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Estimates of the spectrum and frequency of pathogenic variants in Parkinsons disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinsons disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

Background: With the arrival of disease-modifying treatments, it is mandatory to find new cognitive markers that are sensitive to Alzheimer's disease (AD) pathology in preclinical stages. Objective: To determine the utility of a newly developed Learning and Associative Memory face test: LAM test. This study examined the relationship between AD cerebrospinal fluid (CSF) biomarkers and performance on LAM test, and assessed its potential clinical applicability to detect subtle changes in cognitively healthy subjects at risk for AD. Methods: We studied eighty cognitively healthy volunteers from the Valdecilla cohort. 61% were women and the mean age was 67.34 years (±6.416). All participants underwent a lumbar puncture for determination of CSF biomarkers and an extensive neuropsychological assessment, including performance on learning and associative memory indices of the LAM-test after 30 min and after 1 week, and two classic word lists to assess verbal episodic memory: the Rey Auditory Verbal Learning Test (RAVLT) and the Free and Cued Selective Reminding Test (FCSRT). We analyzed cognitive performance according to amyloid status (A+ versus A–) and to ATN model (A–T–N–; A+T–N–; A+T+N–/A+T+N+). Results: Performance on the LAM-test was significantly correlated with CSF Aβ ratio. A+ participants performed worse on both learning (mean difference = 2.19, p = 0.002) and memory LAM measures than A– (mean difference = 2.19, p = 0.004). A decline in performance was observed along the Alzheimer's continuum, with significant differences between ATN groups. Conclusions: Our findings suggest that LAM test could be a useful tool for the early detection of subjects within the AD continuum, outperforming classical memory tests. [ABSTRACT FROM AUTHOR]

Background: Video-oculography constitutes a highly-sensitive method of characterizing ocular movements, which could detect subtle premotor changes and contribute to the early diagnosis of Parkinson's disease (PD). Objective: To investigate potential oculomotor differences between idiopathic PD (iPD) and PD associated with the G2019S variant of LRRK2 (L2PD), as well as to evaluate oculomotor function in asymptomatic carriers of the G2019S variant of LRRK2. Methods: The study enrolled 129 subjects: 30 PD (16 iPD, 14 L2PD), 23 asymptomatic carriers, 13 non-carrier relatives of L2PD patients, and 63 unrelated HCs. The video-oculographic evaluation included fixation, prosaccade, antisaccade, and memory saccade tests. Results: We did not find significant differences between iPD and L2PD. Compared to controls, PD patients displayed widespread oculomotor deficits including larger microsaccades, hypometric vertical prosaccades, increased latencies in all tests, and lower percentages of successful antisaccades and memory saccades. Non-carrier relatives showed oculomotor changes with parkinsonian features, such as fixation instability and hypometric vertical saccades. Asymptomatic carriers shared multiple similarities with PD, including signs of unstable fixation and hypometric vertical prosaccades; however, they were able to reach percentages of successful antisaccade and memory saccades similar to controls, although at the expense of longer latencies. Classification accuracy of significant oculomotor parameters to differentiate asymptomatic carriers from HCs ranged from 0.68 to 0.74, with BCEA, a marker of global fixation instability, being the parameter with the greatest classification accuracy. Conclusions: iPD and LRRK2-G2019S PD patients do not seem to display a differential oculomotor profile. Several oculomotor changes in asymptomatic carriers of LRRK2 mutations could be considered premotor biomarkers. [ABSTRACT FROM AUTHOR]

Chiari Malformation type I (CM-I) is a neurological disorder characterized by cerebellar tonsillar herniation. Chronic pain, particularly headaches, is a prevalent symptom in CM-I patients, significantly impacting their quality of life. The objective of this study was to evaluate the perceived quality of life in adults with CM-I and examine the influence of chronic pain and comorbid symptoms on their well-being. 26 CM-I patients (8 with decompressive surgery) and 26 matched healthy controls were recruited. Participants completed the following questionnaires: WHOQOL-BREF, HDI, NDI, OLBPDQ and HADS. CM-I patients exhibited significantly lower scores across all domains of quality of life when compared to healthy controls. Chronic pain, including headache, neck pain, and low back pain, was more pronounced among CM-I patients and demonstrated a significant correlation with depressive symptoms. Notably, after controlling for chronic pain, the differences in quality of life between CM-I patients and controls diminished. The results suggest that chronic pain, especially headaches, and comorbid depressive symptoms exert a substantial impact on the quality of life of CM-I patients. Surgical intervention alone may not fully address these issues, highlighting the importance of considering psychological interventions as part of the comprehensive treatment. Further research with larger samples and pre-post-surgery assessments is needed to validate these findings and explore the potential benefits of psychological therapies in enhancing the quality of life for CM-I patients., Competing Interests: The authors have no conflicts of interest to disclose., (2024, International Research and Cooperation Association for Bio & Socio - Sciences Advancement.)

