Familial forms of ALS are potential candidates for gene-directed therapies, but many recently identified genes remain poorly characterized. Here, we provide a comprehensive clinical, neuropathological, and biochemical description of fALS caused by the heterozygous p.R15L missense mutation in the gene CHCHD10. Using a cross-sectional study design, we evaluated five affected and nine unaffected individuals from a large seven-generation pedigree with at least 68 affected members. The pedigree suggests a high (68 - 81%) but incomplete disease penetrance. Through cloning of the disease-allele from distant members of the family, we establish the disease haplotype in the family. Notably, the haplotype was distinct from that of a previously reported p.R15L mutation carrier with ALS, demonstrating that the variant is in a mutational hotspot. The clinical presentation was notable for being highly stereotyped; all affected individuals presented with the rare ALS variant Flail Arm Syndrome (FAS; also known as, brachial amyotrophic diplegia or Vulpian-Bernhardt Syndrome), suggesting greater involvement of the cervical spinal cord. Consistently, neuropathology from one family member demonstrated substantially increased CHCHD10 protein aggregation and neuronal loss (though absent TDP-43 pathology) in the cervical vs. lumbar spinal cord. This FAS phenotype could be captured by a simple timed finger tapping task, suggesting potential utility for this task as a clinical biomarker. Additionally, through analysis of fibroblast lines from 12 mutation carriers, isogenic iPSC cells, and a knockin mouse model, we determined that CHCHD10 with the R15L variant is stably expressed and retains substantial function both in cultured cells and in vivo, in contrast to prior reports. Conversely, we find loss of function (LoF) variants are more common in the population but are not associated with a highly penetrant form of ALS in the UK Biobank (31 in controls; 0 in cases). Together, this argues against LoF and in favor of toxic gain-of-function as the mechanism of disease pathogenesis, similar to the myopathy-causing variants in CHCHD10 (p.G58R and p.S59L). Finally, through proteomic analysis of CSF of variant carriers, we identify that CHCHD10 protein levels are elevated approximately 4-fold in mutation carriers, and that affected and unaffected individuals are differentiated by elevation of two neurofilaments: neurofilament light chain (NfL) and Peripherin (PRPH). Collectively, our findings help set the stage for gene-directed therapy for a devasting form of fALS, by establishing the likely disease mechanism and identifying clinical and fluid biomarkers for target engagement and treatment response.
Pathological forms of TAR-binding protein 43 (TDP-43), involving its aberrant mislocalization to the cytoplasm, inclusion formation, hyperphosphorylation and fragmentation, are present in ∼45-50% frontotemporal dementia (FTD) and Alzheimer's disease individuals, and most (97%) amyotrophic lateral sclerosis (ALS) cases. Hence, identifying mechanisms that induce TDP-43 pathology are central to neurodegeneration and developing new therapeutic targets in these conditions. Cofilin is a multi-functional protein with a crucial role in regulating the actin cytoskeleton. Actin has important neuronal-specific activities in dendritic spines, axonal growth cones and synapses and it is in constant equilibrium between two forms: monomeric globular actin (G-actin) and polymeric filamentous actin (F-actin). Cofilin controls actin dynamics by depolymerising and severing actin filaments. When cofilin is phosphorylated (at Serine-3) by LIM kinase1 (LIMK1), it becomes inactive, leading to production of more F-actin. Defects in cofilin are well described in other neurodegenerative disorders, unlike in ALS. We examined phosphorylation of cofilin and actin dynamics in post-mortem spinal cord tissue from sporadic ALS (SALS) patients, the TDP-43 rNLS8 transgenic mouse model, and NSC34 motor neuronal cells expressing cytoplasmic TDP-43. F-actin was pharmacologically stabilized to mimic cofilin hyperphosphorylation, and TDP-43 pathology was assessed. Neuronal cells were treated with a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN), and TDP-43 pathology and apoptosis were evaluated. Here, we show that cofilin is hyper-phosphorylated in human ALS and disease models compared to controls. This was detected in spinal motor neurons from sporadic ALS (SALS) patients and a TDP-43 mouse model (rNLS8) displaying key ALS phenotypes, and in motor neuronal NSC34-cells expressing cytoplasmic TDP-43. Supporting this observation, more F-actin relative to G-actin was present in cortical/spinal cord lysates from SALS patients and TDP-43 rNLS8 mice, and NSC34-cells expressing TDP-43. We also show that mimicking cofilin hyperphosphorylation by pharmacological stabilization of F-actin induced TDP-43 pathology: cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, and fragmentation, and promoted its recruitment into stress granules (SGs). Furthermore, we detected increased levels of LIMK1 phosphorylation and tropomyosin isoforms 4.1 and 4.2 in SALS patients. These findings reveal aberrant cofilin hyperphosphorylation disrupts actin dynamics, triggering TDP-43 pathology and SG recruitment in SALS. They imply that preventing cofilin phosphorylation is a novel therapeutic strategy applicable to most ALS cases. Treatment of neuronal cells with the S3A peptide prevented features of TDP-43 pathology and apoptosis compared to control peptides. These findings thus describe a novel pathogenic mechanism producing TDP-43 pathology, applicable to most ALS cases and other neurodegenerative diseases.
