Hirsch S, Rahmanzade R, Grund K
… +23 more, Sutter C, Schramm K, Selt F, Ecker J, Jones BC, Schrimpf D, Demmert M, Guerreiro Stücklin AS, Hernaiz Driever P, Mezger M, Brecht I, Adib SD, Brummel B, Sturm D, Dikow N, Hempel M, Milde T, Pajtler K, Jones DTW, Pfister SM, von Deimling A, Sahm F, Schaaf CP
Acta Neuropathol
· 2025 Mar · PMID 40085243
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Ghatamaneni S, Coleman C, Shin I
… +18 more, Bruinsma T, Scott N, Lee J, Fang P, Min HK, Moloney CM, Wood AC, Constantopoulos E, Reichard RR, Schwarz CG, Jones DT, Graff-Radford J, Knopman DS, Jack CR, Petersen RC, Dickson DW, Murray ME, Lowe VJ
Acta Neuropathol
· 2025 Mar · PMID 40085238
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Recent developments in tau positron emission tomography (PET) radiotracers have enhanced the visualization of tau aggregates in Alzheimer's disease (AD). The maturity level of neurofibrillary tangles can affect its recog...Recent developments in tau positron emission tomography (PET) radiotracers have enhanced the visualization of tau aggregates in Alzheimer's disease (AD). The maturity level of neurofibrillary tangles can affect its recognition by biomarkers. Early detection of tau aggregates regarding tangle pathology is of interest in early diagnosis and comparison of tau radiotracers in this aspect is important. This study focused on head to head pathologic comparison of [F]MK-6240 and [F]Flortaucipir postmortem binding as seen on high resolution autoradiography as compared to CP-13 (early tangle maturity) and PHF-1 (middling tangle maturity) immunohistochemistry (IHC) to evaluate the tangle maturity pathology specificity of binding for tau aggregates in AD, atypical AD and non-AD tauopathies. Analyses were performed on serial 5 μm formalin-fixed paraffin-embedded human brain sections acquired from the Mayo Clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. Evaluation of the tracers' off-target binding profiles were performed. Both tracers had similar binding properties for tau aggregates with preference to middling tangle maturity as shown by comparison to immunohistochemical distributions. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non-AD tauopathies which corroborates with other studies.
Emrani S, Koutures A, Tripodis Y
… +19 more, Uretsky M, Abdolmohammadi B, Nowinski C, Daneshvar DH, Dwyer B, Katz DI, Goldstein LE, Cantu RC, Martin BM, Palmisano JN, Dams-O'Connor K, Crary JF, Stern RA, Mez J, Alvarez VE, Huber BR, McKee AC, Stein TD, Alosco ML
Acta Neuropathol
· 2025 Mar · PMID 40047953
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Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between R...Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between RHI and white matter/vascular neuropathologies and their relative contribution to dementia status in deceased men 50 + years old with and without exposure to RHI from various types of contact and collision sports. Our sample included two RHI groups from the UNITE brain bank: (1) American Football players (RHI-AF, n = 79), and (2) non-AF contact and collision sport athletes (e.g., boxing, rugby; RHI-CCS, n = 49). Controls included similarly aged (± 5 years) male brain donors without RHI. A modified ischemic injury scale (mIIS) served as a global measure of white matter and vascular neuropathologies, encompassing nine subcomponents. Dementia was determined through diagnostic consensus conference based on interviews with families. Using linear regression models controlling for age at death, mIIS was different in RHI-AF versus non-RHI only (p = 0.036). Subsequent logistic regression of each mIIS subcomponent, controlling for age at death, demonstrated that worse white matter rarefaction (RHI-AF; Beta = 1.42, [95% CI 2.03-8.43]; RHI-CCS; Beta = 1.93, [95% CI 2.35-20.17]) and hippocampal sclerosis (RHI-AF; Beta = 2.01, [95% CI 2.69-20.81]; RHI-CCS; Beta = 2.19, [95% CI 2.49-32.10]) was more common in RHI groups from their controls. Further, logistic regressions found that higher global mIIS correlated with increased odds of dementia in only the RHI-AF group (p = 0.02), driven by white matter rarefaction (β = 0.94, [95% CI 1.66-4.00]) and hippocampal sclerosis (β = 1.08, [95% CI 1.35-6.42]). There were similar findings in RHI-CCS group for odds of dementia (p = 0.048), including white matter rarefaction (β = 0.68, [95% CI 1.22-3.21], p = 0.05). Overall, these results demonstrate that white matter rarefaction and hippocampal sclerosis are linked to RHI exposure across all types of contact sports. Further, these pathologies contribute to dementia independent of p-tau pathology in American football players.
