Annals of Neurology最新文献

Multiple sclerosis (MS) and Alzheimer's disease are neurodegenerative diseases with age-related disability accumulation. In MS, inflammation spans decades, whereas AD is characterized by Aβ plaques and neurofibrillary tangles (NFT). Few studies explore accumulation of amyloids in MS. We examined Aβ deposition and NFT density in temporal and frontal cortices from postmortem MS (n = 75) and control (n = 66) cases. Compared with controls, MS cases showed reduced Aβ, especially in those aged <65 years, and reduced NFT, notably in cases aged >65 years. Aβ deposition predicted greater NFT density both in MS cases and controls. MS-related factors may affect Aβ/NFT deposition and/or clearance, offering new therapeutic insights for both diseases. ANN NEUROL 2025.

Objective: Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5, a key autophagy gene responsible for Vici syndrome, are associated with PD.

Methods: Whole-exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early-onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole-genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late-onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls.

Results: We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD-F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy-lysosome function in cells derived from EPG5-PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α-synuclein in skin tissue from EPG5-PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain.

Interpretation: Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025.

Objective: This study aimed to evaluate the association between computed tomography perfusion (CTP) parameters and outcomes in basilar artery occlusion (BAO), and to select patients with BAO who may benefit from thrombectomy.

Methods: We performed a post-hoc analysis of patients from the ATTENTION trial with available admission CTP data. CTP parameters evaluated included time to maximum (T_max) >6 s/8 s/10 s, relative cerebral blood flow (rCBF) <20%/30%/34%/38%/50%, Critical Area Perfusion Score (CAPS), and CTP-posterior circulation acute stroke prognosis early computed tomography score (CTP-pc-ASPECTS), pons-midbrain-thalamus (PMT) hypoperfusion. Multivariable Firth logistic regression was used to analyze associations between CTP parameters and outcomes and to explore treatment interactions. The primary outcome was favorable outcome, defined as modified Rankin Scale score of 0-3, at 90 days.

Results: The study included 109 patients (70 thrombectomy, 39 control). Multivariable analysis showed that lower CAPS, smaller rCBF <34% volume, and higher CTP-pc-ASPECTS were associated with favorable outcome. Patients who underwent thrombectomy had a higher likelihood of favorable outcome with increasing CAPS (T_max > 6 s) compared to control (P_interaction = 0.048 for continuous variable). When CAPS (T_max > 6 s) was treated as a categorical variable, the interaction remained significant (P_interaction = 0.03). Similarly, the treatment effect was also modified by PMT hypoperfusion (T_max >6 s) (P_interaction = 0.03). In patients with CAPS (T_max >6 s) >3 or with PMT hypoperfusion (T_max >6 s), thrombectomy was associated with favorable outcome.

Interpretation: Higher CAPS correlated with a decrease in the rate of favorable outcomes. However, patients with higher CAPS were more likely to benefit from thrombectomy compared to medical management alone, suggesting that severe hypoperfusion should not preclude endovascular treatment. ANN NEUROL 2025.

Objective: Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses.

Methods: This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere).

Results: We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores.

Interpretation: Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025.

This final part 3 review builds on the practical applications discussed in part 2 and explores how artificial intelligence (AI) is transforming data management, neurological education, and neurological care across large healthcare networks and datasets. The review also highlights AI's role in real-world and synthetic data, digital twins, and innovative clinical trial designs, such as in silico and adaptive trials. The review emphasizes AI's ability to drive continuous improvements in care and discovery through comparative effectiveness research and learning health systems. The global healthcare implications discussed here tie back to earlier discussions on human-AI collaboration and precision care, underscoring the neurological sciences' responsibility to adopt AI advances judiciously, while managing their ethical, economic, and environmental impacts. ANN NEUROL 2025.

Objective: We aimed to quantify differences in the brain and spinal cord between Friedreich ataxia and controls, stratified by age and disease stage, including for the first time in young children.

Methods: TRACK-FA is the largest prospective, longitudinal, multi-modal neuroimaging study in Friedreich ataxia to date. We assessed individuals with Friedreich ataxia and controls, 5 to 42 years, at 7 sites across 4 continents. The 17 imaging primary outcome measures (POMs) were selected from metrics that showed a significant longitudinal change in previous small-scale studies. These included brain and spinal cord morphometry (structural magnetic resonance imaging [MRI]) and microstructure (diffusion MRI); brain iron levels (quantitative susceptibility mapping); and spinal cord biochemistry (magnetic resonance spectroscopy). This study is registered with ClinicalTrials.gov (NCT04349514).

Results: Between February 2021 and August 2023, we assessed 169 individuals with Friedreich ataxia and 95 controls. Compared to controls, individuals with Friedreich ataxia had lower volume of dentate nucleus and superior cerebellar peduncles; smaller cross-sectional area of spinal cord; lower fractional anisotropy and higher diffusivity in spinal cord and superior cerebellar peduncles; and lower total N-acetyl-aspartate/myo-inositol ratio in spinal cord. Morphometric differences in spinal cord and superior cerebellar peduncles increased dramatically with age during childhood, with rapid development in controls, but not in Friedreich ataxia. Many imaging POMs showed significant associations with clinical severity.

Interpretation: Our findings provide strong imaging evidence of impaired development of spinal cord and superior cerebellar peduncles during childhood in Friedreich ataxia and open the way for the use of neuroimaging biomarkers in clinical trials. ANN NEUROL 2025.

A host of acquired abnormalities in visual function are known to occur in persons who suffer stroke, traumatic brain injury, and neurodegenerative disorders. Cerebral visual impairment occurs in children with early neurological injury or disorders, especially neonatal hypoxic-ischemic injury. With the improved survival of pre-term infants through meticulous neonatal intensive care unit care, cerebral visual impairment in children has become much more common in developed countries. In recent months a number of National Institutes of Health institutes and the American Academy of Pediatrics have brought new attention to this major public health problem, which is highly relevant to child neurologists, neuro-ophthalmologists, as well as the general neurologists who will care for affected individuals as they enter adulthood. ANN NEUROL 2025.