Neuropathological validation studies of pathology-specific biomarkers for neurodegenerative diseases are essential but are often limited by long sampling-to-death intervals and the lack of semi-quantitative pathology measures. We assessed the associations of five cerebrospinal fluid (CSF) (Aβ42/Aβ40, p-tau181, p-tau217, Aβ42/p-tau181 and Aβ42/p-tau217) and three plasma (p-tau217, p-tau217/Aβ42 and Aβ42/Aβ40) biomarkers with post-mortem Aβ and tau pathology burden in 250 participants with ante-mortem CSF (n=230) and/or plasma (n=101), affected by prion (n=162) or non-prion diseases (n=88). Aβ and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of Aβ and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5 months for CSF and 1 month for plasma. CSF Aβ42/Aβ40 decreased at the second quartile of Aβ burden (p<0.001), whereas p-tau181 (p<0.01) and p-tau217 (p<0.001) increased only from the third quartile. CSF Aβ42/Aβ40 achieved its highest accuracy at low/intermediate Aβ burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced Aβ (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau217 and Aβ42/p-tau217 consistently showed higher accuracy than their p-tau181 counterparts across Aβ and tau pathology scores. Plasma p-tau217 and p-tau217/Aβ42 significantly increased in the highest Aβ and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer’s disease neuropathological continuum. CSF Aβ42/Aβ40 best reflects low/intermediate Aβ burden, while CSF p-tau markers are more closely related to high Aβ and intermediate tau load. Plasma markers primarily identify advanced Aβ and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of Aβ deposition.
ARPP21 has recently emerged as a new amyotrophic lateral sclerosis (ALS) associated gene but its pathogenic role remains unclear. In this study we performed familial, clinical, neuropathological and cellular analyses to characterize the recurrent p.P529L and p.P713L variants (also known as p.P563L variant and p.P747L variant, respectively) in our French ALS cohort of 1190 ALS cases and 50 additional family members available for segregation analysis, resulting in the description of 29 ARPP21-linked patients. ARPP21 emerged as the most frequent rare ALS-associated gene in France after exclusion of the four major ALS genes, accounting for 2.7
Mutations in superoxide dismutase−1 (SOD1) are a common cause of amyotrophic lateral sclerosis (ALS). Inheritance is as a rule dominant, but in carriers of the most prevalent mutation, D90A, disease primarily develops in homozygotes. Increasing evidence suggests that prion-like propagation of SOD1 aggregation is the central pathogenic mechanism. Two structurally different strains of aggregates have been found to arise in human SOD1 (hSOD1) transgenic (Tg) mouse models of ALS. Strain A is formed by most mutants including hSOD1G85R and homozygous hSOD1WT Tg mice, whereas homozygous hSOD1D90A Tg mice form a distinct strain B, but also A. Inoculation of strain A and B seed preparations from Tg mice into lumbar spinal cord of adult hSOD1G85R mice induced templated spreading hSOD1 aggregation and premature ALS-like disease. Seeds from an ALS patient carrying the hSOD1G127X truncation mutation likewise transmitted strain A aggregation and disease. In the present study, we investigated whether seeds prepared from spinal ventral horns from six patients homozygous for the hSOD1D90A mutation could transmit aggregation and disease to adult hSOD1G85R Tg mice. Despite the extensive degeneration and loss of motor neurons in the long-lived D90A patients, two of the seeds significantly shortened the survival of the Tg mice, one transmitting A and the other B-pattern hSOD1 aggregation. Nine different preparations from four human controls lacked effects. The results demonstrate that two distinct aggregate strains can arise and propagate in homozygous hSOD1D90A ALS patients, further supporting the hypothesis that prion-like transmission of hSOD1 aggregation is the primary pathogenic mechanism in SOD1-linked ALS.
