RESUMO
V-ATPase is an ATP hydrolysis-driven proton pump involved in the acidification of intracellular organelles and systemic acid-base homeostasis through H+ secretion in the renal collecting ducts. V-ATPase dysfunction is associated with hereditary distal renal tubular acidosis (dRTA). ATP6V1B1 encodes the B1 subunit of V-ATPase that is integral to ATP hydrolysis and subsequent H+ transport. Patients with pathogenic ATP6V1B1 mutations often exhibit an early onset of sensorineural hearing loss. However, the mechanisms underlying this association remain unclear. We employed morpholino oligonucleotide-mediated knockdown and CRISPR/Cas9 gene editing to generate Atp6v1ba-deficient (atp6v1ba-/-) zebrafish as an ortholog model for ATP6V1B1. The atp6v1ba-/- zebrafish exhibited systemic acidosis and significantly smaller otoliths compared to wild-type siblings. Moreover, deficiency in Atp6v1ba led to degeneration of inner ear hair cells, with ultrastructural changes indicative of autophagy. Our findings indicate a critical role of ATP6V1B1 in regulating lysosomal pH and autophagy in hair cells, and the results provide insights into the pathophysiology of sensorineural hearing loss in dRTA. Furthermore, this study demonstrates that the atp6v1ba-/- zebrafish model is a valuable tool for further investigation into disease mechanisms and potential therapies for acidosis-related hearing impairment.
Assuntos
Acidose Tubular Renal , Acidose , Perda Auditiva Neurossensorial , Compostos Organometálicos , ATPases Vacuolares Próton-Translocadoras , Animais , Humanos , Peixe-Zebra/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , ATPases Vacuolares Próton-Translocadoras/metabolismo , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Mutação , Acidose Tubular Renal/genética , Células Ciliadas Auditivas/patologia , Concentração de Íons de Hidrogênio , Cabelo/metabolismo , Trifosfato de AdenosinaRESUMO
The DHCR7 enzyme converts 7-DHC into cholesterol. Mutations in DHCR7 can block cholesterol production, leading to abnormal accumulation of 7-DHC and causing Smith-Lemli-Opitz syndrome (SLOS). SLOS is an autosomal recessive disorder characterized by multiple malformations, including microcephaly, intellectual disability, behavior reminiscent of autism, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD)-like hyperactivity. Although 7-DHC affects neuronal differentiation in ex vivo experiments, the precise mechanism of SLOS remains unclear. We generated Dhcr7 deficient (dhcr7-/-) zebrafish that exhibited key features of SLOS, including microcephaly, decreased neural stem cell pools, and behavioral phenotypes similar to those of ADHD-like hyperactivity. These zebrafish demonstrated compromised myelination, synaptic anomalies, and neurotransmitter imbalances. The axons of the dhcr7-/- zebrafish showed increased lysosomes and attenuated autophagy, suggesting that autophagy-related neuronal homeostasis is disrupted.
Assuntos
Axônios , Colesterol , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Peixe-Zebra , Animais , Autofagia , Axônios/metabolismo , Colesterol/metabolismo , Lisossomos/metabolismo , Neurogênese , Neurônios/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/deficiência , Síndrome de Smith-Lemli-Opitz/metabolismo , Síndrome de Smith-Lemli-Opitz/genética , Síndrome de Smith-Lemli-Opitz/patologia , Peixe-Zebra/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
AIMS: Corticobasal degeneration (CBD) is a rare neurodegenerative disorder. The status of the inferior olivary nucleus (ION) in CBD has been inadequately investigated. In this study, we conducted a pathological investigation of the ION in CBD. MATERIALS AND METHODS: We reviewed the data of Japanese patients with pathologically confirmed CBD who underwent consecutive autopsies between 1985 and 2020 at our institute. We retrospectively examined clinical data from medical records and clinicopathological conferences and semi-quantitatively assessed the ION, central tegmental tract, superior cerebellar peduncle, and dentate nucleus. RESULTS: Of the 32 patients included, 14 (43.8%) had hypertrophy of the ION (HION), of whom 6 showed laterality. In the 14 HION cases, with or without laterality, except in 1 unevaluable case, atrophy/myelin pallor of the central tegmental tract was observed on the same side as the hypertrophy. Ten patients with HION, with or without laterality, had atrophy/myelin pallor of the superior cerebellar peduncle on the contralateral side to the hypertrophy. CONCLUSION: The ION presents with hypertrophic changes in CBD. The lesion is a primary degeneration in CBD and is related to the degeneration of the Guillain-Mollaret triangle. This finding contributes to the elucidation of the specific pathological characteristics of CBD.
