Peek K, Massey A, Connolly R
… +15 more, Fulcher M, Putukian M, Bahtijarevic Z, Reinsberger C, Goedhart E, Kara S, Chiampas G, Nakayama H, Clarke M, Takwoingi Y, Pagura J, Calderón N, Drave A, Bouya SM, Serner A
IMPORTANCE: Concussion is a high-profile and important brain injury, yet the on-pitch assessment of concussion in football (soccer) remains challenging due to the absence of a standardized, evidence-based assessment prot...IMPORTANCE: Concussion is a high-profile and important brain injury, yet the on-pitch assessment of concussion in football (soccer) remains challenging due to the absence of a standardized, evidence-based assessment protocol that can be completed within a time-restrained on-pitch football-match environment. The objective of this study was to develop a football-specific, standardized on-pitch concussion assessment protocol informed by research evidence and expert opinion using an international consensus process and steering committee deliberation, which included medical experts from each of the 6 football confederations. OBSERVATIONS: Nominated global medical representatives with experience in the on-pitch assessment of concussion in football (≥5 assessments within previous year) from Fédération Internationale de Football Association (FIFA)-member associations completed a 2-round Delphi questionnaire to score all identified assessment items that have been used to assess an athlete with a suspected concussion within an on- or off-pitch environment (in any sport) along with expert recommendations. Consensus (≥80% agreement) was required for assessment items to be included in a football-specific on-pitch concussion assessment protocol. Results demonstrated that from 101 identified assessment items, 41 achieved greater than or equal to 80% agreement for inclusion in round 1, and 6 additional items achieved greater than or equal to 80% agreement in round 2. Four items (scoring 75%-79%) were added after steering committee review. Twelve items were merged to avoid duplication of items that assess the same issue. This resulted in the final Football-Specific Standardized On-Pitch Concussion Assessment Protocol (FOCUS) comprising 45 items categorized into 11 domains as follows: player medical history, mechanism of injury, visible signs, level of consciousness, cervical spine assessment, symptoms, orientation, balance, proprioception, oculomotor function, and activity-based assessment, with each structured for rapid on-pitch evaluation. CONCLUSIONS AND RELEVANCE: FOCUS provided a standardized, evidence-informed protocol for the on-pitch assessment of a suspected concussion during football match play, addressing a critical gap in player health and safety. Adoption of FOCUS has the potential to harmonize concussion management globally; however, implementation feasibility and diagnostic accuracy require further evaluation.
Rosen-Lang Y, Vrillon A, Pasternak S
… +18 more, Blazhenets G, Soleimani-Meigooni DN, Rabinovici GD, Weiner MW, Hantke N, Silbert LC, Schwartz DL, Livny-Ezer A, Lesman-Segev O, Ganmore I, Ravona-Springer R, Yaffe K, Landau SM, Korecka M, Shaw LM, La Joie R, Gardner RC, Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DOD ADNI) Investigators and the Department of Defense Alzheimer’s Disease Blood-Testing Initiative (DOD ADBI)
IMPORTANCE: Traumatic brain injury (TBI) is a risk factor for dementia and is known to impact levels of several Alzheimer disease (AD) blood biomarkers. The plasma phosphorylated tau 217 (p-tau217)/amyloid-β 42 (Aβ42) ra...IMPORTANCE: Traumatic brain injury (TBI) is a risk factor for dementia and is known to impact levels of several Alzheimer disease (AD) blood biomarkers. The plasma phosphorylated tau 217 (p-tau217)/amyloid-β 42 (Aβ42) ratio has been reported to be 90% accurate for the detection of brain amyloid in civilian cohorts. OBJECTIVE: To evaluate the accuracy of emerging AD blood biomarkers in veterans with and without a TBI history. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional cohort study of a diagnostic test assessed the performance of the US Food and Drug Administration-approved plasma p-tau217/Aβ42 ratio and plasma levels of p-tau217 and Aβ42/40 ratio for detecting brain Aβ positivity (eg, amyloid-positron emission tomography [PET] consensus visual read). The accuracy of biomarkers was compared in veterans without TBI, those with TBI with loss of consciousness (LOC) for 0 to 5 minutes, and those with TBI with LOC for greater than 5 minutes. Existing data and banked plasma from the Alzheimer Disease Neuroimaging Initiative Department of Defense (ADNI-DOD) study were used. Years of enrollment were 2013 to 2020. Included in this study were Vietnam War veterans without dementia (cognitively unimpaired and those with mild cognitive impairment) who had amyloid-PET and concurrently collected banked