Reported prevalence estimates of Lewy body pathology (LBP) vary widely, often without considering brain regional distributions or demographic influences. Large, population-representative autopsy cohorts are needed to provide estimates and clarify the distribution and clinical implications of LBP. Neuropathological, genetic, and clinical data were pooled from nine community- or population-based brain autopsy cohorts in the USA (n=6), Brazil, Austria, and Finland (n=7309 total; 59% women; mean age of death 84.2 years). Cognitive status was available for 6166 participants: dementia (38.5%), mild cognitive impairment (14.8%), and cognitively unimpaired (47.0%). Frequency of LBP was examined by anatomical distribution (neocortical, limbic, brainstem, amygdala, olfactory) and stratified by covariates. Prevalence was calculated in meta-analysis, and mixed-effect logistic regression examined associations with sex, cognitive status, Alzheimer's disease neuropathological change (ADNC), and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) co-pathology. Overall, 27.3% of participants had LBP: neocortical 8.4%, limbic 6.8%, brainstem 4.8%, amygdala 3.7%, and olfactory 3.6%. Neocortical LBP was associated with dementia (present in 15%; OR=4.06 [95%CI 3.24-5.10]) and with increased odds of ADNC (OR=2.30 [95%CI 1.88-2.81]) and LATE-NC (OR=2.03 [95%CI 1.69-2.44]). Sex differences were not observed in the frequencies of neocortical or limbic LBP. However, amygdala-predominant LBP was more frequent in women (OR=1.53 [95%CI 1.06-2.21]) whereas brainstem-predominant LBP was more common in men (OR=0.64 [95%CI 0.49-0.84]). Additionally, amygdala-predominant LBP was associated with increased odds of comorbid ADNC (OR=12.7 [95%CI 5.30-30.6]) while brainstem-predominant LBP was not associated with greater odds of ADNC co-pathology (OR=0.88 [95%CI 0.67-1.16]). Pooling data from large, international community-based autopsy cohorts allows for more robust estimates of region-specific LBP prevalence and their associations with cognitive status. The observed sex- and co-pathology-specific differences in brainstem and amygdala-predominant LBP highlight potential biological heterogeneity and suggest that distinct disease pathways may underlie these patterns.
Since the coronavirus disease 2019 (COVID-19) pandemic began in 2020, several studies from various countries have described changes in the epidemiology of Guillain-Barré syndrome (GBS); however, it remains unclear whether the incidence and clinical profiles were altered by the pandemic. This study aimed to elucidate the impact of the COVID-19 pandemic on the epidemiology and clinical profile of GBS in Japan. We conducted a nationwide survey on the incidence of GBS between 2017 and 2022, encompassing the pre-pandemic [2017‒2019] and pandemic [2020‒2022] periods. Questionnaires were sent to the neurology and paediatrics departments at hospitals throughout Japan. A primary questionnaire was used to estimate the number of patients and incidence, and a second questionnaire was administered to collect detailed clinical information. The annual number of newly diagnosed GBS cases and their incidence were estimated at 1,885 (95% confidence interval [CI], 1,766‒2,004) and 1.49 (95% CI, 1.40‒1.58) per 100,000 population, respectively, during the pre-pandemic, 1,603 (95% CI, 1,463‒1,743) and 1.28 (95% CI, 1.17‒1.39) per 100,000 population during the pandemic periods; the relative risk for GBS incidence during the pandemic period was 0.91 (95% CI, 0.83‒0.99; 9% reduction). Detailed clinical profiles were available for 2,623 patients (1,420 during the pre-pandemic period and 1,203 during the pandemic period). Compared with patients in the pre-pandemic period, those diagnosed during the pandemic period were older (median age, 56 years vs. 53 years; P = 0.02), had a higher proportion of cases without antecedent infectious episodes (38.2% vs. 24.5%; P < 0.0001), longer time to reach nadir (median, 8 days vs. 7 days; P = 0.0418), and higher frequency of the demyelinating subtype of GBS (37.8% vs. 32.6%; P = 0.0068). No significant differences were observed in the outcomes at 6 months post-onset. The Japanese national registry data showed a markedly reduced number of Campylobacter-related enteritis cases following the pandemic. This study demonstrated a decrease in the overall incidence of GBS during the earlier phase of the COVID-19 pandemic in Japan. The increased number of GBS cases without infectious episodes or demyelinating subtypes during the pandemic period may be caused by reduced exposure to conventional infectious triggers of GBS, such as C. jejuni and increased asymptomatic COVID-19-related demyelinating GBS.
