Potnis O, Biondo G, Sukonik R
… +7 more, Grzeskowiak C, Cutter G, Altalib H, Kuzniecky R, Lowenstein D, French J, HEP2 Investigators
JAMA Neurol
· 2025 Dec · PMID 41114972
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IMPORTANCE: Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understandin...IMPORTANCE: Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses. OBJECTIVE: To determine whether seizure frequency in FTRE improves over time. DESIGN, SETTING, AND PARTICIPANTS: The Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed up for 18 to 36 months at 10 US-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample. EXPOSURES: Participants were treated with multiple interventions at their physicians' discretion. MAIN OUTCOMES AND MEASURES: The primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes. RESULTS: Of 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices. CONCLUSIONS AND RELEVANCE: Findings from the HEP2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretation of open-label studies positing disease-modifying effects and further research into FTRE treatment response.
Chen PR, Artime CA, Sheth SA
… +20 more, Pedroza C, Ortega-Gutierrez S, Wolfe S, Sitton C, Kan P, Tanweer O, Chebl A, Schirmer CM, Morrow JT, Alderazi YJ, Bohnstedt B, Erkmen K, Samaniego EA, Garrido E, Savitz SI, Engstrom A, Aguilar E, Nguyen T, Barreto AD, SEGA Investigators
JAMA Neurol
· 2025 Dec · PMID 41082222
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IMPORTANCE: The optimal anesthetic strategy for patients undergoing endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusion (LVO) remains unclear. OBJECTIVE: To determine if general anesthe...IMPORTANCE: The optimal anesthetic strategy for patients undergoing endovascular therapy (EVT) for acute ischemic stroke (AIS) from large vessel occlusion (LVO) remains unclear. OBJECTIVE: To determine if general anesthesia (GA) or moderate sedation for patients who undergo EVT for AIS with LVO is associated with a different functional outcome in 90 days. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter randomized clinical trial conducted from July 2018 to August 2023 of patients with AIS who were receiving EVT due to LVO. Patients were recruited from 10 comprehensive stroke centers in the US. Adult patients with occlusion of the carotid artery and the proximal middle and anterior cerebral artery who underwent EVT were eligible for enrollment. INTERVENTIONS: Patients were randomized to receive either moderate sedation or GA in 1:1 ratio. MAIN OUTCOMES AND MEASURES: The primary outcome was the ordinal modified Rankin Scale (mRS) score at 90 days. RESULTS: A total of 1931 patients were screened for eligibility, and 1671 were excluded due to failure meeting the inclusion criteria. Among 260 individuals with a mean (SD) age of 66.8 (13.3) years included in this intention-to-treat study, 133 were male (52%), and 130 (50%) were randomized to GA and sedation each. At 90 days, a shift in the distribution of ordinal mRS was found favoring GA (odds ratio [OR], 1.22; 95% credible interval [CrI], 0.79-1.87) with an 81% posterior probability of GA superiority. The probability that GA was superior to sedation was 89% (relative risk [RR], 1.2; 95% CrI, 0.9-1.66) and 69% (RR, 1.01; 95% CrI, 0.96-1.08) for 90-day mRS 0 to 2 and successful reperfusion, respectively. Other secondary outcomes were similar. Symptomatic intracerebral hemorrhage was 0.8% (1 of 125 patients) in GA vs 2.4% (3 of 125 patients) in sedation with a posterior probability of GA was superior to sedation of 72% (RR, 0.71; 95% CrI, 0.23-2.16). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that patients with LVO AIS who were treated with EVT using GA had improved rates of 90-day outcomes and higher rates of successful reperfusion compared with those treated using moderate sedation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03263117.
Lu M, Kim MJ, Collins EC
… +8 more, Shcherbinin S, Ellinwood AK, Yokoi Y, Brooks DA, Hansson O, Knopman DS, Sims JR, Mintun MA
JAMA Neurol
· 2025 Dec · PMID 41082199
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IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. OBJECTIVE: To assess the correlation of postt...IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. OBJECTIVE: To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. INTERVENTIONS: Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. MAIN OUTCOMES AND MEASURES: Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. RESULTS: Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]). CONCLUSIONS AND RELEVANCE: The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.
