Lotsch C, Warta R, Liu F
… +19 more, Jungwirth G, Rommel C, Barthel M, Lamszus K, Kessler AF, Grabe N, Loehr M, Ketter R, Senft C, Maas SLN, Sievers P, Westphal M, Krieg SM, Unterberg A, Simon M, von Deimling A, Sahm F, Raleigh DR, Herold-Mende C
Acta Neuropathol
· 2025 Oct · PMID 41065822
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Tumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies, but there is rare knowledge on the functional and, in particular, the prognostic role of TAMs in the meningioma...Tumor-associated macrophages (TAMs) represent the main immune cell population in various brain malignancies, but there is rare knowledge on the functional and, in particular, the prognostic role of TAMs in the meningioma (MGM) microenvironment. Here, we investigated TAM frequencies, activation state, survival-associated changes, and their association with tumor-infiltrating T lymphocytes (TILs) in two independent study samples comprising altogether 680 MGMs. To this end, we performed tissue cytometry analyses, quantified tissue cytokine levels, and integrated previously published TIL infiltration and microarray datasets in the discovery cohort comprising n = 195 clinically well-annotated cases. This was complemented by a DNA methylation-based deconvolution approach to predict TAM and TIL infiltration rates using immune cell-specific CpG sites as well as survival associations in an independent validation cohort of n = 485 MGMs. Our findings revealed substantial but heterogeneous TAM infiltration in newly diagnosed MGMs, with increased numbers of pro-tumoral TAMs in clinically aggressive tumors. Additional cytokine and transcriptome analyses corroborated the presence of an immunosuppressive niche in TAM-enriched MGMs. Importantly, a high frequency of pro-tumoral TAMs was associated with poor patient outcome, and high TAM infiltration was further identified as an independent prognostic factor for inferior survival, counteracting the beneficial prognostic effect of TILs. Moreover, methylation-based deconvolution analyses confirmed the opposing prognostic roles of TAMs and TILs in the validation cohort. Altogether, higher numbers of TAMs appear to be a hallmark of clinically aggressive behavior in newly diagnosed and recurrent MGMs. Unlike TILs, immunosuppressive TAMs seem to play a dominant role in the immunological landscape of MGMs with a significant negative impact on patient outcome, highlighting pro-tumoral TAMs to be an attractive treatment target in MGMs. Furthermore, our deconvolution approach presents a pipeline to computationally determine TAM and TIL infiltrates in the MGM microenvironment, which might be highly valuable for patient stratification for future immunotherapeutic treatments.
Inoue Y, Wang H, Heckman MG
… +14 more, Ren Y, White LJ, Lu W, Wang P, Tcw J, Koga S, Alnobani A, DeTure M, Murray ME, Petersen RC, Dickson DW, Bu G, Han X, Kanekiyo T
Acta Neuropathol
· 2025 Oct · PMID 41060400
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Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the depo...Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-β (Aβ) in the leptomeningeal and cortical arteries and is highly prevalent in AD, affecting over 90% of cases. While the ε4 allele of apolipoprotein E (APOE) represents the strongest genetic risk factor for AD, it is also associated with cerebrovascular dysregulations. APOE plays a crucial role in brain lipid transport, particularly in the trafficking of cholesterol and phospholipids. Lipid metabolism is increasingly recognized as a critical factor in AD pathogenesis. However, the precise mechanism by which APOE influences cerebrovascular lipid signatures in AD brains remains unclear. In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different APOE genotypes: APOE ε2/ε3 (N = 9), APOE ε2/ε4 (N = 14), APOE ε3/ε3 (N = 21), APOE ε3/ε4 (N = 23), and APOE ε4/ε4 (N = 22). Lipidomics detected 10 major lipid classes with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the most abundant lipid species. While we observed a positive association between age and total acyl-carnitine (CAR) levels (p = 0.0008), the levels of specific CAR subclasses were influenced by the APOE ε4 allele. Notably, APOE ε4 was associated with increased PE (p = 0.049) and decreased sphingomyelin (SM) levels (p = 0.028) in the cerebrovasculature. Furthermore, cerebrovascular Aβ40 and Aβ42 levels showed associations with sphingolipid levels including SM (p = 0.0079) and ceramide (CER) (p = 0.024). Weighted correlation network analysis revealed correlations between total tau and phosphorylated tau and lipid clusters enriched for PE plasmalogen and lysoglycerophospholipids. Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.
