Annals of Clinical and Translational Neurology最新文献

{"title":"Pre-Diagnostic Features of Multiple Sclerosis in a Diverse UK Cohort: A Nested Case-Control Study.","authors":"Pooja Tank, Benjamin M Jacobs, Jonathan Bestwick, Ruth Dobson","doi":"10.1002/acn3.70175","DOIUrl":"https://doi.org/10.1002/acn3.70175","url":null,"abstract":"<p><strong>Background: </strong>Many patients with Multiple Sclerosis (MS) experience nonspecific symptoms prior to diagnosis. This period-the 'MS prodrome'-has been described in socio-economically homogeneous cohorts to date. It remains unclear to what extent events prior to an MS diagnosis differ according to social determinants of health.</p><p><strong>Methods: </strong>We conducted a retrospective, longitudinal, population-based nested case-control study using data from Clinical Practice Research Datalink (CPRD) Aurum. Associations between pre-diagnostic symptoms and MS risk were evaluated using multivariable logistic regression models in MS cases and matched controls. To determine whether associations differed by potential health determinants, we tested for statistical interactions and used stratified models.</p><p><strong>Results: </strong>The study population consisted of 15,029 patients with MS (median index age 44.6, 80.3% female) and 81,027 age-matched controls. In the 5 years preceding diagnosis, MS cases were more likely than controls to have coded autonomic (OR 1.87 [1.80-1.94]), cognitive (OR 2.57 [2.06-3.20]), neurological (OR 7.91 [7.58-8.26]), pain (OR 2.21 [2.12-2.29]) and psychiatric (OR 1.75 [1.69-1.82]) symptoms. The direction of effect was consistent across gender, ethnicity, deprivation and location (urban vs. rural) strata, with over-representation of neurological symptoms in males and those living in urban areas. No statistically significant interaction between factors was found.</p><p><strong>Conclusion: </strong>We report a consistent relationship between the occurrence of prodromal symptoms and MS risk across a diverse UK cohort. No associations were specific to a particular ethnic, gender or socio-economic group. These findings strengthen the concept of pre-diagnostic symptoms reflecting a potential opportunity to identify those at the earliest stages of MS.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognitive Impairment in Multiple Sclerosis: The Role of Clinical and Sociodemographic Factors - A Systematic Review and Meta-Analysis.","authors":"Katalin Lugosi, Marie A Engh, Tamás Kói, Zsolt Molnár, Gábor Csukly, Klaudia Horváth, Emma Hargitai, Péter Hegyi, Zsolt Mezei","doi":"10.1002/acn3.70172","DOIUrl":"https://doi.org/10.1002/acn3.70172","url":null,"abstract":"<p><strong>Objective: </strong>Cognitive impairment (CI) affects the quality of life in multiple sclerosis (MS). Identifying influencing factors is key to improving CI monitoring. This systematic review and meta-analysis examines clinical and sociodemographic variables impacting the cognitive screening Symbol Digit Modalities Test (SDMT) performance across MS subtypes, identifying subgroups at greater risk of cognitive impairment.</p><p><strong>Methods: </strong>Registered on PROSPERO (CRD42023451696), a literature search was conducted on August 6, 2023, using PubMed, Embase, and CENTRAL. Following the PRISMA 2020 guideline, a random-effects meta-analysis addressed heterogeneity in correlation and meta-regression analyses. Multivariable regression model results were qualitatively synthesized (systematic review). The JBI Critical Appraisal Tool assessed bias risk. Primary outcome was SDMT raw scores, with EDSS and disease duration as primary exposures, extended with age, sex, education, depression, fatigue, mobility scores, and treatment as secondary exposures, according to our protocol. Associations were evaluated via univariate study-level correlations, univariate meta-regressions, study-level multivariable regression models, and multivariate meta-regressions, assessing covariate interdependence. Heterogeneity was quantified with I². Only observational cross-sectional data (or baseline data from longitudinal studies) were included.</p><p><strong>Results: </strong>A total of 155 studies with 22,828 patients were analyzed. In mixed and relapsing-remitting MS (RRMS), EDSS was the strongest negative correlate of SDMT (mixed MS: -0.44 CI:[-0.50; -0.36]; RRMS: -0.47 [-0.66; -0.23]). Education showed a moderate positive correlation (mixed MS: 0.31 [0.20; 0.42]; RRMS: 0.32 [-0.02; 0.59]). Due to cross-sectional design, heterogeneity, and potential aggregation/ecological bias, findings are exploratory.