Sunday, 24 April 2016

The Incidence of Parkinson's Disease: A Systematic Review and Meta-Analysis

Results from meta-analysis confirming age-related increase in PD incidence but also supporting the notion of a 'levelling-off' after the age of 80 years. Gender differences also observed consistent with what we know...

Neuroepidemiology. 2016 Apr 23;46(4):292-300. [Epub ahead of print]
Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T.


BACKGROUND:
Parkinson's disease (PD) is a common neurodegenerative disorder. Epidemiological studies on the incidence of PD are important to better understand the risk factors for PD and determine the condition's natural history.

OBJECTIVE:
This systematic review and meta-analysis examine the incidence of PD and its variation by age and gender.

METHODS:
We searched MEDLINE and EMBASE for epidemiologic studies of PD from 2001 to 2014, as a previously published systematic review included studies published until 2001. Data were analyzed separately for age group and gender, and meta-regression was used to determine whether a significant difference was present between groups.

RESULTS:
Twenty-seven studies were included in the analysis. Meta-analysis of international studies showed rising incidence with age in both men and women. Significant heterogeneity was observed in the 80+ group, which may be explained by methodological differences between studies. While males had a higher incidence of PD in all age groups, this difference was only statistically significant for those in the age range 60-69 and 70-79 (p < 0.05).

CONCLUSION:

PD incidence generally increases with age, although it may stabilize in those who are 80+.

Wednesday, 20 April 2016

DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology

First neuropathological description of DJ-1 and I was not expecting this result... I guess Lewy body pathology has been described in younger onset parkin cases too so hopefully further study of DJ-1 brains will be informative...

Brain. 2016 Apr 16. pii: aww080. [Epub ahead of print]
Taipa R, Pereira C, Reis I, Alonso I, Bastos-Lima A, Melo-Pires M, Magalhães M.



Mutations in DJ-1 (encoded byPARK7) are a very rare cause of early-onset recessive Parkinson's disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in thePARK7gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levelsin vitroshowing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinson's disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions.

Tuesday, 19 April 2016

Association between REM sleep behaviour disorder and impulse control disorder in patients with Parkinson's disease

Interesting result here... although perhaps unsurprising given that both occur (to a greater extent) in more severe PD... important to note that dopamine agonists cause other sleep-related side effects that may be mis-reported as RBD especially in self-report brief screening tests. Previous groups have actually reported benefit from dopamine agonists in those with RBD... I guess in light of these data such approaches might need a rethink...

Neurologia. 2016 Apr 14. pii: S0213-4853(16)00117-1. doi: 10.1016/j.nrl.2016.02.008. [Epub ahead of print]
Bellosta Diago E, Lopez Del Val LJ, Santos Lasaosa S, López Garcia E, Viloria Alebesque A.

INTRODUCTION:
The relationship between impulse control disorder (ICD) and REM sleep behaviour disorder (RBD) has not yet been clarified, and the literature reports contradictory results. Our purpose is to analyse the association between these 2 disorders and their presence in patients under dopaminergic treatment.

METHODS:
A total of 73 patients diagnosed with Parkinson's disease and treated with a single dopamine agonist were included in the study after undergoing clinical assessment and completing the single-question screen for REM sleep behaviour disorder and the short version of the questionnaire for impulsive-compulsive behaviours in Parkinson's disease.

RESULTS:
Mean age was 68.88 ± 7.758 years. Twenty-six patients (35.6%) were classified as probable-RBD. This group showed a significant association with ICD (P=.001) and had a higher prevalence of non-tremor akinetic rigid syndrome and longer duration of treatment with levodopa and dopamine agonists than the group without probable-RBD. We found a significant correlation between the use of oral dopamine agonists and ICD. Likewise, patients treated with oral dopamine agonists demonstrated a greater tendency toward presenting probable-RBD than patients taking dopamine agonists by other routes; the difference was non-significant.

CONCLUSIONS:

The present study confirms the association between RBD and a higher risk of developing symptoms of ICD in Parkinson's disease.

Thursday, 14 April 2016

APOE, MAPT, and COMT and Parkinson's Disease Susceptibility and Cognitive Symptom Progression

Gene variants that predict cognitive decline in PD. It is said that much of the heterogeneity that underlies PD is genetically determined. We are finding out more about this all the time. It may be useful in due course to test for certain variants to allow better prognostication, and hopefully one day, tailored treatment...

J Parkinsons Dis. 2016 Apr 2. [Epub ahead of print]
Paul KC, Rausch R, Creek MM, Sinsheimer JS, Bronstein JM, Bordelon Y, Ritz B.


BACKGROUND:
Cognitive decline is well recognized in Parkinson's disease (PD) and a major concern for patients and caregivers. Apolipoprotein E (APOE), catechol-O-methyl transferase (COMT), and microtubule-associated protein tau (MAPT) are of interest related to their contributions to cognitive decline or dementia in PD.

