Annals of Neurology最新文献

Objective: The objective of this study was to characterize the phenotypic spectrum of the rare sporadic Creutzfeldt-Jakob disease cortical subtype (sCJDMM/MV2C) in a large multicentric autopsy cohort.

Methods: We evaluated clinical histories, biofluid markers, brain diffusion-weighted (DW)-magnetic resonance imaging (MRI), and electroencephalogram (EEG) findings in 56 patients. The histomolecular assessment included misfolded prion protein (PrP) typing by immunoblotting, histopathology, and PrP immunohistochemistry in several brain areas.

Results: Misfolded PrP typing showed a dominant 19 kDa unglycosylated PrP fragment (type 2) in all brains, focally associated with a 21 kDa (type 1) fragment in 53% of participants (MM/MV2C + 1). Immunohistochemistry revealed coarse/perivacuolar PrP deposits in the neocortices and a patchy/coarse pattern in the cerebellar molecular layer. The mean disease duration was 16.0 months. At onset and early stages, most patients manifested only progressive cognitive decline, consistent with the predominant distribution and relative severity of spongiform change in the cerebral cortex. Brain DW-MRI showed cortical hyperintensities in 94% of cases. Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) assay was positive in 70% of cases. Compared with pure MM/MV2C, the mixed MM/MV2C + 1 phenotype showed a shorter disease duration (14 vs 19 months), and a higher frequency of striatal DW-MRI hyperintensity (56% vs 19%), EEG periodic sharp-waves complexes (41% vs 6%), and CSF RT-QuIC positivity (86% vs 53%).

Interpretation: The clinicopathologic phenotype of sCJDMM/MV2C diverges from that of typical sCJDMM/MV1. Moreover, the histomolecular heterogeneity within MM/MV2C influences clinical features and results of diagnostic investigations, challenging its identification in vivo. Nonetheless, results suggest that DW-MRI and CSF RT-QuIC allow an accurate clinical diagnosis of Creutzfeldt-Jakob disease in most patients. ANN NEUROL 2026;99:883-896.

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 2026;99:897-911.

Objective: SOD1 is the second most frequently mutated gene in European patients with amyotrophic lateral sclerosis (ALS). Given the recent authorization of SOD1-targeted antisense oligonucleotides for SOD1-ALS, prompt screening for SOD1 mutations in patients with ALS patients is highly recommended. Large-scale genomic analysis could inform on the population-based prevalence of SOD1 mutation carriers, who would potentially benefit from treatment. We aim to determine the number of people with pathogenic SOD1 variants in the UK Biobank (UKB), to address a critical gap between clinical and genetic prevalence of SOD1-ALS.

Methods: We analyzed SOD1 variants within exome sequencing data from 470,000 individuals aged over 40 years. Pathogenicity was evaluated using referenced databases and American College of Medical Genetics and Genomics (ACMG) guidelines. Leveraging the UKB carrier frequency and age at onset data, we estimated the genetic prevalence of SOD1-ALS. We examined factors that may influence penetrance.

Results: We identified 122 individuals with monoallelic SOD1 coding variants, 93.4% of whom were asymptomatic. Additionally, the low-penetrance p.Asp91Ala variant was observed in heterozygosis in 535 subjects, whereas it was never found in homozygosis. Excluding this variant, the expected number of people developing SOD1-ALS is 1.04:100,000 in the UK population, 4 times higher than clinically reported figures. Symptomatic carriers had significantly increased levels of serum neurofilament at baseline. Age-related penetrance was higher in non-p.Asp91Ala carriers versus p.Asp91Ala carriers. Long-term survivor status was associated with p.Asp91Ala genotype, older age, and lower neurofilament levels.

Interpretation: Incomplete and age-related penetrance, along with underascertainment due to disease heterogeneity and limitations in data collection, likely account for the reduced number of symptomatic patients identified. Our findings highlight the need to identify genetic and environmental factors, as well as biological indicators, able to influence disease penetrance and phenoconversion risk in presymptomatic carriers and to predict treatment response in patients. ANN NEUROL 2026.

Objective: Clinically relevant Alzheimer's disease co-pathology is common in Lewy body disorders. Plasma P-tau217 is a sensitive biomarker for amyloid and tau pathology in Alzheimer's disease. The objective was to determine if plasma P-tau217 associates with Alzheimer's disease co-pathology and cognition in Lewy body disorders.

Methods: Participants had (1) a clinicopathological diagnosis of Parkinson's disease or dementia with Lewy bodies in the pathology series, or (2) a clinical diagnosis of Parkinson's disease in the clinical series and were followed as part of the longitudinal, observational cohort study at the University of Pennsylvania between 2007 and 2024. Plasma concentration of P-tau217 was measured in previously collected samples.

