Annals of Neurology最新文献

Objective: Aneurysm wall enhancement (AWE) may predict aneurysm growth and rupture in the short-term, but there is a lack of long-term follow-up studies. We aimed to determine whether unruptured intracranial aneurysms (UIAs) with AWE have a higher probability of aneurysm instability during long-term follow-up compared with those without AWE.

Methods: For this longitudinal cohort study, we obtained individual patient data from two international cohorts. We included patients with ≥ 1 untreated UIA who underwent gadolinium-enhanced aneurysm wall imaging and magnetic resonance angiography (MRA) between 2012 and 2016, and had follow-up imaging and/or had a rupture during follow-up. The outcome was aneurysm instability, defined as time to growth, morphological change, or rupture during follow-up. We calculated the 7.5-year probability of aneurysm instability with 95% confidence interval (CI) with the Kaplan-Meier estimator. We used Cox regression survival analysis to calculate the crude hazard ratio (HR) with corresponding 95% CI of AWE for aneurysm instability, and the HR adjusted for age and aneurysm size at baseline.

Results: We included 198 patients (median age = 58 years, interquartile range = 50-68, 139 women, 70%) with 224 aneurysms. Aneurysm instability was observed in 15 of 72 aneurysms (21%) with AWE and 13 of 152 aneurysms (9%) without AWE during a median follow-up duration of 6.8 years (IQR = 3.3-7.9). The 7.5-year probability of instability was 29.2% (95% CI = 14.5%-41.3%) in aneurysms with AWE and 9.3% (95% CI = 2.9%-15.3%) in aneurysms without AWE (crude HR = 4.29, 95% CI = 1.90-9.72, adjusted HR = 5.06, 95% CI = 2.13-12.02).

Interpretation: UIAs with AWE have a higher probability of 7.5-year aneurysm instability compared with those without AWE. ANN NEUROL 2026;99:863-870.

Objective: Plasma biomarkers of Alzheimer's disease (AD) pathology are frequently tested in specialized research settings, which limits the generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers-phosphorylated tau 217 (p-tau₂₁₇), β-amyloid 1-42/1-40 (Aβ₄₂/Aβ₄₀) and p-tau₂₁₇/Aβ₄₂-in a real-world, diverse clinical population with multimorbidities.

Methods: Participants (n = 617; 44% Black/African American; 41% female) were selected from the University of Pennsylvania Medicine BioBank with plasma assayed using Fujirebio Lumipulse. International Classification of Diseases (ICD) Ninth and Tenth Revision codes determined AD dementia (ADD) (n = 43), mild-cognitive impairment (MCI) (n = 140), unspecified/non-AD cognitive impairment (CI) (n = 106), and cognitively normal cases (n = 328), and other medical histories. APOE ε4, body mass index (BMI), metrics of kidney function (eg, estimated glomerular filtration rate [eGFR]), and liver disease were derived from electronic health records. Multivariable models identified factors related to plasma levels. Previously established cutpoints classified AD status ("AD+," "AD-," or "Intermediate").

Results: Plasma p-tau₂₁₇/Aβ₄₂ had the strongest association with known AD-related factors-MCI, ADD, future progression to MCI/ADD, age, and APOE ε4-compared to p-tau₂₁₇ and Aβ₄₂/Aβ₄₀. Plasma p-tau₂₁₇/Aβ₄₂ was also associated with eGFR, diabetes, and history of hearing loss. Importantly, AD-related factors were most frequent/severe for AD+ classification by p-tau₂₁₇/Aβ₄₂, whereas medical morbidities were most frequent/severe for Intermediate classification. Exploratory analyses test p-tau₂₁₇/Aβ₄₂ adjusted for eGFR to eliminate its influence on plasma levels.

Interpretation: In this real-world dataset, we identified effects of multimorbidities on plasma biomarkers, especially kidney function. The p-tau₂₁₇/Aβ₄₂ ratio had low rates of Intermediate classification and may help to account for multimorbidity effects on plasma levels. ANN NEUROL 2026;99:1030-1045.

Objective: This 24-month longitudinal study involving isolated rapid eye movement sleep behavior disorder (iRBD), early-stage Parkinson's disease (PD), and matched healthy control subjects aimed to assess whether acoustic speech features from real-world smartphone calls provide passive progressive biomarkers in synucleinopathies.

Methods: Participants underwent clinical assessments at baseline, 1, and 2 years. Speech was continuously captured during phone calls via a standardized smartphone application, segmented, and analyzed for speech impairment severity end points and key acoustic features of monopitch, vowel articulation, voice quality, and articulation rate. We used linear mixed-effect modeling to estimate speech progression and calculated sample size requirements to demonstrate slowing of progression under anticipated treatment effects.

