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Andrew D Robertson,1,2 Sean J Udow,3 Alberto J Espay,4 Aristide Merola,4 Richard Camicioli,5 Anthony E Lang,6–8 Mario Masellis2,6,91Schlegel-UW Research Institute for Aging, University of Waterloo, Waterloo, ON, Canada; 2Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, ON, Canada; 3Division of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; 4Department of Neurology, James and Joan Gardner Family Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, USA; 5Department of Medicine (Neurology), University of Alberta, Edmonton, AB, Canada; 6Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada; 7Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; 8Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; 9Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, ON, CanadaAbstract: Orthostatic hypotension (OH) is a common condition, particularly in patients with α-synucleinopathies such as Parkinson’s disease, and has a significant impact on activities of daily living and quality of life. Recent data suggest an association with cognitive impairment. Herein, we review the evidence that OH increases the odds of incident mild cognitive impairment and dementia. Potential mechanisms underlying the putative relationship are discussed, including cerebral hypoperfusion, supine hypertension, white matter hyperintensities, and neurodegeneration. Finally, we highlight the challenges with respect to treatment and the negative impact on the quality of life and long-term prognosis presented by the coexistence of OH and dementia. Large population-based studies have reported that OH is associated with about a 20% increased risk of dementia in the general population, while smaller cohort studies suggest an even greater effect in patients with α-synucleinopathies (3- to 7-fold higher than controls). Ultimately, OH exposure is difficult to quantify, predominantly limited to pressure regulation during a one-time orthostatic challenge, and the causative association with dementia may turn out to be bidirectional, especially in α-synucleinopathies. Early diagnosis and treatment of OH may improve long-term prognosis.Keywords: α-synucleinopathies, cognitive impairment, dementia, orthostatic hypotension, review

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson's disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson's disease patients with impulse control disorders. We describe results of a [(11)C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson's disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson's disease patients may provide a model into the pathophysiology of this disorder. [ABSTRACT FROM AUTHOR]

Introduction: Elevated plasma homocysteine (Hcy) is associated with an increased risk of developing neurodegenerative diseases; however, its relationship with the apolipoprotein E (APOE) ε4 allele has not been well characterized., Methods: Participants clinically diagnosed with Alzheimer's disease or mild cognitive impairment (AD/MCI), frontotemporal dementia, Parkinson's disease, or cerebrovascular disease were stratified by the presence of the APOE ε4 allele. Volumetric magnetic resonance imaging, plasma amyloid/tau/neurodegeneration biomarkers, and cognitive performance were quantified., Results: Across all diagnostic groups, Hcy was associated with lower brain parenchymal fraction and greater neurofilament light chain in APOE ε4 non-carriers only. In AD/MCI, Hcy was associated with phosphorylated tau 217 in APOE ε4 non-carriers, but not in carriers. Exploratory analyses revealed interactions between Hcy and APOE ε4 on memory and visuospatial function., Discussion: Hcy may contribute to neurodegeneration depending on the presence of the APOE ε4 allele and specific disease processes. Trials on vitamin B12 supplementation may consider stratifying by APOE genotype. Highlights Homocysteine (Hcy) was associated with neurodegenerative biomarkers across disease groups. Relationships with Hcy were predominantly found in apolipoprotein E (APOE) ε4 non-carriers. In Alzheimer's disease, associations between Hcy and phosphorylated tau 217 were found in APOE ε4 non-carriers only. Significant interactions existed between Hcy and APOE ε4 status on cognition., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Oculomotor behaviour changes in patients with Parkinson's disease (PD) are a promising source of prodromal disease markers. Capitalizing on this phenomenon to facilitate early diagnosis requires oculomotor assessment in prodromal cohorts. We examined oculomotor behaviour in non-manifesting LRRK2 G2019S mutation carriers (LRRK2-NM), who have heightened PD risk.Seventeen LRRK2-NM participants, 47 patients with idiopathic PD, and 63 healthy age-matched control participants completed an interleaved pro- and antisaccade task while undergoing video-based eye-tracking. We analyzed between-group differences in saccade, pupil, blink, and fixation acquisition behaviour. Patients with PD showed previously demonstrated abnormalities (saccade hypometria, antisaccade errors). Relative to controls, LRRK2-NM participants and patients with PD both displayed increased short-latency prosaccades and reduced pupil velocity, plus altered fixation acquisition-less preemptive returning of gaze to the future fixation point location. Interestingly, the effect on blink probability was opposite-higher than controls in LRRK2-NM participants but lower in patients with PD. Future longitudinal studies must confirm the viability of these features as prodromal PD markers., Competing Interests: Competing interests: D.C.B., B.C.C. and D.P.M. are co-founders of Dynamiris Inc., which is currently developing a clinical tool for neurological and psychiatric disease diagnosis using eye movement data such as that described in this study. All other authors have no other competing interests., (© 2024. The Author(s).)

