NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characte...NF2-related schwannomatosis (NF2-SWN) is a genetic predisposition syndrome characterized by the development of bilateral vestibular schwannomas (VSs). Despite their benign nature and consistent histopathological characteristics, these tumours display significant clinical and therapeutic heterogeneity. To elucidate the molecular heterogeneity within NF2-SWN schwannomas, we performed comprehensive molecular analyses on a cohort of 70 patients with NF2-SWN, including bulk RNA sequencing, whole genome or exome sequencing, single nuclear RNA (snRNA) sequencing and immunohistochemistry. Our analysis identified two distinct molecular subgroups: immune-enriched schwannomas (IESs) and immune-depleted schwannomas (IDSs). IESs were commonly diagnosed in adulthood, followed a favorable prognosis, and were characterized by abundant macrophage infiltration within the tumour microenvironment. In contrast, IDSs were predominantly composed of Schwann cells, harbored germline NF2 mutations, occurred primarily during childhood and had poorer outcomes. Immunohistochemical staining for ionized calcium-binding adaptor molecule 1 (Iba1) and CD68, CD163 antibodies effectively differentiated these two subgroups of NF2-SWN schwannomas. Furthermore, we demonstrated that blockade of the colony stimulating factor 1 receptor (CSF1R) resulted in macrophage depletion and significantly suppressed tumour growth in both in vitro and in vivo models of IESs. Collectively, our study reveals two discrete molecular subgroups within NF2-SWN schwannomas, highlighting the importance of considering these subgroups in future therapeutic research and clinical trial design.
Barba-Reyes JM, Harder L, Marco Salas S
… +8 more, Jaisa-Aad M, Muñoz-Castro C, Garma LD, Rafati N, Nilsson M, Hyman BT, Serrano-Pozo A, Muñoz-Manchado AB
Acta Neuropathol
· 2025 May · PMID 40323467
·
Full text
Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinson's disease (PD) is poorly understood. We performed sn-RNA-seq and image-based spatial transcriptom...Oligodendroglia are the responsible cells for myelination in the central nervous system and their involvement in Parkinson's disease (PD) is poorly understood. We performed sn-RNA-seq and image-based spatial transcriptomics of human caudate nucleus and putamen (dorsal striatum) from PD and control brain donors to elucidate the diversity of oligodendroglia and how they are affected by the disease. We profiled a total of ~ 200.000 oligodendroglial nuclei, defining 15 subclasses, from precursor to mature cells, 4 of which are disease-associated. These PD-specific populations are characterized by the overexpression of heat shock proteins, as well as distinct expression signatures related to immune responses, myelination alterations, and disrupted cell signaling pathways. We have also identified impairments in cell communication and oligodendrocyte development, evidenced by changes in neurotransmitter receptors expression and cell adhesion molecules. In addition, we observed significant disruptions in oligodendrocyte development, with aberrant differentiation trajectories and shifts in cell proportions, particularly in the transition from mature oligodendrocytes to disease-associated states. Quantitative immunohistochemical analysis revealed decreased myelin levels in the PD striatum, which correlated with transcriptomic alterations. Furthermore, spatial transcriptomics mapping revealed the distinct localization of disease-associated populations within the striatum, with evidence of impaired myelin integrity. Thus, we uncover oligodendroglia as a critical cell type in PD and a potential new therapeutic target for myelin-based interventions.
