Kalf RS, Luinenburg MJ, Dematteis G
… +10 more, Scheper M, Anink JJ, Cavallo G, Mattarei A, Van Hecke W, Mühlebner A, Tapella L, Mills JD, Lim D, Aronica E
Acta Neuropathol
· 2026 Feb · PMID 41688845
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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. Hyper...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 (Ca) 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 Ca⁺ signalling, characterized by impaired store-operated calcium entry (SOCE) and an increase in mitochondrial Ca⁺ 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.
Fujimoto K, Honda-Kitahara M, Hattori N
… +16 more, Matsushita Y, Hibiya Y, Satomi K, Matsunaga H, Tsutsumi S, Okamoto A, Inoue T, Yamada M, Watanabe M, Wakimoto H, Onuki R, Kato M, Sato TA, Ushijima T, Kitabayashi I, Ichimura K
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...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.
Masone A, Grasso A, Comerio L
… +13 more, Bruno R, Lavigna G, Vanni I, D'Agostino C, Orrù CD, Caughey B, Altmeppen HC, Castilla J, Giaccone G, Tagliavini F, Di Bari MA, Nonno R, Chiesa R
Acta Neuropathol
· 2026 Feb · PMID 41665793
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Genetic prion diseases are caused by mutant prion protein (PrP) misfolding, eventually leading to the formation of PrP, the infectious prion isoform that propagates by inducing misfolding of native PrP. Different mutatio...Genetic prion diseases are caused by mutant prion protein (PrP) misfolding, eventually leading to the formation of PrP, 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 (CJD) accumulate misfolded, mildly proteinase-K (PK)-resistant PrP in their brains. These mice develop spontaneous neurological illnesses resembling FFI and CJD, 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 CJD 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 as a seed, they generated highly PK-resistant mutant prions (RML and RML) 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 and RML 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 CJD. 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.
Takai Y, Hametner S, Riedl C
… +19 more, Misu T, Takahashi T, Suzuki H, Chihara N, Watanabe M, Miyahara H, Yoshida M, Iwasaki Y, Suzuki T, Di Pauli F, Bramow S, Laureys G, Banwell B, Mariotto S, Fujihara K, Aoki M, Bradl M, Lassmann H, Höftberger R
Acta Neuropathol
· 2026 Feb · PMID 41661329
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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 disorder...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.
Giordano A, Stridh P, Preziosa P
… +32 more, Pisa M, Lerma-Martin C, Sorosina M, Mascia E, Santoro S, Misra K, Clarelli F, Ferrè L, Needhamsen M, Manouchehrinia A, Missaglia M, Moridi T, Shchetynsky K, Ouellette R, Harroud A, de Vries E, Kuttikkatte SB, Piehl F, Alfredsson L, Hillert J, Olsson T, Fugger L, Attfield K, Granberg T, Schirmer L, Absinta M, Jagodic M, DeLuca GC, Rocca MA, Filippi M, Kockum I, Esposito F
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...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.
Reitsam NG, Gäble A, Siebenhüter L
… +13 more, Schaller T, Liesche-Starnecker F, Sipos E, Dintner S, Walz C, Babic J, Trepel M, Kircher M, Fincke VE, Johann PD, Märkl B, Lapa C, Enke JS
Acta Neuropathol
· 2026 Jan · PMID 41591566
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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 investi...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.
Jin Y, Chen K, Wixom AQ
… +14 more, Li Z, Koga S, Sekiya H, Xhafkollari G, Castanedes-Casey M, Santhakumar H, Meneses AD, Neff AJ, Bu G, Heckman MG, Liu Y, Ross OA, Dickson DW, Zhao N
Acta Neuropathol
· 2026 Jan · PMID 41588135
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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 str...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 ferro...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 Fe 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.