plasma available for analysis. Plasma biomarker analysis took place from 2024 to 2025, and data analysis was performed from July 2025 to February 2026. EXPOSURES: AD blood biomarkers and TBI history. MAIN OUTCOMES AND MEASURES: p-Tau217/Aβ42 accuracy in the detection of amyloid-PET consensus visual read positivity across groups with/without TBI exposure. RESULTS: In 272 participants, mean (SD) age was 70 (4.5) years, 270 were male (99.3%), and 83 (30.5%) were amyloid-PET positive. The plasma p-tau217/Aβ42 ratio was highly accurate in veterans with no TBI (90%; 95% CI, 84%-96%) but not in veterans with TBI with LOC for 0 to 5 minutes (78% accuracy; 95% CI, 69%-87%; P = .03 vs no TBI), nor in veterans with TBI with LOC greater than 5 minutes (63% accuracy; 95% CI, 53%-73%; P < .001 vs no TBI). Results were similar for plasma p-tau217 alone and plasma Aβ42/40 ratio. Results were also similar after excluding veterans with TBI within the past 10 years or when amyloid-PET positivity was defined using a quantitative threshold rather than consensus visual read. CONCLUSIONS AND RELEVANCE: Results of this cross-sectional cohort study of a diagnostic test suggest that among individuals who are cognitively unimpaired or have mild cognitive impairment and a TBI history, the p-tau217/Aβ42 ratio test may miss over half of amyloid-PET-positive cases. Caution is advised in interpreting AD blood test results in this context.
Olzinski M, Downer J, Cobigo Y
… +33 more, Rajbanshi B, Li J, Loureiro J, Worringer KA, Heuer H, Ljubenkov P, Vandevrede L, Staffaroni A, Lario-Lago A, Leichter D, Wolf A, Wise A, Sanderson-Cimino M, Barragan E, Spina S, Grinberg LT, Seeley WW, Casaletto KB, Kramer J, Ramos EM, Geschwind D, Cook C, Petrucelli L, Forsberg LK, Gendron T, Boeve BF, Perneel J, Rademakers R, Rosen HJ, Saloner R, Boxer AL, Rojas JC, ALLFTD consortium
JAMA Neurol
· 2026 Jun · PMID 42329632
·
Full text
IMPORTANCE: TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associat...IMPORTANCE: TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. OBJECTIVE: To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72, GRN, or MAPT; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. EXPOSURES: CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). MAIN OUTCOMES AND MEASURES: Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. RESULTS: In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, -0.15; 95% CI, -0.24 to -0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, -2.21; 95% CI, -3.70 to -0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. CONCLUSIONS AND RELEVANCE: Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.
Colonel JT, Becker J, Chan L
… +8 more, Faherty C, Hackett K, Carnavali F, Van Vleck TT, Curtis L, Wisnivesky J, Federman A, Lin B
JAMA Neurol
· 2026 Jun · PMID 42295801
·
Full text
IMPORTANCE: Cognitive impairment (CI) is often underdetected in primary care due to time and resource constraints. Passive analysis of clinical dialogue may offer an accessible approach for screening. OBJECTIVE: To asses...IMPORTANCE: Cognitive impairment (CI) is often underdetected in primary care due to time and resource constraints. Passive analysis of clinical dialogue may offer an accessible approach for screening. OBJECTIVE: To assess whether audio recordings of patient-physician dialogue during routine primary care visits can be used to identify CI using acoustic speech features and machine learning (ML). DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study, conducted from August 2020 through December 2021 among older primary care patients, involved audio recording primary care visits using a microphone and portable device. An external validation cohort was recruited in a separate city to assess reproducibility of findings. Analysis was performed from January 2025 through June 2025. The study was conducted in primary care practices in New York, New York, with additional participants recruited from primary care practices in Chicago, Illinois, for validation. Eligible patients were recruited from primary care practices during routine visits with no prior diagnosis of mild CI or dementia. The study included English-speaking patients aged 55 years and older without documented history of dementia or mild CI. For validation, patients meeting the same eligibility criteria were recruited from primary care practices in Chicago. EXPOSURE: Multiple 30-second speech segments were extracted from recordings. Acoustic features were derived using foundation models (Whisper, HuBERT, wav2vec 2.0) and expert-defined methods (eGeMAPS, prosody). MAIN OUTCOMES AND MEASURES: The primary outcome, CI, was defined as Montreal Cognitive Assessment score 1.0 or more standard deviations below age- and education-adjusted norms. ML classifiers were trained to predict CI status from audio recordings. Area