Annals of Neurology最新文献

Objective: Vitamin B12 (B12) plays a critical role in fatty- and amino-acid metabolism and nucleotide synthesis. While the association between B12 deficiency and neurological dysfunction is well-known, the exact threshold for adequacy remains undefined in terms of functional impairment and evidence of injury. The objective was to assess whether B12 levels within the current normal range in a cohort of healthy older adults may be associated with measurable evidence of neurological injury or dysfunction.

Methods: We enrolled 231 healthy elderly volunteers (median age 71.2 years old) with a median B12 blood concentration of 414.8 pmol/L (as measured by automated chemiluminescence assay). We performed multifocal visual evoked potential testing, processing speed testing, and magnetic resonance imaging to assess neurological status. Moreover, we measured serum biomarkers of neuroaxonal injury, astrocyte involvement, and amyloid pathology.

Results: Low (log-transformed) B12, especially decreased holo-transcobalamin, was associated with visual evoked potential latency delay (estimate = -0.04; p = 0.023), processing speed impairment (in an age-dependent manner; standardized β = -2.39; p = 0.006), and larger volumes of white matter hyperintensities on MRI (β = -0.21; p = 0.039). Remarkably, high levels of holo-haptocorrin (biologically inactive fraction of B12) correlated with serum levels of Tau, a biomarker of neurodegeneration (β = 0.22, p = 0.015).

Interpretation: Healthy older subjects exhibit neurological changes at both ends of the measurable "normal" B12 spectrum. These findings challenge our current understanding of optimal serum B12 levels and suggest revisiting how we establish appropriate nutritional recommendations. ANN NEUROL 2025.

Objective: To investigate the role of neuroinflammation in the substantia nigra pars compacta (SNc) across different parkinsonian disorders-Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA)-by examining SNc dopaminergic neuron counts, neuroinflammatory T cells, and microglial activity.

Methods: Postmortem neuropathological samples were collected from 79 individuals (PD, n = 38; PSP, n = 15; MSA, n = 14; controls, n = 12). The density of SNc tyrosine hydroxylase (TH)-positive neurons, T cells (CD3+, CD4+, and CD8+), and Iba1 expression (Iba1-positive microglia/macrophages) were examined in the SNc and crus cerebri. Demographic and clinical data were gathered from patient histories.

Results: PSP patients had 89 to 212% more nigral CD3+, CD4+, and CD8+ T cells compared to MSA patients (p < 0.04), 125 to 178% more CD3+ and CD4+ T cells than healthy controls (p < 0.002), and 95% more CD4+ T cells than PD patients (p = 0.001). Iba1 expression in the SNc was higher in PD patients than in MSA patients (p = 0.004), with no significant differences observed across other conditions. There was a negative association between disease duration and SNc CD3+ T cell density (p = 0.002), and a positive correlation between nigral dopaminergic neuron density and CD3+ density, CD8+ density, and Iba1 expression in PD patients.

Interpretation: The study reveals distinctive neuroinflammatory patterns in the SNc, with T cell-mediated inflammation prominent in PSP and microglia-mediated inflammation in PD. PSP and MSA show greater SNc dopaminergic neuron loss compared to PD. Increased neuroinflammatory response is seen in earlier disease stages, diminishing with greater neuron loss, which may inform disease progression understanding and therapeutic strategies. ANN NEUROL 2025.

Objective: Traumatic spinal cord injury (SCI) is diagnosed by imaging and clinical scoring using the American Spinal Injury Association Impairment Scale (AIS). These methods have limited value for prognosis. Here, the prognostic value of plasma neurofilament-light (NfL), glial fibrillary acidic protein (GFAP), and contactin-1 (CNTN-1) was analyzed.

Methods: Biomarker levels were determined in the plasma of traumatic SCI patients (n = 37) and healthy controls (n = 22). SCI samples (n = 112) were collected at different time points from 0 to 4 days to 18 weeks post-injury. NfL and GFAP were measured by single molecule array (Simoa) technology, CNTN-1 by Luminex. Baseline and outcome AIS and motor scores were collected as a measure of injury severity.

Results: NfL, GFAP, and CNTN-1 showed different kinetics in SCI patients over time. Baseline biomarker levels could identify AIS-A SCI patients (NfL + GFAP) and discriminate between patients with a motor score change <5 and those with a change ≥5 (NfL + GFAP+CNTN-1). Longitudinally, NfL could identify AIS-A patients up to 12 weeks post-SCI and discriminate between patients with a motor score change <5 and those with a change ≥5 up to 18 weeks post-SCI. Further, baseline biomarker levels positively (NfL + GFAP) or negatively (CNTN-1) correlated with outcome injury severity and together could accurately predict AIS conversion (AUC 0.863) and motor score change (AUC 0.857). This predictive ability was maintained in subacute/chronic SCI stages.