Gain-of-function (GOF) variants in GABAA receptors are increasingly recognised as a cause of severe developmental and epileptic encephalopathies (DEE). However, the mechanisms by which enhanced GABAA receptor activity leads to neuronal network hyperexcitability remains unclear. We engineered a novel mouse model based on the human GOF GABRB3 p.(Glu77Lys) variant (β3E77K), identified in two individuals diagnosed with DEE, to explore the mechanisms underlying GABAA receptor GOF disease. The phenotypes of β3E77K mice included embryonic lethality consistent with a severe early developmental impact of the GOF GABAA receptor variant. These mice display spike-wave-like discharges that were exacerbated by vigabatrin and ameliorated by valproate matching the clinical observations of GOF GABRB3 patients. β3E77K mice also have increased proconvulsant-induced seizure susceptibility and a broad increase in ECoG spectral power amplitude, indicative of cortical hyperexcitability. Additionally, neurological assessments revealed hypoactivity and weakened grip-strength. Ex-vivo electrophysiological recordings demonstrated increased GABAA receptor-mediated current amplitudes at both excitatory and inhibitory synapses in CA1 hippocampus, consistent with the GOF molecular phenotype previously identified in functional studies. In cortical layer 2/3, inhibitory interneurons showed increased synaptic GABAA receptor-mediated current amplitude, while synapses onto pyramidal neurons exhibited reduced inhibitory currents. Enhanced GABAA receptor-mediated synaptic activity among layer 2/3 interneuron populations caused a use-dependent collapse of feed-forward inhibition resulting in increased pyramidal neuron excitability. Computational modelling supported this disinhibition mechanism, showing that enhanced GABAA receptor synaptic strength between interneurons diminishes inhibitory synaptic conductance onto pyramidal cells. Our findings highlight the critical role of interneuron network dysfunction in driving cortical hyperexcitability caused by GOF GABAA receptor variants. They provide a novel pathogenic mechanism in DEE that could have broader implications for disorders involving dysfunction in GABAergic neurons. The β3E77K mouse also provides a unique preclinical model to test therapeutic strategies in GOF GABAA receptor disease.
Efforts to predict schizophrenia risk using biological data have been hampered by the heterogeneity of current "clinical-high-risk" (CHR-P) criteria, which pool phenomenologically and biologically distinct syndromes under a single label. In particular, the field has focused almost exclusively on ultra-high-risk (UHR) symptoms, while cognitive basic symptoms (COGDIS)-despite their close alignment with schizophrenia's core features such as formal thought disorder-have remained underutilised. To date, no study has directly compared brain signatures of different CHR-P definitions with respect to their similarity to schizophrenia and their diagnostic, biopsychosocial, and prognostic profiles. We applied machine learning to structural MRI data from 1,425 patients (CHR-P subgroups, recent-onset psychosis, depression) and 907 healthy controls to derive and compare diagnostic brain signatures for Cognitive Disturbances (COGDIS), Ultra-High-Risk (UHR), their overlap (MIXED), and schizophrenia. The MIXED and UHR signatures lacked diagnostic separability and similarity with schizophrenia. Contrarily, the COGDIS signature distinguished patients from controls (BAC=69%, P < .001) and aligned with the schizophrenia signature (r = 0.60), involving shared fronto-parieto-perisylvian volume reductions. UHR was characterised by volume enlargements, whereas MIXED exhibited a mixed pattern of reductions and enlargements relative to healthy controls. COGDIS and schizophrenia signature expressions were predictable with 12%-21% variance explained based on polygenic, cognitive, and exposomal factors both in a transdiagnostic patient cohort and in healthy controls. Their expressions increased from health to schizophrenia. MIXED signature expression was also predictable from biopsychosocial data, but with higher explained variance in patient samples (21%) than in healthy controls (3%). UHR signature expression showed no significant biopsychosocial predictability in either group. Cell-enriched polygenic risk profiles differed across signatures, with COGDIS and schizophrenia showing enrichment patterns implicated in neurodevelopmental processes, while MIXED being associated with immune- and blood-brain-barrier-related enrichments. Longitudinally, COGDIS and schizophrenia brain scores stratified patients with functional disability, while UHR scores predicted better outcomes. Together, these findings indicate that psychosis-risk syndromes differ markedly in the diagnostic specificity, biopsychosocial informativeness and prognostic value of their underlying brain signatures. UHR symptoms are linked to a weak and diagnostically unspecific brain pattern, while the MIXED phenotype is characterised by a dimensional, transdiagnostic signature enriched across early psychotic and affective disease states. In contrast, COGDIS aligns with a neurodevelopmentally grounded vulnerability pattern that converges with schizophrenia's cognitive-disorganisation dimension. These distinctions support a biologically informed reconceptualization of psychosis risk, with cognitive basic symptoms capturing a core liability dimension of schizophrenia, while other risk states reflecting more transient processes underlying psychotic symptom expression.
