Moser T, Hitzl W, Lerda-Casaccia T
… +11 more, Unterhofer M, Demjaha R, Martinez-Serrat M, Khalil M, Harrer A, Böhm B, Hofbauer P, Cadamuro J, Huber-Schönauer U, Trinka E, Wipfler P
Propionic acid (PA), a microbial-derived short-chain fatty acid, contributes to intestinal barrier integrity, systemic immune regulation, and neuronal function. Individuals with multiple sclerosis show reduced PA levels,...Propionic acid (PA), a microbial-derived short-chain fatty acid, contributes to intestinal barrier integrity, systemic immune regulation, and neuronal function. Individuals with multiple sclerosis show reduced PA levels, and open-label data have suggested beneficial immunomodulatory and clinical effects of supplementation. The Multiple sclerosis And DisAbility Improvement (MADAI) trial was a randomized, double-blind, placebo-controlled, single-centre, phase 2b study designed to evaluate the efficacy and safety of PA as an add-on therapy in adults with clinically stable multiple sclerosis. Between April 5 and 29 May 2024, 101 adults (64% women; mean age 45 years) were randomly assigned in a 2:1 ratio to receive PA 500 mg twice daily or matching placebo for 90 days. The primary outcome was the change in serum neurofilament light chain (sNfL) concentration, a biomarker of neuroaxonal damage, adjusted for age, body mass index, creatinine, and baseline sNfL. Secondary outcomes included physical and cognitive performance measures and patient-reported outcomes, including fatigue and quality of life scores. sNfL levels were significantly reduced in the PA group {-17.9%; from 9.77 pg/ml [95% confidence interval (CI) 9.00 to 10.60] to 8.02 pg/ml (95% CI 7.36 to 8.73); mean difference 1.75 pg/ml (95% CI 0.9 to 2.6); P = 0.000025}, while no significant change was observed in the placebo group. The adjusted mean difference in sNfL levels between the PA and placebo groups at follow-up was 0.91 pg/ml (95% CI 0.02 to 1.79; P = 0.045). Reductions in sNfL were also observed among participants in the PA arm receiving moderate-to-high efficacy disease-modifying therapies (n = 41; P = 0.0001), including those on anti-CD20 treatment (n = 27; P = 0.0005). There was a trend towards improvement in motor fatigue in the PA group. No serious adverse events related to the study medication occurred. PA supplementation was well tolerated and associated with significant reductions in sNfL, suggesting attenuation of neuroaxonal injury in multiple sclerosis. These findings support further evaluation of PA as an add-on treatment in larger, long-term studies.
WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms, thus, the speci...WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms, thus, the specific molecular pathways affected by WWOX deficiency and how they contribute to disease pathogenesis remain largely unknown. Using neural organoids derived from a broad iPSC cohort, including wildtype iPSCs, CRISPR-edited isogenic WWOX-knockout lines, and patient-derived lines, we applied molecular profiling and single-cell transcriptomics to map the early neurodevelopmental pathways disrupted upon loss of WWOX. We identified radial glial cells (RGs) as preferentially affected, with disrupted cell cycle dynamics leading to an accumulation of cells in the G2/M and S phases, overexpression of the proto-oncogene MYC, and concomitant reduction in neuronal generation. Patient-derived organoids exhibited milder phenotypes compared to knockout organoids, showing functional neuronal impairments like hyperexcitability and delayed differentiation rather than RG dysfunction. Remarkably, gene therapy restored neuronal function, normalizing hyperexcitability and promoting maturation, without disturbing RG populations. We propose a model in which WWOX mutations impair neurogenesis via RG through cell-type specific dysregulation of the MYC and Wnt signaling pathways. These insights highlight potential therapeutic strategies for WWOX-related disorders and open avenues for interventions targeting these key molecular pathways.