Cecchini E, Geffers S, Coras R
… +12 more, Schultheis D, Holtzhausen C, Karandasheva K, Herrmann H, Paulsen F, Stadelmann C, Kobow K, Hartlieb T, Bien CG, Lal D, Blumcke I, Hoffmann L
Acta Neuropathol
· 2025 Mar · PMID 40042641
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Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) is a recently described disease entity primarily affecting young children with drug-resistant epilepsy, mainly affecting the...Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) is a recently described disease entity primarily affecting young children with drug-resistant epilepsy, mainly affecting the frontal lobe. The condition is histopathologically defined by focal lesions with patchy areas of increased oligodendroglial cell density at the grey-white matter boundary and heterotopic neurons in the white matter. Approximately half of the individuals with MOGHE carry brain somatic variants in the SLC35A2 gene, which affects the UDP-galactose transporter and thus sphingolipid glycosylation. To investigate the impact of SLC35A2 variants on protein expression, we analysed MOGHE brain tissue with and without SLC35A2 mosaicism, distinguishing missense from nonsense variants. We developed an antibody targeting the N-terminus of the SLC35A2 galactose transporter and applied it for immunofluorescence (IF) analyses in a MOGHE cohort comprising 59 genetically tested individuals selected from three centres in Germany. The cohort included 13 individuals with SLC35A2 missense variants and 15 with SLC35A2 nonsense variants. Our findings confirm the localisation of the SLC35A2 protein in the Golgi apparatus of all neuroepithelial cell types as well as within Golgi outposts along oligodendroglial processes. The protein distribution was altered in MOGHE samples dependent on the SLC35A2 variant and its allelic frequency. Western blot and IF analyses revealed a significant SLC35A2 reduction in MOGHE tissues carrying nonsense variants. Ultrastructural analyses from three MOGHE samples demonstrated hypomyelination in regions with increased oligodendroglial cell densities, regardless of the harbouring of SLC35A2 variants. Notably, this hypomyelination pattern decreased with age. These results suggested a role for the SLC35A2 protein in the pathogenesis of MOGHE and indicated the presence of additional myelin-associated pathomechanisms in those individuals who do not carry a pathogenic SLC35A2 variant.
Abdeen AH, Trist BG, Nikseresht S
… +27 more, Harwood R, Roudeau S, Rowlands BD, Kreilaus F, Cottam V, Mor D, Richardson M, Siciliano J, Forkgen J, Schaffer G, Genoud S, Li AA, Proschogo N, Antonio B, Falkenberg G, Brueckner D, Kysenius K, Liddell JR, Fat SCM, Wu S, Fifita J, Lockwood TE, Bishop DP, Blair I, Ortega R, Crouch PJ, Double KL
Acta Neuropathol
· 2025 Mar · PMID 40042537
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Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation o...Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We also engineered two of these factors - brain copper deficiency and upregulated SOD1 protein levels - into a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction, and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.
