ABSTRACT
Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative condition that presents with several neurological symptoms, such as cerebellar ataxia, parkinsonism, and cognitive impairment. It is caused by a CTA/CTG repeat expansion on chromosome 13q21 (ataxin 8 opposite strand [ATXN8OS]). However, the pathological significance of this expansion remains unclear. Moreover, abnormal CTA/CTG repeat expansions in ATXN8OS have also been reported in other neurodegenerative diseases, including progressive supranuclear palsy. In this study, we analyzed all available autopsy cases in Japan to investigate common pathological features and profiles of tau pathology in each case. Severe neuronal loss in the substantia nigra and prominent loss of Purkinje cells, atrophy of the molecular layer, and proliferation of Bergmann glia in the cerebellum were common features. Regarding tauopathy, one case presented with progressive supranuclear palsy-like 4-repeat tauopathy in addition to mild Alzheimer-type 3- and 4-repeat tauopathy. Another case showed 3- and 4-repeat tauopathy accentuated in the brainstem. The other two cases lacked tauopathy after extensive immunohistochemical studies. The present study confirmed common pathological features of SCA8 as degeneration of the substantia nigra in addition to the cerebellum. Our study also confirmed unique tauopathy in two of four cases, indicating the necessity to further collect autopsy cases.
Subject(s)
Spinocerebellar Ataxias , Spinocerebellar Degenerations , Supranuclear Palsy, Progressive , Tauopathies , Humans , Supranuclear Palsy, Progressive/genetics , Supranuclear Palsy, Progressive/pathology , Spinocerebellar Degenerations/genetics , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/pathologyABSTRACT
The mutation p.K27M in H3F3A (H3 K27M mutation) is mainly detected in diffuse midline glioma. However, recent studies have demonstrated that H3 K27M mutation could also be observed in a subset of gangliogliomas. Importantly, most H3 K27-mutated ganglioglioma cases also harbor BRAF V600E mutation. Herein, we report a rare case of H3 K27M-mutated ganglioglioma grade 3 without BRAF mutation arising in the medial temporal lobe in an elderly man. A small biopsy specimen was sampled. The pathological diagnosis was diffuse astrocytoma. The tumor progressed gradually during an 18-month follow-up period. Gadolinium enhancement on magnetic resonance imaging was noted 36 months after the biopsy. The patient was referred to a hospital for tumor resection. Histological analysis of resected specimens led to a diagnosis of ganglioglioma grade 3 with H3 K27M mutation. The patient underwent concurrent temozolomide chemotherapy with radiotherapy. Although the patient's condition deteriorated after chemotherapy due to disease progression, he survived for more than 23 months after tumor resection. We present this rare case and discuss the involvement of H3 K27M mutation in ganglioglioma grade 3.
Subject(s)
Brain Neoplasms , Ganglioglioma , Glioma , Aged , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Contrast Media , Gadolinium , Ganglioglioma/genetics , Glioma/genetics , Histones/genetics , Humans , Male , Mutation , Proto-Oncogene Proteins B-raf/genetics , Temporal Lobe/pathologyABSTRACT
PURPOSE: Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). METHODS: CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. RESULTS: We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. CONCLUSION: We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.
