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

Authors: van Munster, Marlena | Stümpel, Johanne | Thieken, Franziska | Ratajczak, Florin | Rascol, Olivier | Fabbri, Margherita | Clemens, Timo | Czabanowska, Katarzyna | Mestre, Tiago A. | Pedrosa, David J. | iCARE-PD consortium

Article Type: Systematic Review

Abstract: Background: Quality of life (QoL) of persons with Parkinson’s disease (PD) is diminished by (non-)motor symptoms, that require personalized care. Parkinson Nurses (PN) may be pivotal promoting tailored care offerings. This systematic review and meta-analysis investigates PD care models and aims at furnishing current concepts of PN to offer personalized care. Objective: The purpose of this study is to identify the various roles and functions that PN may hold for personalized PD care. Methods: We performed a systematic literature review, utilizing: PubMed, Web of Science, The Cochrane Library, and PsycINFO. The review qualitatively evaluated articles, which …described personalized care models involving PNs and was guided by the personalized care management model. A meta-analysis compared patient-reported QoL (quantified using the 39-item Parkinson’s Disease Questionnaire) between personalized care interventions involving PN versus standard care with. Results: Twenty-seven publications were identified, including six randomized, controlled trials ascertaining with health related QoL (n  = 1830 PwPs). The qualitative evaluation revealed that PN contribute to all aspects of personalized care. The meta-analysis showed no improved QoL in personalized care models compared to standard care, thought a great heterogeneity among study design and interventions was outlined (Standardized Mean Difference = –0.8935; 95% Confidence Interval, –2.1177 to 0.3307; z = –1.43, p  = 0.1526). Conclusion: PN fulfil important functions in personalized PD care. For the future, a clear role definition will be necessary to adjust training for PN across healthcare systems and care settings but especially to realize their full potential for PD care. Show more

Keywords: Parkinson’s disease, Parkinson nurse, role of specialized care nurse, personalized care, quality of life, PDQ-39

DOI: 10.3233/JPD-223215

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

Authors: Williams, Gregory P. | Schonhoff, Aubrey M. | Sette, Alessandro | Lindestam Arlehamn, Cecilia S.

Article Type: Review Article

Abstract: Inflammation has increasingly become a focus of study in regards to Parkinson’s disease (PD). Moreover, both central and peripheral sources of inflammation have been implicated in the pathogenesis of PD. Central inflammation consisting of activated microglia, astroglia, and T cell responses within the PD central nervous system; and peripheral inflammation referring to activated innate cells and T cell signaling in the enteric nervous system, gastrointestinal tract, and blood. This review will highlight important work that further implicates central and peripheral inflammation in playing a role in PD. We also discuss how these two distant inflammations appear related and how that …may be mediated by autoantigenic responses to α-syn. Show more

Keywords: Neuroimmunology, neuroinflammation, Parkinson’s disease, T cells, central inflammation, peripheral inflammation

DOI: 10.3233/JPD-223241

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

Authors: Gollan, Romina | Ernst, Moritz | Lieker, Emma | Caro-Valenzuela, Julia | Monsef, Ina | Dresen, Antje | Roheger, Mandy | Skoetz, Nicole | Kalbe, Elke | Folkerts, Ann-Kristin

Article Type: Systematic Review

Abstract: Background: Previous reviews indicated positive effects of resistance training (RT) on motor outcomes in Parkinson’s disease (PD). However, inconsistencies between the included studies exist, and non-motor outcomes have only scarcely been considered in a review on RT in PD. Objective: To analyze the RT effects on motor- and non-motor outcomes in PD patients compared to passive and physically active control groups (i.e., other structured physical interventions). Methods: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL for randomized controlled trials of RT in PD. After identifying 18 studies, a meta-analysis was conducted for the outcomes muscle strength, motor …impairment, freezing of gait (FoG), mobility and balance, quality of life (QoL), depression, cognition, and adverse events. Meta-analyses with random models were calculated using mean differences (MD) or standardized mean differences (SMD) with 95% confidence intervals (CI). Results: When comparing RT with passive control groups, the meta-analyses showed significant large effects on muscle strength (SMD = –0.84, 95% CI –1.29––0.39, p  = 0.0003), motor impairment (SMD = –0.81, 95% CI –1.34––0.27, p  = 0.003), mobility and balance (MD = –1.81, 95% CI –3.13––0.49, p  = 0.007), and small significant effects on QoL (SMD = –0.48, 95% CI –0.86––0.10, p  = 0.01). RT compared with physically active control groups reached no significant results for any outcome. Conclusions: RT improves muscle strength, motor impairment, mobility and balance, QoL, and depression in PD patients. However, it is not superior to other physically active interventions. Therefore, exercise is important for PD patients but according to this analysis, its type is of secondary interest. Show more

Keywords: Parkinson’s disease, resistance training, muscle strength, motor outcomes, non-motor outcomes

DOI: 10.3233/JPD-223252

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2022

Authors: Tosserams, Anouk | Nonnekes, Jorik

Article Type: Research Article

DOI: 10.3233/JPD-223296

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2022

Authors: Stefanova, Nadia

Article Type: Review Article

Abstract: Microglia are the primary resident immune cells of the central nervous system. Neuropathological reports have identified augmented microglial activation in brains of patients with neurodegenerative disorders including Parkinson’s disease (PD). Extensive research over the years has strengthened the current view on microglia as a player in the pathogenesis of PD and other α-synucleinopathies. In this review, we summarize key findings of the recent three years on microglia in PD with specific relevance to understanding its heterogeneity, dual nature, and specific interactions with pathological α-synuclein strains to mediate its clearance and spreading. This review provides evidence on the relevance of microglia …as a putative biomarker and therapeutic target in PD and related disorders. Show more

Keywords: Alpha-synuclein, biomarker, disease modifying therapy, microglia, multiple system atrophy, neuroinflammatory, Parkinson’s disease, PET

DOI: 10.3233/JPD-223237

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Salvatore, Michael F. | Soto, Isabel | Kasanga, Ella A. | James, Rachael | Shifflet, Marla K. | Doshier, Kirby | Little, Joel T. | John, Joshia | Alphonso, Helene M. | Cunningham, J. Thomas | Nejtek, Vicki A.

Article Type: Research Article

Abstract: Background: Rodent Parkinson’s disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. Objective: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. Method: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr ≤1.5) exercising in non-contact boxing training for ≥3 months, ≥3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased …HR to an extent similar in human subjects. Results: After completing aerobic exercise for ∼30 min, PD subjects had increased HR∼35% above baseline (∼63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naïve PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8–10 m/min increased HR up to 25% above baseline (∼67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naïve cohort at 5 months old. Conclusion: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models. Show more

Keywords: Exercise, Pink1, cardiovascular, Parkinson’s disease, aging, locomotor

DOI: 10.3233/JPD-223157

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

Authors: Janzen, Annette | Vadasz, David | Booij, Jan | Luster, Markus | Librizzi, Damiano | Henrich, Martin T. | Timmermann, Lars | Habibi, Mahboubeh | Sittig, Elisabeth | Mayer, Geert | Geibl, Fanni | Oertel, Wolfgang

