Journal of Parkinson's Disease - Volume Pre-press, issue Pre-press

Authors: van de Wetering-van Dongen, Veerle A. | Nijkrake, Maarten J. | Koenders, Niek | van der Wees, Philip J. | Bloem, Bastiaan R. | Kalf, Johanna G.

Article Type: Research Article

Abstract: Background: Abnormal respiratory function tests can be observed early in the course of Parkinson’s disease (PD). A better understanding of the impact of respiratory dysfunction on daily life in PD is needed to prevent later occurring complications as a (aspiration) pneumonia. Objective: To explain which respiratory symptoms people with PD or a form of atypical parkinsonism experience and how these symptoms impact on their daily lives. Methods: This qualitative study used a grounded theory approach. A purposeful sample strategy was used to capture information-rich cases. Data were collected in semi-structured interviews with participants diagnosed with either …PD (n  = 11) or atypical parkinsonism (n  = 3), all of whom had confirmed respiratory symptoms. Data were analyzed using grounded theory analysis by creating codes, categories, theoretical themes, and, ultimately, a conceptual model. Results: Four respiratory profiles emerged, describing different types of respiratory dysfunction, with various positive and negative influencing factors. First, a loss of breathing automatism was experienced. Second, episodes of breathlessness or a rapid, shallow breathing pattern were triggered by either physical exertion, fatigue, or postural deformities. Third, stress and anxiety also triggered episodes of breathlessness. Fourth, a decreased cough strength and frequent coughing. Based on these findings, we constructed a conceptual model that visualizes the relations between these four types of respiratory dysfunction and their impact on daily life, with ‘discomfort’ and ‘avoidance of social activities’ as crucial elements. Conclusion: A tailored approach for each profile of respiratory dysfunction is recommended to improve respiratory dysfunction and to reduce its social impact in people with PD. Show more

Keywords: Respiratory function, respiratory symptoms, Parkinson’s disease, qualitative research, multidisciplinary

DOI: 10.3233/JPD-213121

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2022

Authors: Ellis, Penelope K. | Davies, Matthew L. | Gray, William K. | Barber, Margaret | Bolnykh, Ifkov | Sadler, Molly | Walker, Richard W.

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease (PD) have higher rates of hospitalisation and healthcare utilisation compared to the general population. The COVID-19 pandemic caused significant changes in admissions to hospital and access to healthcare. People with PD are some of the most vulnerable to such changes. There is no pre-existing data on the cause and duration of admission to hospital of people with PD during the COVID-19 pandemic. Objective: To determine the cause, duration, and outcome of hospital admissions to Northumbria Healthcare NHS Foundation Trust (NHCFT) for people with idiopathic Parkinson’s disease (IPD) in 2020. Methods: All …people with IPD who had an emergency admission to NHCFT between 01/01/2020 and 31/12/2020 were identified. Demographic and disease characteristics, the number, duration, cause of admission and the location prior to admission were collected from an audit of medical notes. Results: 271 people with IPD had one or more emergency admissions to NHCFT between 01/01/2020 and 31/12/2020. There was a total of 453 emergency admissions, with a median duration of 5 (IQR 2-13) days. The most common causes of admission to hospital were PD-related motor dysfunction (includes falls with no other underlying cause or associated injury) and injury (includes falls with fracture), at 78 (17.2%) and 70 (15.5%) respectively. Conclusions: People with IPD had a short duration but high number of emergency admissions to hospital. Our chronological data on number of admissions shows a peak in admissions during August 2020. As a result of these findings and emerging data we suggest that individuals with PD deconditioned during 2020. Show more

