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Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration. Methods: The study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD‐PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer. Results: In basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD‐PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD‐PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations. Conclusions: Altogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD‐PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: It is debated whether external anal sphincter (EAS) electromyography can distinguish between multiple system atrophy (MSA) and Parkinson's disease (PD), whereas its usefulness for MSA prognosis is unknown. Objectives: We explored the diagnostic and prognostic value and clinical correlations of EAS electromyography patterns in MSA. Methods: We collected clinical data and EAS electromyography findings in 72 patients with MSA and 21 with PD. Results: We identified four EAS patterns. The normal pattern was frequently observed in PD and associated with prolonged survival when identified in MSA. Abnormal patterns were predominant in MSA. The most severe pattern was associated with the highest likelihood of MSA diagnosis and with the worst prognosis in the MSA cohort. MSA patients with EAS abnormalities often showed urogenital symptoms and fecal incontinence. Conclusions: The increasing severity of EAS electromyography patterns paralleled diagnostic accuracy and survival in MSA, and correlated with prevalence of bladder and bowel symptoms. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to describe the clinical and demographic features of idiopathic non‐task‐specific upper limb dystonia compared with the task‐specific form. Methods: In this retrospective study, adult patients with idiopathic upper limb dystonia, either focal or as part of a segmental/multifocal dystonia, from the Italian Dystonia Registry were enrolled. In patients with focal upper limb dystonia, dystonia spread was estimated by survival analysis. Results: Of the 1522 patients with idiopathic adult‐onset dystonia included in the Italian Dystonia Registry, we identified 182 patients with upper limb dystonia. Non‐task‐specific dystonia was present in 61.5% of enrolled cases. Women predominated among non‐task‐specific patients, whereas men predominated in the task‐specific group. Peak age of upper limb dystonia onset was in the sixth decade in the non‐task‐specific group and in the fourth decade in the task‐specific group. In both groups, upper limb dystonia started as focal dystonia or as part of a segmental dystonia. Segmental onset was more frequent among non‐task‐specific patients, whereas focal onset predominated among task‐specific patients. Dystonic action tremor was more frequent among non‐task‐specific patients. No significant differences between groups emerged in terms of sensory trick frequency, rest tremor, or family history of dystonia. In patients with focal upper limb dystonia, dystonia spread was greater in the non‐task‐specific group. Conclusion: Novel information on upper limb dystonia patients suggests that non‐task‐specific and task‐specific upper limb dystonia have different demographic and clinical features. However, it remains to be determined whether these differences also reflect pathophysiological differences. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion α‐Synuclein seed amplification assay on cerebrospinal fluid (CSF‐αSyn‐SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF‐αSyn‐SAA parameters may provide useful insight to dissect the heterogeneity of synucleinopathies.To assess differences in CSF‐αSyn‐SAA amplification parameters in participants with PD stratified by rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, GBA, and LRRK2 variants.Clinical and CSF‐αSyn‐SAA data from the Parkinson's Progression Marker Initiative dataset were used. CSF‐αSyn‐SAA parameters included maximum fluorescence (Fmax), time to reach 50% of Fmax (T50), time to threshold (TTT), slope, and area under the curve (AUC). Sporadic PD (n = 371) was stratified according to RBD and dysautonomia (DysA) symptoms. Genetic PD included carriers of pathogenic variants of GBA (GBA‐PD, n = 52) and LRRK2 (LRRK2‐PD, n = 124) gene.CSF‐αSyn‐SAA was positive in 77% of LRRK2‐PD, 92.3% of GBA‐PD, and 93.8% of sporadic PD. The LRRK2‐PD cohort showed longer T50 and TTT, and smaller AUC than GBA‐PD (P = 0.029, P = 0.029, P = 0.016, respectively) and sporadic PD (P = 0.034, P = 0.033, P = 0.014, respectively). In the sporadic cohort, CSF‐αSyn‐SAA parameters were similar between PD with (n = 157) and without (n = 190) RBD, whereas participants with DysA (n = 193) presented shorter T50 (P = 0.026) and larger AUC (P = 0.029) than those without (n = 150).CSF‐αSyn‐SAA parameters vary across genetic and non‐genetic PD subtypes at the group level. These differences are mostly driven by the presence of LRRK2 variants and DysA. Significant overlaps in the amplification parameter values exist between groups and limit their use at the individual level. Further studies are necessary to understand the mechanisms of CSF‐αSyn‐SAA parameter differences. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies underlined the relevance of Nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor pathway in the pathogenesis of Parkinson's disease (PD).Objective: The objective of this study was to explore Nrf2 pathway in vivo in PD, looking for novel disease biomarkers and therapeutic targets.Methods: The levels of Nrf2, the downstream effectors (NAD(P)H dehydrogenase [quinone] 1 (Nqo1) enzyme, glutathione metabolism enzymes Glutamate-cysteine ligase (GCL) and Glutathione Reductase (GR)), the upstream activators (redox state and mitochondrial dysfunction), and α-synuclein oligomers were assessed in the blood leukocytes of PD patients comparatively to controls. Biochemical data were correlated to clinical parameters.Results: In PD, Nrf2 was highly transcribed and expressed as well as its target effectors. The mitochondrial complex I activity was reduced and the oxidized form of glutathione prevailed, disclosing the presence of pathway's activators. Also, α-synuclein oligomers levels were increased. Nrf2 transcript and oligomers levels correlated with PD duration.Conclusions: Blood leukocytes mirror pathogenic mechanisms of PD, showing the systemic activation of the Nrf2 pathway and its link with synucleinopathy and clinical events. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a+/Δgag) mice heterozygous for ΔE-torsinA and their controls (Tor1a+/+ mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1-preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1-dependent potentiation of N-methyl- d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]