The pathophysiological mechanisms underlying the hypercoagulable state and thrombotic events associated with COVID-19 remain incompletely understood. To investigate prothrombotic alterations during SARS-CoV-2 infection, we performed an exploratory and integrated analysis of cerebral thrombi retrieved, during the first wave of the pandemic, by mechanical thrombectomy from stroke patients with (n=6) and without (n=6) COVID-19. We combined histological and ultrastructural assessment with quantitative proteomics and elemental profiling to identify differences in cellular organization and in protein and metal composition. Immunohistochemical quantification revealed a trend toward increased macrophage abundance, a more diffuse CD68⁺ staining pattern, and reduced platelet content in COVID-19 thrombi. In contrast, neutrophil extracellular traps (NETs) burden, neutrophil number, and erythrocyte content did not differ significantly between groups. Transmission electron microscopy showed a disorganized ultrastructural fibrillar network in thrombi from COVID-19 stroke patients, consistent with the irregular and less densely packed extracellular matrix observed by Masson's trichrome staining. Furthermore, quantitative proteomics by liquid chromatography–tandem mass spectrometry (LC–MS/MS) identified 48 differentially expressed proteins among 720 shared proteins, with marked upregulation of hemoglobin subunits (α, β, γ, and δ), haptoglobin, biliverdin reductase and redox-regulating proteins, alongside downregulation of platelet-related proteins in COVID-19 thrombi. Total reflection X-ray fluorescence (TXRF) confirmed increased iron levels in COVID-19-associated thrombi. Notably, glycophorin A immunostaining did not indicate increased erythrocyte abundance, and erythrocyte structural proteins were not differentially expressed in proteomic analysis, suggesting that hemoglobin and iron were largely present in a cell-free form within the retrieved thrombi of COVID-19 stroke patients. In addition, acute-phase reactants, classical complement components, and immunoglobulins were detected exclusively in COVID-19 samples, consistent with a distinctive immune-inflammatory and oxidative signature. Overall, these findings support a novel pathophysiological mechanism underlying COVID-19-associated hypercoagulability and thrombosis, involving elevated circulating cell-free hemoglobin and increased iron content. Furthermore, this study highlights the potential contribution of hemoglobin/iron-related processes to the COVID-19 prothrombotic state and may provide molecular targets for future therapeutic strategies.
Papillary tumors of the pineal region (PTPR) are rare CNS neoplasms with adult and pediatric presentations, but whether age defines distinct molecular biology is unclear. We assembled a multicenter retrospective cohort of 86 histologically confirmed PTPR with genome-wide DNA methylation data, comprising 62 adult and 24 pediatric tumors. Molecular subgroup, array platform, sex, and tumor purity were incorporated into multivariable models. Analyses included DNA methylation class assignment, differential methylation, copy-number variation (CNV), epigenetic mitotic-clock scores, methylation-based tumor microenvironment deconvolution, and descriptive survival evaluation. Adult and pediatric tumors mapped within the established PTPR-A and PTPR-B methylation framework rather than forming age-defined methylation classes. Pediatric tumors were enriched for PTPR-B (22 of 24 tumors [91.7
Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (n = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (n = 5) and RNA-based fusion profiling (n = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5–75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (n = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.
Neurodegenerative diseases are increasingly recognized as disorders shaped not only by intrinsic neuronal vulnerability, but also by chronic neuroinflammation mediated by maladaptive neuroimmune signaling. Granzymes, a family of serine proteases classically studied for their cytotoxic roles in anti-viral and anti-tumor immunity, are emerging as important mediators of central nervous system (CNS) pathology. In addition to their canonical intracellular functions, granzymes can act extracellularly to cleave the extracellular matrix (ECM), activate cell-surface receptors, disrupt epithelial barrier function, amplify inflammatory cascades, and alter glial and neuronal responses to injury. In this review, we synthesize current knowledge on the roles of Granzyme A (GzmA), Granzyme B (GzmB), Granzyme H (GzmH), and Granzyme K (GzmK) in neurodegeneration and neuroinflammation across diverse CNS disease and injury contexts, such as Alzheimer’s disease (AD), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and age-related macular degeneration (AMD). GzmB is the most extensively characterized, with evidence supporting both intracellular neurotoxicity and extracellular pathogenic functions mediated through protease-activated receptor signaling, ECM cleavage, outer blood–retina barrier disruption, angiogenesis, fibrosis, and chronic inflammation. GzmA is implicated in tau proteolysis and structural destabilization of neurons and astrocytes, while GzmK has emerged as a context-dependent regulator of neuroinflammation through PAR-1 activation, microglial modulation, and complement cascade activation. GzmH remains the least understood but may contribute to nerve injury through mechanisms that are only beginning to be defined. We also discuss endogenous and pharmacological granzyme inhibition, highlighting the therapeutic promise of selective extracellular granzyme targeting, particularly for GzmB, while emphasizing the current lack of selective inhibitors for GzmA, GzmK, and GzmH. Collectively, these findings position granzymes as underappreciated neuroimmune effectors and potential therapeutic targets in neurodegenerative diseases and CNS injury.
Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer’s disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau “biosensor” cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.
Neuropathic pain from affection of single nerve roots regularly expands to the neighboring dermatomes. In this study, we aimed to investigate the psychophysical consequences of this pain spread. We performed quantitative sensory testing (QST) in 10 patients with disc herniation—related L5 radiculopathy (four women; age 56.9 ± 2.9 years) and 12 healthy controls (six women; age 55.9 ± 2.7 years) bilaterally in the L5 and S1 dermatomes. Average time between onset of pain and study inclusion was 32 days (+/−6.6). Pain intensity was rated as visual analog scale (VAS) (0–10) 6.5+/−0.6. Affection of the L5 nerve root was verified via clinical investigation, MRI and paravertebral needle electromyography (EMG). The cold ( F = 8.158; p = 0.011) and warm detection ( F = 13.636; p = 0.02) thresholds were higher within the affected L5 dermatome in nucleus pulposus prolapse (NPP) patients compared with controls, and for warm detection also compared with the contralateral side ( p = 0.021). Hyperalgesia to blunt pressure was detected on the affected side in NPP patients compared with controls ( F = 5.664; p = 0.029) and to the contralateral leg ( p = 0.011). Comparing L5 and S1 dermatomes on the affected side, only functional hypoesthesia measure via mechanical detection threshold was increased within the impaired L5 dermatome ( p = 0.043). In the neighboring S1 dermatomes, the warm detection thresholds were significantly increased on the affected side compared with the controls ( F = 14.471; p = 0.001) and to the contralateral unaffected limb ( p = 0.039). In conclusion, unilateral symptomatic L5 damage affects sensory perception in unaffected neighboring dermatomes on the affected limb.
Pediatric central nervous system tumors remain a leading cause of cancer-related mortality in children, while their diagnosis, risk stratification, and therapeutic management increasingly depend on integrated molecular characterization. However, representative tumor tissue is often difficult to obtain because of tumor location, surgical risk, limited biopsy material, and the impracticality of repeated sampling during disease evolution. Cerebrospinal fluid (CSF) has therefore emerged as a particularly informative liquid biopsy compartment for many CNS malignancies, enriched in tumor-derived cell-free DNA and, for tumors in contact with the CSF spaces, more directly reflective of intracranial tumor biology than plasma; its yield nonetheless varies with tumor biology and anatomical proximity to CSF pathways. Here, we review the evidence supporting CSF cell-free DNA sequencing as an emerging extension of molecular neuropathology in pediatric CNS tumors. Targeted next-generation sequencing, low-pass whole-genome sequencing, methylation-based classifiers, and nanopore sequencing now enable complementary assessment of somatic mutations, copy number alterations, epigenetic tumor class, and longitudinal tumor burden from low-input pediatric CSF samples. Recent studies have moved the field beyond analytical proof of concept towards defined clinical scenarios, including molecular diagnosis when biopsy is infeasible, molecular staging of high-CSF-shedding tumors, minimal residual disease monitoring in medulloblastoma and other embryonal tumors, and clarification of ambiguous radiological progression. CSF-based sequencing does not replace tissue neuropathology, but provides a liquid molecular layer that can complement, extend, or in selected situations partially substitute tissue-based diagnosis. Its broader adoption now depends on workflow standardization, assay-specific reporting standards, external quality assurance, and prospective evidence that CSF-guided decisions improve patient outcomes.
