of cases), but were minor and transient.

CONCLUSIONS:

Submandibular gland needle biopsies identified phosphorylated alpha-synuclein staining in 74% of early PD subjects. False positives may be true false positives or may represent prodromal PD. If confirmed in larger studies with eventual autopsy confirmation, the potential value of submandibular gland biopsies for early PD may be to aid in clinical trial inclusion/exclusion and eventually serve as a gold standard for biomarker studies short of autopsy confirmation. © 2016 International Parkinson and Movement Disorder Society.

Gut Feelings About α-Synuclein in Gastrointestinal Biopsies: Biomarker in the Making?

This is a really good and measured review on the topic... which highlights the need for cautious optimism and overall reflects some my own thoughts on the relevance of gut alpha-syn in PD (just worded more eloquently than I could!)...

Mov Disord. 2016 Jan 22. doi: 10.1002/mds.26480. [Epub ahead of print]

Ruffmann C, Parkkinen L.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26480/abstract

In recent years, several studies have investigated the potential of immunohistochemical detection of α-synuclein in the gastrointestinal tract to diagnose Parkinson's disease (PD). Although methodological heterogeneity has hindered comparability between studies, it has become increasingly apparent that the high sensitivity and specificity reported in preliminary studies has not been sustained in subsequent large-scale studies. What constitutes pathological α-synuclein in the alimentary canal that could distinguish between PD patients and controls and how this can be reliably detected represent key outstanding questions in the field. In this review, we will comment on and compare the variable technical aspects from previous studies, and by highlighting some advantages and shortcomings we hope to delineate a standardized approach to facilitate the consensus criteria urgently needed in the field. Furthermore, we will describe alternative detection techniques to conventional immunohistochemistry that have recently emerged and may facilitate ease of interpretation and reliability of gastrointestinal α-synuclein detection. Such techniques have the potential to detect the presence of pathological α-synuclein and include the paraffin-embedded tissue blot, the proximity ligation assay, the protein misfolding cyclic amplification technique, and the real-time quaking-induced conversion assay. Finally, we will review 2 nonsynonymous theories that have driven enteric α-synuclein research, namely, (1) that α-synuclein propagates in a prion-like fashion from the peripheral nervous system to the brain via vagal connections and (2) that gastrointestinal α-synuclein deposition may be used as a clinically useful biomarker in PD. © 2016 International Parkinson and Movement Disorder Society.

© 2016 International Parkinson and Movement Disorder Society.