Assuntos
Degeneração Corticobasal , Hipertrofia , Núcleo Olivar , Humanos , Núcleo Olivar/patologia , Feminino , Masculino , Hipertrofia/patologia , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Degeneração Corticobasal/patologia , Complexo Olivar InferiorRESUMO
We report an autopsy case of a 70-year-old man who was clinically diagnosed with atypical progressive supranuclear palsy (PSP). He initially presented with gait ataxia and then showed vertical gaze palsy, rigidity, akinesia, dysphagia, and mild cognitive impairment, followed by prominent upper motor signs later in the course of the disease. Cranial magnetic resonance imaging revealed tegmental atrophy of the midbrain. Autopsy revealed severe neuronal loss and gliosis in the motor cortex and corticospinal degeneration and mild to moderate neuronal loss and gliosis in the basal ganglia, substantia nigra, midbrain, and pons. Tufted astrocytes were primarily found in the motor cortex and basal ganglia. Globose-type neurofibrillary tangles were observed in the locus coeruleus and nucleus olivaris inferior. In the cerebellar cortex, mild Purkinje cell loss and scattered axonal torpedoes were observed with tau-positive Purkinje cells. The dentate nucleus displayed severe neuronal loss and gliosis. The present case showed characteristics of both PSP with prominent cerebellar ataxia (PSP-C) and PSP-primary lateral sclerosis (PSP-PLS).
RESUMO
TDP-43 is mislocalized from the nucleus and aggregates within the cytoplasm of affected neurons in cases of amyotrophic lateral sclerosis. TDP-43 pathology has also been found in brain tissues under non-amyotrophic lateral sclerosis conditions, suggesting mechanistic links between TDP-43-related amyotrophic lateral sclerosis and various neurological disorders. This study aimed to assess TDP-43 pathology in the spinal cord motor neurons of tauopathies. We examined 106 spinal cords from consecutively autopsied cases with progressive supranuclear palsy (n = 26), corticobasal degeneration (n = 12), globular glial tauopathy (n = 5), Alzheimer's disease (n = 21) or Pick's disease (n = 6) and neurologically healthy controls (n = 36). Ten of the progressive supranuclear palsy cases (38%) and seven of the corticobasal degeneration cases (58%) showed mislocalization and cytoplasmic aggregation of TDP-43 in spinal cord motor neurons, which was prominent in the cervical cord. TDP-43 aggregates were found to be skein-like, round-shaped, granular or dot-like and contained insoluble C-terminal fragments showing blotting pattern of amyotrophic lateral sclerosis or frontotemporal lobar degeneration. The lower motor neurons also showed cystatin-C aggregates, although Bunina bodies were absent in haematoxylin-eosin staining. The spinal cord TDP-43 pathology was often associated with TDP-43 pathology of the primary motor cortex. Positive correlations were shown between the severities of TDP-43 and four-repeat (4R)-tau aggregates in the cervical cord. TDP-43 and 4R-tau aggregates burdens positively correlated with microglial burden in anterior horn. TDP-43 pathology of spinal cord motor neuron did not develop in an age-dependent manner and was not found in the Alzheimer's disease, Pick's disease, globular glial tauopathy and control groups. Next, we assessed SFPQ expression in spinal cord motor neurons; SFPQ is a recently identified regulator of amyotrophic lateral sclerosis/frontotemporal lobar degeneration pathogenesis, and it is also reported that interaction between SFPQ and FUS regulates splicing of MAPT exon 10. Immunofluorescent and proximity-ligation assays revealed altered SFPQ/FUS-interactions in the neuronal nuclei of progressive supranuclear palsy, corticobasal degeneration and amyotrophic lateral sclerosis-TDP cases but not in Alzheimer's disease, Pick's disease and globular glial tauopathy cases. Moreover, SFPQ expression was depleted in neurons containing TDP-43 or 4R-tau aggregates of progressive supranuclear palsy and corticobasal degeneration cases. Our results indicate that progressive supranuclear palsy and corticobasal degeneration may have properties of systematic motor neuron TDP-43 proteinopathy, suggesting mechanistic links with amyotrophic lateral sclerosis-TDP. SFPQ dysfunction, arising from altered interaction with FUS, may be a candidate of the common pathway.