Beauchamp LC, Ellett LJ, Juan SMA
… +10 more, Liu XM, Hunt CPJ, Parish CL, Jacobson LH, Shepherd CE, Halliday GM, Bush AI, Vella LJ, Finkelstein DI, Barnham KJ
Acta Neuropathol
· 2025 Mar · PMID 40024917
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Hyposmia is one of the most prevalent non-motor symptoms of Parkinson's disease and antecedes motor dysfunction by up to a decade. However, the underlying pathophysiology remains poorly understood. In this study, we inve...Hyposmia is one of the most prevalent non-motor symptoms of Parkinson's disease and antecedes motor dysfunction by up to a decade. However, the underlying pathophysiology remains poorly understood. In this study, we investigated the mechanisms of dopamine metabolism in post-mortem olfactory bulbs from ten Parkinson's disease and ten neurologic control subjects. In contrast to the loss of dopaminergic neurons in the midbrain, we observed an increase in tyrosine hydroxylase-positive neurons in the Parkinson's disease olfactory bulb, suggesting a potential role for dopamine in the hyposmia associated with the condition. Using immunohistochemistry, high-performance liquid chromatography, western blot, and enzyme-linked immunosorbent assays, we demonstrate a reduction in catechol-O-methyltransferase catabolism of dopamine to homovanillic acid, potentially due to a depletion of the methyl donor substrate S-adenosyl methionine. We hypothesized that reduction in catechol-O-methyltransferase activity would result in increased dopamine occupation of the D receptor, and consequent inhibition of olfactory processing. Next, we conducted pharmacological interventions to modify dopamine dynamics in hyposmic tau knockout mice, which exhibit altered dopamine metabolism. Our hypothesis was supported by the observation that the D receptor antagonist haloperidol temporarily alleviated olfactory deficits in these tau knockout mice. This study implicates a potential role of catechol-O-methyltransferase-mediated dopamine metabolism in the early olfactory impairments associated with Parkinson's disease.
Bernhardt AM, Longen S, Trossbach SV
… +15 more, Rossi M, Weckbecker D, Schmidt F, Jäck A, Katzdobler S, Fietzek UM, Weidinger E, Palleis C, Ruf V, Baiardi S, Parchi P, Höglinger GU, Matthias T, Levin J, Giese A
Acta Neuropathol
· 2025 Feb · PMID 39976789
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Misfolded α-synuclein (αSyn) is the hallmark of α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While seed amplification assays (SAA) have demonst...Misfolded α-synuclein (αSyn) is the hallmark of α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While seed amplification assays (SAA) have demonstrated ultrasensitive detection of misfolded αSyn, they have been primarily used reliably to provide binary (positive/negative) results for diagnostic purposes. We developed an SAA with enhanced specificity for Lewy-fold α-synucleinopathies and introduced a quantifiable measure correlating with clinical severity. Cerebrospinal fluid (CSF) of 170 patients with neurodegenerative diseases and controls was analyzed. Blinded measurements demonstrated 97.8% sensitivity and 100% specificity for Lewy-fold α-synucleinopathies, correctly identifying PD and DLB while excluding MSA. In addition, we validated the strain specificity of the assay by testing brain homogenates from 30 neuropathologically confirmed cases. A novel Lewy-fold pathology (LFP) score based on positive signals in a dilution series provided a quantitative measure of αSyn seeds. The LFP score significantly correlated with motor and cognitive impairment presented by Hoehn and Yahr stage, MDS-UPDRS III, and MoCA. Longitudinal tracking in seven PD cases showed progressive LFP score increases corresponding with clinical deterioration, highlighting the assay's potential for monitoring disease progression at an individual level. Our Lewy-fold-specific SAA enhances ante-mortem diagnosis and differentiates Lewy-fold α-synucleinopathies from MSA. Unlike previous assays, the LFP score offers a quantitative assessment, showing promise as a progression marker and pharmacodynamic biomarker for αSyn-targeting therapies. This represents an important step toward developing an αSyn SAA that could help to track disease progression quantitatively, with potential applications in both clinical diagnostics and therapeutic trials.