under the receiver operating characteristic curve (AUROC) and maximum F1 score (Fmax) were calculated for identifying participants with CI. RESULTS: The study included 787 English-speaking patients aged 55 years and older without documented history of dementia or mild CI and an additional 179 patients meeting the same eligibility criteria for validation. In total, 966 participants were recruited, among whom 530 (55%) were female, mean (SD) age was 67.2 (8.1) years, and CI prevalence was 21%. Models using Whisper-derived acoustic features performed best (AUROC, 0.733; 95% CI, 0.714-0.752; Fmax[CI], 0.502; 95% CI, 0.471-0.533). Results generalized to the external site with similar performance (AUROC, 0.727; 95% CI, 0.714-0.740; Fmax[CI], 0.459; 95% CI, 0.441-0.477). Model interpretation identified pitch, timing, and variability features as key predictors. When used for screening, the algorithm achieved positive predictive value of 30.4% (95% CI, 28.7%-32.1%), sensitivity of 68.2% (95% CI, 61.8%-74.6%), and specificity of 63.6% (95% CI, 59.8%-67.4%) on the holdout cohort. CONCLUSIONS AND RELEVANCE: In this diagnostic study, ML models trained on acoustic features from brief clinical conversations identified CI with high accuracy. These findings support the feasibility of passive, speech-based screening during routine primary care.
Kellner CP, Rai AT, Shoirah H
… +29 more, Srinivasan VM, Gupta R, Starke RM, Al-Mufti F, Matouk CC, Yim B, Fusco MR, Wan J, Liptrap E, Bhuva P, Grandhi R, Cerejo R, Liu JJ, Cherian J, Zhang Q, Kaminsky I, Prestigiacomo CJ, Orru' E, Lin E, Howington J, Evans A, Mehta T, Boo S, Finch I, Liu T, Chitale R, Majidi S, Jankowitz BT, MEMBRANE Study Group
JAMA Neurol
· 2026 Jun · PMID 42295790
·
Full text
IMPORTANCE: Middle meningeal artery embolization (MMAE) is a minimally invasive adjunctive treatment for chronic subdural hematoma (cSDH). The TRUFILL n-butyl cyanoacrylate (n-BCA) liquid embolic system is indicated for...IMPORTANCE: Middle meningeal artery embolization (MMAE) is a minimally invasive adjunctive treatment for chronic subdural hematoma (cSDH). The TRUFILL n-butyl cyanoacrylate (n-BCA) liquid embolic system is indicated for embolization of cerebral arteriovenous malformations for presurgical devascularization and may be appropriate for MMAE in patients with cSDH. OBJECTIVE: To evaluate safety and effectiveness of the study device for MMAE plus standard of care vs standard of care alone in patients with cSDH. DESIGN, SETTING, AND PARTICIPANTS: The Middle Meningeal Artery Embolization for the Treatment of Subdural Hematomas With TRUFILL n-BCA (MEMBRANE) trial was a prospective, multicenter, open-label, randomized clinical trial conducted from May 27, 2021, to February 6, 2024, at 30 hospitals (28 in the United States and 2 in China). Participants aged 18 to 90 years with symptomatic cSDH and a modified Rankin Scale score of 3 or less were enrolled. INTERVENTIONS: Site physicians determined whether each patient required surgical or nonsurgical management. Participants in the surgical and nonsurgical cohorts were then randomized 1:1 to receive MMAE plus standard of care or standard of care alone. MAIN OUTCOMES AND MEASURES: The primary effectiveness end point was residual or re-accumulation of hematoma (>10 mm; assessed by an independent core laboratory) at 6 months or requiring a surgical procedure on the cSDH within 6 months (conducted as an intention-to-treat analysis). The primary safety end point was incidence of adverse events through 6 months (conducted as an as-treated analysis). RESULTS: A total of 376 participants (188 in MMAE plus standard of care and 188 in standard of care alone) were included. In the MMAE plus standard of care and standard of care alone groups, the mean (SD) age was 70.9 (10.6) and 70.3 (12.1) years, and 45 (23.9%) and 49 (26.1%) were female, respectively. Primary effectiveness end point events occurred in 17 of 146 participants receiving MMAE plus standard of care (11.6%) and 29 of 131 receiving standard of care alone (22.1%) (final estimate of common odds ratio: 0.53 [90% CI, 0.31-0.91]; P = .04), indicating statistically significant benefit for MMAE plus standard of care vs standard of care alone. Adverse events occurred in 130 of 181 participants in the MMAE plus standard of care group (71.8%) and 124 of 190 in the standard of care alone group (65.3%) through 6 months. MMAE plus standard of care treatment was noninferior to standard of care alone based on analysis of good functional outcome at 3 months, as assessed by the modified Rankin Scale. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, MMAE plus standard of care significantly reduced rates of recurrence and reoperation vs standard of care alone, without a significant increase in adverse events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT04816591.