Assuntos
Doença de Alzheimer , Esclerose Lateral Amiotrófica , Degeneração Corticobasal , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Doença de Pick , Paralisia Supranuclear Progressiva , Proteinopatias TDP-43 , Tauopatias , Proteínas de Ligação a DNA , Humanos , Neurônios Motores , Proteínas tauRESUMO
Progressive supranuclear palsy (PSP) can be diagnosed despite the presence of asymmetrical parkinsonism depending on the clinical diagnostic criteria. Some studies have reported that atrophy of the superior cerebellar peduncle (SCP) is more frequent in PSP than in Parkinson's disease. There have also been reports of PSP cases with an asymmetrically atrophic SCP. Therefore, we analyzed 48 specimens from consecutive autopsy cases that were neuropathologically diagnosed as PSP to investigate the laterality of brain lesions, including the SCP. We measured the width of the SCP and evaluated the laterality of atrophy. We semi-quantitatively evaluated neuronal loss, atrophy/myelin pallor, and tau pathology in three steps. Asymmetrical atrophy of the SCP was present in seven (14.6%) of 48 cases. The atrophic side of the SCP corresponded to the dominant side of the tau pathology in the cerebellar dentate nucleus. It was opposite to the dominant side of the myelin pallor and tau pathology in the red nucleus and of the tau pathology in the central tegmental tract and inferior olivary nucleus, coinciding with the neurologically systematic anatomy of the Guillain-Mollaret triangle. Neurodegeneration of PSP can progress asymmetrically from one side to the initially intact side in PSP with an initial predominance of Richardson's syndrome, progressive gait freezing, ocular motor dysfunction, parkinsonism, or corticobasal syndrome. To our knowledge, no previous study has reported asymmetrical PSP neuropathology; this is the first study to report the presence of PSP cases with asymmetrical SCP atrophy and systematically asymmetrical degeneration of the Guillain-Mollaret triangle.
Assuntos
Transtornos Parkinsonianos , Tegmento Pontino , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/complicações , Paralisia Supranuclear Progressiva/patologia , Palidez/patologia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/patologia , Tegmento Pontino/patologia , Atrofia/patologiaRESUMO
The transactive response DNA-binding protein of 43 kDa (TDP-43) is a pathological protein of amyotrophic lateral sclerosis (ALS). TDP-43 pathology is characterized by a combination of the cytoplasmic aggregation and nuclear clearance of this protein. However, the mechanisms underlying TDP-43 pathology have not been fully clarified. The aim of this study was to evaluate the relationships between the expression level of nuclear TDP-43 and the pathological properties of cytoplasmic aggregates in autopsied ALS cases. We included 22 consecutively autopsied cases with sporadic TDP-43-related ALS. The motor neuron systems were neuropathologically assessed. We identified 790 neurons with cytoplasmic TDP-43 inclusions from the lower motor neuron system of included cases. Nuclear TDP-43 disappeared in 84% (n = 660) and expressed in 16% (n = 130) of neurons with cytoplasmic inclusions; the former was defined as TDP-43 cytoplasmic immunoreactivity (c-ir), and the latter was defined as nuclear and cytoplasmic immunoreactivity (n/c-ir). Morphologically, diffuse cytoplasmic inclusions were significantly more prevalent in TDP-43 n/c-ir neurons than in c-ir neurons, while skein-like and round inclusions were less prevalent in n/c-ir neurons. The cytoplasmic inclusions of TDP-43 n/c-ir neurons were phosphorylated but poorly ubiquitylated when compared with those of c-ir neurons. TDP-43 n/c-ir neurons became less dominant than the c-ir neurons among cases with a prolonged disease duration. The expression level of nuclear TDP-43 was significantly lower in n/c-ir neurons than in normal neurons without cytoplasmic inclusions. Our results indicate that the maturation of cytoplasmic TDP-43 inclusions correlates with the depletion of nuclear TDP-43 in each affected neuron. This finding supports the view that an imbalance between nuclear and cytoplasmic TDP-43 may be an essential pathway to TDP-43 pathology.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/metabolismo , UbiquitinaçãoRESUMO
The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.
