Annals of Clinical and Translational Neurology最新文献

{"title":"Molecular Diagnosis in Children With Febrile Seizures: Beyond the Conventional Clinical Classification.","authors":"Jia Wang, Mengna Zhang, Yangyang Wang, Xiuyu Shi, Baoguang Li, Xiuxia Wang, Dan Sun, Sanqing Xu, Jianbo Zhao, Lijun Du, Qiming Pang, Xiaoming Liu, Chunhui Tang, Xiaohua Li, Jiuwei Li, Yanli Ma, Jianxiang Liao, Gulixian Abudureyimu, Jianmin Liang, Yuan Wang, De Wu, Jian Wu, Liping Zou","doi":"10.1002/acn3.70572","DOIUrl":"https://doi.org/10.1002/acn3.70572","url":null,"abstract":"<p><strong>Objective: </strong>Febrile seizures (FS) are currently classified as simple or complex primarily to describe seizure characteristics, with limited ability to identify the underlying etiology. We evaluated whether molecular diagnosis could complement conventional classification and improve the diagnosis and management of FS.</p><p><strong>Methods: </strong>This nationwide, multi-center, prospective cohort study, conducted from January 2019 to February 2023, enrolled patients who were clinically diagnosed with FS. The panel targeted 189 genes associated with fever-induced seizures. Initially, children were categorized into simple febrile seizures (SFS) and complex febrile seizures (CFS) groups based on medical history and clinical evaluation. Variant classification followed the ACMG guidelines. We analyzed the cohort demographic characteristics, potential genetic etiologies across different clinical phenotypes, and clinical utility of genetic diagnosis.</p><p><strong>Results: </strong>Our study included 3300 children with FS, and ultimately analyzed sequencing data from 2552 children, of whom 273 received a positive diagnosis. The molecular diagnostic yield was 11% (273 out of 2552 patients), with the top 10 genes accounting for 70.4% of all confirmed genetic diagnoses. No significant difference in molecular diagnostic yield was observed between the SFS (9.5%, 111/1163) and CFS (11.7%, 162/1389) groups (p = 0.085). Molecular diagnostics had immediate clinical utility, influencing management (76.2%) and informing prognosis (72.6%). The cost of a single panel sequencing for a three-person family was $240, with a turnaround time of 14 days.</p><p><strong>Interpretation: </strong>Molecular diagnosis may improve the diagnosis of FS by identifying genetic fever-sensitive epilepsies that may be missed by phenotype-based classification, with implications for risk stratification and individualized management.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149369721","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":"Automatic Lesion Morphometrics Reliably Predict Sensorimotor Recovery After Spinal Cord Injury: A Longitudinal, Multicenter Neuroimaging Study.","authors":"Dario Pfyffer, Jan Valošek, Lynn Farner, Enamundram Naga Karthik, Gergely David, Norbert Weidner, Rainer Abel, Doris Maier, Armin Curt, Margret Hund-Georgiadis, Mirko Aach, Michael Baumberger, Julien Cohen-Adad, Patrick Freund","doi":"10.1002/acn3.70569","DOIUrl":"10.1002/acn3.70569","url":null,"abstract":"<p><strong>Objective: </strong>To evaluate automatic magnetic resonance imaging (MRI)-derived lesion morphometrics against manual measurements and their prognostic value for characterizing distinct acute to chronic neurological recovery trajectories after spinal cord injury (SCI).</p><p><strong>Methods: </strong>We studied a retrospective, multicenter cohort of cervical and thoracolumbar SCI patients who underwent routine clinical MRI at 3-4 weeks post-SCI and neurological examinations over 6 months. Lesion severity was quantified using both established manual measurements and a novel automatic approach. We assessed the between-method agreement of MRI-derived lesion morphometrics, including lesion length, lesion width, and tissue bridge width, and their ability to stratify patients according to 6-month motor and sensory outcomes. Data-driven prediction models were used to identify clinically meaningful lesion measures and their respective thresholds, differentiating subgroups of specific recovery profiles.