Keywords: Parkinson’s disease, COVID-19, admissions

DOI: 10.3233/JPD-223173

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2022

Authors: Radisavljevic, Nina | Cirstea, Mihai | Bauer, Kylynda | Lo, Christine | Metcalfe-Roach, Avril | Bozorgmehr, Tahereh | Bar-Yoseph, Haggai | Brett Finlay, B.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a multi-system disorder consisting of not only classic motor symptoms but also a variety of non-motor symptoms including gastrointestinal (GI) dysfunction and mood disorders. The gut microbiota has been suggested to play a role in modulating PD motor and non-motor features, although the causality and mechanisms behind these proposed interactions remains largely understudied. Objective: In this study, we aimed to provide in-depth characterization of an established mouse model of PD (transgenic (TG) SNCA A53T) and experimentally address how changes to the gut microbiota impact the PD-like phenotype. Methods: We profiled …the PD-like phenotype of transgenic mice through a panel of motor, GI, and behavioral tests. We then investigated how antibiotic treatment or gut microbial community transfer (via cohousing with wild-type mice) impacted the PD-like phenotype. Results: We found that this mouse model demonstrated early (6 weeks of age) motor symptoms when compared to a wild-type control mouse strain. Transgenic mice also exhibited early GI dysfunction, as well as behavioral alterations, including reduced anxiety-like behavior, and increased depression-like and apathy-like behavior. Compared to wild-type mice, the transgenic fecal microbiota was less diverse and compositionally distinct. Interestingly, drastic alterations to the gut microbiota, through antibiotic treatment or cohousing with wild-type mice, had a minimal effect on the motor, GI, and behavioral phenotype of transgenic mice. Conclusion: We concluded that this mouse model effectively recapitulates motor and non-motor features of PD; however, the gut microbiota appears to exhibit a minor impact on the pathophysiology of this PD model. Show more

Keywords: Parkinson’s disease, genetic models, gut microbiota, microbiota-gut-brain axis

DOI: 10.3233/JPD-223165

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2022

Authors: Liebermann-Jordanidis, Hannah | Roheger, Mandy | Boosfeld, Lukas | Franklin, Jeremy | Kalbe, Elke

Article Type: Systematic Review

Abstract: Background: Visuo-cognitive impairment is common in Parkinson’s disease patients with mild cognitive impairment (PD-MCI) and constitutes a prognostic factor for the conversion to Parkinson’s disease dementia (PDD). However, systematic analyses on which neuropsychological tests are most suitable to assess visuo-cognition in PD-MCI and PDD and to differentiate these cognitive stages are lacking. Objective: To review neuropsychological tests used to assess visuo-cognition including visuo-perceptual and visuo-spatial processing, visuo-constructive copying and drawing on command abilities; and to identify the visuo-cognitive subdomain as well as tests most suitable to discriminate between PD-MCI and PDD. Methods: MEDLINE, PsycINFO, Web of …Science Core Collection, and CENTRAL were systematically searched for relevant studies assessing visuo-cognitive outcomes in patients with PD-MCI and PDD. Risk of bias was assessed using a customized form based on well-established tools. Random-effect meta-analyses were conducted. Results: 33 studies were included in the systematic review. Data of 19 studies were entered in meta-analyses. Considerable heterogeneity regarding applied tests, test versions, and scoring systems exists. Data indicate that visuo-constructive command tasks are the subdomain best suited to discriminate between PD-MCI and PDD. Furthermore, they indicate that the Rey-Osterrieth-Complex-Figure Test (ROCF), Corsi Block-Tapping Test, Judgment of Line Orientation (JLO), and Clock Drawing Test (CDT) are tests able to differentiate between the two stages. Conclusion: We provide suggestions for suitable visuo-cognitive tests (Corsi Block-Tapping Test, or JLO, ROCF, CDT) to improve diagnostic accuracy. Methodological challenges (e.g., heterogeneity of definitions, tests) are discussed and suggestions for future research are provided. Registration: https://www.crd.york.ac.uk/prospero/ , ID: CRD42018088244 Show more

Keywords: Parkinson disease, cognition, cognitive aging, spatial learning, spatial processing, neuropsychological tests

DOI: 10.3233/JPD-223238

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-34, 2022

Authors: Alushi, Ledia | Alexander, James | Jones, Julie | Lafortune, Louise

Article Type: Research Article

Abstract: Background: Educational interventions promoting the role of physical activity (PA) aim to address, knowledge, poor exercise self-efficacy, and low outcome expectations, which are well-researched barriers to PA participation in healthy and people with chronic conditions. However, little is known about the effectiveness of educational interventions in addressing these barriers in people with Parkinson’s (PwP). Objective: To examine the content of education interventions that promote PA behavior in PwP, and to assess their effectiveness on physical and psychosocial outcomes. Methods: An electronic search (12/2021) of MEDLINE, EMBASE, CINAHL, PubMed PsycINFO, the Web of Science and the Cochrane …Library was conducted from 1990 to 2021. Education interventions, alone or combined with other strategies, promoting PA in PwP were included. Quality was assessed using the Johanna Briggs Institute and National Institute of Health quality assessment tools. A narrative synthesis was performed. Results: Six studies were identified. Five interventions were comprised of education and exercise sessions. Improvement in physical and psychosocial outcomes were suggested but delineating the exact impact of education was impeded due to lack of assessment. Conclusion: Few interventions exist that provide knowledge, and skills promoting PA participation, and fewer are addressed towards newly diagnosed PwP. There is lack of assessment over the effectiveness of education as a tool to facilitate PA participation in PwP. Lack of assessment poses the risk of potentially disregarding effective interventions or adopting ineffective approaches without the evidence. Education interventions can boost PA engagement by increasing factors such as exercise self-efficacy, but further interventions are required to assess this model of relationship. Show more

