Salvadó G, Janelidze S, Bali D
… +29 more, Dolado AO, Therriault J, Brum WS, Pichet Binette A, Stomrud E, Mattsson-Carlgren N, Palmqvist S, Coomans EM, Teunissen CE, van der Flier WM, Rahmouni N, Benzinger TLS, Gispert JD, Blennow K, Doré V, Feizpour A, Rowe CC, Alcolea D, Fortea J, Villeneuve S, Johnson SC, Rosa-Neto P, Petersen RC, Jack CR, Schindler SE, Suárez-Calvet M, Ossenkoppele R, Hansson O, ADNI, ALFA, and PREVENT-AD Study Groups
JAMA Neurol
· 2025 Nov · PMID 40952756
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IMPORTANCE: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. O...IMPORTANCE: Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. OBJECTIVE: To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). EXPOSURES: Plasma p-tau217 levels measured by immunoassay. MAIN OUTCOME AND MEASURES: Aβ status, determined by CSF or Aβ PET biomarkers. RESULTS: Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). CONCLUSIONS AND RELEVANCE: The findings highlight the potential of plasma p-tau217 as a stand-alone test-or when used in a sequential 2-step approach alongside PET or CSF testing-as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.
Starr PA, Shivacharan RS, Goldberg E
… +47 more, Tröster AI, House PA, Giroux ML, Hebb AO, Whiting DM, Leichliter TA, Ostrem JL, Metman LV, Sani S, Karl JA, Siddiqui MS, Tatter SB, Haq IU, Machado AG, Gostkowski M, Tagliati M, Mamelak AN, Okun MS, Foote KD, Moguel-Cobos G, Ponce FA, Pahwa R, Lyons K, Buetefisch CM, Gross RE, Luca CC, Jagid JR, Revuelta GJ, Takacs I, Pourfar MH, Mogilner AY, Duker AP, Mandybur GT, Rosenow JM, Zadikoff C, Khandhar SM, Sedrak M, Phibbs FT, Neimat J, Durphy J, Ramirez-Zamora A, Pilitsis JG, Uitti RJ, Wharen R, Park MC, Vitek JL, INTREPID Study Group
JAMA Neurol
· 2025 Nov · PMID 40952750
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IMPORTANCE: The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for th...IMPORTANCE: The Implantable Neurostimulator for the Treatment of Parkinson's Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). OBJECTIVE: To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson's Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. INTERVENTION: Bilateral STN-DBS for moderate to advanced PD. MAIN OUTCOMES AND MEASURES: Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. RESULTS: A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P < .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P < .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P < .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P < .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P < .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P < .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P < .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. CONCLUSIONS AND RELEVANCE: Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.
Barbuto S, Lee S, Stein J
… +4 more, Kuo SH, Quinn L, Spinner M, Stern Y
JAMA Neurol
· 2025 Nov · PMID 40946705
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IMPORTANCE: Clinical practice guidelines advise balance training for cerebellar ataxia, but little is known regarding high-intensity aerobic exercise. OBJECTIVE: To compare home high-intensity aerobic training to home ba...IMPORTANCE: Clinical practice guidelines advise balance training for cerebellar ataxia, but little is known regarding high-intensity aerobic exercise. OBJECTIVE: To compare home high-intensity aerobic training to home balance training on improvements of ataxia symptoms using the Scale for the Assessment and Rating of Ataxia (SARA). DESIGN, SETTING, AND PARTICIPANTS: This assessor-masked randomized clinical trial was conducted between January 1, 2021, and September 1, 2024, through home training, with in-person assessments at a single ataxia care center in a large urban US city. Individuals with various cerebellar ataxia types were eligible for inclusion. Data analysis was performed from November 2024 to February 2025. INTERVENTIONS: Individuals in the aerobic group trained for 30 minutes/session, 5 times/week, at up to 85% predicted maximum heart rate. Individuals in the balance group performed 30 minutes of balance exercises of varying difficulty 5 times/week. Participants were given study support of biweekly phone calls for only the first 6 months of this 12-month study. MAIN OUTCOMES AND MEASURES: The primary outcome was SARA score to measure ataxia symptoms (range, 0-40 points, with higher scores indicating more ataxia). Secondary outcomes included number of adverse events, training adherence, balance measures, gait