</p><p><strong>Results: </strong>Eighty-three patients from eight sites were included. Automatically derived lesion morphometrics showed moderate to strong agreement with established manual measures (Spearman's ρ: 0.540-0.821, p < 0.001), capturing inter-individual differences in lesion severity and demonstrating comparable prognostic value. Lesion width represented the strongest predictor of 6-month neurological outcomes, splitting patients into recovery-specific subgroups. Patients with a smaller lesion width (threshold: 5.88-6.41 mm) demonstrated higher 6-month sensorimotor scores and superior recovery trajectories, while tissue bridges (threshold: 0.17 mm) further refined motor prediction-based stratification of more severely affected patients.</p><p><strong>Interpretation: </strong>Automatic MRI measures of lesion severity hold promise as scalable, time-efficient in vivo biomarkers of SCI prognosis, with potential for clinical adoption to guide treatment decisions and multicenter trial planning.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13739854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149339981","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}

{"title":"Four-Year Cognitive Outcomes in Multiple Sclerosis: Associations With Lesion Myelin Integrity.","authors":"Iliana Pliska-Bloch, Hannah Schwartz, Kimberly H Markowitz, Abhishek Jaywant, Christopher D Hildenbrand, Jai Perumal, Ulrike W Kaunzner, Thanh D Nguyen, Sandra Hurtado Rúa, Susan A Gauthier","doi":"10.1002/acn3.70577","DOIUrl":"10.1002/acn3.70577","url":null,"abstract":"<p><strong>Objectives: </strong>Cognitive impairment is prevalent in patients with multiple sclerosis (MS) but whether lesion myelin integrity influences future cognitive outcomes remains unclear. We investigated the relationship between baseline lesion myelin water fraction (MWF) and cognitive performance 4 years later.</p><p><strong>Methods: </strong>We conducted a longitudinal study of 118 patients with MS. Cognitive function was evaluated annually for 5 years using the symbol digit modalities test (SDMT), California verbal learning test-II (CVLT-II) immediate recall, and brief visuospatial memory test-revised (BVMT-R). Lesion level MWF maps were the primary variable of interest, while paramagnetic rim lesions (PRLs) and structural imaging measures were included as covariates. We used a functional linear regression model with both scalar and functional covariates, followed by a stepwise variable selection procedure.</p><p><strong>Results: </strong>After adjustment for baseline cognition and clinical covariates, participants with higher baseline lesion-level MWF values in the mid-range of the lesion distribution exhibited better SDMT at 4 years (p = 0.006). Greater heterogeneity in lesion-level MWF was associated with worse visuospatial memory performance on the BVMT-R at Year 4. Conversely, lesion MWF was not associated with CVLT-II performance. Additional covariates in the final models included PRLs and cortical thinning for SDMT, PRLs and disease duration for BVMT-R, and thalamic atrophy for CVLT-II.</p><p><strong>Interpretation: </strong>Lesion myelin integrity was associated with future cognitive performance, particularly in domains of processing speed and visuospatial memory. These findings suggest that lesion demyelination contributes to cognitive outcomes in MS, which may provide a potential focus for future work improving risk stratification for cognitive impairment.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149331776","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}