Assuntos
Doença por Corpos de Lewy , Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Tauopatias , Humanos , Doença por Corpos de Lewy/patologia , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/patologia , Transtornos Parkinsonianos/diagnóstico , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/patologiaRESUMO
We report an autopsy case of multiple sclerosis (MS) manifesting as a long spinal cord lesion. The patient was a Japanese woman. At the age of 59 years, she presented with a one-month history of progressive paraplegia, dysesthesia in the lower extremities, and urinary retention. Magnetic resonance imaging revealed a long, hyperintense lesion on T2-weighted images that extended from the inferior portion of the medulla oblongata to the cervical segments of the spinal cord and an isolated lesion at the T6 level. Cerebrospinal fluid (CSF) examination revealed the presence of oligoclonal bands and increased myelin basic protein levels (999 pg/mL). Serum antibody against aquaporin 4 (AQP4) was undetectable in this patient. She was diagnosed as having atypical MS and experienced symptom improvement following immunotherapy with corticosteroids and plasma exchange. She died of pneumonia and renal failure at the age of 62 years. Postmortem examination revealed a long demyelinating lesion that extended from the inferior portion of the medulla oblongata to the sacral segments of the spinal cord. The lesion was comprised of numerous demyelinating plaques with inflammatory cell infiltration. A long spinal cord lesion is usually indicative of neuromyelitis optica spectrum disorder (NMOSD), and there are limited reports of postmortem observations of long spinal cord lesions among patients with anti-AQP4 antibody-seronegative MS. Our findings suggest that the pathomechanisms of such long spinal cord lesion formation differ between anti-AQP4 antibody-seronegative MS and NMOSD.
Assuntos
Esclerose Múltipla , Neuromielite Óptica , Aquaporina 4 , Autoanticorpos/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/patologia , Medula Espinal/patologiaRESUMO
Neurolymphomatosis is a neurological manifestation of lymphoma that involves the cranial or spinal peripheral nerves, nerve roots, and plexus with direct invasion of neoplastic cells. Neurolymphomatosis is rare among patients with low-grade lymphoma. We report an autopsied case of neurolymphomatosis that arose from follicular lymphoma. A 49-year-old woman who presented with pain of her neck and shoulder and numbness of her chin. Computed tomography revealed enlarged lymph nodes in her whole body, and biopsy from the axillary lymph node revealed grade 2 follicular lymphoma. Although the patient underwent chemotherapy, she gradually developed muscle weakness in the upper limbs and sensory disturbances of the trunk and limbs. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed increased tracer uptake of the cervical nerve roots. Repeated FDG-PET after additional therapy revealed progression of disease within the nerve roots and brachial plexus, whereas gadolinium-contrast magnetic resonance imaging (MRI) showed weak enhancement of the cervical nerve roots without formation of mass lesions. She died after a total disease duration of 12 months. Postmortem observations revealed invasion of lymphoma cells into the cervical nerve roots, dorsal root ganglia, and subarachnoid spaces of the spinal cord. Neurolymphomatosis was prominent at the segments of C6-Th2. Combined loss of axons and myelin sheaths was observed in the cervical nerve roots and posterior columns. Lymphoma cells also invaded the cranial nerves. The subarachnoid and perivascular spaces of the brain demonstrated focal invasion of the lymphoma. Mass lesions were not observed in the central nervous system. The lymphoma cells did not show histological transformation to higher grades, and the density of the centroblasts remained at grade 2. Our report clarifies that low-grade follicular lymphoma can manifest as neurolymphomatosis and central nervous system invasion in the absence of transformation toward higher histological grades. FDG-PET may be more sensitive to non-mass-forming lesions, including neurolymphomatosis, than gadolinium-contrast MRI.