Article Type: Research Article

Abstract: Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We investigated the use of cardiac [123 I]meta-iodo-benzyl-guanidine scintigraphy ([123 I]MIBG) and olfactory testing— in comparison to [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single photon emission computed tomography ([123 I]FP-CIT-SPECT)— for identifying iRBD patients as prodromal phenotype of PD/DLB. Methods: 37 RBD subjects underwent cardiac [123 I]MIBG and brain [123 I]FP-CIT-SPECT at baseline. Olfactory (Sniffin’ Sticks), cognitive and motor functions were tested annually for ∼4 years. Results: 29/37 (78.4%) subjects had a pathological [123 I]MIBG, of …whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123 I]FP-CIT-SPECT, always combined with a pathological [123 I]MIBG. In subjects with pathological [123 I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p  = 0.005). Olfaction was more impaired in subjects with pathological [123 I]MIBG compared to those with normal [123 I]MIBG at baseline (p  = 0.001) and follow-up (p  <  0.001). UPDRS-III scores increased in subjects with both pathological [123 I]MIBG and [123 I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all— except for one— presented with at least moderate hyposmia at baseline. Conclusion: A combination of the biomarkers “pathological [123 I]MIBG” and “hyposmia” likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123 I]MIBG had a normal [123 I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123 I]MIBG, olfactory impairment is progressive independent of the [123 I]FP-CIT-SPECT status. Show more

Keywords: Biomarker, cardiac [123I]MIBG scintigraphy, [123I]FP-CIT-SPECT, hyposmia, isolated rapid eye movement sleep behavior disorder, prodromal progression marker

DOI: 10.3233/JPD-223201

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

Authors: Vinke, R. Saman | Georgiev, Dejan | Selvaraj, Ashok K. | Rahimi, Tahmina | Bloem, Bastiaan R. | Bartels, Ronald H.M.A. | Esselink, Rianne A.J.

Article Type: Short Communication

Abstract: There is evidence that men are more likely to undergo deep brain stimulation (DBS) for Parkinson’s disease (PD), suggesting that women are relatively undertreated. 121 consecutive PD patients undergoing awake with microelectrode recording and intraoperative clinical testing (30 patients, 5 women) or asleep MRI-guided and CT-verified (91 patients, 38 women) bilateral subthalamic nucleus DBS were included in this study. The results showed an increase of the proportion of female patients from 16.7% to 41.8% after changing our operative technique (OR = 5.61; 95% CI: 1.52–20.78; p  = 0.010) from awake to asleep, suggesting that women are more likely to undergo DBS when operated …asleep. Show more

Keywords: Deep brain stimulation, gender, asleep, awake, MRI-guided, microelectrode recording

DOI: 10.3233/JPD-223315

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2022

Authors: Shannon, Kathleen M.

Article Type: Review Article

Abstract: The cause of Parkinson’s disease (PD) is unknown, but environmental factors are purported to influence risk. Interest in PD as a sequel of infection dates back to reports of parkinsonism arising from encephalitis lethargica. The objective of this paper is to review the literature as it relates to infections and changes in microbiome and the genesis of PD. There is evidence to support prior infection with Helicobacter pylori , hepatitis C virus, Malassezia , and Strep pneumonia in association with PD. A large number of studies support an association between changes in commensal bacteria, especially gut bacteria, and PD. …Extant literature supports a role for some infections and changes in commensal bacteria in the genesis of PD. Studies support an inflammatory mechanism for this association, but additional research is required for translation of these findings to therapeutic options. Show more

Keywords: Parkinson’s disease, review, infections, microbiota, neuroinflammation

DOI: 10.3233/JPD-223271

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Deng, Xiao | Saffari, Seyed Ehsan | Ng, Samuel Yong Ern | Chia, Nicole | Tan, Jayne Yi | Choi, Xinyi | Heng, Dede Liana | Xu, Zheyu | Tay, Kay-Yaw | Au, Wing-Lok | Liu, Nan | Ng, Adeline | Tan, Eng-King | Tan, Louis C.S.

Article Type: Research Article

Abstract: Background: Lipid biomarkers have potential neuroprotective effects in Parkinson’s disease (PD) and there is limited evidence in the field. Objective: This study aims to investigate the association between comprehensive blood lipid biomarkers and PD. Methods: A total of 205 PD patients and 102 non-PD subjects were included from Early Parkinson’s disease Longitudinal Singapore (PALS) cohort. We investigated 6 serum lipid biomarkers including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). PD patients were further classified into mild cognitive impairment (MCI) and normal …cognition (NC) subgroups. We conducted a cross-sectionals study to examine the association between lipids and PD and further explored the relationship between lipids and PD-MCI. Results: PD patients had significantly lower level of lipid panel including TC, TG, HDL-C, Apo A1, LDL-C, and Apo B (all p  <  0.05). TC, TG, Apo A1, and Apo B levels were independent protective factors (p  <  0.05) for PD in the logistic regression model. PD-MCI group had significantly higher mean TC, TG, and Apo A1 levels compared to PD-NC group. Higher TC, TG, and Apo A1 levels were independent risk factors (p  <  0.05) for PD-MCI. Conclusion: We demonstrated that PD patients had significantly lower levels of lipid biomarkers while PD-MCI patients had higher levels of TC, TG, and Apo A1. TC, TG, and Apo A1 may be useful biomarkers for PD-MCI. Show more

Keywords: Parkinson’s disease, cognitive impairment, blood lipid biomarkers

DOI: 10.3233/JPD-213135

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2022

Authors: Terkelsen, Miriam Højholt | Klaestrup, Ida H. | Hvingelby, Victor | Lauritsen, Johanne | Pavese, Nicola | Romero-Ramos, Marina

Article Type: Review Article

Abstract: Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson’s disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and …peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson’s disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered. Show more

Keywords: Microglia, monocytes, T-cells, alpha-synuclein, Parkinson’s disease, LRRK2, GBA, prodromal

DOI: 10.3233/JPD-223245

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

Authors: Wilkins, Kevin B. | Petrucci, Matthew N. | Kehnemouyi, Yasmine | Velisar, Anca | Han, Katie | Orthlieb, Gerrit | Trager, Megan H. | O’Day, Johanna J. | Aditham, Sudeep | Bronte-Stewart, Helen

Article Type: Research Article

Abstract: Background: Assessment of motor signs in Parkinson’s disease (PD) requires an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous monitoring for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic. Objective: Investigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics …of all cardinal motor signs in PD. Methods: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years. Results: QDG-RAFT metrics showed differences between PD and controls and provided correlated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment, and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy and showed differences between akinetic-rigid and tremor-dominant phenotypes, as well as people with and without FOG. Conclusions: QDG is a reliable technology, which could be used in the clinic or remotely. This could improve access to care, allow complex remote disease management based on data received in real time, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive motor metrics needed for therapeutic trials. Show more

Keywords: Alternating finger tapping, cardinal motor signs, freezing of gait, keyboard, Parkinson’s disease, phenotype, remote measurement, rigidity, Unified Parkinson’s Disease Rating Scale, wearables

DOI: 10.3233/JPD-223264

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Shoulson, Ira | Arbatti, Lakshmi | Hosamath, Abhishek | Eberly, Shirley W. | Oakes, David