Aras FK, Friedel D, Keller F
… +19 more, Zettl F, Banan R, Sievers P, Suwala AK, Hinz F, Friedrich L, Abdulrazak I, Esmaeilibenvidi M, Etminan N, Herold-Mende C, Wick W, Krieg S, Pfister SM, Korshunov A, Bludau I, Sahm F, Reuss DE, Sigismondo G, von Deimling A
Acta Neuropathol
· 2025 Sep · PMID 41026275
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Jiang W, Kalsbeek MJ, Correa-da-Silva F
… +5 more, Jiao H, Kalsbeek A, Swaab DF, Siegelaar SE, Yi CX
Acta Neuropathol
· 2025 Sep · PMID 41023469
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People with type 1 or type 2 diabetes mellitus (T1DM or T2DM) often experience cognitive impairment. We profiled cells in the nucleus basalis of Meynert (NBM) in postmortem human brain tissue to investigate the neuropath...People with type 1 or type 2 diabetes mellitus (T1DM or T2DM) often experience cognitive impairment. We profiled cells in the nucleus basalis of Meynert (NBM) in postmortem human brain tissue to investigate the neuropathological changes. Sixty-eight postmortem NBM samples were grouped as T1DM, T2DM, and controls without diabetes, with Braak stage 0-II or III-VI. T1DM subjects had only Braak stage 0-II and were thus compared only to controls with a similar Braak stage and not subjects with Braak stage III-VI. We analyzed neurons expressing choline acetyltransferase (ChAT), phosphorylated tau, amyloid-beta, glial cells, and vasculature with their respective markers. We found significantly lower neuronal expression of ChAT in T1DM individuals than in controls and T2DM individuals with Braak stage 0-II. Later-stage hyperphosphorylated tau levels were higher in T2DM compared to controls with Braak stage III-VI. Our results suggest that reduced acetylcholine production by NBM neurons may underlie the cognitive complaints of people with T1DM. In contrast, T2DM may exacerbate neuropathological changes associated with Alzheimer's disease-like alterations.
Brum WS, Montoliu-Gaya L, Brinkmalm G
… +22 more, Piotrowska D, Camporesi E, Jäger C, Isaksson HS, Martin S, Kindberg J, Lantero-Rodriguez J, Ferrari-Souza JP, Moscoso A, Benedet AL, Janelidze S, Gobom J, Zetterberg H, Hansson O, Zimmer ER, Ashton NJ, Arendt T, Lashley T, Stieler JT, Holzer M, Fröbert O, Blennow K
Acta Neuropathol
· 2025 Sep · PMID 41023457
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Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer's disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique tr...Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer's disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique translational model to study tau metabolism. However, limited data exist on insoluble and soluble tau alterations during hibernation and on patterns of tau fragment concentrations in the hibernating mammalian brain. We quantified tau biomarkers in plasma samples from ten free-ranging brown bears (Ursus arctos), captured during both their active summer period and hibernation in the winter, using clinically validated immunoassays and immunoprecipitation mass spectrometry (IP-MS) techniques. We also analyzed brain tissue from ten golden Syrian hamsters (Mesocricetus auratus) subjected to induced torpor (hibernation) versus euthermic (non-hibernating) states by quantifying multiple phosphorylated and non-phosphorylated tau peptides with an IP-MS method previously applied in human brain tissue. In brown bears, plasma levels of phosphorylated tau (p-tau) biomarkers p-tau181 and p-tau217 significantly increased during hibernation compared to summer (median increases of 362% and 294% by IP-MS, respectively), with similar increases found with immunoassays. Additional plasma p-tau biomarkers associated with AD pathology, including p-tau205 and p-tau231, were also increased during bear hibernation. In hamster brains, p-tau217, and p-tau231 were similarly elevated during torpor, while tau fragments from the microtubule-binding region (MTBR), associated with tangle aggregation, were not increased. In contrast, brain tissue from n = 10 AD patients, analyzed with the same IP-MS method, exhibited striking increases in p-tau (~ 50,000% for p-tau217) and MTBR fragments (~ 20,000% for MTBR tau354-369) compared with n = 10 human controls. We show that hibernation-linked tau hyperphosphorylation involves some of the same phospho-sites altered in AD, but occurs without MTBR tau aggregation. This highlights hibernation as a reversible, non-pathological model to study tau biology and mechanisms underlying AD due to its reversibility and lack of tau aggregation despite hyperphosphorylation in key AD tau phospho-sites.