Variants in SMPD4 cause severe neurodevelopmental disorders characterized by microcephaly, simplified gyral patterns, and cortical malformations in humans, yet Smpd4 knockout mice exhibit minimal cortical abnormalities,...Variants in SMPD4 cause severe neurodevelopmental disorders characterized by microcephaly, simplified gyral patterns, and cortical malformations in humans, yet Smpd4 knockout mice exhibit minimal cortical abnormalities, displaying phenotypes primarily restricted to cerebellar defects. This striking species-specific disparity has hindered understanding of the cellular and molecular mechanisms underlying SMPD4-related cortical pathology due to the lack of appropriate gyrencephalic animal models that accurately recapitulate human brain development. We utilized in utero electroporation combined with CRISPR-Cas9 genome editing technology to efficiently knock out Smpd4 in the developing gyrencephalic neocortex of ferrets at embryonic day 34. Ferrets were analyzed at postnatal days 1, 2, 6, and 16 using immunohistochemistry, live-cell imaging, and single-cell RNA sequencing to comprehensively characterize the cellular and molecular consequences of SMPD4 deficiency. SMPD4-deficient ferret cortices successfully recapitulated key human phenotypes, exhibiting markedly reduced progenitor cell proliferation with significantly prolonged mitotic duration. Quantitative analysis revealed a profound reduction in basal intermediate progenitors and decreased neuronal output. Mechanistically, loss of SMPD4 compromised nuclear envelope integrity, disrupted mitotic spindle orientation leading to aberrant cell division patterns, impaired primary cilia formation, and substantially reduced intermediate progenitor morphological complexity. Additionally, Smpd4 knockout induced severe migration defects in cortical neurons, with many neurons failing to reach their appropriate cortical layers. Single-cell RNA sequencing analysis of over 20,000 cells from control and Smpd4 knockout cortices revealed that SMPD4 deficiency significantly reduced intermediate progenitor cell numbers and caused widespread dysregulation of genes previously associated with human lissencephaly, simplified gyration, microcephaly, developmental delay, and epilepsy. Gene ontology enrichment analyses identified disrupted pathways involved in cell cycle regulation, neurogenesis, chromosome organization, apoptosis, and neuronal migration. These findings provide critical mechanistic insights into how SMPD4 deficiency disrupts cortical development through impaired intermediate progenitor generation and neuronal migration, establishing ferrets as an invaluable gyrencephalic model system for investigating SMPD4-related neurodevelopmental disorders. This model offers significant translational potential for understanding human cortical malformations and developing therapeutic interventions for affected patients.
Pediatric-onset multiple sclerosis is associated with high inflammatory activity early in the disease course, yet sensitive biomarkers of early disease pathology are limited. Hyper-reflective foci on optical coherence to...Pediatric-onset multiple sclerosis is associated with high inflammatory activity early in the disease course, yet sensitive biomarkers of early disease pathology are limited. Hyper-reflective foci on optical coherence tomography have been proposed as markers of inflammation in adult multiple sclerosis, but their relevance in pediatric populations remains unclear. We aimed to identify and quantify retinal layer-specific hyper-reflective foci burden in children with pediatric-onset multiple sclerosis and evaluate associations with MRI markers of disease severity. In this cross-sectional study, 53 children with pediatric-onset multiple sclerosis and 36 age- and sex-matched healthy controls underwent spectral-domain optical coherence tomography and MRI, including three-dimensional T1-weighted and fluid-attenuated inversion recovery sequences, near disease onset. Patients with a history of optic neuritis were excluded. Hyper-reflective foci were quantified within the ganglion cell-inner plexiform layer and inner nuclear layer as counts and as a normalized hyper-reflective foci index (count divided by retinal layer volume). Brain MRIs underwent parcellation and multiple sclerosis lesion segmentation. Generalized estimating equation models accounted for inter-eye correlation and adjusted for demographic and retinal structural covariates. Linear regression assessed associations between hyper-reflective foci burden and magnetic resonance imaging measures, including thalamic volume, cortical volume, and white matter lesion volume. Hyper-reflective foci counts and indexes were significantly increased in pediatric-onset multiple sclerosis compared with controls across both retinal layers. Higher ganglion cell-inner plexiform layer hyper-reflective foci index correlated with greater white matter lesion volume (r = 0.38, P = 0.006) and lower thalamic volume (r = -0.35, P = 0.012), but not cortical volume. In adjusted models, multiple sclerosis was independently associated with higher ganglion cell-inner plexiform and inner nuclear layer hyper-reflective foci counts and indexes (both P < 0.001). Inner nuclear layer hyper-reflective foci were negatively associated with macular retinal nerve fiber layer thickness and volume (β = -0.18, P < 0.01; β = -0.006, P < 0.01). Higher ganglion cell-inner plexiform layer hyper-reflective foci index remained associated with lower thalamic volume (β = -0.321, P = 0.024), greater lesion volume (β = 5.253, P = 0.011), and lower cortical volume (β = -6.403, P = 0.016). Children with multiple sclerosis demonstrate increased retinal hyper-reflective foci burden early in disease, in the absence of optic neuritis. The observed relationships between ganglion cell-inner plexiform layer hyper-reflective foci burden, thalamic and cortical atrophy, and white matter lesion volume suggest that hyper-reflective foci capture aspects of both inflammatory and neurodegenerative disease activity. Hyper-reflective foci represent a promising non-invasive biomarker of disease severity in pediatric-onset multiple sclerosis.