Kavanagh T, Thierry M, Balcomb K
… +7 more, Ponce J, Kanshin E, Tapia-Sealey A, Halliday G, Ueberheide B, Wisniewski T, Drummond E
Acta Neuropathol
· 2025 May · PMID 40317322
·
Full text
Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated. The emerging studies suggest that phosphorylation of specific residues ma...Hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) brain tissue is a complex mix of multiple tau species that are variably phosphorylated. The emerging studies suggest that phosphorylation of specific residues may alter the role of tau. The role of specific pTau species can be explored through protein interactome studies. The aim of this study was to analyse the interactome of tau phosphorylated at T217 (pT217), which biomarker studies suggest is one of the earliest accumulating tau species in AD. pT217 interactors were identified in fresh-frozen human brain tissue from 10 cases of advanced AD using affinity purification-mass spectrometry. The cases included a balanced cohort of APOE ε3/ε3 and ε4/ε4 genotypes (n = 5 each) to explore how apolipoprotein E altered phosphorylated tau interactions. The results were compared to our previous interactome dataset that profiled the interactors of PHF1-enriched tau to determine if individual pTau species have different interactomes. 23 proteins were identified as bona fide pT217 interactors, including known pTau interactor SQSTM1. pT217 enriched tau was phosphorylated at fewer residues compared to PHF1-enriched tau, suggesting an earlier stage of pathology development. Notable pT217 interactors included five subunits of the CTLH E3 ubiquitin ligase (WDR26, ARMC8, GID8, RANBP9, MAEA), which has not previously been linked to AD. In APOE ε3/ε3 cases pT217 significantly interacted with 46 proteins compared to 28 in APOE ε4/ε4 cases, but these proteins were significantly overlapped. CTLH E3 ubiquitin ligase subunits significantly interacted with phosphorylated tau in both APOE genotypes. pT217 interactions with SQSTM1, WDR26 and RANBP9 were validated using co-immunoprecipitation and immunofluorescent microscopy of post-mortem human brain tissue, which showed colocalisation of both protein interactors with tau pathology. Our results report the interactome of pT217 in human Alzheimer's disease brain tissue for the first time and highlight the CTLH E3 ubiquitin ligase complex as a significant novel interactor of pT217 tau.
Sekiya H, Franke L, Hashimoto Y
… +10 more, Takata M, Nishida K, Futamura N, Hasegawa K, Kowa H, Ross OA, McLean PJ, Toda T, Wszolek ZK, Dickson DW
Acta Neuropathol
· 2025 May · PMID 40314842
·
Full text
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). While the clinical features of patients with LRRK2-PD resemble those of typical PD, there are...Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). While the clinical features of patients with LRRK2-PD resemble those of typical PD, there are significant differences in the pathological findings. The pathological hallmark of definite PD is the presence of α-synuclein (αSYN)-positive Lewy-related pathology; however, approximately half of patients with LRRK2-PD do not have Lewy-related pathology. Lewy-related pathology is a late-stage αSYN aggregation that can be visualized with hematoxylin and eosin stains or conventional immunohistochemistry (IHC). Increasing evidence has indicated that αSYN oligomers, which represent the early-stage of αSYN aggregation, may have neurotoxicity. Visualization of αSYN oligomers requires specialized staining techniques, such as αSYN-proximity ligation assay (PLA). Distribution and severity of αSYN oligomers in the brain of patients with LRRK2-PD remain unknown. In this study, we performed phosphorylated αSYN-IHC and αSYN-PLA staining on postmortem brain sections of patients with three pathogenic LRRK2 mutants: p.G2019S (n = 5), p.I2020T (n = 5), and p.R1441C (n = 4). The severity of Lewy-related pathology and αSYN oligomers was assessed semi-quantitatively in the brainstem, limbic lobe, basal ganglia, and cerebral cortex. αSYN oligomers were detected in patients with LRRK2-PD even in those without Lewy-related pathology; a negative correlation was observed between Lewy-related pathology and αSYN oligomers (r = - 0.26 [- 0.39, - 0.12]; P < 0.0001). Our findings suggest that αSYN oligomers may represent a common pathological feature of LRRK2-PD. Notably, patients harboring p.G2019S and p.I2020T had significantly higher levels of αSYN oligomers in those without Lewy-related pathology compared to those with Lewy-related pathology. These patients also had a trend toward shorter disease duration. These results imply that in LRRK2-PD, αSYN oligomers may initially accumulate in the brain but do not progress to form Lewy-related pathology. The present study suggests that targeting αSYN oligomers may be a therapeutic strategy for LRRK2-PD even if there is no Lewy-related pathology.
