Intracranial atherosclerotic stenosis is a leading cause of stroke and an increasingly recognized contributor to cognitive impairment and dementia. The mechanisms underlying cognitive dysfunction in intracranial atherosclerotic stenosis remain poorly understood, particularly whether they involve direct vascular brain injury or accelerate neurodegeneration and neuroinflammation. Ultrasensitive plasma biomarkers, including the amyloid-β 42/40 ratio, phosphorylated tau at threonine 217, glial fibrillary acidic protein and neurofilament light chain, offer insights into these processes, but their role in intracranial atherosclerotic stenosis has not been elucidated. We recruited 403 patients with intracranial atherosclerotic stenosis (84 with <50% asymptomatic stenosis, 154 with ≥50% asymptomatic stenosis and 165 with ≥50% symptomatic stenosis) and 98 intracranial atherosclerotic stenosis-free controls across nine centres. Plasma biomarkers were quantified using single-molecule array technology. Cognitive function was assessed with a standardized neuropsychological battery, and multimodal MRI was performed to evaluate infarcts and cerebral small vessel disease burden. Multivariable models examined associations among intracranial atherosclerotic stenosis severity, biomarkers levels, and cognitive impairment. Plasma biomarker levels in patients with asymptomatic stenosis <50% were comparable to those in controls. Glial fibrillary acidic protein was elevated in asymptomatic stenosis ≥50%, while both glial fibrillary acidic protein and neurofilament light chain were increased in symptomatic stenosis. The amyloid-β 42/40 ratio was reduced in symptomatic stenosis ≥50%, whereas phosphorylated tau at threonine 217 was unchanged across groups. In multivariable analyses, none of the plasma biomarkers were significantly associated with cognitive impairment. In contrast, intracranial atherosclerotic stenosis itself was independently associated with cognitive impairment in a graded manner (asymptomatic stenosis <50%: OR = 2.48; asymptomatic stenosis ≥50%: OR = 2.65; symptomatic stenosis: OR = 4.14). These findings indicate that although plasma biomarkers of neurodegeneration and neuroinflammation are altered in advanced intracranial atherosclerotic stenosis, they do not explain the associated cognitive impairment. Instead, cognitive deficits appear to be driven primarily through vascular mechanisms. Our results support reconceptualizing intracranial atherosclerotic stenosis not only as a stroke-prone vascular disorder but also as a covert threat to brain health and cognition. Early identification and aggressive management of intracranial atherosclerotic stenosis, even before conventionally ‘significant’ stenosis or symptoms, are warranted.

AXL, a receptor tyrosine kinase expressed in neurons and glial cells, involved in neuronal survival, myelination, and regulation of immune responses, can undergo shedding due to the activation of metalloproteases in neuroinflammatory conditions. Indeed, CSF and serum levels of soluble AXL (sAXL) have been correlated with neurodegeneration and cognitive decline in Alzheimer’s disease (AD). Based on these observations, we explored whether sAXL is implicated in amyotrophic lateral sclerosis (ALS). sAXL levels were measured in biofluids (CSF and serum) from two biorepositories, totalling 107 ALS patients, 76 healthy controls, 25 AD patients, 22 patients with multiple sclerosis and 51 patients with ALS disease mimicking disorders (i.e. patients that displayed symptoms resembling ALS, in whom eventually ALS was excluded after a thorough clinical examination). Gender and age were considered as covariate in the statistical analyses. Our results provide the first evidence of sAXL alterations in the CSF and serum of ALS patients at diagnosis and demonstrate a significant association between CSF sAXL levels and disease progression, as well as its prognostic value in ALS. While these observations require validation through multicentre studies, they suggest the involvement of the AXL pathway in ALS pathology and pave the way for leveraging CSF sAXL levels as a biomarker to aid ALS disease stratification.

