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The ruptured blood vessels of a 57-year-old Japanese man who had died 5 days after bilateral hypertensive thalamic hemorrhage (HTH) were investigated by preparing 9 paraffin-embedded tissue blocks, all containing the hematomas. Each block was cut serially into 6-μm-thick sections. The first of every 18 sections was stained with Victoria blue and hematoxylin-eosin, the second with elastica-Goldner, and the third with phosphotungstic acid-hematoxylin. Several additional stainings, including immunostaining for α-smooth muscle actin and synaptophysin, were performed as necessary. In the large hematoma on the right, 18 cross-sections of ruptured blood vessels, comprising 12 arteries and 6 veins, were observed in the area supplied by the thalamoperforate arteries, thalamogeniculate arteries, and some of the posterior choroidal arteries. With an anteroposterior distribution, these ruptured vessels were observed in the middle third to posterior third of the thalamus, with arteries especially concentrated in the middle third. The small hematoma on the left was distributed mainly in the internal capsule. Two cross-sections of ruptured arteries, one of which had ruptured on the internal capsule side, were observed in the lateral part of the ventral posterolateral nucleus of the thalamus. In the hematomas, degeneration of medial smooth muscle cells due to arteriolosclerosis was observed in 14 cross-sections of ruptured arteries encountered, one of which showed a ruptured dissecting aneurysm. Microaneurysm or lipohyalinosis was not evident in any of them as well as the other non-ruptured arteries within the hematomas. The arteries surrounding the hematomas showed fibrinoid degeneration, lipohyalinosis, disruption of the internal elastic lamina, and degeneration and loss of smooth muscle cells in the media. Even though serial sections were examined at the rupture sites, no aneurysm-like structure was found. We concluded that HTH essentially arises from arterial wall fragility due to hypertension, and that aneurysm formation may not be essential.
Herein, we report two autopsy cases of familial ALS with a p. L127S (L126S) SOD1 variant. Case 1 involved a 62-year-old woman who presented with lower-extremity muscle weakness with lower motor neuron signs. The patient developed bulbar palsy and died of respiratory failure 9 years after onset. Case 2 (the second son of Case 1) presented with lower-extremity muscle weakness at the age of 38 years, with upper and lower motor neuron signs and died of respiratory failure 8 years after onset. The pathological findings in both cases predominantly consisted of lower motor neuron loss and degeneration of the lateral and posterior funiculi. Numerous conglomerate hyaline inclusions (CHIs) were observed in the remaining motor neurons. Vacuole formation was observed inside the inclusions, sometimes with granular structures. Some inclusions were positive for ubiquitin, p62, and SOD1. Electron microscopy revealed that CHIs were composed of neurofilaments and expanded mitochondria. By literature review, ALS with p. L127S disclosed a male-dominant incidence rate, a variety of ages at onset, and low penetrance. The initial symptom was exclusively lower limb weakness. One-third of the patients only showed lower motor neuron signs and half did not present with bulbar symptoms. The neuropathological findings commonly observed in ALS with p. L127S variants were mainly the degeneration of lower motor neurons and the sensory system, including the posterior column, Clarke's nucleus, and the associated cerebellar system. The formation of intracytoplasmic hyaline inclusions was also a prominent feature. ALS with p. L127S variant should be included in the possible diagnosis of slowly progressive muscle weakness in the lower extremities, with or without family history or upper motor neuron signs. The loss of lower motor neurons and the accumulation of neurofilaments in the remaining neurons are key to the pathological diagnosis for ALS with p. L127S variant.
Multiplication of the α-synuclein gene (SNCA) can cause familial Parkinson's disease (PD). In the present study, we investigated the neuropathological and biochemical profiles in the central and peripheral nervous systems of an autopsy case with SNCA duplication. The patient began to show gait disturbance and resting tremors at the age of 34. The motor symptoms of the patient responded well to levodopa therapy. However, the condition progressed to Hoehn and Yahr stage V at age 44, and the patient died of toxic shock syndrome at age 46. Post-mortem neuropathological examination revealed some common features of SNCA duplication, such as prominent neuronal loss in the substantia nigra and locus coeruleus, and widespread Lewy pathology from the brainstem to the neocortex. Marked Lewy neurites were also observed in the cornu Ammonis 2/3 region of the hippocampus; however, without apparent neuronal loss. Large Lewy bodies were frequently observed in the tuberomammillary nucleus of the hypothalamus. Additionally, Lewy pathology was frequently visible in the peripheral nervous system, including the sympathetic and dorsal root ganglia. Western blotting revealed bands, and immunoelectron microscopy analyses showed filaments typical of Lewy body disease in the central and peripheral nervous systems. These results show that duplication of the SNCA gene facilitates the formation of Lewy bodies in the central and peripheral nervous systems. These Lewy bodies show the same biochemical profiles as sporadic Lewy body disease.