Assuntos
Linfoma Folicular , Neurolinfomatose , Autopsia , Feminino , Fluordesoxiglucose F18 , Gadolínio , Humanos , Pessoa de Meia-Idade , Neurolinfomatose/patologiaRESUMO
BACKGROUND: Mutations in PRKN are the most common cause of autosomal recessive juvenile parkinsonism. The objective of this study was to investigate the association between genotype and pathology in patients with PRKN mutations. METHODS: We performed a sequence and copy number variation analysis of PRKN, mRNA transcripts, Parkin protein expression, and neuropathology in 8 autopsied patients. RESULTS: All the patients harbored biallelic PRKN mutations. Two patients were homozygous and heterozygous, respectively, for the missense mutation p.C431F. Seven patients had exon rearrangements, including 2 patients from a single family who harbored a homozygous deletion of exon 4, and 3 patients who carried a homozygous duplication of exons 6-7, a homozygous duplication of exons 10-11, and a heterozygous duplication of exons 2-4. In the other 2 patients, we found a compound heterozygous duplication of exon 2, deletion of exon 3, and a heterozygous duplication of exon 2. However, sequencing of cDNA prepared from mRNA revealed 2 different transcripts derived from triplication of exon 2 and deletion of exons 2-3 and from duplication of exons 2-4 and deletion of exons 3-4. Western blotting and immunohistochemistry revealed faint or no expression of Parkin in their brains. In the substantia nigra pars compacta, a subfield-specific pattern of neuronal loss and mild gliosis were evident. Lewy bodies were found in 3 patients. Peripheral sensory neuronopathy was a feature. CONCLUSIONS: Genomic and mRNA analysis is needed to identify the PRKN mutations. Variable mutations may result in no or little production of mature Parkin and the histopathologic features may be similar. © 2021 International Parkinson and Movement Disorder Society.
Assuntos
Variações do Número de Cópias de DNA , Ubiquitina-Proteína Ligases , Variações do Número de Cópias de DNA/genética , Homozigoto , Humanos , Mutação/genética , Deleção de Sequência , Ubiquitina-Proteína Ligases/genéticaRESUMO
The hot cross bun (HCB) sign encompasses a cross-shaped hyperintensity area in the pons on axial T2-weighted magnetic resonance imaging (MRI). The HCB sign is characteristic of multiple system atrophy (MSA) and has occasionally been observed in other neurological disorders. Here, we report an autopsied case of corticobasal degeneration (CBD) that showed the HCB sign. A female patient presented with progressive gait disturbance and cognitive impairment at the age of 60 years. A neurological examination revealed dysarthria, muscle rigidity of the limbs, akinesia, truncal ataxia, urinary incontinence, and dementia. The HCB sign was observed on a brain MRI at the age of 65 years, and a clinical diagnosis of possible MSA was made. She died of pneumonia at the age of 67 years. A postmortem observation, provided neuropathological findings characteristic of CBD, including the presence of astrocytic plaques, pretangles, neuropil threads, and ballooned neurons in association with four-repeat-tau aggregation. Interestingly, the pons displayed severe neuronal loss and astrogliosis that were prominent in the pontine and raphe nuclei. Myelin sheath depletion was prominent in the transverse fibers of the pontine base and the myelinated fibers of the pontine tegmentum in contrast to relative sparing of the pontine corticospinal tract and medial lemniscus. The cerebellar dentate nucleus exhibited neuronal loss and grumose degeneration. Western blot analysis of sarkosyl-insoluble fractions from brain tissue lysates using an anti-phosphorylated tau antibody identified immunoreactive signal bands in approximately 37-40, 43, 64, and 68 kDa, consistent with CBD. Genetic analysis did not reveal any known pathogenic mutations in the microtubule-associated protein tau gene (MAPT). Our case was characterized by the HCB sign and concordant neuropathological changes in the pons. CBD should be considered an underlying pathology of the HCB sign, even though the pontocerebellar changes would be unusual in CBD cases.
