Journal of Parkinson's Disease - Volume 10, issue 2

Authors: Singh, Serena | Khayachi, Anouar | Milnerwood, Austen J. | DeMarco, Mari L.

Article Type: Research Article

Abstract: Introduction: Improved analytical tools for detailed characterization of synucleins in pre-clinical models of Parkinson’s disease (PD) and related synucleinopathies are needed. Objective: Develop a multiple reaction monitoring (MRM) liquid chromatography tandem mass spectrometry (LC-MS/MS) assay to quantify species-specific sequences and structural heterogeneity in soluble α - and β-synucleins in brain tissue. Methods: Using a proteolytic digestion workflow, the MRM LC-MS/MS method assayed six proteotypic peptides from the α -synuclein sequence; three unique to mouse or human α -synuclein and three conserved in α - and β-synuclein. For quantification, we used labeled α -synuclein as the internal …standard and an external calibration curve. As proof of concept, the synuclein LC-MS/MS method was applied to brain tissue specimens from M83 transgenic PD mice, which overexpresses human α -synuclein, relative to wild-type littermate controls. Results: The synuclein MRM assay was linear over a wide concentration range (at least one order of magnitude). The assay had several advantages over ligand binding analytical methods, such as western blotting and enzyme-linked immunosorbent assays. These advantages included the ability to: quantify 1) total α -synuclein, 2) combined α - and β-synucleins, 3) species-specific contributions to total α -synuclein (e.g., in mice expressing both mouse and human α -synuclein), and 4) identify peptide-specific profile differences that may reflect post-translational modifications, all within a single analysis. Conclusion: With improved and expanded analytical characteristics coupled with a streamlined sample preparation workflow, the quantitative synuclein profiling LC-MS/MS assay provides a versatile and efficient platform to characterize synuclein biology in pre-clinical models and the potential for application to human tissues and fluids. Show more

Keywords: Protein sequence, transgenic mice, mass spectrometry, tandem mass spectrometry, Parkinson’s disease, synucleins

DOI: 10.3233/JPD-191835

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 613-621, 2020

Authors: Padmanabhan, Shalini | Lanz, Thomas A. | Gorman, Donal | Wolfe, Michele | Joyce, Alison | Cabrera, Carlos | Lawrence-Henderson, Rosemary | Levers, Najah | Joshi, Neal | Ma, Thong C. | Liong, Christopher | Narayan, Sushma | Alcalay, Roy N. | Hutten, Samantha J. | Baptista, Marco A.S. | Merchant, Kalpana

Article Type: Research Article

Abstract: The phosphorylated form of LRRK2, pS935 LRRK2, has been proposed as a target modulation biomarker for LRRK2 inhibitors. The primary aim of the study was to characterize and qualify this biomarker for therapeutic trials of LRRK2 inhibitors in Parkinson’s disease (PD). To this end, analytically validated assays were used to monitor levels of pS935 LRRK2 and total LRRK2 in peripheral blood mononuclear cells (PBMCs) from the following donor groups: healthy controls, idiopathic PD, and G2019S carriers with and without PD. Neither analyte correlated with age, gender, or disease severity. While total LRRK2 levels were similar across the four groups, there …was a significant reduction in pS935 LRRK2 levels in disease-manifesting G2019S carriers compared to idiopathic PD. In aggregate, these data indicate that phosphorylation of LRRK2 at S935 may reflect a state marker for G2019S LRRK2 -driven PD, the underlying biology for which requires investigation in future studies. This study also provides critical foundational data to inform the integration of pS935 and total LRRK2 levels as biomarkers in therapeutic trials of LRRK2 kinase inhibitors. Show more

Keywords: pharmacodynamic, biomarker, Parkinson’s disease, blood cells

DOI: 10.3233/JPD-191786

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 623-629, 2020

Authors: Lord, Stephen R. | Bindels, Helen | Ketheeswaran, Mira | Brodie, Matthew A. | Lawrence, Andrew D. | Close, Jacqueline C.T. | Whone, Alan L. | Ben-Shlomo, Yoav | Henderson, Emily J.