Okazaki S, Tanaka K, Yazawa Y
… +22 more, Doijiri R, Koga M, Ihara M, Yamamoto S, Kamiyama K, Honda Y, Uchida K, Yoshimoto T, Asakura K, Omae K, Tanaka K, Maeda H, Yamamoto H, Hirano T, Toyoda K, Iguchi Y, Noguchi T, Okada Y, Kitagawa K, Sakai N, Yamagami H, ATIS-NVAF Trial Investigators
JAMA Neurol
· 2025 Dec · PMID 41051787
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IMPORTANCE: Patients with ischemic stroke and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease are at an elevated risk of recurrent ischemic events. Although combined anticoagulant an...IMPORTANCE: Patients with ischemic stroke and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease are at an elevated risk of recurrent ischemic events. Although combined anticoagulant and antiplatelet therapy may reduce ischemic risk, it also increases bleeding, and the optimal antithrombotic strategy remains uncertain. OBJECTIVE: To determine whether adding an antiplatelet agent to anticoagulant therapy influences the net clinical benefit in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, open-label randomized clinical trial was conducted at 41 sites across Japan from November 2016 to March 2025. Eligible patients had an ischemic stroke or transient ischemic attack within 8 to 360 days of onset, nonvalvular atrial fibrillation, and at least 1 manifestation of atherosclerotic cardiovascular disease (carotid or intracranial artery stenosis, noncardioembolic stroke, ischemic heart disease, or peripheral artery disease). Data were analyzed from April 16, 2024, to October 14, 2024. INTERVENTIONS: Patients were randomized to receive combination therapy (anticoagulant plus antiplatelet) or anticoagulant monotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of ischemic cardiovascular events and major bleeding within 2 years. Secondary outcomes included ischemic cardiovascular events; safety outcomes included major and clinically relevant nonmajor bleeding. RESULTS: In total, 316 patients were randomized to combination therapy (n = 159) or monotherapy (n = 157) (mean [SD] age, 77.2 [7.4] years; 90 female patients [28.5%]). The trial was terminated on July 18, 2023, after an interim analysis for futility. The cumulative incidence of the primary outcome was 17.8% in the combination therapy group and 19.6% in the monotherapy group (hazard ratio [HR], 0.91; 95% CI, 0.53-1.55; P = .64). Ischemic cardiovascular events occurred in 11.1% and 14.2% (HR, 0.76; 95% CI, 0.39-1.48; P = .41), and major and clinically relevant nonmajor bleeding occurred in 19.5% and 8.6% (HR, 2.42; 95% CI, 1.23-4.76; P = .008) of combination therapy and monotherapy groups, respectively. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, in patients with ischemic stroke or transient ischemic attack and concurrent nonvalvular atrial fibrillation and atherosclerotic cardiovascular disease, adding an antiplatelet agent to anticoagulant therapy provided no net clinical benefit over anticoagulant monotherapy, with higher bleeding risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03062319.
