Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data

This is a very interesting story and unveils another genetic risk factor for PD... these patients tend to have younger-onset PD, with prominent neuro-psychiatric features in some. The patient I have been involved with has had a pretty tough time, with multiple attempts at commencing advanced therapy, all of which have run into problems. It is important to suspect this in young patients with features of the 22q.11 deletion syndrome (aka Di George syndrome, aka CATCH-22, aka velocardiofacial syndrome). These include characteristic facial features (including cleft palate and ear pits), immune dysfunction, endrocrine dysfunction and cardiac abnormalities...

Lancet Neurol. 2016 Mar 23. pii: S1474-4422(16)00071-5. doi: 10.1016/S1474-4422(16)00071-5. [Epub ahead of print]

Mok KY, Sheerin U, Simón-Sánchez J, Salaka A, Chester L, Escott-Price V, Mantripragada K, Doherty KM, Noyce AJ, Mencacci NE, Lubbe SJ; International Parkinson's Disease Genomics Consortium (IPDGC), Williams-Gray CH, Barker RA, van Dijk KD, Berendse HW, Heutink P, Corvol JC, Cormier F, Lesage S, Brice A, Brockmann K, Schulte C, Gasser T, Foltynie T, Limousin P, Morrison KE, Clarke CE, Sawcer S, Warner TT, Lees AJ, Morris HR, Nalls MA, Singleton AB, Hardy J, Abramov AY, Plagnol V, Williams NM, Wood NW.

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)00071-5/fulltext

BACKGROUND:

Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2.

METHODS:

We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients.

FINDINGS:

We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005).

INTERPRETATION:

Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both.

FUNDING:

UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

Copyright © 2016 Mok et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms

There is fascinating momentum in this area right now... let's hope it leads to some breakthroughs in our understanding about Parkinson's disease...

Parkinsonism Relat Disord. 2016 Mar 16. pii: S1353-8020(16)30066-9. doi: 10.1016/j.parkreldis.2016.03.012. [Epub ahead of print]

Felice VD, Quigley EM, Sullivan AM, O'Keeffe GW, O'Mahony SM.

Parkinson's disease is the second most common neurodegenerative disorder, affecting 1-2% of the population over 65 years of age. The primary neuropathology is the loss of midbrain dopaminergic neurons, resulting in characteristic motor deficits, upon which the clinical diagnosis is based. However, a number of significant non-motor symptoms (NMS) are also evident that appear to have a greater impact on the quality of life of these patients. In recent years, it has become increasingly apparent that neurobiological processes can be modified by the bi-directional communication that occurs along the brain-gut axis. The microbiota plays a key role in this communication throughout different routes in both physiological and pathological conditions. Thus, there has been an increasing interest in investigating how microbiota changes within the gastrointestinal tract may be implicated in health and disease including PD. Interestingly α-synuclein-aggregates, the cardinal neuropathological feature in PD, are present in both the submucosal and myenteric plexuses of the enteric nervous system, prior to their appearance in the brain, indicating a possible gut to brain route of "prion-like" spread. In this review we highlight the potential importance of gut to brain signalling in PD with particular focus on the role of the microbiota as major player in this communication.

Abnormal Salivary Total and Oligomeric Alpha-Synuclein in Parkinson’s Disease

Saliva is a promising fluid for biomarker discovery in PD and alpha-synuclein an obvious choice in terms of potential markers to investigate, because (1) we know it is a protein involved in the disease process, (2) we know synuclein inclusions occur in the salivary glands and (3) because it has shown potential as a biomarker in other fluids such as CSF.

It is really interesting that this group have chosen to look separately at a-syn monomers and oligomers (and not just total a-syn). Their finding of an increase in a-syn oligomers but a decrease in total a-syn reflects similar findings (an increase in oligomers but decrease in total a-syn) in CSF.

Personally, I also wonder whether their assays for a-synuclein might not be particularly accurate - I had difficulty detecting a-synuclein in saliva myself! They measure concentrations of oligomeric a-syn which are orders of magnitude higher than the total a-syn (which doesn't make sense) and also orders of magnitude different from the values for salivary a-syn reported in other studies.

PLoS One. 2016 Mar 24;11(3):e0151156. doi: 10.1371/journal.pone.0151156. eCollection 2016.