</p><p><strong>Interpretation: </strong>Poor SDMT performance is mainly driven by physical disability and cognitive reserve (education), modulated by sex, depression, and age, highlighting the need to integrate clinical and sociodemographic data in MS cognitive monitoring.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"INF2-Related Charcot-Marie-Tooth Disease in a Japanese Cohort: Genetic and Clinical Insights.","authors":"Chikashi Yano, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Takahiro Hobara, Risa Nagatomo, Fumikazu Kojima, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Chika Matsuoka, Toru Yamashita, Takashi Kimura, Ayako Miyazaki, Chinatsu Kinjo, Kenji Yokochi, Nanami Yamanaka, Nozomu Matsuda, Tomoki Suichi, Yoshiyuki Hanaoka, Haruka Kojima, Kenichi Todo, Hiroyuki Ishiura, Jun Mitsui, Shoji Tsuji, Hiroshi Takashima","doi":"10.1002/acn3.70205","DOIUrl":"https://doi.org/10.1002/acn3.70205","url":null,"abstract":"<p><strong>Background: </strong>INF2 mutations cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth disease (CMT). Accurate genetic diagnosis is critical, as INF2-related FSGS is typically resistant to immunotherapy yet rarely recurs after transplantation, and its associated neuropathy can mimic treatable immune-mediated disorders such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).</p><p><strong>Methods: </strong>We performed a multicenter study investigating 3329 Japanese patients with inherited peripheral neuropathies/CMT who underwent gene panel sequencing or whole-exome analysis between 2007 and 2024. Clinical data, including electrophysiological assessments, were obtained from the patients' medical records.</p><p><strong>Results: </strong>We identified six pathogenic INF2 variants in eight patients, all of which were located within the diaphanous inhibitory domain. Structural modeling revealed clustering of variants near the diaphanous autoregulatory domain-binding pocket, which is critical for INF2 autoinhibition. Clinically, all cases were sporadic, with a median age at neurological onset of 9 years. All patients exhibited lower limb weakness, and 6/8 (75%) had sensory disturbances. All patients also developed kidney dysfunction, with 7/8 (88%) progressing to end-stage renal disease at a median age of 15 years. Furthermore, all patients showed demyelinating neuropathy, and 2/8 (25%) received immunotherapy due to suspected immune-mediated neuropathy.</p><p><strong>Conclusion: </strong>Although INF2 variants are a rare cause of CMT in Japan, they should be considered in pediatric patients with demyelinating neuropathy and early-onset proteinuria, even in the absence of a family history. Blood and urine tests assessing renal dysfunction can provide guidance for appropriate genetic testing.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Purkinje Cell Loss in Essential Tremor: Collective Data From 215 Brains Over a 21-Year Period.","authors":"Chloë A Kerridge, Roberto S Hernandez, Nora C Hernandez, Phyllis L Faust, Elan D Louis","doi":"10.1002/acn3.70204","DOIUrl":"https://doi.org/10.1002/acn3.70204","url":null,"abstract":"<p><strong>Objective: </strong>Essential tremor is a highly prevalent movement disorder. Pathological changes observed in essential tremor cerebella center around Purkinje cells and neighboring neuronal populations. Postmortem studies have variably, but not always, shown reduced Purkinje cell counts in essential tremor compared to controls. Here we present collective data on 215 essential tremor brains obtained over a 21-year period.</p><p><strong>Methods: </strong>Purkinje cell loss was assessed through linear densities and empty basket percentages in a standard cerebellar tissue block from 215 essential tremor brains and brains from two comparison groups, 72 spinocerebellar ataxia and 165 controls (452 brains). An age-matched sub-sample comprised 195 essential tremor and 79 control brains.</p><p><strong>Results: </strong>Essential tremor cerebella had 15.0% lower Purkinje cell linear density and 37.8% higher empty basket percentage than age-matched controls (both p < 0.0001). In the full dataset, Purkinje cell decline with age was identified in controls, with a 4.2% decrease in linear density and a 12.5% increase in empty basket percentage per decade (p < 0.0001), but not in essential tremor. Comparisons of Purkinje cell linear density and empty basket percentage with spinocerebellar ataxias placed essential tremor on the milder end of a cerebellar neurodegenerative spectrum. Purkinje cell decline in essential tremor was not driven by Alzheimer's disease neuropathological changes, Lewy pathology, or clinical confounders.