Kim H, Nelson J, McCulloch CE
… +16 more, Hess C, Hetts SW, Flemming K, Lanzino GS, Koroknay-Pál P, Oulasvirta E, Laakso A, Lawton MT, Mohr JP, Morgan MK, Moayeri N, Zaroff JG, Stefani MA, Chen X, Zhao Y, Al-Shahi Salman R
JAMA Neurol
· 2025 Dec · PMID 41051760
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IMPORTANCE: Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailab...IMPORTANCE: Annual rates of first intracranial hemorrhage (ICH) from unruptured brain arteriovenous malformations (AVMs) are often quoted as 2% to 4% in clinical practice. Precise estimates and risk factors are unavailable to inform treatment decisions. OBJECTIVE: To provide estimates of rates and risk factors for first ICH in a large cohort study of unruptured brain AVMs. DESIGN, SETTING, AND PARTICIPANTS: The Multicenter Arteriovenous Malformation Research Study (MARS) included data from 9 cohorts, each contributing 100 or more unruptured brain AVMs. The study was conducted from 2017 to 2023 with retrospective and prospective data collection for existing cohorts and/or new recruitment. This was an international study (2 population-based and 7 referral-based cohorts) that included participants diagnosed with an unruptured brain AVM. EXPOSURES: Demographic, clinical, and angiographic characteristics. MAIN OUTCOME AND MEASURE: The primary outcome was time to first ICH after diagnosis of unruptured brain AVM. Data were collected using standardized definitions; missing data were imputed. Cox regression analysis was performed, censoring at first brain AVM treatment, death, or last visit, and allowing baseline hazards to vary by cohort. RESULTS: A total of 3225 individuals were eligible for participation in this study. After 195 exclusions, 3030 participants (median [IQR] age, 38 [25-50] years; 1524 female [50.3%]) were included. Among 2989 participants with unruptured brain AVMs, 1333 (45%) presented with seizure. The median (IQR) maximal brain AVM diameter was 3.1 (2.2-4.4) cm, 248 of 2466 AVMs (10%) had exclusively deep venous drainage, 297 of 2690 (11%) were in supratentorial deep or cerebellar locations, and 457 of 2440 (19%) had associated arterial aneurysms. First ICH occurred in 159 participants over 11 339 person-years of follow-up for an ICH rate of 1.40 (95% CI, 1.20-1.64) per 100 person-years. Significant independent risk factors included (1) increasing age category at diagnosis (hazard ratio [HR], 0.87; 95% CI, 0.53-1.41 for those aged 20 to 39 years; HR, 1.23; 95% CI, 0.74-2.04 for those aged 40 to 59 years; and HR, 2.01; 95% CI, 1.14-3.57 for those aged 60 years vs younger than 20 years; P = .008), (2) presence of associated aneurysms (HR, 1.66; 95% CI, 1.06-2.59; P = .03), and (3) cerebellar or supratentorial deep location (HR, 1.87; 95% CI, 1.16-3.00; P = .01). CONCLUSIONS AND RELEVANCE: The annual ICH rate from unruptured brain AVM was lower than that commonly cited in clinical practice. Increasing age, associated arterial aneurysms, and cerebellar or supratentorial deep brain AVM location were associated with risk of first ICH. These results may be used to counsel patients about the natural history of unruptured brain AVMs.
Bridge F, Sanfilippo PG, Zhu C
… +15 more, Skibina O, Nguyen AL, Kalincik T, Buzzard K, Taylor BV, MacIntyre J, Hall LA, Slee M, Macdonell R, Maltby V, Lechner-Scott J, McCombe P, Butzkueven H, van der Walt A, Jokubaitis VG
JAMA Neurol
· 2025 Dec · PMID 41021242
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IMPORTANCE: Most women with multiple sclerosis (MS) will experience menopause while living with MS. Despite this, the impact of menopause on MS disease trajectory remains unclear. OBJECTIVE: To assess whether menopause m...IMPORTANCE: Most women with multiple sclerosis (MS) will experience menopause while living with MS. Despite this, the impact of menopause on MS disease trajectory remains unclear. OBJECTIVE: To assess whether menopause modifies the risk of disability progression for women with relapse-onset MS. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used prospective clinical data that were collected within the MSBase Registry. Data were extracted from MSBase on July 1, 2023. These data were analyzed from January 2023 through February 2025. Female participants were recruited from 8 Australian neuroimmunology specialist centers (1 private practice and 7 tertiary referral centers) from 2018 through 2021. Participants included 1468 women aged 18 years or older who completed dedicated retrospective women's health surveys. Of these, 987 women with relapse-onset MS, 3 or more Expanded Disability Status Scale (EDSS) measurements recorded, and reported menopausal status were included in the primary analysis. The secondary analysis included 209 women with 1 or more EDSS measurements recorded in the MSBase database predate and postdate of menopause onset. EXPOSURE: Crude and adjusted Cox proportional hazards models were used to assess the impact of menopause, modeled as a time-varying covariate, on progressive disability