Acta Neuropathologica最新文献

Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer’s-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants (ρ = 0.41–0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant (ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant (ρ = – 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants (β = 0.35–1.06, P ≤ 0.026), with tau independently associated with QSM in the VM (β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80% of the effect being direct. These findings underscore the contributions of tau pathology, pigmented neuron density, and iron deposition to nigral magnetic susceptibility and highlight the potential for QSM to serve as a sensitive biomarker for diverse neuropathologies.

Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with prominent neurological manifestations, most notably epilepsy, and is frequently accompanied by a wide range of neuropsychiatric comorbidities. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway plays a central role in TSC pathology, disrupting both general brain development and specific molecular processes such as metabolism. While much attention has focused on neurons and astrocytes in these TSC-related alterations, the contribution of microglia remains relatively underexplored. In this study, we first analysed the transcriptomic profiles from resected TSC brain tissue and identified evidence of calcium (Ca²⁺) dysregulation in TSC microglia. In order to investigate the functional consequences, we then examined induced pluripotent stem cell (iPSC) derived microglia-like (iMGL) cells from TSC patients. Our findings reveal that these iMGL cells displayed markedly altered Ca²⁺ signalling, characterized by impaired store-operated calcium entry (SOCE) and an increase in mitochondrial Ca²⁺ uptake. These changes are accompanied by elevated mitochondrial respiratory activity, suggesting a shift in metabolic state. In addition, TSC iMGL cells displayed increased phagocytic activity and an altered inflammatory responsiveness, consistent with a dysregulated microglial activation state. Supporting these functional alterations in iMGL cells, transcriptomic analysis of TSC brain tissue revealed upregulation of several genes associated with lipid metabolism, phagocytosis, and innate immune activation, with partial overlap with stage 2 disease-associated microglia (DAM)-like programs. Together these findings suggest that microglial dysfunction may represent a relevant component of TSC pathophysiology.

Heterozygous mutations in isocitrate dehydrogenase (IDH) 1 and 2 are hallmarks of astrocytoma, IDH-mutated, and oligodendroglioma, IDH-mutated, as defined by the World Health Organization Classification of Tumors of the Central Nervous System, 5th Edition. Mutant IDH confers a neomorphic enzymatic activity that converts α-ketoglutarate (α-KG) into the oncometabolite d-2-hydroxyglutarate (d-2-HG), which inhibits α-KG–dependent dioxygenases and induces a global DNA hypermethylation phenotype, also known as Glioma CpG Island Methylator Phenotype (G-CIMP). To elucidate mechanisms underlying the antitumor effects of DS-1001b—a novel, brain-penetrant, orally available inhibitor of mutant IDH1 R132H and R132C—we performed preclinical analyses using IDH1 R132H-mutant glioma cells in vitro and orthotopic mouse xenograft models (MGG152, BT142, and A1074). DS-1001b treatment reduced 2-HG levels in vitro and in vivo and significantly prolonged survival in A1074 and BT142 intracranial xenograft models (p = 0.0064 and 0.0004, respectively), confirming effective target inhibition in the brain. In vitro, prolonged DS-1001b exposure partly reversed genome-wide DNA hypermethylation and revealed that H3K4me3 modulation was mostly associated with differential gene expression, affecting pathways related to apoptosis, necrosis, cell cycle arrest, and migration in MGG152. Metabolomic analyses further demonstrated a significant reduction in asparagine in A1074, consistent with the activation of l-asparaginase–mediated pathways. Collectively, these findings indicate that sustained DS-1001b administration exerts antitumor effects in IDH1-mutant glioma mouse models and induces transcriptomic, epigenetic, and metabolic reprogramming.

Genetic prion diseases are caused by mutant prion protein (PrP) misfolding, eventually leading to the formation of PrP^Sc, the infectious prion isoform that propagates by inducing misfolding of native PrP. Different mutations are thought to generate distinct prion strains with unique self-replicating and neurotoxic properties, contributing to the phenotypic diversity of genetic prion diseases. We previously showed that transgenic mice expressing the mouse PrP homologs of the D178N–M129 and D178N–V129 mutations linked to fatal familial insomnia (FFI) and genetic Creutzfeldt–Jakob disease (CJD¹⁷⁸) accumulate misfolded, mildly proteinase-K (PK)-resistant PrP in their brains. These mice develop spontaneous neurological illnesses resembling FFI and CJD¹⁷⁸, but their diseases have not been found to be transmissible to various mouse lines. In this study, we further assessed their prion propagation potential by inoculating bank voles—shown here to be susceptible to human FFI and CJD¹⁷⁸ prions—and by using RT-QuIC. Negative results from both approaches corroborate the idea that these mice do not generate infectious prions. However, when brain homogenates from Tg(FFI) and Tg(CJD) mice were subjected to protein misfolding cyclic amplification with RML PrP^Sc as a seed, they generated highly PK-resistant mutant prions (RML^FFI and RML^CJD) able to propagate in Tga20 mice overexpressing wild-type PrP. To determine whether these in vitro-converted prions modeled the human diseases better, we examined their transmissibility, biochemical traits, and neuropathological features. Despite successful serial propagation in Tga20 mice, RML^FFI and RML^CJD displayed long incubation times, poor transmissibility to C57BL/6 mice, identical PK-resistant PrP fragments, and distinctive neuropathological changes including large submeningeal and perivascular plaques enriched in endogenous proteolytically shed PrP lacking membrane anchorage. These findings indicate that, regardless of the M129V polymorphism, the D178N mutation imparts novel, stable strain properties to RML that do not recapitulate the features of FFI and CJD¹⁷⁸. Our results offer new insights into how genetic PrP mutations influence prion strain characteristics and suggest that spontaneous and templated prionogenesis may follow distinct mechanistic pathways.