Article Type: Research Article

Abstract: Background: Freezing of gait (FOG) is a common symptom of Parkinson’s disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework. Objective: Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG. Methods: 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and …a FOG elicitation condition. Video and accelerometry recordings were examined to document freezes and other gait disruptions. Results: Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis. Conclusion: The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation. Show more

Keywords: Parkinson’s disease, gait disorders, freezing of gait, dual task

DOI: 10.3233/JPD-191813

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 631-640, 2020

Authors: Alves, Mariana | Caldeira, Daniel | Rato, Miguel Leal | Duarte, Gonçalo S. | Ferreira, Afonso N. | Ferro, José | Ferreira, Joaquim J.

Article Type: Research Article

Abstract: Background: Parkinson’s disease and cardiovascular disease are highly prevalent conditions in the elderly. Evidence shows inconsistent findings regarding the association between Parkinson’s disease and cardiovascular events. Objective: We sought to evaluate the proportion of cardiovascular adverse events among Parkinson’s disease patients included in the placebo arm of randomized controlled trials. Methods: For this systematic review and meta-analysis, we searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to February 2017. Randomized, placebo-controlled trials in Parkinson’s disease were included. The primary outcome was the proportion of major cardiovascular adverse events, defined as myocardial …infarction, stroke, peripheral artery disease, and sudden death. A random-effects meta-analysis was performed to derive pooled estimates of the proportion of adverse events and corresponding 95% confidence intervals (CIs). Results: 236 randomized controlled trials were included, 80% (n  = 189; 14704 patients) of which reported data on cardiovascular adverse events. The pooled proportion of major cardiovascular events ranged from 0.00% to 0.06% and the proportion of all cardiovascular adverse events was 3.33% (95% CI: 2.14, 4.70%), and ranged from 1.71% in de novo Parkinson’s disease patients to 4.56% in patients receiving levodopa as their only antiparkinsonian medication. The most common adverse events were hypertension and orthostatic hypotension. Conclusions: These results suggest that the proportion of major cardiovascular adverse events is low and that blood pressure abnormalities are the most frequent cardiovascular adverse event. Show more

Keywords: Parkinson’s disease, randomized controlled trials, stroke, myocardial infarction, hypertension, orthostatic hypotension, cardiovascular diseases

DOI: 10.3233/JPD-191907

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 641-651, 2020

Authors: Kraepelien, Martin | Schibbye, Robert | Månsson, Kristoffer | Sundström, Christopher | Riggare, Sara | Andersson, Gerhard | Lindefors, Nils | Svenningsson, Per | Kaldo, Viktor

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is often associated with psychological distress and lowered daily functioning. The availability of psychological interventions tailored for people with Parkinson is very limited. Objective: To study if guided individually-tailored internet-based cognitive behavioral therapy (ICBT) provide additional value to standard medical treatment for PD. Methods: Seventy-seven individuals with PD and self-reported problems with general function measured with the Work and Social Adjustment Scale (WSAS > 15) were randomized to 10 weeks of either ICBT combined with standard medical treatment, or standard medical treatment plus being on waitlist to ICBT (CONTROL). Change in the main outcome …WSAS, as well as secondary measures such as quality of life, depression, anxiety and insomnia symptoms were investigated post treatment. Results: Participants receiving ICBT reported significantly higher functioning after treatment (WSAS group difference –4.56, controlled effect size g  = 0.69, significant group by time interaction, Wχ 2 = 26.23, p  = 0.001). However, only around one third of participants in the treatment group were classified as treatment responders, defined as having a 30% reduction on the WSAS post treatment. Patient involvement and ratings of ICBT credibility were high. Symptoms of anxiety, depression and insomnia symptoms were significantly lower after treatment compared to CONTROL. There were also positive effects on Parkinson-specific function and quality of life in the treatment group. Conclusions: ICBT as an addition to standard medical treatment was credible and improved functioning for some individuals with PD. Still, the treatment needs further development in order to help a larger proportion of individuals with PD. Trial registration number: ClinicalTrials.gov NCT02627885. Show more