Ito T, Higashiyama Y, Urano M
… +13 more, Imai T, Hamada T, Mori M, Morihara K, Kobayashi E, Saito A, Kitazawa Y, Miyaji Y, Kimura K, Doi H, Ueda N, Johkura K, Tanaka F
Stroke-induced writing disorders offer valuable insights into the neural mechanisms of writing. The Japanese writing system is particularly useful for such investigations, as it includes both kana (phonograms) and kanji...Stroke-induced writing disorders offer valuable insights into the neural mechanisms of writing. The Japanese writing system is particularly useful for such investigations, as it includes both kana (phonograms) and kanji (morphograms). Kana is primarily associated with phonological processing, whereas kanji relies on lexical-orthographic pathways. Although previous research suggests there are distinct neural substrates for kana and kanji, most studies have focused on small cohorts with pure agraphia, and large-scale investigations of aphasia remain underexplored. To address this gap, we examined a large stroke cohort to identify anatomical differences underlying phonogram versus morphogram processing. We analysed 315 patients with post stroke aphasia who underwent a comprehensive battery of language assessments, including kana and kanji writing tests, and MRI at multiple stroke centres between 2016 and 2024. Using multivariate support vector regression-based lesion-symptom mapping and structural disconnection analyses based on a continuous permutation-based family-wise error correction, we investigated associations between lesion/disconnectome maps and various language scores, with a particular focus on writing scores. To complement voxel-wise mapping, we prespecified a tract-level multivariable regression to quantify disconnection load across language-related white matter tracts. We evaluated 315 patients (mean age 67.2 ± 13.3, 34.6% female). Lesion-symptom mapping suggested that impairments in kana writing were associated with left frontal regions, whereas lesion clusters associated with kanji writing emerged primarily in the white matter underlying the supramarginal and angular gyri. Disconnectome analyses implicated left dorsal pathways (e.g. arcuate fasciculus, superior longitudinal fasciculus) in kana writing impairments, with left ventral pathways (e.g. inferior fronto-occipital fasciculus, inferior longitudinal fasciculus) implicated in kanji writing impairments. Complementary tract-level regression mirrored this dissociation: kana outcomes showed significant associations with dorsal pathways, whereas kanji outcomes were predominantly associated with ventral pathways. These findings highlight distinct neural pathways for writing phonograms (kana) and morphograms (kanji), providing novel insights into the neural mechanisms of writing disorders. In this large multicentre aphasia cohort, disconnectome mapping and tract-level regression provide convergent evidence for a dorsal-ventral dissociation between pathways associated with phonogram- and morphogram-related writing impairments. Our results contribute to understanding script-specific neural processing and may inform future assessment and rehabilitation strategies for aphasia in languages with complex writing systems.