</p><p><strong>Interpretation: </strong>A diminished Purkinje cell population in essential tremor was demonstrated using two methods in this extensive dataset. Continued histopathological studies of Purkinje cell-associated morphological changes, in the context of both neurodegeneration and normal aging, will help elucidate the degenerative cascade in essential tremor.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of Cerebral Palsy in the Midwestern US.","authors":"Susie Kim, Kelsey Steffen, Lauren Gottschalk-Henneberry, Jennifer Miros, Amy Robichaux-Viehoever, Karen Taca, Bhooma R Aravamuthan","doi":"10.1002/acn3.70182","DOIUrl":"10.1002/acn3.70182","url":null,"abstract":"<p><strong>Objective: </strong>Cerebral palsy (CP) is the most common lifelong motor disability worldwide. Yet, data is limited on how CP manifests in the US. Our objective was to characterize and determine factors affecting functional outcomes in a large population of young people with CP in the Midwestern US.</p><p><strong>Methods: </strong>We integrated caregiver and clinician-facing standardized data entry into routine clinical care at a tertiary care CP center (https://bit.ly/CP-Intake-Methodology). We extracted this data for people with an ICD10 diagnosis of CP seen between March 22, 2023 and December 28, 2023 and used it to describe CP characteristics and determine factors affecting the odds of walking, oral feeding, and speech by Age 5.</p><p><strong>Results: </strong>Of 686 unique individuals with an ICD10 diagnosis of CP, 663 (97%) had caregiver- and clinician-entered data, of whom 633 had a clinician-confirmed CP diagnosis (mean age 9.1, 53.4% Male, 78.5% White). It was common to have quadriplegia (288/613, 47.0%), both spasticity and dystonia (257/632, 40.7%), pain (230/629, 36.6%), poor sleep (190/629, 30.0%), anxiety (157/633, 24.8%), walk independently (368/633, 58.1%), eat food and drink safely by mouth (288/578, 55.9%), produce understandable speech (249/584, 42.6%), and/or require anti-seizure medications (268/633, 42.3%). Cortical gray matter injury, initial critical care stay duration, and CP etiology affected the odds of walking, oral feeding, and speech (binary logistic regression, p < 0.001).</p><p><strong>Interpretation: </strong>Noting that most population data on CP is from outside of the US, analysis of this detailed American dataset may help better inform prognostication and clinical screening for co-existing conditions in people with CP in the US.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annual 12-Week Dosing Gap of Natalizumab: Clinical Efficacy, Blood Biomarkers, and CSF Cell Composition.","authors":"Regina Berkovich, Tilman Schneider-Hohendorf, Eric Baetscher, Evan L Riddle, Marie Deffner, Emily Katsnelson, Janine Ferrant-Orgettas, Julie Czerkowicz, John Anderson, Susan E Goelz, Nicholas Schwab","doi":"10.1002/acn3.70207","DOIUrl":"https://doi.org/10.1002/acn3.70207","url":null,"abstract":"<p><strong>Objective: </strong>Natalizumab (NTZ) is a highly effective therapy for multiple sclerosis (MS); however, its use is limited by the risk of a rare potentially severe opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Alternative dosing strategies are evaluated to reduce PML risk while still maintaining efficacy, which include extending the dosing interval (EID) or a lesser-known annual dosing gap (aGAP), which is the focus of this prospective observational single-site cohort study. We evaluated whether aGAP affects the efficacy of NTZ, which biomarkers could be useful for a personalized dosing strategy, and potential cellular mechanisms that might contribute to reducing the risk of PML during aGAP.</p><p><strong>Methods: </strong>Clinical assessments, quantifications of NTZ, neurofilament light chain (NfL), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were performed for ten study participants of a clinical trial (NCT04048577); CSF single-cell RNA-sequencing data from nine participants (15 samples) were analyzed together with 48 healthy and 35 MS controls.</p><p><strong>Results: </strong>Although NTZ serum levels were decreased below EID levels and sVCAM-1 levels were increased, aGAP was not associated with MS activity as measured by EDSS and MRI. After aGAP, while CSF cell counts remained stable, the CSF immune cell composition changed and NfL values were increased 3 months post gap. CSF proportions of CD4, CD8, and natural killer cell subsets increased towards levels of untreated MS patients, while B-cell proportions remained unchanged.