Keywords: Internet, psychological treatment, cognitive-behavioral therapy, Parkinson’s disease

DOI: 10.3233/JPD-191894

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 653-664, 2020

Authors: Dobkin, Roseanne D. | Amondikar, Ninad | Kopil, Catherine | Caspell-Garcia, Chelsea | Brown, Ethan | Chahine, Lana M. | Marras, Connie | Dahodwala, Nabila | Mantri, Sneha | Standaert, David G. | Dean, Marissa | Shoulson, Ira | Marek, Kenneth | Katz, Andrea | Korell, Monica | Riley, Lindsey | Tanner, Caroline M. | on behalf of the Fox Insight Study

Article Type: Research Article

Abstract: Background: Clinical research in Parkinson’s disease (PD) faces practical and ethical challenges due to two interrelated problems: participant under-recruitment and lack of diversity. Fox Insight (FI) is a web-based longitudinal study collecting patient-reported outcomes and genetic data worldwide to inform therapeutic studies. FI’s online platform provides an opportunity to evaluate online strategies for recruiting large, diverse research cohorts. Objective: This project aimed to determine 1) whether FI’s digital marketing was associated with increased enrollment overall and from under-represented patient groups, compared to traditional recruitment methods; 2) the clinical and demographic characteristics of samples recruited online, and 3) the …cost of this online recruitment. Method: FI recruitment during a 6-week baseline period without digital promotion was compared to recruitment during several periods of digital outreach. Separate online recruiting intervals included general online study promotion and unique Facebook and Google ad campaigns targeting under-represented subgroups: early PD, late/advanced PD, and residents of underrepresented/rural geographic areas. Results: Early PD, late PD, and geotargeting campaigns enrolled more individuals in their respective cohorts compared to baseline. All online campaigns also yielded greater total FI enrollment, attracting more participants who were non-White, Hispanic, older, female, and had lower educational attainment and income, and more medical comorbidities. Cost per new participant ranged from $21 (Facebook) to $108 (Google). Conclusion: Digital marketing may allow researchers to increase, accelerate, and diversify recruitment for PD clinical studies, by tailoring digital ads to target PD cohort characteristics. Show more

Keywords: Parkinson’s disease, diversity, recruitment, clinical trial

DOI: 10.3233/JPD-191901

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 665-675, 2020

Authors: Chahine, Lana M. | Chin, Iris | Caspell-Garcia, Chelsea | Standaert, David G. | Brown, Ethan | Smolensky, Luba | Arnedo, Vanessa | Daeschler, Daisy | Riley, Lindsey | Korell, Monica | Dobkin, Roseanne | Amondikar, Ninad | Gradinscak, Stephen | Shoulson, Ira | Dean, Marissa | Kwok, Kevin | Cannon, Paul | Marek, Kenneth | Kopil, Catherine | Tanner, Caroline M. | Marras, Connie | on behalf of the Fox Insight Study

Article Type: Research Article

Abstract: Background: Online tools for data collection could be of value in patient-oriented research. The Fox Insight (FI) study collects data online from individuals with self-reported Parkinson’s disease (PD). Comparing the FI cohort to other cohorts assessed through more traditional (in-person) observational research studies would inform the representativeness and utility of FI data. Objective: To compare self-reported demographic characteristics, symptoms, medical history, and PD medication use of the FI PD cohort to other recent observational research study cohorts assessed with in-person visits. Methods: The FI PD cohort (n  = 12,654) was compared to 3 other cohorts, selected based …on data accessibility and breadth of assessments: Parkinson’s Progression Markers Initiative (PPMI; PD n  = 422), Parkinson’s Disease Biomarker Program (PDBP; n  = 700), and PD participants in the LRRK2 consortium without LRRK2 mutations (n  = 508). Demographics, motor and non-motor assessments, and medications were compared across cohorts. Where available, identical items on surveys and assessments were compared; otherwise, expert opinion was used to determine comparable definitions for a given variable. Results: The proportion of females was significantly higher in FI (45.56%) compared to PPMI (34.36%) and PDBP (35.71%). The FI cohort had greater educational attainment as compared to all other cohorts. Overall, prevalence of difficulties with motor experiences of daily living and non-motor symptoms in the FI cohort was similar to other cohorts, with only a few significant differences that were generally small in magnitude. Missing data were rare for the FI cohort, except on a few variables. Discussion: Patterns of responses to patient-reported assessments obtained online on the PD cohort of the FI study were similar to PD cohorts assessed in-person. Show more