To identify imaging endophenotypes in juvenile myoclonic epilepsy using individualized Z-maps of cortical/subcortical regions and examine their relationships with cognitive, psychiatric and epilepsy-related variables. Sixty-two juvenile myoclonic epilepsy patients (aged 12–25 years) and 41 age- and sex-matched healthy controls underwent 3T MRI, neuropsychological assessment, psychiatric evaluation and clinical interviews. Cortical thickness and subcortical volumes were processed with FreeSurfer, adjusted for age, sex and brain volume. Kolmogorov–Smirnov tests were used to compare regional distributions. Z-scores were calculated relative to healthy controls, and K-means clustering identified endophenotypes. In juvenile myoclonic epilepsy, there were reduced subcortical volumes most prominently in motor-related thalamus (P < 0.001) and greater variability in cortical thickness in the frontal/parietal regions. Three endophenotypes emerged: subcortical reduction (n = 27, 43.5%), increased cortical thickness (n = 21, 33.9%) and decreased cortical thickness (n = 14, 22.6%). Subcortical reduction showed marked motor thalamic and subcortical grey matter loss. Increased cortical thickness exhibited frontal and parietal cortical thickening with associated subcortical reduction. Decreased cortical thickness showed less subcortical change, but overall reduced cortical thickness. Cognitive differences were notable: Increased Cortical Thickness was the most impaired cognitively, suggesting a disruption of neurodevelopment, while decreased cortical thickness performed the best, particularly in speed/response inhibition—consistent with the least disruption of brain maturation and dysregulation of synaptic pruning. Seizure burden, socioeconomic status, age of onset and psychiatric diagnoses did not show any differences between groups. Juvenile myoclonic epilepsy exhibits heterogeneous imaging endophenotypes, with motor thalamic and subcortical reductions and variability cortical thickness in the frontal and parietal regions, reflecting neurodevelopmental dysregulation with cognitive consequences.

NDUFAF6 encodes a mitochondrial complex I assembly factor essential for the proper biogenesis and stability of the nicotinamide adenine dinucleotide (NAD) + hydrogen (H) (NADH)–ubiquinone oxidoreductase complex. Pathogenic variants in NDUFAF6 have been increasingly recognized as a cause of mitochondrial disease, particularly Leigh syndrome, a severe neurodegenerative disorder characterized by bilateral symmetrical lesions in the central nervous system. To date, fewer than 50 patients with NDUFAF6-related mitochondrial disease have been reported, displaying a broad phenotypic spectrum ranging from early-onset neurodevelopmental regression to milder, more chronic presentations. The molecular mechanisms underlying these phenotypes are linked to impaired complex I assembly and reduced enzymatic activity, highlighting the critical role of NDUFAF6 in mitochondrial function.Here we present a cohort of 27 patients (14 males and 13 females) from 18 families harbouring biallelic variants in the NDUFAF6 gene. The patient’s mean age was 9.15 ± 8.30 years (range: 4 weeks to 25 years); 12 patients (37%) had died by the time the data were collected for this article. The clinical presentation showed wide phenotypic variability, from mild to severe psychomotor regression (74%) most commonly before the age of 5 years, hypotonia (22%), movement disorders (30%), and hypertonia (15%). Bilateral striatal necrosis lesions were the most characteristic features on cranial MRI (67%) although white matter abnormalities were also noted (15%), occasionally accompanied by cystic formations, suggestive of early neurodevelopmental anomalies.Genomic sequencing was applied, leading to the identification of 19 distinct variants in the NDUFAF6 gene, including nine novel variants not previously reported and either absent or extremely rare in public population databases. Functional studies confirmed the pathogenicity of these variants, demonstrating a deleterious effect on NDUFAF6 protein expression and a consequent impairment in complex I assembly and stability.To date, this represents the largest reported cohort of patients with NDUFAF6-associated mitochondrial disease. Our findings provide a comprehensive overview of clinical characteristics—including age of symptom onset, phenotypic variability, and patient outcomes—aiming to improve prognostic information and facilitate genetic counselling in clinical practice.

