Journal of Neuropathology and Experimental Neurology最新文献

We investigated the expression and distribution of 5 cytoadhesion receptors for the Plasmodium falciparum erythrocyte membrane protein 1 in 12 regions of post-mortem brains of 50 Malawian children, that is, 27 with the clinical and pathological diagnosis of cerebral malaria (CM) and 23 with a non-malarial cause of death. We quantified the expression of each receptor by microvascular endothelium and the colocalization of receptor-expressing microvessels with sequestered infected red blood cells (iRBC) and calculated a receptor-independent sequestration ratio. There were differences in the level of expression and regional distribution of the five receptors: ICAM-1 was the most widely expressed receptor, followed by CD36, VCAM-1, E-selectin, and thrombospondin. Receptor-expressing microvessels were most numerous in the frontal lobe and least numerous in the brainstem and cerebellum. Colocalization of receptor-expressing endothelial cells with iRBC was present in all brain regions; it was highest for ICAM-1 and CD36 and greatest in the frontal lobe. The sequestration ratios were close to 100% for all receptors across all brain regions and were similar in cerebral and extracerebral microvessels. Receptor expression and colocalization ratios were greater in the brain than in the lung, heart, liver, spleen, and subcutaneous tissue. These differences in cerebral endothelial expression of cytoadhesion receptors and their preferential regional distribution may underpin differences in iRBC sequestration and lesion development in CM. Moreover, greater expression of these receptors in the brain vs peripheral organs may explain a comparatively greater degree of iRBC sequestration in the brain.

This review examines the cholinergic (Ch) basal forebrain and its role in neurodegeneration. Terminology used to describe Ch cells and the complex region of the basal forebrain are reviewed. Practical autopsy sampling and labeling strategies for Ch cells are discussed and illustrated with the goal of facilitating diagnostic work and autopsy-based studies of this region. The anatomic connectivity of the system is reviewed with an emphasis placed on the dense cholinergic input to the amygdala, the major target of the Ch basal forebrain, as well as the hippocampus. Ch and basal forebrain neuropathology in various neurodegenerative diseases is then briefly discussed, including more recent studies of TDP-43 proteinopathies. Finally, areas for further study that might further the understanding of the Ch system in neurodegeneration are emphasized.

Myxoid glioneuronal tumor (MGNT) is a recently recognized rare neural tumor in the 2021 WHO Classification of CNS Tumors. Myxoid glioneuronal tumor has low-grade histology and a generally good overall survival rate. However, some tumors exhibit leptomeningeal or intraventricular dissemination at presentation or during disease progression and the underlying biology is unknown. Finding activated signaling pathways and metabolic processes in disseminating MGNTs may reveal potential therapy targets for disseminated tumors. We compared the DNA methylome and transcriptome of disseminating (n = 4) and non-disseminating (n = 7) MGNTs to identify differentially methylated regions and differentially expressed genes. Gene set enrichment analysis (GSEA) was used to identify associated specific signaling and metabolic pathway activation. Myxoid glioneuronal tumors showed similar DNA methylome profiles regardless of dissemination status. Transcription factor MSX1 activation was found in disseminating MGNTs at the transcriptome level. Gene set enrichment analysis revealed the activation of the MAPK, PI3K/AKT/mTOR, MYC, and RAS pathways, as well as multiple metabolic pathways, including OXPHOS, translation, and cell cycle pathways, in disseminating MGNTs. In summary, disseminating MGNT shows simultaneous activation of multiple signaling and metabolic pathways, which may serve as potential therapeutic targets for disseminated disease.

In the early days of the 2019 coronavirus disease (COVID-19) pandemic, there were few published guidelines for safely performing autopsies of infected individuals. To limit the risk to autopsy personnel, major changes to our autopsy protocol were initiated. Between January 26, 2020 and February 28, 2022, the Arizona Study of Aging and Neurodegenerative Disorders and its Brain and Body Donation Program performed autopsies on 162 subjects; of these, 36 tested positive for SARS-CoV-2 on FDA-certified PCR tests; 2 were undiagnosed. A key protocol change was the use a heavy-duty clear polyethylene bag sealed at the subject's neck and saw handle for containment of bone saw-generated aerosols during skullcap removal. During this time period, there were 94 COVID-19 autopsy exposures involving 19 staff members with only 2 occurrences of a single autopsy team member testing positive for SARS-CoV-2 within 7 days of participation in a SARS-CoV-2-positive autopsy. During the same period, 9 autopsy personnel without temporal proximity to autopsy participation tested positive. This suggests that our revised protocols reduced any enhanced risk of SARS-CoV-2 infection to autopsy personnel beyond the risk within the community. Therefore, we recommend the use of our protocol for performing autopsies on subjects with health-threatening communicable conditions.

