Annals of Neurology最新文献

{"title":"Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Have Distinct Prediagnostic Blood Biochemical Profiles","authors":"Christos V. Chalitsios PhD,&nbsp;Jiali Gao MB, BChir,&nbsp;Carol A.C. Coupland PhD,&nbsp;Julia Hippisley Cox MD,&nbsp;Martin R. Turner PhD,&nbsp;Alexander G. Thompson DPhil","doi":"10.1002/ana.78082","DOIUrl":"10.1002/ana.78082","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]_{per 1-SD} = 1.07, 95% confidence interval [CI] = 1.02–1.11) and total cholesterol levels (HR_{per 1-SD} = 1.06, 95% CI = 1.02–1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HR_{per 1-SD} = 1.08, 95% CI = 1.04–1.13, P_interaction = 0.003). Higher creatinine was inversely associated with FTD risk (HR_{per 1-SD} = 0.90, 95% CI = 0.83–0.97), supported by MR (odds ratio [OR] inverse variance weighted (_IVW)_{, per 1-SD} = 0.73, 95% CI = 0.56–0.96). HbA1c showed a U-shaped association with FTD (P_{non-linearity} = 0.006).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2026;99:844–856</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 4","pages":"844-856"},"PeriodicalIF":7.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gelsolin-3: A Novel Myelin Autoantigen in Demyelinating Guillain-Barré Syndrome.","authors":"Yuzhong Wang, Xiaomin Gao, Norito Kokubun, Fangzhen Shan, Baojun Qiao, Nobuhiro Yuki","doi":"10.1002/ana.78198","DOIUrl":"10.1002/ana.78198","url":null,"abstract":"<p><strong>Objective: </strong>Although immunoglobulin G (IgG) autoantibodies against gangliosides are well-established in axonal Guillain-Barré syndrome (GBS), specific autoantibodies in demyelinating GBS-including acute inflammatory demyelinating polyneuropathy (AIDP) and its variant, bifacial weakness with paresthesias (BFP)-remain unidentified. We aimed to identify novel autoantibodies and clarify the immunological link between AIDP and BFP.</p><p><strong>Methods: </strong>Immunoprecipitation and mass spectrometry identified gelsolin from BFP serum IgG targeting non-compact, periaxonal myelin surrounding the nodes of Ranvier. Western blotting confirmed specific recognition of gelsolin-3, with no cross-reactivity to the other 2 isoforms. Anti-gelsolin-3 IgG prevalence was screened in 388 GBS patients and correlated with clinical and electrophysiological phenotypes. In vivo pathogenicity was assessed by intraneural IgG injection.</p><p><strong>Results: </strong>Anti-gelsolin-3 IgG antibodies were detected in 24 GBS patients (6%, p < 0.001 vs both disease and healthy controls), with no positive controls. These autoantibodies were strongly associated with facial weakness (63% vs 18%, p < 0.001) and the AIDP electrophysiological classification (73% vs 31%, p < 0.001). In vivo, these IgG1 autoantibodies bound to the nodal regions, triggering complement-dependent nodal injury, voltage-gated sodium channel cluster disruption, and concomitant demyelination. These early pathogenic events preceded macrophage infiltration.</p><p><strong>Interpretation: </strong>Anti-gelsolin-3 IgG1 represents a novel biomarker linking AIDP and BFP. Our results provide the first evidence that AIDP can be formally classified as a nodo-paranodopathy. This IgG1-mediated, complement-dependent nodal injury establishes a unifying paradigm across GBS: nodal complement activation represents a shared mechanism underlying conduction block despite targeting distinct domains-the axolemma in AMAN and myelin components at the axon-myelin interface in AIDP. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Phenotypic Spectrum of Sporadic Creutzfeldt-Jakob Disease Cortical Subtype","authors":"Simone Baiardi MD, PhD,&nbsp;Claudia Marina Vargiu MSc,&nbsp;Brian S. Appleby MD,&nbsp;Marcelo Barria PhD,&nbsp;Giuseppe Mario Bentivenga MD,&nbsp;Ignazio Calì PhD,&nbsp;Benedetta Carlà MSc,&nbsp;Mark Cohen MD,&nbsp;Armin Giese MD,&nbsp;Jochen Herms MD,&nbsp;Aino-Minerva Kortelainen MD,&nbsp;Anna Ladogana MD,&nbsp;Angela Mammana PhD,&nbsp;Diane Ritchie MD,&nbsp;Otto Windl PhD,&nbsp;Sabina Capellari MD,&nbsp;Piero Parchi MD, PhD","doi":"10.1002/ana.78117","DOIUrl":"10.1002/ana.78117","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to characterize the phenotypic spectrum of the rare sporadic Creutzfeldt-Jakob disease cortical subtype (sCJDMM/MV2C) in a large multicentric autopsy cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated clinical histories, biofluid markers, brain diffusion-weighted (DW)-magnetic resonance imaging (MRI), and electroencephalogram (EEG) findings in 56 patients. The histomolecular assessment included misfolded prion protein (PrP) typing by immunoblotting, histopathology, and PrP immunohistochemistry in several brain areas.