Annals of Neurology最新文献

Narcolepsy type 1 (NT1) is presumed to be an autoimmune disorder caused by hypothalamic loss of hypocretin (Hcrt; orexin). In postmortem NT1 brains, we observed an 11-fold increase of CD4⁺ T-cells in the Hcrt region compared with control hypothalami, without a corresponding rise in CD8⁺ T-cells. CD4⁺ and CD8⁺ T-cell numbers were unchanged in other hypothalamic regions, including the paraventricular nucleus and median eminence, and in extra-hypothalamic areas such as the substantia nigra and locus coeruleus. Hcrt-region CD4⁺ T-cells expressed the tissue-resident memory markers CD49a and CXCR6. These findings support the autoimmune hypothesis of NT1. ANN NEUROL 2026.

Objective: Pre-mortem diagnosis of parkinsonism is often challenging due to atypical presentations, overlapping syndromes, and co-pathologies. This study aimed to develop a machine learning-based algorithm predicting neuropathology in parkinsonism using chronological clinical presentations, which has previously been underexplored.

Methods: Clinical information was automatically abstracted from medical records of the Mayo Clinic Brain Bank using fine-tuned Generative Pre-trained Transformer 4 models. Patients who developed parkinsonism within 3 years of disease onset were included. Six machine learning models were trained with age, sex, family history, and 197 clinical presentations paired with onset information to predict neuropathologic diagnoses, including co-pathologies.

Results: Among 7,825 donors, 949 met inclusion criteria, representing 9 neuropathologic categories: Lewy body disease (LBD; n = 128), LBD with Alzheimer's disease (AD; n = 136), progressive supranuclear palsy (PSP; n = 303), PSP with AD (n = 56), PSP with LBD (n = 27), multiple system atrophy (MSA; n = 120), corticobasal degeneration (CBD; n = 99), AD (n = 43), and frontotemporal lobar degeneration (FTLD; n = 37). The CatBoost algorithm achieved an area under the receiver operating characteristic curve of 0.83 across the 9 diagnostic categories at 3 years after onset. Important predictors included age at onset, restricted eye movement, and tremor. The model remained robust to incomplete data, requiring only 23 of 200 parameters for reliable predictions with an area under the curve of 0.80. The algorithm was implemented into a user-friendly program providing diagnostic probabilities with visualizations of parameter contributions.

Interpretation: This neuropathology-confirmed diagnostic algorithm provides a cost-effective and interpretable screening tool for parkinsonism, bridging biomarker testing and molecular-targeted therapies. ANN NEUROL 2026.

Objective: Cerebral ischemic stroke causes neuronal oxygen/energy deprivation, disrupting mitochondrial function including reduced membrane potential and bioenergetics, exacerbating neuronal injury. Mitochondrial defects are, therefore, a central neuropathological node and potential therapeutic target. Previous studies have shown that mitochondria transplantation rescued infarction in cerebral ischemic stroke. However, interactions between transplanted and endogenous mitochondria remain unclear. Here, we proposed astrocytic mitochondria as the optional donor for mitochondria transplantation in ischemic stroke treatment because of their ischemic resistance.

Methods: We transplanted mitochondria derived from astrocytes into an ischemic stroke cell and mouse model to investigate the feasibility and mechanisms of astrocytic mitochondria transplantation for ischemic cerebral stroke. We assessed the uptake of transplanted mitochondria by neurons, their impact on endogenous mitochondrial dynamics (fusion/fission), mitochondrial functions, neuronal dendritic structure, neuronal survival, and mice motor function.

Results: Transplanted astrocytic mitochondria were successfully taken up by neurons, and within neurons, they flexibly regulated endogenous mitochondrial dynamics. This intervention rescued the stroke-induced reduction in mitochondrial membrane potential and oxidative phosphorylation capacity. Consequently, it significantly decreased neuronal dendritic injuries and cell death. These cellular improvements translated into alleviated motor deficits in the stroke model.

Interpretation: Astrocytic mitochondria transplantation is an effective therapeutic strategy for ischemic stroke. Its neuroprotective effects stem from the internalization of functional mitochondria into neurons and the subsequent flexibly regulation of endogenous mitochondrial dynamics, restoring bioenergetics and promoting neuronal survival. This approach holds significant promise for treating ischemic stroke and potentially other brain disorders involving mitochondrial dysfunction. ANN NEUROL 2026.

