Wu LY, du Toit T, Georgiades T
… +38 more, Stafford EJ, Levine K, Fang ZH, Jasaityte S, Martinez AG, Cullinane P, De Pablo-Fernandez E, Blauwendraat C, Singleton AB, Scholz SW, Traynor BJ, Wood N, Hardy J, Chinnery P, Houlden H, Cain R, Troakes C, Chelban V, Serrano GE, Gveric D, McLean C, Love S, King A, Robinson AC, Roncaroli F, Shepherd C, Halliday G, Parkkinen L, Morris CM, Smith C, Beach TG, Gentleman S, Warner TT, Lashley T, Jaunmuktane Z, Real R, Morris HR, Global Parkinson’s Genetic Program (GP2)
JAMA Neurol
· 2026 Jun · PMID 42258190
·
Full text
IMPORTANCE: Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features. OBJECT...IMPORTANCE: Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of in vivo biomarkers, overlapping clinical features, and a delay in the emergence of pathognomonic features. OBJECTIVE: To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multiancestry brain bank cohort. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study on donors enrolled between 1985 and 2024. Included were donors from 11 academic brain banks in the UK, US, and Australia. Among brain donors with available genetic data from participating brain banks, included were individuals with clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. EXPOSURES: Genetic variant carrier status and clinical diagnostic category. MAIN OUTCOMES AND MEASURES: Outcomes included clinical diagnostic accuracy, Lewy body and Alzheimer disease pathology burden, survival, association with genetic variants, and genetically inferred ancestry. RESULTS: Among 5648 brain donors with available genetic data, a total of 3353 eligible donors (mean [SD] age at death, 76.8 [10.6] years; 2072 male [61.8%]) were included. Misdiagnosis rates for movement disorders ranged approximately from 10% to 20%. Clinical diagnoses of dementia with parkinsonism (ie, Parkinson disease dementia and DLB) were more strongly associated with Lewy body pathology than Parkinson disease without dementia (odds ratio [OR], 1.96; 95% CI, 1.30-3.04; P = 7.2 × 10-4). Lewy pathology was identified in 33 of 745 of neurologically normal controls (4.4%). Alzheimer disease copathology was present in 426 of 1064 cases (40.0%) with Lewy body disease. Carriers of the GBA1 variant exhibited greater Lewy body burden compared with noncarriers (OR, 1.94; 95% CI, 1.24-3.03; P = .01) or carriers of the LRRK2 variant (OR, 7.44; 95% CI, 2.16-25.64; P = .01). Pathological diagnoses differed by ancestry, with South Asian donors more likely to have progressive supranuclear palsy pathology and Ashkenazi Jewish donors more likely to have Lewy body disease (χ22 = 35.5; P < .001), independent of GBA1 and LRRK2 variant status. CONCLUSIONS AND RELEVANCE: Findings of this cross-sectional brain bank study highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer disease copathology and ancestry-associated differences in pathology point to the need for biologically informed diagnostic tools. These results suggest supporting the integration of genetically and pathologically stratified approaches, correlating pathology with in vivo biomarkers, for future therapeutic trials.