milestones. Analyses were adjusted for age at MS onset, baseline disease duration, baseline EDSS score, baseline relapse, and exposure to high-efficacy disease-modifying therapy modeled as a time-varying covariate. MAIN OUTCOME MEASURES: In the primary analysis, the main outcome was time to 6-month confirmed disability progression (CDP). The secondary outcome was time to secondary progressive MS (SPMS). The secondary inflection point analysis examined longitudinal changes in EDSS in women who were followed up with throughout their menopausal transition. RESULTS: Primary analysis included 583 premenopausal and 404 postmenopausal women with MS. The median age at menopause was 48.5 years. Following multivariable adjustment, menopause was not associated with an increased risk of CDP or SPMS (hazard ratio, 0.95; 95% CI, 0.70-1.29; P = .70 and hazard ratio, 1.00; 95% CI, 0.60-1.67; P = 1.00), respectively. In the secondary analysis, menopause did not represent an inflection point in EDSS worsening following multivariable adjustment. CONCLUSIONS AND RELEVANCE: While reproductive aging may be additive to the effects of somatic aging, these results do not support menopause as the leading factor for disability progression in older women with MS.
Bronte-Stewart HM, Beudel M, Ostrem JL
… +31 more, Little S, Almeida L, Ramirez-Zamora A, Fasano A, Hassell T, Mitchell KT, Moro E, Gostkowski M, Chattree G, de Bie RMA, de Neeling M, Piña-Fuentes D, Swinnen B, Starr PA, Hammer LH, Foote KD, Richardson RM, Flaherty A, Boogers A, Sa'di Q, Meoni S, Castrioto A, Stanslaski S, Summers RLS, Tonder L, Tan Y, Berrier H, Goble TJ, Raike RS, Herrington TM, ADAPT-PD Investigators
JAMA Neurol
· 2025 Nov · PMID 40982287
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IMPORTANCE: Adaptive deep brain stimulation (aDBS) automatically adjusts stimulation amplitude in response to changes in relevant neural activity in people with Parkinson disease (PD). Whether long-term at-home aDBS is s...IMPORTANCE: Adaptive deep brain stimulation (aDBS) automatically adjusts stimulation amplitude in response to changes in relevant neural activity in people with Parkinson disease (PD). Whether long-term at-home aDBS is safe and delivers effective therapy in people with PD remains unknown. OBJECTIVE: To determine the tolerability, efficacy, and safety of long-term aDBS in people with PD who were previously stable receiving continuous DBS (cDBS). DESIGN, SETTING, AND PARTICIPANTS: This international, open-label, prospective, pivotal trial enrolled participants from December 2020 to July 2022 in the US, Canada, and Europe. Referred participants with PD were first assessed while receiving stable cDBS and those who tolerated 2 aDBS modes were randomized and blinded to 30 days in each mode (single-blind crossover design); those who tolerated only 1 mode were assessed in that mode only; assessments completed holding medication stable. Participants were given the option to continue their selected mode of aDBS for long-term follow-up (10 months). Data used for analysis were from March 2024. Multiple imputation was used if more than 5% of data was missing for the primary or secondary end points. A referred sample of 68 participants with PD, stable while receiving cDBS and medication, was included. INTERVENTIONS: Two modes of aDBS controlled by an embedded closed-loop stimulation system: single threshold (ST-aDBS) and dual threshold (DT-aDBS). MAIN OUTCOMES AND MEASURES: The primary end point required that at least 50% of participants meet a performance goal of on-time (ie, time when symptoms were well controlled) without troublesome dyskinesias with no less than 1-SD reduction (and post hoc threshold less than 2 hours per day reduction) reported during aDBS therapy compared to cDBS, determined from a self-reported motor diary. The secondary end point was total electrical energy delivered (TEED) compared between aDBS and cDBS. Safety assessments were conducted by characterizing adverse events (AEs), stimulation-related AEs, serious AEs, and device deficiencies. RESULTS: A total of 68 participants enrolled (mean [SD] age, 62.2 [8.4] years; 48 [70.6%] male); 40 and 35 were evaluated with DT-aDBS and ST-aDBS, respectively. The primary end point performance goal was met in the DT-aDBS group (91% of participants) and ST-aDBS (79% of participants) with the post hoc performance threshold; no difference between aDBS modes (χ21 = 1.0; P = .51). TEED was reduced during ST-aDBS compared to cDBS (mean change, -15%; nominal P = .01) and not different from DT-aDBS. All but 1 stimulation-related AE resolved during the aDBS setup and adjustment phase with no serious device AEs through long-term follow-up. Exploratory analyses suggested improvement in on-time without troublesome dyskinesias with DT-aDBS compared to cDBS. CONCLUSIONS AND RELEVANCE: In this study, long-term aDBS was tolerable, effective, and safe in people with PD who were previously stable while receiving cDBS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04547712.