Acta Neuropathol
· 2025 May · PMID 40314782
·
Full text
Lewy body diseases are common neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies, which lead to both motor and non-motor symptoms. They are neuropathologically characterized by l...Lewy body diseases are common neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies, which lead to both motor and non-motor symptoms. They are neuropathologically characterized by loss of neuromelanized neurons in the substantia nigra pars compacta and α-synuclein-immunopositive inclusions (Lewy bodies) in several types of neurons in the brain. A fraction of monogenic PD cases, however, represent a conundrum, as they can present with clinical Lewy body disease but do not have Lewy bodies upon neuropathological examination. For LRRK2, the presence or absence of Lewy bodies is not related to any specific mutation in the gene and different clinical presentation and neuropathology can be present even in the same family. Here, we present the first evidence of widespread α-synuclein accumulation detected with proximity ligation assay (PLA) using the MJFR14-6-4-2 antibody in six Lewy body-negative LRRK2 cases and compare the levels with five patients with neuropathologically verified Lewy body disease and six healthy controls. We show that non-inclusion aggregated α-synuclein in the form of particulate PLA signal is dominant in the LRRK2 cases, while both Lewy-like and particulate PLA signal is found in late-stage Lewy body disease. Furthermore, LRRK2 cases displayed prominent particulate PLA signal in pontocerebellar tracts and inferior olivary nuclei in the brainstem, which was not seen in idiopathic Lewy body disease cases. These results suggest that Lewy-body negative LRRK2-related PD is not associated with a lack of α-synuclein aggregation in neurons but rather a deficiency in the formation of inclusions.
Hansen CE, Konings J, Toth G
… +13 more, Chornyi S, Karsten M, van Het Hof B, van der Pol SMA, Beekhuis-Hoekstra SD, Kok N, Fung WK, Dijksman NS, Baron W, Witte ME, Lanekoff I, de Vries HE, Kooij G
Acta Neuropathol
· 2025 Apr · PMID 40299057
·
Full text
Bioactive lipid mediators (LMs) derived from polyunsaturated fatty acids (PUFAs) are key molecules in both the initiation and resolution of inflammatory responses. Previous findings suggest that a dysregulated LM balance...Bioactive lipid mediators (LMs) derived from polyunsaturated fatty acids (PUFAs) are key molecules in both the initiation and resolution of inflammatory responses. Previous findings suggest that a dysregulated LM balance, especially within the arachidonic acid (AA) pathway, may contribute to an impaired resolution response and subsequent chronic neuroinflammation in multiple sclerosis (MS). However, to date, the local biosynthesis and signaling of LMs within the brain of people with MS (PwMS) remains unexplored. In this study, we, therefore, mapped the distribution of AA and its key downstream LM prostaglandin E (PGE) in white matter MS brain tissue and of non-neurological controls (NNCs) for the first time using mass spectrometry imaging. We found that AA levels are lower in MS cases compared to NNCs and reduced in MS lesions compared to peri-lesional tissue. Furthermore, the PGE/AA ratio, indicating the PGE synthesis from the AA substrate, was increased in lesion areas compared to fully myelinated regions in MS. In line with that, the expression of prostaglandin synthesizing enzymes as measured by RT-qPCR was partially increased in MS tissue compared to NNCs. In addition, the expression of prostaglandin E2 receptor 4 (EP4) decreased, while prostaglandin E2 receptor 2 (EP2) showed increased expression levels in MS lesions compared to NNCs and localized specifically to microglia. We also found that PGE addition to pro-inflammatory human-induced pluripotent stem cell (iPSC)-derived microglia resulted in enhanced cytokine signaling pathways, but also the upregulation of its synthase PTGES and homeostatic/resolving signaling, the latter of which might mainly occur through EP2 signaling. Collectively, our results provide detailed information about the region-specific levels of AA and PGE in MS lesions and we propose enhanced PGE-EP2 signaling in inflamed microglia in MS.
Shahidehpour RK, Katsumata Y, Dickson DW
… +15 more, Ghayal NB, Aung KZ, Wu X, Phe P, Jicha GA, Neltner AM, Archer JRC, Corrada MM, Kawas CH, Ahmad Sajjadi S, Woodworth DC, Bukhari SA, Montine TJ, Fardo DW, Nelson PT
Acta Neuropathol
· 2025 Apr · PMID 40293530
·
Full text
A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LAT...A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer's Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.