Parkinson's disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy. In the current case-control study, we expanded the PD cohort to further corroborate the structure-symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7T fMRI to assess LC responsivity to arousing auditory and visual stimuli in two fMRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order. In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in caudal LC relative to the control group (P = 0.010). This structural disintegration correlated with orthostatic hypotension (P = 0.009) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.105). In an exploratory analysis of a smaller sub-sample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.007). Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures impaired functional responsivity of caudal LC. The presence of arousal-induced hypoactivation of caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.
Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology.
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an established treatment for patients with drug-refractory epilepsy (DRE), yet long-term therapeutic outcomes are highly variable and challenging to predict. This variability is compounded by the delayed and gradual effects of DBS, the difficulty of consistent seizure monitoring, and the absence of physiological biomarkers to inform treatment. In this study, we analyzed longitudinal intracranial recordings over a four-year observational period from a cohort of 22 patients with ANT-DBS. Our primary goal is the identification of neurophysiological signatures that could predict and track clinical DBS response. Our results show that DBS-responders and non-responders exhibit distinct ANT spectral trajectories over time, with responders showing a progressive increase in higher frequencies (β₁,γ) and decreased lower-frequency (δ,θ) activity, as compared to non-responders. Notably, these dynamic biomarkers, particularly high-to-low frequency ratios (e.g., β₁/θ), enabled the early discrimination of clinical outcomes. Additionally, we provide evidence of robust circadian and multidien rhythms in ANT local field potentials, with further analyses supporting the feasibility of adaptive stimulation protocols to improve therapeutic outcomes. Together, these findings propose ANT spectral dynamics in outpatient settings as a promising tool for early prediction of therapeutic efficacy and pave the way for biomarker-guided optimization of DBS therapy in epilepsy.
Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscillation is coupled to the phase of a slower brain oscillation, is implicated in various higher-order cognitive functions and was shown to be pathologically altered in neurological and psychiatric disease. In Parkinson's disease (PD), the coupling between gamma amplitude (50-150 Hz) and beta phase (13-35 Hz) is exaggerated. Enhanced β-γ PAC was found in the subthalamic nucleus and various cortical sources and shown to be responsive to dopaminergic therapy and deep brain stimulation (DBS). Therefore, exaggerated β-γ PAC has been proposed to be a disease marker and a potential target for brain circuit interventions. Despite these promising findings, a significant knowledge gap remains, as the spatial and frequency-specific dynamics of β-γ PAC and its association with motor symptoms and therapy remain elusive. To address this knowledge gap, we employed high-density electroencephalography (EEG) with source localisation techniques for patients with PD at rest. We highlight three key findings: (1) a frequency-specific increase in high β (23-35 Hz)-γ PAC within and between sources of the cortical motor network, (2) a link between elevated high β-γ PAC and bradykinesia and rigidity when OFF medication, but not tremor, and (3) a medication-induced reduction in high β-γ PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides novel insights into the pathophysiology of PD as an oscillopathy and identifies high β-γ PAC as a potential marker of Parkinsonian symptoms and treatment effects. This has important implications for invasive as well as non-invasive therapeutic strategies as high β-γ PAC targeting might hold greater promise than targeting β-γ PAC per se.