Objective: The extent of neuronal loss in Parkinson's disease (PD) and the pathogenic processes underlying neuronal dysfunction and loss remain poorly understood. Here, we analyzed the expression of key molecules representing different cell death signaling pathways and their association with Lewy pathology, dopaminergic (DA) neuron loss and stage of PD progression in human postmortem brain tissue.

Methods: We performed neuropathological and molecular analyses on 47 postmortem substantia nigra (SN) tissue samples from PD cases and healthy controls to investigate neuronal cell death pathways.

Results: An average loss of 54% of dopaminergic neurons was found in the SN of PD cases, which correlated strongly with PD Braak staging. The apoptosis markers, cleaved subunits of caspases 3 and 8, were absent. Levels of the active necroptosis kinase, phosphorylated RIPK3 (pRIPK3), were significantly increased in advanced-stage PD. Although phosphorylated MLKL (pMLKL) levels were not significantly different, both active markers were detected in small numbers of PD neurons by immunofluorescence, suggesting focal necroptotic pathway activation. In contrast, evidence for ferroptosis was more pronounced, particularly in advanced-stage PD. This was supported by significantly increased transferrin receptor 1 (TFR1) protein levels and significantly decreased glutathione peroxidase 4 (GPX4) RNA and protein levels.

Interpretation: Our findings implicate ferroptosis, and to a lesser extent necroptosis, in PD neuronal death, with ferroptosis potentially playing a larger role in advanced disease. We propose a "2-hit" model where early synucleinopathy-driven insults are amplified in advanced disease by a neuromelanin-iron-driven feedback loop, establishing ferroptosis as the predominant cell death mechanism. This stage-dependent shift provides critical insights into PD pathogenesis and suggests distinct therapeutic windows for neuroprotection. ANN NEUROL 2026.

Objective: The prodromal phase of amyotrophic lateral sclerosis (ALS) is poorly defined. We aimed to characterize prescription drug use patterns in the pre-diagnostic period by analyzing nationwide prescription data to identify the earliest divergence between individuals who developed ALS and matched healthy controls. We used this divergence as an indirect marker to estimate the onset and duration of the prodrome.

Methods: We conducted a nested case-control study using nationwide Norwegian registries (2005-2019). ALS cases were individually matched to 100 controls by sex, age, and education level using incidence density sampling. Drug prescription data were gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates up to 10 years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS based on drug prescription patterns.

Results: We identified 2,084 incident patients with ALS and 208,400 matched healthy controls. Overall, changes in prescription patterns occurred 2 to 3 years before ALS diagnosis. Among specific drug groups, 25 of 42 therapeutic drug classes were prescribed more frequently to patients with ALS than matched controls. Muscle relaxants and bone disease treatments were prescribed significantly more frequently 6 and 5 years before diagnosis, respectively.

Interpretation: Prescription pattern changes occurred as early as 6 years before ALS diagnosis. These findings are consistent with a prodromal phase preceding the clinical stage of ALS, which may last several years. In contrast, the broad increase in medication use during the final year before diagnosis likely reflects increased health care utilization as patients seek treatment for the various emerging symptoms of the clinically manifest disease. ANN NEUROL 2026.

Objective: To evaluate whether white matter hyperintensities (WMH) and apolipoprotein E (APOE) ε4 status have an additive or multiplicative effect on the risk of incident all-cause dementia.

Methods: We conducted a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study and confirmed findings in the UK Biobank (UKB). The exposures were APOE ε4 status (0 vs. ≥1 allele) and WMH on magnetic resonance imaging (MRI). The primary outcome was incident all-cause dementia. After confirming an additive interaction, we created combined exposure groups: WMH-/ε4-, WMH+/ε4-, WMH-/ε4+, and WMH+/ε4+. Cox proportional hazards models were adjusted for age, sex, race, education, cognition (ARIC only), hypertension, diabetes, and prior stroke.

Results: In ARIC (n = 1,736, mean age 63, 58.8% female, 48.7% non-Hispanic White individuals, median follow-up 18.6 years), the dementia incidence rate was 10.4 (95% CI, 9.2-11.6) per 1,000 person-years. Compared to WMH-/ε4-, adjusted hazard ratios (HRs) for dementia were: WMH-/ε4+, 1.5 (95% CI, 1.1-2.1); WMH+/ε4-, 2.0 (95% CI, 1.4-2.7); and WMH+/ε4+, 3.2 (95% CI, 2.2-4.6). In UKB (n = 40,307, mean age 55, 52.7% female, 97.1% non-Hispanic White individuals, median follow-up 3.2 years), the dementia incidence rate was 0.42 (95% CI, 0.32-0.55) per 1,000 person-years. Adjusted HRs were: WMH-/ε4+, 2.3 (95% CI, 1.2-4.5); WMH+/ε4-, 2.1 (95% CI, 1.0-4.6); and WMH+/ε4+, 6.7 (95% CI, 3.2-13.9).