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Misfolded PrP typing showed a dominant 19 kDa unglycosylated PrP fragment (type 2) in all brains, focally associated with a 21 kDa (type 1) fragment in 53% of participants (MM/MV2C + 1). Immunohistochemistry revealed coarse/perivacuolar PrP deposits in the neocortices and a patchy/coarse pattern in the cerebellar molecular layer. The mean disease duration was 16.0 months. At onset and early stages, most patients manifested only progressive cognitive decline, consistent with the predominant distribution and relative severity of spongiform change in the cerebral cortex. Brain DW-MRI showed cortical hyperintensities in 94% of cases. Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) assay was positive in 70% of cases. Compared with pure MM/MV2C, the mixed MM/MV2C + 1 phenotype showed a shorter disease duration (14 vs 19 months), and a higher frequency of striatal DW-MRI hyperintensity (56% vs 19%), EEG periodic sharp-waves complexes (41% vs 6%), and CSF RT-QuIC positivity (86% vs 53%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The clinicopathologic phenotype of sCJDMM/MV2C diverges from that of typical sCJDMM/MV1. Moreover, the histomolecular heterogeneity within MM/MV2C influences clinical features and results of diagnostic investigations, challenging its identification in vivo. Nonetheless, results suggest that DW-MRI and CSF RT-QuIC allow an accurate clinical diagnosis of Creutzfeldt-Jakob disease in most patients. ANN NEUROL 2026;99:883–896</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 4","pages":"883-896"},"PeriodicalIF":7.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145802717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Brain Contusions Contain Pathogenic Transmissible Species that Induce Progressive Cognitive Decline and Tau Pathology in Mice","authors":"Gloria Vegliante PhD,&nbsp;Francesca Pischiutta PhD,&nbsp;Elena Restelli PhD,&nbsp;Federico Moro PhD,&nbsp;Maria Antonietta Chiaravalloti PhD,&nbsp;Ilaria Raimondi PhD,&nbsp;Ilaria Bertani Ms,&nbsp;Ilaria Lisi MSc,&nbsp;Eliana Sammali PhD,&nbsp;Rosaria Pascente MSc,&nbsp;Serena Scozzari MSc,&nbsp;Laura Pasetto PhD,&nbsp;Carly Douglas BSc,&nbsp;Marco Locatelli MD,&nbsp;Fabrizio Ortolano MD,&nbsp;Valentina Bonetto PhD,&nbsp;David J. Loane PhD,&nbsp;Nino Stocchetti MD,&nbsp;Roberto Chiesa PhD,&nbsp;Elisa R. Zanier MD","doi":"10.1002/ana.78132","DOIUrl":"10.1002/ana.78132","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Traumatic brain injury (TBI) is an established risk factor for dementia, although the underlying mechanisms remain unclear. Our previous research demonstrated that a single severe TBI in wild-type (WT) mice induces a prion-like form of tau (tau^TBI) that spreads throughout the brain, leading to memory deficits. Here, we investigated whether similar self-propagating tau^TBI conformers are generated in humans after severe TBI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We biochemically assessed tau and phosphorylated tau (P-tau) levels in human brain contusions surgically removed acutely after severe TBI. Inoculation studies were performed using human TBI brain homogenates in WT and tau knockout (KO) mice to investigate the role of endogenous tau in tau^TBI propagation. Cognitive function was evaluated using the novel object recognition test, the radial arm water maze, and the Y-maze. Pathological changes in the brain of the inoculated mice were analyzed by histological and biochemical analyses, and targeted transcriptomics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Inoculation of human TBI brain homogenates in WT mice caused widespread tau deposition and cognitive impairment, hippocampal synaptic loss, and disease-associated transcriptomic changes. Effects were similar upon secondary inoculation in WT but not tau KO mice, confirming a tau-dependent mechanism.