Ebner BA, Erdahl SA, Lundgreen CS
… +10 more, Vassilaki M, Kremers WK, Knopman DS, Petersen RC, Berry DJ, Lewallen DG, Jannetto PJ, Murray ME, Reichard RR, Maradit Kremers H
Acta Neuropathol
· 2025 Feb · PMID 39954128
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We examined whether total joint arthroplasty (TJA) is associated with increased metal accumulation in the brain and histopathologic changes of Alzheimer's disease. We measured ultra-trace metal concentrations (aluminum,...We examined whether total joint arthroplasty (TJA) is associated with increased metal accumulation in the brain and histopathologic changes of Alzheimer's disease. We measured ultra-trace metal concentrations (aluminum, chromium, cobalt, manganese, molybdenum, nickel, titanium, and vanadium) on postmortem frozen tissues of the occipital lobe of 177 subjects (89 non-TJA and 88 TJA) using a triple-quadrupole inductively coupled plasma mass spectrometry and correlated elemental concentrations to the degree of Alzheimer's disease neuropathic change (ADNC). To effectively assess the relationship between TJA and brain metal concentrations, subjects with and without TJA were matched for baseline clinical characteristics and showed no difference in postmortem Alzheimer's disease neuropathic change. TJA subjects had increased concentrations of cobalt and titanium and both metals were associated with increased amyloid plaques. In both the TJA and non-TJA subjects, increased concentrations of cobalt, titanium, manganese, and molybdenum were associated with increased odds of neuritic and diffuse plaques. Lastly, the brain's inter-metal correlations were altered in the presence of increased neuritic plaques and/or implantable artificial joints. These findings suggest that metal concentrations and homeostasis vary in presence of TJA.
Fixemer S, Miranda de la Maza M, Hammer GP
… +8 more, Jeannelle F, Schreiner S, Gérardy JJ, Boluda S, Mirault D, Mechawar N, Mittelbronn M, Bouvier DS
Acta Neuropathol
· 2025 Feb · PMID 39954093
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In Alzheimer's disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM...In Alzheimer's disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.
Tauziède-Espariat A, Appay R, Bouvier C
… +10 more, Testud B, Girard N, Métais A, Servant E, Scavarda D, Meurgey A, Pissaloux D, Hasty L, Varlet P, RENOCLIP-LOC
Acta Neuropathol
· 2025 Feb · PMID 39928140
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Osterman C, Hamlin D, Suter CM
… +9 more, Affleck AJ, Gloss BS, Turner CP, Faull RLM, Stein TD, McKee A, Buckland ME, Curtis MA, Murray HC
Acta Neuropathol
· 2025 Feb · PMID 39921702
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Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical s...Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration.
Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new histopathological entity identified in the surgically resected brain tissue of patients with drug-resistant epileps...Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new histopathological entity identified in the surgically resected brain tissue of patients with drug-resistant epilepsy. Somatic variants in SLC35A2 have been increasingly identified in MOGHE brain resections. SLC35A2 protein transports uridine 5'-diphosphogalactose (UDP-Gal) into the Golgi lumen, playing a crucial role in the process of N-glycosylation. Currently, research on the pathogenic mechanism of SLC35A2 variants in MOGHE is limited. Here we conducted genetic testing on brain samples and paired blood samples from 28 pediatric patients pathologically diagnosed with MOGHE. We performed an in-depth functional analysis of somatic variants identified in SLC35A2, integrating glycan labeling and intact glycopeptide profiling to assess N-glycosylation defects. With whole-exome sequencing and validation with ultra-deep amplicon sequencing, we identified 101 potentially pathogenic somatic variants (PPSVs) across 87 genes. Nine PPSVs in SLC35A2 were found in 10 samples. The 9 identified variants of SLC35A2, characterized by various mutation types (4 frameshift, 3 missense and 2 nonsense variants), were all confirmed to be loss-of-function via altered glycan chains. Intact glycopeptide analysis at the cellular level indicated an increase in truncated N-glycan glycoforms. Analysis of brain tissue revealed N-glycosylated proteins and glycosites modified with agalactosylated glycoforms, and glycoproteins bearing agalactosylated N-glycans were significantly enriched in cell adhesion and axon guidance-related pathways. Additionally, chemoenzymatic glycan labeling in lesions demonstrated N-glycan damage of heterotopic neurons, suggesting a potential diagnostic approach for MOGHE. Our findings provide a comprehensive somatic landscape of MOGHE and a rich resource of somatic SLC35A2 variant-related glycoform and glycoprotein abnormalities, thereby unveiling valuable insights into compromised N-glycosylation and MOGHE formation.