White matter hyperintensities (WMH) of presumed vascular origin are a magnetic resonance imaging (MRI)-based biomarker of cerebral small vessel disease (CSVD). WMH are associated with cognitive decline and increased risk of stroke and dementia, and are commonly observed in aging, vascular cognitive impairment, and neurodegenerative diseases. The reliable and rapid measurement of WMH in large-scale multisite clinical studies with heterogeneous patient populations remains challenging, where the diversity of imaging characteristics across studies adds additional complexity to this task. We present segcsvd WMH , a convolutional neural network-based tool developed to provide reliable and accurate WMH quantification across diverse clinical datasets. segcsvd WMH was developed using a large dataset consisting of over 700 fluid-attenuated inversion recovery MRI scans from seven multisite studies, spanning a wide range of clinical populations, WMH burdens, and imaging protocols. Model training incorporated anatomical information through a novel hierarchical segmentation approach, together with extensive data augmentation techniques to improve performance across varied imaging conditions. Benchmarked against three widely available segmentation tools, segcsvd WMH demonstrated superior accuracy, achieving mean Dice score improvements of 7.8% ± 9.7% over HyperMapp3r, 21.8% ± 8.6% over SAMSEG, and 43.5% ± 7.1% over WMH-SynthSeg across four diverse test datasets. segcsvd WMH also maintained consistently high Dice scores across these test datasets (mean DSC = 0.86 ± 0.08), and exhibited strong, stable correlations with periventricular, deep, and total WMH ground truth volumes (mean r = 0.99 ± 0.01). Additionally, segcsvd WMH was robust to low and moderate levels of simulated MRI spike noise artifacts and maintained strong performance across a range of binary segmentation thresholds and WMH burden levels. These findings suggest that segcsvd WMH may provide more accurate and robust WMH segmentation performance for heterogeneous clinical datasets characterized by varying degrees of CSVD severity., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: The Montreal Cognitive assessment (MoCA) is a well-validated global cognitive screening instrument. Its validity in progressive supranuclear palsy (PSP) has not been assessed., Objectives: To evaluate the MoCA as an outcome measure in PSP clinical trials., Methods: Cognitive data from 162 participants in the placebo arm of the Biogen PASSPORT study (NCT03068468) were analyzed using linear mixed-effects modeling (LMM) and repeated measures correlation., Results: There was a significant decline in the MoCA score over time of -1.4 (95% CI -0.84 to -1.97) points over a 48-week period ( p  < 0.0001). Small but significant changes ( p  < 0.01) were observed in all MoCA domains except abstraction. The MoCA correlated weakly with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) over time ( r rm  = 0.1, p  = 0.02) but exhibited a stronger correlation with the PSP Rating Scale (PSPRS) ( r rm  = -0.25, p  < 0.0001)., Conclusion: The MoCA appears to have limited sensitivity in capturing cognitive decline in PSP., Competing Interests: Unrelated to this study CS has provided scientific advisory for SwanBio Therapeutics and received research funding from Sanofi-Genzyme for a study of video oculography in late-onset GM2 gangliosidosis. His institution has received financial support from Sanofi-Genzyme, SwanBio therapeutics and Encora Therapeutics and previously from Biogen and Biohaven, for the conduct of clinical trials. He has received honoraria from the American Academy of Neurology and The International Parkinson and Movement Disorders Society. He has received grant support from the National Institutes of Health K23 NS118045. Unrelated to this study MD has funding from NIH NINDS K23NS121402 and has served as a consultant for Synergic Medical Technologies and Cognito Therapeutics. EB receives research funding from the NIA (K99AG073453) and Lewy Body Dementia Association. Unrelated to this study AP is supported by NIH/NINDS U01 NS102035 and NIH/NIA R44 AG080861. IG-C is funded by the Clinical Research Training Scholarship in FTD from the Holloway Family Fund of The Association for Frontotemporal Degeneration, the Bob Burros Family Memorial Fund of the American Brain Foundation, and the American Academy of Neurology. Unrelated to this study MT has participated in clinical trials funded by Janssen, Biogen, Avanex, Green Valley, UCB, Novo Nordisk, GSK, BMS, and Passage Bio, and has served as a consultant for Eisai, Lilly, and Novo Nordisk. Unrelated to this study AL has served as an advisor for AbbVie, Amylyx, Aprinoia, Biogen, BioAdvance, Biohaven, BioVie, BlueRock, BMS, Denali, Janssen, Lilly, Pharma 2B, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Krembil Brain Institute, Michael J. Fox Foundation, Parkinson Foundation, Parkinson Canada, and The Rossy Foundation; is serving as an expert witness in litigation related to paraquat and Parkinson’s disease, received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. Unrelated to this study MS has served as investigator on clinical trials sponsored by Sage Therapeutics, Biogen Inc., and BIA R&D. LG: Consultancies: AI Therapeutics, Amylyx, Apellis, Aprinoia, Ferrer, IQVIA, UCB, Woolsey. Advisory Boards: Amylyx, CurePSP (unpaid), Roche, Rossy Centre, Springer. Royalties: Rutgers University Press for single-author text, A Clinician’s Guide to PSP (2019). Copyright material licensing fees (via Rutgers University). Travel expenses: CurePSP. AW has research funding from NIA/NIH 1R01AG085029 and R44AG080861, from the Parkinson’s Foundation, has participated in clinical trials funded by Roche/Genentech, Biogen/Denali, Bial, Amylyx Pharmaceuticals, Ferrer, Ono Pharmaceuticals, and received consultant payments from Accordant, CVS/Caremark, Genentech, Amylyx Pharmaceuticals and Ono Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ibrahim, Isroff, Stephen, Iyer, Dale, Gunzler, Bayram, Xie, Pantelyat, Montaser-Kouhsari, Garcia-Cordero, Tartaglia, Lang, Swan, Boxer, Golbe and Wills.)