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Severe TBI induces transmissible tau^TBI conformers in humans acutely after injury, potentially exacerbating post-traumatic pathology, and increasing the risk for dementia later in life. ANN NEUROL 2026;99:897–911</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 4","pages":"897-911"},"PeriodicalIF":7.7,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145861710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Parkinson's Progression Markers Initiative: Why Then? Why Now?","authors":"Michael J Fox","doi":"10.1002/ana.78192","DOIUrl":"10.1002/ana.78192","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Prevalence of SOD1 Pathogenic Variants in the UK Biobank: Implications for Early Intervention in Amyotrophic Lateral Sclerosis.","authors":"Delia Gagliardi, Chiara Villella, Matteo Zanovello, Virginia Iacobelli, Stefania Corti, Giacomo Pietro Comi, Pietro Fratta, Henry Houlden, Arianna Tucci, Dario Ronchi","doi":"10.1002/ana.78195","DOIUrl":"https://doi.org/10.1002/ana.78195","url":null,"abstract":"<p><strong>Objective: </strong>SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.</p><p><strong>Methods: </strong>We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.</p><p><strong>Results: </strong>We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.</p><p><strong>Interpretation: </strong>Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between Plasma P-tau217 and Alzheimer's Copathology and Cognitive Decline in Parkinson's Disease.","authors":"Thomas F Tropea, Patricia Aldea Stevenson, Matthew Flitter, David Meehan, Amanda Morris, Ming Lu, Leonardo Iaccarino, Emily C Collins, Michael E Hodsdon, David Irwin, Meredith Spindler, Andres Deik, Nabila Dahodwala, Katheryn A Q Cousins, David A Wolk, Leslie Shaw, Daniel Weintraub, Edward B Lee, Alice Chen-Plotkin, Mark Mintun, Andrew Siderowf","doi":"10.1002/ana.78201","DOIUrl":"https://doi.org/10.1002/ana.78201","url":null,"abstract":"<p><strong>Objective: </strong>Clinically relevant Alzheimer's disease co-pathology is common in Lewy body disorders. Plasma P-tau217 is a sensitive biomarker for amyloid and tau pathology in Alzheimer's disease. The objective was to determine if plasma P-tau217 associates with Alzheimer's disease co-pathology and cognition in Lewy body disorders.</p><p><strong>Methods: </strong>Participants had (1) a clinicopathological diagnosis of Parkinson's disease or dementia with Lewy bodies in the pathology series, or (2) a clinical diagnosis of Parkinson's disease in the clinical series and were followed as part of the longitudinal, observational cohort study at the University of Pennsylvania between 2007 and 2024. Plasma concentration of P-tau217 was measured in previously collected samples.</p><p><strong>Results: </strong>Neuropathology cases included 46 Parkinson's disease and 10 dementia with Lewy bodies, and clinical cases included 173 Parkinson's disease, and 64 controls. P-tau217 was greater in cases with (median, 0.3 [interquartile range (IQR), 0.2-0.4]) versus without (median, 0.1 [IQR, 0.1-0.2]) Alzheimer's disease co-pathology (p < 0.01) and discriminates Lewy body disorders participants with Alzheimer's disease co-pathology (area under curve, 0.84). Parkinson's disease participants with incident cognitive impairment had greater increases in serial P-tau217 than those who remained cognitively stable (group × time interaction β = -0.010, p = 0.0027). Higher baseline P-tau217 concentrations associated with longitudinal change in dementia rating scale (group × time interaction β = -4.947, p = 0.0166) and higher risk for cognitive progression (hazard ratio = 1.597, p = 0.003).</p><p><strong>Interpretation: </strong>Plasma P-tau217 detects Alzheimer's disease co-pathology in Lewy body disorders and predicts cognitive decline. Future studies will evaluate associations between plasma P-tau217 and imaging and clinical outcomes, in consideration for use of amyloid-targeting therapies in Lewy body disorders. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Dynamics of Neurofilament Light Chain in Spinal Muscular Atrophy.","authors":"Arlene D'Silva, Karen Herbert, Lakshmi Balaji, Jia Mei He, Tejaswi Kandula, Hugo A Sampaio, Hooi-Ling Teoh, Esther Tantsis, Jihee Sohn, Nancy Briggs, Nickson Ning, Matthew C Kiernan, Didu S Kariyawasam, Michelle A Farrar","doi":"10.1002/ana.78207","DOIUrl":"https://doi.org/10.1002/ana.78207","url":null,"abstract":"<p><strong>Objective: </strong>Newborn screening (NBS) for spinal muscular atrophy (SMA) facilitates early diagnosis and treatment for affected individuals. However, fluid biomarkers that provide early insights into disease activity and outcomes in a neonatal cohort and those unable to access (due to reimbursement criteria) or deferring immediate treatment are lacking. This study evaluated neurofilament light chain (NfL) levels to provide insights into disease activity and outcomes in newborns and children with SMA.