We previously published a sex-specific genetic analysis of memory performance, a strong endophenotype of Alzheimer's disease (AD), whereby we identified numerous sex-specific genetic loci, candidate genes, and biological pathways associated with late-life memory performance. Here, we expand on this work by conducting a sex-specific, cross-ancestral genetic analysis of three cognitive domains related to cognitive change in AD: memory, executive functioning, and language. This analysis was comprised of 10 aging and AD cohorts, including 33,918 older adults with a mean age of 73 years old, 57% females and 59% cognitively unimpaired. First, we evaluated SNP-based heritability across all three cognitive domains, both with baseline performance and longitudinal cognitive decline, and determined that the heritability across all measures was comparable across sexes. Next, we conducted cross-ancestry, genome-wide meta-analyses across the 10 cohorts, identifying three novel genome-wide significant loci relating to cognition in a sex-specific manner. First, we identified a locus (rs13387871), associated with female-specific language decline, and functional annotation suggested VRK2 as a candidate gene of interest; VRK2 is a published candidate gene for multiple neuropsychiatric traits, especially those involving language ability. Then we identified two sex-specific loci among individuals with cognitive impairment. The first locus was associated with male-specific memory decline (rs12501200), and functional annotation suggested DCHS2 as a gene of interest; notably DCHS2 is a published candidate gene for AD age-at-onset and tau pathology burden. Finally, among cognitively impaired individuals, we identified a sex-interaction with baseline executive functioning (rs1380012), and functional annotation suggested AGA as a candidate gene of interest. We additionally identified numerous biological pathways associated with sex-specific AD-related cognitive performance, including regulation of meiosis, fatty acid synthesis, and chromatin silencing. Our comprehensive genetic analysis of memory, executive functioning, and language performance highlighted genetic loci, genes, and biological pathways that relate to sex-specific cognitive change in both preclinical and clinical AD.
Psychiatric disorders often arise from the interaction between genetic predisposition and chronic psychosocial stress, yet the molecular programs determining resilience versus susceptibility remain incompletely understood. Building on evidence that the transcriptional corepressor LSD1 links environmental stress to neuronal gene regulation, we investigated whether isoform-specific regulation of LSD1 splicing contributes to stress adaptation. Using a mouse model of chronic social defeat stress, we analyzed LSD1 microexon E8a splicing in the hippocampus of resilient and susceptible animals. RNA-seq was performed after the last stress session to capture genome-wide transcriptional responses during the window of LSD1 splicing regulation. Comparative analyses with published LSD1 knockdown, LSD1 ChIP-seq and chronic stress datasets were conducted. Hippocampal samples from suicide victims were analyzed to assess translational relevance. Analysis of LSD1 splicing dynamics revealed that resilient mice, but not susceptible animals, retained the ability to reiterate acute stress-induced exon E8a skipping after repeated stress exposure, preserving the capacity to upregulate the enzymatically active ubLSD1 isoform in the hippocampus. In susceptible mice this inducible splicing response was absent. Mechanistically, splicing regulation involved the long non-coding RNA MALAT1, which controls the neurospecific splicing factor nSR100, a regulator of LSD1 exon E8a inclusion. Reduced MALAT1 expression in susceptible mice coincided with marked overactivation of stress-responsive genes revealed by RNA-seq. Approximately 15% (86 of 595) of genes deregulated in susceptible versus resilient hippocampi overlapped with transcripts modulated by LSD1 knockdown in an independent neuronal system. Of these, 25 were direct LSD1 ChIP-seq targets. ESR1 emerged as a regionally divergent upstream regulator associated with susceptibility. The MALAT1-nSR100-LSD1 axis represents a regulatory pathway modulating stress adaptation. Downregulation of ubLSD1 and MALAT1 in the hippocampus of suicide victims recapitulates the molecular phenotype observed in stress-susceptible mice, linking disruption of this pathway to pathological behavioral outcomes.
