Abu Raya M, Suemoto CK, Paes VR
… +9 more, Leite REP, Pasqualucci CA, Naslavsky MS, Rodriguez RD, Nitrini R, Ferriolli E, Allen IE, La Joie R, Grinberg LT
JAMA Neurol
· 2026 Apr · PMID 41729539
·
Full text
IMPORTANCE: Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. OBJECTIVE: To test whether neuritic plaq...IMPORTANCE: Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. OBJECTIVE: To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 (APOEε4), informant-reported race, and African ancestry. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. EXPOSURES: Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. MAIN OUTCOMES AND MEASURES: Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score), and cognitive function (Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. RESULTS: The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. CONCLUSIONS AND RELEVANCE: The findings indicate that female sex, APOEε4, and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease.
Chen H, Cortese M, Flores-Torres MH
… +9 more, Tessier AJ, Wang DD, Kang JH, Eliassen AH, Stampfer M, Ascherio A, Willett W, Yuan C, Bjornevik K
JAMA Neurol
· 2026 Apr · PMID 41729538
·
Full text
IMPORTANCE: Healthier diets are generally believed to benefit cognitive health; however, the evidence remains inconsistent, and a systematic examination of multiple healthy dietary patterns within the same context is lac...IMPORTANCE: Healthier diets are generally believed to benefit cognitive health; however, the evidence remains inconsistent, and a systematic examination of multiple healthy dietary patterns within the same context is lacking. OBJECTIVE: To evaluate the associations of 6 healthy patterns with subjective cognitive decline (SCD) and objective cognitive function. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study based on the Nurses' Health Study (NHS, 1986-2014), NHSII (1991-2017), and the Health Professionals Follow-Up Study (HPFS, 1986-2012). Included were adults with available data on diet and cognitive function. Data analyses were performed from September 2024 to November 2025. EXPOSURES: Six dietary pattern scores, including the Alternate Healthy Eating Index 2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH) diet score, the Healthful Plant-Based Diet Index (hPDI), the Planetary Health Diet Index (PHDI), and the reversed empirical dietary indices for hyperinsulinemia (rEDIH) and inflammatory pattern (rEDIP). MAIN OUTCOMES AND MEASURES: SCD was assessed using 7 questions on perceived cognitive changes. Cognitive function was objectively measured via telephone in the NHS. RESULTS: A total of 159 347 individuals (mean [SD] age, 44.3 [9.3] years; 131 560 female [82.6%]) were included in this analysis. Among the study participants, higher adherence to all 6 dietary patterns was associated with a lower SCD risk. The DASH diet showed the strongest magnitude (risk ratio [RR] comparing 90th vs 10th percentile of adherence: 0.59; 95% CI, 0.57-0.62), followed by the hPDI (RR, 0.76; 95% CI, 0.65-0.85), rEDIH (RR, 0.76; 95% CI, 0.73-0.80), PHDI (RR, 0.80; 95% CI, 0.75-0.86), AHEI-2010 (RR, 0.84; 95% CI, 0.80-0.89), and rEDIP (RR, 0.89; 95% CI, 0.85-0.93). Higher DASH diet score at ages 45 to 54 years showed the strongest association with SCD. Higher adherence to the DASH diet also showed the strongest association with a higher objectively measured global cognition (mean z score difference comparing 90th vs 10th percentile: 0.05; 95% CI, 0.02-0.09). Key food groups associated with better cognitive function included higher vegetable and fish intake and lower red and processed meats intake. CONCLUSIONS AND RELEVANCE: Results reveal that healthy diets, exemplified by the DASH diet for blood pressure control and diets with lower hyperinsulinemia and inflammation potentials, were associated with a lower SCD risk and better cognitive function. These findings underscore the importance of a healthy diet for maintaining long-term cognitive health.