Short tandem repeat expansions are associated with over 50 diseases, many with primary neurological presentations. Despite the prevalence of short tandem repeat expansion disorders, genetically diagnosing these conditions is complicated by a lack of efficient and comprehensive diagnostic screening approaches. We integrated a new short tandem repeat genotyping tool, STRipy, into the analytical workflow for short-read sequencing data generated by the comprehensive neurological disease gene panel used in the Diagnostic Genomics Department, PathWest Laboratory Medicine. We tested STRipy on Versions 6 and 7 of the panel. Version 6 already included probes covering five short tandem repeat expansion loci in the following genes: CACNA1A, PPP2R2B, TBP, NOP56 and RFC1. Additional probes targeting 13 neurological disease short tandem repeat expansion loci were designed and included in Version 7. All expansions detected by STRipy were validated and sized using PCR-based diagnostic techniques. Four hundred and eighteen patients with ataxia were tested on Version 6 of the panel, and 61 (14.6%) had reportable pathogenic variants, including 11 patients with pathogenic repeat expansions detected by STRipy. Sixty-seven ataxia patients were tested on Version 7 of the panel, and 15 (22.4%) had reportable pathogenic variants, including three repeat expansions detected by STRipy. Therefore, STRipy contributed 18.0% and 20.0% of the solved cases from Version 6 and 7 of the ataxia subpanels, respectively. STRipy accurately identified and sized loci with shorter pathogenic repeat thresholds where the expansion was smaller than the read length. In addition to increased diagnostic yield, implementation of STRipy into diagnostic analysis pipelines has streamlined clinical diagnosis of short tandem repeat expansion disorders.

Alzheimer's disease is characterized by amyloid-β and tau protein accumulation. Growing evidence suggests that white matter degeneration contributes to disease progression. Despite Alzheimer's disease being more prevalent in women, understanding of sex differences in white matter microstructure across the Alzheimer's disease continuum remains limited. This study investigated sex-specific patterns of white matter integrity in individuals genetically predisposed to autosomal dominant Alzheimer's disease. We analysed data from 63 individuals (30 presenilin-1 glutamic acid to Alanine at codon 280 (PSEN1 E280A) mutation carriers, 33 non-carriers) from a Colombian kindred with early-onset autosomal dominant Alzheimer's disease. Participants underwent diffusion-weighted imaging, amyloid and tau positron emission tomography and cognitive assessment. Using fixel-based analysis, we examined fibre density, fibre-bundle cross-section and combined fibre density and cross-section across major white matter tracts. Linear regression models assessed sex differences in white matter microstructure and examined how sex moderated relations between pathological burden, white matter integrity and cognitive performance. Females showed trends towards higher fibre cross-section than males in the anterior thalamic radiation (β = 0.057, P = 0.004), forceps minor of the corpus callosum (β = 0.047, P = 0.012) and inferior fronto-occipital fasciculus (β = 0.030, P = 0.015), but lower values in the cingulum (cingulate gyrus portion) (β = −0.07, P = 0.031). Sex appeared to moderate the association between pathology and white matter in multiple tracts. However, these findings did not survive correction for multiple comparisons and should be interpreted as exploratory. In the right temporal superior longitudinal fasciculus, females showed relatively preserved integrity compared to males as tau burden increased (β = 0.23, P = 0.016), while males exhibited greater amyloid-β-associated disruption than females in the uncinate fasciculus (β = −0.14, P = 0.05). Sex also moderated relations between white matter integrity and cognition, with males showing stronger structure–function coupling than females in tracts such as the cingulum (hippocampus portion), forceps major and corticospinal tract. Our findings revealed significant sex-specific patterns of white matter microstructural alterations in autosomal dominant Alzheimer's disease, with females showing preserved fibre cross-section in key tracts and slower rates of white matter deterioration with increasing tau pathology in memory-related circuits, whereas males demonstrated advantages in structure–function coupling. These data highlight the importance of considering sex differences in understanding white matter alterations in Alzheimer's disease and suggest the potential utility of considering sex differences in the development of personalized interventions and clinical trials for persons with Alzheimer's disease.

