Annals of Neurology最新文献

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.

Objective: The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Identifying novel targets to modify disease progression is of great clinical and translational interest. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied.

Methods: We first investigated cellular senescence markers in resected hippocampi from patients with medically intractable TLE through multiplexed immunofluorescence. We next used a mouse model of TLE (pilocarpine induced status epilepticus [SE]) for a combination of immunohistochemistry, behavioral testing, and electroencephalogram (EEG) monitoring. We implemented 2 strategies for removal of senescent cells (SCs), a genetic mouse model allowing for targeted senolysis, and a pharmacological approach using dasatinib and quercetin.

Results: We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In mice, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following SE. Senolytic treatment produced a 50% reduction in SCs, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.

Interpretation: Our data demonstrate that SCs accumulate in both human TLE and in a mouse model of TLE and suggest that clearing SCs may be a viable strategy to reduce seizures and associated cognitive comorbidities. ANN NEUROL 2025.