Neuropathology最新文献

ADSS1 myopathy, previously known as adenylosuccinate synthetase-like 1 (ADSSL1) myopathy, is an autosomal recessive muscle disease caused by variants in ADSS1 (adenylosuccinate synthase 1). ADSS1 myopathy is complicated by respiratory muscle weakness or cardiomyopathy as well as limb muscle weakness. We analyzed two siblings with ADSS1 myopathy, both harboring compound heterozygous pathogenic variants (c.781G>A/c.919delA) in ADSS1 and provided details of their phenotypes together with muscle imaging and autopsy findings. Although it was reported that ADSS1 myopathy usually began with lower limb muscle weakness, our cases showed early involvement of the cervical paraspinal muscle, triceps brachii muscle, flexor digitorum superficialis and profundus muscles, rectus abdominis muscle, gluteus maximus and medius muscles, and cardiomyopathy. While a previous study reported that the trunk and hip muscles were relatively spared, atrophy of paraspinal muscles, gluteus medius and maximus muscles, and adductor muscles were observed. Our two siblings allowed for long-term follow-up and will be useful reference cases. We evaluated the frequency of fibers with nemaline bodies in various autopsied muscles and found that the ratio of fibers with nemaline bodies was lower compared to other nemaline myopathies. Postmortem examination revealed, for the first time, nemaline bodies in the diaphragm and myocardium, associated with respiratory failure and cardiomyopathy.

Transthyretin (TTR) can bind to Aβ and prevent the formation of Aβ fibrils in vitro; it is thus a highly interesting molecule in the field of Alzheimer's disease (AD) research. However, the distribution of TTR and its affinity to Aβ in both healthy human brains and those of AD patients remain unclear. We therefore examined TTR in human brains using postmortem brain samples. Paraffin sections and extracted protein samples were prepared from AD and control (non-AD) brains. Immunohistochemistry was performed to detect TTR expression patterns, and immunofluorescent staining was used to reveal the relationships between the intracellular and extracellular localizations of TTR and Aβ. We also performed western blotting for TTR using brain extracts. In immunohistochemical staining of the human brain, TTR signal was detected not only in extracellular tissue but also in the cytoplasm of neurons and glia. The TTR-positive area was significantly greater in AD brains than in non-AD brains. However, expression of TTR transcripts did not differ between AD and non-AD brains in our previously obtained RNA-sequencing and microarray data. Immunofluorescent staining with multiple antibodies revealed that TTR was co-localized with Aβ in the cytoplasm of neurons. In extracellular Aβ plaques, TTR presented in the same region but was not co-localized with dense Aβ fibrils. Together, our results indicate that TTR is widely expressed in the human brain rather than being limited to the choroid plexus and that TTR is more abundant in AD brains. Our results also suggest that the affinity between TTR and Aβ changes depending on the structure of Aβ. Our data will be valuable for the future development of TTR-related AD preventative methods and medications.

Pituitary blastoma is a rare embryonal tumor of the pituitary gland, typically occurring in children under 2 years of age and strongly associated with germline DICER1 mutations. Only a limited number of cases have been reported, with very few occurring beyond early childhood. We present the case of a 27-year-old male who presented with severe headaches, vomiting, visual disturbances, and altered behavior. Magnetic resonance imaging revealed a large suprasellar mass with sellar extension, diffusion restriction, and hemorrhagic components. The radiological differential diagnoses included papillary craniopharyngioma, pilocytic astrocytoma, and high-grade glioma. Surgical decompression was performed, and histopathological examination revealed a highly cellular tumor with blastemal, glandular, and rosette-forming components, consistent with pituitary blastoma. Immunohistochemistry showed patchy positivity for OLIG2, synaptophysin, and LIN28A, along with a high Ki-67 proliferation index (~90%). Next-generation sequencing confirmed a pathogenic DICER1 mutation (p.Glu1813Asp, p.Pro817fs), supporting the diagnosis. Unlike most reported cases, which present with Cushing's syndrome or ophthalmoplegia, this patient had an elevated prolactin level, a feature not previously described in pituitary blastoma. The tumor followed an aggressive course, and the patient succumbed within a month post-surgery. This case expands the clinicopathologic spectrum of pituitary blastoma, emphasizing unusual age and known genetic associations, and highlights the need for a high index of suspicion in atypical cases.