In order to prepare specimens to clarify the anatomical localization of intracerebral hematomas (ICHs), we examined 18 autopsy cases ranging from 1 day to 2.5 months after onset: Five cases of hypertensive ICH (two cases of putaminal hematoma, one case of thalamic hematoma, one case of mixed-type hematoma, and one case of cerebellar hematoma), two cases of subarachnoid hemorrhage with ICH, three cases of cerebral amyloid angiopathy-related hemorrhage, two cases of ICH associated with blood coagulation abnormalities, and six cases of brain death with ICH (brain death period: 10 h to 13 days). Paraffin blocks containing hematomas that have hardened and have poor formalin penetration can be easily sectioned at 6 μm thickness by using Histoheme, an ammonia-based softening reagent. By mounting the sections on MAS-coated glass slides or New Silan III-coated glass slides, we were able to minimize the peeling of hematomas from the slides. Conventional staining (Klüver-Barrera staining, Elastica-Masson Goldner staining) showed decreased staining of the brain tissue surrounding the hematoma due to the effects of edema, making the localization of the hematoma unclear. Synaptophysin (SYP) immunostaining was visualized with 3,3'-diaminobenzidine tetrahydrochloride (DAB)-CoCl2 and double stained with eosin azur 50 (EA50) (DAB-CoCl2 SYP + EA50). This method revealed gray matter as black and fresh to relatively recent hematoma as red, and clearly demonstrated the anatomical localization of the hematoma without any reduction in staining due to edema. In contrast, hematomas in cases more than 29 days after onset showed heterogeneous staining in red or green, and the boundary between the brain tissue and the hematoma was unclear. However, with double staining using DAB-CoCl2 SYP and Masson Goldner staining, the hematoma stained dark red, and the boundary with the brain tissue was more clearly visible than with DAB-CoCl2 SYP + EA50.
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by progressive degeneration of both upper and lower motor neurons, along with skeletal muscles innervated by them. The identification of key molecules involved in disease pathology remains crucial for ALS, as no curative treatment is currently available. Pleiotrophin (PTN) and midkine (MK) are closely related, heparin-binding cytokines with overlapping effects. These molecules have been shown to be neuroprotective by modulating neuroinflammation, supporting neuronal survival, growth, and differentiation, and enhancing synaptic strength and plasticity. Despite their reported neuroprotective properties, the involvement of PTN and MK signaling in ALS has not been previously investigated. In this study, we characterized the expression of the PTN/MK pathway in the lumbar spinal cords (SCs) of TDP-43A315T mice across different disease stages. We report a significant upregulation of Ptn, Mdk, and its receptor protein tyrosine phosphatase zeta (Ptprz1) mRNA levels at end-stage of disease in the lumbar SC of TDP-43A315T mice compared with age-matched wild-type littermates. Protein levels of PTN and MK were also upregulated at end-stage of disease. By immunofluorescence analysis, we also observed an upregulation of the immunostaining of both cytokines in neurons, astrocytes, microglia, and pericytes-like structures at end-stage of disease in the SC of TDP-43A315T mice. These findings open a new avenue to further study the potential role of the PTN/MK signaling axis in the pathogenesis of ALS. Trial Registration: Animal Ethics Committee of the Hospital Nacional de Parapléjicos in Toledo (Spain): Approval No. 26/OH 2018.