Article Type: Research Article

Abstract: Background: The Parkinson’s Disease Patient Report of Problems (PD-PROP) captures the problems and functional impact that patients report verbatim. Online research participation and advances in language analysis have enabled longitudinal collection and classification of symptoms as trial outcomes. Objective: Analyze verbatim reports longitudinally to examine postural-instability symptoms as 1) precursors of subsequent falling and 2) newly occurring symptoms that could serve as outcome measures in randomized controlled trials. Methods: Problems reported by >25,000 PD patients in their own words were collected online in the Fox Insight observational study and classified into symptoms by natural language processing, …clinical curation, and machine learning. Symptoms of gait, balance, falling, and freezing and associated reports of having fallen in the last month were analyzed over three years of longitudinal observation by a Cox regression model in a cohort of 8,287 participants. New onset of gait, balance, falling, and freezing symptoms was analyzed by Kaplan-Meier survival techniques in 4,119 participants who had not previously reported these symptoms. Results: Classified verbatim symptoms of postural instability were significant precursors of subsequent falling among participants who were older, female, and had longer PD duration. New onset of symptoms steadily increased and informed sample size estimates for clinical trials to reduce the onset of these symptoms. Conclusion: The tools to analyze symptoms reported by PD patients in their own words and capacity to enroll large numbers of research participants online support the feasibility and statistical power for conducting randomized clinical trials to detect effects of therapeutic interventions. Show more

Keywords: Falling, gait, machine learning, natural language processing, Parkinson’s disease, patient reported outcome measures, randomized controlled trials

DOI: 10.3233/JPD-223274

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

Authors: Chua, Shaun Kai Kiat | Saffari, Seyed Ehsan | Lee, Selene Joon Yan | Tan, Eng-King

Article Type: Research Article

Abstract: Background: The relationship between Parkinson’s disease (PD) and coronary artery disease (CAD) is unclear. Objective: This study aims to investigate whether PD and CAD are associated through systematic review and meta-analysis of observational studies. Methods: Electronic database search of PubMed, EMBASE, and Web of Science for observational studies published from 1 January 2010 to 1 August 2021 was conducted using terms related to PD and CAD. Unadjusted risk ratios (RR) and odds ratios (OR) of included cohort and case-control studies respectively were used to ascertain the association between PD and CAD. Study heterogeneity was evaluated using …the I2 test. Results: Forty-one full-text studies were initially retrieved for eligibility assessment. Five studies that satisfied the inclusion criteria, consisting of three cohort and two case-control studies, were eventually included in this meta-analysis. The five studies enrolled 35,237 PD patients and 650,866 non-PD patients. PD and CAD were found to be significantly associated in cohort studies (RR = 2.23, 95% CI = 1.08–4.59, p  = 0.03; Fig. 2 ), which held after sensitivity analysis (RR = 1.45, 95% CI = 1.31–1.60, p  <  0.001; Fig. 3 ). Case-control studies found a trend towards association of PD and CAD approaching significance (OR = 1.47, 95% CI = 0.84–2.56, p  = 0.18; Fig. 2 ). Conclusion: Overall, this meta-analysis suggests that PD is associated with CAD. The underlying mechanisms, as well as the role of ethnicity and other comorbidities on the relationship between PD and CAD should be further explored. Show more

Keywords: Coronary artery disease, meta-analysis, observational studies, Parkinson’s disease, systematic review

DOI: 10.3233/JPD-223291

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Wang, Jian | Battioui, Chakib | McCarthy, Andrew | Dang, Xiangnan | Zhang, Hui | Man, Albert | Zou, Jasmine | Kyle, Jeffrey | Munsie, Leanne | Pugh, Melissa | Biglan, Kevin

Article Type: Research Article

Abstract: Background: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks. Objective: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD. Methods: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n  = 160) enrolled in a sub-study using an iPad trial app with 3 …tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed. Results: Actigraphy and trial app compliance was >  90% and >  60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p  <  0.01). Physical activity correlated with improvement on Movement Disorder Society –Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p  <  0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale –Cognitive 13-Item Scale (ADAS-Cog13 ) (p  <  0.001). Mevidalen treatment (30 mg) improved SWM (p  <  0.01), while dose-dependent decreases in daytime sleep (10 mg: p  <  0.01, 30 mg: p  <  0.05, 75 mg: p  <  0.001), and an increase in walking minutes (75 mg dose: p  <  0.001) were observed, returning to baseline post-intervention. Conclusion: Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects. Show more

Keywords: Actigraphy, activity, cognition, digital biomarkers, Lewy body dementia, sleep

DOI: 10.3233/JPD-213126

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Zimmermann, Milan | Brockmann, Kathrin

Article Type: Review Article

Abstract: Given the clear role of inflammation in the pathogenesis of Parkinson’s disease (PD) and its impact on incidence and phenotypical characteristics, this review provides an overview with focus on inflammatory biofluid markers in blood and cerebrospinal fluid (CSF) in PD patient cohorts. In preparation for clinical trials targeting the immune system, we specifically address the following questions: 1) What evidence do we have for pro-inflammatory profiles in blood and in CSF of sporadic and genetic PD patients? 2) Is there a role of anti-inflammatory mediators in blood/CSF? 3) Do inflammatory profiles in blood reflect those in CSF indicative of a …cross-talk between periphery and brain? 4) Do blood/CSF inflammatory profiles change over the disease course as assessed in repeatedly taken biosamples? 5) Are blood/CSF inflammatory profiles associated with phenotypical trajectories in PD? 6) Are blood/CSF inflammatory profiles associated with CSF levels of neurodegenerative/PD-specific biomarkers? Knowledge on these questions will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures for clinical trials. Show more

Keywords: Parkinson’s disease, inflammation, interleukin, chemokine, cytokine, blood, cerebrospinal fluid

DOI: 10.3233/JPD-223277

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2022

Authors: Kouli, Antonina | Williams-Gray, Caroline H.

Article Type: Research Article

Abstract: Ageing is a major risk factor for most neurodegenerative diseases, including Parkinson’s disease (PD). Progressive age-related dysregulation of the immune system is termed immunosenescence and is responsible for the weakened response to novel antigens, increased susceptibility to infections and reduced effectiveness of vaccines seen in the elderly. Immune activation, both within the brain and periphery, is heavily implicated in PD but the role of immunosenescence has not been fully explored. Studies to date provide some evidence for an attenuation in immunosenescence in PD, particularly a reduction in senescent CD8 T lymphocytes in PD cases compared to similarly aged controls. Here, …we discuss recent evidence of age-related immune abnormalities in PD with a focus on T cell senescence and explore their potential role in disease pathogenesis and development. Show more

Keywords: Parkinson’s disease, immunosenescence, ageing, T lymphocytes

DOI: 10.3233/JPD-223228

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Gonzalez-Latapi, Paulina | Marras, Connie

Article Type: Review Article

Abstract: There is a growing interest in the role the immune system and inflammatory response play on the pathophysiology of Parkinson’s disease (PD). Epidemiological evidence lends support for the hypothesis that PD is an immune-mediated condition. An association between inflammatory bowel disease, including Crohn’s and Ulcerative colitis, and the risk of PD has been described and replicated in several population-based cohorts. Other autoimmune conditions, such as Sjogren syndrome, ankylosing spondylitis, and rheumatoid arthritis also seem to be associated with an increased risk of PD. Immunosuppressant medications seem to be associated with a decreased risk of PD. Finally, variants in genes involved …in immune system regulation are also shared between PD and autoimmune conditions. In this review, we will provide an overview of epidemiological evidence from population-based cohort studies, meta-analyses, and genome-wide association studies that analyze the association between the immune system and PD, discuss current gaps in the literature and future research directions in this field. Show more

Keywords: Parkinson’s disease, autoimmune, epidemiology, LRRK2, inflammatory bowel disease, immunosuppressants

DOI: 10.3233/JPD-223180

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

Authors: García-Revilla, Juan | Herrera, Antonio J. | de Pablos, Rocío M. | Venero, José Luis

