Neuropathology最新文献

Neuronal intranuclear inclusions (NIIs) are common key structures in polyglutamine (polyQ) diseases such as Huntington disease (HD), spinocerebellar ataxia type 1 (SCA1), and SCA3. Marinesco bodies (MBs) of dopaminergic neurons in the substantia nigra are also intranuclear structures and are frequently seen in normal elderly people. Ribosomal dysfunction is closely related to two differential processes; therefore, we aimed to identify the pathological characteristics of ribosomal protein SA (RPSA), a ribosomal protein, in both states. To this end, we evaluated the autopsy findings in four patients with HD, two SCA3, and five normal elderly cases (NCs). Immunohistochemical studies demonstrated that both NIIs and MBs contain RPSA. In polyQ diseases, RPSA was co-localized with polyQ aggregations, and 3D-reconstructed images revealed their mosaic-like distribution. Assessments of the organization of RPSA and p62 in NIIs showed that RPSA was more localized toward the center than p62 and that this unique organization was more evident in the MBs. Immunoblotting of the temporal cortices revealed that the nuclear fraction of HD patients contained more RPSA than that of NCs. In conclusion, our study revealed that RPSA is a common component of both NIIs and MBs, indicating that a similar mechanism contributes to the formation of polyQ NIIs and MBs.

The endogenous regenerative capacity of the brain is quite weak; however, a regenerative reaction, the production of new neurons (neurogenesis), has been reported to occur in brain lesions. In addition, leukocytes are well known to infiltrate brain lesions. Therefore, leukocytes would also have a link with regenerative neurogenesis; however, their role has not been fully elucidated. In this study, we investigated leukocyte infiltration and its influence on brain tissue regeneration in a trimethyltin (TMT)-injected mouse model of hippocampal regeneration. Immunohistochemically, CD3-positive T lymphocytes were found in the hippocampal lesion of TMT-injected mice. Prednisolone (PSL) treatment inhibited T lymphocyte infiltration and increased neuronal nuclei (NeuN)-positive mature neurons and doublecortin (DCX)-positive immature neurons in the hippocampus. Investigation of bromodeoxyuridine (BrdU)-labeled newborn cells revealed the percentage of BrdU/NeuN- and BrdU/DCX-positive cells increased by PSL treatment. These results indicate that infiltrated T lymphocytes prevent brain tissue regeneration by inhibiting hippocampal neurogenesis.

A 72-year-old woman with dermatomyositis (DM) developed neurological manifestation, and magnetic resonance imaging (MRI) revealed multiple T2/fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions predominantly in the deep white matter of the cerebral hemisphere. Punctate or linear contrast enhancement was observed surrounding the T1-hypointense area. Multiple T2/FLAIR-hyperintense lesions were aligned along with the corona radiata. Malignant lymphoma was first suspected, and a brain biopsy was performed. Pathological investigation suggested the provisional diagnosis of "suspicious of malignant lymphoma." Owing to emergent clinical conditions, high-dose methotrexate (MTX) therapy was conducted, and then T2/FLAIR-hyperintense lesions were dramatically reduced. However, the diagnosis of malignant lymphoma was concerning since multiplex PCR demonstrated clonal restriction of the Ig H gene for B cells and TCR beta genes for T cells. Histopathology revealed the infiltration of both CD4⁺ and CD8⁺ T cells, and the CD4⁺ /CD8⁺ ratio was 4.0. Moreover, prominent plasma cells were observed, in addition to CD20⁺ B cells. Atypical cells with enlarged nuclei were present, and they were not hematopoietic but found as glial cells. JC virus (JCV) infection was verified with both immunohistochemistry and in situ hybridization; the final diagnosis was progressive multifocal leukoencephalopathy (PML). The patient was treated with mefloquine and discharged. This case is informative in understanding the host anti-viral response. Variable inflammatory cells were observed, including CD4⁺ and CD8⁺ T cells, plasma cells, and a small amount of perivascular CD20⁺ B cells. PD-1 and PD-L1 expression was observed in lymphoid cells and macrophages, respectively. PML with inflammatory reactions was thought fatal, and autopsy cases of PML with immune reconstitution inflammatory syndrome (IRIS) demonstrated excessive infiltration of only CD8⁺ T cells. However, this case revealed infiltration of variable inflammatory cells, and a favorable prognosis would be expected under PD-1/PD-L1 immune-checkpoint regulation.