Subject(s)
Biomarkers, Tumor/cerebrospinal fluid , Biomarkers, Tumor/genetics , Brain Neoplasms/diagnosis , Glioma/diagnosis , Polymerase Chain Reaction/methods , Adolescent , Adult , Aged , Brain Neoplasms/cerebrospinal fluid , Brain Neoplasms/genetics , Circulating Tumor DNA/cerebrospinal fluid , DNA Mutational Analysis/methods , Female , Glioma/cerebrospinal fluid , Glioma/genetics , Histones/genetics , Humans , Isocitrate Dehydrogenase/genetics , Liquid Biopsy/methods , Male , Middle Aged , Mutation , Pathology, Molecular/methods , Telomerase/genetics , Young AdultABSTRACT
OBJECTIVES: To examine the utility of FDG-PET/MRI in patients with epilepsy by comparing the diagnostic accuracy of PET/MRI and PET/CT in epileptogenic zone (EZ) detection. METHODS: This prospective study included 31 patients (17 males, 14 females) who underwent surgical resection for EZ. All patients were first scanned using FDG-PET/CT followed immediately with FDG-PET/MRI. Two series of PET plus standalone MR images were interpreted independently by five board-certified radiologists. A 4-point visual score was used to assess image quality. Sensitivities and visual scores from both PETs and standalone MRI were compared using the McNemar test with Bonferroni correction and Dunn's multiple comparisons test. RESULTS: The EZs were confirmed histopathologically via resection as hippocampal sclerosis (n = 11, 35.5%), gliosis (n = 8, 25.8%), focal cortical dysplasia (n = 6, 19.4%), and brain tumours (n = 6, 19.4%) including cavernous haemangioma (n = 3), dysembryoplastic neuroepithelial tumour (n = 1), ganglioglioma (n = 1), and polymorphous low-grade neuroepithelial tumour of the young (n = 1). The sensitivity of FDG-PET/MRI was significantly higher than that of FDG-PET/CT and standalone MRI (FDG-PET/MRI vs. FDG-PET/CT vs. standalone MRI; 77.4-90.3% vs. 58.1-64.5% vs. 45.2-80.6%, p < 0.0001, respectively). The visual scores derived from FDG-PET/MRI were significantly higher than those of FDG-PET/CT, as well as standalone MRI (2.8 ± 1.2 vs. 2.0 ± 1.1 vs. 2.1 ± 1.2, p < 0.0001, respectively). Compared to FDG-PET/CT, FDG-PET/MRI increased the visual score (51.9%, increased visual scores of 2 and 3). CONCLUSIONS: The diagnostic accuracy for the EZ detection in focal epilepsy could be higher in FDG-PET/MRI than in FDG-PET/CT. KEY POINTS: ⢠Sensitivity of FDG-PET/MRI was significantly higher than that of FDG-PET/CT and standalone MRI (FDG-PET/MRI vs. FDG-PET/CT vs. standalone MRI; 77.4-90.3% vs. 58.1-64.5% vs. 45.2-80.6%, p < 0.0001, respectively). ⢠Visual scores derived from FDG-PET/MRI were significantly higher than those of FDG-PET/CT and standalone MRI (2.8 ± 1.2 vs. 2.0 ± 1.1 vs. 2.1 ± 1.2, p < 0.0001, respectively). ⢠Compared to FDG-PET/CT, FDG-PET/MRI increased the visual score (51.9%, increased visual scores of 2 and 3).
Subject(s)
Epilepsies, Partial , Fluorodeoxyglucose F18 , Epilepsies, Partial/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Positron Emission Tomography Computed Tomography , Positron-Emission Tomography , Prospective Studies , Radiopharmaceuticals , Sensitivity and SpecificityABSTRACT
BACKGROUND AND PURPOSE: To investigate prion protein (PrP) deposits in cutaneous tissues of patients of glycosylphosphatidylinositol (GPI)-anchorless prion diseases with neuropathy. METHODS: Cutaneous tissue samples from three patients with GPI-anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits. RESULTS: PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI-anchorless prion disease with neuropathy. The abnormal PrP accumulation was frequently localized at the basement membrane, and colocalized with laminin. CONCLUSION: Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI-anchorless PrP disease with neuropathy.
Subject(s)
Prion Diseases , Prion Proteins/analysis , Animals , Glycosylphosphatidylinositols , Humans , Mice , Mice, Transgenic , Prion Diseases/diagnosisABSTRACT
Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11.