Inoue M, Hirano T, Fukuda-Doi M
… +32 more, Kawano H, Tanaka K, Sakai N, Koga M, Iwasaki K, Yoshie T, Kamogawa N, Ihara M, Ohta T, Chin M, Kimura N, Kimura K, Tateishi Y, Terasaki T, Hatano T, Kuwashiro T, Yoshimura S, Ueda T, Nagata E, Nagakane Y, Takahashi S, Miyashita F, Sonoda K, Fukuda K, Tanaka K, Une Y, Kobari S, Nagao T, Sasaki M, Yamamoto H, Toyoda K, T-FLAVOR trial Investigators
JAMA Neurol
· 2026 Jun · PMID 42223935
·
Full text
IMPORTANCE: Tenecteplase has advantages over standard-dose alteplase for acute ischemic stroke. A low-dose alteplase regimen (0.6 mg/kg) remains the standard in Japan and is commonly used in several Asian countries. OBJE...IMPORTANCE: Tenecteplase has advantages over standard-dose alteplase for acute ischemic stroke. A low-dose alteplase regimen (0.6 mg/kg) remains the standard in Japan and is commonly used in several Asian countries. OBJECTIVE: To determine whether standard-dose tenecteplase at 0.25 mg/kg achieves a higher rate of recanalization on the initial angiogram than low-dose alteplase at 0.6 mg/kg in patients scheduled for mechanical thrombectomy. It is inevitable to generate evidence required to support potential regulatory approval of tenecteplase in Japan. DESIGN, SETTING, AND PARTICIPANTS: This investigator-initiated, multicenter, randomized, controlled, open-label, superiority trial was conducted from August 19, 2022, through March 13, 2025, with 3-month follow-up and was the first ever to compare tenecteplase (0.25 mg/kg) with alteplase (0.6 mg/kg) for acute ischemic stroke. Participants included patients with large-vessel-occlusion stroke eligible for intravenous thrombolysis within 4.5 hours of symptom onset followed by mechanical thrombectomy. A total of 221 patients were randomized and 218 who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). These data were analyzed from July 2025 to December 2025. INTERVENTIONS: Patients were randomly assigned in a 1:1 ratio to receive either intravenous tenecteplase or alteplase. MAIN OUTCOMES AND MEASURES: The primary outcome was substantial reperfusion (modified Treatment in Cerebral Ischemia grade 2b to 3 or no retrievable thrombus) on the initial angiogram. Secondary outcomes included the 90-day modified Rankin Scale. Safety outcomes were symptomatic intracranial hemorrhage within 24 to 36 hours and mortality at 90 days. RESULTS: A total of 218 patients (mean [SD] age, 77.1 [12.0] years; 92 female and 126 male) who received trial drugs were included in the full analysis set (107 tenecteplase; 111 alteplase). Substantial reperfusion occurred in 10.3% of the standard-dose tenecteplase group vs 3.6% of the low-dose alteplase group (absolute difference, 6.5 percentage points; 90% CI, 0.89-12.1), meeting the prespecified success criterion. The estimated common odds ratio for a shift toward better 90-day functional outcome with tenecteplase was 1.47 (95% CI, 0.92-2.35). Rates of symptomatic intracranial hemorrhage (2.8% vs 1.8%) and mortality (6.5% vs 9.9%) were similar between tenecteplase and alteplase groups. CONCLUSIONS AND RELEVANCE: In this study, standard-dose tenecteplase (0.25 mg/kg) prior to thrombectomy resulted in a higher rate of early substantial reperfusion compared with low-dose alteplase (0.6 mg/kg), with comparable functional and safety outcomes. Standard-dose tenecteplase is a promising thrombolytic option in regions where low-dose alteplase is currently the standard of care. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: 051210055.
Algeciras-Schimnich A, Bornhorst JA, Figdore DJ
… +14 more, Rea Reyes RE, Ashrafzadeh-Kian S, Wilson R, Burkett BJ, Johnson DR, Botha H, McCarter SJ, Day GS, Graff-Radford J, Ramanan VK, Jack CR, Johnson SC, Zetterberg H, Petersen RC
JAMA Neurol
· 2026 Jun · PMID 42223932
·
Full text
Chen L, Liu Q, Pei L
… +25 more, Geng H, Liu Y, Yang Z, Ding M, Shen R, Chen M, Lu J, You D, Wu X, Zhou J, Hu L, Guo B, Sun S, Chen F, Zhao Z, Zhai Y, Chen Z, Li Z, Yao W, Feng H, Lu C, Liu Y, Shi J, Guo J, Sun J
JAMA Neurol
· 2026 May · PMID 42189557
·
Full text
IMPORTANCE: Postherpetic neuralgia (PHN) is a refractory neuropathic pain condition with limited therapeutic options. Although electroacupuncture has demonstrated potential analgesic effects, high-quality evidence from r...IMPORTANCE: Postherpetic neuralgia (PHN) is a refractory neuropathic pain condition with limited therapeutic options. Although electroacupuncture has demonstrated potential analgesic effects, high-quality evidence from rigorous randomized clinical trials remains limited. OBJECTIVE: To determine whether electroacupuncture reduces pain severity compared with sham electroacupuncture and evaluate its safety in patients with PHN. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized, sham-controlled clinical trial took place at 7 tertiary hospitals in China and enrolled participants from October 2020 to July 2022, with the last follow-up in September 2022. Data analyses were performed from August to December 2025. Participants with PHN aged 45 to 75 years and moderate to severe pain (11-point Numeric Rating Scale [NRS-11] score ≥4) were recruited. Of 1072 patients screened, 624 were excluded. The remaining 448 participants were randomized to electroacupuncture (n = 225) or sham electroacupuncture (n = 223); 383 participants (85.49%) completed the trial. INTERVENTION: Twenty sessions of electroacupuncture or sham electroacupuncture over 4 weeks, followed by a 4-week posttreatment follow-up. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in the NRS-11 scores from baseline to week 4, with responders defined as participants achieving a 30% or more reduction in NRS-11 scores. RESULTS: Of 448 participants, the mean (SD) age was 63.19 (9.26) years, 233 (52.01%) were male, and 215 were female (47.99%). At week 4, the electroacupuncture group had a greater decrease in the NRS-11 scores (-1.52) than the sham electroacupuncture group (-0.99) with an adjusted mean difference of -0.53 (95% CI, -0.61 to -0.43; P < .001), and the responder rate was significantly higher in the electroacupuncture group (46.68%) than in the sham electroacupuncture group (24.28%) (adjusted risk difference, 22.40%; 95% CI, 13.02%-31.79%; P < .001). These treatment benefits persisted through a 1-month follow-up; no clinically significant adverse events were observed. CONCLUSIONS AND RELEVANCE: Among patients with PHN in this study, electroacupuncture provided a statistically significant reduction in pain severity, increased responder rates, and improved pain-related functional outcomes. These benefits suggest that electroacupuncture may be a useful nonpharmacological option for integrated management of PHN. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560361.
Kiel S, Wainwright KL, Angermaier A
… +7 more, Chenot JF, Wischmann HA, Schulz RS, Filser PJ, Flöel A, Kurth T, von Podewils F
JAMA Neurol
· 2026 May · PMID 42189536
·
Full text
IMPORTANCE: Incorporating teleneurology into primary care aimed to improve access to neurological care in a rural region in Germany. A telemedicine network connecting neurologists, general practitioners (GPs), and patien...IMPORTANCE: Incorporating teleneurology into primary care aimed to improve access to neurological care in a rural region in Germany. A telemedicine network connecting neurologists, general practitioners (GPs), and patients was established. OBJECTIVE: To determine whether teleneurology services in rural primary care increased the proportion of patients with neurological symptoms managed solely in general practice. DESIGN, SETTING, AND PARTICIPANTS: The NeTKoH study (Neurological Teleconsultation With General Practitioners to Strengthen Specialist Care in Western Pomerania, Germany) was a stepped-wedge cluster randomized clinical trial conducted from January 1, 2021, through July 31, 2025, to compare teleconsultations vs standard care. Patients were continuously approached and eligible if they were aged 18 years or older and presented at one of 41 participating GP practices in northeast Germany with symptoms for which a neurological consultation was deemed necessary. The duration of patient follow-up was 3 months. Data analysis was conducted from January to July 2025. INTERVENTION: Practices were equipped with a telemedicine system to enable a video conference between the GP and patient on 1 side and a neurologist on the other side to obtain immediate neurological assessment and guide further care decisions. MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of patients who continued to be managed solely within general practice. RESULTS: Between October 15, 2021, and October 25, 2024, 986 patients were enrolled (intervention: 517 patients; control: 469 patients); 3 of these patients were excluded, leaving 983 patients for analysis (605 [61.5%] female; median [range] age, 55 [18-90] years). Teleconsultations, compared with standard care, resulted in fewer patients managed solely within general practice (38.3% vs 50.7%; adjusted odds ratio, 0.58; 95% CI, 0.38-0.88). Referrals to neurologists decreased with teleconsultations compared with standard care (36.4% vs 41.4%), while referrals to other specialists (11.9% vs 4.7%) and hospitals (12.8% vs 2.6%) increased. No significant differences were observed in quality of life or health status. Adherence to recommendations was lower in the intervention phase. At follow-up, more than half of the patients in either group were still managed solely in general practice. CONCLUSIONS AND RELEVANCE: This stepped-wedge cluster randomized clinical trial suggests that neurological teleconsultations in general practice may have helped triage patients (eg, to other specialists or hospitals) and therefore contributed to improved medical care, particularly in structurally underserved areas; however, an immediate reduction in the use of secondary care was not found. The inability to blind GPs to the randomization may have introduced selection effects, which should be considered in future studies. TRIAL REGISTRATION: German Clinical Trials Register Identifier: DRKS00024492.