Su Y, Rodrigues MA, Samarasekera N
… +11 more, Loan JJM, Hosking A, Moullaali TJ, Humphreys CA, McDade K, Millar T, Wardlaw JM, Cheng X, van Veluw SJ, Al-Shahi Salman R, Smith C
Acta Neuropathol
· 2026 Jan · PMID 41580571
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Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics...Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics of CAA, and its clinical and neuropathological associations. Participants underwent research autopsy in the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study. Neuropathologists rated tissue for CAA using standardised consensus criteria, as well as non-amyloid small vessel disease, Thal phase, and Braak stage. We compared the presence, distribution, and severity of CAA among different brain regions, and in the lobe or hemisphere affected by lobar ICH to corresponding contralateral regions. We evaluated the diagnostic accuracy of Vonsattel CAA grade on a post-mortem cortical specimen (simulating surgical biopsy) versus the reference standard of moderate-to-severe parenchymal CAA at autopsy. Among 162 participants, parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy were diffusely distributed among all cerebral lobes irrespective of the ICH location, but capillary CAA showed an occipital predominance. In lobar ICH, all CAA measures did not differ between the ICH lobe or hemisphere and the contralateral unaffected region. CAA measures did not increase with age, but they were higher in carriers of APOE ε2 or ε4 alleles and in individuals with higher Thal phase or Braak stage. Using a rule-out category of Vonsattel grade ≥ 1 to diagnose CAA on a simulated cortical biopsy achieved 100% sensitivity (95%CI 93.4-100), and a rule-in category of Vonsattel grade ≥ 2 had 79.5% specificity (95%CI 63.5-90.7) versus the reference standard. The distribution and severity of parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy are diffuse regardless of ICH location, indicating the need to better understand the factors underlying bleeding in CAA-affected vessels.
Fertan E, Kedia S, Nolan G
… +8 more, Meisl G, Cotton MW, Müller KH, Zhang Z, Muresan L, Quaegebeur A, Spillantini MG, Klenerman D
Acta Neuropathol
· 2026 Jan · PMID 41575570
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Alzheimer's disease (AD) is phenotypically characterised by progressive memory loss, which has been linked to tau aggregation and synaptic dysfunction. Here we characterised the nanoscopic tau aggregates in individual sy...Alzheimer's disease (AD) is phenotypically characterised by progressive memory loss, which has been linked to tau aggregation and synaptic dysfunction. Here we characterised the nanoscopic tau aggregates in individual synaptosomes from AD cases and controls, measuring their number and size using SynPull with direct stochastic optical reconstruction microscopy (dSTORM). A total of 7888 synaptosomes from pre-frontal cortex samples were studied, showing the presence of AT8-positive tau aggregates in a small fraction of synaptosomes (~ 3%) from control brains, reaching ~ 20% by Braak stage 6. These key findings of the intra-synaptic localisation of aggregates and existence of synaptic tau pathology at Braak stage 3-preceding tangle formation in this region, were confirmed using aggregate-specific single-molecule array (SIMOA) with proteinase K digestion, three-dimensional super-resolution microscopy, stimulated emission depletion microscopy (STED), and immunohistochemistry. The aggregates also grew in size with AD progression with an average length of 117 nm at stage 0, 154 nm at stage 3 and 182 nm at stage 6, however they mostly remained non-elongated (circular) with average eccentricity values remaining below 0.8. We then investigated the multi-phosphorylation of synaptic tau aggregates for AT8 and T181 and quantified their co-localisation with phosphatidylserine and CD47, synaptic "eat me" and "don't eat me" signals respectively, along with synaptogyrin-3, which contributes to tau-mediated synaptic dysfunction. T181, phosphatidylserine, and synaptogyrin-3 co-localisation with AT8-positive tau were higher during stage 3 and CD47 was lower, indicating early synaptic pathology is associated with the formation of small tau aggregates, contributing to microglia-driven synaptic loss.
Brand F, Rose LS, Akbarzadeh AH
… +22 more, Weber CAM, Eckert I, Schmidt G, Auber B, Förster A, Beyer U, Geffers R, Bartels S, Lalk M, Polemikos M, Friese M, Sabel M, Schwenkenbecher P, Kremer P, Nabavi A, Samii A, Lehmann U, Reifenberger G, Krauss JK, Wiese B, Hartmann C, Weber RG
Acta Neuropathol
· 2026 Jan · PMID 41546701
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Familial occurrence of gliomas has been reported in around 5% of patients. Studies on the genetic landscape of glioma predisposition are scarce. Here, leukocyte DNA of 213 adult glioma patients with a familial and/or per...Familial occurrence of gliomas has been reported in around 5% of patients. Studies on the genetic landscape of glioma predisposition are scarce. Here, leukocyte DNA of 213 adult glioma patients with a familial and/or personal tumor history from 206 families was subjected to whole-exome sequencing. Germline variants (GVs) were analyzed using two approaches: (1) GVs in 164 established cancer predisposition genes (CPGs) or suspected glioma risk genes were extracted and classified; (2) the enrichment of genes with loss-of-function or deleterious missense GVs that were ultrarare or ClinVar likely pathogenic/pathogenic in the glioma versus a control cohort (n = 391) was determined. In 23% (48/213) of glioma patients with a familial/personal tumor history, GVs predicted to be deleterious in CPGs were detected. Of the mutated CPGs, 37% were involved in DNA damage response, including ATM, BRCA2, PMS2, POLE. ATM GVs (n = 6) preferentially predisposed to IDH-mutant astrocytoma (P = 0.007) in patients that were significantly younger at diagnosis than patients without GVs (P = 0.022). BRCA2 GVs (n = 5) were also significantly enriched in glioma patients in approach 2 (P = 0.005). The other mutated CPGs, glioma risk or enriched novel genes play roles in diverse processes, including metabolism and signal transduction. Syn-/metachronous non-brain tumors were diagnosed in 29% of glioma patients with GVs. In 11% of patients, the identified CPG GVs potentially sensitized to targeted therapies, such as PARP, immune checkpoint, or EGFR inhibitors. In conclusion, our study identifies CPGs and novel genes relevant in germline testing of glioma patients with a familial/personal tumor history, possibly resulting in targeted treatment options.
