Importance Blood-based biomarkers show high performance for detecting Alzheimer disease (AD) pathology, but evidence on their impact on diagnostic certainty, clinical management, and emotional outcomes in routine care is limited. Objective To determine whether earlier disclosure of plasma phosphorylated tau at threonine 217 (p-tau217) and neurofilament light chain (NfL) increases etiologic diagnostic certainty, influences clinical management, and affects emotional outcomes in individuals evaluated for cognitive symptoms. Design, Setting, and Participants This was a prospective randomized clinical trial conducted at a single memory clinic in Spain between February and October 2024, with 9 months of follow-up. Consecutive new outpatients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or mild dementia without a prior etiologic diagnosis were enrolled. Of 265 eligible participants, 220 were randomized to earlier disclosure of blood-based biomarkers at the 3-month visit or delayed disclosure at the 9-month visit. Intervention Disclosure of blood-based biomarkers for AD pathology (p-tau217) and neurodegeneration (NfL) to the treating neurologist and participant, alongside standard clinical evaluation. Main Outcomes and Measures The primary outcome was the proportion of participants achieving a very high-confidence etiologic diagnosis (>= 90%). Secondary outcomes included changes in clinical management and emotional outcomes (anxiety, depression, perceived stress, and quality of life). Results Among the 220 randomized participants (median [IQR] age, 73 [68-78] years; 123 [55.9%] women), baseline diagnoses were SCD (100 [45.5%]), MCI (68 [30.9%]), and mild dementia (52 [23.6%]). At 3 months, a very high-confidence etiologic diagnosis was achieved in 56 of 112 participants in the earlier-disclosure arm (50.0%) compared with 5 of 108 in the delayed-disclosure arm (4.6%) (P < .001). Diagnostic certainty converged after disclosure in both arms, except among participants with MCI, in whom higher certainty persisted in the earlier-disclosure arm. Earlier disclosure was associated with more frequent initiation of symptomatic AD treatment (16/112 [14.3%] vs 5/108 [4.6%]; difference, 9.7; 95% CI, 1.8 to 17.8; P = .01), fewer planned follow-up neuropsychological reassessments for diagnostic clarification (34/112 [30.4%] vs 57/108 [52.8%]; difference, -22.4; 95% CI, -34.4 to -9.4; P < .001), and more planned discharge from the memory clinic to primary care (35/112 [31.3%] vs 13/108 [12.0%]; difference, 19.2; 95% CI, 8.4 to 29.5; P < .001). Earlier disclosure was not associated with worse emotional outcomes. Conclusions and Relevance In this randomized clinical trial, earlier disclosure of blood-based biomarkers increased etiologic diagnostic certainty and led to earlier, targeted clinical management without increasing emotional distress. These findings support the integration of blood-based biomarkers into memory clinic diagnostic pathways.
This case report describes 11.7-T in vivo human brain magnetic resonance imaging (MRI) of the basal ganglia in 2 healthy volunteers.
