Objective Amyotrophic lateral sclerosis (ALS) has a markedly distinctive clinical and neuroradiological signature, with the preferential involvement of specific brain networks and the apparent sparing of others. The molecular underpinnings of the strikingly selective anatomical vulnerability have not been fully elucidated to date despite the potential therapeutic relevance of characterizing neurotransmitter receptor‐defined susceptibility to degeneration. Methods A large neuroimaging study was undertaken with 258 participants to systematically evaluate topological associations between neurodegeneration and neurotransmitter expression distributions. Patients were stratified based on their genetic profile into sporadic and C90rf72 hexanucleotide repeat expansion carriers. Anatomical associations were evaluated between patterns of atrophy and topological neurotransmitter receptor distributions. Cross‐sectional and longitudinal trends were comprehensively evaluated over 4 consecutive timepoints. Results Our analyses reveal topological associations between neurodegeneration in sporadic ALS and GABA‐A receptor α5‐selective component (GABAa5), serotonin 1a receptor, and kappa opioid receptor expression maps. In addition to these networks, neuronal loss in patients with GGGGCC hexanucleotide repeat expansions exhibit predilection to glutamatergic, endocannabinoid, and microglial systems. Our multi‐timepoint longitudinal analyses reveal dynamic temporal associations between focal volume loss and neurotransmitter expression with increasing spatial associations with noradrenaline transporter and GABAa5, but high attrition rates preclude definite longitudinal inferences. Interpretation Our data suggest the preferential vulnerability of GABAergic, serotonergic, kappa opioid mediated networks in sporadic ALS. In C9orf72 ‐assocaited ALS, glutamatergic, endocannabinoid circuits are also susceptible and microglia‐mediated neuroinflammation is also implicated. The comprehensive evaluation of neurotransmitter‐receptor associations not only offer academic insights regarding pathophysiological processes in ALS, but may inform targeted therapy development strategies. ANN NEUROL 2026;100:948–961
Adolescent mental health has deteriorated globally, with rising rates of depression, suicidal behaviors, and non-suicidal self-injury (NSSI), particularly in the context of a rapidly evolving post-pandemic sociocultural context and the widespread prevalence of dysregulated social media use. However, existing models do not fully explain why adolescents exposed to similar stressors exhibit markedly different psychological outcomes. To propose an integrated developmental–ecological framework of mental pain in adolescence that explains variability in clinical outcomes by linking developmental vulnerability, emotion regulation, affective control, and mental pain tolerance, with particular emphasis on the transition from psychological distress to intolerable mental pain and suicidal behavior. An overview of empirical and theoretical literature on adolescent mental health, including studies on emotion regulation, developmental neuroscience, suicidality, social context, and digital environments. Priority was given to recent longitudinal and clinical studies, as well as foundational theoretical models. Mental pain in adolescence emerges as a multidimensional process involving emotional distress, social disconnection, cognitive overload, and self-regulatory difficulties. Emotion regulation functions as a central transdiagnostic mechanism, while affective control provides the cognitive foundation supporting emotion regulation processes. A key refinement of the proposed framework is the distinction between mental pain intensity and mental pain tolerance, with tolerance acting as a critical moderator of developmental and clinical outcomes. Environmental stressors, including pandemic-related disruptions and digitally mediated experiences, interact with developmental vulnerability to amplify or attenuate psychological distress. Variability in outcomes, including suicidal behaviors and self-harm, may be better understood through differences in regulatory capacity, distress tolerance, social and relational determinants, existential concerns, and the subjective experience of unbearable psychological pain. Adolescent mental pain reflects a dynamic imbalance between emotional demands and regulatory capacity within a socio-relational context. Integrating emotion regulation, cognitive control, and mental pain tolerance provides a more precise framework for understanding psychological distress and suicidality. Beyond symptom reduction, this model highlights the clinical importance of identifying and relieving the causes of intolerable psychological suffering while strengthening regulatory skills, distress tolerance, relational connectedness, and supportive social environments.