Choroid plexus tumors are neuroepithelium-derived tumors arising in the ventricles of the central nervous system. They are commonly seen in childhood and correspond to low rates in all central nervous system tumors. Due to their rareness and similar histomorphologic features to other tumors, their diagnosis might be challenging. Here, we used the OTX-2 antibody to evaluate the diagnostic role of OTX-2 expression in choroid plexus tumors. We performed a retrospective review of 34 patients operated for choroid plexus tumors in our center between 2011 and 2023. Additionally, as different tumor types are also arising in the ventricles, we selected five cases each of AT/RT, germ cell tumor, ependymoma, and metastatic adenocarcinoma from the pathology archive. Immunohistochemistry conditions were adjusted for each specific antibody based on the manufacturers' recommendations for concentrations and antigen retrieval/blocking. OTX-2, S-100, and transthyretin antibody staining was performed on sections from each case.

Diffuse hemispheric glioma, H3 G34-mutant (DHG), is a newly defined pediatric-type tumor in the 2021 WHO classification of central nervous system (CNS) tumors. DHGs harbor missense mutations at codon 35 of H3F3A (H3.3 G35R/V mutations) and exhibit diverse histopathological features, such as glioblastomas or CNS embryonal tumors. Regardless of histological variation, they demonstrate uniform immunohistochemical and molecular findings: Olig2 negative, ATRX loss, p53 positive, and MGMT promoter methylated. These tumors occur predominantly in the cerebral hemispheres of adolescents and young adults, while they are extremely rare in middle-aged and elderly individuals. Here, we report a middle-aged case of DHG with prominent perivascular invasion. The tumor initially demonstrated a focal glioblastoma-like area, whereas the recurrent tumor predominantly showed perivascular spread of spindle cells. We reviewed previously reported DHG cases in middle-aged and elderly patients and compared their clinicopathological features with those of adolescents and young adults.

Mutations in the Integral membrane protein 2B (ITM2B) gene are linked to the development of familial British and Danish dementias, two relatively early-onset dementia disorders known also to be associated with Tau neurofibrillary tangles (NFTs). However, to date, the involvement of ITM2B in limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) remains unclear. To address this question, we used brain samples from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. We investigated the patterns and co-localizations of ITM2B immunohistochemistry in subiculum, CA1, CA2, CA3 and dentate gyrus of the hippocampus from brains with Alzheimer's disease neuropathologic changes (ADNC), LATE-NC, and comorbid ADNC+LATE-NC, as well as low-pathology controls (n = 4 per disease state). There was frequent co-localization between ITM2B protein and intracellular Tau pathology in ADNC; however, there was a far weaker rate of co-localization between ITM2B and TDP-43 pathology. There also was, as previously described, an association between ITM2B immunostaining and neuritic-appearing amyloid plaques. Additionally, co-localization of intracellular ITM2B pathology with Thioflavin-S in NFTs suggested a potential role for ITM2B in marking neurons undergoing transition from relatively healthy (early NFT-bearing cells) to more severely affected (later NFT-bearing) cellular disease states. This study indicates that ITM2B has a relatively specific pattern of involvement in Tau-related neurodegeneration and in neuritic amyloid plaques, while implying minimal, if any, role for ITM2B in the synergistic relationship between Tau and TDP-43 pathologies.

The relationship between Alzheimer's disease and cardiac transthyretin amyloidosis (ATTR) has been reported epidemiologically. However, the details of its clinicopathological characteristics are unclear. To clarify the pathogenesis of Alzheimer's disease combined with cardiac ATTR, 50 autopsy cases of Alzheimer's disease with cardiac hypertrophy were examined. Transthyretin amyloid deposition was studied by immunostaining in cases where amyloid deposition was suspected in various organs by HE staining. ATTR in systemic organs was also examined. The pathological diagnosis of Alzheimer's disease was done based on the National Institute on Aging and Alzheimer's Association (NIA-AA) guidelines. Cerebral amyloid angiopathy (CAA) was rated on a 3-point scale according to the Vonsattel scale. The pathological diagnosis of cardiac ATTR was done using a 3-point scale based on previously published findings on amyloid amounts. Six out of 50 patients were found to have cardiac ATTR by immunostaining and protein mass analysis of myocardial tissue. The sex distribution of the six patients was two males (Cases 3 and 6) and four females (Cases 1, 2, 4, and 5), and their ages were 97, 89, 91, 104, 86, and 77 years in Cases 1-6, respectively. In Cases 1-6, the NIAA score/CAA assessment/ATTR stages were intermediate/severe/G3, intermediate/moderate/G3, high/severe/G3, high/severe/G2, high/severe/G2, and intermediate/moderate/G2, respectively. Cases 1-5 also had cerebral infarction. In all cases, Transthyretin amyloid deposition was seen mainly in the vessel walls of various organs throughout the body. In the heart, transthyretin amyloid deposition was observed in the myocardial vessel walls and between myocardial fibers. On autopsy, cardiogenic cerebral infarction or heart failure was considered to be the main cause of death in Cases 1-5. These results indicate that Alzheimer's disease could be regarded as a systemic disease rather than just a localized disease presenting with dementia.