Hinz F, Friedel D, Korshunov A
… +47 more, Ippen FM, Bogumil H, Banan R, Brandner S, Hasselblatt M, Boldt HB, Dirse V, Dohmen H, Aronica E, Brodhun M, Broekman MLD, Capper D, Cherkezov A, Deng MY, van Dis V, Felsberg J, Frank S, French PJ, Gerlach R, Göbel K, Goold E, Hench J, Kantelhardt S, Kohlhof-Meinecke P, Krieg S, Mawrin C, Morrison G, Mühlebner A, Ozduman K, Pfister SM, Poliani PL, Prinz M, Reifenberger G, Riemenschneider MJ, Sankowski R, Schrimpf D, Sill M, Snuderl M, Verdijk RM, Voisin MR, Wesseling P, Wick W, Reuss DE, von Deimling A, Sahm F, Maas SLN, Suwala AK
Acta Neuropathol
· 2025 Feb · PMID 39899075
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IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in IDH1 or IDH2 and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of bris...IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in IDH1 or IDH2 and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of brisk mitotic activity (grade 3) and necrosis and/or microvascular proliferation (grade 4). In addition, homozygous deletion of the CDKN2A/B locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas. Here, we describe a subgroup of high-grade IDH-mutant astrocytomas characterised by a primitive neuronal component based on histology and a distinct DNA methylation profile (n = 51, ASTRO PNC). Misinterpretation as carcinoma metastasis was common, since GFAP expression was absent in the primitive neuronal component, whereas TTF-1 expression was detected in 15/19 cases (79%) based on immunohistochemistry. Apart from mutations in IDH1, TP53, and ATRX, we observed enrichment for alterations in RB1 (n = 19/51, 37%) and MYCN (n = 14/51, 27%). Homozygous CDKN2A/B deletion (n = 1/51, 2%) and CDK4 amplification (n = 3/51, 6%) were relatively rare events. Clinical (n = 31 patients) and survival data (n = 23 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n = 7) and extra-axial (n = 2) spread. Taken together, ASTRO PNC is defined by a distinct molecular and histological appearance that can mimic metastatic disease and typically follows an aggressive clinical course.
Friker LL, Perwein T, Waha A
… +35 more, Dörner E, Klein R, Blattner-Johnson M, Layer JP, Sturm D, Nussbaumer G, Kwiecien R, Spier I, Aretz S, Kerl K, Hennewig U, Rohde M, Karow A, Bluemcke I, Schmitz AK, Reinhard H, Hernáiz Driever P, Wendt S, Weiser A, Guerreiro Stücklin AS, Gerber NU, von Bueren AO, Khurana C, Jorch N, Wiese M, Kratz CP, Eyrich M, Karremann M, Herrlinger U, Hölzel M, Jones DTW, Hoffmann M, Pietsch T, Gielen GH, Kramm CM
Acta Neuropathol
· 2025 Feb · PMID 39894875
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Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The...Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients' families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including MSH2 hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.
Özen I, Hamdeh SA, Ruscher K
… +1 more, Marklund N
Acta Neuropathol
· 2025 Jan · PMID 39841284
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Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebr...Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer's-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated. Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA).These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ Aβ and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ peptides were also observed in the leptomeningeal arteries of young TBI patients. These pathological changes also included higher β-secretase (BACE1) when compared to α-secretase A Disintegrin And Metalloprotease 10 (ADAM10) expression in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.