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs., Competing Interests: Competing interests: L.V.K. has received research support from Canadian Institutes of Health Research (CIHR), Cure Parkinson’s, Krembil Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF), Natural Sciences and Engineering Research Council of Canada, and Parkinson Canada; consultancy fees from Cure Ventures, Ipsen, Knight Therapeutics, Right Brain Bio, and UCB; and honoraria from Canadian Movement Disorders Society, Critical Path for Parkinson’s, International Parkinson and Movement Disorder Society, and IOS Press. A.B.-O. has received personal fees for advisory board participation and/or consulting from Abata, Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb (BMS)/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, and Viracta; and institutional grant support from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. R.B. has received research support from Biogen, Eli Lilly, and Roche Genentech, and consulting fees from EMD Serono, Novartis, TG Therapeutics, and Horizon, Jansen. S.F. has received consultancy or speaker fees from Abbvie, Bial, Ipsen, and Lundbeck. U.J.K. holds stock options as a Scientific Advisory Board member for Amprion and has received consultancy fees as a Scientific Advisory Board member for NurrOn and as a member of the data monitoring committee for UCB. E.C.K. has received research funding from Abbvie, Biogen, and Genentech and consulting fees from Banner Life Sciences, EMO Serano, Galen/Atlantica, Greenwich Biosciences, INmune Bio, Myrobalan Therapeutics, OM 1, and TG Therapeutics. M.K. has received travel support and honoraria for advisory boards from Biogen, Roche, Novartis, and EMD Serono. S.K. has received institutional grant support from Biogen, Roche, and Sanofi-Genzyme. A.E.L. has acted as an adviser for AbbVie, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, BMS, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; has received honoraria from Sun Pharma, AbbVie, and Sunovion; has received grants from Brain Canada, CIHR, Edmond J Safra Philanthropic Foundation, MJFF, Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; has acted as an expert witness in litigation related to paraquat and Parkinson disease; and has received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. M.J.M. has received travel support and honoraria for advisory boards from Ipsen, Merz, and Abbvie. D.O. has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb, and Novartis and consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Novartis, Pipeline Therapeutics, and Merck. R.S. has received grants from MS Society of Canada and J.P. Bickell Foundation; consulting fees from Novartis; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Biogen Idec, Sanofi-Genzyme, EMD Serono, and Roche; has served on advisory boards for Novartis; and has received support to attend a scientific meeting from EMD Serono. J.O. has received personal compensation for consulting from Biogen Idec, BMS, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi-Genzyme, and institutional grant support from Biogen Idec and Roche. A.A., N.A., D.G.D.L., E.A.F., K.K.L., Z.G.-O., J.L.G., M.R.L., P.A.M., T.A.M., V.E.M., M.W.C.R., M.G.S. and A.J.S. declare no competing interests., (© 2024. Springer Nature Limited.)

The ordered assembly of α-synuclein protein into filaments encoded by SNCA characterizes neurodegenerative diseases called synucleinopathies. Lewy body disease (LBD) shows predominantly neuronal α-synuclein pathology and multiple system atrophy (MSA) predominantly oligodendrocytic α-synuclein pathology affecting subcortical brain structures. Based on cryo-electron microscopy, it was reported that structures of α-synuclein filaments from LBD differ from MSA and juvenile onset synucleinopathy (JOS) caused by a 21-nucleotide duplication in the second exon of one allele of SNCA gene 1-3 . Importantly, a rare subtype of MSA, called atypical MSA 4 shows abundant neuronal argyrophilic α-synuclein inclusions in the limbic system. Current concepts indicate that disease entities are characterized by unique protofilament folds. Here we demonstrate that in addition to the MSA fold, α-synuclein can form a new Lewy-MSA hybrid fold in the same brain region, leading to the atypical histopathological form of MSA. Distinct biochemical characteristics of α-synuclein, as demonstrated by protease-sensitivity digestion assay, seed amplification assays (SAAs) and conformational stability assay (CSA), are also linked to cytopathological differences (e.g. neuronal or oligodendroglial). We expand the current structure-based classification of α-synucleinopathies and propose that cell-specific protein pathologies can be associated with distinct filament folds., Competing Interests: Competing interests The authors declare no competing interests.

