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.

http://content.iospress.com/articles/journal-of-parkinsons-disease/jpd150708

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.

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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817438/

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.

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.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151841

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.

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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791329/

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.

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.

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)00080-6/abstract

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.

A short interview I did on PREDICT-PD at end of last year

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.

http://link.springer.com/article/10.1007%2Fs00401-016-1552-2

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.

Loss of Dorsolateral Nigral Hyperintensity on 3.0 Tesla Susceptibility-Weighted Imaging in Idiopathic Rapid Eye Movement Sleep Behavior Disorder

Very interesting... I feel strongly that MRI will give us appropriate markers for PD and related disorders with time...

Ann Neurol. 2016 Mar 26. doi: 10.1002/ana.24646. [Epub ahead of print]

De Marzi R, Seppi K, Högl B, Müller C, Scherfler C, Stefani A, Iranzo A, Tolosa E, Santamarìa J, Gizewski E, Schocke M, Skalla E, Kremser C, Poewe W.

http://onlinelibrary.wiley.com/doi/10.1002/ana.24646/abstract

We assessed loss of dorsolateral nigral hyperintensity (DNH) on high-field susceptibility-weighted imaging (SWI), a novel MRI marker for Parkinson's Disease (PD), in 15 subjects with idiopathic REM sleep behavior disorder (iRBD) and compared findings to 42 healthy controls (HC) and 104 PD patients. We found loss of DNH in at least two thirds of iRBD subjects, which approaches the rate seen in PD and is in contrast to findings in HC. We propose that absence of DNH on high-field SWI could identify prodromal degenerative parkinsonism in iRBD.

Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder

This is a good use of PPMI and fits with what one would expect clinically...these patients do tend to be at the more severe end of the spectrum and so it is little surprise that the cognitive features are more prominent...

Parkinsonism Relat Disord. 2016 Mar 12. pii: S1353-8020(16)30060-8. doi: 10.1016/j.parkreldis.2016.03.006. [Epub ahead of print]

Chahine LM, Xie SX, Simuni T, Tran B, Postuma R, Amara A, Oertel WH, Iranzo A, Scordia C, Fullard M, Linder C, Purri R, Darin A, Rennert L, Videnovic A, Del Riva P, Weintraub D.

http://www.sciencedirect.com/science/article/pii/S1353802016300608

INTRODUCTION:

Cognitive decline is common in Parkinson's disease (PD), and identifying patients at highest risk for it is essential. We aimed to examine the effect of possible REM sleep behavior disorder (pRBD) on rate of cognitive decline in early PD, for both global cognition and in specific cognitive domains.

METHODS:

Parkinson's Progression Markers Initiative (PPMI) is a multi-site, international study of PD patients untreated at enrollment. pRBD was assessed with the REM sleep behavior disorder questionnaire (RBDSQ). Global cognition was assessed at baseline and annually using the Montreal Cognitive Assessment (MoCA) and a cognitive battery. Linear mixed effects models were used to examine the relationship between pRBD (RBDSQ≥6) and rate of change in cognitive variables. Age, sex, years of education, and baseline motor and cognitive scores were included as covariates.

RESULTS:

The baseline sample consisted of 423 individuals with PD, mean age 61.7 years and 65.5% male. Data was available on 389, 366, and 196 participants at 1-year, 2-year, and 3-year follow-up respectively. Possible RBD occurred in 108 (25.5%) at baseline. In multivariate analyses, baseline RBD was associated with greater annual rate of decline in MoCA score (β = -0.34, 95%CI -0.54, -0.13, p < 0.001), Symbol Digit Modalities Test (β = -0.69, 95%CI -1.3, -0.09, p = 0.024), and Hopkins Verbal Learning Test-Revised, delayed free recall (β = -0.21, 95%CI -0.41, -0.013, p = 0.037).

CONCLUSIONS:

Possible RBD is common in early PD and predicts future cognitive decline, particularly in attention and memory domains.

Pathological alpha-synuclein in gastrointestinal tissues from prodromal parkinson's disease patients

Important result this... I haven't seen the paper in full yet but conformation of staining in the past appeared just as important as whether there is any staining or not... previous studies have found a high proportion of controls also stain positive. Particularly interesting here is that a significant proportion of patients had alpha synuclein prior to diagnosis!!

Ann Neurol. 2016 Mar 26. doi: 10.1002/ana.24648. [Epub ahead of print]

Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P.

http://onlinelibrary.wiley.com/doi/10.1002/ana.24648/abstract

OBJECTIVE:

It has been hypothesized that Lewy pathology initiates in the enteric nervous system years prior to debut of clinical motor symptoms in Parkinson's disease patients. This study investigates whether Lewy pathology is present in various gastrointestinal tract tissues from Parkinson's disease patients in the prodromal phase.

METHODS:

We used the Danish National Pathology Registry, to identify archived paraffin embedded tissue blocks from 57 Parkinson's disease patients (98 blocks) and 90 control subjects (98 blocks). We employed two different immunohistochemistry techniques visualizing aggregated α -synuclein and phosphorylated α -synuclein.

RESULTS:

Thirty-nine Parkinson's disease patients contributed tissues obtained in the prodromal disease phase, whilst 18 Parkinson's disease patients contributed tissues obtained solely after Parkinson's diagnosis. Prodromal tissues were obtained on average 7.0 years prior to diagnosis (range: 20 years - 4 months), and post-diagnosis tissue on average 2.8 years after diagnosis (range: 2 days - 18 years). Phosphorylated- α -synuclein positivity was seen in 22/39 (56%) prodromal Parkinson's disease subjects and 30/67 (45%) prodromal tissue blocks. These fractions were significantly higher compared to control subjects (p=0.0001 and p=0.0032, respectively). In contrast, no significant difference was seen in the positivity rate between prodromal Parkinson's disease patients and controls when using the aggregated α -synuclein immunohistochemistry technique.

INTERPRETATION:

We detected Lewy pathology in the gastrointestinal tract of patients up to 20 years prior to their Parkinson's disease diagnosis. These findings are in accordance with a hypothesized prodromal disease phase spanning 10-20 years.