Dugast E, Shah S, Vogel I
… +31 more, Loret A, Monvoisin C, Garcia A, Fourgeux C, Gourain V, Boussamet L, Amoriello R, Le Luduec JB, Nataf S, Jacq-Foucher M, Moyon M, Le Frère F, Wiertlewski S, Ballerini C, Tarte K, Thouvenot E, Agherbi H, Casey R, Vukusic S, Ruet A, Le Page E, Labauge P, Mathey G, Raposo C, Poschmann J, Renand A, Nicot A, Michel L, Gourraud PA, Berthelot L, Laplaud DA
Memory CD8+ T cells are central to multiple sclerosis (MS) and undergo clonal expansion, but disease-associated states remain incompletely defined. By single-cell profiling of circulating memory CD8+ T cells from patient...Memory CD8+ T cells are central to multiple sclerosis (MS) and undergo clonal expansion, but disease-associated states remain incompletely defined. By single-cell profiling of circulating memory CD8+ T cells from patients with relapsing-remitting MS, healthy volunteers, and neuroinflammatory controls, we identified an MS-associated cytotoxic subset with NK-like features. These cells increase around relapse activity and belong to an oligoclonal reservoir. In an independent cohort sampled at the first clinical event, an elevated frequency of NK-like CD8+ T cells predicted an aggressive MS course two years later and was associated with a migratory/inflammatory program. Bulk and single-cell RNA-seq confirmed the NK-like transcriptional signature, and functional assays demonstrated TCR-independent cytotoxicity. Immunostaining and spatial transcriptomics revealed enrichment of these cells in MS lesions and a spatial association with macrophages/microglia. Together, our results identify a cytotoxic NK-like CD8+ T-cell subset that links peripheral inflammation to CNS lesions and may serve as an early biomarker of MS severity.
Descending cortical control plays a critical role in shaping neuropathic pain. However, how specific circuits within the insular cortex (IC), a critical cortical hub that integrates the sensory and affective dimensions o...Descending cortical control plays a critical role in shaping neuropathic pain. However, how specific circuits within the insular cortex (IC), a critical cortical hub that integrates the sensory and affective dimensions of pain, contribute to this process remains poorly understood. Here, we show that posterior IC glutamatergic (pICGlu) neurons are selectively and contralaterally activated in a chronic constriction injury (CCI) model and bidirectionally regulate pain sensitivity, whereas anterior IC glutamatergic (aICGlu) neurons preferentially mediate CCI-induced anxiety-like behaviors. Circuit mapping revealed that pICGlu neurons project to rostral ventromedial medulla GABAergic (RVMGABA) neurons, particularly a Slc32a1+/Penk- subpopulation, which in turn innervate spinal dorsal horn GABAergic (DHGABA) interneurons. Consistent with this organization, pathway-specific manipulations demonstrated that activation of the pIC-RVM-DH circuit enhances nociceptive hypersensitivity, whereas its inhibition alleviates CCI-induced allodynia. Together, these findings identify a previously uncharacterized pICGlu-RVMGABA-DHGABA circuit that mediates the sensory dimension of neuropathic pain and provides a circuit-level framework for descending cortical control of pain hypersensitivity.
Failla P, Muto V, Lauri A
… +28 more, Saccuzzo L, Arena A, Fasano G, Guerrot AM, Lecoquierre F, Ciolfi A, Mancini C, Zara E, Cordeddu V, Motta M, Elia M, Greco D, Avola E, Mattina T, Spalletta A, Schinocca P, Salemi M, Salluzzo MG, Galesi O, De Billy E, Petrini S, Coppola S, Priolo M, Bertini ES, Radio FC, Romano C, Fichera M, Tartaglia M
The G-protein-coupled receptor kinase-interacting protein 1, GIT1, is a multifunctional scaffold protein that plays key roles in the regulation of actin cytoskeletal dynamics, focal adhesion assembly, membrane traffickin...The G-protein-coupled receptor kinase-interacting protein 1, GIT1, is a multifunctional scaffold protein that plays key roles in the regulation of actin cytoskeletal dynamics, focal adhesion assembly, membrane trafficking, and intracellular signaling. In mice, loss of Git1 function causes a microcephaly-like phenotype characterized by a smaller brain due to reduced neuronal cell size, accompanied by behavioral deficits, altered gait, and impairment in motor coordination, learning and memory. To date, variants in GIT1 have not been definitely linked to human disease. By applying a combined genomic approach based on linkage analysis and exome sequencing, we provide evidence that biallelic GIT1 variants affecting transcript processing or causing premature termination underlie a syndromic neurodevelopmental disorder. Nine affected individuals from three families were identified to share a clinically homogeneous syndromic phenotype with major features including microcephaly, brain MRI anomalies, developmental delay/intellectual disability, a recognizable facial gestalt, and intrauterine growth restriction with postnatal growth failure. We used complementary in vitro and in vivo approaches to validate this causal relationship. Cell-based functional analyses using patient-derived fibroblasts confirmed the inactivating behavior of the disease-associated variants and demonstrated that loss of GIT1 function disrupts actin cytoskeleton dynamics, leading to defective cell spreading and flawed formation of focal adhesions as a result of reduced RAC1 activation. A zebrafish git1 knockdown model recapitulated the clinical phenotype observed in affected patients and further validated the loss-of-function effect of the identified variants. Collectively, our findings establish an essential role for GIT1 in development and cognitive function.