The complement system is involved in the pathogenesis of inflammatory demyelinating diseases (IDDs) of the CNS. While complement inhibition significantly reduces the relapse rate in neuromyelitis optica spectrum disorders (NMOSDs), no clear consensus has been reached regarding the role of complement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS). Therefore, we examined CNS tissues from patients with NMOSD (18 autopsies and one biopsy, median age: 56 years), MOGAD (seven autopsies and 20 biopsies, median age: 34 years) and MS (24 autopsies, median age: 54.5 years) to assess the involvement of the complement system from a histopathological perspective. To investigate complement activity at multiple steps, the tissue deposition of three different complement components (C4d, C3d, and C9neo) was examined using immunohistochemistry. In NMOSD, the typical perivascular rosette/rim pattern of complement deposition was confirmed by the three different complement products within acute astrocyte-lytic lesions. In MOGAD, we observed C4d deposition around perivenous demyelinating lesions in 83% (20/24 tissues). However, C9neo deposition differed between patients, with 73% (11/15 patients with perivenous demyelination-predominant MOGAD) showing limited deposition of C9neo with relatively well-preserved oligodendrocytes (MOGAD type A), while 27% showing strong deposition accompanied by the disappearance of oligodendrocytes (MOGAD type B). The more destructive type B pathology was more frequent among deceased than living patients who, by contrast, had type A pathology in the vast majority. In MS, only C4d showed clear deposits on myelin sheaths in the peri-plaque white matter bordering the edges of the demyelinating lesions. These findings seemed to be characteristic of MS, and the extent and intensity tended to decrease in accordance with lesion activity. Complement deposition in MS lesions was linked to shorter interval between onset and death. These characteristic patterns of complement deposition in the three IDDs likely reflect the distinct pathogeneses of the diseases.

Multiple sclerosis (MS) shows a highly heterogeneous course, with some patients accumulating severe disability early while others remain relatively preserved even after decades. A key driver of disability progression is smoldering inflammation, a chronic, compartmentalized immune process at the edge of chronic active lesions. However, the factors driving smoldering inflammation in MS remain incompletely understood. We investigated the role of genetic variation in smoldering inflammation–related genes across two independent MS cohorts, using a discovery-replication design in a total of 2,817 patients. We identified a locus in the HIF1A (Hypoxia-Inducible Factor 1-alpha) gene that is associated with a more favorable disease course at over 20 years from disease onset. Using additional independent cohorts, we found that carriers of the HIF1A protective allele exhibited lower paramagnetic rim lesion volume on MRI, lower plasma and cerebrospinal fluid neurofilament levels, and reduced microglial/macrophage inflammation with less axonal injury in post-mortem progressive MS tissue. By integrating single-nucleus RNA sequencing and spatial transcriptomics, we showed that the HIF1A variant dynamically modulates gene expression in a cell-type specific and context-dependent manner in the MS brain. Collectively, these findings highlight a protective HIF1A variant associated with a more favourable long-term disease course and reduced smoldering inflammation, opening new avenues to translate this genetic discovery into new potential strategies to tackle disease progression.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and a major cause of mortality in neurofibromatosis type 1 (NF-1). Distinguishing MPNSTs from benign neurofibromas remains challenging. We investigated fibroblast activation protein alpha (FAP) as a malignancy biomarker and theranostic target in peripheral nerve sheath tumors. Therefore, we integrated publicly available bulk transcriptomics, spatial transcriptomics, and single-cell RNA sequencing with immunohistochemistry (IHC) on independent archival samples. We further directly assessed clinical translatability using FAP-targeted PET/CT in an NF-1 patient undergoing work-up for suspected malignant transformation. Across independent bulk datasets, FAP was consistently up-regulated in MPNSTs compared with neurofibromas. In the TCGA sarcoma dataset, FAP varied by histotype but was clearly expressed in MPNSTs. Spatial transcriptomics revealed enrichment of FAP-high regions in MPNSTs and co-localization with tumor cell markers. Single-cell analysis showed FAP expression in MPNST tumor cells and cancer-associated fibroblasts, with the highest levels in neural crest-like tumor subpopulations previously linked to adverse prognosis; pseudotime analysis indicated decreasing FAP expression along trajectories toward Schwann cell precursor-like states linking FAP expression to a more primitive, dedifferentiated tumor cell state. IHC confirmed strong, predominantly tumor cell-intrinsic FAP expression in MPNSTs, with minimal staining in neurofibromas and normal tissues. Plexiform neurofibromas exhibited intermediate FAP expression. In clinical imaging, FAP-PET demonstrated higher tracer uptake in histologically proven MPNSTs than in benign lesions within the same patient, including a neurofibroma that was FDG-avid but FAP-negative, supporting added diagnostic specificity over FDG-PET/CT. In summary, FAP is robustly overexpressed in MPNSTs at transcript and protein levels, potentially concentrates in high-risk tumor cell states, and is detectable by targeted PET imaging. These findings identify FAP as a clinically relevant biomarker for malignancy in NF-1-associated tumors and support implementation of FAP-directed diagnostics and therapeutics in peripheral nerve sheath tumor work-up.