Interpretation: WMH burden and APOE ε4 status additively increase dementia risk. These findings support the potential benefit of vascular risk management to reduce WMH and delay dementia onset, even among genetically at-risk individuals. ANN NEUROL 2026;99:656-667.

Objective: The effects of deep brain stimulation (DBS) manifest across multiple timescales, spanning seconds to months, and involve direct electrical effects, neuroplasticity, and network reorganization. In epilepsy, the delayed impact of DBS on seizures presents challenges for optimization. Single-pulse stimulation and resulting brain stimulation evoked potentials (BSEPs) provide a means to assess effective connectivity and network excitability. This study integrates BSEPs and short trials of DBS during stereoelectroencephalography (sEEG) to map seizure network engagement, modulate network dynamics, and monitor excitability and interictal abnormalities for biomarker informed neuromodulation.

Methods: Ten individuals with drug resistant epilepsy undergoing clinical sEEG were enrolled in this retrospective cohort study of epilepsy neuromodulation biomarkers. Each patient underwent a trial of high frequency (145Hz) thalamic DBS. BSEPs were acquired before and after DBS trials. Baseline BSEP amplitude assessed seizure network engagement, and modulation of amplitude (pre vs post DBS) assessed change in network excitability. Interictal epileptiform discharges were tracked by an automated classifier.

Results: Baseline BSEPs delineated distinct patterns of network engagement between thalamic subfields with maximal frontotemporal engagement achieved with stimulation of the anterior nucleus of the thalamus-ventral anterior nucleus junction. DBS delivered for >1.5 hours reduced BSEP amplitudes compared to baseline, and the degree of modulation correlated with baseline connectivity strength. Shorter DBS trials did not induce reliable BSEP amplitude suppression, but did immediately suppress interictal epileptiform discharge rates in well-connected seizure networks.

Interpretation: BSEPs and trials of DBS during sEEG provide novel network biomarkers to evaluate the modulation of large-scale networks across multiple timescales, advancing biomarker informed neuromodulation. ANN NEUROL 2026;99:748-760.

Objective: The first-pass effect (FPE), defined as excellent reperfusion after a single attempt, is associated with improved outcomes in large vessel occlusion stroke. We evaluated whether intravenous tenecteplase (TNK) compared with alteplase (TPA) increases the likelihood of FPE in basilar artery occlusion (BAO).

Methods: We analyzed 163 consecutive BAO patients treated with intravenous TNK or TPA within 4.5 h of last known well across 14 U.S. stroke systems (January 2020-August 2024). Patients with early reperfusion (n = 27) or aborted procedures (n = 3) were excluded. Multivariable ordinal and logistic regression identified predictors of FPE (expanded Thrombolysis in Cerebral Infarction [eTICI] 2c-3) and modified FPE (mFPE, eTICI 2b-3), and FPE/mFPE association with 90-day outcomes (modified Rankin Scale [mRS] 0-3).

Results: FPE occurred in 55 of 133 patients (41.4%) and was more frequent with TNK than TPA (51.7% vs 32.9%, p = 0.029). TNK was independently associated with higher odds of FPE (adjusted odds ratio [aOR] 2.37, 95% confidence interval [CI] 1.13-4.98, p = 0.023) and mFPE (aOR 2.74, 95% CI 1.20-6.25, p = 0.017). Both FPE and mFPE were independently associated with ambulatory outcomes at 90-days (FPE: aOR 2.94, 95% CI 1.18-7.33, p = 0.021; mFPE: aOR 5.11, 95% CI 1.81-14.43, p = 0.002). TNK compared with TPA did not show an independent association with functional outcome.

Interpretation: In this multicenter BAO cohort, TNK increased the odds of achieving FPE compared with TPA. As FPE strongly predicted functional recovery, these findings suggest TNK may confer a reperfusion advantage with potential clinical benefit, although a direct outcome effect was not demonstrated. ANN NEUROL 2026;99:692-704.