</p><p><strong>Interpretation: </strong>The differential CSF composition associated with sVCAM-1 serum level changes suggests that selective immune cell trafficking may occur during aGAP, potentially contributing to PML prevention.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"HPDL Variant Type Correlates With Clinical Disease Onset and Severity\".","authors":"","doi":"10.1002/acn3.70084","DOIUrl":"https://doi.org/10.1002/acn3.70084","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Change in Cognition Following Ischaemic Stroke.","authors":"Wenci Yan, Terence Quinn, Alex McConnachie, Niall Broomfield, Yun Wong, David Dickie, Kirsten Forbes, Matthew Walters, Jesse Dawson","doi":"10.1002/acn3.70192","DOIUrl":"https://doi.org/10.1002/acn3.70192","url":null,"abstract":"<p><strong>Objective: </strong>Cognitive decline can occur following ischaemic stroke. How cognition changes over time and associations with cognitive change are poorly understood. This study aimed to explore these issues over 2 years following ischaemic stroke.</p><p><strong>Methods: </strong>This analysis used data from the XILO-FIST study, a clinical trial of allopurinol versus placebo in people with ischaemic stroke according to Tissue-Based Definition. Participants underwent clinical assessment, brain MRI at baseline, and Montreal Cognitive Assessment (MoCA) at baseline, year 1 and year 2. We defined cognitive impairment as a MoCA score < 26 and cognitive change as a difference in MoCA score of 2 points or more at year 1 or year 2 after randomisation. Associations with cognitive impairment and cognitive change were assessed by univariable analysis and multiple logistic regression.</p><p><strong>Results: </strong>Three hundred and sixty participants with complete MoCA data were included. Mean age was 65.4 (SD 8.36) years, and mean baseline MoCA score was 26.4 (SD 2.7). Seventy-seven participants had second-year cognitive improvement. Eighty-four had second-year cognitive decline. After adjustment for age and education year, second-year cognitive improvement was associated with smaller brain volume, lower albumin level, smoking and greater white-matter hyperintensity, and second-year cognitive decline was associated with peripheral arterial disease, higher cholesterol level, small-vessel stroke and greater white-matter hyperintensity.</p><p><strong>Interpretation: </strong>Cognition is dynamic following stroke, with different patterns of change. Brain reserve and vascular risk factors relate to later post-stroke cognitive change. This complex nature of cognitive trajectory has implications for cognitive rehabilitation provision and cognitive impairment detection after stroke.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"The Importance of Verifying the Novelty of a Finding and the Value of Combining Results\".","authors":"","doi":"10.1002/acn3.70201","DOIUrl":"https://doi.org/10.1002/acn3.70201","url":null,"abstract":"","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequency of Seroconversion in Aquaporin-4 Antibody Testing: Insights From Real-World Data","authors":"Tatchaporn Ongphichetmetha,&nbsp;Mengke Du,&nbsp;Nisa Vorasoot,&nbsp;Sean J. Pittock,&nbsp;Jeffrey A. Cohen,&nbsp;Amy Kunchok","doi":"10.1002/acn3.70185","DOIUrl":"10.1002/acn3.70185","url":null,"abstract":"<p>Clinicians often repeat aquaporin-4-immunoglobulin G (AQP4-IgG) testing in case of possible seroconversion. Compared with older, less sensitive immunofluorescence assays (IFA), cell-based assays (CBA) offer higher sensitivity. This study assessed the frequency of seroconversion in a retrospective Cleveland Clinic cohort (2006–2024) of 451 patients with an initial negative AQP4-IgG result who underwent serial testing. Seroconversion occurred in 4.3% (7/170) of patients initially tested by tissue IFA, but in none (0/263) of those tested by CBA. The lack of AQP4-IgG seroconversion after a negative CBA, with only rare cases after a negative IFA, suggests that repeat AQP4-IgG testing is low yield unless prior testing used older methods such as IFA.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 10","pages":"2158-2163"},"PeriodicalIF":3.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70185","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}