Background: Severe hypomagnesemia is an increasingly recognized cause of acute and reversible cerebellar ataxia, often accompanied by cerebellar oculomotor signs such as jerky horizontal or downbeat nystagmus and very rarely ocular flutter., Phenomenology Shown: This video illustrates horizontal pendular nystagmus in a patient with acute onset cerebellar ataxia associated with severe hypomagnesemia., Educational Value: Acquired pendular nystagmus can be distinguished from macrosaccadic oscillations and ocular flutter in that the former is composed of two slow phases of equal velocity and the latter of two fast phases of saccadic type with or without intersaccadic interval, respectively. It is most commonly associated with demyelinating, toxic, metabolic, and genetic disorders, but has not been reported in association with severe hypomagnesemia., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies., Competing Interests: Declaration of interests T.G.B. is a consultant for Aprinoia Therapeutics, Vivid Genomics, and Avid Radiopharmaceutical and is a scientific advisory board member for Vivid Genomics. J.A.H., H.R.M., B.J.T., and H.R.M. hold US, EU, and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. B.J.T. and S.W.S. receive research support from Cerevel Therapeutics. B.J.T. is an editorial and advisory board member for Brain, eClinicalMedicine, Journal of Neurology, Neurosurgery, and Psychiatry, and Neurobiology of Aging. H.R.M. reports paid consultancy from Biogen, Biohaven, Lundbeck, UCB, and Denali as well as lecture fees and honoraria from the Wellcome Trust and the Movement Disorders Society. H.R.M. received research grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, the Drake Foundation, and the Medical Research Council. H.K. is editor-in-chief of Clinical Autonomic Research, serves as principal investigator (PI) of a clinical trial sponsored by Biogen MA Inc. (TRACK MSA, S19-01846), and received consultancy fees from Lilly USA LLC, Biohaven Pharmaceuticals Inc., Takeda Pharmaceutical Company Ltd., Ono Pharma UK Ltd., Lundbeck LLC, and Theravance Biopharma US Inc. A.F. reports royalties from Springer Verlag; speaker fees and honoraria from Theravance Biopharma, GE Health Care, Broadview Ventures, Austrian Autonomic Society, Stopp-HSP, and Elsevier; and research grants from the FWF-Austrian Science Fund, Medical University of Innsbruck, US MSA Coalition, Dr. Johannes and Hertha Tuba Foundation, and Austrian Exchange Program, outside of the present work. J.-A.P. is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. I.B. received consultancy fees from Theravance Biopharma US Inc., Amenal Pharmaceutics, Regeneron Pharmaceuticals, Takeda Pharmaceuticals, and Neurawell Therapeutics. S.W.S. serves on the scientific advisory board of the Lewy Body Dementia Association and the Multiple System Atrophy Coalition. S.W.S. is an editorial board member for the Journal of Parkinson’s Disease and JAMA Neurology. A.P. serves on the board of directors for CurePSP, has received research grants from the National Institutes of Health and the Michael J. Fox Foundation, and has received consultancy fees from AbbVie Inc., Biogen Inc., SciNeuro Pharmaceuticals, Ono Pharma, and Ferrer Internacional, S.A. A.T. serves on the scientific advisory board for Vivid Genomics. R.H.R. is currently employed by CoSyne Therapeutics; all work performed for this publication was performed on her own time and not as a part of her duties as an employee. Z.K.W. is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Mayo Clinic Center for Regenerative Medicine, the gifts from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and the Albertson Parkinson's Research Foundation. He serves as PI or co-PI on Biohaven Pharmaceuticals Inc. (BHV4157-206) and Vigil Neuroscience Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) projects/grants. He serves as co-PI of the Mayo Clinic APDA Center for Advanced Research, as an external advisory board member for Vigil Neuroscience Inc., and as a consultant on neurodegenerative medical research for Eli Lilli & Company. F.K. received personal fees from Institut de Recherches Internationales Servier, Takeda Pharmaceuticals, Sanofi, Teva, Vial, and the Austrian Society of Neurology in the past 12 months, and he has ongoing grant support from the Austrian Science Fund (FWF) and the National Institutes of Health outside of the submitted work. W.G.M. has received fees for editorial activities with Elsevier and has served as an advisor for Lundbeck, Biohaven, Roche, Alterity, Servier, Inhibikase, Takeda, and Teva., (Published by Elsevier Inc.)

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat. In this study, we identified 553 patients carrying biallelic RFC1 expansions and measured the repeat expansion size in 392 cases. Pearson's coefficient was calculated to assess the correlation between the repeat size and age at disease onset. A Cox model with robust cluster standard errors was adopted to describe the effect of repeat size on age at disease onset, on age at onset of each individual symptoms, and on disease progression. A quasi-Poisson regression model was used to analyse the relationship between phenotype and repeat size. We performed multivariate linear regression to assess the association of the repeat size with the degree of cerebellar atrophy. Meiotic stability was assessed by Southern blotting on first-degree relatives of 27 probands. Finally, somatic instability was investigated by optical genome mapping on cerebellar and frontal cortex and unaffected peripheral tissue from four post-mortem cases. A larger repeat size of both smaller and larger allele was associated with an earlier age at neurological onset [smaller allele hazard ratio (HR) = 2.06, P < 0.001; larger allele HR = 1.53, P < 0.001] and with a higher hazard of developing disabling symptoms, such as dysarthria or dysphagia (smaller allele HR = 3.40, P < 0.001; larger allele HR = 1.71, P = 0.002) or loss of independent walking (smaller allele HR = 2.78, P < 0.001; larger allele HR = 1.60; P < 0.001) earlier in disease course. Patients with more complex phenotypes carried larger expansions [smaller allele: complex neuropathy rate ratio (RR) = 1.30, P = 0.003; cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) RR = 1.34, P < 0.001; larger allele: complex neuropathy RR = 1.33, P = 0.008; CANVAS RR = 1.31, P = 0.009]. Furthermore, larger repeat expansions in the smaller allele were associated with more pronounced cerebellar vermis atrophy (lobules I-V β = -1.06, P < 0.001; lobules VI-VII β = -0.34, P = 0.005). The repeat did not show significant instability during vertical transmission and across different tissues and brain regions. RFC1 repeat size, particularly of the smaller allele, is one of the determinants of variability in RFC1 disease and represents a key prognostic factor to predict disease onset, phenotype and severity. Assessing the repeat size is warranted as part of the diagnostic test for RFC1 expansion., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)