Cree BAC, Fox E, Hartung HP
… +12 more, Alvarez E, Qian P, Wray S, Robertson D, Selmaj K, Wynn D, Mok K, Rowland C, Bodhinathan K, Sportelli P, Miskin HP, Steinman L
JAMA Neurol
· 2026 Apr · PMID 41697690
·
Full text
IMPORTANCE: In the 2-year Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (ULTIMATE) I and II randomized clinical studies, disease activity was significan...IMPORTANCE: In the 2-year Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (ULTIMATE) I and II randomized clinical studies, disease activity was significantly reduced with ublituximab vs teriflunomide in participants with relapsing multiple sclerosis (RMS). OBJECTIVE: To evaluate long-term ublituximab clinical efficacy and safety. DESIGN, SETTING, AND PARTICIPANTS: The 2-year, multicenter, randomized, active-controlled, double-blind period (DBP) of the ULTIMATE I and II phase 3 studies occurred September 2017 to November 2020. Enrollment in the ongoing ULTIMATE open-label extension (OLE) study began November 2019; data cutoff for this analysis was January 1, 2024. INTERVENTION: ULTIMATE OLE participants continued ublituximab (UBL-UBL) or switched from teriflunomide to ublituximab (TER-UBL). MAIN OUTCOMES AND MEASURES: Efficacy (annualized relapse rate [ARR], 24-week confirmed disability progression [CDP24], and 24-week confirmed disability improvement [CDI24]) and safety were key outcomes. RESULTS: Of 985 adults with RMS who completed ULTIMATE I and II, 851 enrolled in the ULTIMATE OLE and were included in the analysis. On DBP completion, more than 85% of participants (UBL-UBL, 422 of 494; TER-UBL, 429 of 491) entered the OLE, of whom more than 70% (UBL-UBL, 297 of 422; TER-UBL, 327 of 429) continued taking ublituximab at year 5 (OLE year 3) at data cutoff, making up the analysis population (mean [SD] age, 38.5 [9.7] years; 532 female [62.5%]). TER-UBL participants experienced a 58.4% ARR reduction at 1 year after the switch (0.182 vs 0.076; rate ratio, 0.42; 95% CI, 0.29-0.60; P < .001), and ARR continued to decrease to 0.048 (year 4) and 0.045 (year 5). UBL-UBL participants had further ARR reductions after the DBP (0.053, 0.032, and 0.020 for years 3, 4, and 5, respectively). At year 5, CDP24 was 8.0% in UBL-UBL participants vs 14.3% in TER-UBL participants (P = .01), and CDI24 was 17.0% in UBL-UBL participants vs 12.2% in TER-UBL participants (P = .02). Adverse events were consistent with the established safety profile from pivotal trials, with exposure-adjusted incidence rates per 100 participant-years of serious infections (excluding COVID events) of 2.10 (UBL-UBL) and 2.58 (TER-UBL). On average, immunoglobulin levels remained above the lower limit of normal, and no significant differences in serious infection rates were observed regardless of immunoglobulin level. CONCLUSIONS AND RELEVANCE: Results reveal that sustained clinical benefits were observed with 5 years of ublituximab treatment: ARR in year 5 showed 1 relapse per 50 participant-years of ublituximab treatment and 92% of UBL-UBL participants remained free from CDP24. Results confirm long-term ublituximab benefits and early initiation of high-efficacy treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04130997.