Giorgio Vivacqua , Anna Latorre , Antonio Suppa , Michela Nardi , Sara Pietracupa , Romina Mancinelli , Giovanni Fabbrini , Carlo Colosimo , Eugenio Gaudio , Alfredo Berardelli

DOI: 10.1371/journal.pone.0151156

ABSTRACT:

In Parkinson’s disease (PD), alpha-synuclein (a-syn) can be detected in biological fluids including saliva. Although previous studies found reduced a-syn total (a-syntotal) concentration in saliva of PD patients, no studies have previously examined salivary a-syn oligomers (a-synolig) concentrations or assessed the correlation between salivary a-syntotal, a-synolig and clinical features in a large cohort of PD patients. Is well known that a-synolig exerts a crucial neurotoxic effect in PD. We collected salivary samples from 60 PD patients and 40 age- and sex-comparable healthy subjects. PD was diagnosed according to the United Kingdom Brain Bank Criteria. Samples of saliva were analyzed by specific anti-a-syn and anti-oligomeric a-syn ELISA kits. A complete clinical evaluation of each patient was performed using MDS-Unified Parkinson's Disease Rating Scale, Beck Depression Inventory, Montreal Cognitive Assessment and Frontal Assessment Battery. Salivary a-syntotal was lower, whereas a-synolig was higher in PD patients than healthy subjects. The a-synolig/a-syntotal ratio was also higher in patients than in healthy subjects. Salivary a-syntotal concentration negatively correlated with that of a-synolig and correlated with several patients’ clinical features. In PD, decreased salivary concentration of a-syntotal may reflect the reduction of a-syn monomers (a-synmon), as well as the formation of insoluble intracellular inclusions and soluble oligomers. The combined detection of a-syntotal and a-synolig in the saliva might help the early diagnosis of PD.

Serum immune markers and disease progression in an incident Parkinson's disease cohort (ICICLE-PD).

This study demonstrates an inflammatory 'signature' present in the blood of patients with PD. Particularly interesting is that some of the immune-related biomarkers identified here might be able to predict slower progression of PD.

Mov Disord. 2016 Mar 21. doi: 10.1002/mds.26563. [Epub ahead of print]

Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, Cummins GA, Duncan GW, Khoo TK, Burn DJ, Barker RA; ICICLE-PD study group.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26563 

BACKGROUND:

The immune system is a promising therapeutic target for disease modification in Parkinson's disease (PD), but appropriate immune-related biomarkers must be identified to allow patient stratification for trials and tracking of therapeutic effects. The objective of this study was to investigate whether immune markers in peripheral blood are candidate prognostic biomarkers through determining their relationship with disease progression in PD.

METHODS:

Serum samples were collected in incident PD cases and age-matched controls. Subjects were clinically evaluated at baseline and 18 and 36 months. Ten cytokines and C-reactive protein were measured, with data reduction using principal-component analysis, and relationships between component scores and motor (MDS Unified Parkinson's Disease Rating Scale - part 3) and cognitive (Mini Mental State Examination [MMSE]) measures of disease severity/progression were investigated.

RESULTS:

TNF-α, IL1-β, IL-2, and IL-10 were higher in PD (n = 230) than in controls (n = 93), P ≤ 0.001). Principal-component analysis of log-transformed data resulted in a 3-component solution explaining 51% of the variance. Higher "proinflammatory" and lower "anti-inflammatory" component scores were associated with more rapid motor progression over 36 months (P < 0.05), and higher "proinflammatory" component scores were associated with lower MMSE at all times (P < 0.05). Multiple linear regression analysis with adjustment for covariates confirmed "anti-inflammatory" component score was the strongest predictor of slower motor progression (β = -0.22, P = 0.002), whereas proinflammatory cytokines were associated with lower baseline MMSE (β = -0.175, P = 0.007).

CONCLUSIONS:

Serum immune marker profile is predictive of disease progression in PD and hence a potential prognostic biomarker. However, interventional trials are needed to clarify whether peripheral immune changes causally contribute to the progression of PD.

Variation in Recent Onset Parkinson's Disease: Implications for Prodromal Detection

Most of these frequencies in this early clinical cohort soon after diagnosis... as seen elsewhere the RBDSQ tends to overestimate presence of true RBD (it lack specificity) and hyposmia is not present in all. The frequency of constipation appears low to me and the screening tool (bowel motions) per day is inadequate on its own to truly detect constipation...This is a really important study (the Tracking Parkinson's Study) and it is great to see results starting to emerge...