Cerebral amyloid angiopathy (CAA) has been implicated as a risk for developing lobar intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) applied for acute ischemic stroke (AIS). However, there is a paucity of cases reported with histopathological CAA diagnosis in this setting, with a single report to imply the role of CAA-related inflammation (CAA-RI). We report clinical, radiological, and neuropathological observations of a 65-year-old woman who presented with acute left-hemispheric symptoms with an initially unrevealing cranial computed tomography (CT) and received IVT for presumed AIS. The course was rapidly complicated by a huge lobar ICH and a fatal outcome. The autopsy revealed severe CAA, unexpectedly with transmural CAA-RI, a.k.a. amyloid-β-related angiitis (ABRA), and histopathological evidence for vascular amyloid-β phagocytosis. Re-evaluation of initial imaging did not reveal signs of asymmetric confluent white matter edema characteristic of CAA-RI, but raised the suspicion of a tiny left central convexity subarachnoid hemorrhage, a substrate of amyloid spells. The genotype of the apolipoprotein E (ApoE) gene (ApoE) was ε3/ε3. Being the second published thrombolysis-associated fatality with ABRA and among the few with definite CAA, the present case confirms CAA/CAA-RI to be a potential hidden risk for IVT-associated ICHs, urging for awareness of CAA-associated pathologies and clinical-radiological hints in an AIS setting. The findings implicate the relevance of vascular Aβ phagocytosis in the pathogenesis, confirm that CAA-RI may present without prominent edema, highlight that CAA/CAA-RI-related focal neurological deficits (including amyloid spells) can be potential AIS mimics within the IVT time window, and urge for rigorous analysis of pre-IVT CT scans for even subtle sulcal hyperdensities suggesting cSAH/amyloid spell in elderly patients, prompting consideration of magnetic resonance imaging.

The degeneration of pyramidal tracts has been reported in frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43) pathology (FTLD-TDP) type C. Herein, we examined the detailed pathology of the primary motor area and pyramidal tracts in the central nervous system in four autopsy cases of FTLD-TDP type C, all of which were diagnosed by neuropathological, biochemical, and genomic analyses. Three patients showed right dominant atrophy of the frontal and temporal lobes, while the other patient showed left dominant atrophy. All four patients showed motor symptoms, and two patients had episodes of repeated aspiration. In the primary motor area, phosphorylated TDP-43 (p-TDP-43) or annexin A11-immunoreactive long dystrophic neurites were observed in all cases, and neuronophagia of the Betz cells was frequently observed in two of four cases. In the lower motor system, p-TDP-43 or annexin A11-positive dystrophic neurites were detected in the anterior horn of the spinal cord. Immuno-electron microscopy of the insoluble fraction extracted from all cases showed p-TDP-43 or annexin A11-labelled filaments. In FTLD-TDP type C, neurodegeneration with TDP and annexin A11 pathology was observed mainly in the upper motor neurons of both patients with right- and left predominant temporal atrophy and a short disease duration. Furthermore, a combination of TDP-43 and annexin A11 pathology was visible in the lower motor neurons, albeit less frequently. In summary, we reported the TDP-43 and annexin A11-associated involvement of anterior horn cells of the spinal cord for the first time. The degeneration of the motor system could contribute to dysphagia and aspiration pneumonia at the late stage of FTLD-TDP type C. Little or no TDP pathology was found in the corticospinal tract, unlike in FTLD-TDP type B, suggesting the occurrence of secondary degeneration in FTLD-TDP type C.