Tilliole P, Mattausch C, Tilly P
… +48 more, Leitão E, Boutaud L, Lehalle D, An I, Argilli E, Aufox S, Callewaert B, Charles P, Cinkornpumin JK, Courtin T, Vecchia MD, Davis EE, Dimitrov BI, Dobyns W, Epifanova E, Grandgirard E, Jung M, Jurgensmeyer Langas S, Kaya S, Keren B, Khan TN, Lejeune E, Li M, Marie Y, Morlet B, Nava C, Pastor WA, Plassard D, Prada CE, Rastetter A, Schwaller N, Sestan N, Sherr E, Temple SL, Tenywa JF, Tielens S, van Haeringen A, Whitley H, Nguyen L, Steenpaß L, Rhinn M, Collins SC, Héron D, Cormier-Daire V, Attie-Bitach T, Yalcin B, Depienne C, Godin JD
Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. RBMX encodes an X-linked RNA-binding protei...Retrotransposition has generated thousands of intronless gene copies in mammalian genomes, yet their contribution to brain development and evolution remains largely unexplored. RBMX encodes an X-linked RNA-binding protein involved in pre-mRNA splicing. RBMX has highly similar retrocopies, RBMXL1, which arose independently in primates and rodents, suggesting convergent evolutionary pressure and potential functional compensation. We identified individuals with RBMX variants through exome sequencing and GeneMatcher. We combined transcriptomic profiling, protein-protein and protein-RNA interaction studies both in human cellular models and mouse embryonic cortices to assess the functional redundancy between RBMX and its retrocopy RBMXL1. Finally, we use mouse genetics to dissect RBMX function and its compensation by RBMXL1 in corticogenesis. Hemizygous RBMX variants lead to neurodevelopmental disorders characterized by intellectual disability and variable brain, ocular, and genital malformations. N-terminal variants include missense changes and in-frame deletions, whereas truncating variants clustered in the final exon. RBMX pathogenic variants disrupt cortical development through both partial loss-of function (C-terminal variants) and gain-of-function (N-terminal variants) mechanisms. Despite severe phenotypes in humans, Rbmx-deficient mice display only mild cortical abnormalities. We demonstrate that RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development, with RBMXL1 buffering the impact of RBMX deficiency. Together, these findings establish RBMXL1 as a functional paralog of RBMX that is likely buffering deleterious variation in a context- and dosage-dependent manner. More broadly, these results identify retrocopies as active contributors to neurodevelopmental robustness and suggest that functional retrocopies may have facilitated the evolutionary diversification of the mammalian brain.
Spinal muscular atrophy (SMA) is an oft-fatal infantile-onset neuromuscular disease caused by homozygous loss of the Survival of Motor Neuron 1 (SMN1) gene and, consequently, low SMN protein. Administration of SMN-induci...Spinal muscular atrophy (SMA) is an oft-fatal infantile-onset neuromuscular disease caused by homozygous loss of the Survival of Motor Neuron 1 (SMN1) gene and, consequently, low SMN protein. Administration of SMN-inducing agents to SMA newborns prevents early mortality, but therapeutic outcomes vary considerably, and disease mechanisms remain poorly understood. Genetic modifiers can provide clues to disease mechanisms and serve as targets for novel treatments. Here, we describe how one such modifier, an Hspa8G470R synaptic chaperone variant we identified, suppresses SMA in model mice. Our results highlight two distinct mechanisms of action of the variant chaperone. First, it raises SMN incrementally, an outcome we discovered is not linked to a previously identified splice modulating function of the modifier but instead to Hspa8G470R-mediated autophagy, effects of the variant on autophagy-associated intermediate complexes and, ultimately, reduced SMN turnover. Interestingly, however, the modifier also stimulated neuromuscular transmission significantly, raising the effective, functional readily releasable pool of motor neuronal synaptic vesicles. Notably, this second outcome was not limited to mutants alone but discernible in healthy controls too, appearing independent of SMN levels and thus indicative of a distinct disease-modifying effect of the chaperone variant that operates specifically at neuromuscular synapses. Combined, the two mechanisms of Hspa8G470R action identified here suppressed the SMA phenotype potently, preventing spinal motor neuron degeneration, ameliorating neuromuscular dysfunction and extending lifespan in model mice more than ten-fold. Results presented in this study shed additional light on pathways gone awry in SMA - ones that might be modulated to develop or refine therapies for neuromuscular disorders at large.
