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.

Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial

Great to see the results of this are encouraging... goodness knows we need better treatment for these tricky axial symptoms... details of randomisation and allocation masking are provided which increase confidence in the conduct of the study. It remains to be seen how relevant a significant change in step time variability will be in reducing falls... roll on phase 3...

Lancet Neurol. 2016 Jan 12. pii: S1474-4422(15)00389-0. doi: 10.1016/S1474-4422(15)00389-0. [Epub ahead of print]

Henderson EJ, Lord SR, Brodie MA, Gaunt DM, Lawrence AD, Close JC, Whone AL, Ben-Shlomo Y.

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(15)00389-0/abstract

BACKGROUND:

Falls are a frequent and serious complication of Parkinson's disease and are related partly to an underlying cholinergic deficit that contributes to gait and cognitive dysfunction in these patients. Gait dysfunction can lead to an increased variability of gait from one step to another, raising the likelihood of falls. In the ReSPonD trial we aimed to assess whether ameliorating this cholinergic deficit with the acetylcholinesterase inhibitor rivastigmine would reduce gait variability.

METHODS:

We did this randomised, double-blind, placebo-controlled, phase 2 trial at the North Bristol NHS Trust Hospital, Bristol, UK, in patients with Parkinson's disease recruited from community and hospital settings in the UK. We included patients who had fallen at least once in the year before enrolment, were able to walk 18 m without an aid, had no previous exposure to an acetylcholinesterase inhibitor, and did not have dementia. Our clinical trials unit randomly assigned (1:1) patients to oral rivastigmine or placebo capsules (both taken twice a day) using a computer-generated randomisation sequence and web-based allocation. Rivastigmine was uptitrated from 3 mg per day to the target dose of 12 mg per day over 12 weeks. Both the trial team and patients were masked to treatment allocation. Masking was achieved with matched placebo capsules and a dummy uptitration schedule. The primary endpoint was difference in step time variability between the two groups at 32 weeks, adjusted for baseline age, cognition, step time variability, and number of falls in the previous year. We measured step time variability with a triaxial accelerometer during an 18 m walking task in three conditions: normal walking, simple dual task with phonemic verbal fluency (walking while naming words beginning with a single letter), and complex dual task switching with phonemic verbal fluency (walking while naming words, alternating between two letters of the alphabet). Analysis was by modified intention to treat; we excluded from the primary analysis patients who withdrew, died, or did not attend the 32 week assessment. This trial is registered with ISRCTN, number 19880883.

FINDINGS:

Between Oct 4, 2012 and March 28, 2013, we enrolled 130 patients and randomly assigned 65 to the rivastigmine group and 65 to the placebo group. At week 32, compared with patients assigned to placebo (59 assessed), those assigned to rivastigmine (55 assessed) had improved step time variability for normal walking (ratio of geometric means 0·72, 95% CI 0·58-0·88; p=0·002) and the simple dual task (0·79; 0·62-0·99; p=0·045). Improvements in step time variability for the complex dual task did not differ between groups (0·81, 0·60-1·09; p=0·17). Gastrointestinal side-effects were more common in the rivastigmine group than in the placebo group (p<0·0001); 20 (31%) patients in the rivastigmine group versus three (5%) in the placebo group had nausea and 15 (17%) versus three (5%) had vomiting.

INTERPRETATION:

Rivastigmine can improve gait stability and might reduce the frequency of falls. A phase 3 study is needed to confirm these findings and show cost-effectiveness of rivastigmine treatment.

FUNDING:

Parkinson's UK.

Simplified conversion method for unified Parkinson's disease rating scale motor examinations.

This is useful... especially because both scores seem to still be in widespread use...

Mov Disord. 2015 Dec;30(14):1967-70. doi: 10.1002/mds.26435. Epub 2015 Nov 17.

Hentz JG, Mehta SH, Shill HA, Driver-Dunckley E, Beach TG, Adler CH.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26435/abstract;jsessionid=F98075AF92325D076D2C76B1604D3A45.f04t02

BACKGROUND:

We evaluated a simplified method for converting Unified Parkinson's Disease Rating Scale Part III Motor Examination total scores (UPDRS III) to the International Parkinson and Movement Disorder Society's (MDS) revised version of the scores.