speed, quality of life, fatigue, and fitness levels (assessed via V̇o2max). Assessments were conducted at baseline and at 6, 9, and 12 months. RESULTS: A total of 114 individuals with various cerebellar ataxia types were approached: 52 individuals declined participation or did not meet inclusion criteria, while 62 individuals were enrolled. The 62 participants included 29 women (46.8%), with a mean (SD) age of 54.4 (12.9) years and mean (SD) SARA score of 12.1 (4.1) points. Linear mixed-effects model analysis revealed that the home aerobic group had significantly larger improvement in outcomes than the balance group, particularly for SARA score (β, -1.53; 95% CI, -2.44 to -0.61; P = .001), fatigue (β, -9.38; 95% CI, -15.1 to -3.7; P = .001), and Vo2max (β, 4.26; 95% CI, 2.1-6.4; P < .001). At 6 months, the aerobic and balance groups had changes in SARA scores of -2.4 points (95% CI, -3.1 to -1.80) and -0.9 points (95% CI, -1.5 to -0.2), respectively. For the aerobic group, individuals who continued training maintained benefits in SARA score (change from baseline, -3.81 points; 95% CI, -2.2 to -5.4), whereas those who limited or stopped training had benefits trend back to baseline levels (change from baseline, 0.4 points; 95% CI, -0.4 to 1.2) at 1 year. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home high-intensity aerobic training improved ataxia symptoms, fatigue, and aerobic fitness more than dose-matched home balance training among individuals with cerebellar ataxias. Individuals in the aerobic group who continued to train regularly maintained benefits at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05002218.
Kim B, Blam K, Elser H
… +10 more, Xie SX, Van Deerlin VM, Penning TM, Weintraub D, Irwin DJ, Massimo LM, McMillan CT, Mechanic-Hamilton D, Wolk DA, Lee EB
JAMA Neurol
· 2025 Nov · PMID 40920417
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IMPORTANCE: Exposure to fine particulate matter air pollution (PM2.5) may increase risk for dementia. It is unknown whether this association is mediated by dementia-related neuropathologic change found at autopsy. OBJECT...IMPORTANCE: Exposure to fine particulate matter air pollution (PM2.5) may increase risk for dementia. It is unknown whether this association is mediated by dementia-related neuropathologic change found at autopsy. OBJECTIVE: To examine associations between PM2.5 exposure, dementia severity, and dementia-associated neuropathologic change. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data associated with autopsy cases collected from 1999 to 2022 at the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Data were analyzed from January to June 2025. Participants included 602 cases with common forms of dementia and/or movement disorders and older controls after excluding 429 cases with missing data on neuropathologic measures, demographic factors, APOE genotype, or residential address. EXPOSURES: One-year mean PM2.5 concentration prior to death or prior to last Clinical Dementia Rating Sum of Boxes (CDR-SB) assessment was estimated using a spatiotemporal prediction model at residential addresses. MAIN OUTCOMES AND MEASURES: Dementia severity was measured by CDR-SB scores. Ten dementia-associated neuropathologic measures representing Alzheimer disease, Lewy body disease, limbic-predominant age-related transactive response DNA-binding protein (TDP)-43 encephalopathy, and cerebrovascular disease were graded or staged. Linear, logistic, and structural equation models were used to examine the associations between PM2.5, CDR-SB, and neuropathologic measures, adjusting for demographic factors and APOE ε4 allele status. RESULTS: In a total of 602 autopsy cases (median [IQR] age at death, 78 [71-85] years; 328 male [54.5%] and 274 female [45.5%]), higher PM2.5 exposure prior to death was associated with increased odds of more severe Alzheimer disease neuropathologic change (ADNC) (odds ratio, 1.19; 95% CI, 1.11-1.28). In a subset of 287 cases with CDR-SB records (median [IQR] age at death, 79 [72-86] years; 154 [53.7%] male and 133 female [46.3%]), higher PM2.5 exposure prior to CDR-SB assessment was associated with greater cognitive and functional impairment (β = 0.48; 95% CI, 0.22-0.74). Lastly, 63% of the association between higher PM2.5 exposure and greater cognitive and functional impairment was statistically mediated by ADNC (β = 0.30; 95% CI, 0.04-0.53). CONCLUSIONS AND RELEVANCE: In this study, PM2.5 exposure was associated with increased dementia severity and increased ADNC. Population-based studies are needed to better understand this relationship.