Objective Epigenetic clocks are biomarkers of biological aging influenced by lifestyle and systemic factors. Accelerated epigenetic aging has been associated with neurodegeneration, but its relevance in frontotemporal dementia is unclear. We investigated biological aging in frontotemporal dementia using the GrimAge2 epigenetic clock, a DNA methylation‐based predictor of mortality, and examined the contribution of smoking‐related DNA methylation. Methods Peripheral blood DNA methylation data from frontotemporal dementia patients and controls from 2 independent cohorts were analyzed (Amsterdam Dementia Cohort: 313 patients, 121 controls; Genetic Investigation in Frontotemporal Dementia study: 102 patients, 102 controls). GrimAge2 was used to estimate epigenetic age acceleration. Associations with diagnosis were assessed using linear regression models adjusted for sex, estimated cell type proportions, and smoking (self‐reported and DNA methylation‐derived), followed by random‐effects meta‐analysis. Component‐level analyses examined smoking‐related DNA methylation, inflammatory markers, and glucose metabolism. Results Patients with frontotemporal dementia showed increased GrimAge2‐derived epigenetic age acceleration ( β = 1.17 ± 0.36, 95% CI 0.46–1.88, p = 0.001) compared with controls. Component‐level analyses showed increased smoking‐related DNA methylation, systemic inflammation (tissue inhibitor of metalloproteinases 1, C‐reactive protein), and glucose metabolism (glycated hemoglobin; all p < 0.05). Adjustment for smoking‐related DNA methylation was associated with attenuation of the effect estimate by approximately 48% (epigenetic age acceleration: β = 0.62 ± 0.32, 95% CI −0.01–1.24, p = 0.053). Interpretation Accelerated epigenetic aging in frontotemporal dementia is associated with GrimAge2‐derived DNA methylation patterns linked to smoking, inflammation, and metabolic pathways. These findings raise the possibility that smoking‐related DNA methylation reflects differences in smoking exposure or disease‐related behavioral changes captured by GrimAge2. ANN NEUROL 2026
Objective A substantial proportion of individuals with suspected genetic conditions, including neuromuscular disorders, lack a definitive molecular diagnosis. Non‐coding variants, particularly those in the 3′ untranslated region (3´UTR), which regulate mRNA stability, translation, and localization, may underlie part of this gap. We investigated the clinical, genetic, and functional relevance of a novel 3′UTR variant in CAPN3 in individuals with persistent hyperCKemia, most of whom also presented with proximal muscle weakness. Methods Clinical assessment, including muscle biopsy and muscle magnetic resonance imaging (MRI), was performed in individuals harboring the CAPN3 c.*534T>C variant. In silico analyses included the assessment of miRNA binding, mRNA secondary structure, creation or disruption of a poly‐A tail, and RNA‐binding protein (RBP) motifs. A luciferase reporter assay with the c.*534T>C and reference sequence, in the presence or absence of RBFOX1 co‐expression, was performed. Results We identified 13 individuals from 11 unrelated families presenting with persistent hyperCKemia, commonly accompanied by proximal muscle weakness and myalgia, all harboring the c.*534T>C variant in combination with a previously identified heterozygous CAPN3 variant. Western blot analyses consistently demonstrated absent or markedly reduced calpain‐3 expression, and muscle RNA sequencing (RNAseq) showed reduced CAPN3 levels. In silico analyses indicated that the c.*534T>C variant creates a novel binding site for the RNA‐binding protein RBFOX1. Luciferase reporter assays supported a regulatory effect of the identified variant on calpain‐3 expression. Interpretation Our results show that a recurrent non‐coding CAPN3 variant causes disease by disrupting post‐transcriptional regulation and demonstrate a generalizable principle, as 3′UTR variants can affect mRNA stability and protein expression across neuromuscular and other Mendelian diseases. Although often difficult to interpret as pathogenic, these variants can be therapeutically actionable, highlighting the importance of systematically investigating non‐coding regions in unsolved genetic cases. ANN NEUROL 2026
Objective Sleep–wake and circadian disturbances are increasingly recognized in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim‐light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home‐based salivary melatonin sampling under dim‐light conditions at 6 predefined time points around habitual sleep onset. Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age‐ and sex‐matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results A total of 50 plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 ± 1:18 vs 20:58 ± 0:50; p = 0.028) despite similar habitual sleep onset and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.11; p = 0.019), and poorer survival/tracheostomy‐free outcome. In the resampled subgroup ( n = 28), DLMO and melatonin‐derived metrics did not change over ~6 months. Interpretation Circadian phase alterations are detectable in early ALS. Baseline DLMO showed exploratory associations with functional, respiratory, and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker. ANN NEUROL 2026
