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Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy., (© 2024. The Author(s).)

Background: Parkinson's disease psychosis (PDP) is a multidimensional construct that is challenging to measure. Accurate assessment of PDP requires comprehensive and reliable clinical outcome assessment (COA) measures., Objective: To identify PDP measurement gaps in available COAs currently used in clinical and research settings., Methods: We conducted a scoping review using Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines. We implemented a three-step search strategy in international databases with keywords related to Parkinson's disease (PD), psychosis, and COA. We analyzed studies using COA to assess PDP, classifying their items according to domains and subdomains., Results: From 5673 identified studies, we included 628 containing 432 PDP core items from 32 COAs. Among the 32 COAs, 19 were PD-specific, containing 266 items, constructed as clinician-reported outcomes (ClinRO) (148 items), patient-reported outcomes (PRO) (112 items), and observer-reported outcomes (ObsRO) (six items). Across all PD-specific COAs, regardless of structure, 89.4% of the items from 27 COAs focused primarily on assessing PDP symptoms' severity, and only 9.7% of items probed the impact of PDP on a person's daily functioning., Conclusions: Symptom-based domains are currently prioritized for measuring the severity of PDP, with limited coverage of the functional impact of PDP on patients' lives. Whereas the International Parkinson and Movement Disorder Society has traditionally developed a "Unified" COA that culls items from prior COAs to form a new one, a new COA will largely need newly developed items if the functional impact of PDP is prioritized. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

One of the main hallmarks of Parkinson's disease (PD) is abnormal alpha-synuclein (α-syn) aggregation which forms the main component of intracellular Lewy body inclusions. This short report used preformed α-syn fibrils, as well as an A53T mutant α-syn adenovirus to mimic conditions of pathological protein aggregation in dopaminergic human derived SH-SY5Y neural cells. Since there is evidence that the mTOR pathway and glutamatergic signaling each influence protein aggregation, we also assessed the impact of the mTOR inhibitor, rapamycin and the mGluR5 allosteric modulator, CTEP. We found that both rapamycin and CTEP induced a significant reduction of α-syn fibrils in SH-SY5Y cells and this effect was associated with a reduction in mTOR signaling and enhancement in autophagic pathway factors. These data support the possibility that CTEP (or rapamycin) might be a useful pharmacological approach to target abnormal α-syn accumulation by promoting intracellular degradation or enhanced clearance., (© 2024. The Author(s).)

Background: Enhancing the interactions between study participants, clinicians, and investigators is imperative for advancing Parkinson's disease (PD) research. The Canadian Open Parkinson Network (C-OPN) stands as a nationwide endeavor, connecting the PD community with ten accredited universities and movement disorders research centers spanning, at the time of this analysis, British Columbia, Alberta, Ontario, and Quebec., Objective: Our aim is to showcase C-OPN as a paradigm for bolstering national collaboration to accelerate PD research and to provide an initial overview of already collected data sets., Methods: The C-OPN database comprises de-identified data concerning demographics, symptoms and signs, treatment approaches, and standardized assessments. Additionally, it collects venous blood-derived biomaterials, such as for analyses of DNA, peripheral blood mononuclear cells (PBMC), and serum. Accessible to researchers, C-OPN resources are available through web-based data management systems for multi-center studies, including REDCap., Results: As of November 2023, the C-OPN had enrolled 1,505 PD participants. The male-to-female ratio was 1.77:1, with 83% (n = 1098) residing in urban areas and 82% (n = 1084) having pursued post-secondary education. The average age at diagnosis was 60.2±10.3 years. Herein, our analysis of the C-OPN PD cohort encompasses environmental factors, motor and non-motor symptoms, disease management, and regional differences among provinces. As of April 2024, 32 research projects have utilized C-OPN resources., Conclusions: C-OPN represents a national platform promoting multidisciplinary and multisite research that focuses on PD to promote innovation, exploration of care models, and collaboration among Canadian scientists.

Background: Cognitive decline is a common but variable non-motor manifestation of Parkinson's disease. Chronic liver disease contributes to dementia, but its impact on cognitive performance in Parkinson's disease is unknown. We assessed the effect of liver fibrosis on cognition in Parkinson's disease., Methods: We conducted a retrospective cohort study using data from the Parkinson's Progression Markers Initiative. Our exposure was liver fibrosis at baseline, based on the validated Fibrosis-4 score. Our primary outcome was the Montreal Cognitive Assessment, and additional outcome measures were the Symbol Digit Modalities Test, the Benton Judgement of Line Orientation, the Letter-Number Sequencing Test, and the Modified Semantic Fluency Test. We used linear regression models to assess the relationship between liver fibrosis and scores on cognitive assessments at baseline and linear mixed models to evaluate the association between baseline Fibrosis-4 score with changes in each cognitive test over five years. Models were adjusted for demographics, comorbidities, and alcohol use., Results: We included 409 participants (mean age 61, 40 % women). There was no significant association between liver fibrosis and baseline performance on any of the cognitive assessments in adjusted models. However, over the subsequent five year period, liver fibrosis was associated with more rapid decline in scores on the Montreal Cognitive Assessment (interaction coefficient, -0.07; 95 % CI, -0.12, -0.02), the Symbol Digit Modalities Test, the Benton Judgement of Line Orientation, and the Modified Semantic Fluency Test., Conclusion: In people with Parkinson's disease, the presence of comorbid liver fibrosis was associated with more rapid decline across multiple cognitive domains., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: No specific funding was received for this work. The PPMI is a public–private partnership that is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including Abbvie, AcureX, Aligning Science Across Parkinson's, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity. NP is supported by the NIH/NIA (K23 AG073524) and the Florence Gould Endowment for Discovery in Stroke. NP has received personal fees for medicolegal consulting and provides blinded end point assessment for the Embolization of the Middle Meningeal Artery With ONYX Liquid Embolic System for Subacute and Chronic Subdural Hematoma trial (Medtronic) for participants enrolled at his institution. HS has done consulting work for Novo Nordisk, Blue Rock Therapeutics, and Neuroderm. HS has also received clinical trial support from Blue Rock Therapeutics, Prevail Therapeutics, Neuroderm, Covance, Insightec, and National Institutes of Health (NIH). HK is the principle investigator of the ARCADIA trial (NIH/NINDS U01NS095869),which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, U01NS106513). HK is Deputy Editor for JAMA Neurology, sits on the clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical, is a member of the endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim, and has household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. AZ, CZ, and HO declare that there are no disclosures to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson's and other neurodegenerative diseases and binds to negatively charged phospholipids. Previously, we reported that α-Syn clusters synthetic proteoliposomes that mimic synaptic vesicles. This vesicle-clustering activity depends on a specific interaction of α-Syn with anionic phospholipids. Here, we report that α-Syn surprisingly also interacts with the neutral phospholipid lysophosphatidylcholine (lysoPC). Even in the absence of anionic lipids, lysoPC facilitates α-Syn-induced vesicle clustering but has no effect on Ca 2+ -triggered fusion in a single vesicle-vesicle fusion assay. The A30P mutant of α-Syn that causes familial Parkinson disease has a reduced affinity to lysoPC and does not induce vesicle clustering. Taken together, the α-Syn-lysoPC interaction may play a role in α-Syn function.