J Parkinsons Dis. 2016 Mar 19. [Epub ahead of print]

Swallow DM, Lawton MA, Grosset KA, Malek N, Smith CR, Bajaj NP, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams N, Wood NW, Grosset DG; PRoBaND Clinical Consortium.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150741

BACKGROUND:

The detection of prodromal Parkinson's disease (PD) is desirable to test drugs with neuroprotective potential, but will be affected by known disease variations.

OBJECTIVE:

To assess the prevalence of four key non-motor prodromal PD markers, and evaluate the sensitivity of case detection when non-motor screening tools for prodromal PD are implemented in an early clinical PD cohort.

METHODS:

Hyposmia (University of Pennsylvania smell identification test ≤15th centile or Sniffin' Sticks at or ≤10th centile corrected for age and sex), rapid-eye movement sleep behaviour disorder (RBD questionnaire >4), constipation (<1 daily spontaneous bowel motion) and depression (Leeds >6) were recorded in recent onset PD cases, and proposed non-motor screening criteria applied.

RESULTS:

In 1,719 PD cases, mean age 68.6 years (SD 8.1), 65.5% male, mean disease duration 1.3 years (SD 0.9), 72.2% were hyposmic, 43.3% had RBD, 22.1% depression, and 21.5% constipation. 11.6% of cases had no key non-motor features, 38.8% one, 32.1% two, 15.5% three, and 2.0% all four. Increasing numbers of non-motor features were associated with younger age (p = 0.019), higher motor scores (p <  0.001), more postural instability gait difficulty (PIGD) (p <  0.001), greater cognitive impairment (p <  0.001) and higher total non-motor burden (p <  0.001). Cases with hyposmia alone were younger (p <  0.001), had less severe cognitive (p = 0.006) and other non-motor features (p <  0.001). All screening criteria selected younger patients (p = 0.001, p <  0.001), three of four greater overall non-motor burden (p = 0.005, p <  0.001), and inclusion of RBD more cognitive impairment (p = 0.003, p = 0.001) and PIGD (p = 0.004, p = 0.001).

CONCLUSIONS:

Varying sensitivity levels, and age and phenotype selectivity, are found when different non-motor screening methods to detect prodromal PD are applied to an early clinical PD cohort.

KEYWORDS:

Parkinson disease; anosmia; constipation; depression; rapid eye movement sleep behavior disorder

A Viewpoint on Wearable Technology-Enabled Measurement of Wellbeing and Health-Related Quality of Life in Parkinson's Disease

More on wearable tech for PD...

J Parkinsons Dis. 2016 Mar 10. [Epub ahead of print]

van Uem J, Isaacs T, Lewin A, Bresolin E, Salkovic D, Espay AJ, Matthews H, Maetzler W.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150740

Abstract

In this viewpoint, we discuss how several aspects of Parkinson's disease (PD) - known to be correlated with wellbeing and health-related quality of life-could be measured using wearable devices ('wearables'). Moreover, three people with PD (PwP) having exhaustive experience with using such devices write about their personal understanding of wellbeing and health-related quality of life, building a bridge between the true needs defined by PwP and the available methods of data collection. Rapidly evolving new technologies develop wearables that probe function and behaviour in domestic environments of people with chronic conditions such as PD and have the potential to serve their needs. Gathered data can serve to inform patient-driven management changes, enabling greater control by PwP and enhancing likelihood of improvements in wellbeing and health-related quality of life. Data can also be used to quantify wellbeing and health-related quality of life. Additionally these techniques can uncover novel more sensitive and more ecologically valid disease-related endpoints. Active involvement of PwP in data collection and interpretation stands to provide personally and clinically meaningful endpoints and milestones to inform advances in research and relevance of translational efforts in PD.

Challenges of modifying disease progression in prediagnostic Parkinson's disease

Delighted to see this one published now... encourage you to have a read...