Lewy body dementia (LBD), encompassing dementia with Lewy bodies and Parkinson’s disease dementia, is neuropathologically defined by neuronal accumulation of α-synuclein encoded by the SNCA gene. Genetic risk factors strongly influence LBD susceptibility, including SNCA multiplication, particularly triplication, and the apolipoprotein E ε4 allele (APOE4), the strongest common genetic risk factor for LBD. While SNCA is predominantly expressed in neurons and APOE primarily in glial cells, how these genetic factors converge to impact neuronal vulnerability and regional pathology in the human brain remains poorly understood. Here, we applied spatial transcriptomics to postmortem temporal cortex tissue from LBD cases with SNCA triplication or different APOE genotypes, alongside age- and sex-matched controls, to map gene expression within intact cortical architecture. We identified layer 5 of the gray matter as a particularly vulnerable region, characterized by elevated SNCA expression, pronounced synaptic and metabolic dysregulation, and exacerbation of these alterations in APOE4 carriers. Reelin signaling emerged as a core Lewy body-associated pathway disrupted across cortical layers, validated in independent postmortem cohorts and human-induced pluripotent stem cell (iPSC)-derived cortical organoids. In contrast, white matter exhibited distinct molecular alterations, including disrupted myelination pathways, with APOE4 carriers showing increased myelin debris and glial responses compared with non-carriers. Cell-type deconvolution informed by single-nucleus RNA sequencing further revealed APOE4-associated impairments in neuronal vulnerability and intercellular communication. Together, these findings define spatially and cell-type-specific mechanisms through which SNCA dosage and APOE4 genotype impact LBD pathology, providing insight into regionally distinct disease processes and potential targets for genetically stratified therapeutic interventions.

Multiple system atrophy (MSA) is a fatal neurodegenerative synucleinopathy characterized by the accumulation of α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions. Although iron dysregulation and ferroptosis, an iron-dependent form of regulated cell death, have been implicated in neurodegeneration, their specific role in MSA oligodendrocytes remains unknown. We investigated ferroptosis pathways in postmortem brain tissues from patients with MSA, Parkinson’s disease (PD), and healthy controls (HCs) by immunofluorescence for GPX4 co-labelled with CNPase (oligodendrocyte marker) or TH (dopaminergic neuron marker). To validate these findings, we employed PLP-hαSyn transgenic mice, an established MSA model, and the human oligodendrocytic cell line MO3.13, subjected to α-synuclein over-expression, preformed fibrils (PFF) exposure, and brain homogenates derived from MSA pons. Mechanistic insights were pursued through immunofluorescence, JC-1, FerroOrange, western blotting, and co-immunoprecipitation. Finally, we developed a novel biomarker assay using nanoscale flow cytometry to quantify FTH1-containing, CNPase-positive (oligodendrocyte-derived) EVs (ODFC-EVs) in plasma samples from 49 MSA patients, 46 PD patients, and 48 HCs. GPX4, the key ferroptosis regulator, was significantly reduced in CNPase⁺ oligodendrocytes of MSA brains versus PD and HCs, while, as expected, GPX4 loss in PD predominated in TH⁺ neurons. PLP-hαSyn mice recapitulated the unique GPX4 suppression in oligodendrocytes. In MO3.13 cells, α-synuclein enhanced erastin-induced GPX4 loss, increased labile Fe²⁺ accumulation and aggravated mitochondrial depolarisation. Mechanistically, α-synuclein was found to directly bind and stabilize NCOA4, impairing its ubiquitination-mediated degradation. This enhanced NCOA4 activity drove excessive ferritinophagy, leading to the lysosomal degradation of the iron-storage protein FTH1 and subsequent iron overload. Translationally, plasma levels of ODFC-EVs were significantly reduced in MSA patients compared to both PD patients (AUC 0.771; sensitivity 65.3%, specificity 84.8%) and HCs (AUC 0.857; sensitivity 67.4%, specificity 91.7%). Our study provides the first in vivo and mechanistic evidence supporting a model in which α-synuclein drives oligodendrocyte-specific ferroptosis in MSA by stabilizing NCOA4, depleting FTH1 and promoting toxic iron accumulation. This cell-type-restricted mechanism distinguishes MSA pathogenesis from that of PD. Furthermore, the parallel reduction of circulating ODFC-EVs offers a readily accessible blood-based biomarker to discriminate MSA from PD. Together, these findings position the α-synuclein-NCOA4-FTH1 axis as a central pathogenic pathway and a compelling therapeutic target for MSA.