Histopathologic staging models of neuronal α-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (n = 62) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; n = 12), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (
Objectives Fatigue adversely affects quality of life after stroke. This study is aimed at assessing the prevalence of poststroke fatigue at 6 months and its determinants in patients with acute ischemic stroke treated with revascularization therapy. Methods Consecutive ischemic stroke patients treated with intravenous thrombolysis and/or mechanical thrombectomy were enrolled. Sociodemographic, clinical, and ischemic lesion characteristics were collected at baseline. Fatigue was assessed at 6‐month follow‐up using the Fatigue Severity Scale (FSS), along with functional outcome, anxiety, and depression. Factors associated with poststroke fatigue were evaluated in the overall cohort and in patients with supratentorial hemispheric stroke using logistic regression models. Results Among 900 enrolled patients, 413 survivors had available fatigue assessment (mean age: 69.2 ± 14.1 years, 52.3% men, median NIHSS score: 9 [IQR: 5–15]). Poststroke fatigue (FSS score ≥ 36) was observed in 161 patients (39%). In the overall cohort, fatigue was independently associated with depression (OR = 5.78, 95% CI: 2.68–12.4) and anxiety (OR = 2.90, 95% CI: 1.52–5.51), whereas being single was negatively associated with fatigue (OR = 0.30, 95% CI: 0.09–0.99). A marginal association was observed with cerebellar stroke location (OR = 11.0, 95% CI: 0.88–137.6). In patients with supratentorial hemispheric stroke, fatigue was independently associated with hypertension (OR = 2.25, 95% CI: 1.13–4.47), right‐sided lesion (OR = 2.08, 95% CI: 1.13–3.83), depression (OR = 5.35, 95% CI: 2.08–13.7), and anxiety (OR = 3.10, 95% CI: 1.42–6.74). Conclusions Poststroke fatigue remains a frequent and clinically meaningful outcome in patients with ischemic stroke treated with revascularization therapy and is strongly associated with psychological factors and right hemispheric location. Whether specific therapeutic interventions may reduce the burden of this symptom warrants further investigation. Trial Registration ClinicalTrials.gov identifier: NCT02856074
Glaucoma is a leading cause of irreversible blindness worldwide, yet available treatments fail to prevent disease progression for all patients. It is characterized by a progressive dysfunction and loss of retinal ganglion cells. Neuroinflammation has been recognized as an underlying neurodegenerative mechanism of glaucoma in animal models and human post-mortem samples, and targeting neuroinflammation may provide additional means to neuroprotection. Galectin-3, a pro-inflammatory mediator encoded by the LGALS3 gene in humans, holds promise as a treatable target as its pharmacological and genetic inhibition is neuroprotective in multiple models of experimental glaucoma. However, the role of Galectin-3 in glaucoma remains unclear, particularly whether its emergence is a consequence of degeneration, or occurs at earlier time points. To address these knowledge gaps, we labeled IBA1, GFAP, and Galectin-3 in retina sections at early glaucoma stages in the rat bead glaucoma model, and in human retina from glaucoma donors. In the rat, IBA1 volume, but not GFAP, increased at an early, pre-degenerative timepoint. Accompanying this, we identified a significant increase of Galectin-3/IBA1 colocalization compared to control at the same timepoint, supporting the upregulation of Galectin-3 in early inflammation, preceding retinal ganglion cell degeneration in experimental glaucoma. However, a significant increase in Galectin-3/GFAP colocalization compared to control at the same timepoint in the rat additionally associates Galectin-3 production with astrocytes and Müller glia. This Galectin-3 to Müller glia relationship was significantly pronounced in human glaucomatous retina, predominating over microglia co-labelling. We further demonstarted that human MIO-M1 Müller glia in vitro express Galectin-3, but this is not altered in response to glaucoma relevant stimuli (TNF-α or mild-metabolic stress from rotenone). Instead, Galectin-3 expression was altered in phagocytosing states from exposure to E. coli particles, brain synaptosomes, or apoptotic neuronal debris. These findings provide further insight into Galectin-3 and gross inflammatory responses in glaucoma pathology.