Interpretation: In conclusion, plasma NfL, GFAP, and CNTN-1 are potential prognostic biomarkers in SCI. This is important for patient stratification in clinical trials, prediction of neurological outcome and informed decision-making in SCI treatment and rehabilitation. ANN NEUROL 2025.

Objectives: Intravenous thrombolysis (IVT) is contraindicated for acute ischemic stroke (AIS) patients taking direct oral anticoagulants (DOACs) within 48 hours before index stroke. Limited data exist on off-label use of IVT for these patients. We compared the safety and outcomes of IVT in AIS patients with DOAC treatment and patients with no OAC before index stroke.

Methods: We analyzed data from the Safe Implementations of Treatments in Stroke (SITS) International Stroke Thrombolysis Registry during 2013-2024. Outcomes were symptomatic intracerebral hemorrhage (SICH) by the SITS Monitoring Study and European Cooperative Acute Stroke Study II definitions, functional independency (modified Rankin Scale score 0-2), and death by 3 months. Propensity score matching with a nearest neighbor matching algorithm with a ratio of 1:2 was used for relevant clinical variables. We also analyzed the time from last DOAC dose to IVT treatment.

Results: A total of 1,311 DOAC and 129,384 no OAC patients were included. We matched 894 patients with DOAC to 1,788 with no OAC. The mean age was 75 years versus 76 years, and the median National Institutes of Health Stroke Scale score 11 versus 12, respectively. Patients with DOAC had a similar proportion of outcomes compared with patients with no OAC: SICH per SITS Monitoring Study (1.1 vs 1.5%, p = 0.50), SICH per European Cooperative Acute Stroke Study II (4.0 vs 4.3%, p = 0.82), any parenchymal hematoma (6.3 vs 7.8, p = 0.22), and functional independency (47.9 vs 46.4%, p = 0.59) and death (25.1 vs 24.0%, p = 0.65) at 3-month follow-up. The time from last DOAC dose to IVT did not affect outcomes.

Interpretation: In this observational study, we did not find any difference in outcomes after IVT therapy in AIS patients with DOAC compared with no OAC treatment before index stroke. ANN NEUROL 2025.

Objective: The involvement of cortical inflammation in migraine, particularly migraine with aura, has been a subject of considerable interest, but has proved challenging to demonstrate. We aimed to detect and characterize signs of cortical inflammation in adults with migraine using a novel, multimodal magnetic resonance imaging (MRI) technique.

Methods: We used T2 mapping to measure water content/cellularity, T1 mapping to measure tissue microstructure integrity, and apparent diffusion coefficient (ADC) mapping to measure intra- or extracellular edema. We compared these values between participants with migraine (with and without aura) and healthy controls using general linear models adjusted for age and sex.

Result: Two hundred ninety-six adult participants with migraine and 155 age- and sex-matched healthy controls provided eligible imaging data. Among the participants with migraine, 103 had migraine with aura, 180 chronic migraine, and 88 were ictal during the scan. Participants with migraine had higher quantitative T2 (qT2) in the left occipital cortex than healthy controls (p < 0.0001). In migraine with aura, the higher qT2 was more widespread and located bilaterally in the occipital cortices, compared with controls (left, p < 0.0001; right p = 0.004). Post-hoc analysis revealed overlapping ADC elevations in migraine with aura compared with controls (p = 0.0069).

Interpretation: Quantitative MRI changes compatible with cortical inflammation were detected in participants with migraine, and appeared driven by the subgroup with aura. Higher occipital qT2 in migraine with aura might represent either extracellular edema or accumulation of inflammatory microglia or astrocytes. These results support the importance of cortical inflammation in migraine pathophysiology, particularly in migraine with aura. ANN NEUROL 2025.

Objective: The objective is to evaluate cognitive and behavioral progression and identify early predictors of these changes in a cohort of amyotrophic lateral sclerosis (ALS) patients.

Methods: A total of 161 ALS patients were tested at diagnosis (T0), and 107 were re-tested after 1 year (T1) using cognitive/behavioral tests. All patients underwent whole-genome sequencing, and 46 patients (ALS-normal cognition [CN]) underwent [18F]Fluorodeoxyglucose positron emission tomography.