Jürgensen L, Benfatto S, Schmid S
… +6 more, Daenekas B, Großer J, Driever PH, Koch A, Capper D, Hovestadt V
Acta Neuropathol
· 2025 Sep · PMID 41014355
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DNA methylation-based classification using the Heidelberg Classifier is a state-of-the-art data-driven method for molecular diagnosis of central nervous system (CNS) tumors. However, many pediatric low-grade glioma (pLGG...DNA methylation-based classification using the Heidelberg Classifier is a state-of-the-art data-driven method for molecular diagnosis of central nervous system (CNS) tumors. However, many pediatric low-grade glioma (pLGG) samples fail to yield a confident methylation-based classification, often suspected due to low tumor cell content. Here, we present a rapid, reference-based in silico purification framework that systematically removes the epigenetic signatures of five non-malignant cell types-microglia, monocytes, neutrophils, T cells, and neurons-from tumor profiles to enable classification of previously non-classifiable pLGG samples. To validate our approach, we analyzed paired DNA methylation profiles from the same biopsy, where one was initially classifiable and the other was not. After purification, predictions for all newly classifiable samples matched the classification of their corresponding initially classifiable counterparts (9/9, 100%). Application of our method to two independent pLGG cohorts allowed confident classification in 24.1% (26/108) and 22.7% (5/22) of previously non-classifiable cases. In conclusion, our in silico purification framework enables confident classification of previously non-classifiable pLGG samples, supporting accurate molecular diagnosis and timely clinical decision-making, and can seamlessly be integrated into current classification workflows. Its independence from tumor type, classifier, and reference signatures further suggests the potential for broader application to other low-purity tumor types.
Wihan J, Battis K, Hoffmann A
… +10 more, Windener F, Himmler M, Varghese A, Koller A, Karnatz I, Schubert DW, Zunke F, Xiang W, Kuhlmann T, Winkler J
Acta Neuropathol
· 2025 Sep · PMID 40973885
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Oligodendroglial alpha-synuclein (aSyn) deposits are a key feature in the atypical parkinsonian disorder, multiple system atrophy (MSA) linked to profound myelin loss and neurodegeneration while precise cellular and mole...Oligodendroglial alpha-synuclein (aSyn) deposits are a key feature in the atypical parkinsonian disorder, multiple system atrophy (MSA) linked to profound myelin loss and neurodegeneration while precise cellular and molecular mechanisms remain unclear. We generated human oligodendrocytes (hOLs) from induced pluripotent stem cells to investigate the impact of aSyn on oligodendroglial morphology, differentiation, and function. We observed an aSyn-induced myelinogenic dysfunction characterized by impaired oligodendroglial process outgrowth, altered cell shape, and increased perinuclear accumulation of the tubulin polymerization promoting protein TPPP/p25α. These changes were associated with a reduced capacity to ensheath axons and were linked to compromised actin remodeling machinery. Actin imbalances were confirmed in post-mortem putaminal tissue from MSA patients. Treatment with a rho-associated protein kinase inhibitor rescued oligodendroglial process formation and improved ensheathment in aSyn-expressing hOLs. Our work emphasizes the aSyn-mediated interference with actin dynamics as a key pathogenic mechanism in MSA, pointing toward a novel therapeutic target for improving myelin maintenance.
The SH3PXD2A-HTRA1 fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of...The SH3PXD2A-HTRA1 fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic NF2 status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; P = 0.012), trigeminal nerve origin (OR, 2.88; P = 0.042), and intratumoral hemorrhage (OR, 18.61; P = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (P = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; P = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (P = 0.046). Only 33% of fusion gene-positive tumors indicated somatic NF2 alteration. The SH3PXD2A-HTRA1 fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of NF2. Our findings provide a basis for future clinical investigations.