Results: Neuropathology cases included 46 Parkinson's disease and 10 dementia with Lewy bodies, and clinical cases included 173 Parkinson's disease, and 64 controls. P-tau217 was greater in cases with (median, 0.3 [interquartile range (IQR), 0.2-0.4]) versus without (median, 0.1 [IQR, 0.1-0.2]) Alzheimer's disease co-pathology (p < 0.01) and discriminates Lewy body disorders participants with Alzheimer's disease co-pathology (area under curve, 0.84). Parkinson's disease participants with incident cognitive impairment had greater increases in serial P-tau217 than those who remained cognitively stable (group × time interaction β = -0.010, p = 0.0027). Higher baseline P-tau217 concentrations associated with longitudinal change in dementia rating scale (group × time interaction β = -4.947, p = 0.0166) and higher risk for cognitive progression (hazard ratio = 1.597, p = 0.003).

Interpretation: Plasma P-tau217 detects Alzheimer's disease co-pathology in Lewy body disorders and predicts cognitive decline. Future studies will evaluate associations between plasma P-tau217 and imaging and clinical outcomes, in consideration for use of amyloid-targeting therapies in Lewy body disorders. ANN NEUROL 2026.

Objective: Newborn screening (NBS) for spinal muscular atrophy (SMA) facilitates early diagnosis and treatment for affected individuals. However, fluid biomarkers that provide early insights into disease activity and outcomes in a neonatal cohort and those unable to access (due to reimbursement criteria) or deferring immediate treatment are lacking. This study evaluated neurofilament light chain (NfL) levels to provide insights into disease activity and outcomes in newborns and children with SMA.

Methods: This study correlated pretreatment NfL levels in the serum and cerebrospinal fluid (CSF) in a cross-sectional cohort of individuals with SMA against clinical, neurophysiological, molecular genetic variables, and treatment characteristics. Longitudinal NfL levels were evaluated in individuals that did not immediately commence treatment (governed by Australian reimbursement policies) and in those treated with nusinersen monotherapy.

Results: Participants included 45 individuals with SMA (age range = 4 days to 42 years). Pretreatment serum NfL (sNfL) in 2 SMN2 copy neonates were significantly higher (2 SMN2, mean[SE] 680.9 [163.7]; ≥ 3 SMN2 146.9 [59.8] pg/ml, p = 0.01), correlating with increasing post-natal age (2 SMN2 r[12] = 0.75, p = 0.005). Combining sNfL and compound muscle action potential (CMAP) with pretreatment CHOP-INTEND in a regression model provided a stronger prediction of motor outcomes for neonates at 2 years (p = 0.02). Pretreatment sNfL in infants with ≥3 SMN2 copies who did not initiate immediate treatment increased despite motor function remaining stable.

Interpretation: There is a malignant disease course with active denervation in children with 2 SMN2 copies within the neonatal period. sNfL gives early insights into underlying pathophysiology prior to a clinical phenotype and may expedite access to the initiation of treatment. ANN NEUROL 2026.

Objective: Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids.

Methods: Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations.

Results: Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum.

Interpretation: Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026.

Objective: This study aimed to compare positron emission tomography (PET) and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease.

Methods: Longitudinal amyloid PET (n = 1,097, mean age ± SD = 72.5 ± 7.38 year, 51.4% male), ¹⁸F-flortaucipir tau-PET (n = 230, 74.3 ± 7.18 year, 52.2% female), and Fujirebio Lumipulse plasma p-tau₂₁₇ (n = 752, 72.8 ± 6.93 year, 51.3% male) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using sampled-iterative Local approximation (SILA). SILA models using plasma p-tau₂₁₇ were compared to amyloid and tau PET-based models to estimate amyloid and tau onset, and factors influencing tau onset and time from tau onset to dementia were evaluated for PET and plasma models.

Results: Plasma and PET models generated similar results for estimated amyloid and tau onset, with stronger model agreement for tau (r = 0.88[0.86, 0.89], t = 57.4, p < 0.001) than amyloid (r = 0.75[0.72, 0.77], t = 37.4, p < 0.001) onset. Accuracy of estimated onset compared to actual onset was high within modality (mean absolute error [MAE] ≤ 2.03) with slightly greater error (MAE 3.09-3.42) when comparing across modalities (ie, plasma to PET). For both plasma and PET, earlier tau onset was associated with younger amyloid onset, female sex, and ≥1 apolipoprotein (ApoE) ε4 allele. Earlier dementia onset after tau was associated with later tau onset for both plasma and PET, while male sex was associated with shorter tau to dementia gap in plasma models.

Interpretation: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age, and can serve as a widely accessible tool for clinical assessment of biological disease severity. ANN NEUROL 2026.