Gilbert DL, Atkinson SD, Kim DJB
… +9 more, Miller MM, Rice PM, Flatt JA, Karkanias GB, Munschauer FE, Bittman RM, Wanaski SP, Cunniff TM, Tomczak KK
JAMA Neurol
· 2026 May · PMID 42189524
·
Full text
IMPORTANCE: Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates. OBJECTIVE: To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 r...IMPORTANCE: Current Tourette syndrome (TS) pharmacotherapy is hindered by adverse effects and high discontinuation rates. OBJECTIVE: To evaluate the safety and maintenance of effect of ecopipam, a selective dopamine D1 receptor antagonist, for up to 24 weeks for TS. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was a phase 3, double-blind, placebo-controlled, randomized withdrawal study conducted between January 31, 2023, and February 4, 2025. Participants were enrolled at 77 sites in 12 countries. Individuals 6 years and older with TS were eligible. INTERVENTION: In the 12-week, open-label period, ecopipam was titrated over 3 to 4 weeks (target dose, 1.8 mg/kg per day). Responders (≥25% improvement in Yale Global Tic Severity Scale Total Tic Score [YGTSS-TTS] at weeks 8 and 12) were randomized to continue ecopipam or taper to placebo for the 12-week double-blind period. MAIN OUTCOMES AND MEASURES: Time to relapse (≥50% loss of open-label period YGTSS-TTS improvement) in participants aged 6 to 18 years (primary) and adults (exploratory). RESULTS: The trial enrolled 216 participants (n = 167 [77.3%] pediatric; 146 [67.6%] male and 70 [32.4%] female) to the open-label ecopipam period. Of these, 43 pediatric participants (mean [SD] age, 14.3 [5.5] years) and 8 adult participants were randomized to receive ecopipam; 47 pediatric (mean [SD] age, 14.0 [5.8] years) and 6 adult participants were randomized to receive placebo. Ecopipam significantly reduced the relapse risk vs placebo in pediatric participants (hazard ratio [HR], 0.47; 95% CI, 0.26-0.84; P = .008; n = 90). In adults, the effect was directionally similar (HR, 0.51; 95% CI, 0.11-2.30; P = .37; n = 14) but not significant. The most frequently reported adverse events with ecopipam (open-label and double-blind periods) were somnolence (n = 24 [11.1%]), anxiety (n = 21 [9.7%]), headache (n = 21 [9.7%]), insomnia (n = 19 [8.8%]), tic (n = 17 [7.9%]), and fatigue (n = 14 [6.5%]). Ecopipam did not have a clinically meaningful impact on weight, metabolic parameters, or psychiatric scale measures. Drug-induced movement disorders were not observed. CONCLUSIONS AND RELEVANCE: Ecopipam maintained clinically meaningful TS symptom improvements and was well tolerated for up to 24 weeks. Adverse events primarily affected the central nervous system. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05615220.