Patients diagnosed with Parkinson's disease (PD) have difficulty initiating and executing movements due to an acquired imbalance of the basal ganglia thalamocortical circuit secondary to loss of dopaminergic input into the striatum. The unbalanced circuit is hyper-synchronized, presenting as larger and longer bursts of beta-band (13-30 Hz) oscillations in the subthalamic nucleus (STN). As a first step toward a novel PD therapy that aims to improve symptoms through beta desynchronization, we sought to determine if individuals with PD could acquire volitional control of STN beta power in a neurofeedback task. We found a significant difference in STN beta power between task conditions, and relevant brain signal features could be detected and decoded in real time. This demonstration of volitional control of STN beta motivates development of a neurofeedback therapy to modulate PD symptom severity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into a complex entity, akin to the heterogeneity of other complex human syndromes of the central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, and basic science researchers evolved arrange of concepts andcriteria for the clinical, genetic, mechanistic, and neuropathological characterization of what, in their best judgment, constitutes PD. However, these specialists have generated and used criteria that are not necessarily aligned between their different operational definitions, which may hinder progress in solving the riddle of the distinct forms of PD and ultimately how to treat them., Objective: This task force has identified current in consistencies between the definitions of PD and its diverse variants in different domains: clinical criteria, neuropathological classification, genetic subtyping, biomarker signatures, and mechanisms of disease. This initial effort for "defining the riddle" will lay the foundation for future attempts to better define the range of PD and its variants, as has been done and implemented for other heterogeneous neurological syndromes, such as stroke and peripheral neuropathy. We strongly advocate for a more systematic and evidence-based integration of our diverse disciplines by looking at well-defined variants of the syndrome of PD., Conclusion: Accuracy in defining endophenotypes of "typical PD" across these different but interrelated disciplines will enable better definition of variants and their stratification in therapeutic trials, a prerequisite for breakthroughs in the era of precision medicine. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Neuropsychiatric symptoms (NPS) are a core feature of most neurodegenerative and cerebrovascular diseases. White matter hyperintensities and brain atrophy have been implicated in NPS. We aimed to investigate the relative contribution of white matter hyperintensities and cortical thickness to NPS in participants across neurodegenerative and cerebrovascular diseases., Methods: Five hundred thirteen participants with one of these conditions, i.e. Alzheimer's Disease/Mild Cognitive Impairment, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, Parkinson's Disease, or Cerebrovascular Disease, were included in the study. NPS were assessed using the Neuropsychiatric Inventory - Questionnaire and grouped into hyperactivity, psychotic, affective, and apathy subsyndromes. White matter hyperintensities were quantified using a semi-automatic segmentation technique and FreeSurfer cortical thickness was used to measure regional grey matter loss., Results: Although NPS were frequent across the five disease groups, participants with frontotemporal dementia had the highest frequency of hyperactivity, apathy, and affective subsyndromes compared to other groups, whilst psychotic subsyndrome was high in both frontotemporal dementia and Parkinson's disease. Results from univariate and multivariate results showed that various predictors were associated with neuropsychiatric subsyndromes, especially cortical thickness in the inferior frontal, cingulate, and insula regions, sex(female), global cognition, and basal ganglia-thalamus white matter hyperintensities., Conclusions: In participants with neurodegenerative and cerebrovascular diseases, our results suggest that smaller cortical thickness and white matter hyperintensity burden in several cortical-subcortical structures may contribute to the development of NPS. Further studies investigating the mechanisms that determine the progression of NPS in various neurodegenerative and cerebrovascular diseases are needed., (© 2023. The Author(s).)