Hultgren M, Blennow Nordström E, Ullén S
… +26 more, Nielsen N, Dankiewicz J, Jakobsen JC, Heimburg K, Moseby-Knappe M, Belohlávek J, Bohm M, Cariou A, Eastwood G, Friberg H, Grejs AM, Hammond N, Hänggi M, Hrecko J, Iten M, Keeble TR, Leithner C, Levin H, Mion M, Rylander C, Schrag C, Thomas M, Wise MP, Young P, Cronberg T, Lilja G
JAMA Neurol
· 2026 Apr · PMID 41697682
·
Full text
IMPORTANCE: Guidelines for temperature control following out-of-hospital cardiac arrest (OHCA) are based on trials with end points of 180 days or fewer. OBJECTIVES: To investigate if targeted hypothermia, compared with t...IMPORTANCE: Guidelines for temperature control following out-of-hospital cardiac arrest (OHCA) are based on trials with end points of 180 days or fewer. OBJECTIVES: To investigate if targeted hypothermia, compared with targeted normothermia with early treatment of fever, affects functional outcome focusing on societal participation or cognitive functioning at 24 months in initially comatose OHCA survivors. An additional objective was to explore recovery trajectories up to 24 months post arrest. DESIGN, SETTING, AND PARTICIPANTS: The randomized clinical Targeted Hypothermia vs Targeted Normothermia After OHCA (TTM2) trial (November 2017-2020) included blinded follow-up at 1, 6, and 24 months post randomization (December 2017-June 2022), with analyses performed in 2024. TTM2 was an international, multicenter study conducted at 61 hospitals in 14 countries. The study included 1861 adults with OHCA of presumed cardiac or unknown cause who were initially comatose. There were 992 survivors at 1 month, 943 at 6 months, and 835 at 24 months. Nonparticipation rates at follow-up were 44 (4%), 107 (11%), and 165 (20%), respectively. INTERVENTION: Participants were randomized 1:1 to undergo temperature control via targeted hypothermia (33 °C) or targeted normothermia and early treatment of fever (≥37.8 °C). MAIN OUTCOMES AND MEASURES: The functional outcome, including societal participation, was assessed using the Glasgow Outcome Scale-Extended (GOSE). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities Test (SDMT). RESULTS: Of the participants who were followed up, 84% were male, with a mean (SD) age of 60 (14) years, and clinical variables were similar between the hypothermia and normothermia temperature groups. No significant differences were found between temperature groups regarding societal participation (GOSE: odds ratio, 0.97 [95% CI, 0.72-1.30]) or cognitive function (MoCA: mean difference, -0.02 [95% CI, -0.67 to 0.63]; SDMT: mean difference, -0.09 [95% CI, -0.33 to 0.16]) at 24 months. Improvement for GOSE was significant within the first 6 months (1 to 6 months: n = 1707 [95% CI, -2.00 to -1.50]; P < .001; 6 to 24 months: n = 1606 [95% CI, -0.50 to <0.001]; P = .10). Intraindividual improvement and decline corresponding to thresholds for minimal important differences were observed for societal participation and cognitive function up to 24 months. CONCLUSIONS AND RELEVANCE: Targeted hypothermia, compared with targeted normothermia, did not affect societal participation or cognitive function at 24 months, suggesting no longer-term effect of hypothermia for the explored outcomes. The intraindividual changes observed indicate variability in recovery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02908308.
Coughlan GT, Ourry V, Townsend D
… +26 more, Klinger H, Brown JA, Cuppels M, Betthauser T, Langhough R, Cody K, Seto M, Birkenbihl C, Li A, Farrell M, Thibault E, Kivisäkk Webb P, Arnold S, Rissman RA, Properzi M, Schultz A, Johnson K, Langford O, Donohue MC, Villeneuve S, Johnson SC, Yang HS, Manson JE, Sperling R, Buckley RF, A4 Study Team, the Alzheimer’s Disease Neuroimaging Initiative, and the PREVENT-AD Research Group
JAMA Neurol
· 2026 Apr · PMID 41697669
·
Full text