Liu Q, Nie X, Vergouwen MDI
… +15 more, Wang Y, He H, Wu J, Yang Y, Mo S, Chen L, Mossa-Basha M, Levitt MR, Edjlali M, Li J, Ren J, Zhao B, Wang S, Liu P, Zhu C
JAMA Neurol
· 2025 Nov · PMID 40920406
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IMPORTANCE: Recent longitudinal studies in patients with unruptured intracranial aneurysms (UIAs) suggested that aneurysm wall enhancement (AWE) on magnetic resonance imaging (MRI) predicts growth and rupture. However, b...IMPORTANCE: Recent longitudinal studies in patients with unruptured intracranial aneurysms (UIAs) suggested that aneurysm wall enhancement (AWE) on magnetic resonance imaging (MRI) predicts growth and rupture. However, because these studies were limited by small sample size and short follow-up duration, it remains unclear whether this radiological biomarker has predictive value for UIA instability. OBJECTIVE: To determine the 4-year risk of instability of UIAs with AWE and investigate whether AWE is an independent predictor of UIA instability. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were obtained from 3 prospective multicenter cohort studies conducted in 83 Chinese centers between January 2017 and December 2024. Included were patients aged 18 to 75 years with at least 1 asymptomatic, saccular UIA greater than or equal to 3 mm. EXPOSURES: All patients had 3-T MRI gadolinium-enhanced aneurysm wall imaging and computed tomography angiography (CTA) at baseline, and CTA at follow-up. MAIN OUTCOMES AND MEASURES: The primary outcome measure was aneurysm growth or rupture (instability) during follow-up. The absolute risk of aneurysm instability in UIAs with circumferential, focal, and no AWE was determined with Kaplan-Meier estimates at 4 years after baseline aneurysm wall imaging. Cox proportional hazards regression was used to investigate AWE as a potential predictor of instability. RESULTS: Of the 1453 patients who had baseline 3-T MRI aneurysm wall imaging, 41 patients were excluded because of loss to follow-up or no follow-up CTA, and 61 patients were excluded because of low-quality CTA. We included 1351 patients (median [IQR] age, 56 [48-63] years; 750 female [56%]) with 1416 UIAs and 4884 aneurysm-years of follow-up. Instability within 4 years occurred in 235 of 1416 UIAs (16.6%). The absolute cumulative risk of instability at 4 years was 36.8% (95% CI, 30.7%-43.0%) in UIAs with circumferential AWE, 17.2% (95% CI, 13.4%-21.1%) in UIAs with focal AWE, and 11.4% (95% CI, 11.9%-16.1%) in UIAs with no AWE. Circumferential AWE predicted 4-year instability (hazard ratio [HR], 3.80; 95% CI, 2.82-5.14) and after adjusting for size ratio, aneurysm location, aneurysm shape, and bifurcation configuration (adjusted HR, 2.21; 95% CI, 1.56-3.13). CONCLUSIONS AND RELEVANCE: Within 4 years after baseline wall imaging, instability occurred in one-third of UIAs with circumferential AWE. These results suggest that MRI aneurysm wall imaging may be used for predicting the risk of aneurysm instability.
