Annals of Neurology最新文献

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 2025.

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 2025.

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 2025.

Objective: Traumatic brain injury (TBI) is an established risk factor for dementia, although the underlying mechanisms remain unclear. Our previous research demonstrated that a single severe TBI in wild-type (WT) mice induces a prion-like form of tau (tau^TBI) that spreads throughout the brain, leading to memory deficits. Here, we investigated whether similar self-propagating tau^TBI conformers are generated in humans after severe TBI.

Methods: We biochemically assessed tau and phosphorylated tau (P-tau) levels in human brain contusions surgically removed acutely after severe TBI. Inoculation studies were performed using human TBI brain homogenates in WT and tau knockout (KO) mice to investigate the role of endogenous tau in tau^TBI propagation. Cognitive function was evaluated using the novel object recognition test, the radial arm water maze, and the Y-maze. Pathological changes in the brain of the inoculated mice were analyzed by histological and biochemical analyses, and targeted transcriptomics.

Results: Inoculation of human TBI brain homogenates in WT mice caused widespread tau deposition and cognitive impairment, hippocampal synaptic loss, and disease-associated transcriptomic changes. Effects were similar upon secondary inoculation in WT but not tau KO mice, confirming a tau-dependent mechanism.

Interpretation: Severe TBI induces transmissible tau^TBI conformers in humans acutely after injury, potentially exacerbating post-traumatic pathology, and increasing the risk for dementia later in life. ANN NEUROL 2025.

We report the first human use of intranasal seletracetam (SEL) to prevent reflex seizures. A patient with epilepsy with reading-induced seizures on levetiracetam (3,000 mg/day) continued to experience reading-induced focal seizures with preserved consciousness. Detectable in serum within 2 minutes of intranasal administration, 30 mg seletracetam delayed seizure onset from 1:56 (placebo) to 4:17 minutes post-stimulus onset. A second 30 mg dose fully prevented seizures during 25 minutes of reading. Electroencephalogram (EEG) spike-frequency declined dose-dependently (3.1/min at placebo to 1.6/min after second dose), with reduced spike-propagation on magnetoencephalography (MEG). Our findings support SEL as a promising non-benzodiazepine acute seizure prevention and provide insight into reflex seizure dynamics. ANN NEUROL 2025.

We used targeted immunopurification-mass spectrometry (IP-MS) to characterize human neurofilament light chain (NfL) proteoforms across various compartments to assess their alterations in amyotrophic lateral sclerosis (ALS). NfL is truncated in cerebrospinal fluid (CSF) and blood in patients with sporadic ALS (sALS) and these proteoforms differ between compartments. Mid-domain species were elevated in CSF whereas plasma NfL proteoforms were mostly comprised of the tail subdomain region. Our results suggest NfL isoforms are proteolyzed and differentially distributed between ALS biofluid compartments and that analyzing by these specific regions or in ratios between regions can provide improvements in biomarker utility. These insights enhance the understanding of NfL and its potential for disease monitoring and therapeutic targeting in ALS. ANN NEUROL 2025.

Objective: Parkinson's disease (PD) is one of the rare diseases in which sleep alteration is a true marker of disease outcome. Yet, how the association between sleep and PD emerges over the healthy lifetime is not established. We examined the association between the polygenic risk score (PRS) for PD and the variability in the electrophysiology of rapid eye movement (REM) sleep in 433 younger (18-31 years) healthy individuals and 85 late-midlife (50-69 years) healthy individuals.

Methods: In this prospective cross-sectional study, in-lab electroencephalography recordings of sleep were recorded to extract REM sleep metrics. PRS was computed using SBayesR approach.

Results: Generalized additive model for location, scale, and shape analysis showed significant association of REM duration (p_corrected = 0.03) and theta energy in REM (p_corrected = 0.004) with PRS for PD in interaction with the age group. In the younger subsample, REM duration and theta energy were positively associated with PD PRS. In contrast, in the late-midlife subsample, the same associations were negative (although only qualitatively for REM theta energy) and may differ between men and women.

Interpretation: REM sleep is associated with the PRS for PD in early adulthood, 2 to 5 decades before typical symptoms onset. The association changes from positive in younger individuals, presumably free of alpha-synuclein, to negative in late-midlife individuals, possibly because of the progressive presence of alpha-synuclein aggregates or of the repeated increased oxidative metabolism imposed by REM sleep. Our findings may unravel core associations between PD and sleep and may contribute to novel intervention targets to prevent or delay PD. ANN NEUROL 2025.

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 2025.