Lancet Neurol. 2016 Mar 15. pii: S1474-4422(16)00060-0. doi: 10.1016/S1474-4422(16)00060-0. [Epub ahead of print]

Salat D, Noyce AJ, Schrag A, Tolosa E.

http://www.sciencedirect.com/science/article/pii/S1474442216000600

Neurodegeneration in Parkinson's disease starts years before a clinical diagnosis can be reliably made. The prediagnostic phase of the disease offers a window of opportunity in which disease-modifying therapies-ie, those aimed at delaying or preventing the progression to overt disease and its many complications-could be most beneficial, but no such therapies are available at present. The unravelling of the mechanisms of neurodegeneration from the earliest stages, however, could lead to the development of new interventions whose therapeutic potential will need to be assessed in adequately designed clinical trials. Advances in the understanding of this prediagnostic phase of Parkinson's disease (for which the clinical diagnostic and prognostic markers used in more advanced disease stages are not applicable) will lead to the identification of biomarkers of neurodegeneration and its progression. These biomarkers will, in turn, help to identify the optimum population to be included and the most appropriate outcomes to be assessed in trials of disease-modifying drugs. Potential risks to minimally symptomatic participants, some of whom might not progress to manifest Parkinson's disease, and individuals who do not wish to know their mutation carrier status, could pose specific ethical dilemmas in the design of these trials.

Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions

New review article on RBD... this is an important model for prodromal PD particularly when it comes to considering therapeutics... but it is non-specific!! 

Lancet Neurol. 2016 Apr;15(4):405-19. doi: 10.1016/S1474-4422(16)00057-0.

Iranzo A, Santamaria J, Tolosa E.

http://www.sciencedirect.com/science/article/pii/S1474442216000570

Abstract

Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) manifests as unpleasant dreams and vigorous behaviours during REM sleep that can result in injuries. Patients with IRBD have no known neurological diseases or motor or cognitive complaints; however, this sleep disorder is not harmless. In most cases, IRBD is the prelude of the synucleinopathies Parkinson's disease, dementia with Lewy bodies, or, less frequently, multiple system atrophy. Patients can show abnormalities that are characteristic of the synucleinopathies, and longitudinal follow-up shows that most patients develop parkinsonism and cognitive impairments with time. Thus, diagnosis of IRBD needs to be accurate and involves informing the patient of the risk of developing a neurodegenerative disease. It is extraordinary for a sleep disorder to precede the full expression of a neurodegenerative disease, which renders IRBD of particular interest in studies of the prodromal stage of the synucleinopathies, and in the development of neuroprotective interventions to stop or slow neurodegenerative deterioration before motor and cognitive symptomatology emerges. Such therapeutics do not currently exist, and thus represent an unmet need in IRBD.

A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease

Systematic review of tech for PD... an ever more congested field... lots currently lacking replication and detailed validation...

J Neuroeng Rehabil. 2016 Mar 12;13(1):24.

Godinho C, Domingos J, Cunha G, Santos AT, Fernandes RM, Abreu D, Gonçalves N, Matthews H, Isaacs T, Duffen J, Al-Jawad A, Larsen F, Serrano A, Weber P, Thoms A, Sollinger S, Graessner H, Maetzler W, Ferreira JJ.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788909/

BACKGROUND:

There is growing interest in having objective assessment of health-related outcomes using technology-based devices that provide unbiased measurements which can be used in clinical practice and scientific research. Many studies have investigated the clinical manifestations of Parkinson's disease using such devices. However, clinimetric properties and clinical validation vary among the different devices.

METHODS:

Given such heterogeneity, we sought to perform a systematic review in order to (i) list, (ii) compare and (iii) classify technological-based devices used to measure motor function in individuals with Parkinson's disease into three groups, namely wearable, non-wearable and hybrid devices. A systematic literature search of the PubMed database resulted in the inclusion of 168 studies. These studies were grouped based on the type of device used. For each device we reviewed availability, use, reliability, validity, and sensitivity to change. The devices were then classified as (i) 'recommended', (ii) 'suggested' or (iii) 'listed' based on the following criteria: (1) used in the assessment of Parkinson's disease (yes/no), (2) used in published studies by people other than the developers (yes/no), and (3) successful clinimetric testing (yes/no).

RESULTS:

Seventy-three devices were identified, 22 were wearable, 38 were non-wearable, and 13 were hybrid devices. In accordance with our classification method, 9 devices were 'recommended', 34 devices were 'suggested', and 30 devices were classified as 'listed'. Within the wearable devices group, the Mobility Lab sensors from Ambulatory Parkinson's Disease Monitoring (APDM), Physilog®, StepWatch 3, TriTrac RT3 Triaxial accelerometer, McRoberts DynaPort, and Axivity (AX3) were classified as 'recommended'. Within the non-wearable devices group, the Nintendo Wii Balance Board and GAITRite® gait analysis system were classified as 'recommended'. Within the hybrid devices group only the Kinesia® system was classified as 'recommended'.