Introduction: 83% of those diagnosed with Parkinson's Disease (PD) eventually progress to PD with mild cognitive impairment (PD-MCI) followed by dementia (PDD) - suggesting a complex spectrum of pathology concomitant with aging. Biomarkers sensitive and specific to this spectrum are required if useful diagnostics are to be developed that may supplement current clinical testing procedures. We used video-based eye tracking and machine learning to develop a simple, non-invasive test sensitive to PD and the stages of cognitive dysfunction., Methods: From 121 PD (45 Cognitively Normal/45 MCI/20 Dementia/11 Other) and 106 healthy controls, we collected video-based eye tracking data on an interleaved pro/anti-saccade task. Features of saccade, pupil, and blink behavior were used to train a classifier to predict confidence scores for PD/PD-MCI/PDD diagnosis., Results: The Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of the classifier was 0.88, with the cognitive-dysfunction subgroups showing progressively increased AUC, and the AUC of PDD being 0.95. The classifier reached a sensitivity of 83% and a specificity of 78%. The confidence scores predicted PD motor and cognitive performance scores., Conclusion: Biomarkers of saccade, pupil, and blink were extracted from video-based eye tracking to create a classifier with high sensitivity to the landscape of PD cognitive and motor dysfunction. A complex landscape of PD is revealed through a quick, non-invasive eye tracking task and our model provides a framework for such a task to be used as a supplementary screening tool in the clinic., Competing Interests: Declaration of competing interest None'., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Purpose: The pathophysiology of Parkinson's disease (PD) negatively affects brain network connectivity, and in the presence of brain white matter hyperintensities (WMHs) cognitive and motor impairments seem to be aggravated. However, the role of WMHs in predicting accelerating symptom worsening remains controversial. The objective was to investigate whether location and segmental brain WMH burden at baseline predict cognitive and motor declines in PD after 2 years., Methods: Ninety-eight older adults followed longitudinally from Ontario Neurodegenerative Diseases Research Initiative with PD of 3-8 years in duration were included. Percentages of WMH volumes at baseline were calculated by location (deep and periventricular) and by brain region (frontal, temporal, parietal, occipital lobes and basal ganglia + thalamus). Cognitive and motor changes were assessed from baseline to 2-year follow-up. Specifically, global cognition, attention, executive function, memory, visuospatial abilities and language were assessed as were motor symptoms evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III, spatial-temporal gait variables, Freezing of Gait Questionnaire and Activities Specific Balance Confidence Scale., Results: Regression analysis adjusted for potential confounders showed that total and periventricular WMHs at baseline predicted decline in global cognition (p < 0.05). Also, total WMH burden predicted the decline of executive function (p < 0.05). Occipital WMH volumes also predicted decline in global cognition, visuomotor attention and visuospatial memory declines (p < 0.05). WMH volumes at baseline did not predict motor decline., Conclusion: White matter hyperintensity burden at baseline predicted cognitive but not motor decline in early to mid-stage PD. The motor decline observed after 2 years in these older adults with PD is probably related to the primary neurodegenerative process than comorbid white matter pathology., (© 2023 European Academy of Neurology.)

Two recent, high-profile manuscripts reported negative results with two parallel approaches of passive immunization targeting α-synuclein in a population of patients with early Parkinson's disease (PD). These phase II studies failed to show a bona fide disease-modifying neuroprotective effect on PD progression, despite the evidence that these antibodies effectively bind native α-synuclein in human serum. Here, we discuss the possible reasons that could help explain the lack of clinical efficacy. In particular, we highlight (1) the wealth of evidence supporting the notion of α-synuclein as a valid therapeutic target; (2) the lack of evidence of target engagement in the aforementioned studies, especially of the elusive oligomeric species, the likely culprits in disease pathogenesis and/or its propagation; (3) the limitations, especially in terms of timing passive immunization, of preclinical models, where the same α-synuclein antibodies succeeded in mitigating disease manifestations; (4) the consideration of possibly intervening at an even earlier stage of disease in future trials; and (5) the multitude of strategies beyond passive immunization that could be used to combat α-synuclein-mediated neurodegeneration, if in the end the current approach is not fruitful. Overall, our perception is that converging developments in the field, among them novel bioassays and biomarkers, improved cellular and animal models and objective measurements of motor activities integrated into clinical trials, if further optimized, will gradually move the momentum of the field forward. This, to better test the concept of whether α-synuclein-targeting therapies can indeed deliver the "holy grail" of neuroprotection to the benefit of the PD community. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Regulatory recommendations favor outcomes combining objective and patient input. The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the most commonly used scale in Parkinson's disease (PD), includes patient and investigator ratings in distinct parts, but original clinimetric analyses failed to confirm the validity of combining parts by simple summing., Objectives: The aim was to develop clinimetrically valid constructs for combining patient-reported Part 2 and investigator-rated Part 3 MDS-UPDRS scores., Methods: Using 7888 MDS-UPDRS scores, we assessed construct validity of combined Part 2 and Part 3 items using exploratory factor analysis (EFA) and graded item response theory (IRT) with threshold criteria: comparative fit index ≥0.9 (EFA) and discrimination parameters ≥0.65 (IRT)., Results: The direct sum of Parts 2 + 3 failed to meet the threshold for a valid outcome of PD severity (comparative fit index, CFI = 0.855). However, a two-domain construct combining item scores for tremor and non-tremor domains from Parts 2 and 3 confirmed validity, meeting both EFA and IRT criteria as distinct but correlated indices of disease severity (CFI = 0.923; discrimination mean 2.197 ± 0.480 [tremor] and 1.737 ± 0.344 [non-tremor] domains)., Conclusions: The sum of Parts 2 + 3 is not clinimetrically sound. However, considering tremor and non-tremor items of both Parts 2 and 3 as two outcomes results in a valid summary of PD motor severity that leverages simultaneous patient- and investigator-derived measures. This analytic application addresses regulatory prioritizations and retains the well-validated MDS-UPDRS items. In future interventional trials, we suggest that tremor and non-tremor components of PD motor severity from Parts 2 + 3 be monitored and analyzed to accurately detect objective changes that integrate the patient's voice. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Genetics are fundamental to understanding the pathophysiology of neurological disease, including movement disorders. Genetic testing in clinical practice has changed dramatically over the last few decades. While the likelihood of establishing an etiological diagnosis is greater now with increased access to testing and more advanced technologies, clinicians face challenges when deciding whether to test, then selecting the appropriate test, and ultimately interpreting and sharing the results with patients and families. In this review, we use a case-based approach to cover core aspects of genetic testing for the neurologist, namely, genetic testing in Parkinson's disease, interpretation of inconclusive genetic test reports, and genetic testing for repeat expansion disorders using Huntington disease as a prototype., Competing Interests: None declared., (Thieme. All rights reserved.)