Article Type: Review Article

Abstract: Accumulating evidence suggests that microglia and peripheral immune cells may play determinant roles in the pathogenesis of Parkinson’s disease (PD). Consequently, there is a need to take advantage of immune-related models of PD to study the potential contribution of microglia and peripheral immune cells to the degeneration of the nigrostriatal system and help develop potential therapies for PD. In this review, we have summarised the main PD immune models. From a historical perspective, we highlight first the main features of intranigral injections of different pro-inflammogens, including lipopolysaccharide (LPS), thrombin, neuromelanin, etc. The use of adenoviral vectors to promote microglia-specific overexpression …of different molecules in the ventral mesencephalon, including α-synuclein, IL-1β, and TNF, are also presented and briefly discussed. Finally, we summarise different models associated with peripheral inflammation whose contribution to the pathogenesis of neurodegenerative diseases is now an outstanding question. Illustrative examples included systemic LPS administration and dextran sulfate sodium-induced colitis in rodents. Show more

Keywords: Parkinson’s disease, animal models, microglia, inflammation, substantia nigra, lipopolysaccharide, thrombin, dextran sulfate sodium, adenovirus

DOI: 10.3233/JPD-213138

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2022

Authors: Salles, Philippe A. | Liao, James | Shuaib, Umar | Mata, Ignacio F. | Fernandez, Hubert H.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as the disease progresses, motor fluctuations and/or levodopa-induced dyskinesias limit the benefit of pharmacotherapy. Device-aided therapies are good alternatives in advanced disease, including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel, and continuous subcutaneous infusion of apomorphine. Candidate selection and timing are critical for the success of such therapies. Genetic screening in DBS cohorts has shown a higher proportion of mutation carriers than in general cohorts, suggesting that genetic factors may influence candidacy for advanced therapies. The response of monogenic …PD to device therapies is not well established, and the contribution of genetic information to decision-making is still a matter of debate. The limited evidence regarding gene-dependent response to device-aided therapies is reviewed here. An accurate understanding of the adequacy and responses of different mutation carriers to device-aided therapies requires the development of specific studies with long-term monitoring. Show more

Keywords: Parkinson’s disease, parkinsonian disorders, genetic disorders, apomorphine, levodopa, infusion pumps, deep brain stimulation

DOI: 10.3233/JPD-212986

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2022

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

Authors: Meira, Bruna | Lhommée, Eugénie | Schmitt, Emmanuelle | Klinger, Hélène | Bichon, Amélie | Pélissier, Pierre | Anheim, Mathieu | Tranchant, Christine | Fraix, Valérie | Meoni, Sara | Durif, Franck | Houeto, Jean-Luc | Azulay, Jean Philippe | Moro, Elena | Thobois, Stéphane | Krack, Paul | Castrioto, Anna | for the Honeymoon study group

Article Type: Research Article

Abstract: Background: Previous studies described a parkinsonian personality characterized as rigid, introverted, and cautious; however, little is known about personality traits in de novo Parkinson’s disease (PD) patients and their relationships with motor and neuropsychiatric symptoms. Objective: To investigate personality in de novo PD and explore its relationship with PD symptoms. Methods: Using Cloninger’s biosocial model, we assessed personality in 193 de novo PD patients. Motor and non-motor symptoms were measured using several validated scales. Cluster analysis was conducted to investigate the interrelationship of personality traits, motor, and non-motor symptoms. Results: PD …patients showed low novelty seeking, high harm avoidance, and normal reward dependence and persistence scores. Harm avoidance was positively correlated with the severity of depression, anxiety, and apathy (rs  = [0.435, 0.676], p  <  0.001) and negatively correlated with quality of life (rs  = –0.492, p  <  0.001). Novelty seeking, reward dependence, and persistence were negatively correlated with apathy (rs  = [–0.274, –0.375], p  <  0.001). Classification of patients according to personality and PD symptoms revealed 3 distinct clusters: i) neuropsychiatric phenotype (with high harm avoidance and low novelty seeking, hypodopaminergic neuropsychiatric symptoms and higher impulsivity), ii) motor phenotype (with low novelty seeking and higher motor severity), iii) benign phenotype (with low harm avoidance and high novelty seeking, reward dependence, and persistence traits clustered with lower symptoms severity and low impulsivity). Conclusion: Personality in early PD patients allows us to recognize 3 patients’ phenotypes. Identification of such subgroups may help to better understand their natural history. Their longitudinal follow-up will allow confirming whether some personality features might influence disease evolution and treatment. Show more

Keywords: Neuropsychiatric symptoms, non-motor symptoms, Parkinson’s disease, personality

DOI: 10.3233/JPD-213070

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: van den Heuvel, Lieneke | Hoefsloot, Wibe | Post, Bart | Meinders, Marjan J. | Bloem, Bastiaan R. | Stiggelbout, Anne M. | van Til, Janine A.

Article Type: Research Article

Abstract: Background: In Parkinson’s disease (PD), several disease-modifying treatments are being tested in (pre-)clinical trials. To successfully implement such treatments, it is important to have insight into factors influencing the professionals’ decision to start disease-modifying treatments in persons who are in the prodromal stage of PD. Objective: We aim to identify factors that professionals deem important in deciding to a start disease-modifying treatment in the prodromal stage of PD. Methods: We used a discrete choice experiment (DCE) to elicit preferences of neurologists and last-year neurology residents regarding treatment in the prodromal phase of PD. The DCE contained …16 hypothetical choice sets in which participants were asked to choose between two treatment options. The presented attributes included treatment effect, risk of severe side-effects, risk of mild side-effects, route of administration, and annual costs. Results: We included 64 neurologists and 18 last year neurology residents. Participants attached most importance to treatment effect and to the risk of severe side-effects. Participants indicated that they would discuss one of the presented treatments in daily practice more often in persons with a high risk of being in the prodromal phase compared to those with a moderate risk. Other important factors for deciding to start treatment included the amount of evidence supporting the putative treatment effect, the preferences of the person in the prodromal phase, and the life expectancy. Conclusion: This study provides important insights in factors that influence decision making by professionals about starting treatment in the prodromal phase of PD. Show more

Keywords: Decision making, disease-modifying treatment, Parkinson’s disease, prodromal PD, professional’s preference

DOI: 10.3233/JPD-223208

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

Authors: Lindberg, Iris | Shu, Zhan | Lam, Hoa | Helwig, Michael | Yucer, Nur | Laperle, Alexander | Svendsen, Clive | Di Monte, Donato A. | Maidment, Nigel T.