Assuntos
Degeneração Corticobasal , Atrofia de Múltiplos Sistemas , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Filamentos do Neurópilo , PonteRESUMO
We report clinicopathological findings of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes/Leigh syndrome (MELAS/LS) associated with a novel m.3482A>G mutation in MT-ND1. A 41-year-old woman had experienced multiple stroke-like episodes since age 16. She developed akinetic mutism two months before admission to our hospital. Neurological examination revealed akinetic mutism, bilateral deafness, and muscular atrophy. Cerebrospinal fluid tests revealed elevated pyruvate and lactate levels. Fluid-attenuated inversion recovery images on magnetic resonance imaging showed hyperintense areas in the right frontal and both sides of temporal and occipital lobes, both sides of the striatum, and the midbrain. Muscle biopsy revealed strongly succinate dehydrogenase-reactive blood vessels. L-arginine therapy improved her consciousness and prevented further stroke-like episodes. However, she died from aspiration pneumonia. Postmortem autopsy revealed scattered infarct-like lesions with cavitation in the cerebral cortex and necrotic lesions in the striatum and midbrain. The patient was pathologically confirmed as having MELAS/LS based on two characteristic clinicopathological findings: presenting MELAS/LS overlap phenotype and effectiveness of L-arginine treatment.
Assuntos
Acidose Láctica/patologia , Doença de Leigh/patologia , Encefalomiopatias Mitocondriais/patologia , Mutação , NADH Desidrogenase , Acidente Vascular Cerebral/patologia , Acidose Láctica/complicações , Acidose Láctica/genética , Adulto , Evolução Fatal , Feminino , Humanos , Doença de Leigh/complicações , Doença de Leigh/genética , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/genética , Mutação/genética , NADH Desidrogenase/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genéticaRESUMO
We report a case of early-phase sporadic Creutzfeldt-Jakob disease (sCJD) complicated by intracerebral hemorrhage (ICH), classified as MM1 + 2C-type based on autopsy. A 61-year-old Japanese man presented to our hospital with speaking difficulties including repeated usage of the same words. He was hospitalized on the seventh day after symptom onset, and diffusion-weighted images on magnetic resonance imaging showed hyperintense regions in the frontal cortex and caudate nucleus. On the 11th day after symptom onset, head computed tomography revealed ICH in the right occipital and parietal lobes. Routine laboratory evaluations and angiography revealed no cause of ICH. Myoclonus of the extremities and drowsiness were observed on the 15th day after symptom onset. He reached the state of akinetic mutism approximately two months after symptom onset. The cerebrospinal fluid test revealed positive real-time quaking-induced conversion and 14-3-3 protein. Electroencephalography revealed periodic sharp wave complexes. A clinical diagnosis of probable Creutzfeldt-Jakob disease was made according to the diagnostic criteria. After a relapse of pneumonia, he passed away on the 103rd day after symptom onset. Postmortem examination revealed ICH in the right posterior cingulate gyrus. No pathological change that might have caused ICH was obtained. Although the effect of sCJD on the onset of ICH is undeniable, the cause of ICH was unknown. Prion protein immunohistochemistry revealed the following results: (1) weak synaptic-type deposits in the tissue rarefacted by ICH; (2) synaptic-type deposits in the cerebral cortex, which showed fine vacuoles; and (3) perivacuolar-type deposits in the inferior temporal gyrus and lingual gyrus, which showed frequent large confluent vacuoles. Although it could be considered MM1-type sCJD clinically, this case was neuropathologically diagnosed as having MM1 + 2C-type sCJD. It was shown that ICH may occur in early-phase sCJD. To improve sCJD prognosis, treatment of complications and careful follow up are important. Furthermore, pathological diagnosis is indispensable for sCJD type diagnosis.
Assuntos
Hemorragia Cerebral/etiologia , Hemorragia Cerebral/patologia , Síndrome de Creutzfeldt-Jakob/complicações , Síndrome de Creutzfeldt-Jakob/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We present an autopsied case with A8344G-mutated myoclonus epilepsy with ragged red fibers (MERRF)/mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) overlap syndrome accompanied by stroke-like episodes localized to the precentral gyrus. A 16-year-old Japanese woman suddenly experienced repetitive consciousness disturbances with increased serum lactate and creatine kinase levels. Magnetic resonance imaging showed abnormal intensity of bilateral precentral gyrus. She was clinically diagnosed as having a mitochondrial disorder and the A8344G mutation was detected in mitochondrial DNA. At 17 years of age, she died from congestive heart failure secondary to a third episode of lactic acidosis. Neuropatho-logically, multifocal laminar necrosis, which is responsible for stroke-like episodes in MELAS, was seen in the frontal cortex including the precentral gyrus, but there was no neuronal loss and gliosis in the basal ganglia, cerebellum, and brainstem, which were compatible with MERRF. Hypertrophy of the vascular smooth muscle and choroidal epithelium were seen, and were strongly visualized by an anti-mitochondrial antibody. Skeletal muscles showed uneven muscular diameters, increased central nuclei, and ragged red fibers (RRFs). Decreased cytochrome c oxidase (COX) activity and strongly succinate dehydrogenase (SDH)-reactive blood vessels were also noted. Stroke-like episodes in MERRF/MELAS overlap syndrome are thought to be rare in the frontal cortex including the precentral gyrus. Only two cases of MERRF/MELAS overlap syndrome with A8344G mutation, including this case, have shown stroke-like episodes in the frontal lobes. Other than the A8344G mutation and frontal lobe involvement, they had a high degree of similarity in terms of presence of RRFs, gastrointestinal dysfunction, and lack of typical MERRF neuropathology. In conclusion, this is an important case describing the clinical spectrum associated with A8344G-mutated MERRF/MELAS overlap syndrome.