{"title":"Axial Function Reflects Global Severity in Inherited Ataxias: The Upright Stability Score in Ambulatory Friedreich vs. Spinocerebellar Ataxia.","authors":"Christian Rummey, S H Subramony, David R Lynch, Louise A Corben, Martin B Delatycki, Jörg B Schulz, Kathrin Reetz, Massimo Pandolfo, Matthis Synofzik, Theresa Zesiewicz, Antoine Duquette, Matthew Burns, Martin Vyhnálek, Lucie Stovickova, Sinead M Murphy, Petya Bogdanova-Mihaylova, Mary Kearney, Richard Walsh, Richard H Roxburgh, Khalaf Bushara, Marie Y Davis, Enrico S Bertini, Gessica Vasco, Shweta Sahni, Mohammed Faruq, Achal K Srivastava, Bart van de Warrenburg, Elisabetta Indelicato, Sylvia Boesch, Andrew Billnitzer, Tetsuo Ashizawa, Anoopum S Gupta, Grace Yoon, Georgios Koutsis, Chrysoula Koniari, Zofia Fleszar, Christopher M Gomez, Andrea Martinuzzi, Gabriella Paparella, Ali G Hamedani, Puneet Opal, Rizwan S Akhtar, Caterina Mariotti, Henry Paulson, Peter Todd, Sharan R Srinivasan, George Wilmot, Ludger Schöls, Susan Perlman, Jeremy D Schmahmann, Sheng-Han Kuo, Liana S Rosenthal, Vikram G Shakkottai","doi":"10.1002/acn3.70563","DOIUrl":"10.1002/acn3.70563","url":null,"abstract":"<p><strong>Objective: </strong>Inherited ataxias are clinically diverse neurodegenerative diseases, complicating the choice of outcome measures for trials. In spinocerebellar ataxia (SCA), regulatory concerns about the Scale for the Assessment and Rating of Ataxia (SARA) caused a shift toward functional SARA (f-SARA), contributing to pivotal trial failure. We investigated whether the Upright Stability Score (USS), validated in Friedreich ataxia (FRDA), retains its psychometric properties in SCA, and how it compares with SARA, f-SARA, and the Friedreich Ataxia Activities of Daily Living scale (FA-ADL).</p><p><strong>Methods: </strong>Cross-sectional data from ambulatory participants in two large international natural-history studies (CRC-SCA and UNIFAI) were analyzed with correlation-based psychometric methods, comparing score distributions across scales and genotypes.</p><p><strong>Results: </strong>Data from 406/343 participants in CRC-SCA/UNIFAI were analyzed. In SCA, the USS captured a wider spectrum of balance performance, while in FRDA, early proprioceptive deficits-particularly impaired stance with eyes closed-constrained score variability. USS correlated strongly with SARA, f-SARA, and FA-ADL in both cohorts. SARA showed moderate skew, and f-SARA showed pronounced floor effects in mildly affected SCA, whereas USS and FA-ADL preserved discrimination at the low end. FA-ADL distributions were broadly comparable across genotypes.</p><p><strong>Interpretation: </strong>USS showed cross-sectional convergent validity with established measures across ambulatory FRDA and SCA, reflecting perceived disease burden (FA-ADL) at least as well as SARA. f-SARA is poorly discriminating in ambulatory SCA and is unlikely to work as an outcome measure, in particular in early cohorts. USS showed the potential to serve as a primary outcome assessment in pivotal SCA trials, but longitudinal evidence is required. Limitations include cross-sectional design and a substantial age difference between cohorts.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13736190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149331775","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}

{"title":"Frequency and Phenotype of Coexisting Aquaporin-4 and Autoimmune Encephalitis Autoantibodies.","authors":"Laura Cacciaguerra, Binxia Yang, Vanda A Lennon, Shruti P Agnihotri, Nusrat Ahsan, Karen S Fernandez, Erin McLeod, Georgios Mangioris, William R Meador, Wendy G Mitchell, Jacqueline A Nicholas, Amy M L Quek, Thomas Shoemaker, Kurt Sieloff, Matt C Edmond, Rebekah A Laggis, Kristin L Flynn, Jessica A Sagen, Emmanuelle Waubant, John J Chen, Sarosh R Irani, Andrew McKeon, Anastasia Zekeridou, Eoin P Flanagan, Sean J Pittock, Amy Kunchok","doi":"10.1002/acn3.70541","DOIUrl":"10.1002/acn3.70541","url":null,"abstract":"<p><p>Among 9457 aquaporin-4 (AQP4) immunoglobulin G-positive patients, 2071 underwent autoimmune encephalitis antibody testing and 85 (4%) had coexisting antibodies, most commonly cerebrospinal fluid glial fibrillary acidic protein-IgG and N-methyl-D-aspartate receptor-IgG, or serum high-titer GAD65-IgG. Compared with AQP4-IgG positive neuromyelitis optica spectrum disorder controls, dual-positive patients were younger and more frequently exhibited encephalopathy, psychiatric symptoms, seizures, ovarian teratomas, and deep gray matter, temporal lobe, or diencephalic MRI abnormalities. GAD65-IgG-positive patients developed stiff-person syndrome. These findings define a distinct mixed glial-neuronal autoimmune phenotype and support additional neural antibody testing in atypical AQP4-IgG-positive presentations.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13732610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316364","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}