Article Type: Research Article

Abstract: Background: Parkinson’s disease involves aberrant aggregation of the synaptic protein alpha-synuclein (aSyn) in the nigrostriatal tract. We have previously shown that proSAAS, a small neuronal chaperone, blocks aSyn-induced dopaminergic cytotoxicity in primary nigral cultures. Objective: To determine if proSAAS overexpression is neuroprotective in animal models of Parkinson’s disease. Methods: proSAAS- or GFP-encoding lentivirus was injected together with human aSyn-expressing AAV unilaterally into the substantia nigra of rats and motor asymmetry assessed using a battery of motor performance tests. Dopamine neuron survival was assessed by nigral stereology and striatal tyrosine hydroxylase (TH) densitometry. To examine transsynaptic spread …of aSyn, aSyn AAV was injected into the vagus of mice in the presence of AAVs encoding either GFP or proSAAS; the spread of aSyn-positive neurites into rostral nuclei was quantified following immunohistochemistry. Results: Coinjection of proSAAS-encoding lentivirus profoundly reduced the motor asymmetry caused by unilateral nigral AAV-mediated human aSyn overexpression. This was accompanied by significant amelioration of the human aSyn-induced loss of both nigral TH-positive cells and striatal TH-positive terminals, demonstrating clear proSAAS-mediated protection of the nigrostriatal tract. ProSAAS overexpression reduced human aSyn protein levels in nigra and striatum and reduced the loss of TH protein in both regions. Following vagal administration of human aSyn-encoding AAV, the number of human aSyn-positive neurites in the pons and caudal midbrain was considerably reduced in mice coinjected with proSAAS-, but not GFP-encoding AAV, supporting proSAAS-mediated blockade of transsynaptic aSyn transmission. Conclusion: The proSAAS chaperone may represent a promising target for therapeutic development in Parkinson’s disease. Show more

Keywords: Alpha synuclein, chaperone, cytoprotection, dopamine, Parkinson’s disease, PCSK1N, proSAAS

DOI: 10.3233/JPD-213053

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

Authors: Petricca, Lara | Chiki, Nour | Hanna-El-Daher, Layane | Aeschbach, Lorène | Burai, Ritwik | Stoops, Erik | Fares, Mohamed-Bilal | Lashuel, Hilal A.

Article Type: Research Article

Abstract: Background: The development of therapeutics for Parkinson’s disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression, and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the α -synuclein (α SYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results. Objective: To determine whether the three commercial kits that have been extensively used for total α SYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant α SYN proteoforms. Methods: We …investigated and compared the ability of the different assays to detect the diversity of α SYN proteoforms using a library of α SYN proteins that comprise the majority of disease-relevant α SYN variants and post-translational modifications (PTMs). Results: Our findings showed that none of the three tested immunoassays accurately capture the totality of relevant α SYN species, and that these assays are unable to recognize most disease-associated C-terminally truncated variants of α SYN. Moreover, several N-terminal truncations and phosphorylation/nitration PTMs differentially modify the level of α SYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the α SYN proteoforms analyzed by the three immunoassays. Conclusion: Our results show that the tested immunoassays do not capture the totality of the relevant α SYN species and therefore may not be appropriate tools to provide an accurate measure of total α SYN levels in samples containing modified forms of the protein. This highlights the need for next generation α SYN immunoassays that capture the diversity of α SYN proteoforms. Show more

Keywords: Alpha-synuclein, antibodies, cerebrospinal fluid, ELISA, immunoassays, Parkinson’s disease, post-translational modifications, truncations

DOI: 10.3233/JPD-223285

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Nie, Jia | Liu, Chunyu | Yu, Canqing | Guo, Yu | Pei, Pei | Yang, Ling | Chen, Yiping | Du, Huaidong | Zhu, Kaifei | Schmidt, Danile | Avery, Daniel | Chen, Junshi | Chen, Zhengming | Lv, Jun | Li, Liming | for the China Kadoorie Biobank (CKB) Collaborative Group

Article Type: Research Article

Abstract: Background: Existing limited evidence suggests that smoking and tea consumption may be associated with a lower risk of Parkinson’s disease (PD). However, less is known about the independent and joint roles of these two habits, which are often clustered among Chinese, on PD risk. Objective: To prospectively examine the independent and joint association of tea consumption and smoking with the risk of PD. Methods: The China Kadoorie Biobank (CKB) study recruited 512,725 participants aged 30 to 79 years from ten areas across China since 2004. Information on smoking and tea consumption was collected at baseline, and PD …cases were ascertained by linkage to the national health insurance system and death registry. Cox proportional hazards models were used to estimate the multivariable-adjusted hazard ratios (HRs) and corresponding 95%confidence intervals (CIs). Results: During a median of 10.8 years of follow-up, 922 PD cases were recorded. Compared with participants who never consumed tea, the HR (95%CI) for daily consumers was 0.68 (0.55, 0.84). Compared with participants who never or occasionally smoked, the HR (95%CI) for current smokers was 0.66 (0.53, 0.82). Those who had a clustering habit of smoking and tea consumption had a 38%(HR = 0.62; 95%CI: 0.49, 0.79) lower PD risk than those who consumed none. However, there were no statistically significant multiplicative or additive interaction for tea consumption and smoking on PD risk. Conclusion: We found that smoking and daily tea consumption were independently inversely associated with the risk of PD. Show more

Keywords: Chinese, Parkinson’s disease, prospective study, smoking, tea consumption

DOI: 10.3233/JPD-223148

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

Authors: Sampedro, Frederic | Martínez-Horta, Saul | Marín-Lahoz, Juan | Pagonabarraga, Javier | Kulisevsky, Jaime

Article Type: Research Article

Abstract: Background: Apathy represents a core neuropsychiatric symptom in Parkinson’s disease (PD). As there is currently no established effective treatment for apathy in PD, further investigating the biological origin of this symptom is needed to design novel therapeutic strategies. Among the multiple neurotransmitter alterations that have been associated with apathy, the involvement of extra-striatal dopaminergic degeneration remains to be fully explored. Objective: To investigate whether apathy in PD reflects increased dopaminergic degeneration extending beyond striatal regions. Methods: In the de novo PD cohort of the Parkinson’s Progression Markers Initiative (PPMI), we performed whole-brain I123 -Ioflupane Single Photon …Emission Computed Tomography (DAT-SPECT) analyses to characterize cross-sectional and longitudinal differences in DAT uptake associated with the presence of apathy. We also assessed the relationship between apathy and cognition in this sample, as apathy has been suggested to herald cognitive decline. Results: Apathetic PD patients (N  = 70) had similar sociodemographic, clinical, and biomarker profiles compared to the non-apathetic group (N  = 333) at baseline. However, apathy was associated with an increased risk of developing cognitive impairment after a four-year follow-up period (p  = 0.006). Compared to non-apathetic patients, apathetic patients showed a widespread reduction of extra-striatal DAT uptake at baseline as well as an increased longitudinal loss of DAT uptake (corrected p  <  0.05). Conclusions: Isolated apathy in PD is associated with extra-striatal dopaminergic degeneration. As this abnormal dopamine depletion was in turn related to cognitive performance, this might explain, at least partially, the increased risk of apathetic PD patients to develop cognitive impairment or dementia. Show more

Keywords: Apathy, DAT, extra-striatal, Parkinson’s disease

DOI: 10.3233/JPD-223223

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

Authors: Templeton, John Michael | Poellabauer, Christian | Schneider, Sandra

Article Type: Research Article

Abstract: Background: Mobile devices and their capabilities (e.g., device sensors and human-device interactions) are increasingly being considered for use in clinical assessments and disease monitoring due to their ability to provide objective, repeatable, and more accurate measures of neurocognitive performance. These mobile-based assessments also provide a foundation for the design of intervention recommendations. Objective: The purpose of this work was to assess the benefits of various physical intervention programs as they relate to Parkinson’s disease (PD), its symptoms, and stages (Hoehn and Yahr (H&Y) Stages 1–5). Methods: Ninety-five participants (n  = 70 PD; n  = 25 control) completed 14 …tablet-based neurocognitive functional tests (e.g., motor, memory, speech, executive, and multi-function) and standardized health questionnaires. 208 symptom-specific digital features were normalized to assess the benefits of various physical intervention programs (e.g., aerobic activity, non-contact boxing, functional strength, and yoga) for individuals with PD. While previous studies have shown that physical interventions improve both motor and non-motor PD symptoms, this paper expands on previous works by mapping symptom-specific neurocognitive functionalities to specific physical intervention programs across stages of PD. Results: For early-stage PD (e.g., H&Y Stages 1 & 2), functional strength activities provided the largest overall significant delta improvement (Δ = 0.1883; p  = 0.0265), whereas aerobic activity provided the largest overall significant delta improvement (Δ = 0.2700; p  = 0.0364) for advanced stages of PD (e.g., H&Y Stages 3–5). Conclusions: As mobile-based digital health technology allows for the collection of larger, labeled, objective datasets, new ways to analyze and interpret patterns in this data emerge which can ultimately lead to new personalized medicine programs. Show more