Yokota O, Miki T, Nakashima-Yasuda H
… +9 more, Ishizu H, Haraguchi T, Miyashita A, Ikeuchi T, Hasegawa M, Nishikawa N, Takenoshita S, Terada S, Takaki M
Acta Neuropathol
· 2025 Apr · PMID 40285882
·
Full text
Dwarshuis G, Kroon LL, Brandsma D
… +3 more, Noske DP, Best MG, Sol N
Acta Neuropathol
· 2025 Apr · PMID 40285800
·
Full text
Clinical evaluation and MR imaging are currently the cornerstone of brain tumor progression monitoring. However, this is complicated by the occurrence of treatment effects such as pseudoprogression and radionecrosis. Whi...Clinical evaluation and MR imaging are currently the cornerstone of brain tumor progression monitoring. However, this is complicated by the occurrence of treatment effects such as pseudoprogression and radionecrosis. While essential for patient management, the distinction from true progression remains a significant challenge. Moreover, MR imaging provides limited real-time insights into tumor heterogeneity, genetic divergence, and treatment resistance. Although surgical histopathological biopsies can yield additional valuable information, they are not always conclusive, invasive, and therefore, not suitable for longitudinal measurements. In the era of precision medicine, there is a critical need for minimally invasive, accurate, and cost-effective monitoring methods for both primary brain tumors and brain metastases. Liquid biopsies have emerged as a potential candidate. Various analytes, including circulating nucleic acids, extracellular vesicles, platelet RNAs, and circulating tumor cells, can be obtained from whole blood and its derivatives, as well as other body fluids such as cerebrospinal fluid. In this narrative review, we outline the potential of liquid biopsies for the management of gliomas and brain metastases in adults and emphasize their utility in monitoring disease progression and treatment response. We discuss the most studied biofluids and analytes, along with their respective advantages and downsides. Furthermore, we address key considerations for future research and biobanking to pave the way for clinical implementation.
Di Liberto G, Egervari K, Vogrig A
… +28 more, Spatola M, Piccinno M, Vincenti I, Wagner I, Kreutzfeldt M, Endmayr V, Ostertag K, Rahimi J, Vicino A, Pröbstel AK, Meyronet D, Frank S, Prinz M, Hewer E, Brouland JP, de Leval L, Parkkinen L, Draganski B, Desestret V, Dubey D, Pittock SJ, Roemer SF, Dickson DW, Höftberger R, Irani SR, Honnorat J, Du Pasquier R, Merkler D
Acta Neuropathol
· 2025 Apr · PMID 40278930
·
Full text
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting ne...Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.
Guney E, Mirchia K, Schmid S
… +16 more, Capper D, Meinhardt J, Cha S, Lee H, Brathwaite C, Altman N, Sloan EA, Sayah A, McGrail K, Caliskan I, Terry M, Perez S, Bollen AW, Tihan T, Pekmezci M, Perry A
Singh O, Dampier C, Abdullaev Z
… +30 more, Dazelle K, Chung HJ, Conway K, Camelo-Piragua S, Neill S, Brown D, Nix JS, Giannini C, Macaulay R, Marker D, Skaugen J, Kulich S, Lee H, Aboud O, Pytel P, Borys E, Perry A, Naqib-Osman L, Fernandes IL, Mao Q, Alashari M, Thomas C, Helgager J, Gubbiotti MA, Newman J, Tiwari N, Cimino PJ, Quezado M, Aldape KD, Nasrallah MP
Acta Neuropathol
· 2025 Apr · PMID 40202541
·
Full text
A putative molecular subtype of IDH-wildtype diffuse glioma with recurrent MAPK pathway alterations has recently been reported. By dimensionality reduction analysis of genome-wide methylation profiling, these tumors form...A putative molecular subtype of IDH-wildtype diffuse glioma with recurrent MAPK pathway alterations has recently been reported. By dimensionality reduction analysis of genome-wide methylation profiling, these tumors form a distinct methylation cluster of gliomas. Characterization of 47 tumors from 45 patients reveals that these gliomas are predominantly supratentorial in young adults, are highly infiltrative, and harbor mitogen-activated protein kinase (MAPK) pathway alterations with high rates of CDKN2A/2B deletion, PDGFRA amplification, MYCN amplification, NF1 variants, and BRAF alterations. The tumors' epigenetics are distinct from other adult and pediatric gliomas in the 2021 World Health Organization (WHO) classification. The histology of the gliomas most often demonstrates high-grade astrocytic features, but can be variable from tumor to tumor, as well as fall into a spectrum of histologic grades. Outcomes show considerable variability based on histologic grade and molecular features, supporting grading within this group of tumors to ensure optimal care choices on an individual patient basis. These unifying epigenetic, sequencing, and infiltrative astrocytic features allow the tumors to be considered diffuse astrocytoma, adolescent, and young adult-type, with MAPK alterations (DAYA).