Keywords: Parkinson’s disease, survey methods, observational studies as topic, patient reported outcome measures

DOI: 10.3233/JPD-191808

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 677-691, 2020

Authors: Silver, Maya R. | Racette, Brad A. | Dube, Umber | Faust, Irene M. | Searles Nielsen, Susan

Article Type: Research Article

Abstract: Background: Well water frequently is considered a risk factor for Parkinson’s disease (PD), but few studies were designed appropriately to test whether geographic factors affect PD risk. Objective: To determine the risk of PD in relation to residential use of private well water. Methods: In a nationwide, population-based case-control study, we identified all incident PD cases (N = 89,790) and all comparable controls (N = 21,549,400) age 66–90 who solely relied on Medicare coverage in the U.S. in 2009. We estimated the probability of use of private well water using zip code of residence at diagnosis/reference and U.S. Census data …on household water source. We modeled this exposure linearly in logistic regression to calculate the odds ratio (OR) and 95% confidence interval (CI) of PD risk in relation to well water use. We adjusted for age, sex and race/ethnicity, and verified that smoking and use of medical care did not confound results. We repeated analyses with a 2-year exposure lag and separately within each U.S. state. Results: Use of well water was inversely associated with PD risk (OR = 0.87, 95% CI 0.85–0.89). We confirmed this association in a Cox survival analysis in which we followed controls for 5 years, death or PD diagnosis. There was little evidence that well water use increased risk of PD in any individual state. Conclusions: Although it remains possible that exposures in well water in more narrow geographic regions increase PD risk, in general these results suggest that exposures more common in urban/suburban areas might also be relevant. Show more

Keywords: Case-control studies, drinking water, epidemiology, geographic factors, ground water, Medicare, Parkinson’s disease

DOI: 10.3233/JPD-191793

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 693-705, 2020

Authors: Kaiyrzhanov, Rauan | Zharkinbekova, Nazira | Shashkin, Chingiz | Khaibullin, Talgat | Kaishibayeva, Gulnaz | Akhmetzhanov, Vadim | Sadykova, Dinara Z. | Seidinova, Zhanar | Taskinbayeva, Anjela | Karimova, Altynay | Rizig, Mie | Houlden, Henry

Article Type: Letter

Keywords: Parkinson’s disease, Parkinson’s disease in Asia, Central Asia, age of onset, progression

DOI: 10.3233/JPD-191782

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 707-709, 2020

Authors: Baldin, Elisa | Zenesini, Corrado | Bauleo, Salvatore | Montanari, Federico | Santi, Sandra | Spampinato, Maurizio | Cortelli, Pietro | D’Alessandro, Roberto | Ascherio, Alberto

Article Type: Short Communication

Abstract: The aim of the study was to determine the feasibility of screening older adults attending general medical practice for features suggesting prodromal Parkinson’s disease (PD). Four general practitioners recruited 392 subjects aged ≥60 years, attending their primary clinics. A self-administered questionnaire collected information on history of probable rapid eye movements sleep behavior disorder (pRBD), constipation, risk markers for PD, and on subjective cognitive function. Olfactory function was tested. Constipation (27.8%), and hyposmia (19.9%), but not pRBD (4.3%), were more prevalent with age. Further supporting the feasibility of a longitudinal study, 299 subjects agreed to be followed.

Keywords: Parkinson’s disease, epidemiology, health policy and practice

DOI: 10.3233/JPD-191868

Citation: Journal of Parkinson's Disease, vol. 10, no. 2, pp. 711-715, 2020