Salvadó G, Horie K, Barthélemy NR
… +15 more, Schindler SE, Janelidze S, Orduña Dolado A, Bali D, Perrin RJ, Morris JC, Benzinger TLS, Gordon BA, Stomrud E, Mattsson-Carlgren N, Palmqvist S, Vogel JW, Bateman RJ, Ossenkoppele R, Hansson O
JAMA Neurol
· 2026 May · PMID 42189519
·
Full text
IMPORTANCE: Biological staging of Alzheimer disease (AD) can improve diagnostic accuracy and prognostic assessment. However, existing approaches often require invasive procedures and specialized infrastructure, limiting...IMPORTANCE: Biological staging of Alzheimer disease (AD) can improve diagnostic accuracy and prognostic assessment. However, existing approaches often require invasive procedures and specialized infrastructure, limiting their routine clinical use. OBJECTIVE: To develop and validate a plasma-based biological staging model that closely mirrors an amyloid and tau positron emission tomography (PET)-based staging system. DESIGN, SETTING, AND PARTICIPANTS: This observational longitudinal study included the research BioFINDER-2 cohort as the main cohort and the Knight Alzheimer Disease Research Center (ADRC) cohort as an independent validation cohort, with data acquired from November 2019 to January 2025 and from September 2007 to March 2020, respectively. Participants ranged from cognitively unimpaired (CU) to experiencing mild cognitive impairment (MCI) and dementia with AD or other neurodegenerative diseases. All individuals had both plasma biomarkers available. A Knight ADRC subsample had neuropathological data available. Data were analyzed from December 2024 to July 2025. EXPOSURES: Plasma endogenously cleaved microtubule-binding region tau containing residue 243 (eMTBR-tau243) and phosphorylated tau at threonine 217 expressed as a percentage of its unphosphorylated form (%p-tau217). MAIN OUTCOME AND MEASURES: The primary outcomes were PET-based biological staging according to the revised Alzheimer's Association criteria, clinical criteria, and biomarker levels assessed cross-sectionally and longitudinally. RESULTS: The BioFINDER-2 main cohort included 872 participants, with an additional 156 participants in the Knight ADRC cohort for independent validation. In the BioFINDER-2 cohort, participants included 383 CU participants, 182 participants with MCI, 151 with AD dementia, and 156 participants with non-AD neurogenerative diseases (mean [SD] age, 72.8 [9.2] years; 438 women [50.2%]; 516 [59.2%] apolipoprotein E [APOE-E4] carriers). A plasma-based model with %p-tau217 and eMTBR-tau243 was derived, which demonstrated high concordance with established PET-based stages (C index, 0.91; 95% CI, 0.90-0.92) and was associated with clinical stage within the AD continuum (C index, 0.84; 95% CI, 0.82-0.86). In the validation cohort, concordance with PET-based stages was high (C index, 0.91; 95% CI, 0.87-0.94), as was concordance with clinical stage (C index, 0.86; 95% CI, 0.82-0.89). Concordance between fluid- and PET-based staging models was higher with this study's %p-tau217 and eMTBR-tau243 model than with a staging model using %p-tau217 alone, especially improving the intermediate or C stage (A+TMOD+) classification. In the neuropathology subsample, plasma staging was strongly aligned with autopsy-confirmed AD pathology using the Alzheimer Disease Neuropathologic Change scale (area under the curve, 0.96; 95% CI, 0.91-1.00). CONCLUSIONS AND RELEVANCE: In this longitudinal study, a plasma-based biological staging model incorporating %p-tau217 and eMTBR-tau243 showed strong concordance with PET-based staging, correlated with clinical severity and biomarker progression, and aligned with neuropathological categorization. This scalable, minimally invasive approach could facilitate broader implementation of biological staging in clinical practice and could enhance participant selection for disease-modifying treatments and clinical trials.