Mitochondrial population maintenance in neurons is essential for neuron function and survival. Contact sites between mitochondria and the endoplasmic reticulum (ER) are poised to regulate mitochondrial homeostasis in neurons. These contact sites can facilitate transfer of calcium and lipids between the organelles and have been shown to regulate aspects of mitochondrial dynamics. Vesicle-associated membrane protein-associated protein B (VapB) is an ER membrane protein present at a subset of ER-mitochondrial contact sites. A proline-to-serine mutation in VapB at amino acid 56 (P56S) correlates with susceptibility to amyotrophic lateral sclerosis (ALS) type 8. Given the relationship between failed mitochondrial health and neurodegenerative disease, we investigated the function of VapB in mitochondrial population maintenance. We demonstrated that transgenic expression of VapB P56S in zebrafish larvae (sex undetermined) increased mitochondrial biogenesis, causing increased mitochondrial population size in the axon terminal. Expression of wild-type VapB did not alter biogenesis but, instead, increased mitophagy in the axon terminal. Using genetic manipulations to independently increase mitochondrial biogenesis, we show that biogenesis is normally balanced by mitophagy to maintain a constant mitochondrial population size. VapB P56S transgenics fail to increase mitophagy to compensate for the increase in mitochondrial biogenesis, suggesting an impaired mitophagic response. Finally, using a synthetic ER-mitochondrial tether, we show that VapB's function in mitochondrial turnover is likely independent of ER-mitochondrial tethering by contact sites. Our findings demonstrate that VapB can control mitochondrial turnover in the axon terminal, and this function is altered by the P56S ALS-linked mutation., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA., Competing Interests: Declaration of competing interest AEL has served as an advisor for AbbVie, AFFiRis, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, BMS, CoA Therapeutics, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; is serving as an expert witness in litigation related to paraquat and Parkinson's disease, received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. GGK received a royalty for 5G4 synuclein antibody and publishing royalties from Wiley, Cambridge University Press, and Elsevier, received grants from Edmond J Safra Philanthropic Foundation, Rossy Family Foundation, Michael J. Fox Foundation, Parkinson Canada, Canada, and Canada Foundation for Innovation. TK, SLF, JL, NN, and MJU declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: The shoulder complex relies on scapular movement controlled by periscapular muscles for optimal arm function. However, minimal research has explored scapular muscle activation ratios during functional tasks, nor how they might be influenced by biological sex. This investigation aims to characterize how sex impacts scapular muscle activation ratios during functional tasks., Methods: Twenty participants (ten females, ten males) were assessed with surface electromyography (EMG) and motion tracking during seven functional tasks. Activation ratios were calculated from normalized EMG for the three trapezius muscles and serratus anterior. Scapular angles were calculated using a YXZ Euler sequence. Two-way mixed methods ANOVAs ( p  < .05) were used to assess the effects of sex and humeral elevation level on ratios and angles., Results: Sex-based differences were present in the Tie Apron task, with males exhibiting higher upper trapezius/lower trapezius and upper trapezius/middle trapezius ratios than females. Males also demonstrated decreased internal rotation in this task. Other tasks showcased significant sex-based differences in scapular upward rotation but not in activation ratios. Humeral elevation generally demonstrated an inverse relationship with scapular muscle activation ratios., Conclusions: This study highlights sex-based differences in scapular muscle activation ratios during specific functional tasks, emphasizing the need to consider sex in analyses of shoulder movements. Normative activation ratios for functional tasks were provided, offering a foundation for future comparisons with non-normative groups. Further research is warranted to confirm and explore additional influencing factors, advancing our understanding of shoulder activation and movement in diverse populations., Competing Interests: The authors declare there are no competing interests., (©2024 Lang et al.)

The US Department of Veterans Affairs (VA) and the US Department of Defense (DoD) approved a joint clinical practice guideline for the management of type 2 diabetes. This was the product of a multidisciplinary guideline development committee composed of clinicians from both the VA and the DoD and was overseen by the VA/DoD Evidence Based Practice Work Group. The development process conformed to the standards for trustworthy guidelines as established by the National Academy of Medicine. The guideline development committee developed 12 key questions to guide an evidence synthesis. An independent third party identified relevant randomized controlled trials and systematic reviews that were published from January 2016 through April 2022. This evidence synthesis served as the basis for drafting recommendations. Twenty-six recommendations were generated and rated by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Two algorithms were developed to guide clinical decision-making. This synopsis summarizes key aspects of the VA/DoD Clinical Practice Guideline for diabetes in 5 areas: prediabetes, screening for co-occurring conditions, diabetes self-management education and support, glycemic treatment goals, and pharmacotherapy. The guideline is designed to help clinicians and patients make informed treatment decisions to optimize health outcomes and quality of life and to align with patient-centered goals of care., (Published by Elsevier Inc.)

