Journal of Neuropathology and Experimental Neurology最新文献

Mutations in the reelin (RELN) extracellular matrix protein gene are known to cause cortical and cerebellar malformations due to disruption of normal neuroblast migration and localization during fetal neurodevelopment. More recently, mutations in genes encoding transmembrane receptors involved in the recognition of reelin, including very low-density lipoprotein receptor (VLDLR), have been linked to various dysequilibrium and ataxia syndromes. Radiologic findings in cases of VLDLR mutations include cerebellar hypoplasia with marked vermis hypoplasia and cortical simplification without lissencephaly. However, the gross and histologic findings in VLDLR-related cerebellar hypoplasia in humans have yet to be described in the literature. Neuropathologic analysis of a confirmed human case could serve to illuminate unique findings and further elucidate the underlying pathophysiologic mechanism of VLDLR gene mutations. We report the autopsy neuropathological findings in a genetically confirmed third-trimester gestation fetal example.

Chronic traumatic encephalopathy-neuropathologic change (CTE-NC) has been studied in contact sport athletes with repetitive head impacts (RHI), but its association with isolated traumatic brain injury (iTBI) and non-sport RHI in the community remains unclear. Forty-seven consecutive donor brains from the Late Effects of TBI Project underwent comprehensive neuropathologic evaluation. Seven (14.9%; median age, seventh decade) had CTE-NC, defined as perivascular neuronal tau at the depth of sulcus. Four had 4 "low" CTE-NC burden, 1 "high," and 2 "indeterminate." Ex vivo neuroimaging in 5 facilitated histological sampling of subtle changes otherwise likely to be overlooked. Five of the 7 CTE-NC donors reportedly had substantial RHI exposure: football (n = 3), boxing (n = 1), military and interpersonal violence (n = 1), and child abuse (n = 1). One CTE-NC case had no known RHI exposure but had 2 severe iTBIs sustained 30 and 3 years prior to death. Donors without CTE-NC had variable patterns of head trauma: RHI exposure (college football, n = 4), some RHI (n = 21, 17 of whom also had ≥1 iTBI), and ≥1 iTBI but no RHI (n = 15). These findings converge with prior reports that CTE is largely associated with extensive RHI and is infrequent in a cohort with varying TBI exposures.

Primary (idiopathic) hypophysitis is traditionally classified into lymphocytic, granulomatous, necrotizing, or IgG4-related disease types. Secondary hypophysitis occurs in patients with systemic conditions, which if known, often obviate the need for biopsy. Primary idiopathic hypophysitis, in contrast, often mimics tumors and mandates histological confirmation of inflammation. We detail four primary hypophysitis cases, discussing challenges in histological classification. Four women, ages 32 to 76 years, presented with weakness, visual changes, fatigue, weight loss, and/or headache. Preoperatively, pituitary macroadenoma/pituitary neuroendocrine tumor was suspected. Biopsies revealed lymphocytic hypophysitis without (Case 1) and with (Case 2) IgG4+ cells (modest numbers) and granulomatous hypophysitis with necrosis, large numbers of IgG4+ cells (Cases 3 and 4), with multinucleated giant cells (Case 4). Steroid therapy, in one case with rituximab, was administered irrespective of histological classification. Lymphocytic hypophysitis comes to biopsy primarily in patients without known risk factors, eg pregnancy or drug usage. Granulomatous or necrotizing types are less common, less histologically uniform, and may contain large numbers of IgG4+ cells, a feature found both in IgG4-related disease and autoimmune disorders, especially granulomatosis with polyangiitis. In certain cases, the use of steroids, followed by rituximab for all types of hypophysitis based on clinical criteria may obviate the need for precise histological distinction.

X-linked myopathy with excessive autophagy (XMEA) is a slowly progressive disease affecting male patients, caused by hemizygous mutations in the VMA21 gene. We studied nine patients from six unrelated French families clinically suspected of having XMEA. Clinical charts were reviewed, and muscle biopsies underwent histological, immunohistochemical, and electron microscopy analysis. Sanger sequencing and next generation VMA21 gene panels were performed, and proteomic profiling was done on muscle extracts from two patients. Clinical onset ranged from childhood to adulthood with most showing proximal lower limb weakness and mild creatine kinase elevation. Three patients had cardiac and respiratory involvement. Muscle biopsies revealed cytoplasmic vacuoles, split fibers, internalized nuclei and variable fiber sizes. Vacuoles stained positively for sarcolemmal and autophagic proteins, as well as for complement C5b-9. Ultrastructural analysis showed basal lamina duplication, subsarcolemmal vacuoles, and extensive autophagosome extrusion. Proteomic analysis revealed complement activation, impaired proteolysis, and mitochondrial/cytoskeletal vulnerabilities. Biglycan and thrombospondin-4 were identified as potential novel diagnostic markers. Molecular studies found two known pathogenic variants (c.164-7T>G and c.163 + 4A>G) and a novel 3'UTR variant (c.*124A>G) in VMA21. This study expands the clinical spectrum of XMEA by reporting adult-onset cases, a novel mutation, and highlights the value of proteomics in understanding the pathophysiology of XMEA.