Cavaillès C, Danilevicz IM, Vidil S
… +7 more, Fayosse A, Chen M, van Hees V, Kivimäki M, Dugravot A, Singh-Manoux A, Sabia S
JAMA Neurol
· 2026 May · PMID 42149581
·
Full text
IMPORTANCE: Disruptions in the sleep-wake cycle have been reported in the preclinical period of dementia; whether they contribute to dementia prediction remains unclear. OBJECTIVE: To examine associations of acceleromete...IMPORTANCE: Disruptions in the sleep-wake cycle have been reported in the preclinical period of dementia; whether they contribute to dementia prediction remains unclear. OBJECTIVE: To examine associations of accelerometer-derived sleep-wake cycle metrics with incident dementia and their contribution to dementia risk prediction in models containing age and known risk factors. DESIGN, SETTING, AND PARTICIPANTS: This study included 2 prospective UK population-based cohort studies: (1) UK Biobank (derivation study) and (2) Whitehall II (validation study). A UK Biobank accelerometer substudy was undertaken from 2013 to 2015, yielding accelerometer data on 103 278 participants. A Whitehall II accelerometer substudy was undertaken from 2012 to 2013 that provided data on 4267 participants. Analyses were performed between August 2024 and November 2025. Included participants were 60 years and older, without dementia, and with valid accelerometer and covariate data. EXPOSURES: Thirty-six accelerometer-derived sleep-wake cycle metrics were extracted. A machine learning approach identified and combined metrics predicting dementia risk. MAIN OUTCOME AND MEASURE: Incident all-cause dementia, ascertained from electronic health records. RESULTS: Analyses were based on 53 448 UK Biobank participants (mean [SD] age, 67.5 [4.2] years; 28 448 female [54.2%]; mean [SD] follow-up, 7.8 [1.1] years) and 3965 Whitehall II participants (mean [SD] age, 69.4 [5.7] years; 1025 female [25.9%]; mean [SD] follow-up, 10.6 [2.4] years). In UK Biobank, 9 sleep-wake cycle metrics were combined in 2 components. Higher values in component 1 represented shorter durations and less frequent bouts of moderate to vigorous physical activity, more time in low-intensity activity, lower diversity of activity intensities, and higher probabilities to transition from activity to rest during daytime. Higher component 2 corresponded to more extreme sleep durations, longer wake bouts during sleep, lower probabilities to transition from wake to sleep, and earlier waking time. Both components were associated with higher dementia risk (component 1: hazard ratio [HR], 1.43; 95% CI, 1.33-1.54; component 2: HR, 1.10; 95% CI, 1.04-1.17) and improved prediction of a model including sociodemographic, behavioral, and health-related factors (increase in C index = 0.018; 95% CI, 0.011-0.025). Results were confirmed in the Whitehall II cohort study. Compared with an age-only prediction model, adding the components led to an increase in C index equivalent to that for APOE genotype. CONCLUSIONS AND RELEVANCE: Results of this cohort study show that accelerometer-derived sleep-wake cycle measures were associated with dementia, and made a modest, statistically significant contribution to its prediction. Future studies should evaluate their clinical utility as scalable markers alongside established predictors for early identification of individuals at risk of dementia.