Keywords: Intervention recommendation, mobile applications, neurocognitive assessment, Parkinson’s disease, physical activity

DOI: 10.3233/JPD-223214

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

Authors: Usnich, Tatiana | Hanssen, Henrike | Lohmann, Katja | Lohse, Christina | Klein, Christine | Kasten, Meike | Brüggemann, Norbert | on behalf of the EPIPARK Study Group

Article Type: Short Communication

Abstract: Patients with Parkinson’s disease (PD) carrying variants in the Glucocerebrosidase (GBA) gene (GBA -PD) suffer from orthostatic symptoms more frequently than idiopathic PD patients (IPD). Systematic measurements of the blood pressure have not yet been performed. In the present study, a prospective analysis of 33 GBA -PD and 313 IPD patients was carried out. Systolic blood pressure upon changing from the supine to the upright position dropped more strongly in GBA -PD compared to IPD patients. Diastolic blood pressure and heart rate did not differ between groups. This study provides further evidence for a pronounced involvement of the autonomic …nervous system in GBA -PD. Show more

Keywords: Autonomic symptoms, GBA, orthostatic hypotension, Parkinson’s disease

DOI: 10.3233/JPD-223197

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2022

Authors: Wuehr, Max | Schmidmeier, Florian | Katzdobler, Sabrina | Fietzek, Urban M. | Levin, Johannes | Zwergal, Andreas

Article Type: Research Article

Abstract: Background: Postural instability is a major disabling factor in patients with advanced Parkinson’s disease (PD) and often resistant to treatment. Previous studies indicated that imbalance in PD may be reduced by low-intensity noisy galvanic vestibular stimulation (nGVS). Objective: To investigate the potential mode of action of this therapeutic effect. In particular, we examined whether nGVS-induced reductions of body sway in PD are compatible with stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can paradoxically enhance sensory information transfer. Methods: Effects of nGVS of varying intensities (0–0.7 mA) on body sway were examined in 15 …patients with PD standing with eye closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal reductions of sway at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR. Results: nGVS-induced reductions of body sway compatible with SR were found in 10 patients (67%) with optimal improvements of 23±13% . In 7 patients (47% ), nGVS-induced sway reductions exceeded the minimally important clinical difference (optimal improvement: 30±10% ), indicative of strong SR. This beneficial effect was more likely in patients with advanced PD (R  = 0.45; p  = 0.045). Conclusions: At least half of the assessed patients showed robust improvements in postural balance compatible with SR when treated with low-intensity nGVS. In particular, patients with more advanced disease stages and imbalance may benefit from the non-invasive and well-tolerated treatment with nGVS. Show more

Keywords: Balance, body sway, galvanic vestibular stimulation, Parkinson’s disease, stochastic resonance

DOI: 10.3233/JPD-213127

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

Authors: Petry-Schmelzer, Jan Niklas | Schwarz, Lisa M. | Jergas, Hannah | Reker, Paul | Steffen, Julia K. | Dafsari, Haidar S. | Baldermann, Juan Carlos | Fink, Gereon R. | Visser-Vandewalle, Veerle | Dembek, Till A. | Barbe, Michael T.

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for patients with Parkinson’s disease. Previous acute challenge studies suggested that short pulse widths might increase the therapeutic window while maintaining motor symptom control with a decrease in energy consumption. However, only little is known about the effect of short pulse width stimulation beyond the setting of an acute challenge. Objective: To compare 4 weeks of STN-DBS with conventional pulse width stimulation (60 μs) to 4 weeks of STN-DBS with short pulse width stimulation (30 μs) regarding motor symptom control. Methods: This study was a …monocentric, double-blinded, randomized crossover non-inferiority trial investigating whether short pulse width stimulation with 30 μs maintains equal motor control as conventional 60 μs stimulation over a period of 4 weeks (German Clinical Trials Register No. DRKS00017528). Primary outcome was the difference in motor symptom control as assessed by a motor diary. Secondary outcomes included energy consumption measures, non-motor effects, side-effects, and quality of life. Results: Due to a high dropout rate, the calculated sample size of 27 patients was not met and 24 patients with Parkinson’s disease and STN-DBS were included in the final analysis. However, there were no differences in any investigated outcome parameter between the two treatment conditions. Conclusion: This study demonstrates that short pulse width settings (30 μs) provide non-inferior motor symptom control as conventional (60 μs) stimulation without significant differences in energy consumption. Future studies are warranted to evaluate a potential benefit of short pulse width settings in patients with pronounced dyskinesia. Show more

Keywords: Non-motor symptoms, speech, gait, quality of life, motor symptoms, motor diary, nucleus subthalamicus

DOI: 10.3233/JPD-213119

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Chendo, Ines | Silva, Carlos | Duarte, Gonçalo S. | Prada, Luisa | Vian, João | Quintão, Ana | Voon, Valerie | Ferreira, Joaquim J.

Article Type: Systematic Review

Abstract: Background: Depressive disorders are recognized as a common neuropsychiatric disorder of Parkinson’s disease (PD). Reported frequencies vary widely among studies and depend on the diagnostic criteria, the methods of ascertainment used, and the population sampled. Objective: We aimed to evaluate the frequency of depressive disorders in PD and to investigate the relationship with PD clinical variables. Methods: A systematic review and meta-analysis of observational studies (community-based, prospective and retrospective cohort, case-control, community-based, and cross-sectional studies) reporting the frequency of depressive disorders in PD patients. Results: Electronic database search wielded 3,536 articles; an additional 91 …were identified through citation chaining. 163 full-text articles were assessed for eligibility. Of these, 49 met the inclusion criteria for our analysis. The pooled frequency of depressive disorders was 30.7% (95% confidence interval [CI] 25.6 to 36.2; I2  = 95% ; 49 studies; combined n  = 10,039). The pooled frequency of major depressive disorder was 14.0% (95% CI 10.5 to 18.5; I2  = 88% ; 23 studies; combined n  = 5,218). Subgroup/meta-regression analyses were conducted to investigate the relationship between frequency and study inclusion criteria, methodology used for diagnosis, and study design. We found a statistically significant correlation between study design and depressive disorders frequency (ranging from 8% in the community-based study to 44% in the retrospective studies) and a statistically significant positive correlation between mean baseline PD duration and major depressive disorder frequency. Conclusion: The current meta-analysis found a global frequency of depressive disorders of 30.7% and major depressive disorder of 14.0% . Study design influenced the frequency of depressive disorders in PD. Mean baseline PD duration and major depressive disorder frequency were positively correlated. Show more

Keywords: Parkinson’s disease, depressive disorders, major depressive disorder, systematic review, meta–analysis

DOI: 10.3233/JPD-223207

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

Authors: Elabi, Osama F. | Pass, Rachel | Sormonta, Irene | Nolbrant, Sara | Drummond, Nicola | Kirkeby, Agnete | Kunath, Tilo | Parmar, Malin | Lane, Emma L.