Ellis BCS, Avila AS, Huang WP
… +12 more, John SJ, Bonsall S, Hodgson RE, Kumar V, Nolan M, West RJH, Campbell SG, De Vos KJ, Lagier-Tourenne C, Robin Highley J, Cooper-Knock J, Shelkovnikova TA
STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear...STMN2 is an abundant neurospecific protein dysregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We previously reported that cellular stress can lead to STMN2 loss due to TDP-43 nuclear condensation. Here, using human and murine neuronal cell models, multiple pharmacological tools, in situ single-molecule analysis of translation and RNA localisation, and longitudinal analysis of neuronal fitness/survival, we establish TDP-43-independent mechanisms of STMN2 depletion under stress. We find that human STMN2 protein level is extremely labile under acute high-magnitude stress. Early in stress, STMN2 is suppressed via activated proteasomal degradation, phosphorylation and translation repression by stress granules, independently of TDP-43 loss of function in splicing. We further show that STMN2 protein level is highly sensitive to chronic translation deficits, such as those elicited by prolonged low-grade stress. We find that low pre-stress STMN2 sensitises neuronal cells to stress-induced apoptosis, whereas moderately increased STMN2 is protective under stress. Finally, we demonstrate that STMN2 mRNA is upregulated in non-TDP ALS (ALS-FUS) models, which may compensate for translation/stress granule defects in this disease subtype. Consistent with the compensation hypothesis, STMN2 mRNA is also upregulated in the relatively spared (cortex), but not severely affected (spinal cord), CNS regions in ALS-TDP. In conclusion, our study implicates two common denominators in neurodegeneration - dysregulation of translation and stress granules - in STMN2 depletion, independent of TDP-43 loss of function. It also describes an RNA-based compensatory mechanism in ALS underling the unique vulnerability of neurons with developing TDP-43 pathology.
Tanaka K, Kopruszinski CM, Luo S
… +11 more, Moutal A, Lee G, Bharadwaj V, Ismail K, Anderson T, Martin LF, Antenucci N, Neugebauer V, Dodick DW, Navratilova E, Porreca F
Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central...Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.
Histopathological assessment has served as the gold standard for diagnosing Alzheimer's disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have ena...Histopathological assessment has served as the gold standard for diagnosing Alzheimer's disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10-11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10-10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10-201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10-8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10-8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10-7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.
Serum antibodies to muscle specific kinase (MuSK) are present in a proportion of patients with acetylcholine receptor antibody seronegative myasthenia gravis (SNMG), but their reported frequencies in different population...Serum antibodies to muscle specific kinase (MuSK) are present in a proportion of patients with acetylcholine receptor antibody seronegative myasthenia gravis (SNMG), but their reported frequencies in different populations vary. From 2002, serum samples were sent to Oxford for MuSK antibody testing from 35 centres in 6 continents. MuSK antibodies were identified in 143/465 (30.8%) previously untested SNMG sera. They were not identified in 147 adult acetylcholine receptor antibody positive patients or in 63 adult ocular MG patients. As expected from subsequent reports, the MuSK antibody positive patients differed in gender, clinical severity, bulbar predominance and treatment requirements from the 322/465 (69.2%) MuSK antibody negative SNMG patients, but they were improved following the more aggressive treatments received, although still showing bulbar predominance. Similar features were seen in the 42 childhood cases tested (17/42 (40%) MuSK-Ab positive from 18 centres); although numbers were small there was bulbar predominance that persisted after the treatments that were more extensive than those given to the juvenile SNMG patients. Although found in each continent, MuSK-MG showed an unexpected and surprising distribution. The frequency of MuSK-Abs within individual centres varied in the Northern Hemisphere with a clear north-south gradient from 0% to 47% in Europe and North America. There were fewer cohorts from Asia but data from 11 publications, including five from East and South East Asia, confirmed a latitudinal distribution of MuSK-Ab frequency consistent with a Gaussian curve peaking at 40 degrees North, and trending towards very low frequencies above this latitude in Europe and below this latitude in South East Asia. Thus, MuSK-Abs, that are predominantly IgG4 rather than IgG1 subclass, show a striking and unexpected relationship with latitude in the Northern Hemisphere. The results raise interesting questions regarding the environmental and genetic factors involved, with possible relevance also for the increasing number of IgG4 antibody-mediated neurological disorders, including forms of neuropathy and autoimmune encephalitis.