Hoppen MI, Königs M, Teunissen CE
… +4 more, Verberk IMW, Twisk J, Oosterlaan J, Vijverberg EGB
JAMA Neurol
· 2026 May · PMID 42149575
·
Full text
IMPORTANCE: Former professional soccer players have increased risk of neurodegenerative disease, potentially due to cumulative exposure to repetitive head impacts such as heading. However, the acute effects of heading on...IMPORTANCE: Former professional soccer players have increased risk of neurodegenerative disease, potentially due to cumulative exposure to repetitive head impacts such as heading. However, the acute effects of heading on neural integrity remain unclear. OBJECTIVE: To assess the acute association of real-life heading with blood biomarkers of neural damage before and after soccer matches. DESIGN, SETTING, AND PARTICIPANTS: In this prospective population-based case-control study, soccer players participated in organized matches (August-December 2024). Blood samples were collected prematch and immediately and delayed postmatch (<1 and 24-48 hours, respectively). Video analysis quantified heading exposure, including frequency and intensity. Exercise intensity was monitored using local position monitoring and heart rate analysis. Players from higher-level amateur soccer competitions were recruited through communication channels of the Royal Dutch Football Association and screened for eligibility. Inclusion criteria included the following: male sex, age older than 18 years, and no history of a neurological condition. EXPOSURE: Real-life heading exposure during a single amateur soccer match. MAIN OUTCOMES AND MEASURES: Blood biomarkers of neural damage were measured and included the following: phosphorylated tau 217 (p-tau217), brain-derived tau (BD-tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), S100B calcium-binding protein (S100B), and neuron-specific enolase (NSE). The main outcome was the association between heading exposure and change in biomarker concentration, assessed with linear mixed models while correcting for exercise intensity. RESULTS: A total of 389 soccer players were screened for eligibility. Among the 302 players participating in 1 of the 11 matches (mean [SD] age, 24.6 [5.2] years), 216 (72%) had heading exposure. Mean (SD) exposure was 2.0 (2.1) headers per player per match, and 48% of players had high-impact heading exposure (ball trajectories >20 m; 80 players [26%] with exposure to a single high-impact header; 65 players [22%] with exposure to multiple high-impact headers). Players exposed to heading showed significantly greater immediate postmatch increases in S100B concentration (n = 299, P = .03; Cohen d = 0.29) compared with unexposed players. Exposure to more headers was associated with greater increases in S100B (n = 299, P = .02; Cohen d = 0.07 per header) and p-tau217 concentration (n = 296, P = .01; Cohen d = 0.09 per header). High-impact headers were also associated with greater increases in p-tau217 (n = 148, P = .03; Cohen d = 0.40) and S100B concentration (n = 149, P = .02; Cohen d = 0.43) compared with no exposure. Observed biomarker elevations normalized within 24 to 48 hours. No other significant associations were found. Results were robust to sensitivity analysis adjusting for blood volume. CONCLUSION AND RELEVANCE: Findings of this case-control study show that soccer heading was associated with acute increases in blood biomarkers of neural damage, including dose-response relationships. These findings suggest that amateur-level heading may acutely affect neural integrity.
Urso D, Giannoni-Luza S, Giannelli T
… +3 more, Brayne C, Ray N, Logroscino G
JAMA Neurol
· 2026 May · PMID 42113545
·
Full text
IMPORTANCE: Reliable global estimates of the incidence and prevalence of dementia with Lewy bodies (DLB) are lacking, limiting understanding of its epidemiology and burden. OBJECTIVE: To estimate pooled incidence and pre...IMPORTANCE: Reliable global estimates of the incidence and prevalence of dementia with Lewy bodies (DLB) are lacking, limiting understanding of its epidemiology and burden. OBJECTIVE: To estimate pooled incidence and prevalence of DLB from population-based studies worldwide, overall and by age and sex. DATA SOURCES AND STUDY SELECTION: PubMed, Embase, and Scopus were systematically searched from inception to October 22, 2024, for population-based studies reporting DLB incidence and/or prevalence based on validated diagnostic criteria. DATA EXTRACTION AND SYNTHESIS: Three reviewers independently screened studies, extracted data, and assessed risk of bias according to PRISMA guidelines. Incidence and prevalence estimates were pooled using random-effects meta-analysis. Subgroup and sensitivity analyses explored variation by age, sex, and study design. MAIN OUTCOMES AND MEASURES: Incident and prevalent DLB cases defined by consensus, Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases diagnostic criteria, with denominators based on census or author-defined population at risk. RESULTS: From 2520 records screened, 16 population-based studies were included and 12 contributed to meta-analyses. In individuals 65 years or older, pooled incidence was 46.85 per 100 000 person-years (95% CI, 23.78-92.30) and pooled prevalence 352.26 per 100 000 population (95% CI, 112.25-1099.79). In individuals younger than 65 years, pooled incidence was 0.34 per 100 000 person-years (95% CI, 0.14-0.83) and prevalence 2.52 per 100 000 population (95% CI, 1.43-4.44). Incidence was higher in males (5.45; 95% CI, 4.13-7.19) than females (4.32; 95% CI, 2.48-7.52). Across all ages, pooled crude incidence was 4.79 (95% CI, 3.90-5.88). Only 1 study reported all-age prevalence (19.13; 95% CI, 15.38-23.51). Between-study heterogeneity was high (I2 ≥ 85%). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis of population-based studies, clinically diagnosed DLB was uncommon, likely reflecting underdiagnosis and diagnostic insensitivity. Reported incidence and prevalence rose steeply with age, were higher in men, and varied widely across settings. These findings provide a robust reference for future epidemiologic research and public health planning, underscoring the need for standardized diagnostic approaches and inclusion of underrepresented populations to refine global burden estimates.