Among amyloid-positive individuals with symptomatic Alzheimer's disease, older age and male sex have been associated with a lower prevalence of Tau-PET-positivity. Whether Tau-PET-negative older and/or male individuals truly do not harbor widespread tau pathology or whether tangle density is below the PET-detection threshold remains unknown. Therefore, we aimed to investigate the neuropathological correlates of age- and sex-differences in Tau-PET in independent PET-only, autopsy-only, and PET-to-autopsy cohorts. In the PET-only cohort, we included amyloid-β-positive participants with MCI or dementia who underwent [18F]flortaucipir-PET (n=672). In the autopsy-only cohort, we included participants with moderate-to-frequent CERAD scores and MCI or dementia with available data on Braak stage and tangle density (n=945). In the PET-to-autopsy cohort, we included participants who underwent antemortem Tau-PET and had undergone a postmortem assessment of Braak staging (n=85) (median PET-to-post-mortem-interval: 2.6 months). A subset additionally had tangle density data available (n=63). Tau-PET SUVr was calculated in a temporal meta-region, and Tau-PET-positivity was defined using a predefined threshold of 1.36 SUVr. Autopsy cases were categorized as Braak 0-IV versus Braak V-VI. In PET-only-analyses (age: 71.9±8.2, 52.8% male), older age and male sex were associated with a lower prevalence of Tau-PET-positivity and lower Tau-PET SUVr (all p<0.05). In autopsy-only-analyses (age: 82.7±7.9, 54.6% male), older age and male sex were associated with a lower prevalence of Braak-V/VI neuropathology (both p<0.05). Among Braak-V/VI autopsy cases (n=598), older age was associated with lower tangle density (β=-0.38, p<0.001). In PET-to-autopsy-analyses (age: 81.7±9.2, 52.9% male), Tau-PET showed excellent specificity for detecting Braak-V/VI neuropathology (100% across age-stratified and sex-stratified models), while the sensitivity decreased at older age (<83y: 92% [95% confidence interval: 80%-100%] vs ≥83y: 42% [23%-62%]) and in males (females: 85% [69%-96%] vs males: 48% [28%-68%]). Older and male participants with Braak-V/VI neuropathology showed both lower Tau-PET SUVr (age: β=-0.46, p=0.003; sex: β=-0.97, p=0.001), and in the same individuals, older participants showed trend-level lower tangle density (β=-0.31, p=0.053). The lack of age/sex-interactions indicate that the relationship between Tau-PET and tangle density is consistent across ages and sexes. Comprehensive and independent PET, autopsy, and PET-to-autopsy analyses demonstrate that the associations of older age and male sex with lower [18F]flortaucipir-PET uptake and positivity rates can be explained by lower tangle densities. [18F]flortaucipir-PET SUVr thus closely reflects tangle density, which accounts for the lower sensitivity of [18F]flortaucipir-PET for detecting low-density Braak-V/VI tau pathology in older individuals and males.
Developing reliable biomarkers capable of differentiating Parkinson's disease from other neurological conditions is crucial for both patient care and research. In this study, we leveraged recent advances in high-throughput proteomic technology and machine learning to develop candidate biomarkers for Parkinson's disease. Using the Olink Explore 3072 assay, we obtained plasma proteomic profiles from 698 study participants, comprising Parkinson's disease cases (n = 149), neurologically healthy controls (n = 230), and participants with other neurological conditions (n = 319). The study cohort was split into Training Set (n = 560) and Test Set (n = 138). We conducted differential protein abundance analysis and pathway enrichment analysis, and subsequently applied the Boruta algorithm to identify differentially abundant proteins that are predictive of Parkinson's disease. To create a diagnostic biomarker panel, we trained a stacking ensemble machine learning (ML) model on the Training Set (n = 118 Parkinson's patients, n = 184 healthy controls, and n = 258 individuals with other neurological disorders) using eleven proteins (APOH, ARG1, CCN1, CXCL1, CXCL8, DDC, GRAP2, IL1RAP, OSM, PRL, and SPRY2) as model features. We used the Shapley Additive Explanations (SHAP) framework and network analysis to evaluate predictive importance and biological relevance of each protein in the ML model. The model demonstrated high accuracy in the held-out Test Set (n = 138) and three external cohorts-the UK Biobank (n = 43,969), the Parkinson's Disease Biomarkers Program (n = 138), and the Parkinson's Progression Markers Initiative (n = 385), with areas under the receiver operating characteristic curve of 0.939, 0.789, 0.909, 0.816, respectively. Additionally, network and pathway analyses helped interpret the model, revealing activity related to inflammatory mediators, ErbB signaling, T-cell receptor signaling, and lipid metabolism. Our findings highlight the potential of plasma protein biomarkers to improve Parkinson's disease diagnosis and deepen biological understanding of this complex neurological disorder. Our model demonstrates high specificity and reliability across multiple independent cohorts, indicating the significant potential of proteomics-based biomarkers and the clinical utility of ML-supported diagnosis in Parkinson's disease care. The model also helps to elucidate potential novel risk factors and pathways associated with Parkinson's disease.