Stascheit F, Roos A, Schroeter CB
… +10 more, Thomas JK, Hahn K, Preßler H, Hentschel A, Schlotter-Weigel B, Schoser B, Ruck T, Meisel A, Stenzel W, Preusse C
Acta Neuropathol
· 2025 Sep · PMID 40971018
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Chronic-inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated polyneuropathy causing substantial disability. While both cell-mediated and humoral mechanisms contribute to CIDP, the role of complement...Chronic-inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated polyneuropathy causing substantial disability. While both cell-mediated and humoral mechanisms contribute to CIDP, the role of complement remains poorly understood. Considering the rise of complement-targeted treatment, it is crucial to examine the role of complement in CIDP. In this cross-sectional, study, sural nerve biopsies from 55 CIDP patients were analyzed using histopathology, gene- and protein-based techniques, comparing them to two non-diseased controls (NDCs), as well as 8 patients with hereditary neuropathy (HN) and idiopathic axonal neuropathy (IPN). Overall, 94% (n = 52) revealed abnormal and prominent deposition of terminal complement complex C5b-9 on endoneurial capillaries. Patients with significant complement deposition presented with a progressive disease course (n = 52) and the number and distribution of infiltrating CD8 + T cells and CD68 + macrophages, since a basic immunological paradigm holds that those two may form an immunological synapse, correlated with clinical disease severity as measured by inflammatory neuropathy cause and treatment sensory sum (INCAT) score (p < 0.001). Furthermore, changes in abundances of complement proteins as unveiled by untargeted proteomics accord with changes on transcript level as identified by targeted gene expression studies. In contrast, there was no complement deposition in NDC nor DC. This study provides an extensive evaluation of sural nerve specimens of CIDP patients finding a marked involvement of complement supporting the postulated concept of complement mediated demyelination in CIDP. Our results support the approach of targeting the complement system as a new and promising therapeutic strategy-at least in a subgroup of CIDP. Further research is warranted to unravel the functional implications and role of complement in CIDP progression and optimize patient care. Clinical Trial Registration: The study is registered under the German clinical trial registry ( https://www.drks.de ), DRKS0003245.
van Wetering J, Deshayes NAC, Boone J
… +6 more, Rodrigues Fernandes I, Hepp DH, Berendse HW, Jonkman LE, Rozemuller AJM, van de Berg WDJ
Acta Neuropathol
· 2025 Sep · PMID 40968282
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The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and p...The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (n = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, p < 0.001), and more frequently APOE-ε4 alleles (p < 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, p ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, p ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, p < 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: p = 0.040; p-tau: p = 0.020) and age at onset (80% in those with onset > 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.
Acta Neuropathol
· 2025 Sep · PMID 40960500
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Immune checkpoint inhibitors have transformed treatment for several cancers, yet clinical trials of programmed cell death protein 1 (PD-1) blockade in glioblastoma (GBM) have consistently failed to show therapeutic benef...Immune checkpoint inhibitors have transformed treatment for several cancers, yet clinical trials of programmed cell death protein 1 (PD-1) blockade in glioblastoma (GBM) have consistently failed to show therapeutic benefit. While some studies have reported treatment-related transcriptional changes, particularly in T cells, findings remain limited and inconsistent. The aim of this study was to investigate changes in tumor cells and tumor-associated macrophages (TAMs) after PD-1 blockade in recurrent GBM using spatial transcriptomics. We performed Digital Spatial Profiling (GeoMx, NanoString) on FFPE tumor samples from 26 patients with matched primary and recurrent IDH-wildtype GBM, including 16 patients who received neoadjuvant nivolumab at recurrence. Tumor (SOX2⁺) and TAM (IBA1⁺) segments were selected for targeted spatial analysis. Following quality control and filtering, transcriptomic profiles were compared between nivolumab-treated and untreated recurrent tumors. PD-1 blockade did not induce detectable gene expression changes in either tumor cells or TAMs. There were no significant differences in global expression profiles or in more targeted analyses of malignant cell states, cell cycle activity, interferon signaling, or myeloid transcriptional programs. These results consistently indicate that neoadjuvant PD-1 blockade does not elicit measurable responses at the spatial transcriptomic level in tumor cells or TAMs in recurrent GBM. These findings align with the lack of clinical benefit observed in trials and highlight the need for alternative strategies to improve immunotherapy outcomes in GBM.