IMPORTANCE: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble p...IMPORTANCE: Among individuals with high levels of amyloid-β (Aβ), women exhibit higher insoluble tau burden and accumulation than age-matched men. It remains unclear whether this sex difference is influenced by soluble phosphorylated tau (p-tau), a biomarker that changes early in Alzheimer disease. OBJECTIVE: To investigate whether sex and aggregated Aβ synergistically predict plasma phosphorylated tau 217 (p-tau217) levels and whether levels of p-tau217 predict cross-sectional and longitudinal tau aggregation in a sex-specific manner (as measured by positron emission tomography [PET]). DESIGN, SETTING, AND PARTICIPANTS: This longitudinal study analyzed data between September 7, 2024, and October 29, 2025, from 1 clinical trial cohort and 4 observational study cohorts including men and women without cognitive impairment who had undergone multiple assessments via tau PET (18F-flortaucipir or 18F-MK-6240) and plasma p-tau217 assay at baseline. Cognitive performance was measured with the Preclinical Alzheimer Cognitive Composite. Data on cognitive performance were available from 3 of the 5 cohorts for a mean of 4.6 years (SD, 3.1 years). Across the 5 cohorts, the mean follow-up for tau PET was 3.6 years (SD, 1.7 years). EXPOSURES: Self-reported sex (male or female), tau PET, and p-tau217 assay. MAIN OUTCOMES AND MEASURES: The primary analyses used linear and mixed-effects models to assess baseline and longitudinal sex × p-tau217 interactions for 9 tau PET regions. The secondary analyses assessed sex × p-tau217 interactions for cognitive change using the Preclinical Alzheimer Cognitive Composite. RESULTS: Across the 5 cohorts, there were a total of 1292 participants (63.6% women; mean age, 70.6 [SD, 6.4] years) with tau PET assessments. Compared with men, women had significantly higher baseline p-tau217 levels at higher aggregated Aβ Centiloid levels (β, -0.21 [95% CI, -0.37 to -0.05], P = .009; highest interaction was found in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [A4/LEARN] cohort). The sex × p-tau217 interactions at baseline were significant for 1 tau PET region in the Harvard Aging Brain Study (HABS) cohort, for 2 tau PET regions in the A4/LEARN cohort, for 6 tau PET regions in the Wisconsin Registry of Alzheimer's Prevention (WRAP) cohort, and for 4 tau PET regions in the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) cohort. Longitudinal interactions were significant for 4 tau PET regions in the A4/LEARN cohort, for 5 tau PET regions in both the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort and the WRAP cohort, and for 2 PET regions in both the HABS cohort and the PREVENT-AD cohort. Compared with men, women displayed greater tau deposition and accumulation at higher p-tau217 levels. Use of a secondary model showed women with higher p-tau217 levels also exhibited faster rates of cognitive decline relative to men in the both the WRAP cohort and the ADNI cohort. CONCLUSION AND RELEVANCE: These findings add to growing evidence that women have a differential tau response to Aβ that may emerge at the point of p-tau secretion. These findings have implications for the therapeutics and diagnostics of preclinical Alzheimer disease.
Cerulli Irelli E, Roberti R, Borioni MS
… +36 more, Anzellotti F, Belcastro V, Beretta S, Boero G, Bonanni P, Chiesa V, D'Aniello A, Dainese F, Deleo F, De Maria G, Di Gennaro G, Di Gennaro G, Didato G, Dono F, Falcicchio G, Ferlazzo E, Fortunato F, La Neve A, Mecarelli O, Montalenti E, Morano A, Nilo A, Operto FF, Paladin F, Pascarella A, Pauletto G, Pietrafusa N, Pignatta P, Pulitano P, Renna R, Rosati E, Sammarra I, Di Bonaventura C, Russo E, Lattanzi S, Comparative REal-World Evidence (CREW) Study Group
JAMA Neurol
· 2026 Apr · PMID 41661607
·
Full text
IMPORTANCE: Treatment decisions in drug-resistant focal epilepsy remain largely empirical, as direct comparative evidence among newer antiseizure medications (ASMs) is limited. Real-world data can complement randomized c...IMPORTANCE: Treatment decisions in drug-resistant focal epilepsy remain largely empirical, as direct comparative evidence among newer antiseizure medications (ASMs) is limited. Real-world data can complement randomized clinical trials by providing insights into long-term effectiveness and safety across diverse populations. OBJECTIVE: To compare effectiveness and safety of brivaracetam, cenobamate, lacosamide, and perampanel as adjunctive therapies in adults with drug-resistant focal epilepsy. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter pooled analysis of 4 previously conducted retrospective real-world medical record-review studies (January 2017-January 2024). Included were adult patients (aged ≥16 years) with drug-resistant focal epilepsy, as defined by the International League Against Epilepsy. Participants were recruited from 71 epilepsy centers. EXPOSURES: Add-on treatment with brivaracetam, cenobamate, lacosamide, or perampanel. MAIN OUTCOMES AND MEASURES: The primary outcome was the responder rate at 6 months, defined as greater than or equal to 50% seizure frequency reduction from baseline. Secondary outcomes included 12-month responder rate, seizure freedom (≥3 months at 6 months and ≥6 months at 12 months), and 12-month ASM retention. Safety was assessed by incidence of adverse effects. Generalized linear mixed models adjusted for demographic and clinical covariates were used to compare treatment outcomes, with cenobamate as reference ASM. RESULTS: Of 2386 ASM prescriptions screened, 1993 prescriptions from 1949 patients (1036 of 1947 female [53.2%]; sex information was missing in 0.1% of prescriptions) with a median (IQR) age of 42 (29-55) years at ASM prescription, met inclusion criteria and were included in the pooled analysis. Brivaracetam accounted for 953 prescriptions (47.8%), followed by perampanel (607 [30.5%]), lacosamide (241 [12.1%]), and cenobamate (192 [9.6%]). After adjustment, cenobamate demonstrated significantly higher odds of 50% or greater response at 6 months compared with brivaracetam (odds ratio [OR], 0.18; 95% CI, 0.12-0.28; P < .001), perampanel (OR, 0.26; 95% CI, 0.16-0.42; P < .001), and lacosamide (OR, 0.29; 95% CI, 0.17-0.49; P < .001). Results were consistent for secondary effectiveness outcomes at 12 months, with cenobamate outperforming other ASMs in terms of 50% or greater response and seizure freedom. Cenobamate was associated with the highest rate of adverse effects during follow-up (111 [57.8%]), and lacosamide was associated with the lowest (35 [14.8%]). Cenobamate was associated with a higher likelihood of treatment retention at 12 months compared with brivaracetam (OR, 0.43; 95% CI, 0.26-0.69; P < .001) and perampanel (OR, 0.56; 95% CI, 0.32-0.99; P = .047), with no significant difference vs lacosamide (OR, 0.81; 95% CI, 0.41-1.59; P = .53). CONCLUSIONS AND RELEVANCE: These study findings suggest superior effectiveness of cenobamate over brivaracetam, lacosamide, and perampanel in adults with drug-resistant focal epilepsy in a large real-world setting.
Miller TM, Cudkowicz ME, Shaw PJ
… +25 more, Genge A, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Salachas F, Bruneteau G, Al-Chalabi A, Amorin M, Nestorov I, Graham D, Lin L, Sun P, McNeill M, Malek S, Inra J, Garafalo S, Fradette S, VALOR and OLE Working Group
JAMA Neurol
· 2026 Feb · PMID 41661214
·
Full text
IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to...IMPORTANCE: Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are attributable to a pathogenic variant in the superoxide dismutase 1 (SOD1) gene. Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene. OBJECTIVE: To evaluate the long-term effects of tofersen in adults with SOD1-ALS. DESIGN, SETTING, AND PARTICIPANTS: The phase 3, randomized, double-blind, placebo-controlled VALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024). INTERVENTION AND EXPOSURE: Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study. All participants in the OLE were treated with tofersen. MAIN OUTCOMES AND MEASURES: Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen. Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival. RESULTS: VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively. Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]). At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR. Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points). Tofersen prolonged survival relative to the expected natural history of SOD1-ALS. Most adverse events were consistent with ALS progression or known procedural adverse effects. All serious neurological adverse events were reversible; few led to tofersen discontinuation. CONCLUSIONS AND RELEVANCE: Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.