Functional neurological disorder (FND) presents disabling symptoms that fluctuate, migrate across systems, and yet routinely show preserved structural integrity-features that can frustrate diagnosis and patient education. Crucially, these symptoms are genuine and reflect altered brain regulation across multiple systems rather than tissue damage or conscious control. This paper offers a clinically usable account of these puzzles by reframing FND as a disorder of precision control within predictive coding. The brain's confidence (precision) in its own predictions is modelled as a dynamic quantity that can surge with arousal, settle back toward baseline, and slowly recalibrate over longer periods. Placing this mechanism in a four-level hierarchy (affective, interoceptive, proprioceptive, spinal) shows how arousal can temporarily make an unhelpful expectation dominate, suppress corrective feedback, and produce motor, sensory, cognitive, or visceral symptoms-often in combination. The same dynamics explain rule-in positive signs such as distractibility, entrainment, and give-way weakness, and clarify the lived experience of reduced agency without implying wilfulness or malingering. For clinicians, the framework provides an intuitive way to explain symptoms to patients ('a temporary gain miscalibration that overweights predictions and underweights sensory feedback'), and to justify why physiotherapy (amplifying proprioceptive feedback), psychotherapy (reducing arousal), and mindfulness or biofeedback (raising the effective threshold for arousal-driven 'gain spikes') can all help by recalibrating that weighting. The framework also yields concrete, falsifiable tests, linking bedside observation to measurable biomarkers and offering ways to refine it further. By centring dynamic precision, the account unifies diagnosis, communication, and treatment planning, and provides a mechanistic foundation for precision-guided care in FND.
The onset of epilepsy in adulthood occurs most commonly after 55 years of age. Given the ageing global population, this disorder represents an increasing burden on healthcare and society. The bidirectional link between epilepsy and dementia is a focus of intense research with underlying tau pathology highlighted as a potential mechanistic link. In this review, we examine the evidence for tau-related neurodegenerative processes in epilepsy beginning with how changes in biochemical and structural properties of the tau protein can lead to abnormal phosphorylation and pathological aggregation. We consider the role of tau in seizure occurrence and cognitive difficulties in experimental animal epilepsy models to human epileptic syndromes. Seizure prevalence is evaluated across established primary and secondary tauopathies to understand the associated hyperexcitability phenotype. We discuss the use of neurophysiology, metabolic imaging and novel fluid biomarkers as non-invasive measures of potential underlying neurodegeneration in epilepsy. It may, for example, be that these can be combined with remote measures of cognition and other physiological parameters to provide accurate longitudinal monitoring of cognition and underlying pathology. We also explore clinical trials that have targeted pathological tau accumulation in neurodegenerative conditions and consider an ongoing clinical study with sodium selenate, an enhancer of protein phosphatase enzyme PP2A, in people with epilepsy. These efforts signify a novel disease-modifying era with treatments that reduce seizures and modify cognitive outcomes in people with epilepsy. Our analysis of the literature underscores the need for more in-depth characterization of tau pathology, at biochemical and structural levels, in brain tissue and peripheral samples from people with epilepsy as an important step to deciphering the role of tau in the pathogenesis of epilepsy and related disorders. Examining the relationships between tau pathology and cognitive impairment in those with epilepsy provides critical perspectives on a potential causal tau pathomechanism that may have important roles in epileptogenesis and dementia.
Imbalance of excitatory and inhibitory neuronal activity (E/I imbalance) plays a critical role in pain pathogenesis. Recent studies have identified a novel form of E/I imbalance in the spinal dorsal horn (SDH) of animal models of HIV-associated pain, manifesting as increased spontaneous excitatory postsynaptic current (sEPSC) frequency in excitatory neurons alongside decreased sEPSC frequency in inhibitory neurons and hence termed neural circuitry polarization (NCP). However, how the opposite forms of synaptic plasticity in NCP is coordinated in the pain neural circuit is unclear. Here, we show that in the SDH of a mouse model of HIV-associated pain, potentiation of excitatory synapses on excitatory neurons (ESE) and depression of excitatory synapses on inhibitory neurons (ESI) employ distinct mechanisms to support their expression. We found the increase of sEPSC frequency in excitatory neurons induced by HIV1 gp120 was mediated by a postsynaptic mechanism, whereas decrease of sEPSC frequency in inhibitory neurons by a presynaptic mechanism. Our studies showed that pharmacological inhibition of calcium-permeable AMPA (CP-AMPA) receptors selectively attenuated potentiation of ESE without significantly affecting ESI depression. We also observed that GluA1 was upregulated in excitatory but not inhibitory neurons, indicating selective CP-AMPA receptor formation in excitatory neurons. Furthermore, we identified a new pain-related signaling pathway in ESE: Wnt5a-PKCδ-GluA1. We elucidated that the GluA1 upregulation and ESE potentiation were controlled by neuronal Wnt5a signaling via protein kinase C delta (PKCδ). Our findings reveal that ESE and ESI in the SDH of HIV pain models use distinct synaptic and molecular mechanisms to support their expression in NCP, demonstrating specialized regulatory pathways for the plasticity of excitatory synapses targeting different neuron types during the pain pathogenesis.