Balck A, Vollstedt EJ, Westenberger A
… +14 more, Lange LM, Trinh J, Kasten M, Lohmann K, Brüggemann N, Trenkwalder C, Mollenhauer B, Alcalay R, Galvelis KG, Beck JC, Bauer P, Klein C, König IR, Global Parkinson’s Genetics Program (GP2), the ROPAD Study Group, and the PDGENEration Study
JAMA Neurol
· 2026 May · PMID 42113543
·
Full text
Virameteekul S, Bonini I, Campese N
… +6 more, Mahlknecht P, Tan M, Poewe W, Noyce AJ, Fanciulli A, de Pablo-Fernández E
JAMA Neurol
· 2026 May · PMID 42081229
·
Full text
IMPORTANCE: Pure autonomic failure (PAF) can be the prodromal presentation of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), although phenoconversion rates and predictors have...IMPORTANCE: Pure autonomic failure (PAF) can be the prodromal presentation of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), although phenoconversion rates and predictors have not been systematically reported. OBJECTIVE: To estimate phenoconversion rates for MSA, PD, and DLB separately and grouped as central α-synucleinopathies and identify clinical predictors of phenoconversion in patients with PAF. DATA SOURCES: PubMed and Embase databases from inception to June 2025. STUDY SELECTION: Longitudinal studies including patients with confirmed PAF reporting data on incidence and/or predictors of phenoconversion. DATA EXTRACTION AND SYNTHESIS: Studies were screened and data extracted by 2 independent investigators according to PRISMA guidelines. A meta-analysis was performed using generic inverse-variance random-effects models. MAIN OUTCOMES AND MEASURES: PD, DLB, MSA, and central α-synucleinopathy phenoconversion incidence rates as per 100 person-years were the main outcomes. Incidence rates were log transformed and pooled using a random-effects meta-analysis. Clinical predictors of phenoconversion were reported as secondary outcomes. Prediction intervals and meta-regression explored study-level moderators. RESULTS: A total of 9 studies comprising 900 individuals with PAF (mean [SD] age at onset, 63.1 [4.3] years; 63.8% male) were included. During the mean (SD) 6.4 (2.0) years of follow-up, 270 of 900 individuals with PAF (30%) experienced phenoconversion to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years (95% CI, 3.79-6.85; approximately 5% per year). Phenoconversion rates for MSA (pooled incidence rate, 1.96; 95% CI, 1.29-2.99) were highest in the first years of follow-up, whereas Lewy body disorders showed more constant phenoconversion rates (DLB pooled incidence rate, 1.56; 95% CI, 0.94-2.61; PD pooled incidence rate, 1.35; 95% CI, 0.75-2.41). Hyposmia was the only predictor with diagnostic value to distinguish between those with phenoconversion to PD and DLB (hyposmia pooled risk ratio, 1.88; 95% CI, 1.26-2.97) and MSA, although rapid eye movement sleep behavior disorder (RBD) and subtle motor signs were consistent predictors of phenoconversion to any central α-synucleinopathy. Heterogeneity was partly explained by follow-up duration. CONCLUSIONS AND RELEVANCE: Findings of this systematic review and meta-analysis suggest that PAF may be a prodromal presentation of PD, DLB, or MSA with phenoconversion incidence rates similar to those of RBD. A combination of clinical (RBD, subtle motor signs, hyposmia) and in-development biomarkers may help refine the phenoconversion trajectories of people with PAF providing an invaluable opportunity for early diagnosis and intervention.