Assuntos
Lobo Frontal/diagnóstico por imagem , Síndrome MELAS/diagnóstico por imagem , Síndrome MERRF/diagnóstico por imagem , Acidente Vascular Cerebral/diagnóstico por imagem , Adolescente , Autopsia , Feminino , Lobo Frontal/patologia , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/patologia , Síndrome MERRF/complicações , Síndrome MERRF/patologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/patologiaRESUMO
We encountered an autopsy case of sporadic Creutzfeldt-Jakob disease (CJD) pathologically classified as MM1+2C-type, where Western blot analysis of prion protein (PrP) mainly showed type-1 scrapie PrP (PrPSc ) but also, partially, mixed type-2 PrPSc . A Japanese woman complained of visual disorder at the age of 86 years and then showed disorientation and memory disturbances. Magnetic resonance imaging (MRI) showed cerebral cortical hyperintensity on diffusion-weighted images. The patient died 2 months after the onset of symptoms; her condition did not reach the akinetic mutism state and periodic sharp-wave complexes on electroencephalography and myoclonus were not recognized. The brain weighed 1100 g and neuropathological examination showed extensive fine vacuole-type spongiform changes in the cerebral cortex. In some cortical regions, large confluent vacuole-type spongiform changes were also present. Gliosis and hypertrophic astrocytosis were generally mild, and tissue rarefaction of the neuropil and neuronal loss were not apparent. PrP immunostaining showed diffuse synaptic-type PrP deposition in the cerebral gray matter, but some regions with large confluent vacuoles showed perivacuolar-type deposition. We speculated, based on the clinicopathological findings and previous reports, that most MM1-type sporadic CJD cases may be associated with type-2 PrPSc , at least partially, within certain regions of the cerebrum.
Assuntos
Síndrome de Creutzfeldt-Jakob/classificação , Síndrome de Creutzfeldt-Jakob/diagnóstico por imagem , Idoso de 80 Anos ou mais , Autopsia , Síndrome de Creutzfeldt-Jakob/patologia , Evolução Fatal , Feminino , HumanosRESUMO
Comprehensive analysis is required for the accurate diagnosis of MV2-type sporadic Creutzfeldt-Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy-confirmed MV2K-type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion-weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole-type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic-type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal-type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque-type PrP with synaptic-type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic-type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrPSc (scrapie type) and intermediate-type PrPSc .
Assuntos
Córtex Cerebral/patologia , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Autopsia , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Priônicas/genéticaRESUMO
MYC amplification is common in Group 3 medulloblastoma and is associated with poor survival. Group 3 and Group 4 medulloblastomas are also known to have elevated levels of histone H3-lysine 27-tri-methylation (H3K27me3), at least in part due to high expression of the H3K27 methyltransferase enhancer of zest homologue 2 (EZH2), which can be regulated by MYC. We therefore examined whether MYC expression is associated with elevated EZH2 and H3K27me3 in medulloblastoma, and if high-MYC medulloblastomas are particularly sensitive to pharmacological EZH2 blockade. Western blot analysis of low (DAOY, UW228, CB SV40) and high (DAOY-MYC, UW228-MYC, CB-MYC, D425) MYC cell lines showed that higher levels of EZH2 and H3K27me3 were associated with elevated MYC. In fixed medulloblastoma samples examined using immunohistochemistry, most MYC positive tumors also had high H3K27me3, but many MYC negative ones did as well, and the correlation was not statistically significant. All high MYC lines tested were sensitive to the EZH2 inhibitor EPZ6438. Many low MYC lines also grew more slowly in the presence of EPZ6438, although DAOY-MYC cells responded more strongly than parent DAOY cultures with lower MYC levels. We find that higher MYC levels are associated with increased EZH2, and pharmacological blockade of EZH2 is a potential therapeutic strategy for aggressive medulloblastoma with elevated MYC.