</p><p><strong>Methods: </strong>This study correlated pretreatment NfL levels in the serum and cerebrospinal fluid (CSF) in a cross-sectional cohort of individuals with SMA against clinical, neurophysiological, molecular genetic variables, and treatment characteristics. Longitudinal NfL levels were evaluated in individuals that did not immediately commence treatment (governed by Australian reimbursement policies) and in those treated with nusinersen monotherapy.</p><p><strong>Results: </strong>Participants included 45 individuals with SMA (age range = 4 days to 42 years). Pretreatment serum NfL (sNfL) in 2 SMN2 copy neonates were significantly higher (2 SMN2, mean[SE] 680.9 [163.7]; ≥ 3 SMN2 146.9 [59.8] pg/ml, p = 0.01), correlating with increasing post-natal age (2 SMN2 r[12] = 0.75, p = 0.005). Combining sNfL and compound muscle action potential (CMAP) with pretreatment CHOP-INTEND in a regression model provided a stronger prediction of motor outcomes for neonates at 2 years (p = 0.02). Pretreatment sNfL in infants with ≥3 SMN2 copies who did not initiate immediate treatment increased despite motor function remaining stable.</p><p><strong>Interpretation: </strong>There is a malignant disease course with active denervation in children with 2 SMN2 copies within the neonatal period. sNfL gives early insights into underlying pathophysiology prior to a clinical phenotype and may expedite access to the initiation of treatment. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Monoclonal Antibody Detects Small Aβ Oligomers More Sensitively Than Lecanemab in Alzheimer's Disease CSF, Serum and Culture Media.","authors":"Yi Ran Xu, Youqi Tao, Alexandra M Lish, Shaomin Li, Beth L Ostaszewski, Amirah K Anderson, Tracy Young-Pearse, Trebor L Lawton, Hyun-Sik Yang, Dominic M Walsh, Ting Yang, Dennis J Selkoe","doi":"10.1002/ana.78196","DOIUrl":"https://doi.org/10.1002/ana.78196","url":null,"abstract":"<p><strong>Objective: </strong>Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids.</p><p><strong>Methods: </strong>Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations.</p><p><strong>Results: </strong>Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum.</p><p><strong>Interpretation: </strong>Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease Using PET and Plasma Biomarkers.","authors":"Christopher A Brown, Katheryn A Q Cousins, Magdalena Korecka, Emily McGrew, Alice Chen-Plotkin, John A Detre, Corey T McMillan, Edward B Lee, Sandhitsu R Das, Dawn Mechanic-Hamilton, Paul A Yushkevich, Ilya M Nasrallah, Leslie M Shaw, David A Wolk","doi":"10.1002/ana.78194","DOIUrl":"10.1002/ana.78194","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to compare positron emission tomography (PET) and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease.</p><p><strong>Methods: </strong>Longitudinal amyloid PET (n = 1,097, mean age ± SD = 72.5 ± 7.38 year, 51.4% male), ¹⁸F-flortaucipir tau-PET (n = 230, 74.3 ± 7.18 year, 52.2% female), and Fujirebio Lumipulse plasma p-tau₂₁₇ (n = 752, 72.8 ± 6.93 year, 51.3% male) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using sampled-iterative Local approximation (SILA). SILA models using plasma p-tau₂₁₇ were compared to amyloid and tau PET-based models to estimate amyloid and tau onset, and factors influencing tau onset and time from tau onset to dementia were evaluated for PET and plasma models.</p><p><strong>Results: </strong>Plasma and PET models generated similar results for estimated amyloid and tau onset, with stronger model agreement for tau (r = 0.88[0.86, 0.89], t = 57.4, p < 0.001) than amyloid (r = 0.75[0.72, 0.77], t = 37.4, p < 0.001) onset. Accuracy of estimated onset compared to actual onset was high within modality (mean absolute error [MAE] ≤ 2.03) with slightly greater error (MAE 3.09-3.42) when comparing across modalities (ie, plasma to PET). For both plasma and PET, earlier tau onset was associated with younger amyloid onset, female sex, and ≥1 apolipoprotein (ApoE) ε4 allele. Earlier dementia onset after tau was associated with later tau onset for both plasma and PET, while male sex was associated with shorter tau to dementia gap in plasma models.</p><p><strong>Interpretation: </strong>Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age, and can serve as a widely accessible tool for clinical assessment of biological disease severity. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}