Urso D, Giannoni-Luza S, Brayne C
… +2 more, Ray N, Logroscino G
JAMA Neurol
· 2025 Nov · PMID 40920400
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IMPORTANCE: Comprehensive incidence and prevalence rates of frontotemporal dementia are currently not available. OBJECTIVE: To estimate the incidence and prevalence of frontotemporal dementia and its clinical variants in...IMPORTANCE: Comprehensive incidence and prevalence rates of frontotemporal dementia are currently not available. OBJECTIVE: To estimate the incidence and prevalence of frontotemporal dementia and its clinical variants in the overall population and age subgroups. DATA SOURCES AND STUDY SELECTION: We systematically searched PubMed, EMBASE, and Scopus between January 1, 1990, and October 22, 2024, for population-based studies estimating the incidence and/or prevalence of FTD. DATA EXTRACTION AND SYNTHESIS: Studies and data were screened and extracted independently by 2 investigators in accordance with PRISMA guidelines. Incident and prevalent cases together with the population at risk were pooled using random-effects meta-analysis. Differences in heterogeneity by FTD variants and populations at risk were estimated. MAIN OUTCOMES AND MEASURES: Prevalent and incident cases as numerator were based on well-defined clinical criteria. Denominators were derived either from census population data or from author-defined populations at risk. RESULTS: From 1854 screened articles, 32 eligible population-based studies were identified. Sixteen were on prevalence and 22 on incidence reporting FTD measures, including those with estimates for the whole population and for specific age subgroups. Pooled crude incidence for FTD was 2.28 (95% CI, 1.55-3.36) per 100 000 person-years and prevalence, 9.17 (95% CI, 3.59-23.42) per 100 000 people. The behavioral-variant FTD pooled crude incidence was 1.20 (95% CI, 0.67-2.16) per 100 000 person-years and prevalence, 9.74 (95% CI, 2.90-32.73) per 100 000 people. The primary progressive aphasia variant pooled crude incidence was 0.52 (95% CI, 0.35-0.79) per 100 000 person-years and prevalence, 3.67 (95% CI, 3.05-4.43). FTD incidence among individuals younger than 65 years was 1.84 (95% CI, 0.79-4.30) per 100 000 person-years and prevalence, 7.47 (95% CI, 4.13-13.49) per 100 000 people. The denominator based on census data showed less heterogeneity than the population at risk defined by the authors (I2: for incidence, 91.6% vs 97.6%, respectively, and for prevalence, 98.8% vs 99.2%, respectively). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, estimates indicate that FTD is comparable in frequency to dementia with Lewy bodies and occurs at higher rates than progressive supranuclear palsy, corticobasal syndrome, and amyotrophic lateral sclerosis. These results provide a foundation for future research and public health strategy, especially for underrepresented populations, to better comprehend the global burden of FTD. Our findings provide robust pooled estimates of the incidence and prevalence of FTD and its subtypes, offering a foundation for future research and public health planning.
Arthur AS, Jahromi BS, Saphier PS
… +12 more, Nickele CM, Ryan RW, Vajkoczy P, Schirmer CM, Kellner CP, Matouk CC, Arias EJ, Ullman JS, Levitt MR, Hage ZA, Fiorella DJ, MIND Study Investigators and Collaborators
JAMA Neurol
· 2025 Nov · PMID 40892424
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IMPORTANCE: It remains uncertain whether surgical evacuation improves functional outcomes in patients with supratentorial intracerebral hemorrhage (ICH). OBJECTIVE: To compare the safety and efficacy of minimally invasiv...IMPORTANCE: It remains uncertain whether surgical evacuation improves functional outcomes in patients with supratentorial intracerebral hemorrhage (ICH). OBJECTIVE: To compare the safety and efficacy of minimally invasive surgery with the Artemis Neuro Evacuation Device to guideline-based medical management alone for spontaneous supratentorial ICH. DESIGN, SETTING, AND PARTICIPANTS: The MIND open-label, multicenter randomized clinical trial randomized patients with spontaneous supratentorial ICH in a 2:1 ratio to either minimally invasive surgery or medical management alone. Participants were enrolled at 32 participating global sites between February 6, 2018, and August 28, 2023. This article reports on the primary trial outcome. Of 4066 eligible adult patients (aged 18-80 years) with moderate- to large-volume supratentorial ICH (20-80 mL), baseline National Institutes of Health Stroke Scale score of 6 or higher, and Glasgow