Maenza C, Winstein CJ, Murphy TE
… +5 more, Kitchen NM, Tanaka J, Yuk J, Varghese R, Sainburg RL
JAMA Neurol
· 2026 Mar · PMID 41627841
·
Full text
IMPORTANCE: Ipsilesional upper-limb motor deficits after stroke are functionally important yet largely neglected in rehabilitation. Remediation may improve motor outcomes in individuals with severe contralesional arm hem...IMPORTANCE: Ipsilesional upper-limb motor deficits after stroke are functionally important yet largely neglected in rehabilitation. Remediation may improve motor outcomes in individuals with severe contralesional arm hemiparesis. OBJECTIVE: To determine whether training of the ipsilesional arm improves motor performance in chronic stroke with severe contralesional impairment and significant ipsilesional arm motor deficits. DESIGN, SETTING, AND PARTICIPANTS: This 2-site, parallel-group randomized clinical trial with blinded outcome assessment was conducted from February 2019 to August 2024, with follow-up through 6 months posttreatment. Data analysis was performed from August 2024 through August 2025. The trial was conducted at outpatient research laboratories at Penn State College of Medicine and the University of Southern California among adults with radiologically confirmed unilateral middle cerebral artery stroke, severe contralesional upper-extremity impairment (Fugl-Meyer score ≤28), and ipsilesional motor deficits. Participants were randomly assigned with equal probability to 2 treatment groups and stratified by sex. INTERVENTIONS: Participants were randomized to a 5-week, 15-session intervention focused on either the ipsilesional (n = 25) or contralesional (n = 28) upper limb. The ipsilesional group received ipsilesional virtual reality and manipulation training; the contralesional group received dose-matched, best practice contralesional arm therapy. MAIN OUTCOMES AND MEASURES: The primary outcomes were ipsilesional motor performance (Jebsen-Taylor Hand Function Test [excluding writing]), functional independence (Barthel Index), contralesional impairment severity (Fugl-Meyer Assessment [Upper Extremity]), and perceived manual ability (ABILHAND-Stroke). RESULTS: Of 100 adults screened, 58 were included, and 53 participants (91%) completed both baseline and immediate posttreatment assessments. Of the 53 participants who completed the study, mean (SD) age was 59 (11) years, and 17 participants (32%) were female. In this modified intent-to-treat analysis, the ipsilesional treatment group showed significant improvement in Jebsen-Taylor Hand Function Test performance (mean difference, -5.87 seconds; 95% CI, -8.89 to -2.85 seconds; P = .003), representing a 12% reduction in time to completion. Relative to its own baseline, this improvement was sustained at the 3-week and 6-month follow-up times within the ipsilesional treatment group only. No significant effects were observed for the remaining outcomes. CONCLUSIONS AND RELEVANCE: In this parallel-group randomized clinical trial, targeted ipsilesional arm training significantly improved ipsilesional motor performance in patients with chronic stroke with severe paresis. This approach may enhance functional capacity in patients who rely on the ipsilesional arm for daily activities. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03634397.
Czaplicki AM, Frahmand Driscoll I, Ma Y
… +6 more, Gaitán JM, Bendlin BB, Johnson SC, Asthana S, Dubal DB, Okonkwo OC
JAMA Neurol
· 2026 Mar · PMID 41627838
·
Full text
IMPORTANCE: Ventricle-brain volume ratio (VBR), a marker of cerebral atrophy, is a robust correlate of cognition and a predictor of Alzheimer disease (AD) progression. Higher circulating concentrations of the longevity p...IMPORTANCE: Ventricle-brain volume ratio (VBR), a marker of cerebral atrophy, is a robust correlate of cognition and a predictor of Alzheimer disease (AD) progression. Higher circulating concentrations of the longevity protein klotho have been linked to better cognition, but whether klotho modifies the known association between age-related brain atrophy and cognitive decline is unclear. OBJECTIVE: To examine whether serum klotho moderates the association between VBR and cognition and whether this association differs in younger adults (age ≤61.6 years; median split) compared with older adults. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study using data from the Wisconsin Alzheimer Disease Research Center and the Wisconsin Registry for Alzheimer Prevention, collected from 2009 to 2023. This was a community-based, longitudinal study at a research center. Included in the analysis were middle-aged and older adults without cognitive impairment, most with a parental history of AD, who underwent neuropsychological testing, magnetic resonance image, and venipuncture. EXPOSURE: Serum soluble α-klotho concentration, measured via enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES: Outcome measures included composite z scores for global cognition, executive function, delayed recall, and immediate learning. VBR was calculated as total ventricular volume divided by total brain volume ×100. RESULTS: Across the entire sample (308 participants; mean [SD] age, 61.3 [6.5] years; 246 female [80%]; parental history of AD, 227 [74%]), the VBR × klotho interaction was significant, whereby those with higher serum klotho levels performed better on tests assessing global cognition (mean [SE], 0.35 [0.14]; 95% CI, 0.08-0.62; P = .01) and executive function (mean [SE], 0.41 [0.15]; 95% CI, 0.11-0.71; P = .01) but not delayed recall or immediate learning, despite having more brain atrophy. VBR × klotho interactions were not significant in the younger group. In the older group, the VBR × klotho interaction was significant, whereby those with higher circulating klotho levels performed better on tests of global cognition (mean [SE], 0.59 [0.24]; 95% CI, 0.12-1.06; P = .01), executive function (mean [SE], 0.71 [0.27]; 95% CI, 0.19-1.24; P = .01), and immediate learning (mean [SE], 0.59 [0.27]; 95% CI, 0.06-1.20; P = .03) but not delayed recall, despite having more brain atrophy. CONCLUSIONS AND RELEVANCE: Results suggest that circulating serum klotho levels modified the known adverse association between age-related brain atrophy and cognition in older, but not younger, adults at risk for AD, suggesting that the neuroprotective effects of klotho may be age dependent.
