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Background: The recent International Parkinson and Movement Disorder Society diagnostic criteria for multiple system atrophy (MDS‐MSA) have been developed to improve diagnostic accuracy although their diagnostic properties have not been evaluated. Objectives: The aims were to validate the MDS‐MSA diagnostic criteria against neuropathological diagnosis and compare their diagnostic performance to previous criteria and diagnosis in clinical practice. Methods: Consecutive patients with sporadic, progressive, adult‐onset parkinsonism, or cerebellar ataxia from the Queen Square Brain Bank between 2009 and 2019 were selected and divided based on neuropathological diagnosis into MSA and non‐MSA. Medical records were systematically reviewed, and clinical diagnosis was documented by retrospectively applying the MDS‐MSA criteria, second consensus criteria, and diagnosis according to treating clinicians at early (within 3 years of symptom onset) and final stages. Diagnostic parameters (sensitivity, specificity, positive/negative predictive value, and accuracy) were calculated using neuropathological diagnosis as gold standard and compared between different criteria. Results: Three hundred eighteen patients (103 MSA and 215 non‐MSA) were included, comprising 248 patients with parkinsonism and 70 with cerebellar ataxia. Clinically probable MDS‐MSA showed excellent sensitivity (95.1%), specificity (94.0%), and accuracy (94.3%), although their sensitivity at early stages was modest (62.1%). Clinically probable MDS‐MSA outperformed diagnosis by clinicians and by second consensus criteria. Clinically established MDS‐MSA showed perfect specificity (100%) even at early stages although to the detriment of low sensitivity. MDS‐MSA diagnostic accuracy did not differ according to clinical presentation (ataxia vs. parkinsonism). Conclusions: MDS‐MSA criteria demonstrated excellent diagnostic performance against neuropathological diagnosis and are useful diagnostic tools for clinical practice and research. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Highly reproducible epidemiological evidence shows that type 2 diabetes (T2D) increases the risk and rate of progression of Parkinson's disease (PD), and crucially, the repurposing of certain antidiabetic medications for the treatment of PD has shown early promise in clinical trials, suggesting that the effects of T2D on PD pathogenesis may be modifiable. The high prevalence of T2D means that a significant proportion of patients with PD may benefit from personalized antidiabetic treatment approaches that also confer neuroprotective benefits. Therefore, there is an immediate need to better understand the mechanistic relation between these conditions and the specific molecular pathways affected by T2D in the brain. Although there is considerable evidence that processes such as insulin signaling, mitochondrial function, autophagy, and inflammation are involved in the pathogenesis of both PD and T2D, the primary aim of this review is to highlight the evidence showing that T2D‐associated dysregulation of these pathways occurs not only in the periphery but also in the brain and how this may facilitate neurodegeneration in PD. We also discuss the challenges involved in disentangling the complex relationship between T2D, insulin resistance, and PD, as well as important questions for further research. © 2022 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Somatic α‐synuclein (SNCA) copy number variants (CNVs, specifically gains) occur in multiple system atrophy (MSA) and Parkinson's disease brains. Objective: The aim was to compare somatic SNCA CNVs in MSA subtypes (striatonigral degeneration [SND] and olivopontocerebellar atrophy [OPCA]) and correlate with inclusions. Methods: We combined fluorescent in situ hybridization with immunofluorescence for α‐synuclein and in some cases oligodendrocyte marker tubulin polymerization promoting protein (TPPP). Results: We analyzed one to three brain regions from 24 MSA cases (13 SND, 11 OPCA). In a region preferentially affected in one subtype (putamen in SND, cerebellum in OPCA), mosaicism was higher in that subtype, and cells with CNVs were 4.2 times more likely to have inclusions. In the substantia nigra, nonpigmented cells with CNVs and TPPP were about six times more likely to have inclusions. Conclusions: The correlation between SNCA CNVs and pathology (at a regional level) and inclusions (at a single‐cell level) suggests a role for somatic SNCA CNVs in MSA pathogenesis. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Heterozygous NKX2‐1 loss‐of‐function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood‐onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease‐causing structural variants whose detection in routine diagnostics remains challenging. Objective: To establish the molecular diagnosis of two first‐degree relatives with clinically suspected NKX2‐1‐related disorder who had negative NKX2‐1 Sanger (SS), whole‐exome (WES), and whole‐genome (WGS) sequencing. Methods: The proband's WES was analyzed for MEIs. A candidate MEI in NKX2‐1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2‐1 haploinsufficiency at RNA and protein levels were performed. Results: A 347‐bp AluYa5 insertion with a 65‐bp poly‐A tail followed by a 16‐bp duplication of the pre‐insertion wild‐type sequence in exon 3 of NKX2‐1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype. Conclusions: We identified a de novo exonic AluYa5 insertion causing NKX2‐1‐related disorder in SS/WES/WGS‐negative cases, suggesting that MEI analysis of short‐read sequencing data or targeted long‐read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6-associated neurodegeneration.Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported.Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review.Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating, which may explain the phenotypic heterogeneity of childhood- and late-onset PLA2G6-associated neurodegeneration. In five deceased patients, median disease duration was 13.0 years. Brain pathology in three cases showed mixed Lewy and tau pathology.Conclusions: Biallelic PLA2G6 mutations cause early-onset parkinsonism associated with dystonia, pyramidal and cerebellar signs, myoclonus, and cognitive impairment. Early psychiatric manifestations and bladder overactivity are common. Cerebro/cerebellar atrophy are frequent magnetic resonance imaging features, whereas brain iron deposition is not. Early, severe dyskinesias are a tell-tale sign. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Despite the considerable overlap with atypical parkinsonism, a systematic characterization of the movement disorders associated with frontotemporal lobar degeneration (FTLD) is lacking. Objective: The aim of this study is to provide a detailed description of the phenomenology and neuropathologic correlations of movement disorders in FTLD. Methods: In this cohort study, movement disorder clinical data were retrospectively collected from medical records of consecutive patients with a postmortem diagnosis of FTLD from the Queen Square Brain Bank between January 2010 and December 2018. At postmortem, neurodegenerative pathologies were systematically evaluated following consensus criteria. Degeneration of the substantia nigra was assessed as a marker of presynaptic dopaminergic parkinsonism using semiquantitative methods. Results: A total of 55 patients (35 men [64%]) were included with median (interquartile range) age at diagnosis of 58.8 (52.6–63.9) years and a disease duration of 9.6 (6.2–12.9) years. Movement disorders were present in 19 (35%) patients without differences among disease subtypes. The most common syndromes were parkinsonism (9 patients [16%]), usually as an additional late feature, and corticobasal syndrome (CBS, 7 patients [13%]), commonly as a presenting feature. Substantia nigra degeneration was present in 37 (67%) patients although it did not show a good clinical correlation with movement disorders. Those with Pick's disease showed milder substantia nigra degeneration and better response to levodopa. Conclusions: Movement disorders can present in all FTLD subtypes, more commonly as a late additional feature (parkinsonism) or as a presenting symptom (CBS). The underlying pathophysiology is complex and likely to involve structures outside the presynaptic striatonigral system. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to determine the prevalence of the GGC‐repeat expansion in NOTCH2NLC in whites presenting with movement disorders. Methods: We searched for the GGC‐repeat expansion in NOTCH2NLC using repeat‐primed polymerase chain reaction in 203 patients with essential tremor, 825 patients with PD, 194 patients with spinocerebellar ataxia, 207 patients with "possible" or "probable" MSA, and 336 patients with pathologically confirmed MSA. We also screened 30,008 patients enrolled in the 100,000 Genomes Project for the same mutation using ExpansionHunter, followed by repeat‐primed polymerase chain reaction. All possible expansions were confirmed by Southern blotting and/or long‐read sequencing. Results: We identified 1 patient who carried the NOTCH2NLC mutation in the essential tremor cohort, and 1 patient presenting with recurrent encephalopathy and postural tremor/parkinsonism in the 100,000 Genomes Project. Conclusions: GGC‐repeat expansion in NOTCH2NLC is rare in whites presenting with movement disorders. In addition, existing whole‐genome sequencing data are useful in case ascertainment. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

This document is a list of references to various scientific studies and articles related to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The studies cover a range of topics including diagnostic tools, biomarkers, genetic research, and imaging techniques. The authors of the document have different affiliations and financial disclosures related to their research. The references provide a comprehensive overview of the current research in the field and may be useful for library patrons conducting research on these topics. [Extracted from the article]

Background Objective Methods Results Conclusions Seed amplification assay (SAA) testing has been developed as a biomarker for the diagnosis of α‐synuclein‐related neurodegenerative disorders.The objective of this study was to assess the rate of α‐synuclein SAA positivity in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) and to analyze clinical and pathological features of SAA‐positive and ‐negative cases.A total of 96 cerebrospinal fluid samples from clinically diagnosed PSP (n = 59) and CBS (n = 37) cases were analyzed using α‐synuclein SAA.Six of 59 (10.2%) PSP cases were α‐synuclein SAA positive, including one case who was MSA‐type positive. An exploratory analysis showed that PSP cases who were Parkinson's disease–type positive were older and had a shorter disease duration compared with SAA‐negative cases. In contrast, 11 of 37 (29.7%) CBS cases were α‐synuclein SAA positive, including two cases who were MSA‐type positive.Our results suggest that α‐synuclein seeds can be detected in PSP and CBS using a cerebrospinal fluid α‐synuclein SAA, and in PSP this may impact on clinical course. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]