α-Synuclein is a neuronal protein that is enriched in presynaptic terminals. Under physiological conditions, it binds to synaptic vesicle membranes and functions in neurotransmitter release, although the molecular details remain unclear, and it is controversial whether α-synuclein inhibits or facilitates neurotransmitter release. Pathologically, in synucleinopathies including Parkinson's disease (PD), α-synuclein forms aggregates that recruit monomeric α-synuclein and spread throughout the brain, which triggers neuronal dysfunction at molecular, cellular, and organ levels. Here, we present an overview of the effects of α-synuclein on SNARE-complex assembly, neurotransmitter release, and synaptic vesicle pool homeostasis, and discuss how the observed divergent effects of α-synuclein on neurotransmitter release can be reconciled. We also discuss how gain-of-function versus loss-of-function of α-synuclein may contribute to pathogenesis in synucleinopathies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Original clinimetric analyses by the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) developers did not confirm the validity of summing the scores of its parts. Recent studies used the summed score of Part III and other parts as efficacy outcomes., Objective: The aim of this study was to establish whether summing scores of MDS-UPDRS parts can be recommended., Methods: Using 7466 full MDS-UPDRS scores, we applied two-step factor analysis as in the original article to reassess the validity analysis with the threshold criterion set at comparative fit index ≥0.9., Results: All comparative fit indexes of any combination including Part III were lower than 0.90., Conclusions: Summing Part III MDS-UPDRS scores with other parts is not clinimetrically sound. The MDS-UPDRS is a validated four-part scale with corresponding individual part scores and needs to be used within the limits originally presented. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

α-Synuclein is an abundant protein at the neuronal synapse that has been implicated in Parkinson's disease for over 25 years and characterizes the hallmark pathology of a group of neurodegenerative diseases now known as the synucleinopathies. Physiologically, α-synuclein exists in an equilibrium between a synaptic vesicle membrane-bound α-helical multimer and a cytosolic largely unstructured monomer. Through its membrane-bound state, α-synuclein functions in neurotransmitter release by modulating several steps in the synaptic vesicle cycle, including synaptic vesicle clustering and docking, SNARE complex assembly, and homeostasis of synaptic vesicle pools. These functions have been ascribed to α-synuclein's interactions with the synaptic vesicle SNARE protein VAMP2/synaptobrevin-2, the synaptic vesicle-attached synapsins, and the synaptic vesicle membrane itself. How α-synuclein affects these processes, and whether disease is due to loss-of-function or gain-of-toxic-function of α-synuclein remains unclear. In this review, we provide an in-depth summary of the existing literature, discuss possible reasons for the discrepancies in the field, and propose a working model that reconciles the findings in the literature., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adenosine A 2A receptors have been studied extensively in the context of motor function and movement disorders such as Parkinson's disease. In addition to these roles, A 2A receptors have also been increasingly implicated in cognitive function and cognitive impairments in diverse conditions, including Alzheimer's disease, schizophrenia, acute brain injury, and stress. We review the roles of A 2A receptors in cognitive processes in health and disease, focusing primarily on the effects of reducing or enhancing A 2A expression levels or activities in animal models. Studies reveal that A 2A receptors in neurons and astrocytes modulate multiple aspects of cognitive function, including memory and motivation. Converging evidence also indicates that A 2A receptor levels and activities are aberrantly increased in aging, acute brain injury, and chronic disorders, and these increases contribute to neurocognitive impairments. Therapeutically targeting A 2A receptors with selective modulators may alleviate cognitive deficits in diverse neurological and neuropsychiatric conditions. Further research on the exact neural mechanisms of these effects as well as the efficacy of selective A 2A modulators on cognitive alterations in humans are important areas for future investigation., (Copyright © 2023. Published by Elsevier Inc.)

Individuals living with Parkinson's disease (PD) experience interpersonal stressors that contribute to depressive risk. Interpersonal psychotherapy (IPT) emphasizes the bidirectional relationship between interpersonal stressors and mood may therefore be a suitable treatment for PD-depression. The primary aim of this study was to evaluate the feasibility of delivering 12 sessions of IPT to depressed PD patients and explore the need for modifications. A secondary aim was to obtain descriptive information about efficacy outcomes. The study used a pre-post design without a comparison group. Participants were 12 PD patients with a major depressive disorder. IPT was well accepted and tolerated by patients and required minimal modifications. Compliance with session attendance and completion of study questionnaires were excellent and treatment satisfaction was high. Depression scores declined from baseline to endpoint, with 7 patients meeting criteria for remission at endpoint. Findings are encouraging and a larger randomized controlled trial is currently underway to ascertain if IPT is an efficacious treatment for PD-depression.