Assuntos
Neoplasias Cerebelares/enzimologia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Inibidores Enzimáticos/administração & dosagem , Meduloblastoma/enzimologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Cerebelares/tratamento farmacológico , Técnicas de Silenciamento de Genes , Humanos , Meduloblastoma/tratamento farmacológicoRESUMO
The patient was a Japanese woman who experienced a decrease in activity and gait disturbance as the initial symptoms at the age of 86, followed by disorientation and memory dysfunction. Magnetic resonance imaging showed extensive cortical regions with hyperintensity in diffusion-weighted images, and these regions showed swelling in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. The medial occipital cortex and striatum showed no apparent hyperintensity on diffusion-weighted imaging (DWI). Mild myoclonus was detected, and the patient died 10 months after the onset of symptoms; she did not enter the akinetic mutism state. The patient's brain weighed 1050 g, and neuropathological examination showed extensive characteristic various-sized and non-confluent (VaSNoC) vacuoles in the cerebral cortex. These vacuoles were observable macroscopically by loupe on images of hematoxylin and eosin-stained tissue. Gliosis, hypertrophic astrocytosis, and neuron loss were generally mild in character. Prion protein (PrP) immunostaining showed very mild diffuse-synaptic-type PrP deposition in the cerebral gray matter. These clinicopathological findings led us to several conclusions relative to the early disease pathology of V180I genetic Creutzfeldt-Jakob disease: (i) spongiform change was not found in the medial occipital cortex, which corresponds to the results of DWI; (ii) VaSNoC-type spongiform changes, extensively recognized in the cerebral cortex, corresponded to the DWI findings showing continued hyperintensity with higher brightness, and T2-weighted and FLAIR images findings showing a swelling; and (iii) spongiform changes first appear in the deeper layer and subsequently in the superficial layer in the cerebral cortex.
Assuntos
Córtex Cerebral/patologia , Síndrome de Creutzfeldt-Jakob/patologia , Idoso de 80 Anos ou mais , Autopsia , Síndrome de Creutzfeldt-Jakob/genética , Feminino , Humanos , Mutação , Proteínas Priônicas/genéticaRESUMO
We present an autopsied case of non-plaque-type dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with extensive amyloid-ß (Aß) deposition in the brain. A 39-year-old Japanese woman presented with memory disturbance and abnormal behavior. The patient had a history of craniotomy with dura matter-graft transplant for a head injury which occurred when she was 19 years old. Magnetic resonance imaging (MRI) showed hyperintensities in the cerebral cortex and striatum on diffusion-weighted images, particularly on the dura mater-grafted right side. Her clinical symptoms, including rapidly progressing cognitive impairment, myoclonus, and periodic sharp wave complexes on electroencephalogram, could not be distinguished from typical sporadic CJD cases. The patient died 11 months after symptom onset, and pathological investigations showed extensive spongiform degeneration with prion protein (PrP) deposition without Kuru plaques; these observations were essentially the same as those of typical sporadic CJD cases. Furthermore, Aß immunohistochemistry showed extensive diffuse staining in the cerebral neocortex, plaque-type deposition, positive staining in the pia mater, and cerebral amyloid angiopathy. Although the MRI findings suggested that the pathological involvement originated from the dura mater-grafted right side, the PrP and Aß depositions showed no apparent regionalization and laterality. Tau-pathology including neurofibrillary tangles was hardly identified. The proteins phosphorylated α-synuclein and phosphorylated transactivation response DNA-binding protein 43 kDa were not detected on immunostaining. Although this report describes only one case, various speculations were made based on detailed clinical and pathological observations in conjunction with previous reports of dCJD. In particular, this report provides significant insight into the characteristics and progression of dCJD pathology and its relationship with Aß pathology.