Herein, we report an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) with a p. L127S (L126S) SOD1 variant, SMN2 deletion and one hybrid SMN. A 43-year-old Japanese man noticed muscle weakness in his left lower extremity. At the age of 51, his muscle strength was moderately diminished in the upper extremities and severely in the lower extremities with hyporeflexia. At the age of 55, he started noninvasive intermittent ventilation (NIV) during nighttime. At the age of 57, he developed dysphagia and died of pneumonia. The total clinical course was 14 years and 8 months (13 years 9 months until NIV). Pathologically we found severe loss of lower motor neurons, moderate neuronal loss in Clarke's nuclei and mild grumose degeneration of the dentate nucleus. The primary motor cortex was well preserved and the pyramidal tracts showed vague myelin pallor in the lumbar cord. There were a few conglomerate hyaline inclusions (CHIs) that were negative for Bodian staining. Immunohistochemically, CHIs were positive for phosphorylated neurofilament (pNF) and were stained with Uq and SOD1 to varying degrees. Some CHIs contained granular-like components positive for p62. A post-mortem genetic test revealed that the patient had 2 copies of SMN1, 0 copies of SMN2, and one hybrid gene with exon 1 to 7 of SMN2 and SMN1 exon 8. Additional gene research elucidated a heterozygous SOD1 p. Leu127Ser (L126S) mutation. Compared to previous reports of ALS with the same mutation, the distribution of degenerative lesions was similar. It has been suggested that SMN2 deletion may not be directly implicated in lower motor neuron pathology, but further research is needed to confirm this. Further accumulation of cases is necessary to determine the effect of SMN2 on SOD1-ALS.
Glioblastoma (GB), IDH-wildtype (IDH-wt), is the most prevalent primary malignant brain neoplasm in adults. Despite adjuvant therapy, the prognosis for these tumors remains dismal, with a median survival of around 15-18 months. Although rare, extracranial metastases from GB are reported with increasing frequency, likely due to advancements in follow-up, treatments, and improved patient survival. The molecular mechanisms driving the dissemination of GB beyond the central nervous system (CNS) remain elusive, and controversy persists regarding whether these metastasizing tumors possess distinct molecular profiles and whether patients exhibit specific clinical characteristics. We present here a detailed analysis of the molecular evolution of a GB, IDH-wt in a woman in her early forties who subsequently developed extracranial metastases to the liver and spine. This case study provides insights into the mechanisms underlying the dissemination of GB beyond the CNS. By comprehensively reviewing the molecular findings of the literature, we identified frequent TP53 mutations in the tumors at initial diagnosis, as well as evidence of the presence of different clones denoting molecular heterogeneity in those metastasizing tumors. Furthermore, a subset of younger female patients whose tumors at diagnosis present PTEN alterations acquires additional TP53 clonal alterations at recurrence and metastasis. Our findings may contribute to improved prognosis, follow-up, and treatment strategies in GB, IDH-wt patients.
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.
A surgical case of lymphoplasmacyte-rich (LPR) meningioma that arose in the region of the clivus of an 81-year-old woman is reported. The tumor consisted largely of a dense and diffuse infiltration of mature lymphocytes and a smaller number of plasma cells. Mainly in the peripheral region of the tumor, small sheets or clusters of large polygonal cells having vesicular nuclei and palely eosinophilic cytoplasm were observed. Some of these cells formed cellular whorls. These cells showed immunoreactivity for progesterone receptor, epithelial membrane antigen, somatostatin receptor type 2A, epithelial cadherin, and podoplanin, thus confirming the diagnosis of LPR meningioma. Although lymph follicles having germinal centers were not evident, the distributions of lymphocytes and plasma cells were heterogeneous, and plasma cells occasionally appeared to surround lymphocytic aggregates. Some intratumoral venules showed features of "high endothelial venules." These findings suggested that a dense accumulation of lymphocytes and plasma cells in LPR meningioma was not a simple inflammatory cell infiltration but might represent formation of "tertiary lymphoid structures." Whereas some inflammatory cells showed cytoplasmic immunoreactivity for programmed cell death ligand-1, meningioma cells did not express it.
Non-neoplastic lesions of the ependyma have been neglected to date in comparison with neoplastic lesions derived from the ependyma, that is, ependymoma. The ependyma has a simple structure: mono-layered cuboidal cells covering the surface of the cerebral ventricles and the central canal of the spinal cord. In this review, the histopathological appearances of various non-neoplastic ependymal lesions are shown based on the author's personal experience, along with a review of the relevant literature. Following the introductory remarks about the normal histology and functions of ependymal cells including tanycytes, non-neoplastic lesions are then presented including, obliteration of the spinal central canal; the "ventriculus terminalis"; shedding of ependymal cells and "granular ependymitis"; "ependymal incorporation"; ependymal cells in hydrocephalus; ependymal reactions to various noxious stimuli; ependymal changes in cerebral dysgenesis; infections involving ependymal cells; glio-ependymal cyst; and finally, various intracellular inclusions in ependymal cells. Non-neoplastic ependymal lesions are intriguing and merit further investigations, which may provide deeper understanding of various brain lesions and of ependymal neoplasms.