OBJECTIVE:
Here, we investigate whether APOE, COMT, or MAPT influence the rate of cognitive decline in PD patients.

METHODS:
We relied on 634 PD patients and 879 controls to examine gene-PD susceptibility associations, and nested longitudinal cohort of 246 patients from the case-control study, which followed patients on average 5 years and 7.5 years into disease. We repeatedly assessed cognitive symptom progression with the MMSE and conducted a full neuropsychological battery on a subset of 183 cognitively normal patients. We used repeated-measures regression analyses to assess longitudinal associations between genotypes and cognitive progression scores.

RESULTS:
The MAPT H1 haplotype was associated with PD susceptibility. APOE 4 carriers (ɛ4+) (p = 0.03) and possibly COMT Met/Met (p = 0.06) carriers exhibited faster annual decline on the MMSE. Additionally, APOEɛ4+ carriers showed faster decline in many of the neuropsychological test scores. No such differences in neuropsychological outcomes were seen for the COMT genotypes.

CONCLUSION:
This work supports a growing set of research identifying overlapping etiology and pathology between synucleinopathies, such as PD, Alzheimer's disease, and tauopathies, especially in the context of cognitive dysfunction in PD. We provide support for the argument that APOE ɛ4+ and COMT Met/Met genotypes can be used as predictors of faster cognitive decline in PD.

KEYWORDS:

APOE; COMT; MAPT; Parkinson’s disease; cognition; cognitive decline

Wednesday, 13 April 2016

Validation of a Smartphone Application Measuring Motor Function in Parkinson's Disease

Another smart phone app to measure motor dysfunction from a good group... the correlations and repeatability they report is impressive...

J Parkinsons Dis. 2016 Apr 2. [Epub ahead of print]
Lee W, Evans A, Williams DR.


BACKGROUND:
Measurement of motor function is critical to the assessment and management of Parkinson's disease. Ambulatory motor assessment has the potential to provide a glimpse of the patient's clinical state beyond the consultation. We custom-designed a smartphone application that quantitatively measures hand dexterity and hypothesized that this can give an indication of a patient's overall motor function.

OBJECTIVE:
The aims of this study were to (i) validate this smartphone application against MDS-UPDRS motor assessment (MDS-UPDRS-III) and the two-target tapping test; (ii) generate a prediction model for MDS-UPDRS-III; (iii) assess repeatability of our smartphone application and (iv) examine compliance and user-satisfaction of this application.

METHODS:
103 patients with Parkinson's disease were recruited from two movement disorders clinics. After initial assessment, a group of patients underwent repeat assessment within two weeks. Patients were invited to use the smartphone application at home over three days, followed by a survey to assess their experience.

RESULTS:
Significant correlation between key smartphone application test parameters and MDS-UPDRS-III (r = 0.281-0.608, p <  0.0001) was demonstrated. A prediction model based on these parameters accounted for 52.3% of variation in MDS-UPDRS-III (R2 = 0.523, F(4,93) = 25.48, p <  0.0001). Forty-eight patients underwent repeat assessment under identical clinical conditions. Repeatability of key smartphone application tests parameters and predicted MDS-UPDRS-III was moderate to strong (intraclass correlation coefficient 0.584-0.763, p <  0.0001). The follow-up survey identified that our patients were very comfortable with the smartphone application and mobile technology.

CONCLUSIONS:

Our smartphone application demonstrated satisfactory repeatability and validity when measured against MDS-UPDRS-III. Its performance is acceptable considering our smartphone application measures hand dexterity only.

Tuesday, 12 April 2016

Risk of Parkinson's Disease Among Patients with Psoriasis: A Systematic Review and Meta-analysis

Limited information available on this topic... an important potential area for misclassification is if seborrheic dermatitis was misdiagnosed as psoriasis in any of the included studies...

Indian J Dermatol. 2016 Mar-Apr;61(2):152-6. doi: 10.4103/0019-5154.177771.
Ungprasert P, Srivali N, Kittanamongkolchai W.


BACKGROUND:
Patients with psoriasis might be at a higher risk of developing Parkinson's disease (PD) as a result of the detrimental effect of chronic inflammation on the neuronal tissue. This meta-analysis aimed to investigate this risk by comprehensively reviewing all available data.

METHODS:
We conducted a systematic review and meta-analysis of cohort and case-control studies that reported relative risk, hazard ratio, odds ratio, or standardized incidence ratio comparing the risk of PD in patients with psoriasis versus subjects without psoriasis. Pooled risk ratio and 95% confidence interval (CI) were calculated using random-effect, generic inverse variance methods of DerSimonian and Laird.