Appleby BS, Manca M, Piazza MS
… +6 more, Kerr TD, Cornacchia A, Bizzi A, Kraus A, Cohen ML, Cali I
Acta Neuropathol
· 2026 Jan · PMID 41528501
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Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is an invariably fatal neurodegenerative disorder affecting 1.5 cases per million individuals per year. About 10-15% of the human prion diseases are c...Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is an invariably fatal neurodegenerative disorder affecting 1.5 cases per million individuals per year. About 10-15% of the human prion diseases are caused by a pathogenic variant in the prion protein (PrP) gene (PRNP), and the most common genetic human prion disease is CJD (gCJD) linked to a glutamic acid to lysine substitution at codon 200 (E200K) of PRNP. The polymorphic codon 129 methionine (M)/valine (V) genotype has a strong effect on disease phenotype. In the present study, we retrospectively evaluated many features of gCJD E200K cases with respect to the 129MV polymorphism, type of scrapie prion protein (PrP), demographic, clinical, laboratory, histopathology, and molecular features, including western blot examination and real-time quaking-induced conversion assay. Analyses were also performed to determine statistically significant features between E200K haplotypes (e.g., codon 129 genotype in cis with the mutated allele) and codon 129 genotypes. This study found that codon 129 polymorphism affects several disease features of gCJD E200K. Specifically, histopathologic differences were found between patients with different 129 haplotypes and genotypes. We have identified five groups or subtypes of E200K associated with either PrP type 1 or 2. Other E200K cases showed mixed (i) PrP types or (ii) pathological features of 129 M and 129 V haplotypes. To our knowledge, this study describes the largest cohort of 177 E200K cases and provides new insight into the wide range of phenotypes associated with this common CJD genetic variant.
Musacchio-Perrucci JB, Martuscello RT, Betzios SI
… +6 more, Hernandez RS, Kuo SH, Cosentino S, Fujita H, Louis ED, Faust PL
Acta Neuropathol
· 2026 Jan · PMID 41524835
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Essential tremor (ET), among the most common movement disorders, is characterized by 8-12 Hz action tremor of the upper extremities. Cognitive dysfunction is increasingly recognized. Postmortem studies of anterior cerebe...Essential tremor (ET), among the most common movement disorders, is characterized by 8-12 Hz action tremor of the upper extremities. Cognitive dysfunction is increasingly recognized. Postmortem studies of anterior cerebellar cortex, which plays a major role in motor function, have systematically identified morphologic changes centered on Purkinje cells (PCs) and adjacent neuronal connections, distinguishing ET from controls. However, the cerebellar cortex is compartmentalized into distinct functional anatomic regions, including control of cognition in posterior lobe. No systematic study of this posterior region has been undertaken in ET. Leveraging resources of the Essential Tremor Centralized Brain Repository, we compared the pathology across anterior and posterior hemispheric cerebellar cortices in each brain in a postmortem series of 123 brains in ET (n = 80) and controls (n = 43). We used 11 quantitative morphologic metrics that reflected PC loss, heterotopic PCs, PC dendritic changes, PC axonal changes (torpedoes, torpedo-associated and non-torpedo related), basket cell axonal hypertrophy, and climbing fiber-PC puncta changes. These metrics distinguished ET cases from controls in both anterior (11/11 metrics) and posterior regions (10/11 metrics) (p values 0.045 to < 0.0001), and 10/11 metrics demonstrated a greater burden of pathology in the ET anterior versus ET posterior cerebellar region (p values 0.045 to < 0.0001). Regional differences among controls were present to a lesser extent than in ET (6/11 metrics; p values 0.035 to < 0.0001). In a principal component analysis, these combined metrics segregated control and ET cases according to both diagnosis and cerebellar region. This is the first study to carefully document that pathology in the ET cerebellum extends beyond the anterior cerebellar region to also involve a posterior cerebellar region. In line with the prominent motor features of ET, the burden of cerebellar pathology was greater in the anterior region. These results advance our nascent understanding of the underlying neuropathological substrate of this highly prevalent disease.