Billioux BJ, Reilly C, van Ryn C
… +17 more, Smith B, Tarfeh-Burnette H, Dorbor J, Bonarwolo K, Taryor V, Schindler MK, Reoma LB, Azodi S, Ohayon J, Enose-Akahata Y, Bishop R, Higgs E, Lane HC, Johnson K, Sneller MC, Fallah M, Nath A
JAMA Neurol
· 2026 Jun · PMID 42268636
·
Full text
IMPORTANCE: Ebola virus disease (EVD) causes multiorgan damage and is highly fatal. EVD's neurological impact among survivors remains poorly characterized due to limited neurological assessment capabilities in the remote...IMPORTANCE: Ebola virus disease (EVD) causes multiorgan damage and is highly fatal. EVD's neurological impact among survivors remains poorly characterized due to limited neurological assessment capabilities in the remote regions where most outbreaks occur. OBJECTIVE: To characterize neurological sequelae in EVD survivors over more than 7 years' longitudinal follow-up. DESIGN, SETTING, AND PARTICIPANTS: Under the Ebola Natural History Study (PREVAIL III; PIII), the Neurology Study of PIII was a prospective longitudinal cohort study in Liberia of adult Ebola survivors and control individuals conducted from September 2015 to March 2023 at the Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) site at John F. Kennedy Medical Center in Monrovia, Liberia. Data were analyzed from April 2023 to September 2025. EXPOSURES: Neurological evaluations were performed by trained neurologists biannually. Questionnaire and neurological examination data were collected on case report forms. MAIN OUTCOMES AND MEASURES: Neurological symptom prevalence and neurological examination scores were compared to those of control individuals. Tests for differences between survivors and control individuals were conducted using generalized linear mixed-effects models controlling for age and sex. Overdispersed Poisson models were used to test for computed neurological examination score differences. Neurological examination scores were developed for this study, representing the cumulative abnormalities on neurological examinations, denoted on standardized case report forms, with the general neurological examination score representing all examination abnormalities and the central nervous system score representing the central nervous system-specific abnormalities on examination. RESULTS: Analysis after serologic testing included 148 Ebola antibody-positive survivors (mean [SD] age, 34.8 [10.5] years; 74 [50%] female) and 81 antibody-negative contacts (mean [SD] age, 35.8 [12.6] years; 41 [51%] female). During acute infection, survivors reported headaches, altered mental status, and strokelike symptoms or meningoencephalitis (rarely). Survivors had significant neurological sequelae involving the entire neuraxis: cognitive dysfunction (83 [56.1%]), persistent headaches (98 [66.2%]), sleep abnormalities (40 [27.0%]), depression (73 [49.3%]), sexual dysfunction (48 [32.4%]), tremor (18 [20.3%]), fatigue (71 [51.1%]), cranial nerve abnormalities (60 [40.5%]), and sensory abnormalities (45 [30.4%]). Over 7 years' follow-up, most survivors demonstrated improvement in neurological status. The final visit included 115 survivors (77.7%) and 61 close contacts (75.3%). Persistent symptoms at final evaluation in survivors compared to contacts were memory loss (66 [57.4%] vs 16 [26.2%], respectively; P < .001), irritability (42 [36.5%] vs 9 [14.8%], respectively; P = .006), and trouble concentrating (34 [29.6%] vs 6 [9.8%], respectively; P = .002). CONCLUSIONS AND RELEVANCE: The findings indicate that Ebola virus infection is associated with neurological complications in survivors, with increased health care burden and socioeconomic consequences. These neurological issues generally improved with time, but some persisted long-term. Close neurological follow-up of EVD survivors may be warranted.