A 57-year-old female chimpanzee presented with a brief history of increasing lethargy and rapidly progressive lower-limb weakness that culminated in loss of use. Postmortem examination revealed no significant gross lesions in the nervous system or other organ systems. Histological analysis revealed round, basophilic to amphophilic polyglucosan bodies (PGBs) in the white and gray matter of the cervical, thoracic, lumbar, and coccygeal regions of spinal cord. Only rare PGBs were observed in forebrain samples. The lesions in the spinal cord were polymorphic, and they were positively stained with hematoxylin, periodic acid Schiff, Alcian blue, toluidine blue, Bielschowsky silver, and Grocott-Gomori methenamine-silver methods, and they were negative for von Kossa and Congo Red stains. Immunohistochemical evaluation revealed reactivity with antibodies to ubiquitin, but they were negative for glial fibrillary acidic protein, neuron-specific enolase, neurofilaments, tau protein, and Aβ protein. Electron microscopy revealed non-membrane-bound deposits composed of densely packed filaments within axons and in the extracellular space. Intra-axonal PGBs were associated with disruption of the axonal fine structure and disintegration of the surrounding myelin sheath. These findings are the first description of PGBs linked to neurological dysfunction in a chimpanzee. Clinicopathologically, the disorder resembled adult PGB disease in humans.

Hyaline protoplasmic astrocytopathy (HPA) describes a rare histologic finding of eosinophilic, hyaline cytoplasmic inclusions in astrocytes, predominantly in the cerebral cortex. It has mainly been observed in children and adults with a history of developmental delay and epilepsy, frequently with focal cortical dysplasia (FCD), but the nature and significance of these inclusions are unclear. In this study, we review the clinical and pathologic features of HPA and characterize the inclusions and brain tissue in which they are seen in surgical resection specimens from five patients with intractable epilepsy and HPA compared to five patients with intractable epilepsy without HPA using immunohistochemistry for filamin A, previously shown to label these inclusions, and a variety of astrocytic markers including aldehyde dehydrogenase 1 family member L1 (ALDH1L1), SRY-Box Transcription Factor 9 (SOX9), and glutamate transporter 1/excitatory amino acid transporter 2 (GLT-1/EAAT2) proteins. The inclusions were positive for ALDH1L1 with increased ALDH1L1 expression in areas of gliosis. SOX9 was also positive in the inclusions, although to a lesser intensity than the astrocyte nuclei. Filamin A labeled the inclusions but also labeled reactive astrocytes in a subset of patients. The immunoreactivity of the inclusions for various astrocytic markers and filamin A as well as the positivity of filamin A in reactive astrocytes raise the possibility that these astrocytic inclusions may be the result of an uncommon reactive or degenerative phenomenon.

The typical clinical manifestations of sporadic Creutzfeldt-Jakob disease (sCJD) are rapid-progressive dementia and myoclonus. However, the diagnosis of atypical sCJD can be challenging due to its wide phenotypic variations. We report an autopsy case of variably protease-sensitive prionopathy (VPSPr) with Met/Met homogeneity at codon 129. An 81-year-old woman presented with memory loss without motor symptoms. Seventeen months after the onset, her spontaneous language production almost disappeared. Diffusion-weighted images (DWI) showed hyperintensity in the cerebral cortex while electroencephalogram (EEG) showed nonspecific change. 14-3-3 protein and real-time qualing-induced conversion (RT-QuIC) of cerebrospinal fluid were negative. She died at age 85, 3.5 years after the onset. Pathological investigation revealed spongiform change, severe neuronal loss, and gliosis in the cerebral cortex. Mild to moderate neuronal loss and gliosis were observed in the basal ganglia. PrP immunostaining revealed plaque-like, dotlike, and synaptic structures in the cerebral cortex and small plaque-like structures in the molecular layer of the cerebellum. Analysis of PRNP showed no pathogenic mutations, and Western blot examination revealed the lack of a diglycosylated band consistent with VPSPr. The present case, which is the first report on a VPSPr case in Japan, supports previously published evidence that VPSPr cases can present variable and nonspecific clinical presentations. Because a small number of VPSPr cases can show typical magnetic resonance imaging (MRI) change in sCJD. We should investigate the possibility of VPSPr in a differential diagnosis with atypical dementia that presented DWIs of high intensity in the cortex, even though 14-3-3 proteins and RT-QuIC are both negative. In addition, VPSPr cases can take a longer clinical course compared to that of sCJD, and long-term follow-up is important.