Results: Over 31,000 phone calls (>1,000 hours) were collected from 71 participants including those with iRBD, PD, and healthy controls. Compared with controls, both individuals with iRBD and PD showed significant declines in speech impairment severity end points based on spectral changes and artificial intelligence-based neural embeddings. The subjects with iRBD also exhibited declines in vowel articulation and articulation rate. For a 2-year neuroprotective trial aiming for 50% drug efficacy, the most efficient sample size estimate based on time-to-event analysis was 74 iRBD and 84 PD participants per arm using the neural embedding end point.

Interpretation: The phone call analysis requiring no patient effort or clinical supervision can detect speech decline in prodromal and early synucleinopathies, providing a potential paradigm shift for clinical trial design and neuroprotective intervention end points. ANN NEUROL 2026;99:935-948.

Objective: Dysautonomia affects many patients with Parkinson's disease and correlates with increased cardiovascular mortality. We describe the frequency and onset time of autonomic dysfunction relative to disease onset in early-onset Parkinson's disease (EOPD) and explore its association with mortality.

Methods: We identified all incident Parkinson cases with motor-symptom onset before age 50 years evaluated at the Mayo Clinic Health System (1990-2022) including sex- and age-matched controls for each patient. Medical record review confirmed clinical diagnosis and assessed the presence and onset of autonomic symptoms, relative to Parkinson onset.

Results: We included 829 patients with EOPD and 829 healthy controls. The median age at disease onset was 42 years (interquartile range [IQR] = 37-46 years). Autonomic symptoms were present in 63.4% of patients, compared with 27.0% of unaffected controls, and proceeded motor symptoms in 91.4%. Forty-seven percent of patients with early-onset Parkinson's disease had constipation, 27.4% had bladder urgency, 19.3% had orthostatic intolerance, and 15.4% had sweat dysfunction. Among male patients, 36.8% had erectile dysfunction. In our EOPD population only, the presence of any autonomic-impairment symptoms correlated with a 2.71-fold increased mortality risk; each additional reported symptom increased the relative mortality risk by 50% (p < 0.001). Patients with constipation or orthostatic intolerance had a 3.22- and 2.78-fold higher mortality than patients without these symptoms.

Interpretation: Autonomic impairment affects 63.4% of patients with EOPD and carries a 3-fold higher mortality risk, which increases with every additional autonomic symptom reported. In our cohort, autonomic symptoms appeared most commonly after motor onset, contrasting with prodromal autonomic impairment seen in late-onset Parkinson's disease (LOPD). ANN NEUROL 2026;99:964-975.

The concept of "normal pressure hydrocephalus" dates back to the description by Hakim and Adams in 1965 of 2 series of patients with enlarged lateral ventricles, high normal cerebral spinal fluid (CSF) pressure and a triad of cognitive impairment, urinary incontinence, and gait apraxia. The validity of this concept is based upon the reversal of its symptoms by a shunting procedure. However, all of these patients had secondary communicating hydrocephalus after previous episodes of meningitis, brain trauma, or subarachnoid hemorrhage. Nevertheless, shunting procedures for "idiopathic normal pressure hydrocephalus" with similar symptoms but no antecedent cause for communicating hydrocephalus became widely performed, although they were not tested by randomized, placebo-controlled trials for their value until a series of recent publications. These trials do not find improvement in either cognitive function or continence after shunting, and show that there is a small (approximately 25%) improvement in gait speed. They also confirm earlier studies that these patients suffer an approximately 10 to 15% incidence of severe adverse events in the first year after shunting, which may further accumulate with time. In the absence of value for shunting in reversing cognitive impairment and incontinence, the entire concept of "idiopathic normal pressure hydrocephalus" is called into question. ANN NEUROL 2026;99:838-843.

Objective: Assess the performance of serum phosphorylated tau 217 (p-tau217) and neurofilament light chain (NfL) in predicting risk of cognitive impairment or phenoconversion to dementia in individuals with iRBD.

Methods: We measured serum p-tau217 and NfL levels by electrochemiluminescence across 4 polysomnographically confirmed iRBD cohorts (n = 300), including individuals who phenoconverted to Parkinson's disease (PD) (n = 51), dementia with Lewy bodies (DLB) (n = 22), and multiple system atrophy (MSA) (n = 5).

Results: Serum p-tau217 levels were increased in individuals with iRBD and cognitive impairment (CI) on testing defined as Montreal Cognitive Assessment <26 or subthreshold parkinsonism. p-Tau217 differentiated individuals with iRBD who developed PD with CI (PD-CI) or DLB from PD phenoconverters with normal cognition (area under curve [AUC] = 0.82; 95% confidence interval, 0.70-0.93) and from iRBD non-phenoconverters with normal cognition (AUC = 0.83; 95% confidence interval, 0.77-0.89). NfL levels did not correlate with cognitive or motor scores and marginally improved p-tau217 performance (AUC = 0.85; 95% confidence interval, 0.78-0.92), but were notably elevated in iRBD individuals who phenoconverted to MSA. Individuals with p-tau217 in the top quartile were 8 times more likely to phenoconvert to PD-CI or DLB compared to the bottom quartile (hazard ratio = 8.30; 95% confidence interval, 2.49-27.65).