Background: Multiple system atrophy (MSA) is a primary oligodendroglial synucleinopathy, characterized by elevated iron burden in early-affected subcortical nuclei. Although neurotoxic effects of brain iron deposition and its relationship with α-synuclein pathology have been demonstrated, the exact role of iron dysregulation in MSA pathogenesis is unknown. Therefore, advancing the understanding of iron dysregulation at the cellular level is critical, especially in relation to α-synuclein cytopathology., Methods: Iron burden in subcortical and brainstem regions were histologically mapped in human post-mortem brains of 4 MSA-parkinsonian (MSA-P), 4 MSA-cerebellar (MSA-C), and 1 MSA case with both parkinsonian and cerebellar features. We then performed the first cell type-specific evaluation of pathological iron deposition in α-synuclein-affected and -unaffected cells of the globus pallidus, putamen, and the substantia nigra, regions of highest iron concentration, using a combination of iron staining with immunolabelling. Selective regional and cellular vulnerability patterns of iron deposition were compared between disease subtypes. In 7 MSA cases, expression of key iron- and closely related oxygen-homeostatic genes were examined., Results: MSA-P and MSA-C showed different patterns of regional iron burden across the pathology-related systems. We identified subcortical microglia to predominantly accumulate iron, which was more distinct in MSA-P. MSA-C showed relatively heterogenous iron accumulation, with greater or similar deposition in astroglia. Iron deposition was also found outside cellular bodies. Cellular iron burden associated with oligodendrocytic, and not neuronal, α-synuclein cytopathology. Gene expression analysis revealed dysregulation of oxygen homeostatic genes, rather than of cellular iron. Importantly, hierarchal cluster analysis revealed the pattern of cellular vulnerability to iron accumulation, distinctly to α-synuclein pathology load in the subtype-related systems, to distinguish MSA subtypes., Conclusions: Our comprehensive evaluation of iron deposition in MSA brains identified distinct regional, and for the first time, cellular distribution of iron deposition in MSA-P and MSA-C and revealed cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes. Our findings suggest distinct iron-related pathomechanisms in MSA clinical subtypes that are therefore not a consequence of a uniform down-stream pathway to α-synuclein pathology, and inform current efforts in iron chelation therapies at the disease and cellular-specific levels., Competing Interests: Declaration of competing interest GGK holds shared patent for the 5G4 antibody., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer's disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-β phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-β peptides between multiple system atrophy and Alzheimer's disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE , MAPT , PSEN1 , PSEN2 and APP . We refer to the four multiple system atrophy cases with discrepancy between amyloid-β and tau pathology as 'amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy' to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer's disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-β peptides revealed more premature amyloid-β plaques in amyloid-β-predominant Alzheimer's disease neuropathologic change-multiple system atrophy compared with Alzheimer's disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-β and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-β in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies., Competing Interests: G.G.K. holds a shared patent for the 5G4 antibody and received royalty for 5G4 synuclein antibody. Other authors report no competing interests in relation to the work described., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases., Methods: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance., Results: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume., Discussion: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition., Highlights: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases., Methods: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ) 42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD)., Results: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ 42/40 ., Discussion: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Inertial measurement units allow for quantitative assessment of body motion in many environments. Determining the ability to measure upper limb motion with inertial measurement units, leveraging procedures traditionally used in the lab such as scapular calibration procedures and humeral axial rotation calculation, would expand the opportunities to assess upper limb function in externally valid environments. This study examined if humeral and scapular motion measured in different field settings is consistent with motion measured in a lab setting in similar tasks., Methods: Twenty-eight adults participated in the study (14 field setting, 14 lab setting). Three different types of field settings were included: home ( n  = 5), work ( n  = 4), and sports ( n  = 5). Field participants were matched to lab participants based on sex and body height. All participants were equipped with five inertial and magnetic measurement units (Xsens Awinda, Xsens Technlogies, NL, Fs = 100 Hz) on the torso, humeri, and scapulae. Humeral and scapular angles were measured during a functional task protocol consisting of seven tasks. Data from all three field settings were combined. Statistical parametric mapping ( α  = .05) was used to assess differences in waveforms between the lab and field data., Results and Discussion: Five out of seven tasks displayed no differences for humeral elevation and humeral axial rotation, while scapular upward rotation and tilt were not statistically different for any tasks. Scapular internal rotation variability was very high for the field setting, but not for the lab setting. Task-based differences in humeral elevation and humeral axial rotation may be related to equipment modifications for the field protocol and between subjects' variability in task performance. Data indicate that humeral elevation, humeral axial rotation, and scapular upward rotation can be measured in externally valid field settings, which is promising for the evaluation of upper limb movement in natural environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lordall, Akinluyi and Lang.)

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer's disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin-proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.

Background: Functional parkinsonism is an important differential diagnosis of Parkinson's disease (PD). Based on anecdotal experience, we hypothesized that arm swing while walking and running could differentiate these two conditions, but this assumption has not been previously explored systematically., Objectives: To examine differences in arm swing while walking and running between patients with PD and functional parkinsonism., Methods: We analyzed blinded video assessments of arm swing and other gait parameters in patients with asymmetrical PD (n = 81) and functional parkinsonism (n = 8) while walking and running. The groups were matched for age, sex and disease duration., Results: In contrast to those with PD, patients with functional parkinsonism (i) were more likely to have a marked asymmetry in arm swing while walking (5/8 vs. 25/81; P = 0.06), (ii) were less likely to improve arm swing while running with full effort (3/8 vs. 72/81; P < 0.001) and (iii) demonstrated normal passive arm swing even when asymmetry of arm swing was marked during running/walking (6/6 vs. 9/33; P = 0.002)., Conclusions: Assessment of arm swing while walking and running and passive arm swing could be important differentiating clinical features between functional parkinsonism and PD., (© 2023 International Parkinson and Movement Disorder Society.)