Multiple system atrophy (MSA) is characterized by neuronal loss with gliosis in the striatonigral and olivopontocerebellar structures, along with phosphorylated α-synuclein accumulation in oligodendroglias and neurons. Although subpial and subependymal astrocytic α-synuclein accumulation has been reported in cases of long-duration MSA, little is known regarding cerebral cortical astrocytic α-synuclein pathology in MSA. A 61-year-old woman developed dizziness and dysarthria at 38 years of age. She was diagnosed with MSA-C based on the typical neurological and imaging findings of MSA. Tracheostomy was performed at 48 years of age. Voluntary movement disappeared completely at 49 years of age. The patient died at age 61. The overall clinical course of the MSA was 22 years. The brain, weighing 780 g after fixation, showed severe atrophy, with discoloration of the brainstem, cerebellum, basal ganglia, cerebral cortex, and cerebral white matter. The substantia nigra and locus ceruleus had severe depigmentation. Microscopically, the frontotemporal regions of the cerebral cortices, striatum, pontine nucleus, inferior olivary nuclei, cerebellar white matter, and Purkinje cells had severe degeneration. The widespread occurrence of phosphorylated α-synuclein-positive neuronal and oligodendroglial inclusions, such as glial cytoplasmic inclusions, is noteworthy, leading to a definite diagnosis of MSA. Regarding astrocytic lesions, astrocyte processes-dominant α-synuclein accumulation in the cerebral cortices and amygdaloid nucleus was observed. Furthermore, several astrocytes in the cerebral white matter showed α-synuclein-positive inclusions in the periphery of the cytoplasm and proximal parts of the processes besides α-synuclein-positive subpial astrocytes in the ventral part of the brainstem. The atypical form of α-synuclein and advanced propagation of the pathogenic protein induced by a long clinical course can be implicated in the astrocytic cytopathology of MSA.
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.
Some patients with corticobasal degeneration (CBD) present with neuropsychiatric symptoms, including frontal lobe symptoms. However, stupor is rarely reported. Here, we report a case of acute restlessness at onset, which was clinically diagnosed as frontotemporal dementia (FTD) but was found to be CBD at autopsy. A 71-year-old woman with COVID-19 presented to our hospital. At the age of 62, she had suddenly become restless and confused without any preceding motor or psychiatric symptoms. She was treated with psychotropic drugs but subsequently entered stupor and was admitted to a psychiatric hospital. Magnetic resonance imaging showed mild atrophy of the frontal lobe. Single-photon emission computed tomography showed decreased blood flow in the frontal lobe, and the patient was clinically diagnosed with FTD. At the age of 71, she was transferred to our hospital from a psychiatric hospital for COVID-19 treatment. Upon transfer to our hospital, the patient presented with akinetic mutism. The patient died of respiratory failure 10 days after the onset of COVID-19. Immunostaining with AT8 and RD4 antibodies revealed astrocytic plaques, pretangles, coiled bodies, and threads, predominantly in the frontal lobes and basal ganglia. Other pathologies include accumulation of pTDP43 in the basal ganglia, thalamus, and frontal lobes. Argyrophilic grains were observed in the amygdala and the hippocampus, which corresponded to Saito stage 2. Other neurodegenerative proteins, such as amyloid β or α-synuclein, were not observed. The patient was pathologically diagnosed with CBD. We present a rare autopsy case involving a patient with CBD who presented with acute psychiatric symptoms and stupor. The psychiatric symptoms were characterized by agitation and fear-related behavior, which differ from the disinhibition and antisocial behavior typically associated with frontal lobe symptoms. Further autopsies are needed to examine the extent of tau pathology spread and accumulation to better understand the psychiatric symptoms of CBD.