{"title":"Cerebrospinal Fluid GAD65-Antibody Levels Accurately Identify Relevant Neurological Diseases.","authors":"Max Charles Herman, Maya Marzello, Zoaib Habib Tharwani, Snigdha Kotaru, Yoav D Piura, Eric Newman, Gregory S Day, Andrew McKeon, A Sebastian Lopez-Chiriboga, Sarosh R Irani","doi":"10.1002/acn3.70578","DOIUrl":"10.1002/acn3.70578","url":null,"abstract":"<p><p>Retrospective cohort study to investigate which factors most reliably distinguish incidental GAD65-antibodies (iGAD65) from true GAD65-antibody neurological disease (tGAD65). 167 adults with positive serum and CSF GAD65-antibodies (> 0.02 nmol/L by radioimmunoassay) were classified as tGAD65 or iGAD65, with diagnostic performance of paraclinical parameters compared in discovery and validation cohorts. CSF GAD65-antibody titers ≥ 1 nmol/L performed best in discovery (AUC 0.956) and validation (AUC 0.949; p = 0.814), with 89.7% sensitivity and 94% specificity for identifying tGAD65. Serum titers > 20 nmol/L and indices of intrathecal synthesis showed lower discriminative ability. Our finding aims to reduce misdiagnosis and identify potential immunotherapy-responsive diseases.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316361","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}

{"title":"Clinical Variability and Genotype Driven Outcomes in an International Cohort of 14 Pediatric FIG4 Patients.","authors":"Andrea Gangfuß, Vykuntaraju K Gowda, Daniel Natera-de Benito, Pinki Munot, Maria Vanegas, Alejandra Darling, Constanze Reutlinger, Laura Carrera-Garcia, Gilbert Wunderlich, Heike Kölbel, Burkhard Stüve, David Muhmann, Lucía Monfort Belenguer, Diana-Gabriela Barca, Viveka Santhosh Reddy C, Varunvenkat M Srinivasan, Cristina Molina Anguita, Heinz Jungbluth, Hormos Salimi Dafsari, Thomas Rossor, Johann Böhm, Ulrike Schara-Schmidt, Andreas Roos","doi":"10.1002/acn3.70561","DOIUrl":"10.1002/acn3.70561","url":null,"abstract":"<p><strong>Background: </strong>Biallelic FIG4 variants classically cause distinct conditions characterized by peripheral neuropathy (Charcot-Marie-Tooth disease type 4J) or skeletal dysplasia (Yunis-Varón syndrome). However, central nervous system involvement is increasingly recognized. The prevalence and specific characteristics of movement disorders within FIG4-related disease remain poorly characterized, prompting a need to redefine its clinical continuum.</p><p><strong>Objective: </strong>To delineate the phenotypic spectrum of FIG4-related disorders beyond established entities (Yunis-Varón syndrome, Charcot-Marie-Tooth disease type 4J, bilateral temporooccipital polymicrogyria, and amyotrophic lateral sclerosis type 11) using an international multicentre cohort.</p><p><strong>Methods: </strong>We retrospectively analyzed clinical, genetic, and neurophysiological data from patients with biallelic FIG4 variants to redefine genotype-phenotype correlations, focusing on motor development, cognitive status, and movement disorders.</p><p><strong>Results: </strong>Evaluating 14 pediatric FIG4 patients revealed a continuous phenotypic spectrum rather than the clinical entities previously described in the literature. Instead of the typical peripheral neuropathy classically associated with pathogenic FIG4 variants, the predominant clinical picture in this age group was a severe neurodevelopmental disorder. Patients showed profound motor and cognitive delay, with a subset additionally displaying distinct movement abnormalities such as dystonia and bradykinesia.</p><p><strong>Conclusion: </strong>Loss of functional FIG4 causes a broader and more severe disease spectrum with central nervous system involvement, including intellectual disability and movement abnormalities such as dystonia and bradykinesia. Recognizing these features should prompt clinicians to consider FIG4-associated disorders, allowing for optimized patient care and tailored therapeutic strategies.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316362","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}