Article Type: Research Article

Abstract: Background: First-in-human studies to test the efficacy and safety of human embryonic stem cells (hESC)-derived dopaminergic cells in the treatment of Parkinson’s disease (PD) are imminent. Pre-clinical studies using hESC-derived dopamine neuron transplants in rat models have indicated that the benefits parallel those shown with fetal tissue but have thus far failed to consider how ongoing L-DOPA administration might impact on the graft. Objective: To determine whether L-DOPA impacts on survival and functional recovery following grafting of hESC-derived dopaminergic neurons. Methods: Unilateral 6-OHDA lesioned rats were administered with either saline or L-DOPA prior to, and for …18 weeks following surgical implantation of dopaminergic neural progenitors derived from RC17 hESCs according to two distinct protocols in independent laboratories. Results: Grafts from both protocols elicited reduction in amphetamine-induced rotations. Reduced L-DOPA-induced dyskinesia preceded the improvement in amphetamine-induced rotations. Furthermore, L-DOPA had no effect on overall survival (HuNu) or dopaminergic neuron content of the graft (TH positive cells) but did lead to an increase in the number of GIRK2 positive neurons. Conclusion: Critically, we found that L-DOPA was not detrimental to graft function, potentially enhancing graft maturation and promoting an A9 phenotype. Early improvement of L-DOPA-induced dyskinesia suggests that grafts may support the handling of exogenously supplied dopamine earlier than improvements in amphetamine-induced behaviours indicate. Given that one of the protocols will be employed in the production of cells for the European STEM-PD clinical trial, this is vital information for the management of patients and achieving optimal outcomes following transplantation of hESC-derived grafts for PD. Show more

Keywords: L-dopa-induced dyskinesia, 6-OHDA lesioned rat, Parkinson’s disease, abnormal involuntary movements, transplantation, human embryonic stem cells

DOI: 10.3233/JPD-212920

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

Authors: Darweesh, Sirwan K.L. | De Vries, Nienke M. | Helmich, Rick C. | Verbeek, Marcel M. | Schwarzschild, Michael A. | Bloem, Bastiaan R.

Article Type: Editorial

DOI: 10.3233/JPD-223216

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2022

Authors: Day, Jacob O. | Smith, Stephen | Noyce, Alastair J. | Alty, Jane | Jeffery, Alison | Chapman, Rebecca | Carroll, Camille

Article Type: Short Communication

Abstract: Digital health technologies (DHTs) have great potential for use as clinical trial outcomes; however, practical issues need to be addressed in order to maximise their benefit. We describe our experience of incorporating two DHTs as secondary/exploratory outcome measures in PD STAT, a randomised clinical trial of simvastatin in people with Parkinson’s disease. We found much higher rates of missing data in the DHTs than the traditional outcome measures, in particular due to technical and software difficulties. We discuss methods to address these obstacles in terms of protocol design, workforce training and data management.

Keywords: Parkinson’s disease, clinical trials, digital outcomes, sensors, data management

DOI: 10.3233/JPD-223162

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2022

Authors: Kawada, Tomoyuki

Article Type: Letter

Keywords: α-synuclein-related neurodegenerative diseases, rapid eye movement sleep behavior disorder, risk factors

DOI: 10.3233/JPD-223306

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2022

Authors: Pengo, Marta | Murueta-Goyena, Ane | Teijeira-Portas, Sara | Acera, Marian | Del Pino, Rocio | Sáez-Atxukarro, Oihane | Diez-Cirarda, Maria | Tijero, Beatriz | Fernández-Valle, Tamara | Gómez Esteban, Juan Carlos | Gabilondo, Iñigo

Article Type: Research Article

Abstract: Background: Visual impairment is frequent and highly disabling in Parkinson’s disease (PD); however, few studies have comprehensively evaluated its impact on vision-related quality of life. Objective: To evaluate the relationship between visual function tests and the visual impairment perceived by PD patients in daily living activities. Methods: We cross-sectionally evaluated 62 PD patients and 33 healthy controls (HC). Visual disability was measured with a comprehensive battery of primary visual function and visual cognition tests (visual outcomes), and vision-related quality of life was evaluated with the National Eye Institute 25-Item Visual Function Questionnaire (NEI VFQ-25). The relationship …between visual outcomes and NEI VFQ-25 sub-scores was analyzed with Pearson’s correlations and stepwise linear regression. Results: In PD patients, and not in HC, most NEI VFQ-25 sub-scores were significantly correlated with Cube Analysis and Dot Counting from Visual Object and Space Perception (VOSP) battery (visual perception), Clock Drawing Test (visuoconstructive capacity) and Trail Making Test part-A (visual attention and processing speed) and to a lesser extent with high- and low-contrast visual acuity. Dot Counting (VOSP) was the test primarily associated with most NEI VFQ-25 sub-scores (5 out of 12). Roth-28 color test was the one that best explained the variance of Peripheral Vision (R2 : 0.21) and Role Difficulties (R2 : 0.36) sub-scores of NEI VFQ-25, while photopic contrast sensitivity explained 41% of Driving sub-score variance. Conclusion: Vision-related quality of life in PD is mainly influenced by alterations in visual perception, visuoconstructive capacity and visual attention and processing speed. Future studies are warranted to confirm and further extend our findings. Show more

Keywords: Activities of daily living, visual acuity, contrast sensitivity, visual cognition, Parkinson’s disease

DOI: 10.3233/JPD-213143

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Gibson, Lucy L. | Pollak, Thomas A. | Heslegrave, Amanda | Hye, Abdul | Batzu, Lucia | Rota, Silvia | Trivedi, Dhaval | Nicholson, Timothy R. | ffytche, Dominic | Zetterberg, Henrik | Chaudhuri, K. Ray | Aarsland, Dag

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively which have yet to be explored in association with the affective and psychotic symptoms in PD. Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD. Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n … = 63) was assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using Non-Motor Symptom Scale with affective symptoms measured in the Hospital Anxiety and Depression Scale. Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p  = 0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms. Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD. Show more

Keywords: Neurofilament light, p-tau, psychosis, neuropsychiatric symptoms, biomarker, Parkinson’s disease

DOI: 10.3233/JPD-223182

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2022

Authors: Lee, Susan J. | Shaw, Peter M. | Thornton, Bob | Kumar, Amit | Eizik, Michal | Goldstaub, Dan | Braun, Tali | Teper, Gally | Pai, Jennifer K. | Chodick, Gabriel | Bienfait, Karina | Levitan, Diane | Beller, Daniella | Chris Min, K. | Jonathan, Daniel | Voss, Tiffini | Fox, Caroline S. | Aubrey Stoch, S. | Struyk, Arie F. | Vainstein, Gabriel

Article Type: Research Article

Abstract: Background: More efficient screening methods are needed to improve the ability to identify and follow genetic cohorts in Parkinson’s disease (PD). Objective: To explore the use of the electronic medical records (EMRs) to identify participants with PD. Methods: Using an algorithm previously developed in collaboration with Maccabi Healthcare Services (MHS), approximately 5,200 participants with PD were identified, more than 3,200 were screened, and 837 participants were enrolled and genotyped for leucine-rich repeat kinase 2 (LRRK2 ) and beta-glucocerebrosidase (GBA) variants. Questionnaires were completed to ascertain Ashkenazi Jewish (AJ) ancestry and family history of PD. …Results: Among 837 participants with PD, 82% were 65 years and older and 72% had a family history of AJ ancestry. Among those with AJ ancestry, 15.6% reported having relatives with PD. The frequency of observed mutations for LRRK2 and GBA genes combined was approximately 15.4% . The frequency of observed LRRK2 mutation was 6.1% overall and 7.2% from those with AJ ancestry; and for GBA mutation was 9.3% overall and 11.2% from those with AJ ancestry. Conclusion: Although the frequency of observed mutations in this study was lower than anticipated, mutation carriers were enriched among those with a family history of AJ ancestry increasing nearly 2-3-fold, from 3% –7% (LRRK2 ) and 4% –11% (GBA ). The identification (and selection) of PD patients through EMRs prior to genotyping is a viable approach, to establish a genetically defined cohort of patients with PD for clinical research. Show more