In multiple sclerosis (MS), the chronic, unresolved nature of neuroinflammation within the central nervous system (CNS) remains a major obstacle for effective therapeutic intervention. This challenge arises primarily due to an incomplete understanding of the dysregulated inflammatory and pro-resolving pathways underlying MS lesion progression. Bioactive lipid mediators (LMs), biosynthesized through the coordinated actions of specific enzymes like lipoxygenases (LOX) and cyclooxygenases (COX), are key regulators of both the initiation and resolution of an inflammatory response; however, their spatial organization and functional role during MS pathology have not been fully elucidated. Here, by using pneumatically assisted nanospray desorption electrospray ionization (PA nano-DESI) mass spectrometry imaging and immunohistochemistry, we reveal an increase in the LM leukotriene B4 (LTB4) in human MS white matter compared to controls, with further enrichment in MS lesions relative to perilesional areas, alongside elevated microglial 5-LOX activating protein (FLAP) expression. Pharmacological antagonism of FLAP suppresses LTB4 biosynthesis in human-induced pluripotent stem cell (iPSC)-derived microglia with only marginal effects on the microglia transcriptional phenotype as determined by RNA sequencing. Moreover, in vivo FLAP antagonism ameliorates disease severity and spinal cord inflammatory gene expression in the experimental autoimmune encephalomyelitis (EAE) model, an animal model of MS, in both a prophylactic and therapeutic settings. This coincided with reduced local LTB4 biosynthesis and reduced levels of inflammatory monocytes within the spinal cord during EAE. Together these findings establish the FLAP/LTB4 axis as a driver of neuroinflammation and a druggable therapeutic target for chronic inflammatory CNS disorders like MS.
Glioblastoma remains a challenging disease to approach with immunotherapy due to pronounced antigen heterogeneity, immunosuppressive tumor microenvironment, and barriers to effective molecule delivery within the central nervous system. T-cell engagers provide an off-the-shelf approach to redirect endogenous T cells toward tumor cells. However, bispecific formats are constrained by intra- and interpatient antigen heterogeneity, which can limit therapeutic efficacy. In this review, we examine trispecific T-cell engagers (TriTEs) as an emerging strategy to address this limitation by simultaneously targeting multiple tumor-associated antigens. We discuss principles guiding antigen selection in glioblastoma, summarize available preclinical evidence supporting multispecific engagement, and outline key design considerations, including molecular architecture, stability, half-life extension, and safety optimization. We further review delivery strategies, such as gene-encoded expression, cellular carriers, and blood–brain barrier modulation, that may improve tumor access and the durability of TriTEs. Together, these considerations position TriTEs as a modular immunotherapy platform relevant to glioblastoma and other heterogeneous solid tumors.
Background and Objectives Guillain–Barré syndrome is the most common cause of acute acquired neuromuscular paralysis worldwide and is frequently associated with significant disability requiring rehabilitation. However, data on rehabilitation requirements and their clinical predictors remain limited, particularly in low‐ and middle‐income countries. We aimed to characterize rehabilitation requirements and identify associated clinical factors. Methods We conducted a retrospective observational cohort study including adult patients with Guillain–Barré syndrome diagnosed between 2006 and 2023 at a neurological center in Argentina with at least 1 year of follow‐up. Demographic data, clinical features, electrophysiological findings, treatments, intensive care requirements, and functional outcomes were analyzed. Motor impairment was assessed using the Medical Research Council sum–score and disability using the Guillain–Barré syndrome disability scale. Patients were classified according to rehabilitation requirements (none, outpatient, or inpatient). Results Among 142 screened patients, 114 were included (median age 48 years; 43.9% female). Forty patients required no rehabilitation, 62 outpatient rehabilitation, and 12 inpatient rehabilitation. Lower Medical Research Council sum–scores, sensory ataxia, abnormal osteotendinous reflexes, severe autonomic dysfunction, and unilateral facial palsy were associated with rehabilitation requirements. Intensive care unit admission, mechanical ventilation, hemodynamic support, disability score ≥ 3 at discharge, and lower Medical Research Council scores at discharge were also associated with rehabilitation requirements. No significant differences were observed among electrophysiological subtypes. Conclusion Rehabilitation requirements in Guillain–Barré syndrome are mainly driven by early clinical severity, autonomic and respiratory involvement, and residual motor disability at discharge. Early identification of these factors may facilitate timely referral to rehabilitation programs and improve functional recovery. These findings may support early stratification of patients and optimize rehabilitation referral in routine clinical practice.