Gerasimenko M, Yi H, Gilliland T
… +3 more, Chen Y, Wang Z, Zou WQ
Acta Neuropathol
· 2026 Jan · PMID 41524805
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Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), share pathological accumulation of misfolded α-synuclein (αSyn) in the brain and overlapping clin...Synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), share pathological accumulation of misfolded α-synuclein (αSyn) in the brain and overlapping clinical features, complicating accurate diagnosis with current methods. In this study, we utilized a real-time quaking-induced conversion (RT-QuIC) assay to demonstrate that autopsied skin samples from PD, DLB, and MSA patients (but not non-synucleinopathy controls) seed aggregation of recombinant αSyn. While RT-QuIC generated similarly positive fluorescence kinetic curves across synucleinopathies, biochemical and morphological analyses of RT-QuIC end products revealed distinct properties in the resulting αSyn aggregates. Notably, αSyn aggregates from DLB samples exhibited the highest resistance to proteinase K digestion, whereas MSA-derived aggregates showed the least aggregated bands on Western blots. Transmission electron microscopy revealed significant differences in length, width, and volume of skin αSyn fibrils of RT-QuIC end products from different synucleinopathies. These findings provide critical insights into disease-specific αSyn structural characteristics and suggest new strategies to improve diagnostic discrimination.
Ruffer N, Pinal-Fernandez I, Preusse C
… +20 more, Mammen AL, Holzer MT, Kleefeld F, Goebel HH, Casal-Dominguez M, Pak K, Kötter I, Siefert J, Furth C, Feldhaus F, Görl N, Fieber F, Alten R, Huber TB, Casteleyn V, Roos A, Krusche M, Schneider U, Milisenda JC, Stenzel W
Acta Neuropathol
· 2025 Dec · PMID 41441888
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Vasculitic myopathy (VM) represents a nonspecific manifestation of various vasculitic syndromes that presents with myalgia, leg tenderness, and muscle weakness. Most cases of VM develop in the context of polyarteritis no...Vasculitic myopathy (VM) represents a nonspecific manifestation of various vasculitic syndromes that presents with myalgia, leg tenderness, and muscle weakness. Most cases of VM develop in the context of polyarteritis nodosa (PAN), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or rheumatoid vasculitis, or manifest as single organ vasculitis. Muscle inflammation in VM is poorly understood, and most studies essentially report the presence of vasculitic changes demonstrated by microscopic analysis of skeletal muscle tissue. However, no detailed characterization or in-depth analyses have been performed so far. We studied the clinicopathologic phenotype of 12 patients and analyzed the gene expression profiles of 36 patients with VM in the context of negative ANCA test results. ANCA-negative VM typically presents with myalgia involving the lower extremities, accompanied by cutaneous manifestations, constitutional symptoms, and marked systemic inflammation. Half of the patients (6/12; 50.0%) met the classification criteria for 'classic PAN'. Serum creatine kinase (CK) activity was normal in most cases (10/12; 83.3%). The presence of skeletal muscle vasculitis was confirmed by histopathology in 9/12 (75.0%) cases. Specifically, ANCA-negative VM predominantly affected small arteries and was consistently associated with small vessel involvement of the epimysial fascia (9/10; 90.0%), which was termed 'vasculitic fasciitis' (VF). Signs of necrotizing vasculitis were occasionally noted (3/9; 33.3%). Mild endomysial fibrosis and muscle fiber necrosis could be compatible with a rather acute disease onset and may account for normal or slightly elevated levels of serum CK activity, respectively. Additionally, nonspecific myopathic changes such as capillary vessel mural thickening and variations of muscle fiber size were detected in all analyzed muscle biopsy specimens. Immunohistochemical studies revealed perifocal sarcolemmal upregulation of major histocompatibility complex class I in the majority of cases (10/11; 90.9%). RNA sequencing of muscle biopsies from 36 ANCA-negative VM patients, compared to 37 healthy controls and 649 samples from other inflammatory myopathies, revealed that ANCA-negative VM is characterized by a dominant interferon-gamma-driven immune response, broad cytokine activation including tumor necrosis factor-related genes, and selective upregulation of angiogenesis- and endothelium-associated transcripts. Our histomorphologic analysis highlights a distinct histopathological pattern of VF that is characteristic for muscle involvement in ANCA-negative vasculitis. Furthermore, we provide evidence for a specific molecular signature that gives new insights into the pathogenesis and treatment of ANCA-negative VM.