Keywords: Parkinson’s disease, glucocerebrosidase, Parkinson mutations, genetic testing

DOI: 10.3233/JPD-212703

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2022

Authors: Kehagia, Angie A. | North, Tracie K. | Grose, Jane | Jeffery, Alison N. | Cocking, Laura | Chapman, Rebecca | Carroll, Camille

Article Type: Research Article

Abstract: Background: Recruitment and retention of participants in clinical trials for Parkinson’s disease (PD) is challenging. A qualitative study embedded in the PD STAT multi-centre randomised controlled trial of simvastatin for neuroprotection in PD explored the motivators, barriers and challenges of participants, care partners and research staff. Objective: To outline a set of considerations informing a patient-centred approach to trial recruitment, retention, and delivery. Method: We performed semi-structured interviews and focus groups with a subset of trial participants and their care partners. Quantitative and qualitative data were obtained through surveys circulated among the 235 participants across 23 UK …sites at the beginning, middle and end of the 2-year trial. We also interviewed and surveyed research staff at trial closure. Results: Twenty-seven people with PD, 6 care partners and 9 researchers participated in interviews and focus groups. A total of 463 trial participant survey datasets were obtained across three timepoints, and 53 staff survey datasets at trial closure. Trial participants discussed the physical and psychological challenges they faced, especially in the context of OFF state assessments, relationships, and communication with research staff. Care partners shared their insights into OFF state challenges, and the value of being heard by research teams. Research staff echoed many concerns with suggestions on flexible, person-centred approaches to maximising convenience, comfort, and privacy. Conclusion: These considerations, in favour of person-centred research protocols informed by the variable needs of participants, care partners and staff, could be developed into a set of recommendations for future trials. Show more

Keywords: Parkinson’s disease, clinical trial, participation, recruitment, retention, OFF assessment, consent, patient-centred, qualitative, PPI

DOI: 10.3233/JPD-212987

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2022

Authors: Kung, Pin-Jui | Elsayed, Inas | Reyes-Pérez, Paula | Bandres-Ciga, Sara

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is increasingly recognised as a systemic disorder in which inflammation might play a causative role rather than being a consequence or an epiphenomenon of the neurodegenerative process. Although growing genetic evidence links the central and peripheral immune system with both monogenic and sporadic PD, our understanding on how the immune system contributes to PD pathogenesis remains a daunting challenge. In this review, we discuss recent literature aimed at exploring the role of known genes and susceptibility loci to PD pathogenesis through immune system related mechanisms. Furthermore, we outline shared genetic etiologies and interrelations between PD and autoimmune …diseases and underlining challenges and limitations faced in the translation of relevant allelic and regulatory risk loci to immune-pathological mechanisms. Lastly, with the field of immunogenetics expanding rapidly, we place these insights into a future context highlighting the prospect of immune modulation as a promising disease-modifying strategy. Show more

Keywords: Parkinson’s disease, immune system, immunogenetics, risk, onset, progression

DOI: 10.3233/JPD-223176

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

Authors: Hobson, Benjamin D. | Sulzer, David

Article Type: Review Article

Abstract: Patients with Parkinson’s disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen’s encephalitis, a pediatric neurological …disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration. Show more

Keywords: MHC, HLA, antigen, epitope, T cell, dopamine neurons, Parkinson’s disease

DOI: 10.3233/JPD-223153

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2022

Authors: Contaldi, Elena | Magistrelli, Luca | Comi, Cristoforo

Article Type: Review Article

Abstract: T cells are key mediators of both humoral and cellular adaptive immune responses, and their role in Parkinson’s disease (PD) is being increasingly recognized. Several lines of evidence have highlighted how T cells are involved in both the central nervous system and the periphery, leading to a profound imbalance in the immune network in PD patients. This review discusses the involvement of T cells in both preclinical and clinical studies, their importance as feasible biomarkers of motor and non-motor progression of the disease, and recent therapeutic strategies addressing the modulation of T cell response.

Keywords: Parkinson’s disease, T cells, CD4 + T cells, CD8 + T cells, neuroinflammation, peripheral immunity

DOI: 10.3233/JPD-223152

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

Authors: Sidoroff, Victoria | Bower, Pam | Stefanova, Nadia | Fanciulli, Alessandra | Stankovic, Iva | Poewe, Werner | Seppi, Klaus | Wenning, Gregor K. | Krismer, Florian

Article Type: Research Article

Abstract: Multiple system atrophy is a rapidly progressive and fatal neurodegenerative disorder. While numerous preclinical studies suggested efficacy of potentially disease modifying agents, none of those were proven to be effective in large-scale clinical trials. Three major strategies are currently pursued in preclinical and clinical studies attempting to slow down disease progression. These target α-synuclein, neuroinflammation, and restoration of neurotrophic support. This review provides a comprehensive overview on ongoing preclinical and clinical developments of disease modifying therapies. Furthermore, we will focus on potential shortcomings of previous studies that can be avoided to improve data quality in future studies of this rare …disease. Show more

Keywords: Atypical Parkinson’s disease, clinical trials, disease modification, multiple system atrophy

DOI: 10.3233/JPD-223183

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

Authors: Santos García, Diego | de Deus Fonticoba, Teresa | Cores, Carlos | Castro, Ester Suárez | Hernández Vara, Jorge | Jesús, Silvia | Mir, Pablo | Cosgaya, Marina | Martí, Maria José | Pastor, Pau | Cabo, Iria | Seijo, Manuel | Legarda, Inés | Vives, Bárbara | Caballol, Nuria | Rúiz Martínez, Javier | Croitoru, Ioana | Cubo, Esther | Miranda, Javier | Alonso Losada, Maria Gema | Labandeira, Carmen | López Ariztegui, Nuria | Morales-Casado, Mabel | González Aramburu, Isabel | Infante, Jon | Escalante, Sonia | Bernardo, Noemí | Blázquez Estrada, Marta | Menéndez González, Manuel | Caldentey, Juan García | Borrué, Carmen | Vela, Lydia | Catalán, Maria José | Gómez Mayordomo, Víctor | Kurtis, Mónica | Prieto, Cristina | Ordás, Carlos | Nogueira, Víctor | López Manzanares, Lydia | Ávila Rivera, Maria Asunción | Puente, Victor | García Moreno, Jose Manuel | Solano Vila, Berta | Álvarez Sauco, María | Carrillo Padilla, Francisco | Carlos Martínez Castrillo, Juan | Sánchez Alonso, Pilar | Gastón, Itziar | Kulisevsky, Jaime | Valero, Caridad | de Fábregues, Oriol | González Ardura, Jessica | López Díaz, Luis Manuel | Martinez-Martin, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed …on time to hospital encounter 1-year after the baseline visit. Results: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p = 0.035) was an independent predictor of AH. Conclusion: Falls is an independent predictor of AH in PD patients. Show more

DOI: 10.3233/JPD-212539

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021