Tomé SO, Gawor K, Ospitalieri S
… +9 more, Ronisz A, Otto M, von Arnim CAF, Ghebremedhin E, Laureyssen C, Sleegers K, Vandenberghe R, Nelson PT, Thal DR
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common substrate of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical features, and their underlying neuropathological chan...Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common substrate of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical features, and their underlying neuropathological changes-LATE-NC and ADNC-commonly co-occur. However, the histomorphological and molecular features of TDP-43 pathology in LATE-NC with or without coexisting ADNC are not yet well understood. We performed immunohistochemistry in paraffin-embedded tissue from the hippocampus, amygdala, and temporal and frontal cortices of 108 human autopsy cases including 20 cognitively unimpaired controls, 20 AD dementia cases with moderate-high severity of ADNC without LATE-NC (ADNC group), 34 AD dementia cases with LATE-NC (ADNC + LATE-NC group), 17 dementia cases with LATE-NC but no/low ADNC (pure LATE-NC group), and 17 FTLD-TDP Type A cases. We assessed TDP-43 aggregate morphology and composition using antibodies against different TDP-43 epitopes: pS409/410, pS403/pS404, and C- and N-terminal TDP-43. We also investigated nuclear clearance of physiological TDP-43 and cytoplasmic colocalization of TDP-43 and tau proteins. Pure LATE-NC cases were on average 10 years older at death than ADNC + LATE-NC, had less cognitive impairment, higher prevalence of argyrophilic grain disease (AGD) pathology, aging-related tau astrogliopathy (ARTAG), and APOEε2 allele. They also tended to show lower APOEε4 frequencies, but similar frequencies of hippocampal sclerosis and LATE-NC stages. Importantly, LATE-NC predominantly displayed a mesh-like neuritic TDP-43 pattern in the hippocampus, extending from CA1/2 to subiculum. This mesh-like pattern was present in 81% of pure LATE-NC cases and only in 18% of ADNC + LATE-NC. This pattern was also observed in 53% of FTLD-TDP Type A cases. Moreover, the aggregate composition differed in pure LATE-NC and ADNC + LATE-NC, with LATE-NC cases exhibiting increased burdens of several phosphorylated and non-phosphorylated TDP-43 species, while only the pS409/pS410 epitope was significantly associated with ADNC + LATE-NC in the amygdala. Nuclear clearance patterns also tended to differ between pure LATE-NC and ADNC + LATE-NC. Similar to ADNC + LATE-NC, TDP-43 and tau proteinopathies colocalized in pure LATE-NC with comorbid primary age-related tauopathy (PART) or low ADNC. These data suggest that LATE-NC tends to be modified in the presence of moderate-high ADNC. These differences may reflect upstream influences (age, genetics, and environmental risk factors), direct protein-protein interactions, and/or other impacts of ADNC-related mechanisms on TDP-43 proteinopathy, potentially relevant for clinical trial design and future therapeutic applications.
Nandakumar S, Mehine M, Kemel Y
… +38 more, Bandlamudi C, Mandelker D, Rosenblum MK, Bale T, Karajannis MA, Sait SF, Elmore KB, Therkelsen KE, Chatila WK, Muldoon D, Young RJ, Imber BS, Brennan C, Moss NS, Yu KKH, Tabar V, Ogilvie S, Bowman A, Akella P, Lin YT, Gavrilovic IT, Pentsova E, Schaff L, Stone J, Nolan C, Boire A, Grommes C, Santomasso BD, Diamond EL, Wilcox J, Piotrowski A, Kaley TJ, DeAngelis LM, Mellinghoff IK, Berger M, Schultz N, Stadler ZK, Lin AL
Acta Neuropathol
· 2025 Sep · PMID 40938445
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Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear....Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76-90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1-12.8%). Affected high- and moderate-penetrance genes included BRCA2 (n = 11; 0.5%), TP53 (n = 8; 0.4%), NF1 (n = 8; 0.4%), CHEK2 (n = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (n = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline NF1 mutation, 7/8 tumors with a germline TP53 alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including BRCA2-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (p = 3.5 × 10) and tumors with a monoallelic alteration (p = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.
Ogg J, Postupna N, Gibbons LE
… +7 more, Ariza J, Xiao M, Fonseca LM, Jayadev S, Keene CD, Bird TD, Latimer CS
Acta Neuropathol
· 2025 Sep · PMID 40906048
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Early onset familial Alzheimer's disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (PSEN2) g...Early onset familial Alzheimer's disease (EOFAD) is rare compared to sporadic AD, but dominant variants in genes involved in amyloid β (Aβ) processing are well-described. One such variant is in the presenilin 2 (PSEN2) gene, N141I, and was first described in a family with Volga German descent. Separately, individuals with Down syndrome (DS) are also at risk for early onset AD, having an extra copy of an amyloid precursor protein gene. While either can drive EOFAD alone, it is extremely rare for both to occur within one individual. Here we describe a unique case of a 48-year-old individual, with both DS and the PSEN2 N141I variant. We investigated whether having two high-risk AD variants results in worsened or distinct pathology compared to single variant carriers. Neuropathologic evaluation, quantitative pathology, and spatial proteomic profiling (NanoString Geomx Digital Spatial Profiling) were performed on post-mortem tissue of the index case compared to individuals with DS and N141I variants alone. Analysis in the index case revealed increased total Aβ burden in multiple brain regions compared to the average levels observed in PSEN2 carriers and DS cases, but not for hyperphosphorylated tau or neuroinflammatory markers. Index case appeared to have more pronounced Aβ pathological burden than the PSEN2 subgroup and was more similar to the DS subgroup in several measurements: the Aβ burden, density of Aβ plaques, fibrillar and dense-core plaques, and the density of ionized calcium binding adaptor molecule 1 (Iba1) labelling in MSTG. As such, it appears that compounded genetic risk for AD was additive for Aβ burden, but not tau or neuroinflammation. This rare case offers new insight into how compounded risk may additively enhance amyloid pathology independently from tau. This underscores the importance of investigating synergistic and additive risk in neurodegenerative disease.