Results: Of the 161 patients, 107 were re-rested at T1; non-retested patients included 10 with frontotemporal dementia and 44 who were either non-testable or deceased. At T0, 67 patients (62.6%) were classified as ALS-CN, whereas 40 (38.4%) showed some degree of cognitive/behavioral impairment. Eighteen ALS-CN patients (26.9%) experienced cognitive decline at T1. Phenoconverters had lower baseline scores in letter fluency (Letter Fluency Test [FAS]) (p < 0.001), Edinburgh Cognitive and Behavioral ALS Screen (ECAS) verbal fluency score (p = 0.017). Both tests were independently predictive of phenoconversion in binary logistic regression models, with optimal cut-off scores of 28.75 and 14.2, with good sensitivity and specificity. Other predictors included older age, lower education, and ALS-related genetic variants. Phenoconverters were hypometabolic in the left temporal lobe. Thirteen (32.5%) of the 40 patients with cognitive impairment at T0 worsened by T1, with FAS (p = 0.02) and the ECAS verbal fluency score (p = 0.023) predicting further decline.

Interpretation: Approximately 30% of ALS patients experienced cognitive/behavioral decline within the first year after diagnosis. FAS and ECAS verbal fluency were predictive of cognitive phenoconversion. Our findings highlight the importance of early detection of at-risk individuals and the need for longitudinal cognitive assessments to monitor disease progression. ANN NEUROL 2025.

Objective: The neurodegenerative processes driving the build-up of disability in progressive multiple sclerosis (P-MS) have not been fully elucidated. Recent data link cellular senescence (CS) to neurodegeneration. We investigated for evidence of CS in P-MS and sought to determine its pattern.

Methods: We used 53BP1, p16, and lipofuscin as markers of CS in white matter lesions (WMLs), normal appearing white matter (NAWM), normal appearing cortical gray matter (NAGM), control white matter (CWM), and control gray matter (CGM) on autopsy material from patient with P-MS and healthy controls. Senescence-associated secretory phenotype (SASP) factors were quantified in cerebrospinal fluid (CSF).

Results: P16⁺ cell counts were significantly increased in WMLs and GMLs, compared with NAWM, CWM, NAGM, and CGM and lipofuscin⁺ cells were significantly increased in WMLs, compared with NAWM and CWM, indicating more abundant CS in demyelinated lesions. The 53BP1⁺ cells in WMLs were significantly increased compared with NAWM and CWM. The 53BP1⁺ and p16⁺ cells were found significantly more abundant in acute active WMLs and GMLs, compared with chronic inactive lesions. Co-localization studies showed evidence of CS in neurons, astrocytes, oligodendrocytes, microglia, and macrophages. Among the quantified CSF SASP factors, IL-6, MIF, and MIP1a levels correlated with 53BP1⁺ cell counts in NAGM, whereas IL-10 levels correlated with p16⁺ cell counts in NAWM. P16⁺ cell counts in WMLs exhibited an inverse correlation with time to requiring a wheelchair and with age at death.

Interpretation: Our data indicates that CS primarily affects actively demyelinating gray and WMLs. A higher senescent cell load in P-MS is associated with faster disability progression and death. ANN NEUROL 2025.

Objective: Some individuals demonstrate greater cognitive resilience-the ability to maintain cognitive performance despite adverse brain-related changes-through as yet unknown mechanisms. We examined whether cortical thickness in several brain regions confers resilience against cognitive decline in amyloid-positive adults by moderating the effects of thinner cortex in Alzheimer's disease (AD)-related brain regions and of higher levels of tau.

Methods: Amyloid-positive participants from the Alzheimer's Disease Neuroimaging Initiative with relevant imaging data were included (n = 160, observations = 473). Risk factors included an AD brain signature and cerebrospinal fluid phosphorylated tau. Cognitive measures were episodic memory and executive function composites. Mixed effects models tested whether region-specific cortical thickness moderated relationships between markers of AD risk and memory or executive function.

Results: Cross-sectionally, thicker cortex in 8 regions minimized the negative impact of thinner cortex/smaller volume in AD signature regions on executive function. Longitudinally, higher baseline thickness in a composite of these 8 regions predicted less memory decline (p = 0.007) and weakened negative effects of phosphorylated tau on memory decline (p = 0.014), independent of baseline cognition and risk markers.

Interpretation: We identified 8 cortical regions that appear to confer cognitive resilience cross-sectionally and longitudinally in the face of established indicators of AD pathology. Brain regions fostering executive function may enable compensation in later memory performance and confer cognitive resilience against effects of phosphorylated tau and AD-related cortical changes. These "resilience" regions suggest the value of focusing on brain regions beyond only those determined to be AD-related and may partially explain variability in AD-related cognitive trajectories. ANN NEUROL 2025.