Feleke R, Jogaudaite S, Velentza-Almpani E
… +13 more, Yeung-Yeung L, Clode D, Ko JH, Shin B, Matthews S, Otero-Jimenez M, Wojewska MJ, Gray-Rodriguez S, Marzi SJ, Spires-Jones MP, Spires-Jones TL, Johnson MR, Alegre-Abarrategui J
Acta Neuropathol
· 2025 Apr · PMID 40183825
·
Full text
The initial molecular alterations of Alzheimer's disease (AD) are unknown. Established AD is characterized by profound structural and transcriptional alterations in the human brain, with the hallmark neuropathological fe...The initial molecular alterations of Alzheimer's disease (AD) are unknown. Established AD is characterized by profound structural and transcriptional alterations in the human brain, with the hallmark neuropathological features being beta-amyloid (Aβ) accumulation in senile plaques and hyperphosphorylated fibrillar tau in neurofibrillary tangles (NFTs). Previous evidence indicates that tau multimerization into small aggregates is one of the earliest molecular alterations, anticipating the accumulation of hyperphosphorylated tau in NFTs. In this study, we investigated the seeding capacity of these early small tau multimers and the transcriptional changes associated with them, aiming to unveil early pathogenic processes in AD-type tau pathology. Early tau multimers visualized with tau proximity ligation assay (tau-PLA) in the post-mortem temporal cortex demonstrated high seeding activity detected by real-time quaking-induced conversion (RT-QuIC) assay and induction of aggregates in a tau biosensor cell line. Using single-nucleus transcriptomics, we showed that brain tissue harboring seeding-competent early tau multimers, but without significant NFT pathology, is associated with substantial gene expression alterations across diverse cell types when compared to control tissue lacking either multimers or NFTs. Differentially expressed genes, such as APP, MAPT, and PSEN1, exhibited significant enrichment of AD heritability in up-regulated genes within excitatory neurons, astrocytes, and oligodendrocytes. Pseudotime analysis exposed a positive correlation between the progression of tau pathology and the expression of genes marking reactive astrocytes. In summary, our results support the hypothesis that seeding-competent tau multimerization may initiate AD-type tau pathology cascades before the accumulation of tau in NFTs. This research contributes valuable insights into the early molecular events associated with AD, with implications for future diagnostic and therapeutic strategies.
Stork L, Stephan S, Kutllovci A
… +2 more, Brück W, Metz I
Acta Neuropathol
· 2025 Apr · PMID 40167776
·
Full text
A reduced regenerative capacity may contribute to faster disease progression and poorer relapse recovery in multiple sclerosis patients with disease onset after the age of 50, a condition known as late-onset multiple scl...A reduced regenerative capacity may contribute to faster disease progression and poorer relapse recovery in multiple sclerosis patients with disease onset after the age of 50, a condition known as late-onset multiple sclerosis (LOMS). We hypothesized that lesions in LOMS patients show more pronounced axonal damage, less remyelination and an altered inflammatory composition, and performed a detailed histopathological analysis of MS biopsies in patients with early-stage LOMS. The number of T cells, B cells, plasma cells, microglia/macrophages, different oligodendrocyte populations as well as the axonal density and acute axonal damage were assessed in 31 LOMS and 30 normal-onset MS (NOMS, 20-40 years old) patients. No major differences in the inflammatory infiltrate or axonal damage were found. BCAS1-positive oligodendrocytes indicating early myelinating oligodendrocytes, and mature oligodendrocytes were significantly lower in the normal-appearing white matter of LOMS compared to NOMS patients (p = 0.05; p = 0.01), with a negative correlation with age (r = - 0.5, p = 0.01). In active demyelinating lesions, the number of BCAS1-positive oligodendrocytes did not differ between LOMS and NOMS, but NOMS lesions showed a higher proportion of ramified cells indicating active remyelination. In LOMS, BCAS1-positive oligodendrocytes decreased with increasing lesion age, with the lowest numbers found in inactive demyelinated lesions. In contrast, NOMS patients showed high numbers of BCAS1-positive cells with an activated morphology, even in inactive demyelinated lesions. At the last follow-up, LOMS patients had a significantly higher EDSS score (median 3.5) than NOMS patients (median 3.0, p = 0.05). A higher EDSS score correlated with fewer mature and oligodendrocyte precursor cells in active demyelinating lesions (r = - 0.4, p = 0.01 and r = - 0.6, p = 0.003). These findings suggest a clinically relevant impaired oligodendrocyte differentiation and remyelination in LOMS. Since remyelination is essential for axonal protection, it will be necessary to consider the complex and dynamic tissue environment when researching therapeutics aimed at fostering the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes.