Keywords: Parkinson’s disease, education, physical activity, exercise, self-efficacy

DOI: 10.3233/JPD-223259

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2022

Authors: Fernández, Belén | Chittoor-Vinod, Vinita G. | Kluss, Jillian H. | Kelly, Kaela | Bryant, Nicole | Nguyen, An Phu Tran | Bukhari, Syed A. | Smith, Nathan | Lara Ordóñez, Antonio Jesús | Fdez, Elena | Chartier-Harlin, Marie-Christine | Montine, Thomas J. | Wilson, Mark A. | Moore, Darren J. | West, Andrew B. | Cookson, Mark R. | Nichols, R. Jeremy | Hilfiker, Sabine

Article Type: Research Article

Abstract: Background: Coding variation in the Leucine rich repeat kinase 2 gene linked to Parkinson’s disease (PD) promotes enhanced activity of the encoded LRRK2 kinase, particularly with respect to autophosphorylation at S1292 and/or phosphorylation of the heterologous substrate RAB10. Objective: To determine the inter-laboratory reliability of measurements of cellular LRRK2 kinase activity in the context of wildtype or mutant LRRK2 expression using published protocols. Methods: Benchmark western blot assessments of phospho-LRRK2 and phospho-RAB10 were performed in parallel with in situ immunological approaches in HEK293T, mouse embryonic fibroblasts, and lymphoblastoid cell lines. Rat brain tissue, with …or without adenovirus-mediated LRRK2 expression, and human brain tissues from subjects with or without PD, were also evaluated for LRRK2 kinase activity markers. Results: Western blots were able to detect extracted LRRK2 activity in cells and tissue with pS1292-LRRK2 or pT73-RAB10 antibodies. However, while LRRK2 kinase signal could be detected at the cellular level with over-expressed mutant LRRK2 in cell lines, we were unable to demonstrate specific detection of endogenous cellular LRRK2 activity in cell culture models or tissues that we evaluated. Conclusion: Further development of reliable methods that can be deployed in multiple laboratories to measure endogenous LRRK2 activities are likely required, especially at cellular resolution. Show more

Keywords: LRRK2, kinase, RAB protein, phosphorylation, proximity ligation assay

DOI: 10.3233/JPD-213128

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2022

Authors: Devignes, Quentin | Daoudi, Sami | Viard, Romain | Lopes, Renaud | Betrouni, Nacim | Kuchcinski, Gregory | Rolland, Anne-Sophie | Moreau, Caroline | Defebvre, Luc | Bardinet, Eric | Bonnet, Marie | Brefel-Courbon, Christine | Delmaire, Christine | Mountassir, Fouzia El | Fluchère, Frédérique | Fradet, Anne | Giordana, Caroline | Hainque, Elodie | Houvenaghel, Jean-François | Jarraya, Béchir | Klinger, Hélène | Maltête, David | Marques, Ana | Meyer, Mylène | Rascol, Olivier | Rouaud, Tiphaine | Tir, Melissa | Wirth, Thomas | Corvol, Jean-Christophe | Devos, David | Dujardin, Kathy | for the PREDISTIM working group

Article Type: Research Article

Abstract: Background: Parkinson’s disease mild cognitive impairment (PD-MCI) is frequent and heterogenous. There is no consensus about its influence on subthalamic deep brain stimulation (STN-DBS) outcomes. Objective: To determine the prevalence of PD-MCI and its subtypes in candidates to STN-DBS. Secondarily, we sought to identify MRI structural markers associated with cognitive impairment in these subgroups. Methods: Baseline data from the French multicentric PREDISTIM cohort were used. Candidates to STN-DBS were classified according to their cognitive performance in normal cognition (PD-NC) or PD-MCI. The latter included frontostriatal (PD-FS) and posterior cortical (PD-PC) subtypes. Between-group comparisons were performed on …demographical and clinical variables as well as on T1-weighted MRI sequences at the cortical and subcortical levels. Results: 320 patients were included: 167 (52%) PD-NC and 153 (48%) PD-MCI patients. The latter group included 123 (80%) PD-FS and 30 (20%) PD-PC patients. There was no between-group difference regarding demographic and clinical variables. PD-PC patients had significantly lower global efficiency than PD-FS patients and significantly worse performance on visuospatial functions, episodic memory, and language. Compared to PD-NC, PD-MCI patients had cortical thinning and radiomic-based changes in the left caudate nucleus and hippocampus. There were no significant differences between the PD-MCI subtypes. Conclusion: Among the candidates to STN-DBS, a significant proportion has PD-MCI which is associated with cortical and subcortical alterations. Some PD-MCI patients have posterior cortical deficits, a subtype known to be at higher risk of dementia. Show more