RESULTS:
Three retrospective studies and one case-control study met our eligibility criteria and were included in this meta-analysis. The pooled risk ratio of PD in patients with psoriasis versus participants without psoriasis was 1.38 (95% CI, 1.15-1.66). The statistical heterogeneity was low with an I (2) of 35%.

CONCLUSIONS:

Our meta-analysis demonstrated a statistically significant increased risk of PD among patients with psoriasis.

Monday, 11 April 2016

Association between Parkinson's Disease and Cigarette Smoking, Rural Living, Well-Water Consumption, Farming and Pesticide Use: Systematic Review and Meta-Analysis

Systematic review and meta-analysis of risk of environmental exposures and Parkinson's disease... with reference to the Bradford Hill criteria for determining causal relationships...

PLoS One. 2016 Apr 7;11(4):e0151841. doi: 10.1371/journal.pone.0151841.
Breckenridge CB, Berry C, Chang ET, Sielken RL Jr, Mandel JS.


OBJECTIVE:
Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson's disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a "positive control" because a strong inverse association has been described consistently in the literature.

METHODS:
PubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson's disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat. Studies were categorized into two study quality groups (Tier 1 or Tier 2); data were abstracted and a forest plot of relative risks (RRs) was developed for each risk factor. In addition, when available, RRs were tabulated for more highly exposed individuals compared with the unexposed. Summary RRs for each risk factor were calculated by meta-analysis of Tier 1, Tier 2 and all studies combined, with sensitivity analyses stratified by other study characteristics. Indices of between-study heterogeneity and evidence of reporting bias were assessed. Bradford Hill's viewpoints were used to determine if a causal relationship between PD and each risk factor was supported by the weight of the evidence.

FINDINGS:
There was a consistent inverse (negative) association between current cigarette smoking and PD risk. In contrast, associations between PD and rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat were less consistent when assessed quantitatively or qualitatively.

CONCLUSION:

The weight of the evidence and meta-analysis support the conclusion that there is a causal relationship between PD risk and cigarette smoking, or some unknown factor correlated with cigarette smoking. There may be risk factors associated with rural living, farming, pesticide use or well-water consumption that are causally related to PD, but the studies to date have not identified such factors. To overcome the limitations of research in this area, future studies will have to better characterize the onset of PD and its relationship to rural living, farming and exposure to pesticides.

Friday, 8 April 2016

Objective and quantitative assessment of motor function in Parkinson's disease-from the perspective of practical applications

Lots of reviews on this topic right now... the biggest problem is knowing which devices are good and which are validated. Most devices have only been used in small numbers of patients and often with inadequate parallel clinical evaluation....

Ann Transl Med. 2016 Mar;4(5):90. doi: 10.21037/atm.2016.03.09.
Yang K, Xiong WX, Liu FT, Sun YM, Luo S, Ding ZT, Wu JJ, Wang J.



Parkinson's disease (PD) is a common neurodegenerative disorder with high morbidity because of the coming aged society. Currently, disease management and the development of new treatment strategies mainly depend on the clinical information derived from rating scales and patients' diaries, which have various limitations with regard to validity, inter-rater variability and continuous monitoring. Recently the prevalence of mobile medical equipment has made it possible to develop an objective, accurate, remote monitoring system for motor function assessment, playing an important role in disease diagnosis, home-monitoring, and severity evaluation. This review discusses the recent development in sensor technology, which may be a promising replacement of the current rating scales in the assessment of motor function of PD.

Thursday, 7 April 2016

Evaluation of alpha-synuclein immunohistochemical methods for the detection of Lewy-type synucleinopathy in gastrointestinal biopsies

It is so important that these groups are all getting together to do this work... a lot of time and money has gone into this (not surprisingly given the importance of a biomarker to PD). It is great to see a systematic, joined up approach... I keep my fingers crossed that it leads to what the field really needs.

Acta Neuropathol Commun. 2016 Apr 4;4(1):35. doi: 10.1186/s40478-016-0305-8.
Corbillé AG, Letournel F, Kordower JH, Lee J, Shanes E, Neunlist M, Munoz DG, Derkinderen P, Beach TG.