Background: Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex-distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex-specific genetic contribution to PD without a known genetic variant is controversial., Objectives: To better understand sex differences in genetic contribution to PD, especially sex-specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2-G2019S variant carriers with PD (LRRK2 PD)., Methods: We assess differences in the sex-specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism., Results: Both idiopathic PD (267/420 men, 63.6%) (P &lt; 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk-variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men., Conclusions: Our study demonstrates that the male-sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female-sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex-specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Telemedicine has become standard in clinical care and research during the coronavirus disease 2019 pandemic. Remote administration of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III (Motor Examination) precludes ratings of all items, because Rigidity and Postural Stability (six scores) require in-person rating., Objective: The objective of this study was to determine imputation accuracy for total-sum and item-specific MDS-UPDRS Motor Examination scores in remote administration., Methods: We applied multivariate imputation by chained equations techniques in a cross-sectional dataset where patients had one MDS-UPDRS rating (International Translational Program, n = 8,588) and in a longitudinal dataset where patients had multiple ratings (Rush Program, n = 396). Successful imputation was stringently defined as (1) generalized Lin's concordance correlation coefficient >0.95, reflecting near-perfect agreement between total-sum score with complete data and surrogate score, calculated without patients' actual Rigidity and Postural Stability scores; and (2) perfect agreement for item-level scores for Rigidity and Postural Stability items., Results: For total-sum score when Rigidity and Postural Stability scores were withdrawn, using one or multiple visits, multivariate imputation by chained equations imputation reached near-perfect agreement with the original total-sum score. However, at the item level, the degree of perfect agreement between the surrogate and actual Rigidity items and Postural Stability scores always fell below threshold., Conclusions: The MDS-UPDRS Part III total-sum score, a key clinical outcome in research and in clinical practice, can be accurately imputed without the Rigidity and Postural Stability items that cannot be rated by telemedicine. No formula, however, allows for specific item-level imputation. When Rigidity and Postural Stability item scores are of key clinical or research interest, patients with PD must be scored in person. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson's disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1 + ) terminals in the mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1 + glutamatergic neurons in the cerebral cortex relative to the vGluT2 + glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1 + axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD., Competing Interests: LC, CN, SD, ZF, RD, LM, JS, ME, MH, MR, HC No competing interests declared, PB has received support as a consultant from AbbVie, Axial Therapeutics, Calico Life Sciences, CuraSen, Enterin Inc, Fujifilm-Cellular Dynamics International, Idorsia Pharmaceuticals, Lundbeck A/S. He has received commercial support for research from Lundbeck A/S and F. Hoffman-La Roche. He has ownership interests in Acousort AB, Axial Therapeutics, Enterin Inc and RYNE Biotechnology. During the time that this paper was undergoing revision he became an employee of F. Hoffman-La Roche, although none of the data were generated by this company, (© 2022, Chen, Nagaraja, Daniels et al.)

Background: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested., Objective: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD., Methods: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study., Results: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition., Conclusions: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Growing evidence supports significant involvement of immune dysfunction in the etiology of neurodegenerative diseases, several of which also display prominent sex differences across prevalence, pathology, and symptomology. In this review, we summarize evidence from human studies of established and recent findings of sex differences in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discuss how sex-specific central nervous system innate immune activity could contribute to downstream sex differences in these diseases. We examine human genomic and transcriptomics studies in each neurodegenerative disease through the lens of sex differences in the neuroimmune system and highlight the importance of stratifying sex in clinical and translational research studies. Finally, we discuss the limitations of the existing studies and outline recommendations for further advancing sex-based analyses to uncover novel disease mechanisms that could ultimately help treat both sexes., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Neuron death is a key feature of neurological disorders like Alzheimer's or Parkinson's disease (PD). As a result, analysis of neurodegeneration is often considered a central experiment in the postmortem characterization of preclinical PD animal models. Stereology provides a precise estimate of particles, like neurons, in three-dimensional objects, like the brain, and is the gold standard quantification approach for the assessment of neuron survival in neurodegenerative disease research. Here, we provide a detailed step-by-step guide for the quantification of dopaminergic neurons in the substantia nigra pars compacta, a brain area prone to neuron loss in PD. In addition, we outline the protocol for the analysis of the dopaminergic terminals in the striatum, the projection area of midbrain dopaminergic neurons, as a readout for the integrity of the nigrostriatal projections., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

An integrated care model for people living with Parkinson's disease (PD) offers the promise of meeting complex care needs in a person-centered way that addresses fragmentation and improves quality of life. The purpose of our research was to co-design a care delivery model that supports both social and medical care from the perspective of patients and care partners. In the first step of our co-design approach, participants from five countries were invited to share their experiences of living with PD during a narrative interview. A qualitative analysis of these narrative interviews based on the Corbin and Strauss model was done to map out patients' trajectories. Three typical trajectories were identified: (a) the "unpredictable" trajectory, (b) the "situated" trajectory, and (c) the "demanding" trajectory. Based on the analysis of these trajectories, we were able to integrate various patient experiences into the design of an integrated care network.