Ki-67 proliferation index (PI) and mitoses are frequent histopathological proliferation markers in meningioma diagnostics. They are used extensively in grading, with mitotic count constituting the major grading criterion in meningiomas but their mutual correlations and associations with phenotypic characteristics are incompletely known. We addressed this by investigating a large retrospective meningioma cohort. We investigated global Ki-67, Ki-67 hotspots, and mitoses, and their associations with WHO grades, histological subtypes, and anatomical locations in 2608 meningiomas from Heidelberg and Mannheim University Hospitals in Germany. As expected, higher WHO grades and inherent subtypes had higher proliferation indices although the variance was high. The transitional subtype had higher proliferation indices than other grade 1 histologies. Skull base meningiomas had significantly lower global Ki-67 PI compared to convexity meningiomas also when stratified for WHO grade. Focal increases of Ki-67, here dubbed hotspots morphology, were more prevalent in higher WHO grades, indicating potential aggressive tumor subclones. Utilizing K-means clustering on paired Ki-67 PIs and mitoses improved alignment with WHO grades. Our analysis identified a heterogenous group of tumors in which certain locations and subtypes were associated with increased Ki-67 PI. They suggests that considering both mitoses and Ki-67 indices improves alignment with WHO grade.

Microbial stimuli modulate CNS neuroinflammation but the exact molecular mechanisms are largely unknown. In this study, we aimed to delineate the effect of systemic pre-disease microbial antigen administration of 2 different microbial strains on systemic and CNS immune responses in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in wtC57/BL5 mice. The mice received either Helicobacter pylori (Hp) or E coli antigen or PBS by 3 weekly intraperitoneal injections prior to EAE induction. Mice subjected to microbial antigen administration displayed decreased disease incidence and severity compared to controls. These results were linked with reduced splenocyte proliferation against MOG peptide in vitro and decreased expression of chemoattractant chemokines in both peripheral lymphoid organs and the CNS compared to controls. EAE amelioration was associated with a relative increase in Iba1+ arginase+ anti-inflammatory microglia in the CNS and with reduced MHC-II expression levels in antigen-presenting cells, indicated by reduction of Tmem+MHC-II+ microglia and Ly6C+MHC-II+ monocyte-derived macrophages. Our data provide mechanistic insight into the immune tolerance induced via systemic administration of 2 different microbial strain antigens in the context of CNS autoimmunity, possibly via the modulation of antigen-presentation via non-myelin peptide-specific mechanisms.

The mechanisms underlying cerebral aneurysm wall fragility remain unclear. Proteomic analysis has revealed predominant expression of myoglobin in thickened aneurysm wall regions. Given its nitric oxide-scavenging function, myoglobin may enhance wall stability. Hence, we aimed to elucidate its biological relevance in aneurysm wall specimens collected during surgical clipping. Immunostaining confirmed the presence of myoglobin and α-smooth muscle actin (α-SMA) in all 21 specimens. Double-immunofluorescence staining demonstrated that myoglobin was primarily localized on the luminal side of the α-SMA-positive layer. The median colocalization rates were 19.7% (interquartile range [IQR], 7.2%-43.4%) in the α-SMA-positive areas and 24.7% (IQR, 10.9%-56.8%) in the α-SMA-positive cells. Periostin staining demonstrated partial colocalization with α-SMA within the smooth muscle layer, with additional periostin-positive cells located luminally, beyond α-SMA expression. The colocalization rates of periostin were 41.8 ± 25.0% in α-SMA-positive areas and 55.8 ± 25.2% in α-SMA-positive cells. Myoglobin and periostin were highly expressed on the luminal sides, with median colocalization rates of 96.4% (IQR, 72.3%-99.0%) and 97.1% (IQR, 87.0%-100%) in periostin-positive areas/cells. Myoglobin density was positively correlated with collagen content. These findings suggest that periostin-expressing migrated myofibroblasts may produce myoglobin that could enhance collagen retention, wall thickening, and cerebral aneurysm wall stability.

Spinal cord injury (SCI) remains a significant medical challenge due to the complexity of its pathology. This study evaluated the effects of photobiomodulation therapy (PBMT) and low-intensity pulsed ultrasound (LIPUS) as non-invasive treatments for SCI. Thirty-six male Wistar rats were randomly assigned to 6 groups: control, SCI, PBMT, and LIPUS at 0.1, 0.3, and 0.5 W/cm2 intensities. SCI was induced using an aneurysm clip, and treatments began 30 minutes post-injury, continuing for 4 weeks. During the seventh week, no treatment was administered. Behavioral assessments, including the acetone and plantar tests for pain and the Basso-Beattie-Bresnahan score for locomotor function, were performed weekly from the first week until the study's end. At termination, lesion size was measured, and protein expression levels of glial fibrillary acidic protein (GFAP), transforming growth factor-β (TGF-β), phosphorylated glycogen synthase kinase-3β (P-GSK-3β), and neurexins were quantified via western blotting. Data were analyzed using Prism software. LIPUS at 0.5 W/cm2 emerged as the most effective treatment, enhancing motor function, reducing pain, and limiting tissue damage through modulation of GFAP, TGF-β, P-GSK-3β, and Neurexin1. LIPUS 0.3 and PBMT significantly reduced pain, while LIPUS 0.1 showed superior outcomes in movement recovery, indicating intensity-specific therapeutic effects.