The observation showing that Lewy type synucleinopathy (LTS), the pathological hallmark of Parkinson's disease (PD), is found in the gut of almost all PD subjects led to a substantial amount of research to develop a diagnostic procedure in living patients based on endoscopically obtained gastrointestinal biopsies. However, the existing studies have provided conflicting results regarding the sensitivity and specificity of gastrointestinal biopsies for the detection of LTS. We therefore undertook a multi-center staining and blinded judging of a common set of slides from colonic biopsies to determine the optimal protocol for the detection of LTS. Four different immunohistochemical methods, developed in four separate expert laboratories, were evaluated for their sensitivity and specificity to detect enteric LTS. Test sets of formalin-fixed, paraffin-embedded sections from biopsies of 9 PD subjects and 3 controls were stained with the 4 methods and graded by 4 different observers. Four types of staining morphology (granular staining in the lamina propria, perivascular/vascular wall staining in the submucosa, lacy-granular pattern in the submucosa and epithelial cell nuclear staining) were variably observed in the slides stained by the 4 methods. Positive alpha-synuclein staining was observed by all 5 judges in most of the slides from control cases, regardless of the staining methods that were used. Moreover, none of the tested method or staining pattern had a specificity and sensitivity more than 80 % regarding to PD. Overall, our study suggest that the tested methods are not adequate for the prediction of PD using gastrointestinal biopsies. Future studies are warranted to test new immunostaining methods.

Assessment of α-synuclein in submandibular glands of patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study

Great result this one... the numbers are a little on the low side, but then again iRBD is not that common... but it is a big score for tissue biomarkers for PD...

Lancet Neurol. 2016 Mar 30. pii: S1474-4422(16)00080-6. doi: 10.1016/S1474-4422(16)00080-6. [Epub ahead of print]
Vilas D, Iranzo A, Tolosa E, Aldecoa I, Berenguer J, Vilaseca I, Martí C, Serradell M, Lomeña F, Alós L, Gaig C, Santamaria J, Gelpi E.


BACKGROUND:
The histological feature of Parkinson's disease is the presence of intraneuronal aggregates of phosphorylated α-synuclein (αSyn). In patients with Parkinson's disease, deposits of αSyn are found in the autonomic nerve fibres of the submandibular gland. Since patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) can develop Parkinson's disease and other synucleinopathies, we investigated whether αSyn deposits could also be detected in their submandibular gland nerve fibres.

METHODS:
We did a case-control study at the Hospital Clinic de Barcelona (Barcelona, Spain) in patients with polysomnographic-confirmed IRBD, patients with clinically diagnosed Parkinson's disease, and controls matched by age with the IRBD group. The controls were either healthy, had had elective neck surgery in the clinic, or were patients who had died in the clinic and had an autopsy. We did a transcutaneous core needle biopsy of the submandibular gland with ultrasound guidance in patients with IRBD or Parkinson's disease, and healthy controls, and without ultrasound guidance in the other controls. We assessed the presence of αSyn with immunohistochemistry using 129-phosphorylated antiserine monoclonal antibody, and analysed quantitative variables with Kruskall-Wallis tests and qualitative variables with Fisher's exact tests.

FINDINGS:
We did our study between July 16, 2014, and May 16, 2015, and recruited 21 patients with IRBD, 24 patients with Parkinson's disease, and 26 controls (seven healthy, 11 patients undergoing neck surgery, and eight autopsies). We obtained submandibular biopsy material containing glandular parenchyma in nine (43%) of 21 patients with IRBD, 12 (50%) of 24 patients with Parkinson's disease, and all (100%) of the 26 controls. αSyn aggregates were detected in nerve fibres of the glandular parenchyma in eight (89%) of nine patients with IRBD and eight (67%) of 12 with Parkinson's disease, but none of the controls. Of the individuals whose biopsy samples did not contain glandular parenchyma, deposits of αSyn were found in extraglandular tissues in an additional three (25%) of 12 patients with IRBD and five (42%) of 12 patients with Parkinson's disease. None of the controls showed αSyn immunoreactivity in extraglandular tissues. Of the 52 participants who had ultrasonography-guided biopsy, 11 (21%) reported mild-to-moderate local pain, and nine (17%) developed a subcutaneous haematoma; however, these adverse events were transient and did not need treatment.

INTERPRETATION:
Our findings suggest that, in patients with IRBD, submandibular gland biopsy is a safe procedure for the detection of αSyn aggregates. αSyn detection could be useful for histological confirmation in individuals clinically diagnosed with Parkinson's disease.

FUNDING:

Centre for Networked Biomedical Research in Neurodegenerative Disorders (CIBERNED), Barcelona, Spain.

Friday, 1 April 2016

CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study

Good to see some of these CSF biomarker initiatives starting to bear fruit. We desperately need markers that reflect the underlying disease and help capture the heterogeneity of PD that we see...

Acta Neuropathol. 2016 Mar 28. [Epub ahead of print]
Kang JH, Mollenhauer B, Coffey CS, Toledo JB, Weintraub D, Galasko DR, Irwin DJ, Van Deerlin V, Chen-Plotkin AS, Caspell-Garcia C, Waligórska T, Taylor P, Shah N, Pan S, Zero P, Frasier M, Marek K, Kieburtz K, Jennings D, Tanner CM, Simuni T, Singleton A, Toga AW, Chowdhury S, Trojanowski JQ, Shaw LM; Parkinson’s Progression Marker Initiative.



The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.