METHODS:

PD patients in the Arizona Study of Aging and Neurodegenerative Disorders were assessed with both scales. The accuracy of the predicted scores was assessed using regression modeling, classical intraclass correlation coefficients, and the Bland-Altman method.

RESULTS:

There was strong correlation between the two scores. Adding 7 points to a UPDRS III total score performed approximately as well as previously published conversion formulas (intraclass correlation: 0.96). The adjusted score is expected to be within 3 points of the MDS-UPDRS III score 50% of the time and within 9 points 95% of the time.

CONCLUSIONS:

Simply adding 7 points to a UPDRS III total score provides a good approximation of the MDS-UPDRS III total score.

Systematic Review of the Relationship between Vitamin D and Parkinson's Disease

Could this underpin a geographical gradient in PD diagnosis...

J Parkinsons Dis. 2016 Jan 9. [Epub ahead of print]

Rimmelzwaan LM, van Schoor NM, Lips P, Berendse HW, Eekhoff EM.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150615

BACKGROUND:

Although vitamin D may have both protective and symptomatic effects in Parkinson's disease (PD), the evidence is scarce and not well understood. Also, 25-hydroxyvitamin D (vitamin D) is suggested to play a neuroprotective and neurotrophic role in the brain. Therefore, this review investigates the relationship between vitamin D and PD.

OBJECTIVE:

Investigate the evidence for a relationship between vitamin D and PD by summarizing observational and interventional studies in humans, as well as relevant experimental studies.

METHODS:

A systematic search was made in the Medline, Cochrane and Embase databases (from inception to March 2014). All identified titles were independently evaluated by two reviewers. Articles were selected based on the presence of PD-related outcome data. Included were observational studies (including genetic studies) and interventional studies in humans, as well as relevant animal studies.

RESULTS:

A total of 20 studies (14 observational, 1 interventional and 5 rodent studies) were selected for analysis. Eight observational studies showed that serum 25(OH) D levels tend to be low in PD. One observational study indicated that low serum 25(OH) D may worsen automatic postural responses and one interventional study suggested that vitamin D supplementation can prevent worsening (based on the Hoehn and Yahr rating scale). Studies in rodent models of PD showed a protective effect of vitamin D treatment on dopaminergic neurons in the substantia nigra. Results of genetic studies on the association between vitamin D receptor polymorphisms and the risk of PD were contradictory.

CONCLUSION:

The literature supports possible protective and symptomatic effects of vitamin D in PD. However, more observational and interventional studies in humans are needed to confirm and further elucidate the suggested beneficial effect of vitamin D on PD.

The spectrum of clinical features seen with alpha synuclein pathology.

New review on the manifestation of synucleinopathies...

Neuropathol Appl Neurobiol. 2016 Jan 10. doi: 10.1111/nan.12303. [Epub ahead of print]

Barker RA, Williams-Gray CH.

It has been recognised for many years that a number of chronic neurodegenerative diseases of the CNS are characterised by the development of intracellular inclusion bodies, but it is only relatively recently that the core proteins defining these pathologies have been defined. One such protein is alpha synuclein, that was found to be the main component of Lewy bodies in the late 1990s, and this discovery reinforced the emerging view that alpha synuclein was intimately linked to diseases characterised by this type of pathology - namely Parkinson's disease (PD) and Lewy body dementia (DLB). Furthermore at around this time this same protein was also found within the glial inclusion bodies of patients dying with Multiple System atrophy (MSA). These three disorders constitute the majority of patients with an 'alpha synucleinopathy', although there are a number of rarer conditions that can also cause this pathology including inherited metabolic disorders such as Gaucher's Disease (GD). In this review we will concentrate on PD, the commonest alpha synucleinopathy, and its associated dementia (PDD),, as well as discussing DLB and MSA and will highlight how the clinical features of these conditions vary as a function of pathology.