Interpretation: Serum p-tau217, but not NfL, is a useful biomarker of cognitive impairment in iRBD that could be integrated into a multimodal prognostic indicator when stratifying risk of phenoconversion. ANN NEUROL 2026;99:912-921.

Objective: The objective of this study was to test the hypothesis that minimally invasive surgery (MIS), an emerging surgical treatment for spontaneous intracerebral hemorrhage (sICH), is associated with better clinical outcomes than open craniotomy with clot evacuation, in a large, nationwide US cohort.

Methods: We performed a retrospective cohort study that included patients with sICH included in the American Heart Association Get With The Guidelines-Stroke registry between January 1, 2011, and December 31, 2021. We excluded patients with a diagnosis of ischemic stroke, subarachnoid hemorrhage, or subdural hemorrhage, and patients transferred to another hospital. The exposure was the type of surgery, classified as either open craniotomy with clot evacuation or MIS (composite of endoscopic evacuation or stereotactic evacuation with fibrinolytic therapy). The primary outcome was in-hospital mortality. Secondary outcomes at discharge included disposition, ambulatory status, and modified Rankin Scale (mRS) score. After overlap-weighted propensity score matching, multiple logistic regression was used to study the association between the type of surgery and outcomes.

Results: Among 564,265 patients with sICH, 7,770 underwent surgical intervention. MIS was performed in 703 patients and open craniotomy was performed in 7,067 patients. In regression analyses, MIS was associated with lower odds of in-hospital mortality (adjusted odds ratio [aOR] = 0.7, 95% confidence interval [CI] = 0.5-0.9), unfavorable discharge (aOR = 0.7, 95% CI = 0.6-0.9), and higher odds of discharge to rehabilitation (aOR = 1.3, 95% CI = 1.1-1.5), but not with functional outcomes.

Interpretation: In this large, representative US cohort of patients with sICH, MIS was associated with reduced in-hospital mortality and better discharge disposition compared to conventional open craniotomy with clot evacuation. ANN NEUROL 2026;99:871-880.

Objective: Dopaminergic imaging is a key biomarker for both the investigation of the biology of Parkinson's disease and related synucleinopathies and the evaluation of potential therapies in clinical trials. This work presents a harmonized approach for quantifying dopaminergic molecular imaging tracers, such as [¹²³I]ioflupane (dopamine transporter scan [DaTscan]) single photon emission computed tomography (SPECT) and [¹⁸F]AV133 positron emission tomography (PET), which assess dopaminergic neuronal loss. The proposed method aims to standardize regional outcome measures using a unified scale called Centamines.

Methods: The Centamines framework comprises 3 analysis levels. Level 1 defines the Centamine scale based on healthy subject data from [¹²³I]ioflupane SPECT (n = 224). Level 2 uses head-to-head data between Tracer X and [¹²³I]ioflupane SPECT to map Tracer X onto the Centamine scale. Level 3 maps additional tracers using prior mappings. A level 2 analysis was performed using [¹²³I]ioflupane SPECT and [¹⁸F]AV133 PET data (n = 68) to convert [¹⁸F]AV133 PET into Centamines.

Results: Level 1 successfully established the Centamine scale using healthy [¹²³I]ioflupane SPECT scans. Level 2 revealed moderate-strong linear correlations (R² = 0.51-0.83) between [¹²³I]ioflupane SPECT and [¹⁸F]AV133 PET across 5 brain regions. Mapped Centamine values showed minimal differences between tracers, ranging from 1.5% (post-commissural putamen) to 3% (caudate).

Interpretation: The Centamine scale holds promise for the harmonized quantification of dopaminergic neuronal imaging markers. The Centamine strategy would enable and accelerate clinical trials in Parkinson's disease using dopaminergic imaging outcomes. ANN NEUROL 2026;99:949-963.

Objective: Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.

Methods: We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.

Results: There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]_{per 1-SD} = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HR_{per 1-SD} = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HR_{per 1-SD} = 1.08, 95% CI = 1.04-1.13, P_interaction = 0.003). Higher creatinine was inversely associated with FTD risk (HR_{per 1-SD} = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (_IVW)_{, per 1-SD} = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (P_{non-linearity} = 0.006).

Interpretation: LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2026;99:844-856.

The risk allele rs10191329*A is associated with disease severity and brain atrophy in people with multiple sclerosis (MS). We investigated the association of rs10191329 with age-related brain atrophy in a population-based cohort using 10,308 magnetic resonance imaging (MRI) scans of 4,815 participants aged ≥ 45 years without MS in cross-sectional and longitudinal analyses. We observed associations between the rs10191329*A allele and lower total brain volume and gray matter volume in middle-aged (< 55 years of age), but not in older participants. These data suggest that rs10191329*A contributes to earlier onset of atrophy in the general population, and that mediating mechanisms of accelerated neurodegeneration extend beyond MS. ANN NEUROL 2026;99:1083-1089.