Coma Scale score between 5 and 15, 154 were randomized to minimally invasive surgery and 82 to medical management. Data were analyzed from February to September 2024. INTERVENTION: Minimally invasive surgery (within 72 hours of symptom onset) plus medical management or medical management alone. MAIN OUTCOMES AND MEASURES: The primary efficacy outcome was 180-day combined death and disability via ordinal modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]). The primary safety outcome was 30-day mortality. RESULTS: Following an independent feasibility analysis prompted by the publication of positive results of a contemporaneous ICH trial, enrollment was stopped early at 236 participants. Overall median (IQR) participant age was 60 (50-70) years, 87 participants (36.9%) were female, 164 (69.5%) had primarily deep bleeds, and 72 (30.5%) had primarily lobar bleeds. Efficacy results of the primary model analysis suggested lack of evidence for the superiority of minimally invasive surgery over medical management (odds ratio [OR], 1.03; 96% CI, 0.62-1.72; P = .45). The adjusted model's mean OR was also nonsignificantly greater than 1 (OR, 1.10; 96% CI, 0.66-1.85; P = .35). By 30 days, 11 participants (7.2%) in the surgery group and 8 (9.8%) in the medical management group died (difference, -2.5%; 95% CI, -11.7% to 4.8%). CONCLUSIONS AND RELEVANCE: In the MIND randomized clinical trial, minimally invasive surgery within 72 hours did not significantly reduce 30-day mortality or improve 180-day disability in patients with supratentorial ICH compared to medical management alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03342664.
Xiao T, Kumar P, Lobbous M
… +4 more, Yogi-Morren D, Soni P, Recinos PF, Kshettry VR
JAMA Neurol
· 2025 Nov · PMID 40892397
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IMPORTANCE: There lacks data clarifying the meningioma risk conferred by depot medroxyprogesterone acetate in the US. OBJECTIVE: To examine the relative risk of meningioma diagnosis in women using depot medroxyprogestero...IMPORTANCE: There lacks data clarifying the meningioma risk conferred by depot medroxyprogesterone acetate in the US. OBJECTIVE: To examine the relative risk of meningioma diagnosis in women using depot medroxyprogesterone acetate and other related progestins. DESIGN, SETTING, AND PARTICIPANTS: This retrospective population-based cohort study used data from TriNetX, a US national database of 68 health care organizations. Data were analyzed from December 2004 to December 2024. The incidence of meningioma diagnosis was compared between treatment groups through propensity-score matched analyses. Participants included a sample of females with use of only 1 of the following progestins/contraceptives: depot medroxyprogesterone acetate, oral medroxyprogesterone acetate, combined oral contraceptives, intrauterine devices, progestin only pills, or subdermal implantable contraceptive. The control group included females without use of these hormonal treatments. Of the 118 289 082 total patients in TriNetX at the time of analysis, 61 588 239 patients were female and eligible. EXPOSURES: Patients were defined using diagnostic codes from the International Classification of Diseases, Current Procedural Terminology, and RxNorm codes within TriNetX. MAIN OUTCOME AND MEASURE: The main outcome was meningioma diagnosis. Relative risks and number needed to harm were calculated. RESULTS: There were 10 425 438 patients that met inclusion criteria with a mean age of 33.4 years at inclusion. After propensity score matching, 88 667 patients with mean age of 26.2 years at inclusion were in the depot medroxyprogesterone acetate group. Use of depot medroxyprogesterone acetate had a relative risk of 2.43 (95% CI, 1.77-3.33) for meningioma diagnosis compared with controls. Notably, this risk was confined for patients with longer than 4 years of exposure or starting the prescription at ages older than 31 years. Oral medroxyprogesterone acetate had increased relative risk of 1.18 (95% CI, 1.10-1.27) compared with controls. No increased risk of meningioma diagnosis was found with any other contraceptive. The number needed to harm for the depot medroxyprogesterone acetate was 1152 patients and 3020 patients for oral medroxyprogesterone acetate. CONCLUSIONS AND RELEVANCE: In this study, women receiving depot medroxyprogesterone acetate had a greater relative risk of subsequent meningioma diagnosis, especially with prolonged exposures and starting the medication at older ages. The high number needed to harm suggests low clinical risk overall.