Yun J, Lee J, Shin D
… +28 more, Lee EH, Kim JP, Ham H, Gu Y, Chun MY, Kang SH, Kim HJ, Na DL, Kim KW, Kim SE, Kim Y, Kim J, Jung NY, Kim YJ, Cho SH, Lee JS, Kim S, Zetterberg H, Blennow K, Gonzalez-Ortiz F, Ashton NJ, Braunstein JB, Verghese PB, West T, Meyer MR, Seo SW, Jang H, K-ROAD Study Groups
JAMA Neurol
· 2026 Mar · PMID 41627837
·
Full text
IMPORTANCE: Plasma phosphorylated p-tau 217 levels vary with biological factors such as kidney dysfunction, body mass index (BMI), and anemia. It remains unclear whether a biological subgroup-specific optimal cutoff or a...IMPORTANCE: Plasma phosphorylated p-tau 217 levels vary with biological factors such as kidney dysfunction, body mass index (BMI), and anemia. It remains unclear whether a biological subgroup-specific optimal cutoff or a double-cutoff strategy could enhance diagnostic accuracy and cost efficiency beyond the standard single cutoff. OBJECTIVE: To compare the diagnostic and economic performance of 3 plasma p-tau217 classification strategies for detecting amyloid-β (Aβ) positivity: standard single cutoff, subgroup-specific optimal cutoff, and double cutoff. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was a multicenter cross-sectional study conducted from 2016 to 2023; analyses were completed in 2025. Participants were recruited from multiple memory clinics and community-based cohorts. All participants had amyloid positron emission tomography (PET) imaging, clinical evaluation, and p-tau217 testing with measures of estimated glomerular filtration rate (eGFR), BMI, and hemoglobin. Measurements of p-tau217 were made using UGOT Simoa and Roche Elecsys, and the %p-tau217 ratio was assessed using a tau multianalyte assay (C2N Diagnostics LLC). EXPOSURES: Kidney function (chronic kidney disease [CKD], eGFR <60 mL/min/1.73 m2; advanced CKD, eGFR <45 mL/min/1.73 m2), underweight (BMI <18.5), obesity (BMI ≥27.5), and anemia (hemoglobin <12 g/dL in women, <13 g/dL in men). MAIN OUTCOMES AND MEASURES: Plasma p-tau217 concentration; standard single cutoff, optimal cutoffs, and double cutoff for Aβ positivity (Centiloid ≥25.5); accuracy; and cost-effectiveness estimated from false-positive, false-negative, and confirmatory imaging costs. RESULTS: A total of 2571 participants were analyzed with UGOT, 1578 with Roche, and 304 with the C2N %p-tau217 ratio. The mean (SD) age was similar across cohorts (71.3 [8.6] years in the UGOT cohort, 71.3 [8.5] years in the Roche cohort, and 71.8 [7.8] years in the C2N cohort); there were 1633 (63.5%), 1006 (63.8%), and 191 (62.8%) women and 938 (36.5%), 572 (36.2%), and 113 (37.2%) men, respectively. In the UGOT cohort, the optimal cutoff improved diagnostic accuracy compared with the standard single cutoff, particularly in CKD and anemia (CKD: from 0.65; 95% CI, 0.57-0.72; to 0.83; 95% CI, 0.76-0.89; anemia: from 0.80; 95% CI, 0.76-0.84; to 0.86; 95% CI, 0.82-0.90), with consistent findings in the Roche cohort. In all biological subgroups, the double-cutoff strategy also increased accuracy relative to the single cutoff and reduced false classifications but yielded 12% to 39% intermediate results. When compared directly, the optimal cutoff provided higher accuracy than the double cutoff for CKD while lowering total diagnostic costs. For anemia, the double cutoff showed slightly higher accuracy but required confirmatory PET in up to 25% of cases, offsetting its economic advantage. In obesity, the double cutoff remained superior for both diagnostic accuracy and cost efficiency. CONCLUSIONS AND RELEVANCE: This study found that both the optimal cutoff and the double-cutoff strategy outperformed the standard single cutoff, each showing distinct strengths across subgroups. These findings support biologically informed thresholds to improve diagnostic accuracy and cost efficiency when implementing plasma p-tau217.