For a long time, epilepsy has been associated with violent behaviour, acquiring a highly stigmatising reputation, shaped mainly by 19th-century medical theories that postulated a direct connection between epilepsy and th...For a long time, epilepsy has been associated with violent behaviour, acquiring a highly stigmatising reputation, shaped mainly by 19th-century medical theories that postulated a direct connection between epilepsy and the criminal personality. Such stigma exerts a negative effect on the quality of life of people with epilepsy and remains a significant concern in forensic settings. This narrative review aims to thoroughly explore the relationship between epilepsy and aggression, highlighting the misconceptions that contribute to this stigma. The evidence presented in this review draws on the authors' experience and a PubMed search conducted in December 2024. The manuscript is organized into five chapters, addressing: (1) the historical and cultural background of epilepsy and violence; (2) the clinical features of aggression as a peri-ictal manifestation; (3) the neural networks underlying aggression in epilepsy; (4) aggression in sleep-related disorders, an area closely related to epilepsy, where clinical interest and reports of sleep-related violent episodes have progressively increased in recent years; and finally, (5) forensic considerations. In total, 326 records were identified though PubMed search. Only papers relevant to the topics were included. Relevant publications were also added manually from the authors' own files. One hundred and thirty-two studies were ultimately included in this narrative review. The review, addressing the topic from a historical perspective, traces the evolution of stigma and the concept of the "epileptic personality", from early observations to contemporary understanding. Next, we explore aggression and violence as peri-ictal manifestations, examining both their clinical characteristics and the brain networks implicated in the generation of aggressive behaviours during seizures. We try to elucidate the neurobiological substrates underlying these manifestations using intracerebral recordings. We then turn to violence associated with parasomnias, analysing and comparing the mechanisms underlying aggression and violence occurring in epileptic seizures with those observed during sleep in parasomnias, integrating evidence from intracranial EEG studies of disorders of arousals. This comparison highlights key similarities, differences, and the risk of a misdiagnosis. Finally, we address the legal and forensic implications of seizure- and sleep-related aggression and violence. Epileptic seizures and parasomnias can cause injuries to the affected person or to those nearby, but they can rarely be truly classified as acts of violence. However, although aggressive behaviour is uncommon during seizures, it may lead to legal consequences. Despite efforts from scientific societies and patient organisations, the stigma toward epilepsy persists, requiring further action and a deeper scientific understanding of this subject.
Epilepsy is one of the most common chronic neurological disorders, and temporal lobe epilepsy (TLE) is its most prevalent form in adults. Although TLE is classified as a focal epilepsy, it has traditionally been defined...Epilepsy is one of the most common chronic neurological disorders, and temporal lobe epilepsy (TLE) is its most prevalent form in adults. Although TLE is classified as a focal epilepsy, it has traditionally been defined by hippocampal and extra-hippocampal atrophy. However, several studies also report regions of increased cortical thickness, or cortical hypertrophy, in TLE, challenging the notion that structural change in epilepsy is unidirectional. In this narrative review, we synthesize evidence for cortical hypertrophy in TLE and place these findings in a broader neurobiological context. We provide an overview of cortical thickness and MRI approaches used to measure it, highlighting differences between surface-based, volume-based, and voxel-based methods. We then review MRI studies reporting cortical hypertrophy in TLE, noting variability in affected regions, patient populations, and analytical techniques. We discuss potential mechanisms that may underlie cortical hypertrophy, including seizure-related structural remodeling, glial or inflammatory processes, compensatory neuroplasticity, network effects, and methodological limitations. Finally, we outline key gaps and controversies regarding the biological validity, temporal dynamics, and clinical relevance of cortical hypertrophy in TLE. We conclude that consideration of both cortical atrophy and hypertrophy may improve broader understanding of TLE as a disorder involving brain remodeling rather than isolated regional atrophy.