Camps-Renom P, Guasch-Jiménez M, Álvarez-Cienfuegos J
… +33 more, López-Hernández N, Rodríguez-Campello A, Tejada-Meza H, López-Mesonero L, Albert-Lacal L, Freijo-Guerrero MM, Tarruella-Hernández D, Flores A, Cabezas-Rodríguez JA, Fernández-Vidal JM, Martínez-Domeño A, Pérez de la Ossa N, Ramos-Pachón A, Aguilera-Simón A, Marín R, Ezcurra-Díaz G, Lambea-Gil Á, Silva Y, Corona-García DJ, Giralt-Steinhauer E, Marta-Moreno J, Vizcaya-Gaona JA, Sanz-Monllor A, Luna A, López Morales M, Ustrell X, Moniche F, Solà-Roca J, Wang X, Anderson CS, Prats-Sánchez L, Martí-Fàbregas J, HOPE Study Group
JAMA Neurol
· 2026 Jun · PMID 42258192
·
Full text
IMPORTANCE: Optimal blood pressure (BP) management after successful endovascular therapy for acute ischemic stroke remains uncertain, as intensive lowering has shown no benefit or potential harm in prior trials. OBJECTIV...IMPORTANCE: Optimal blood pressure (BP) management after successful endovascular therapy for acute ischemic stroke remains uncertain, as intensive lowering has shown no benefit or potential harm in prior trials. OBJECTIVE: To determine whether a reperfusion-guided systolic BP control strategy improves functional outcomes compared with guideline-recommended management after successful endovascular therapy for acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS: This investigator-initiated, multicenter, prospective, randomized, open-label clinical trial with blinded end point assessment was conducted among adults with acute ischemic stroke due to anterior circulation large-vessel occlusion who achieved successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score ≥2b) after endovascular therapy at 11 comprehensive stroke centers in Spain between June 14, 2021, and October 1, 2025, with 90-day follow-up. Data analysis was conducted from February 1 to March 12, 2026. INTERVENTIONS: Participants were randomly assigned (1:1) to a reperfusion-guided systolic BP strategy (140-160 mm Hg for mTICI score of 2b; 100-140 mm Hg for mTICI score of 2c/3) or guideline-recommended management (systolic BP <180 mm Hg) for 72 hours using antihypertensive agents or vasopressors as needed. MAIN OUTCOMES AND MEASURES: The primary outcome was a favorable functional outcome, defined as a modified Rankin Scale score of 0 to 2 at 90 days, assessed in the intention-to-treat population. Of 446 enrolled patients, 440 were included in the intention-to-treat analysis (mean age, 75 years; 53% women); 6 were excluded due to withdrawal or consent withdrawal. RESULTS: Among 440 patients (mean [SD] age, 75 [12] years; 233 [53.0%] women), 215 were assigned to the intervention group and 225 to the control group. At 90 days, 129 patients (60.0%) in the intervention group and 106 (47.1%) in the control group achieved a favorable functional outcome (absolute risk difference, 13.3%; 95% CI, 4.1%-22.6%; P = .005). Hemorrhagic transformation occurred in 48 patients (22.3%) in the intervention group and 71 (31.6%) in the control group (odds ratio, 0.62; 95% CI, 0.41-0.95). The rates of symptomatic intracranial hemorrhage (3.5% vs 3.9%) and 90-day mortality (15.4% vs 15.6%) did not differ between groups. Serious adverse events occurred in 34 patients (15.8%) in the intervention group and 27 (12.0%) in the control group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, a reperfusion-guided BP strategy improved functional outcomes and reduced hemorrhagic transformation without increasing major safety events, supporting a tailored approach to postthrombectomy BP management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04892511.