This study investigated the molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease (AD). We analyzed Aβ deposition in the temporal cortex and striatum in 116 autopsies, including Lewy body disease (LBD; N = 51), multiple system atrophy (MSA; N = 10), frontotemporal lobar degeneration-TDP-43 (FTLD-TDP; N = 16), and progressive supranuclear palsy (PSP; N = 39). The LBD group exhibited the most Aβ deposition in the temporal cortex and striatum (90/76%, respectively), followed by PSP (69/28%), FTLD-TDP (50/25%), and the MSA group (50/10%). We conducted immunohistochemical analysis using antibodies targeting eight Aβ epitopes in the LBD and PSP groups. Immunohistochemical findings were evaluated semi-quantitatively and quantitatively using digital pathology. Females with LBD exhibited significantly more severe Aβ deposition, particularly Aβ 42 and Aβ 43 , along with significantly more severe tau pathology. Furthermore, a quantitative analysis of all Aβ peptides in the LBD group revealed an association with the APOE-ε4 genotypes. No significant differences were observed between males and females in the PSP group. Finally, we compared striatal Aβ deposition in cases with LBD (N = 15), AD without α-synuclein pathology (N = 6), and PSP (N = 5). There were no differences in the pan-Aβ antibody (6F/3D)-immunolabeled deposition burden among the three groups, but the deposition burden of peptides with high aggregation capacity, especially Aβ 43 , was significantly higher in the AD and LBD groups than in the PSP group. Furthermore, considerable heterogeneity was observed in the composition of Aβ peptides on a case-by-case basis in the AD and LBD groups, whereas it was relatively uniform in the PSP group. Cluster analysis further supported these findings. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aβ deposition, impacted also by sex and APOE genotypes., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course., Objectives: To estimate the probability of preserving ambulatory ability and survival in NBIA., Methods: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods., Results: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03)., Conclusions: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death., (© 2023 International Parkinson and Movement Disorder Society.)

Misfolded α-synuclein (α-syn) is believed to contribute to neurodegeneration in Lewy body disease (LBD) based on considerable evidence including a gene-dosage effect observed in relation to point mutations and multiplication of SNCA in familial Parkinson's disease. A contradictory concept proposes early loss of the physiological α-syn as the major driver of neurodegeneration. There is a paucity of data on SNCA transcripts in various α-syn immunoreactive cytopathologies. Here, the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD (n = 5) were evaluated using RNAscope combined with immunofluorescence for disease-associated α-syn. Single-nucleus RNA sequencing was performed to elucidate cell-type specific SNCA expression in non-diseased frontal cortex (n = 3). SNCA transcripts were observed in the neuronal nucleus and cytoplasm in neurons without α-syn, those containing punctate α-syn immunoreactivity, irregular-shaped compact inclusion, and brainstem-type and cortical-type LBs. However, SNCA transcripts were only rarely found in the α-syn immunoreactive LB areas. The total cell body SNCA transcript area densities in neurons with punctate α-syn immunoreactivity were preserved but were significantly reduced in neurons with compact α-syn inclusions both in the substantia nigra and amygdala. This reduction was also observed in the cytoplasm but not in the nucleus. Only single SNCA transcripts were detected in astrocytes with or without disease-associated α-syn immunoreactivity in the amygdala. Single-nucleus RNA sequencing revealed that excitatory and inhibitory neurons, oligodendrocyte progenitor cells, oligodendrocytes, and homeostatic microglia expressed SNCA transcripts, while expression was largely absent in astrocytes and microglia. The preserved cellular SNCA expression in the more abundant non-Lewy body type α-syn cytopathologies might provide a pool for local protein production that can aggregate and serve as a seed for misfolded α-syn. Successful segregation of disease-associated α-syn is associated with the exhaustion of SNCA production in the terminal cytopathology, the Lewy body. Our observations inform therapy development focusing on targeting SNCA transcription in LBD., (© 2023. The Author(s).)

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Roy N. Alcalay received consulting fees from Avrobio, Caraway, Ono Therapeutics, GSK, Merck, Sanofi, Janssen and grants from the Michael J. Fox Foundation, DOD, the Parkinson’s Disease Foundation, and the NIH. Melinda Barkhuizen received a PhD scholarship from the National Research Foundation of South Africa (grant numbers 89230 and 98217) and internal funding from the research center where the study was conducted (DST/NWU Preclinical Drug Development Platform, North-West University, South Africa); Ampath Pathology laboratories in South Africa donated services in the form of drawing participant blood for DNA extractions, Several neurologists in South Africa assisted the authors with identifying patients with Parkinson`s disease and referring them to the genotyping study; the North-West University, South Africa provided Ethical oversight and approval of the genotyping project. Vincenzo Bonifati received grants from Stichting Parkinson Fonds (Netherlands) and Alzheimer Nederland, he received honoraria from the