Buchman AS, Yu L, Oveisgharan S
… +7 more, Tickotsky N, de Paiva Lopes K, Zammit AR, VanderHorst V, Klein HU, Nag S, Bennett DA
Acta Neuropathol
· 2025 Dec · PMID 41428086
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To advance the nosology of pathologic Parkinson's disease (PD), we examined the associations of Lewy bodies (LBs), nigral neuronal loss (NNL), and co-pathologies with cognitive decline and progression of parkinsonian sig...To advance the nosology of pathologic Parkinson's disease (PD), we examined the associations of Lewy bodies (LBs), nigral neuronal loss (NNL), and co-pathologies with cognitive decline and progression of parkinsonian signs in older decedents without clinical PD during life. Nineteen cognitive tests and 26 Unified Parkinson's Disease Rating Scale items were measured annually. We measured both elements of pathologic PD, i.e., LBs and NNL, and eight other Alzheimer's disease and related dementias (ADRD) co-pathologies in 1717 brains. A semiquantitative scale (0-3) was used to assess NNL. Pathologic PD was based on the presence of LBs plus moderate or severe NNL. Possible pathologic PD was based on LBs alone or LBs with mild NNL. A series of bivariate linear mixed effect models jointly quantified cognitive decline and progressive parkinsonian signs in each decedent. Almost 30% of decedents without a diagnosis of clinical PD showed elements of pathologic PD [pathologic PD (8%); possible pathologic PD (19%)]. On average, pathologic PD accounted for 4.9% of the variance of cognitive decline and 9.4% of the variance of progression of parkinsonian signs controlling for ADRD pathologies. Adding another term for possible pathologic PD accounted for an additional 1.8% variance of cognitive decline but did not account for additional variance of progressive parkinsonian signs. Co-pathologies accounted for an additional 19% of cognitive decline and 7% of progressive parkinsonism. Thirty-three percent of the association of LBs with cognitive decline was attributable to NNL. In contrast, more than 70% of its association with progressive parkinsonism was attributable to NNL. Subclinical pathologic PD in older adults is heterogeneous. The associations of LBs with cognition and parkinsonism may vary with the severity of NNL and together with its co-pathologies account for a minority of late-life progressive parkinsonism and cognitive decline. Synucleinopathies in older adults without clinical PD may be underestimated.
Mohanty R, Wheatley S, Chiotis K
… +3 more, Marseglia A, Westman E, Alzheimer’s Disease Neuroimaging Initiative Cohort
Acta Neuropathol
· 2025 Dec · PMID 41379352
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The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We...The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.
Liang H, Hunt JB, Ma C
… +22 more, Kovalenko A, Calahatian J, Pedersen C, Liu H, Li J, Serrano M, Blazier D, Watler M, Rocha-Rangel P, Saunders C, Blair LJ, Breydo L, Nash K, Quadri Z, Kraemer B, Nelson P, Norris C, Abner EL, Uversky VN, Chaput D, Selenica MB, Lee DC
Acta Neuropathol
· 2025 Dec · PMID 41350808
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Alzheimer's disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathie...Alzheimer's disease (AD) includes a defining hallmark that correlates most closely to cognitive decline, namely misfolded tau protein. However, the "upstream" etiology and downstream clinical manifestations of tauopathies are quite diverse. Tau deposition elicits different pathological phenotypes and outcomes depending on the tau strain, proteoforms, and regional susceptibility. Posttranslational modifications (PTM) can alter tau structure, function, networks, and its pathological sequelae. We uncovered tau citrullination on multiple epitopes caused by peptidyl arginine deiminase (PAD) enzymes. PAD-induced citrullination irreversibly converts arginine residues to citrulline, producing a net loss of positive charge, elimination of pi-pi interactions, and increased hydrophobicity. We observed increased PAD2 and PAD4 in Alzheimer's disease (AD) brain and that they both can citrullinate tau. Tau can become citrullinated by PADs at all 14 arginine residues throughout the N-terminal domain (N-term), proline-rich domain (PR), microtubule-binding repeats domain (MBR), and C-terminal domain (C-term) on full-length tau (2N4R). Citrullination of tau impacts fibrillization and oligomerization rates in aggregation assays. Utilizing a panel of novel citrullinated tau (citR tau) antibodies, we identified citrullination of tau in vitro, several animal models of tauopathies, and Alzheimer's disease (AD). CitR tau increased with Braak stage and was enriched in AD brains with higher pathological tau burden. This work provides a new area of tau biology that signifies further consideration in the emerging spectrum of tauopathies and its clinical understanding.