We present the case of an 81-year-old man diagnosed with probable amyotrophic lateral sclerosis (ALS) based on the Updated Awaji criteria. The patient exhibited progressive motor neuron degeneration with muscle weakness, atrophy, and fasciculations primarily in the right lower limb and later extending to the right upper limb. Three months after being referred to a home care clinic, he collapsed in front of his family members and died. An autopsy revealed phosphorylated TDP-43 pathology consistent with ALS, with involvement of the hypoglossal nucleus, facial nerve nucleus, and medulla oblongata. Interestingly, widespread a-synuclein pathology indicative of diffuse neocortical type Lewy body disease (LBD; Braak stage 6) was identified, despite the absence of clinical parkinsonism or dementia with Lewy bodies (DLB) during his lifetime. The presence of autonomic symptoms such as constipation and urinary retention shortly before death may be attributable to a-synuclein pathology affecting the autonomic nervous system. The coexistence of ALS and LBD underscores the clinical challenge of diagnosing overlapping pathologies, as motor symptoms may obscure signs of LBD. Dopamine transporter imaging or MIBG myocardial scintigraphy might aid in identifying preclinical LBD in ALS patients with atypical symptoms. The patient died of respiratory failure due to extensive organizing pneumonia, but the possibility of sudden cardiac arrest could not be excluded. This case highlights the potential for coexisting neurodegenerative pathologies in ALS, emphasizing the importance of comprehensive evaluation when autonomic symptoms or other atypical features are present.
We performed a systematic review of the literature to better define the scope of MYB alterations in angiocentric glioma and their associated clinical characteristics, as well as to include a novel MYB mutation in an angiocentric glioma case. We also review MYB alterations in the context of oncologic disease. Following PRISMA guidelines, we searched PubMed and Web of Science for relevant literature from 2010 to October 2024. Included articles reported original data on human subjects with angiocentric glioma and a detected MYB mutation. We include one additional angiocentric glioma case showcasing a novel MYB mutation. A total of 14 studies met the inclusion criteria, with a total of 114 patients with individual data for pooled analysis. The mean age was 10.3 years (SD ±9.7 years); 60% of patients were male. MYB::QKI was the most common fusion in 68% of patients. Other MYB mutations included MYB rearrangements, MYB::ESR1, MYB::PCDHGA1, MYB::LOC105378099, and MYB::MMP16. The most common anatomical location was in the cerebral cortex in 68% of patients. MYB fusions in other relevant neuro-oncologic diseases highlight the importance of MYB fusions in adenoid cystic carcinomas, which frequently occur at the skull base, head and neck, and breast. In conclusion, we characterize the breadth of angiocentric glioma patterns in terms of demographics, anatomic location, and MYB fusion patterns. The updated molecular diagnosis of angiocentric glioma as of 2021 warrants continued exploration of the scope of MYB oncogene fusions as drivers of prognosis and targets for future therapies.
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.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by a late onset and slow progression caused by a premutation (55-200 CGG repeat) in the fragile X mental retardation (FMR1) gene. Here, we report the case of a Japanese patient with FXTAS which is the first case autopsied in Japan. The patient was a 74-year-old man with a family history of fragile X syndrome at the time of death. The clinical features included postural tremors, mild cognitive decline, and ataxia. Magnetic resonance imaging (MRI) showed a high-intensity lesion in the bilateral middle cerebellar peduncles and deep white matter around the ventricle on T2-weighted images. A gene analysis revealed that the patient had a pre-mutation of the CGG expansion (83 CGG repeats) in the FMR1 gene. Neuropathologically, ubiquitin- and p62-positive intranuclear inclusions were widely present, especially in the hippocampus. The middle cerebellar peduncle (MCP), where the "MCP sign" was seen on MRI, showed marked spongiosis with accompanied demyelination and axon loss, and a similar pathology was seen in the cerebral and cerebellar white matter. In an electron microscopy study, intranuclear inclusions were found to consist of a non-membrane-bound filamentous material. The clinical, MRI, and neuropathological findings were similar to those of neuronal intranuclear inclusion disease. Awareness of the disease is gradually increasing, and the number of autopsy cases is likely to increase, contributing to the elucidation of the pathology and development of treatments.