Subject(s)
DNA-Binding Proteins , Spastic Paraplegia, Hereditary , Humans , Lysosomes , Mutation , Proteins , TDP-43 Proteinopathies , Transcriptional ActivationABSTRACT
Glioblastoma (GBM) most commonly appears to be intraparenchymal tumor, and intraventricular GBMs are rarely reported. In previous reports, the sites of origin were not identified. Here, we report a rare case of intraventricular mucin-producing GBM in a 73-year-old woman who had a strongly enhancing tumor in the right anterior horn of the lateral ventricle. The tumor had previously been identified one and a half years ago as a small asymptomatic lesion attached to the septum pellucidum. It had been documented to gradually enlarge during subsequent follow-up examinations. The patient underwent a gross total resection of the tumor, and a soft and gelatinous mass was observed. The pathological diagnosis was compatible with GBM, and numerous tumor cells having cytoplasmic mucin vacuoles were observed. Genetic analysis revealed TP53 and NFKBIA deletions. The patient received postoperative concurrent chemotherapy with temozolomide and radiotherapy, followed by maintenance administration of temozolomide. A follow-up examination seven months later detected an asymptomatic local recurrent lesion, which was treated with gamma-knife therapy, followed by bevacizumab administration for six months. The patient has remained clinically well for five years following surgery. The origin of a rare tumor entity, intraventricular GBM, and the specific spatial and pathological findings in our case are discussed in this report.
Subject(s)
Brain Neoplasms , Glioblastoma , Aged , Female , Humans , Lateral Ventricles , Mucins , Neoplasm Recurrence, Local , Septum PellucidumABSTRACT
We report the general autopsy findings of abnormal prion protein (PrP) deposits with their seeding activities, as assessed by the real-time quaking-induced conversion (RT-QuIC) method, in a 72-year-old female patient with sporadic Creutzfeldt-Jakob disease (sCJD). At 68 years of age, she presented with gait disturbance and visual disorders. Electroencephalography showed periodic synchronous discharge. Myoclonus was also observed. A genetic test revealed that PRNP codon 129 was methionine/methionine (MM). She died of pneumonia three years and four months after disease onset, and a general autopsy was performed. The brain weighed 650 g and appeared markedly atrophic. Immunohistochemistry for PrP revealed synaptic PrP deposits and coarse PrP deposits in the cerebral cortices, basal ganglia, cerebellum, and brainstem. Western blot analysis identified type 1 proteinase-K-resistant PrP in frontal cortex samples. PrP deposits were also observed in systemic organs, including the femoral nerve, psoas major muscle, abdominal skin, adrenal medulla, zona reticularis of the adrenal gland, islet cells of the pancreas, and thyroid gland. The RT-QuIC method revealed positive seeding activities in all examined organs, including the frontal cortex, femoral nerve, psoas major muscle, scalp, abdominal skin, adrenal gland, pancreas, and thyroid gland. The following 50% seeding dose (SD50 ) values were 9.5 (frontal cortex); 8 ± 0.53 (femoral nerve); 7 ± 0.53 (psoas major muscle); and 7.88 ± 0.17 (scalp). The SD50 values for the adrenal gland, dermis, pancreas, and thyroid gland were 6.12 ± 0.53, 5.25, 4.75, and 4.5, respectively. PrP deposits in general organs may be associated with long-term disease duration. This case indicated the necessity for general autopsies in sCJD cases to establish strict infection control procedures for surgical treatment and to examine certain organs.
Subject(s)
Creutzfeldt-Jakob Syndrome/pathology , Femoral Nerve/pathology , Muscle, Skeletal/pathology , Prion Proteins/metabolism , Aged , Autopsy/methods , Cerebral Cortex/pathology , Creutzfeldt-Jakob Syndrome/diagnosis , Female , Femoral Nerve/metabolism , Humans , Scalp/metabolism , Scalp/pathologyABSTRACT
Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease, characterized by the progressive ossification of skeletal muscles, fascia, tendons, and ligaments. In most cases, the great toes of patients show symmetrical congenital malformations. The causative gene for FOP has been identified as the activin A receptor, type 1 (ACVR1) gene (ACVR1). The ACVR1 R206H mutation is the most common mutation among FOP patients, and the ACVR1 G356D mutation has been identified as a rare mutation in a Japanese FOP patient with slow progression. In addition to musculoskeletal abnormalities, a series of autopsy studies described one FOP case, without genetic testing to identify ACVR1 mutation, showing nodular heterotopia at the edge of the fourth ventricle. Here, we report the general autopsy findings for a 75-year-old man with FOP, caused by the ACVR1 G356D mutation, including the precise examination of brainstem lesions. Postmortem examination revealed unique symmetrical glial hyperplasia of the pons and medulla oblongata. Microscopically, lesions of the pons involving residual neurons and lesions of the medulla oblongata consisted of subependymal cells. Immunohistochemical analysis of these lesions revealed developmental anomalies, with different cellular components. In this report, for the first time, we present the neuropathological description of a patient with genetically confirmed FOP and symmetrical glial hyperplasia of the pons and medulla oblongata. The presented pathological findings, in conjunction with previous reports implying that the glial hyperplasia of the brainstem is common in FOP, suggest that ACVR1 may play an unclarified developmental role in the human brainstem.