Background: Drooling is a clinically relevant non-motor symptom of people with Parkinson's disease (PwP). Several drooling rating scales are available. Nevertheless, the compelling scientific evidence supporting their validity is limited. This study aims to evaluate clinical rating scales for drooling, assessing their characteristics, clinimetric properties, and clinical utility classification., Methods: A systematic review was undertaken. Two reviewers performed independent literature searches using the CENTRAL®, CINAHL®, Embase®, MEDLINE®, SciElo®, and SPEECH BITE® databases. We used consensus-based standards for the selection of health measurement instruments (COSMIN) and the International Parkinson's disease and the Movement Disorders (MDS) criteria to evaluate the included rating scales., Results: The following six rating scales were identified: Drooling Impact Scale (DIS), Sialorrhea Scoring Scale (SSS), Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale (DRS), Sialorrhea Clinical Scale for Parkinson Disease (SCS-PD), and the Radboud Oral Motor inventory for Parkinson's disease - Saliva (ROMP-saliva). The scales had heterogeneous characteristics: (i) not all were created/adapted for PwP; (ii) different dimensions associated with drooling are assessed; (iii) cross-cultural adaptations are limited to some languages. The clinimetric properties showed: (i) target population size limitations; (ii) incomplete reliability analysis; (iii) lack of robust validity; (iv) sensitivity to change not fully explored. Following the MDS criteria, only one tool was classified as "recommended", the ROMP-saliva., Conclusions: This review provides information for an adequate selection of a drooling rating scale for clinical and/or research purposes. To date, ROMP-saliva is the only scale with substantial evidence of its clinimetric properties adequacy and data in PwP., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Expectations of benefit have an important therapeutic impact. How well study participants understand the concept of slowing disease progression and how their expectations of benefit are shaped in related clinical trials is not well known., Objective: We aimed to assess expectancy and treatment arm preference of participants in a disease-modification trial in Parkinson disease (PD)., Methods: Participant expectations and treatment preference were assessed before treatment randomization in the SURE-PD3 trial (NCT02642393)., Results: We included 297 PD patients (0.71 ± 0.67 years after diagnosis). Pre-randomization, 90% of participants expressed a preference for inosine (active treatment) allocation (n = 266/297), and 53% (n = 158) expected to be "somewhat" or "a lot better" in their symptoms over 2 years of treatment with inosine., Conclusions: Participants of a disease-modification trial in PD had likely unrealistic expectations of benefit (ie, improvement in symptoms over years), which may affect clinical trial interpretation and calls for improved education in future disease-modification trials in PD. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is one of the fastest-growing neurodegenerative disorders of increasing global prevalence. It represents the second most common movement disorder after tremor and the second most common neurodegenerative disorder after Alzheimer's disease. The incidence rate of idiopathic PD increases steadily with age, however, some variants of autosomal recessive inheritance are present with an early age-at-onset (ARPD). Approximately 50 percent of ARPD cases have been linked to bi-allelic mutations in genes encoding Parkin, DJ-1, and PINK1. Each protein has been implicated in maintaining proper mitochondrial function, which is particularly important for neuronal health. Aberrant post-translational modifications of these proteins may disrupt their cellular functions and thus contributing to the development of idiopathic PD. Some post-translational modifictions can be attributed to the dysregulation of potentially harmful reactive oxygen and nitrogen species inside the cell, which promote oxidative and nitrosative stress, respectively. Unlike oxidative modifications, the covalent modification by Nitric Oxide under nitrosative stress, leading to S-nitrosylation of Parkin, DJ-1; and PINK1, is less studied. Here, we review the available literature on S-nitrosylation of these three proteins, their implications in the pathogenesis of PD, and provide an overview of currently known, denitrosylating systems in eukaryotic cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Traditionally, medical care and research in Parkinson's disease (PD) have been conducted with in-person encounters. The recent COVID-19 pandemic has profoundly impacted the delivery of in-person clinical care and clinical research. We conducted an online survey of active clinician members of the Parkinson Study Group (PSG) to evaluate the adoption of various non-face-to-face methods in clinical practice and research in PD during the COVID-19 pandemic., Methods: We conducted a survey using the open-access online SurveyMonkey tool (http://www.surveymonkey.com). The survey had 27 items and was designed to elucidate clinical/research care before and during the COVID-19 pandemic. The survey was sent to 414 active PSG members with weekly reminders and it remained accessible for 30 days from May 2020., Results: We received 142 responses, of which 133 (93.7%) provided demographic data. The clinical use of virtual visits via synchronous video conferencing increased from 39.5% pre-COVID-19 to 94.6% during the COVID-19 pandemic. Lack of access for patients (68.2%) and patient resistance (51.4%) were the top barriers for its use. Approximately 70% respondents stated that 75-100% of their research activities were suspended during the COVID-19 pandemic. Many sites had to fill out protocol deviations (38.2%), protocol exceptions (25.5%) or change their research profile due to layoffs (16.8%). The overall use of video conferencing increased from 30.3% to 64.1%., Conclusion: The current results suggest a need for flexibility in conducting office visits and clinical trials in PD patients. Technology has the potential to enhance patient care and convenience, when in-person visits can be challenging., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Parkinson's disease (PD) is a chronic neurodegenerative disorder that challenges care provision. A multidisciplinary care model needs to be impactful, feasible, and viable economically for widespread utilization. Supportive evidence is lacking., Objective: The objective of this study was to evaluate the implementation and impact of a pragmatic network for PD care, the Integrated Parkinson Care Network (IPCN)., Methods: A 6-month, pre-post design, single-center, phase 2 study for complex interventions for patients with newly diagnosed (<1 year) and advanced (diagnosis >8 years) PD was used to assess a patient-centered care model based on integrated care, self-management support, and technology-enabled care. We comprehensively assessed the implementation of care paths, change in selected health and care quality outcomes after the Integrated Parkinson Care Network program, and costs analyses., Results: We recruited 100 participants in 6 months. Overall, the top care priorities were speech and communication (33.7%), anxiety and depression (31.6%), and mobility, balance, and falls (29.6%), and the most commonly (>45%) used resources were speech-language pathology, community seniors services, and physiotherapy. Care priorities were met successfully in 90.6% of the cases, and there was a positive change in the Parkinson's Disease Questionnaire-8 (2.7; 95% confidence interval, 0.4-5.0; statistically significant in the advanced group), the perception of support for chronic care (Patient Assessment of Chronic Illness Case score, 1.1; 95% confidence interval, 0.9-1.4), and self-management (5As score, 1.2; 95% confidence interval, 1.0-1.4). The total cost of the Integrated Parkinson Care Network was C$1367 per patient., Conclusions: A pragmatic development of a care delivery network based on integrated care and self-management support is promising for its feasibility, impact, and a sustainable cost. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Parkinson's disease (PD) is a complex and debilitating condition that requires care from a multispecialty team. The Integrated Parkinson Care Network (IPCN) is an innovative pragmatic care model that focuses on integrated care, self-management support and technology-enabled care., Objective: This study aims to estimate the costs of the IPCN and assess whether benefits gained from the intervention offset its costs based on a single center experience., Methods: We conducted a return on investment (ROI) analysis of the IPCN from a societal perspective. The ROI for the IPCN was estimated as a ratio of the net savings and the intervention cost. The intervention cost was calculated as a sum of set-up and implementation costs. Cost savings was measured as the absolute reduction in the societal costs realized by PD patients. A positive ROI indicated that savings generated from the intervention offset its cost., Results: The total cost of the IPCN for 100 PD patients was C$135,669, or C$226 per patient per month. IPCN was associated with the reduction in societal cost of C$915 per patient per month (95%CI: -2,782, 951). The ROI per PD patient per month for the IPCN was 3.08 (95%CI: -0.60, 22.93), suggesting that for every C$1 invested in the IPCN, C$4.08 is gained through reduction in societal costs. The returns were greater among advanced PD patients., Conclusion: The IPCN has the potential to offer a good return on investment for PD patients, and its value for money is higher among advanced PD patients.