Martá-Ariza M, Leitner DF, Kanshin E
… +10 more, Suazo J, Giusti Pedrosa A, Thierry M, Lee EB, Devinsky O, Drummond E, Fortea J, Lleó A, Ueberheide B, Wisniewski T
Acta Neuropathol
· 2025 Jan · PMID 39825890
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Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ p...Down syndrome (DS) is strongly associated with Alzheimer's disease (AD) due to APP overexpression, exhibiting Amyloid-β (Aβ) and Tau pathology similar to early-onset (EOAD) and late-onset AD (LOAD). We evaluated the Aβ plaque proteome of DS, EOAD, and LOAD using unbiased localized proteomics on post-mortem paraffin-embedded tissues from four cohorts (n = 20/group): DS (59.8 ± 4.99 y/o), EOAD (63 ± 4.07 y/o), LOAD (82.1 ± 6.37 y/o), and controls (66.4 ± 13.04). We identified differentially abundant proteins when comparing Aβ plaques and neighboring non-plaque tissue (FDR < 5%, fold-change > 1.5) in DS (n = 132), EOAD (n = 192), and LOAD (n = 128), with 43 plaque-associated proteins shared across all groups. Positive correlations were observed between plaque-associated proteins in DS and EOAD (R = .77), DS and LOAD (R = .73), and EOAD and LOAD (R = .67). Top gene ontology biological processes (GOBP) included lysosomal transport (p = 1.29 × 10) for DS, immune system regulation (p = 4.33 × 10) for EOAD, and lysosome organization (p = 0.029) for LOAD. Protein networks revealed a plaque-associated protein signature involving APP metabolism, immune response, and lysosomal functions. In DS, EOAD, and LOAD non-plaque vs. control tissue, we identified 263, 269, and 301 differentially abundant proteins, with 65 altered proteins shared across all cohorts. Non-plaque proteins in DS showed modest correlations with EOAD (R = .59) and LOAD (R = .33) compared to the correlation between EOAD and LOAD (R = .79). Top GOBP term for all groups was chromatin remodeling (p < 0.001), with additional terms for DS including extracellular matrix, and protein-DNA complexes and gene expression regulation for EOAD and LOAD. Our study reveals key functional characteristics of the amyloid plaque proteome in DS, compared to EOAD and LOAD, highlighting shared pathways in endo/lysosomal functions and immune responses. The non-plaque proteome revealed distinct alterations in ECM and chromatin structure, underscoring unique differences between DS and AD subtypes. Our findings enhance our understanding of AD pathogenesis and identify potential biomarkers and therapeutic targets.
Pagani F, Orzan F, Lago S
… +17 more, De Bacco F, Prelli M, Cominelli M, Somenza E, Gryzik M, Balzarini P, Ceresa D, Marubbi D, Isella C, Crisafulli G, Poli M, Malatesta P, Galli R, Ronca R, Zippo A, Boccaccio C, Poliani PL
The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of differ...The foremost feature of glioblastoma (GBM), the most frequent malignant brain tumours in adults, is a remarkable degree of intra- and inter-tumour heterogeneity reflecting the coexistence within the tumour bulk of different cell populations displaying distinctive genetic and transcriptomic profiles. GBM with primitive neuronal component (PNC), recently identified by DNA methylation-based classification as a peculiar GBM subtype (GBM-PNC), is a poorly recognized and aggressive GBM variant characterised by nodules containing cells with primitive neuronal differentiation along with conventional GBM areas. In addition, the presence of a PNC component has been also reported in IDH-mutant high-grade gliomas (HGGs), and to a lesser extent to other HGGs, suggesting that regardless from being IDH-mutant or IDH-wildtype, peculiar genetic and/or epigenetic events may contribute to the phenotypic skewing with the emergence of the PNC phenotype. However, a clear hypothesis on the mechanisms responsible for this phenotypic skewing is still lacking. We assumed that the biphasic nature of these entities represents a unique model to investigate the relationships between genetic alterations and their phenotypic manifestations. In this study we show that in HGGs with PNC features both components are highly enriched in genetic alterations directly causing cell cycle deregulation (RB inactivation or CDK4 amplification) and p53 pathway inactivation (TP53 mutations or MDM2/4 amplification). However, the PNC component displays further upregulation of transcriptional pathways associated with proliferative activity, including overexpression of MYC target genes. Notably, the PNC phenotype relies on the expression of EBF3, an early neurogenic transcription factor, which is directly controlled by MYC transcription factors in accessible chromatin sites. Overall our findings indicate that the concomitant presence of genetic alterations, impinging on both cell cycle and p53 pathway control, strongly predisposes GBM to develop a concomitant poorly differentiated primitive phenotype depending on MYC-driven EBF3 transcription in a subset of glioma stem-like progenitor cells.