VasCog-2-WSO Criteria Consortium, Sachdev PS, Bentvelzen AC
… +60 more, Kochan NA, Jiang J, Hosoki S, Koncz R, Chander RJ, Saks D, Aben HP, Acosta D, Andersen P, Assal F, Bae HJ, Biessels GJ, Blacker D, Bordet R, Briceno EM, Brodaty H, Brodtmann A, Caramelli P, Castro-Costa E, Chabriat H, Chen C, Clancy U, Cysique L, DeCarli C, Ding D, Duering M, Engelhardt E, Gauthier S, Geranmayeh F, Godefroy O, Gorelick P, Greenberg SM, Jelic V, Jokinen H, Kalaria RN, Krishna M, Lancaster K, de Leeuw FE, Lim JS, Marseglia A, Marta-Moreno J, O'Brien JT, Pantoni L, Pase MP, Pendlebury ST, Rosenberg G, Sabayan B, Salvadori E, Samaras K, Sebastian IA, Seshadri S, Smith EE, Srikanth V, Stokes K, Sudo FK, Sveikata L, Valenzuela M, Wallin A, Wardlaw JM, Xu Q
JAMA Neurol
· 2025 Nov · PMID 40955506
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IMPORTANCE: Several sets of diagnostic criteria have been proposed for vascular cognitive impairment and dementia (VCID). The International Society for Vascular Behavioural and Cognitive Disorders (VasCog) working group...IMPORTANCE: Several sets of diagnostic criteria have been proposed for vascular cognitive impairment and dementia (VCID). The International Society for Vascular Behavioural and Cognitive Disorders (VasCog) working group published comprehensive operationalized criteria in 2014. Considering subsequent advances in the field, a revision was needed. OBJECTIVE: To update the VasCog criteria to achieve consensus on diagnosis of VCID. DESIGN, SETTING, AND PARTICIPANTS: VasCog criteria and other published diagnostic guidelines, aided by literature review of recent developments in VCID, were used as reference points for an online Delphi survey (minimum 3 rounds, ≥75% threshold for agreement), including operationalization of criteria and guidance on potential biomarkers. Seventy international experts from diverse international regions were invited to participate in 2023. RESULTS: Three survey rounds included 49 to 54 participants that agreed on VasCog-2 diagnostic criteria for preclinical, mild, and major dementia levels of vascular cognitive impairment (under the overarching term VCID). Research guidelines, including the use of novel neuroimaging and fluid biomarkers, were also agreed on. The World Stroke Organization (WSO) endorsed the criteria, hence named VasCog-2-WSO. CONCLUSIONS AND RELEVANCE: The VasCog-2-WSO criteria update the VasCog criteria for the diagnosis of VCID, providing operationalization and additional guidance on potential neuroimaging and fluid biomarkers. VasCog-2-WSO should provide an international standard for VCID diagnosis, facilitating diagnostic consistency among clinicians and researchers.