Alzheimer's disease (AD) is characterised by the intraneuronal aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles and by the extracellular deposition of β-amyloid (Aβ). Tau pathology restricted to the hippocampal formation is frequently observed in the elderly brain in the absence of any Aβ deposition and considered as "primary age-related tauopathy" (PART). Here, we applied an unbiased proteomic approach to determine how concomitant Aβ pathology modifies the neurofibrillary tangle proteome. Neurofibrillary tangles were isolated by dissecting Tau pSer202/pThr205 "AT8" immunopositive neuronal profiles, combining chromogenic immunohistochemistry with laser capture microdissection, from hippocampal sections of 17 post-mortem brains spanning three groups: PART (n = 5; A0, B1-2, C0 scores), intermediate AD (n = 6; A1-2, B2-3, C1-2 scores) and advanced AD (n = 6; A3, B3, C3 scores). A label-free quantitative liquid chromatography-mass spectrometry based proteomic analysis, using data independent acquisition (DIA) on a Bruker timsTOF, was performed. A conserved core of 63 proteins was identified as enriched in tangles across all groups, mostly associated with "RNA binding" and "regulation of mRNA metabolic process", based on the Gene Ontology database. Group-specific signatures were also observed: 33 proteins were significantly enriched only in tangles collected from PART cases and were predominantly linked to "structural molecule activity", whereas Aβ-positive cases showed specific enrichment of "RNA binding" and "cytoplasmic translation" pathways-with intermediate AD cases displaying a transitional profile. Our findings are consistent with PART having distinct tangle proteomic features; however, the majority of its proteomic signature is in common with tangles within the AD continuum. By addressing how Aβ accumulation alters the tangle proteome, this study provides mechanistic insights into the expansion of Tau pathology, paving the way towards the identification of biomarkers and therapeutic strategies that would allow for stabilisation of Tau pathology in the elderly.
Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a recently defined malformation of cortical development that is an important cause of childhood-onset drug-resistant epilepsy. Clinically, the epilepsies associated with MOGHE are heterogeneous, with infantile epileptic spasms syndrome (IESS) being the most common manifestation. Histopathologically, MOGHE demonstrates subtle cortical dyslamination, heterotopic neurons in the white matter, hypomyelination, and a distinctive increase in the density and clustering of oligodendroglial cells, features that distinguish it from other malformations of cortical development such as focal cortical dysplasia (FCD). Recent genetic analyses of epileptogenic tissue resected from individuals with MOGHE have identified somatic mosaic loss-of-function variants in SLC35A2. This gene encodes the Golgi transmembrane UDP-galactose transporter, suggesting disrupted N-glycosylation as a distinct pathogenic mechanism underlying epilepsy in this disorder. In this review, we present the current clinical, histopathological, and molecular understanding of MOGHE, with a particular focus on recent insights gained from experimental rodent and human cellular models of SLC35A2 deficiency. We contextualise these findings against established models of mTORopathies including FCD type 2, placing MOGHE within the broader malformation of cortical development spectrum. Synthesising this evidence, we observe that neuronal activity in models of both MOGHE and mTORopathies such as FCD type 2 converge on reduced action potential firing, despite their distinct genetic aetiologies. Finally, we discuss how these findings inform our understanding of epileptogenesis, especially the emergence of infantile epileptic spasms, and the development of future precision therapeutic strategies across malformations of cortical development.