Purkait S, Praeger S, Felsberg J
… +5 more, Pauck D, Kaulich K, Wolter M, Koppstein D, Reifenberger G
Acta Neuropathol
· 2025 Mar · PMID 40137996
·
Full text
Spinal ependymoma and myxopapillary ependymoma are the two most common spinal ependymal tumor types that feature distinct histological characteristics, genetic alterations and DNA methylation profiles. Their histological...Spinal ependymoma and myxopapillary ependymoma are the two most common spinal ependymal tumor types that feature distinct histological characteristics, genetic alterations and DNA methylation profiles. Their histological distinction may be difficult in individual cases and molecular diagnostic assessment, in particular DNA methylome profiling, may then be required to assign the correct diagnosis. Expression of the homeobox gene HOXB13 at the mRNA and protein levels has been reported as a frequent finding in myxopapillary ependymoma that may serve as a diagnostic marker for these tumors. Here, we evaluated the diagnostic role of HOXB13 immunostaining in 143 spinal neoplasms, comprising 54 histologically classified myxopapillary ependymomas, 46 histologically classified spinal ependymomas, and various other tumor types. Immunohistochemical results for HOXB13 protein were compared to molecular findings obtained by bead array-based DNA methylation and DNA copy number profiling, as well as next generation gene panel sequencing-based mutational analysis. Our findings indicate strong nuclear HOXB13 expression as a reliable diagnostic marker for molecularly confirmed myxopapillary ependymoma. Moreover, we provide evidence that differential HOXB13 protein expression is related to differential HOXB13-associated CpG site methylation in myxopapillary vs. spinal ependymomas, which can be assessed by targeted DNA methylation analysis. Taken together, immunohistochemistry for HOXB13 protein expression and targeted DNA methylation analysis of HOXB13 represent useful surrogate approaches that may substitute for DNA methylome profiling in routine diagnostics and facilitate precise classification of spinal ependymal tumors. In particular, strong nuclear HOXB13 immunoreactivity may serve as a novel diagnostic criterion for the classification of myxopapillary ependymoma.
Lantero-Rodriguez J, Montoliu-Gaya L, Ashton NJ
… +21 more, Pola I, Therriault J, Rahmouni N, Brum WS, Servaes S, Stevenson J, Di Molfetta G, Arslan B, Klostranec J, Vitali P, Montembeault M, Gauthier S, Tissot C, Macedo AC, Pascoal TA, Jeromin A, Gobom J, Blennow K, Zetterberg H, Rosa-Neto P, Benedet AL
Acta Neuropathol
· 2025 Mar · PMID 40095069
·
Full text
Recently, conceptual systems for the in vivo staging of Alzheimer's disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available fluid biomarkers can successfully stage AD in...Recently, conceptual systems for the in vivo staging of Alzheimer's disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available fluid biomarkers can successfully stage AD into clinically and biologically relevant categories. In the TRIAD cohort, we explored whether p-tau217, p-tau205 and NTA-tau (biomarkers of early, intermediate and late AD pathology, respectively) have potential for biofluid-based staging in cerebrospinal fluid (CSF; n = 219) and plasma (n = 150), and compared them in a paired CSF and plasma subset (n = 76). Our findings suggest a good concordance between biofluid staging and underlying pathology when classifying amyloid-positivity into three categories based on neurofibrillary pathology: minimal/non-existent (p-tau217 positive), early-to-intermediate (p-tau217 and p-tau205 positivity), and advanced tau tangle deposition (p-tau217, p-tau205 and NTA-tau positive), as indexed by tau-PET. Discordant cases accounted for 4.6% and 13.3% of all CSF and plasma measurements respectively (9.2% and 11.8% in paired samples). Notably, CSF- and plasma-based staging matched one another in 61.7% of the cases, while approximately 32% of the remaining participants were one to three biofluid stages higher in CSF as compared to plasma. Overall, these exploratory results suggest that biofluid staging of AD holds potential for offering valuable insights into underlying AD hallmarks and disease severity. However, its applicability beyond molecular characterization at research settings has yet to be demonstrated.