Acta Neuropathologica最新文献

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Median age at diagnosis was 7.5 years (range: 0.9–20 years). Disease was localized at diagnosis in 16 patients (53.3%), predominantly in the spinal cord (14/16, 87.5%). KIAA1549::BRAF fusion occurred in 27 (96.4%) of 28 patients. DNA methylation profiling of 23 tumors classified 4 (17.4%) as DLGNT MC-1, 3 (13.0%) as DLGNT MC-2, and 16 (69.6%) as DLGNT, but not to a specific subclass. Median follow-up was 57.5 months. Most patients (90.0%) received adjuvant therapy. Chemotherapy was the first-line adjuvant therapy in 19 patients (70.4%); targeted therapy in 5 patients (18.5%), and radiotherapy in 2 patients (7.4%). Median progression-free survival (PFS) after first chemotherapy, targeted therapy, or radiotherapy was 44 (1–77) months, 18 (4–39) months, and 16.5 (9–23) months, respectively. Five-year PFS was 15.9% ± 8.0, and 5 year overall survival (OS) was 83.3% ± 8.8. Patients older than 9 years at diagnosis (p = 0.002) and those with MC-2 (p = 0.04) had worse 5 year OS. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.

Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also ‘normal’ appearing tissue in both white and gray matter, referred to as ‘normal-appearing white matter’ and ‘normal-appearing gray matter’, respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these ‘normal-appearing’ CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Cell-type deconvolution revealed loss of excitatory neurons and a higher proportion of astrocytes in aFTLD-U relative to controls. Differential gene expression and co-expression network analysis, adjusted for the shift in cell-type proportions, showed dysregulation of mitochondrial pathways, transcriptional regulators, and upregulation of the Sonic hedgehog (Shh) pathway, including the GLI1 transcription factor, in aFTLD-U. Overall, oligodendrocyte and astrocyte-enriched genes were significantly over-represented among the differentially expressed genes. Differential splicing analysis confirmed the dysregulation of non-neuronal cell types with significant splicing alterations, particularly in oligodendrocyte-enriched genes, including myelin basic protein (MBP), a crucial component of myelin. Immunohistochemistry in frontal cortex brain tissue also showed reduced myelin levels in aFTLD-U patients compared to controls. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.

Charcot–Marie–Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. We observed sex-specific differences in muscle function in a CMT2Z mouse model carrying the microrchidia CW-type zinc finger protein 2A (Morc2a) p.S87L variant, with males exhibiting more severe weakness, suggesting a protective role of estradiol in females. Thus, we hypothesized that identifying and utilizing this factor could contribute to CMT2Z drug development. We found that estradiol stabilizes the Morc2a variant protein by inhibiting autophagy, independently of specific estrogen receptors, thereby mitigating hydroxyl radical–induced mitochondrial aggregation and apoptosis while restoring ATPase function. Subcutaneous implantation of estradiol pellets in the CMT2Z mouse model significantly improved Morc2a protein stability in the quadriceps femoris and sciatic nerve, reversed mitochondrial aggregation, and ameliorated both muscular and peripheral nerve degeneration. Notably, symptomatic Morc2a p.S87L mice exhibited robust peripheral nerve regeneration, demonstrating estradiol’s ability to restore function rather than merely delay disease progression. Moreover, the therapeutic effects were reproduced in human MORC2 p.R252W variants, further confirming its translational potential. As an FDA-approved compound with well-characterized pharmacokinetics, estradiol represents a rapidly deployable strategy for treating CMT2Z. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.

CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). Through our screening, we identified a subset of CNS tumors (n=12) epigenetically distinct from other known CNS tumor types, but clustering close to the PLAGL1- and PLAGL2-amplified ET, PLAGL subtypes in our t-SNE analysis. Copy number profiles indicated putative PLAG1 fusions, which were confirmed in 9/12 tumors (not determined in 3/12). Different 5’ fusion partners (ASAP1, ADGRG1, TMEM68, TCF4, CHD7, NCALD, HNRNPK, LOC105378102) were identified that upregulate wild-type PLAG1 through promoter hijacking. Expression analysis shows upregulation of PLAG1 as well as IGF2, DLK1, Desmin, CYP2W1, and RET, which are also robustly expressed in PLAGL1/2-amplified tumors. Patient characteristics, survival data, and clinical/imaging analysis show additional similarities to PLAGL1/2-amplified tumors. Median age at diagnosis was 5 years, tumors were located throughout the neuroaxis, and original histological diagnoses were heterogeneous. The tumors demonstrated morphologic heterogeneity, with most composed of densely cellular areas of primitive small blue cells, alongside focal regions showing clear cell morphology, microcystic changes, and ependymoma-like perivascular pseudorosettes. Applied treatment regimens were also heterogeneous, but some favorable responses to therapy were observed. In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.

Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. This novel tool was applied to septal samples of the Vantaa 85 + study (n = 138), which is a population-based autopsy study representing all subjects aged 85 years or older living in the city of Vantaa (southern Finland) in 1991. In addition, the tool was applied to left ventricle samples of the Helsinki Biobank (n = 87) and the forensic Tampere Sudden Death Study (TSDS, n = 127). The level of myocardial TH reactivity was compared between subjects with and without Lewy pathology in the central nervous system in all datasets. In the Vantaa 85 + study, TH reactivity was also compared between subjects with caudo-rostral and amygdala-based subtypes, and potential confounding factors (age at death, sex, myocardial infarction, senile systemic amyloidosis, and diabetes medication) were controlled for using multiple linear regression models. Presence of Lewy pathology was strongly associated with loss of TH reactivity at the myocardial level in all three autopsy cohorts (Vantaa 85 + p = 0.001, Helsinki Biobank p < 0.001, TSDS p < 0.001)). In the Vantaa 85 + study, the caudo-rostral subtype (p < 0.001), but not the amygdala-based subtype (p = 0.60), was associated with myocardial denervation/dysfunction, and this association was independent of other known causes of sympathetic denervation/dysfunction. Caudo-rostral subtype and myocardial infarction were the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population (Vantaa 85 +). In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in the ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.