Keywords: Cortical thickness, dual syndrome hypothesis, radiomics, shape analysis, voxel-based morphometry

DOI: 10.3233/JPD-223232

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2022

Authors: Tseng, Kuan-Yin | Kuo, Tung-Tai | Wang, Vicki | Huang, Eagle Yi-Kung | Ma, Kuo-Hsing | Olson, Lars | Hoffer, Barry J. | Chen, Yuan-Hao

Article Type: Research Article

Abstract: Background: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson’s disease. Objective: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson’s disease. Methods: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following …treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. Results: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. Conclusions: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development. Show more

Keywords: Parkinson’s disease, dopamine, L-DOPA-induced dyskinesia, tetrabenazine, serotonin transporter

DOI: 10.3233/JPD-223195

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2022

Authors: Bange, Manuel | Gonzalez-Escamilla, Gabriel | Lang, Nadine Sandra Claudia | Ding, Hao | Radetz, Angela | Herz, Damian Marc | Schöllhorn, Wolfgang Immanuel | Muthuraman, Muthuraman | Groppa, Sergiu

Article Type: Research Article

Abstract: Background: Gait impairments are common in Parkinson’s disease (PD). The pathological mechanisms are complex and not thoroughly elucidated, thus quantitative and objective parameters that closely relate to gait characteristics are critically needed to improve the diagnostic assessments and monitor disease progression. The substantia nigra is a relay structure within basal ganglia brainstem loops that is centrally involved in gait modulation. Objective: We tested the hypothesis that quantitative gait biomechanics are related to the microstructural integrity of the substantia nigra and PD-relevant gait abnormalities are independent from bradykinesia-linked speed reductions. Methods: Thirty-eight PD patients and 33 age-matched …control participants walked on a treadmill at fixed speeds. Gait parameters were fed into a principal component analysis to delineate relevant features. We applied the neurite orientation dispersion and density imaging (NODDI) model on diffusion-weighted MR-images to calculate the free-water content as an advanced marker of microstructural integrity of the substantia nigra and tested its associations with gait parameters. Results: Patients showed increased duration of stance phase, load response, pre-swing, and double support time, as well as reduced duration of single support and swing time. Gait rhythmic alterations associated positively with the free-water content in the right substantia nigra in PD, indicating that patients with more severe neurodegeneration extend the duration of stance phase, load response, and pre-swing. Conclusion: The results provide evidence that gait alterations are not merely a byproduct of bradykinesia-related reduced walking speed. The data-supported association between free-water and the rhythmic component highlights the potential of substantia nigra microstructure imaging as a measure of gait-dysfunction and disease-progression. Show more

Keywords: Parkinson’s disease, gait, substantia nigra, free-water, diffusion-weighted imaging

DOI: 10.3233/JPD-223225

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2022

Authors: Menees, Kelly B. | Lee, Jae-Kyung

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation and accumulation of the alpha-synuclein (α-syn) protein into Lewy bodies. It is established that there is an association between inflammation and PD; however, the time course of the inflammatory process as well as the immune cells involved is still debated. Natural killer (NK) cells are innate lymphocytes with numerous functions including targeting and killing infected or malignant cells, antimicrobial defense, and resolving inflammation. NK cell subsets differ in their effector function capacities which …are modulated by activating and inhibitory receptors expressed at the cell surface. Alterations in NK cell numbers and receptor expression have been reported in PD patients. Recently, NK cell numbers and frequency were shown to be altered in the periphery and in the central nervous system in a preclinical mouse model of PD. Moreover, NK cells have recently been shown to internalize and degrade α-syn aggregates and systemic NK cell depletion exacerbated synuclein pathology in a preclinical mouse model of PD, indicating a potential protective role of NK cells. Here, we review the inflammatory process in PD with a particular focus on alterations in NK cell numbers, phenotypes, and functions. Show more

Keywords: Parkinson’s disease, NK cells, immune system, inflammation

DOI: 10.3233/JPD-223212

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2022