Insel PS, Mattsson-Carlgren N, Langford O
… +8 more, Caruso VM, Leuzy A, Young CB, Boxer A, Aisen PS, Sperling RA, Mormino EC, Donohue MC
JAMA Neurol
· 2025 Oct · PMID 40853684
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IMPORTANCE: Developing disease-modifying treatments is a priority for Alzheimer disease research. OBJECTIVE: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PE...IMPORTANCE: Developing disease-modifying treatments is a priority for Alzheimer disease research. OBJECTIVE: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023. Recruited from 67 sites in the US, Canada, Australia, and Japan, participants included older individuals (age 65-85 years) who were cognitively unimpaired at screening and underwent an amyloid PET scan. Participants without elevated amyloid PET were included from a companion to the A4 study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. EXPOSURE: 18F-florbetapir PET imaging. MAIN OUTCOMES AND MEASURES: 18F-florbetapir PET imaging was used to classify participants as having elevated amyloid β (Aβ+). Measures of tau included longitudinal plasma p-tau217 and 18F-flortaucipir PET. Cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: A total of 1169 individuals were included from A4 Study and 538 without elevated amyloid PET were included from the LEARN Study. Among these 1707 participants, the baseline mean (SD) age was 71.5 (4.7) years, 1024 (60%) were female, and 683 (40%) male; 1169 participants were Aβ+, and the mean (SD) Mini-Mental State Examination score was 28.8 (1.2). The tau PET substudy included 443 participants; plasma p-tau217 levels were available for 1643 participants. The largest effect size of longitudinal tau PET accumulation at 36 months in Aβ+ participants was in the inferior temporal gyrus. Baseline associations with longitudinal change in PACC score in Aβ+ participants were strongest in the entorhinal cortex (correlation [ρ] = -0.55; 95% CI, -0.63 to -0.45) and plasma p-tau217 levels (ρ = -0.47; 95% CI, -0.56 to -0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent cognitive changes. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ2 = 21.7; P < .001) and were not associated with concurrent cognitive change in the tau PET substudy (ρ = -0.03; 95% CI, -0.23 to 0.16) but were modestly associated with concurrent cognitive changes in the full plasma sample (n = 1119; ρ = -0.24; 95% CI, -0.34 to -0.14). CONCLUSIONS AND RELEVANCE: This study found that tau PET is valuable for both prognostic and real-time tracking of disease progression. Plasma p-tau217 predicts cognitive changes prior to overt cognitive impairment and can efficiently guide participant selection. Imaging-based tau measures may enhance detection of disease-modifying effects and refine therapeutic targets in future Alzheimer disease trials.
Barnard SN, Chen Z, Holmes M
… +6 more, Kanner AM, Hegde M, Kuzniecky R, Lowenstein D, French JA, Human Epilepsy Project (1) Investigators
JAMA Neurol
· 2025 Oct · PMID 40853673
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IMPORTANCE: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains...IMPORTANCE: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. OBJECTIVE: To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. DESIGN, SETTING, AND PARTICIPANTS: The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. EXPOSURE: ASM (variable). MAIN OUTCOMES AND MEASURES: The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). RESULTS: Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21-44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33-3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7-16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8-3.2) than those who did (median, 7.4 months; 95% CI, 4.0-10.7). Those with infrequent pretreatment seizures were 0.30-fold less likely to be treatment resistant than those with very frequent seizures (hazard ratio, 0.30; 95% CI, 0.14-0.64; P = .002; Holm-Bonferroni-corrected P = .006). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (relative risk, 1.78; 95% CI, 1.26-2.52; P = .001). CONCLUSIONS AND RELEVANCE: In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02126774.