García-Toledo I, Godoy-Corchuelo JM, Fernández-Beltrán LC
… +12 more, Ali Z, Guindo-Arroyo A, Jiménez-Coca I, Jiménez-Rodríguez J, Javaloyes-García K, Viñuela M, Gómez-Pinedo U, Saiz-Aúz L, Rábano A, Área-Gómez E, Cunningham TJ, Corrochano S
Acta Neuropathol
· 2025 Sep · PMID 40906043
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TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (AL...TDP-43 is a nuclear protein encoded by the TARDBP gene, which forms pathological aggregates in various neurodegenerative diseases, collectively known as TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These diseases are characterized by multiple pathological mechanisms, with disruptions in lipid regulatory pathways emerging as a critical factor. However, the role of TDP-43 in the regulation of the brain lipid homeostasis and the potential connection of TDP-43 dysfunction to myelin alterations in TDP-43 proteionopathies remain poorly understood, despite the fact that lipids, particularly cholesterol, comprise nearly 70% of myelin. To investigate the causal relationship between TDP-43 dysfunction and disruptions in brain cholesterol homeostasis, we conducted multi-omics analyses (lipidomics, transcriptomics, and functional splicing) on the frontal cortex from the Tardbp knock-in mouse model. Lipidomic analysis revealed alterations in lipid pathways related to membrane composition and lipid droplet accumulation, particularly affecting cholesterol-related species. We found higher lipid droplet accumulation in primary fibroblasts derived from these mice, as well as in the brain of the mutant mice. Similarly, the immunohistochemical detection of a lipid droplet marker was higher in the postmortem frontal cortex, gray matter, and white matter of FTLD-TDP patients compared to non-neurological controls. Transcriptomic analyses showed that TDP-43 pathology led to transcriptional dysregulation of genes essential for myelin production and maintenance. We identified impaired cholesterol metabolism, mainly through the downregulation of endogenous cholesterol synthesis, alongside upregulated cholesterol transport pathways, which we further replicated in FTLD-TDP patients transcriptomic datasets. Collectively, our findings suggest that TDP-43 dysfunction disrupts brain cholesterol homeostasis, potentially compromising myelin integrity.
Weber KJ, Dettki M, Münzberg M
… +6 more, Zeiner PS, Forster MT, Steidl E, Divé I, Harter PN, Scherer M
Acta Neuropathol
· 2025 Aug · PMID 40849395
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IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is esse...IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is essential for selecting an appropriate treatment maximizing anti-tumor efficacy while minimizing adverse effects. However, grading of oligodendrogliomas with 1p/19q codeletion currently relies on qualitative tumor characteristics that may be influenced by observer subjectivity, sampling bias, and tumor heterogeneity. This study aimed to explore DNA methylation-based tumor deconvolution into latent methylation components (LMCs) to evaluate their potential as objective grading tools in a cohort of 137 IDH-mutant gliomas. LMCs were analyzed in relation to malignancy markers, cellular composition, and underlying methylation signatures of the chromatin landscape. Glioma subtypes were associated with distinct LMCs. Two LMCs correlated with higher cellular density and advanced epigenetic age as well as with microvascular proliferation, necrosis, and epigenetically defined high-grade astrocytoma. The epigenetic patterns defining high-grade astrocytoma or oligodendroglioma, respectively, were similar. Higher-grade oligodendrogliomas, identified by LMC-based grading, were associated with more copy number alterations. Among patients of an external cohort who died during the assessment period, higher LMC1 proportions were associated with poorer overall survival. Therefore, LMCs hold the potential to support IDH-mutant glioma grading by incorporating objective epigenetic markers.