We report an autopsy case of a man in his early 80s who was found deceased, submerged in a bathtub at home. He had no history of regular medical care or smoking. One month before death, he experienced vomiting, malaise, and reduced appetite; however, due to limited clinical information, it was unclear whether he exhibited symptoms suggestive of cerebellar dysfunction. The autopsy showed fibrinous pericarditis resulted from left atrial metastasis from lung squamous cell carcinoma (LSCC) originating in the left lower lobe, which was determined to be the cause of death. Neuropathological examination exhibited no gross abnormalities in the cerebrum or brainstem; however, mild atrophy of the cerebellar vermis, extending from the lobulus centralis to the culmen, was observed. Histologically, focal loss of Purkinje cells accompanied by gliosis was noted, predominantly affecting the superficial layers of the superior vermis and simple lobule, while other cerebellar regions were largely preserved. Mild-to-moderate CD8-positive T-lymphocyte-predominant perivascular infiltration was present in the cerebellar white matter and leptomeninges, whereas no significant inflammation was detected in the cerebrum or brainstem. No abnormal protein aggregates (phosphorylated tau, α-synuclein, polyglutamine, or p62) were identified in the cerebellum. Postmortem serum testing revealed the presence of anti-amphiphysin antibodies. Collectively, although the clinical manifestations were unclear and a definitive diagnosis remains difficult, these findings support a pathological diagnosis of paraneoplastic cerebellar degeneration (PCD) associated with previously undiagnosed LSCC. Although autopsy data are limited, the preferential involvement of the superficial superior vermis may represent an early-stage pattern of PCD. This case highlights the importance of autopsy with detailed neuropathological examination in patients with malignancy, even when cerebellar symptoms are mild or absent and imaging or gross abnormalities are lacking. To our knowledge, this is the first reported autopsy case of anti-amphiphysin antibody-associated PCD in association with LSCC.
Isocitrate dehydrogenase (IDH) mutations and KIAA1549::BRAF fusions are traditionally regarded as independent and mutually exclusive genetic events in gliomas. IDH mutations are hallmark features of diffuse gliomas in adults, while KIAA1549::BRAF fusions are characteristic of pediatric pilocytic astrocytomas and diffuse leptomeningeal glioneuronal tumors (DLGNTs). This report presents a rare case of a 31-year-old male with diffuse astrocytoma, CNS WHO Grade 4, exhibiting co-occurrence of an IDH1 mutation (p.R132L) and KIAA1549::BRAF fusion, identified via next-generation sequencing. Histopathology revealed a diffusely infiltrating glial tumor with high mitotic activity, endothelial proliferation, and necrosis. Immunohistochemistry supported the diagnosis, showing ATRX loss, diffuse p53 positivity, and a high Ki67 index. Molecular profiling confirmed the IDH1 mutation, TP53 mutation, CDKN2A loss, and the rare KIAA1549::BRAF fusion. Fluorescence in situ hybridization also confirmed the KIAA1549::BRAF fusion. The coexistence of these alterations challenges the conventional view of mutual exclusivity, highlighting the need for comprehensive molecular profiling in gliomas. IDH mutations lead to oncometabolite accumulation, while KIAA1549::BRAF fusion activates the MAPK pathway. This dual alteration necessitates multimodal therapeutic approaches targeting both pathways. This case emphasizes the importance of integrated diagnostics in glioma classification and personalized treatment, with further research needed to explore the implications of such rare co-occurrences.
Low-grade glioneuronal tumors of the cranial nerves are rare, with only a few case reports describing their association with trigeminal neuralgia and no prior reports including genetic analysis. We present a case of a low-grade glioneuronal tumor located adjacent to the trigeminal nerve root in a 70-year-old man who had been experiencing severe left-sided trigeminal neuralgia for several months. He had initially presented with cranial polyneuropathy, for which oral steroid therapy was initiated. Magnetic resonance imaging of the head revealed the left superior cerebellar artery running near the left trigeminal nerve; however, no mass lesions were detected. During microvascular decompression, an 8-mm white tumor was identified on the trigeminal nerve and subsequently removed. Histopathological examination of the surgical specimen revealed round tumor cells with slightly eosinophilic or vacuolated cytoplasm, arranged in nests or rosettes. Foci of calcification, hemorrhage, and hemosiderin deposition were present, but eosinophilic granular bodies, Rosenthal fibers, necrosis, pleomorphism, or mitosis was absent. The tumor cells were immunopositive for synaptophysin and anti-Neuronal Nuclei, focally positive for glial fibrillary acidic protein and S-100 protein, and immunonegative for Olig2 and epithelial membrane antigen, with a Ki-67 labeling index of < 1%. Molecular analyses confirmed the fusion of KIAA1549 exon 16 with BRAF exon 9, with no mutations detected in IDH1/2, H3F3A, BRAF (V600), or FGFR1. These findings provide novel molecular and embryological insights into low-grade glioneuronal tumors of the trigeminal nerve, which may aid in their classification and understanding of the development of the tumor and neuralgia.