Saver JL, Kent DM, Kasner SE
… +18 more, Koethe B, Carroll JD, Chatellier G, Furlan AJ, Herrmann HC, Jüni P, Kim JS, Lee PH, Lefebvre B, Nelson J, Mas JL, Mattle HP, Meier B, Reisman M, Smalling RW, Sondergaard L, Song JK, Thaler DE
JAMA Neurol
· 2026 Mar · PMID 41587059
·
Full text
IMPORTANCE: Patent foramen ovale (PFO) closure decreases recurrent stroke but increases atrial fibrillation (AF). Careful selection of patients in whom PFO is more likely to be the cause of stroke may improve outcomes by...IMPORTANCE: Patent foramen ovale (PFO) closure decreases recurrent stroke but increases atrial fibrillation (AF). Careful selection of patients in whom PFO is more likely to be the cause of stroke may improve outcomes by avoiding closure in patients unlikely to benefit. OBJECTIVE: To determine whether the PFO-Associated Stroke Causal Likelihood (PASCAL) classification system identifies who will experience net benefit and net harm from PFO closure. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis was a secondary analysis of individual participant-level data from the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) consortium meta-analysis, including all 6 randomized trials of transcatheter PFO closure vs antithrombotic therapy alone. Participants were young and middle-aged adults (mean [SD] age, 45 [10] years) with a PFO and an otherwise cryptogenic stroke. The trials were conducted in hospitals in North America, Europe, Australia, Brazil, and South Korea from 2000 to 2017. The current analysis, involving all trial participants, was performed from January to August 2025. INTERVENTIONS: Transcatheter PFO closure plus antithrombotic therapy vs antithrombotic therapy alone. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was recurrent ischemic stroke. The primary safety end point was first-ever detection of AF beyond the periprocedural period (>45 days after randomization). RESULTS: The 6 trials enrolled 3740 patients (1889 who had PFO closure, 1851 who had medical therapy); 2058 patients (55.0%) were male, and 1682 (45.0%) were female. Among patients in all 6 trials, PASCAL classified PFO relatedness to the index stroke as probable in 1382 patients (37.0%), possible in 1811 (48.4%), and unlikely in 547 (14.6%); among the 2967 patients in the 4 trials with broad entry criteria, PASCAL classified PFO relatedness as probable in 860 patients (29.0%), possible in 1565 (52.7%), and unlikely in 543 (18.3%). The reduction in the absolute rate of recurrent ischemic strokes over 5 years was greater than the increase in first-ever detection of AF in the postperiprocedural period as follows: in the probable group, fewer strokes, -2.5% (95% CI, -4.2% to -1.3%) vs more late AF, 1.3% (95% CI, 0.0% to 2.5%), and in the possible group, fewer strokes -3.4% (95% CI, -5.4% to -1.3%) vs more late AF, 1.1% (95% CI, -0.5% to 2.6%). Reduction in recurrent ischemic strokes was not observed and increase in first-ever detected postperiprocedural AF was magnified in the unlikely group (more strokes, 0.4%; 95% CI, -4.0% to 4.8%, vs more late AF, 4.6%; 95% CI, 0.3% to 8.9%). CONCLUSION AND RELEVANCE: Among young and middle-aged patients with PFO and otherwise cryptogenic stroke, the PASCAL classification algorithm distinguished the 4 of every 5 patients in the probable and possible groups with net benefit and the 1 of every 5 patients in the unlikely group with net harm from closure.