International Parkinson and Movement Disorder Society (MDS), for lectures and as Chair of the International Congress Scientific Program Committee (2020-2021), and from Elsevier Ltd. as co-Editor in Chief of the journal Parkinsonism & Related Disorders (2018-current); he is unpaid member of the Stichting Parkinson Fonds (Netherlands). Kathrin Brockmann received grants from the German Federal Ministry of Education and Research (BMBF; PDStrat; FKZ 031L0137B) and from the German Center for Neurodegenerative Diseases (DZNE), consulting fees from Abbvie, Lundbeck, UCB, Zambon, Roche, and honoraria from Abbvie and UCB. Jordi Clarimon is full-time employee at Lundbeck A/S (Denmark). Mario Cornejo-Olivas has subcontracts with Cleveland Clinic and San Marcos Foundation for recruiting participants for the LARGE PD study in Peru. Jean-Christophe Corvol received grants from Sanofi and the Michael J. Fox Foundation, consulting fees from Biogen, UCB, Denali, Idorsia, Prevail therapeutics, Theranexus, and honoraria from Biogen. Joana Damásio received honoraria from Zambon Pharmaceuticals. Anna De Rosa received grants for ROPAD – the Rostock International Parkinson’s Disease Study, sponsored by Centogene and grants from Zambon and AIFA (Italian Agency of Drug), and she is member of the advisory board at BIAL. Joaquim Ferreira received grants from Fundação MSD (Portugal), Novartis, Medtronic, and Abbvie, and lecture fees from Lundbeck, Abbvie, BIAL, Biogen, Sunovion Pharmaceuticals, ONO, Affiris, and Zambon, payment for expert testimony from Novartis, and he participates in advisory boards of Lundbeck, Abbvie, BIAL, Affiris, Sunovion Pharmaceuticals, and Zambon; he is employed by CNS (Campus Néurologico Sénior) and the Medical Faculty of Lisbon. Emilia Gatto received consulting fees from Bago Argentina, honoraria from Bago Argentina,UCB, IPMDS, and Europharm, and participates in advisory boards of Bago Argentina and UCB. Nir Giladi received grants from the Michael J Fox Foundation, The National Parkinson Foundation, The European Union, The Israel Science Foundation Teva, NNE program, Biogen, Ionis, Sieratzki Family Foundation, and The Aufzien Academic Center in Tel-Aviv University; he holds royalties or licenses at Lysosomal Therapeutics (LTI); he received consulting fees from Sionara, NeuroDerm, Pharma2B, Denali, Neuron23, Sanofi-Genzyme, Biogen, and Abbvie; he received honoraria from Abbvie, Sanofi-Genzyme, and the Movement Disorder Society. Nobutaka Hattori received grants from the Japan Society for the Promotion of Science (JSPS; 18H04043, 21H04820, 19K22603), the Japan Agency for Medical Research and Development (AMED; JP20dm0307101, JP20dm0207070, JP20ek0109358, JP19ek0109393, JP19gm0710011, JP19km0405206), Health Labour Sciences Research Grant (20FC1049, H29-FC1-062, H29-FC1-033), and the Japan Science and Technology Agency (JPMJMS2024-5); he participates in advisory boards at Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, TEIJIN PHARMA LIMITED, Novartis Pharma, Ono Pharmaceutical, Biogen Idec Japan, and Kissei Pharmaceutical; he receives consulting fees from Hisamitsu Pharma; he received honoraria from Dai-Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, AbbVie GK, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb, Ono Pharmaceutical, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Nihon Medi-physics, and Daiichi Sankyo; he received payment for expert testimony from Mitsubishi Tanabe Pharma; he received support for attending meeting from Takeda Pharmaceutical, and Kyowa Kirin; he has 17 patents planned or pending and 5 issued; he is Team Leader at the Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science; he holds equity stock (8%) of PARKINSON Laboratories Co. Ltd., unrelated to the submitted work. Silvia Jesús has received grants from “Consejería de Salud y Familias” PI-0459-2018, “acción B Clínicos-Investigdores” B-0007-2019 and from the “instituto de Salud Carlos III” PI-18/01898; she received honoraria from Abbvie, Bial, Merz, UCB, Italfarmaco, Zambon and Server. Valtteri Kaasinen received grants from Turku University Foundation, Päivikki and Sakari Sohlberg Foundation, and the Finnish Cultural Foundation; he received consulting fees from Nordic Infucare, Abbvie, and Adamant Health; he received honoraria from Nordic Infucare and Abbvie; he received Support for attending meetings and/or travel from Nordic Infucare; he participates on a Data Safety Monitoring Board or Advisory Board at Nordic Infucare and Abbvie; he is board member of the Finnish Neurological Society. Christine Klein received royalties from Oxford University Press; she received consulting fees from Centogene and Retromer Therapeutics; she received payment or honoraria from Desitin Pharma; she received support to attend meetings from the Movement Disorder Society; she participates on a Data Safety Monitoring Board or Advisory Board at the Else Kroener Fresenius Foundation. Peter Klivenyi received honoraria from Abbvie and Medtronic. Vladimir Kostic received Grant 17590 from the Ministry of Education, Science and Technological Development of Serbia; he received honoraria from Novartis and Boehringer Ingelheim. Shen-Yang Lim received the following grants, (i) Stipend - Global Parkinson’s Genetics Program (GP2) Working Group Co-Lead Award, from the Michael J. Fox Foundation, (ii) Michael J. Fox Foundation (Grant 18305: "Identifying leucocyte and urine biomarkers in PD patients with LRRK2 G2385R variant"). George Mellick received grants from the National Health and Medical Research Foundation, Australia (APP1151854, APP1084560). Lukasz Milanowski received