{"title":"Disentangling the Genetic Relationship Between Sleep and Epilepsy.","authors":"Khang N Le, Victoria E Jackson, Rachel E Stirling, Zachary F Gerring, Remi Stevelink, Samuel F Berkovic, Ingrid E Scheffer, Philippa J Karoly, Melanie Bahlo, Karen L Oliver","doi":"10.1002/acn3.70568","DOIUrl":"10.1002/acn3.70568","url":null,"abstract":"<p><strong>Objective: </strong>A bidirectional relationship between sleep and epilepsy is well recognised, yet the biological mechanisms linking them remain poorly understood. Both have a genetic basis, with genome-wide association studies (GWAS) capturing polygenic contributions. By leveraging GWAS summary statistics, we aimed to investigate their shared genetic architecture.</p><p><strong>Methods: </strong>We analysed seven sleep traits (morningness chronotype, sleep duration, habitual short/long sleep, insomnia, daytime napping/sleepiness) with common epilepsy types (focal epilepsy and genetic generalised epilepsy [GGE]). For each trait pair, we estimated genome-wide genetic correlation, tested bidirectional causality, quantified polygenic overlap, performed gene-trait associations to identify putative pleiotropic genes, estimated local genetic correlations and investigated whether regions of significance were driven by shared causal variants using colocalisation and fine-mapping.</p><p><strong>Results: </strong>Genome-wide analyses supported a positive genetic correlation between higher GGE risk and habitual short sleep, with extensive polygenic overlap (75%-97%) across seven sleep traits. Gene-trait analyses identified RMI1 as a putative sleep-epilepsy candidate, with 13 additional sleep-associated genes linked to monogenic epilepsies (e.g., KANSL1, GRIN2A). Locus-specific analyses identified 16 genomic loci of interest (13 sleep-GGE, 3 sleep-focal epilepsy). Morningness-GGE shared the largest number of locus-specific associations. No significant causal relationships were identified, and causal variants did not colocalise.</p><p><strong>Interpretation: </strong>Our findings support complex shared genetic contributions between sleep and epilepsy, with distinct patterns for focal compared to generalised epilepsy. These differences may help explain syndrome-specific sleep-wake associations, including seizure timing and predisposition. By localising shared loci and highlighting specific overlapping genes, we provide a foundation for future research into the mechanisms underlying epilepsy-sleep comorbidities.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13728479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149316363","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}

{"title":"The Association of Amyloid-β and Tau With Synaptic Dysfunction in Alzheimer's Disease.","authors":"Fausto Roveta, Augusto J Mendes, Valentina Garibotto, Cecilia Boccalini, Aurelien Lathuiliere, Innocenzo Rainero, Elisa Rubino, Henrik Zetterberg, Nicholas J Ashton, Federica Ribaldi, Giovanni B Frisoni","doi":"10.1002/acn3.70558","DOIUrl":"10.1002/acn3.70558","url":null,"abstract":"<p><strong>Objective: </strong>To clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD).</p><p><strong>Methods: </strong>We included 109 cognitively unimpaired and impaired individuals from the Geneva Memory Center with available CSF synaptic biomarkers (neurogranin, SNAP-25, GAP-43). Participants were stratified according to amyloid (A) and tau (T) status, and group comparisons and correlations between synaptic and AD biomarkers were assessed. Multiple linear regression models evaluated the independent associations of amyloid and tau with synaptic markers: Model I (n = 109) included CSF Aβ42 and p-tau181, while Model II (n = 69) included amyloid PET centiloid and CSF p-tau181. Mediation analyses were performed to further investigate these relationships. Findings were replicated in the ADNI cohort (n = 787).