RECQL4 plays an important role in maintaining the integrity of the genome and regulating DNA replication. However, the role of RECQL4 in CNS tumors remains unknown. Sequencing data were reviewed and immunohistochemistry was performed on a variety of glial and nerve sheath tumors. Functional studies were performed in glioma (U251) and malignant peripheral nerve sheath tumors (MPNSTs) (NF90-8, ST88-14) cell lines following RECQL4 knockdown and treatment with ATR-inhibitors. Across 1580 CNS tumors, RECQL4 gene variants were identified in 71 cases (4.5%), with 21 (29.6%) of probable pathogenic significance. RECQL4 expression differed significantly across glioma subgroups (P = 0.012). Low-grade gliomas (diffuse: median H-score 57.5; circumscribed: median 130) showed lower expression than high-grade gliomas (median 145, P < 0.05). Neurofibromas displayed higher RECQL4 expression (median 160) compared with MPNSTs (median 97.5, P < 0.001). Among MPNSTs, NF1-associated cases (n = 24, median 95) expressed significantly less RECQL4 than sporadic cases (n = 8, median 162.5, P < 0.001). RECQL4 knockdown in glioma and MPNST cell lines resulted in increased apoptosis and susceptibility to ATR-inhibitors. Our findings show that RECQL4 expression has divergent patterns across tumor types and that targeting RECQL4 may dampen tumor survival and enhance susceptibility to ATR inhibitor therapy in CNS tumors.

Abnormalities of myofiber size are often of diagnostic significance on skeletal muscle biopsies, mainly when myofibers are excessively small. The establishment of standards for myofiber size in children has been hampered until recently by the lack of tools to assess large numbers of fibers across a sizeable number of samples. This study describes the assessment of myofiber size in 349 histologically normal patient biopsy specimens obtained between 4 weeks and 25 years of life and corresponding primarily to locations in the thigh/quadriceps/vastus lateralis region. Biopsy specimens were selected for inclusion based on histologically normal light microscopic findings and minimal technical artifacts. H&E-stained slides were scanned and evaluated for minFeret diameter using a Visiopharm software app (APP #10164). MinFeret diameter fiber size data were then grouped into 18 age cohorts to establish normal ranges for males and females within each age cohort. A pilot study to compare known abnormal cases to these normal ranges was then performed to demonstrate how cases with abnormal fiber size might compare to these standards. This dataset provides a user-friendly and applicable set of standard fiber size ranges to assist in diagnostic and scientific work in children and young adults.

Combination antiretroviral therapy (cART) has reduced the incidence of HIV-related mortality, leading to a growing population of older virally suppressed people with HIV (PWH). cART has also decreased the prevalence of HIV-associated dementia; however, many virally suppressed PWH still experience milder forms of cognitive impairment. It remains unclear whether aging virally suppressed PWH demonstrate distinct risks or patterns of neurodegenerative pathology. We examined brain tissue of 13 virally suppressed PWH and 13 matched HIV-negative controls from a community-based cohort and characterized β-amyloid (Aβ), tau, α-synuclein, and TDP-43 pathology. Both groups had similar demographics, medical comorbidities, and routine histologic brain findings. PWH demonstrated trends toward an increased prevalence of both Alzheimer disease (AD) and non-AD neurodegenerative pathologies, including Aβ pathology, higher stage tau pathology, aging-related tau astrogliopathy, and α-synuclein pathology. They showed similar trends toward increased severity of Aβ and tau pathology. We also identified a negative correlation between the burden of entorhinal cortical neurofibrillary tangles and end-of-life body mass index in PWH. Thus, PWH may have a greater burden of neurodegenerative pathology, including both AD and non-AD neurodegenerative pathologies; there is a need for the assessment of neurodegenerative pathology in community-based cohort studies to understand mechanisms of HIV-associated neuropathology and cognitive impairment in aging virally suppressed PWH.

Alzheimer disease plasma biomarkers have emerged as minimally invasive, cost-effective tools for early diagnosis and disease monitoring yet their stability under common "real world" pre-analytical conditions remains incompletely characterized. We evaluated the stability of six plasma biomarkers, Aβ40, Aβ42, pTau181, pTau217, NfL, and glial fibrillary acidic protein (GFAP) using the Fujirebio Lumipulse G1200 platform. Plasma samples were initially collected from four healthy and cognitively unimpaired volunteers. Samples were stored under four conditions: room temperature (0-4 h), +4 °C (1-10 days), -20 °C (1-3 weeks), and -80 °C (4-8 weeks). In this pilot study, Aβ40 and Aβ42 remained generally stable. In contrast, pTau181 readings exhibited marked elevations in frozen samples, while pTau217 showed modest early fluctuations followed by significant decreases with prolonged storage. Next, we recruited 12 additional participants (six cognitively normal and six with mild cognitive impairment [MCI]), and their plasma samples were analyzed both fresh and after 4 weeks of storage at -80 °C. Among these participants, pTau181 readouts were significantly higher, and pTau217 were lower, in -80 °C frozen in comparison to never-frozen samples. These findings underscore the critical need for biomarker-specific sample workup and handling protocols and indicate that results for fresh plasma cannot be assumed to be the same as for frozen samples.