Mitochondrial dysfunction is central to the pathogenesis of Parkinson's disease (PD), integrating both genetic and environmental factors. Therefore, reliable blood-based biomarkers reflecting mitochondrial alterations are needed. Emerging evidence suggests that somatic changes to mitochondrial DNA (mtDNA) may reflect early disease-associated processes relevant to PD conversion and clinical manifestation. In this study, we analysed somatic mtDNA major arc deletions as a measure of mitochondrial genome integrity and evaluated 7S DNA abundance as well as copy number as complementary readouts in whole blood (n=776) from a large cohort, including idiopathic and genetic PD patients, individuals at risk, PD converters, patients with primary mitochondrial disease, and healthy controls. This work was complemented by analyses in CSF samples (n=72). Finally, mtDNA measures were integrated with genetic, protein, and clinical data, including mitochondrial polygenic risk scores, alpha-synuclein seeding assays, and serum neurofilament light chain levels. In blood, the strongest effects occurred in PINK1/PRKN-PD (deletions: P<0.0001; 7S DNA: P<0.0001) and early-onset idiopathic PD (7S DNA: P=0.0009-0.0030). Individuals with prodromal signs conferring a high risk for PD also showed increased mtDNA deletions (P=0.0045) and reduced 7S DNA (P=0.0046). In PD converters, these alterations were detectable prior to clinical diagnosis (deletions: P=0.0024; 7S DNA: P=0.0091). In CSF-derived extracellular vesicles, we observed an age-associated increase in mtDNA copy number in healthy controls (R2=0.121, P=0.035) that was absent in idiopathic PD (R2=0.014, P=0.548). Across all PD patients, those with the highest mtDNA deletion burden and lowest 7S DNA exhibited a higher risk of developing cognitive impairment and depression, while also showing a longer time to postural instability (deletions: P=0.0187; 7S DNA: P=0.0281). Integration of mtDNA readouts, mitochondrial polygenic risk scores, alpha-synuclein seeding, and serum neurofilament light chain levels revealed complementary contributions to biological heterogeneity in PD, with receiver operating characteristic analyses showing moderate group-level discrimination using mtDNA measures alone (AUC=0.66) and substantially improved discrimination when combined with alpha-synuclein and neurodegeneration markers (AUC up to 0.96). Alpha-synuclein seeding activity was associated with later age at onset, whereas mtDNA deletion burden showed an inverse association, indicating that these biomarkers capture distinct biological dimensions of PD. MtDNA damage markers, particularly deletion burden, capture mitochondrial dysfunction arising from both genetic and environmental influences and are detectable across early clinical stages of PD. While not serving as stand-alone diagnostic biomarkers, mtDNA measures provide complementary biological information within a multimodal framework and may support patient stratification based on mitochondrial involvement using a minimally invasive approach.
The maternal gut microbiome plays a crucial role in regulating offspring neurodevelopment through microbial metabolite signaling, yet its influence on CNS myelinogenesis, a pivotal process for neural circuit maturation, remains poorly understood. Here, using antibiotic-induced maternal dysbiosis models, we identify propionate (PA), a short-chain fatty acid (SCFA) derived from the maternal microbiome, as a key epigenetic modulator of oligodendrocyte precursor cell (OPC) differentiation. Maternal antibiotic-induced gut dysbiosis led to significant hypomyelination in offspring, an effect that could be rescued by postnatal PA supplementation. PA not only enhanced developmental myelination but also promoted remyelination following lysolecithin-induced demyelination by inducing OPC differentiation. Mechanistically, PA induced histone H4K12 lactylation (H4K12la), thereby activating transcription of cGMP-PKG signaling components (e.g., Gna12) and upregulating Sox family transcription factors essential for oligodendrocyte differentiation. Taken together, our findings delineate a PA-H4K12la-cGMP-PKG pathway that links maternal microbial metabolism to offspring myelination, offering a promising SCFA-mediated epigenetic strategy for the treatment of CNS demyelinating disorders.
Alzheimer's disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.