Subject(s)
Brain Stem/pathology , Hyperplasia/pathology , Myositis Ossificans/pathology , Neuroglia/pathology , Aged , Genetic Testing/methods , Humans , Hyperplasia/genetics , Male , Mutation/genetics , Myositis Ossificans/diagnosis , Myositis Ossificans/geneticsABSTRACT
Six subgroups of sporadic Creutzfeldt-Jakob disease have been identified by distinctive clinicopathologic features, genotype at polymorphic codon 129 [methionine (M)/valine (V)] of the PRNP gene, and type of abnormal prion proteins (type 1 or 2). In addition to the pure subgroups, mixed neuropathologic features and the coexistence of two types of abnormal prion proteins in the same patient also have been reported. Here, we found that a portion of the patients previously diagnosed as MM1 had neuropathologic characteristics of the MM2 thalamic form (ie, neuronal loss of the inferior olivary nucleus of the medulla). Furthermore, coexistence of biochemical features of the MM2 thalamic form also was confirmed in the identified cases. In addition, in transmission experiments using prion protein-humanized mice, the brain material from the identified case showed weak infectivity and generated characteristic abnormal prion proteins in the inoculated mice resembling those after inoculation with brain material of MM2 thalamic form. Taken together, these results show that the co-occurrence of MM1 and MM2 thalamic form is a novel entity of sporadic Creutzfeldt-Jakob disease prion strain co-occurrence. The present study raises the possibility that the co-occurrence of the MM2 thalamic form might have been overlooked so far because of the scarcity of abnormal prion protein accumulation and restricted neuropathology.
Subject(s)
Creutzfeldt-Jakob Syndrome/metabolism , Mutation, Missense , Prion Proteins/metabolism , Thalamus/metabolism , Aged , Amino Acid Substitution , Animals , Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/pathology , Female , Humans , Male , Mice , Mice, Transgenic , Middle Aged , Prion Proteins/genetics , Thalamus/pathologyABSTRACT
In 2008, we reported a clinically and genetically new type of autosomal dominant disorder of motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. To identify the nucleotide variant causative of this disease, we reanalyzed the linkage of the original Japanese pedigree including seven newly ascertained subjects with updated information. We assigned the locus of the disease to 1p13.3-q23 (maximum logarithm-of-odds score = 2.71). Exome sequencing for five patients and one healthy relative from the pedigree revealed 2526 patient-specific single-nucleotide variants (SNVs). By rigorous filtering processes using public databases, our linkage results, and functional prediction, followed by Sanger sequencing of the pedigree and 520 healthy Japanese individuals, we identified an intronic SNV in IQGAP3, a gene known to be associated with neurite outgrowth. Upon pathological examination of the sural nerve, moderate, chronic, mainly axonal neuropathy was observed. By histochemical analyses, we observed a patient-specific increase of IQGAP3 expression in the sural nerve. We concluded that the variant of IQGAP3 is associated with the disease in our pedigree.