Age, Gender, Comorbidity, and the MDS-UPDRS: Results from a Population-Based Study

Interesting work on mild parkinsonian signs... action and postural tremor, and non-specific changes in gait can elevate scores... important to determine which domains indicate sub-clinical PD.

Neuroepidemiology. 2016 Mar 12;46(3):222-227. [Epub ahead of print]

Keezer MR, Wolfson C, Postuma RB.

BACKGROUND:

Understanding sources of variation in International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores is essential for planning clinical trials in Parkinson's disease and interpreting studies of mild parkinsonian signs.

METHODS:

We describe the characteristics of the MDS-UPDRS in a population-based sample of individuals without parkinsonism. Multiple linear regression and Spearman's rank correlation coefficients were used to examine potential associations.

RESULTS:

Among 194 consecutive individuals without parkinsonism, the mean total MDS-UPDRS score was 12.5 (SD 9.8). Sixty-nine percent (134/193) had motor examination (Part III) scores of 2 or more, 16% (30/194) had scores of 10 or more. Female sex, arthritis or spondylosis, diabetes mellitus, and essential tremor were found to be associated with statistically significant increases in MDS-UPDRS Part III scores. For every 10-year increase in age, the Part III score was greater on average by 2.2 (1.5-2.8).

CONCLUSIONS:

Elevated MDS-UPDRS scores are common in the general population. The overall burden of motor signs of parkinsonism is especially high in older age groups, in women, and in those with particular comorbidities. Whether this represents evidence of a subclinical neurodegenerative process or the effect of comorbid conditions requires further examination.

Chronic constipation and co-morbidities: A prospective population-based nested case-control study

Another observational study reporting an association between constipation and PD... although the methods here looks largely cross-sectional looking at prevalent constipation. If so I am unsurprised by the results... we know patients with PD suffer from constipation. What has been interesting in recent years is the clear association of PD with preceding constipation... sometimes by as much as 10-20 years. We systematically reviewed and meta-analysed these studies last year...http://jnnp.bmj.com/content/early/2015/09/07/jnnp-2015-311680.full

United European Gastroenterol J. 2016 Feb;4(1):142-51. doi: 10.1177/2050640614558476. Epub 2015 Nov 11.

Choung RS, Rey E, Richard Locke G 3rd, Schleck CD, Baum C, Zinsmeister AR, Talley NJ.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766536/

BACKGROUND:

Chronic constipation (CC) is common in the community but surprisingly little is known about relevant gastro-intestinal (GI) and non-GI co-morbidities.

OBJECTIVE:

The purpose of this study was to assess the epidemiology of CC and in particular provide new insights into the co-morbidities linked to this condition.

METHODS:

In a prospective, population-based nested case-control study, a cohort of randomly selected community residents (n = 8006) were mailed a validated self-report gastrointestinal symptom questionnaire. CC was defined according to Rome III criteria. Medical records of each case and control were abstracted to identify potential CC comorbidities.

RESULTS:

Altogether 3831 (48%) subjects returned questionnaires; 307 met criteria for CC. Age-adjusted prevalence in females was 8.7 (95% confidence interval (CI) 7.1-10.3) and 5.1 (3.6-6.7) in males, per 100 persons. CC was not associated with most GI pathology, but the odds for constipation were increased in subjects with anal surgery relative to those without (odds ratio (OR) = 3.3, 95% CI 1.2-9.1). In those with constipation vs those without, neurological diseases including Parkinson's disease (OR = 6.5, 95% CI 2.9-14.4) and multiple sclerosis (OR = 5.5, 95% CI 1.9-15.8) showed significantly increased odds for chronic constipation, adjusting for age and gender. In addition, modestly increased odds for chronic constipation in those with angina (OR = 1.4, 95% CI 1.1-1.9) and myocardial infarction (OR = 1.5, 95% CI 1.0-2.4) were observed.

CONCLUSIONS:

Neurological and cardiovascular diseases are linked to constipation but in the community constipation is unlikely to account for most lower GI pathology.