Objectives: To evaluate the acceptability of the Integrated Parkinson's disease Care Network (IPCN) from the perspectives of persons with Parkinson's disease (PD), their care partners and healthcare providers, including identification of important components and areas for improvement., Methods: We used a descriptive qualitative approach with interviews (n = 15) and focus groups (n = 31) with persons with PD who were newly diagnosed and those with advanced PD, care partners and healthcare providers. Questions were designed to gather feedback on each component of the IPCN., Results: Four overarching categories emerged: CCI support, New knowledge, Goal identification and achievement, and Readiness for self-management. These represent important aspects of participants' experiences of the IPCN., Conclusion: Most participants experienced the IPCN as helpful for managing living with PD and accessing resources. The relationship with the CCI was a critical component; the CCI was perceived to be knowledgeable, accessible, and responsive., Practice Implications: The IPCN is a model to promote coordinated care and self-management. This study supports the key components of the IPCN as important for supporting patients in managing their lives with PD. Incorporation of other strategies to support self-management may enhance the model. Availability of and access to community resources was identified as an ongoing challenge., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Orexins regulate a wide variety of biological functions, most notably the sleep-wake cycle, reward and stress processing, alertness, vigilance, and cognitive functioning. Alterations of central and peripheral orexin levels are linked to conditions such as narcolepsy, anorexia nervosa, age-related cognitive decline, and neurodegenerative disease. Preliminary studies suggest that orexin mimetics can safely promote the wake signal via orexin agonism during the day and that orexin receptor antagonists can promote the sleep signal during the night. Thus, novel orexin therapies have the potential to either improve memory, cognition, and daytime performance directly or indirectly, through promotion of good sleep. The full scope of the therapeutic potential of orexin therapies remains to be elucidated., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Lipid peroxidation is a key to a portfolio of neurodegenerative diseases and plays a central role in α-synuclein (α-syn) toxicity, mitochondrial dysfunction and neuronal death, all key processes in the pathogenesis of Parkinson's disease (PD). Polyunsaturated fatty acids (PUFAs) are important constituents of the synaptic and mitochondrial membranes and are often the first molecular targets attacked by reactive oxygen species (ROS). The rate-limiting step of the chain reaction of ROS-initiated PUFAs autoxidation involves hydrogen abstraction at bis-allylic sites, which can be slowed down if hydrogens are replaced with deuteriums. In this study, we show that targeted overexpression of human A53T α-syn using an AAV vector unilaterally in the rat substantia nigra reproduces some of pathological features seen in PD patients. Chronic dietary supplementation with deuterated PUFAs (D-PUFAs), specifically 0.8% D-linoleic and 0.3% H-linolenic, produced significant disease-modifying beneficial effects against α-syn-induced motor deficits, synaptic pathology, oxidative damage, mitochondrial dysfunction, disrupted trafficking along axons, inflammation and DA neuronal loss. These findings support the clinical evaluation of D-PUFAs as a neuroprotective therapy for PD.

Objective: The objective of this study was to assess the 12-week efficacy and safety of oral glycopyrrolate for moderate-to-severe sialorrhea in Parkinson's disease (PD)., Background: Chronic moderate-to-severe sialorrhea has a negative impact on quality of life in PD. There is no robust evidence for oral treatments for sialorrhea longer than 1 week., Methods: This was a 12-week, double-blinded, placebo-controlled, parallel phase II study in patients with PD and Movement Disorder Society-Unified Parkinson's Disease Rating Scale item 2.2 > 2. The intervention was glycopyrrolate up to 4.5 mg/d; the primary outcome was sialorrhea related-disability (Radboud Oral Motor Inventory for Parkinson's Disease-Saliva). We used an intention-to-treat analysis. A P < 0.05 was deemed significant., Results: We recruited 28 patients (age, 71.1 ± 6.9 years; PD duration, 11.4 ± 7.2 years; Radboud Oral Motor Inventory for Parkinson's Disease-Saliva, 22.4 ± 5.7). Glycopyrrolate was superior to placebo at 12 weeks in the Radboud Oral Motor Inventory for Parkinson's Disease-Saliva (between-group difference, 5.3; 95% confidence interval, 1.0-9.6). Dry mouth was the most common adverse event (glycopyrrolate, n = 6; placebo, n = 2)., Conclusions: The results support the efficacy of glycopyrrolate to treat sialorrhea-related disability up to 12 weeks and contribute to addressing unmet nonmotor care needs in PD. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease., Methods: We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort., Results: We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = -0.2)., Conclusion: The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