Importance Autoimmune cerebellar ataxias are debilitating neurological syndromes that need early detection and intervention. Antineural antibodies are a crucial diagnostic marker, however, lack of knowledge of specific autoantibodies in seronegative patients remains a significant challenge. Objective To pair a cutting-edge, standardized, and rigorous autoantibody detection pathway with global clinical networks to identify novel autoantibody markers of autoimmune ataxia. Design, Setting, and Participants This was a multicenter case series study that included samples of patients with uncharacterized central nervous system disorders, collected between 2015 and 2020 at the University of California, San Francisco (UCSF). A comprehensive screening for additional patients was conducted using a blinded cell-based and tissue-based assay in the French reference center on paraneoplastic neurological syndrome (PNS) and autoimmune encephalitis (AE). Analysis was completed in 2026. Referred participants included those with idiopathic neurological disease with suspicion of autoimmune etiology, controls with noninflammatory disease, and patients with known paraneoplastic autoantibody associations who served as positive controls. Sera and cerebrospinal fluid were collected for autoantibody screening and validation experiments. Exposures Autoantibody screening and candidate antibody validations. Main Outcomes and Measures Detection of autoantibodies and characterization of their usefulness as biomarkers of autoimmune clinical symptoms. Results A total of 35 patients were referred, and 8 patients (median [IQR] age, 65 [47-74] years; 6 male [75%]) were identified to have IgG targeting the intracellular neural protein ribosomal modification protein RimK-like family member A (RIMKLA). Initially, cerebrospinal fluid (CSF) from a UCSF index patient with small cell lung cancer and inflammatory cerebellar ataxia showed a specific staining pattern in the deep nuclei of the cerebellum and brainstem but was seronegative on all known panels of PNS biomarkers. Subsequent screening identified 7 additional patients sharing a similar clinical profile characterized by progressive cerebellar ataxia, diplopia, cranial VI paresis, and sensory and motor abnormalities. The majority of patients (6 of 8 [75%]) had associated small cell lung cancer. All patients also exhibited inflammatory CSF and immunoglobulin synthesis. Conclusions and Relevance In this case series, novel PNS autoantibodies targeting the neural protein RIMKLA were identified in patients with small cell lung cancer and cerebellar ataxia. RIMKLA-IgG represents a new diagnostic biomarker for an intracellular-antigen PNS associated with cerebellar and hindbrain encephalitis with possible peripheral and motor involvement.
Importance Despite more than 30 approved antiseizure medications, many individuals with focal epilepsy continue to experience seizures, indicating a persistent need for novel therapies. Objective To determine efficacy and safety of the novel, potent K V 7 channel opener azetukalner for treatment of focal seizures. Design, Setting, and Participants This phase 3, placebo-controlled randomized clinical trial of azetukalner was conducted over a 12-week double-blind period (November 18, 2022, to February 3, 2026) at 138 sites in North America, South America, Europe, and Asia Pacific. Adults with focal epilepsy experiencing 4 or more focal seizures per month despite stable treatment with 1 to 3 antiseizure medications were enrolled. Data were analyzed using a dataset derived from the database lock dated February 26, 2026. Interventions Participants were randomized 1:1:1 to receive placebo or 15 or 25 mg of azetukalner once daily with the evening meal for 12 weeks with no titration period. Participants completing the double-blind period could enter an open-label extension. Main Outcomes and Measures The primary efficacy end point was median percentage change from baseline in monthly (28-day) focal seizure frequency during the double-blind period for azetukalner vs placebo. Safety and tolerability were assessed by recording treatment-emergent adverse events, changes in clinical laboratory findings, vital signs, and electrocardiogram. Results Of 607 adults screened, 374 participants (190 [50.8%] female; mean [SD] age, 40.0 [12.9] years) were enrolled, randomized and treated with placebo (125 participants), 15-mg azetukalner (125 participants), or 25-mg azetukalner (124 participants). Participants had a baseline median (IQR) of 12.75 (7.56 to 32.97) seizures per month and had previously tried and stopped a median (IQR) of 5 (3 to 8) antiseizure medications. Most (336 participants [89.8%]) were receiving 2 to 3 concomitant antiseizure medications. The median (IQR) change from baseline in monthly seizure frequency was −10.4% (−39.1% to 8.3%) for the placebo group, −34.5% (−61.6% to −12.3%) for the 15-mg azetukalner group ( P < .001 vs placebo), and −53.2% (−77.2% to −28.8%) for the 25-mg azetukalner group ( P < .001 vs placebo). Azetukalner was generally well tolerated, and treatment-emergent adverse events were comparable to those observed in the phase 2b X-TOLE trial. Conclusions and Relevance This randomized clinical trial found that azetukalner demonstrated robust, rapid, and durable reductions in seizure frequency with a favorable benefit-risk profile. Treatment with azetukalner resulted in one of the largest median percentage reductions in seizure frequency vs placebo reported to date in patients with drug-resistant epilepsy, supporting azetukalner as a promising novel antiseizure medication with significant opportunity to improve clinical outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT05614063