Alcohol use disorder (AUD) often emerges in adolescence and young adulthood, yet early neural predictors remain scarce. The olfactory system, through its connections with limbic and reward circuits, may provide a novel window into compulsive alcohol use. These brain regions are altered in AUD, but the role of olfactory pathways is poorly understood. Anxiety, a common comorbidity in AUD, may further modulate these circuits. This study investigates whether anxiety moderates the relationship between olfactory–reward brain connectivity and risky alcohol use and dependence. We analysed multimodal data from 1003 participants (22–36 years) in the Human Connectome Project. Resting-state functional MRI was used to compute functional connectivity among 41 regions implicated in olfaction, emotion, memory and reward. Odour identification scores were used to isolate connectivity features most correlated with olfactory function. These features served as predictors in ElasticNet and LASSO classification models for three alcohol-related outcomes: (i) lifetime Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV alcohol dependence, (ii) past-year risky drinking and (iii) past-week risky drinking. Models were trained on a Synthetic Minority Over-sampling Technique (SMOTE)-balanced subset (n = 704) and validated on a propensity score-matched holdout dataset (n = 83). Post hoc logistic regression examined anxiety (DSM scores) as a moderator of connectivity–outcome associations. Connectivity between the precuneus–cingulate–accumbens and lateral occipital–hippocampal regions predicted lifetime alcohol dependence (odds ratio = 1.12, P < 0.001). Models showed strong performance (area under the curve > 0.90 training; >0.80 validation). Anxiety moderated key connections: it attenuated the risk effect of memory–reward circuitry and amplified risk via inferior frontal–parietal connectivity. Odour identification scores did not differ across alcohol risk groups. Model performance replicated in a propensity-matched validation set. Our findings reveal a novel olfactory–limbic circuit predictive of alcohol dependence in young adults. Anxiety modulates these pathways, suggesting dynamic brain–behaviour interactions that may underlie individual vulnerability and resilience. This framework supports the integration of sensory, emotional and transdiagnostic features in neurobiological models of addiction.

The final editorial from our founding editor-in-chief introduces the new editor-in-chief, Professor David Belin from University of Cambridge, UK.

Individuals with spinal cord injury are subject to a higher risk of cognitive impairment, with executive functions being amongst the most affected ones. Even though the occurrence of cognitive impairment following spinal cord injury has been confirmed in several studies, the related alterations in the brain are not known yet. This prospective observational study aims to tackle this issue by investigating the neural correlates of executive functions in spinal cord injury. Twenty-six individuals with chronic spinal cord injury (mean age = 45.8 11.0 years, mean time since injury = 13.3 11.1 years) and 26 age- and sex-matched non-injured controls (mean age = 43.1 11.5 years) performed a phonemic verbal fluency task as a proxy for executive functions during functional magnetic resonance imaging. We compared task performance, as well as differences in brain activity and seed-based functional connectivity between groups using general linear models. Additionally, we correlated performance and functional connectivity using Pearson correlation. Performance on the verbal fluency task was significantly lower (15% less correct words) in individuals with spinal cord injury, compared to non-injured controls (P = 0.02). For the imaging analysis, two individuals with spinal cord injury were removed due to excessive motion and non-attentiveness during the imaging task, leading to a sample size of 24 for the spinal cord injury group. There was significantly lower activity in the right putamen in individuals with spinal cord injury compared to non-injured controls (P = 0.015 corrected with family-wise error). Functional connectivity between the left insula and the superior frontal gyrus was lower in spinal cord injury individuals compared to controls (P < 0.001 corrected with family-wise error). In spinal cord injury individuals, verbal fluency performance negatively correlated with functional connectivity between the right insula and the right postcentral gyrus (r = -0.82, P = 0.001 corrected with family-wise error), and between the left putamen and the bilateral precentral gyrus (r = -0.74, P = 0.002 corrected with family-wise error). Altered brain activity and functional connectivity were found in regions typically associated with executive functions in individuals with spinal cord injury. As the insula acts as a switch between brain networks, including the central executive network, to reallocate cognitive resources, its altered functional connectivity with prefrontal areas may be linked to deficits in executive functions in spinal cord injury. Interestingly, the functional connectivity of sensorimotor regions correlated with verbal fluency performance, suggesting an interference of the disrupted sensorimotor domain with cognitive functions.

Pyruvate kinase M2 (PKM2) has emerged as a critical regulator of Alzheimer’s disease pathophysiology. This review synthesizes current evidence demonstrating how PKM2 dysregulation contributes to cognitive decline by driving Warburg-like metabolic reprogramming, altering post-translational modifications and modulating protein–protein interactions. These processes collectively impair cell-cycle control, transcriptional regulation and cytoskeletal stability in neuronal cells. We further examine the impact of PKM2 on neuroinflammation, highlighting its context-dependent roles in microglia and astrocytes. In addition, we provide a comprehensive evaluation of natural and synthetic PKM2 modulators with therapeutic potential in Alzheimer’s disease, summarizing their mechanisms and reported outcomes. Clarifying the molecular basis of PKM2-mediated neurodegeneration and rigorously testing these modulators in preclinical models will be essential steps towards developing PKM2-targeted strategies for Alzheimer’s disease intervention.