On May 26, 2020, Dr. Oleh Hornykiewicz died at the age of 93 years. His twin discoveries in the early 1960s of dopamine deficiency in the brains of subjects with Parkinson's disease and the amelioration of patients' symptoms by levodopa therapy represent milestone events in the history of medicine. These breakthroughs enabled much-needed relief for millions of patients suffering from neurological disorders every year and have given rise to the field of dopamine signaling in the regulation of complex behaviors in primates. What did Dr. Hornykiewicz, who was actively engaged in research until shortly before his 91st birthday, wish to pass on to younger scientists? What were his thoughts regarding the elusive cause of Parkinson's disease? How did he wish to be remembered? Here, the authors, one a former student and the other an admired colleague, recall messages conveyed by Dr. Hornykiewicz in public lectures; they also share the content of conversations and letters exchanged with him since 2004, as he began to reflect on his legacy. Through Dr. Hornykiewicz's own words and writings, the picture emerges of an extraordinarily committed scientist, who was exemplary in his professional integrity, who knew how to deploy a gallous sense of humor, who displayed little patience for physicians offering advice, and who kept any sense of pride over his monumental contributions private. When asked at the age of 91 years about the secrets of his long and fulfilled career in neuroscience, he identified himself as "a mad scientist.…I am someone who continuously fantasizes. I am someone who chases fantastical ideas and who keeps on dreaming…", and as a man who was supported by the loving companionship of his wife, Christine. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Early descriptions of subtypes of Parkinson's disease (PD) are dominated by the approach of predetermined groups. Experts defined, from clinical observation, groups based on clinical or demographic features that appeared to divide PD into clinically distinct subsets. Common bases on which to define subtypes have been motor phenotype (tremor dominant vs akinetic-rigid or postural instability gait disorder types), age, nonmotor dominant symptoms, and genetic forms. Recently, data-driven approaches have been used to define PD subtypes, taking an unbiased statistical approach to the identification of PD subgroups. The vast majority of data-driven subtyping has been done based on clinical features. Biomarker-based subtyping is an emerging but still quite undeveloped field. Not all of the subtyping methods have established therapeutic implications. This may not be surprising given that they were born largely from clinical observations of phenotype and not in observations regarding treatment response or biological hypotheses. The next frontier for subtypes research as it applies to personalized medicine in PD is the development of genotype-specific therapies. Therapies for GBA-PD and LRRK2-PD are already under development. This review discusses each of the major subtyping systems/methods in terms of its applicability to therapy in PD, and the opportunities and challenges designing clinical trials to develop the evidence base for personalized medicine based on subtypes.

Background: Quality of life in Parkinson's disease (PD) is affected by motor and nonmotor symptoms, necessitating an integrated care approach. Existing care models vary considerably in numerous domains. The objectives of this study were to perform a systematic review and meta-analysis of PD integrated care models and develop recommendations for a representative model., Methods: We conducted a systematic review of published integrated care models and a meta-analysis of randomized, controlled trials examining integrated care versus standard care. The primary outcome was health-related quality of life using a validated PD scale. We evaluated levels of care integration using the Rainbow Model of Integrated Care., Results: Forty-eight publications were identified, including 8 randomized, controlled trials with health-related quality of life data (n = 1,149 total PD patients). Qualitative evaluation of individual care model integration guided by the Rainbow Model of Integrated Care revealed frequent clinical and professional integration, but infrequent organizational and population-based integration elements. Meta-analysis of randomized, controlled trials revealed significant heterogeneity (I 2  = 90%, P < 0.0001). Subgroup analysis including only outpatient care models (n = 5) indicated homogeneity of effects (I 2  = 0%, P = 0.52) and improved health-related quality of life favoring integrated care, with a small effect size (standardized mean difference [SMD], -0.17; 95% CI, -0.31 to -0.03; P = 0.02)., Conclusions: Outpatient integrated PD care models may improve patient-reported health-related quality of life compared with standard care; however, because of variable methodological approaches and a high risk of bias related to inherent difficulties in study design (eg, blinding of participants and interventionists), generalizability of these results are difficult to establish. The Rainbow Model of Integrated Care is a promising method of evaluating elements and levels of integration from individual patient care to population health in a PD context. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC. on behalf of International Parkinson and Movement Disorder Society.)

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Autosomal recessive mutations in the glucocerebrosidase gene, Beta-glucocerebrosidase 1 (GBA1), cause the lysosomal storage disorder Gaucher's disease. Heterozygous carriers of most GBA1 mutations have dramatically increased Parkinson's disease (PD) risk, but the mechanisms and cells affected remain unknown. Glucocerebrosidase expression is relatively enriched in astrocytes, yet the impact of its mutation in these cells has not yet been addressed., Objectives: Emerging data supporting non-cell-autonomous mechanisms driving PD pathogenesis inspired the first characterization of GBA1-mutant astrocytes. In addition, we asked whether LRRK2, likewise linked to PD and enriched in astrocytes, intersected with GBA1 phenotypes., Methods: Using heterozygous and homozygous GBA1 D409V knockin mouse astrocytes, we conducted rigorous biochemical and image-based analyses of lysosomal function and morphology. We also examined basal and evoked cytokine response at the transcriptional and secretory levels., Results: The D409V knockin astrocytes manifested broad deficits in lysosomal morphology and function, as expected. This, however, is the first study to show dramatic defects in basal and TLR4-dependent cytokine production. Albeit to different extents, both the lysosomal dysfunction and inflammatory responses were normalized by inhibition of LRRK2 kinase activity, suggesting functional intracellular crosstalk between glucocerebrosidase and LRRK2 activities in astrocytes., Conclusions: These data demonstrate novel pathologic effects of a GBA1 mutation on inflammatory responses in astrocytes, indicating the likelihood of broader immunologic changes in GBA-PD patients. Our findings support the involvement of non-cell-autonomous mechanisms contributing to the pathogenesis of GBA1-linked PD and identify new opportunities to correct these changes with pharmacological intervention. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)