</p><p><strong>Results: </strong>Synaptic biomarker levels were significantly higher in A+/T+ individuals compared with A-/T- and A+/T- groups (p < 0.001). CSF p-tau181 strongly correlated with synaptic markers. In Model I, GAP43 was positively associated with both CSF Aβ42 (β = 0.31, 95% CI 0.23-0.40) and p-tau181 (β = 0.94, 95% CI 0.84-1.04; p < 0.001). In Model II, lower amyloid PET centiloid (β = -0.31, 95% CI -0.46 to -0.16) and higher p-tau181 (β = 1.02, 95% CI 0.86-1.19) predicted increased GAP43 (p < 0.001), with the same pattern of associations observed for neurogranin and SNAP-25. The association between amyloid burden and synaptic biomarkers was largely indirect, statistically mediated by CSF p-tau181. Results were replicated in ADNI.</p><p><strong>Interpretation: </strong>Tau pathology showed strong associations with synaptic biomarkers, with a potential mediating role in the association between amyloid pathology and synaptic dysfunction. These findings support a central role of tau-related processes in synaptic dysfunction in AD.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13720864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293423","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}

{"title":"Acute Endocrine Alterations After Traumatic Brain Injury and 6-Month Functional Outcome.","authors":"Biao Xu, Peng Guo, Rui Pan, Zhenghao Wang, Jingchao Zhou, Pengcheng Zhang, Xingzhe Zhang, Qinghua Zhang, Haibin Ma, Zhanfeng Niu","doi":"10.1002/acn3.70570","DOIUrl":"10.1002/acn3.70570","url":null,"abstract":"<p><strong>Objective: </strong>Acute multi-axis endocrine alterations after traumatic brain injury (TBI) remain incompletely characterized. This study aimed to examine their temporal patterns and explore their associations with 6-month functional outcome and early inflammatory markers.</p><p><strong>Methods: </strong>We conducted a single-center prospective observational cohort study of hospitalized adults with traumatic brain injury. Among 130 enrolled patients, 125 with complete 6-month Glasgow Outcome Scale-Extended follow-up were included. Blood samples were collected on Day 1, 7, and 14 after injury to assess hypothalamic-pituitary-adrenal, thyroid, gonadal, and growth hormone axes. Day-1 inflammatory markers were measured. Associations of individual biomarkers with unfavorable 6-month outcome were evaluated using separate Firth penalized logistic regression models adjusted for admission Glasgow Coma Scale (GCS).</p><p><strong>Results: </strong>Serum cortisol levels at 08:00 and 16:00 decreased significantly over time (Kendall's W = 0.205 [95% CI 0.085-0.388] and 0.239 [95% CI 0.126-0.408], respectively; both p < 0.001), whereas triiodothyronine, free triiodothyronine, and thyroid-stimulating hormone increased during the acute phase. Patients with unfavorable 6-month outcome had higher day-1 interleukin-6, neutrophil count, and procalcitonin levels and lower day-1 triiodothyronine and free triiodothyronine levels than those with favorable outcome. After adjustment for admission GCS in separate Firth models, interleukin-6, white blood cell count, neutrophil count, procalcitonin, day-1 triiodothyronine, and day-1 free triiodothyronine were not significantly associated with unfavorable 6-month outcome.</p><p><strong>Interpretation: </strong>Endocrine alterations after acute TBI were heterogeneous across injury severity groups and time points. Although selected day-1 inflammatory and thyroid-axis measures differed between outcome groups, their associations with unfavorable 6-month functional outcome were not statistically significant after adjustment for admission GCS. These outcome-related findings require validation in larger cohorts.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149284451","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}