grants from the Polish National Agency for Academic Exchange Iwanowska’s Fellowship PPN/IWA/2018/1/00006/U/00001/01, the APDA, the Foundation for Polish Science (FNP) and the Haworth Family Professorship in Neurodegenerative Diseases Fund. Pablo mir received grants from the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER, PI19/01576), and the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PE-0210-2018); he received payment or honoraria for lectures from Abbvie, Abbott, and Zambon; he received Support for attending meetings and travel from Abbvie. Shalini Padmanabhan is employed by the Michael J. Fox Foundation. Andreas Puschmann received grants from Region Skåne, Sweden, Skåne University Hospital, Sweden, The Swedish Parkinson Academy, The Swedish Parkinson Foundation (Parkinsonfonden), MultiPark – a strategic research environment at Lund University, and Bundy Academy, Sweden; he received honoraria from Elsevier (Associate editor for Parkinsonism and Related Disorders), from the International Parkinson and Movement Disorder Society (MDS), and from the International Association of Parkinsonism and Related Disorders; he received support for travels from the International Association of Parkinsonism and Related Disorders; he is board member of the International Association of Parkinsonism and Related Disorders. Mariana Spitz received funding from Centogene for the ROPAD study; she received support for travels from Roche. Justin Solle is employed by the Michel J. Fox Foundation. Oksana Suchowersky received grants from Roche and WaveLifeSciences; she holds royalties or licenses at UpToDate; she received consulting fees from Abbvie and Sunovion; she received honoraria from the World Parkinson Conference; she participates in advisory boards at Alexion; she is board member of the Parkinson Society Alberta. Pichet Termsarasab received book royalties from Elsevier and Springer Nature Switzerland; he received honoraria for manuscript writing from MedLink Neurology and for lectures from Viatris. Bart van de Warrenburg received grants from Radboudumc, ZonMW, Hersenstichting, Gossweiler Foundation, and the Michael J Fox Foundation; he holds royalties or licenses at BSL Springer Nature; he received consulting fees from uniQure; he received honoraria from UKM Medical Center Kuala Lumpur; he participates in Medical advisory board of patient organizations (unpaid); he is unpaid member of Steering committees or executive boards of various research consortia; he received a wearable sensor set by Brugling Fund/Hersenstichting. Caroline H. Williams-Gray collaborates with Astra-Zeneca on the microbiome in Parkinson’s disease; she received consultancy fees from Modus Outcomes and Evidera, Inc./GlaxoSmithKline; she received honoraria from Profile Pharma Limited. Eva-Juliane Vollstedt, Harutyun Madoev, Anna Aasly, Azlina Ahmad-Annuar, Bashayer Al-Mubarak, Victoria Alvarez, Ignacio Amorin, Grazia Annesi, David Arkadir, Soraya Bardien, Roger A. Barker, A. Nazli Basak, Agnita Boon, Laura Brighina, Andrea Carmine Belin, Jonathan Carr, Leonor Correia Guedes, David Crosiers, Parimal Das, Patricia de Carvalho Aguiar, Jolanta Dorszewska, Sibel Ertan, Rosangela Ferese, Gençer Genç, Pilar Gómez-Garre, Hasmet Hanagasi, Faycal Hentati, Dorota Hoffman-Zacharska, Sergey N. Illarioshkin, Joseph Jankovic, Anneke Kievit, Dariusz Koziorowski, Andrea A. Kühn, Anthony E. Lang, Chin-Hsien Lin, Katja Lohmann, Vladana Markovic, Mika Henrik Martikainen, Marcelo Merello, Özgür Öztop-Çakmak, Márcia Mattos Gonçalves Pimentel, Teeratorn Pulkes, Ekaterina Rogaeva, Esther M. Sammler, Maria Skaalum Petersen, Matej Skorvanek, Ai Huey Tan, Avner Thaler, Vitor Tumas, Enza Maria Valente, Ruey-Mei Wu, Baorong Zhang, and Alexander Zimprich report no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Vollstedt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

Background: Amantadine is a widely prescribed medication in Parkinson's disease (PD). A distinctive craniofacial distribution of myoclonus with speech impairment is an underrecognized iatrogenic complication in amantadine-treated patients with PD., Cases: We report 7 patients with idiopathic PD (disease duration, 6-21 years) who developed speech-induced craniofacial-predominant myoclonus with "stuttering-like" dysarthria and speech arrests days to months after amantadine initiation or dose increase. Renal insufficiency was identified as a risk factor in 4 cases. In all cases, reduction or discontinuation of amantadine markedly attenuated the myoclonus and restored speech intelligibility., Literature Review: Amantadine can induce subcortical segmental or generalized myoclonus. A report in 1996 of "vocal myoclonus" in an amantadine-treated patient with PD was the first observation of a focal distribution of myoclonus, particularly affecting speech. Since then, few cases of craniofacial myoclonus with speech impairment have been reported, none with accompanying video. With 1 exception, the craniofacial distribution was part of a generalized pattern of amantadine-induced myoclonus. Comorbid renal insufficiency is a recognized risk factor., Conclusions: Speech-induced craniofacial myoclonus, with marked "stuttering-like" dysarthria and speech arrests, is a disabling iatrogenic complication in PD that resolves upon amantadine discontinuation., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Biallelic mutations in PINK1/PRKN cause recessive Parkinson's disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson's disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74-0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)