Brain Pathology最新文献

Perinatal hypoxia-ischemia is a leading cause of preterm white matter injury (PWMI), yet mechanisms underlying oligodendrocyte precursor cells (OPCs) dysfunction remain poorly understood. Here, we identify endothelial-derived Netrin-4 (Ntn4) as a critical regulator of OPCs proliferation and differentiation in PWMI. Developmental analysis revealed that Netrin-4, predominantly expressed in cerebrovascular endothelial cells (ECs), peaks during postnatal myelination and correlates with OPCs marker PDGFR-α. Conditional endothelial deletion of Ntn4 in mice impaired spatial memory, induced anxiety-like behavior, and reduced mature oligodendrocytes, accompanied by disrupted myelin ultrastructure. In a PWMI model, endothelial Ntn4 knockout exacerbated myelination deficits and suppressed OPCs proliferation, while inducible deletion at later stages enhanced OPCs differentiation. Mechanistically, Netrin-4-overexpressing ECs elevated ET-1 secretion, which promoted OPCs proliferation but inhibited differentiation via ET-1 receptor EDNRB. Our findings reveal that endothelial Netrin-4 is a dual regulator of OPCs dynamics in PWMI, driving proliferation via ET-1 while impairing differentiation. Targeting the Netrin-4/ET-1 axis restores OPCs maturation, offering a potential strategy to mitigate myelination deficits in PWMI.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia, typically manifesting before the age of 65, with a mean onset at 58 years. FTD may encompass a spectrum of neurodegenerative disorders resulting from frontotemporal lobar degeneration (FTLD), affecting behavior, language, and motor function. Among its clinical variants, the behavioral variant (bvFTD) is the most frequently inherited, often associated with mutations in MAPT, GRN, and C9ORF72, the latter being the most prevalent genetic cause of FTD and FTD-motor neuron disease (FTD-MND). While bvFTD is classically defined by profound behavioral changes and executive dysfunction, cases linked to C9ORF72 expansions exhibit atypical neuropsychiatric features. This study documents two cases within the same family presenting with bvFTD and atypical parkinsonism, associated with a C9ORF72 expansion. Neurocognitive assessments, genetic testing, and neuroimaging (MRI, SPECT) were performed to characterize the clinical phenotype. A detailed review of the familial aggregation of neurodegenerative and psychiatric disorders provided further insight into the genetic contributions to symptomatology. The findings highlight the phenotypic heterogeneity associated with C9ORF72 expansions, demonstrating a spectrum ranging from bvFTD to atypical parkinsonism, with variable neuropsychiatric involvement. While movement disorders in FTD have historically been underestimated, these cases reinforce the association between parkinsonism and familial bvFTD. Given the limited epidemiological data on genetic FTD in Latin America, this study underscores the importance of genetic testing in cases with prominent behavioral and psychiatric symptoms, supporting early identification and genetic counseling for affected families.

Malignant craniopharyngiomas, de novo or via malignant transformation, are exceedingly rare with a dismal prognosis and unclear treatment standards. Little is known about the factors involved in their pathogenesis. A natural language search, performed in our institutional CoPath system, identified 65 adamantinomatous craniopharyngiomas from 56 patients (25 males, 31 females; median age at initial diagnosis = 22 years). Among those, a unique case of malignant craniopharyngioma was identified in a 36-year-old male initially diagnosed with a benign adamantinomatous craniopharyngioma 16 years prior. A literature review identified 44 cases of malignant craniopharyngiomas (current case included) with a median age of 28 years and a median overall survival of 6 months, independent of sex, age, histologic variant, tumor size, or radiation therapy. Eighteen (41%) malignant craniopharyngiomas occurred in patients without a history of radiation, suggesting mechanisms other than radiation contribute to their pathogenesis. Since BRCA1-Associated Protein 1 (BAP1) and TP53 mutations have recently been reported in a case of malignant craniopharyngioma, we assessed these genes in the current case. Next-generation sequencing identified variants in BAP1 (c.1850delGinsCA;p.R617fs), TP53 (c.428delT;p.V143fs), and CTNNB1 (c.110C>T;p.S37F). In conclusion, our results demonstrate that malignant craniopharyngioma tends to occur in young adults with a median overall survival of only 6 months. The current case is the second reported to harbor BAP1 and TP53 mutations by sequencing. BAP1 and TP53 mutations may play an important role in the pathogenesis of malignant craniopharyngioma and may offer potential targets for therapeutic intervention.

Despite the success of combination antiretroviral therapy (ART) in suppressing systemic HIV replication, neurocognitive impairment (NCI) remains common among people with HIV (PWH). In the pre-ART era, severe forms such as HIV-associated dementia (HAD) were prevalent and characterized by distinct neuropathological features, including multinucleated giant cells, microglial nodules, and extensive neuronal loss. In the ART era, milder forms of NCI are more frequent; however, the underlying histopathology remains poorly understood. These milder impairments are primarily associated with synaptodendritic damage and neuronal dysregulation, typically in the absence of productive infection in neurons. Instead, microglia and macrophages are implicated as key drivers of neuroinflammation and neuronal injury. In this study, we investigated the neuropathological features of brain tissue from PWH with and without symptomatic cognitive impairment. Immunohistochemical analysis revealed microglial nodules with active neuronal phagocytosis, which was associated with dendritic loss and neuronal damage. Complementary in vitro studies demonstrated that HIV-infected microglia demonstrated enhanced phagocytic activity, supporting their direct role in neurodegeneration beyond cytokine-mediated mechanisms. Together, these findings highlight microglial phagocytosis as one of the critical contributors of HIV-associated NCI in the ART era.

We report a novel FGFR2::TXLNB fusion in a child with hippocampal PLNTY. This fusion likely drives tumorigenesis via homodimerization and activation of MAPK/PI3K pathways, expanding PLNTY's molecular spectrum and suggesting a potential therapeutic target.

Growing data suggest companion dogs may be a promising model of human brain aging and Alzheimer's disease (AD). However, although pathology is somewhat similar in canine cognitive dysfunction (CCD) and AD, the transcriptomic similarities between these two conditions have not been thoroughly evaluated. Two emerging transcriptome-related mechanisms of human brain aging and AD involve transposable elements (TEs) and microRNAs (miRNAs), which have the potential to be carried systemically and between cells by extracellular vesicles (EVs). To determine if evidence of these AD-related transcriptomic events might be present in CCD, we generated transcriptome (RNA-seq) data on prefrontal cortex tissue and plasma EVs from young, older, and older CCD dogs. We show that: (1) global transcriptome changes with CCD indicate reduced neuronal health; (2) TE transcripts increase with CCD in both the brain and plasma EVs; (3) brain- and disease-relevant miRNAs are present in the same EVs, and some of these miRNAs correlate with indices of cognitive function/CCD. Collectively, our data suggest that transcriptomic changes in CCD, including those related to novel RNA mechanisms of brain aging and AD, may be similar to those observed in humans.