Subject(s)
Cough/complications , GTPase-Activating Proteins/genetics , Introns/genetics , Peripheral Nervous System Diseases/genetics , Sural Nerve/pathology , Urologic Diseases/complications , Adolescent , Adult , Aged , Cough/genetics , Female , Genes, Dominant , Genetic Linkage , Humans , Immunohistochemistry , Male , Middle Aged , Muscular Atrophy/genetics , Muscular Atrophy/pathology , Pedigree , Peripheral Nervous System Diseases/complications , Peripheral Nervous System Diseases/physiopathology , Polymorphism, Single Nucleotide , Urologic Diseases/genetics , Exome SequencingABSTRACT
PURPOSE: Diffusion-weighted imaging (DWI) plays an important role in the preoperative assessment of gliomas; however, the diagnostic performance of histogram-derived parameters from mono-, bi-, and stretched-exponential DWI models in the grading of gliomas has not been fully investigated. Therefore, we compared these models' ability to differentiate between high-grade and low-grade gliomas. METHODS: This retrospective study included 22 patients with diffuse gliomas (age, 23-74 years; 12 males; 11 high-grade and 11 low-grade gliomas) who underwent preoperative 3 T-magnetic resonance imaging from October 2014 to August 2019. The apparent diffusion coefficient was calculated from the mono-exponential model. Using 13 b-values, the true-diffusion coefficient, pseudo-diffusion coefficient, and perfusion fraction were obtained from the bi-exponential model, and the distributed-diffusion coefficient and heterogeneity index were obtained from the stretched-exponential model. Region-of-interests were drawn on each imaging parameter map for subsequent histogram analyses. RESULTS: The skewness of the apparent diffusion, true-diffusion, and distributed-diffusion coefficients was significantly higher in high-grade than in low-grade gliomas (0.67 ± 0.67 vs. - 0.18 ± 0.63, 0.68 ± 0.74 vs. - 0.08 ± 0.66, 0.63 ± 0.72 vs. - 0.15 ± 0.73; P = 0.0066, 0.0192, and 0.0128, respectively). The 10th percentile of the heterogeneity index was significantly lower (0.77 ± 0.08 vs. 0.88 ± 0.04; P = 0.0004), and the 90th percentile of the perfusion fraction was significantly higher (12.64 ± 3.44 vs. 7.14 ± 1.70%: P < 0.0001), in high-grade than in low-grade gliomas. The combination of the 10th percentile of the true-diffusion coefficient and 90th percentile of the perfusion fraction showed the best area under the receiver operating characteristic curve (0.96). CONCLUSION: The bi-exponential model exhibited the best diagnostic performance for differentiating high-grade from low-grade gliomas.
Subject(s)
Brain Neoplasms/diagnostic imaging , Brain Neoplasms/pathology , Diffusion Magnetic Resonance Imaging/methods , Glioma/diagnostic imaging , Glioma/pathology , Adult , Aged , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Neoplasm Grading , Retrospective StudiesABSTRACT
Here, we report a juvenile (18-year-old male) case of epilepsy-associated, isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF mutation and a focal atypical feature resembling diffuse astrocytoma. The patient presented with refractory temporal lobe epilepsy. Subsequently, magnetic resonance imaging revealed a hyperintense lesion in the right temporal lobe on fluid attenuated inversion recovery images. The patient underwent right lateral temporal lobectomy and amygdalohippocampectomy. Histopathologically, the tumor showed isomorphic, diffuse, infiltrative proliferation of glial tumor cells and intense CD34 immunoreactivity. The tumor cells were immunonegative for isocitrate dehydrogenase 1 (IDH1) R132H and BRAF V600E. Notably, the tumor cells showed the lack of nuclear staining for α-thalassemia/mental retardation syndrome, X-linked (ATRX). In addition, the Ki-67 labeling index, using a monoclonal antibody MIB-1, was elevated focally at tumor cells with p53 immunoreactivity. Molecular analyses identified a BRAFA598T mutation, the first case reported in a glioma. BRAFA598T is predicted to result in loss of kinase action; however, inactive mutants can stimulate mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling through CRAF activation. Thus, according to the recent update of the consortium to inform molecular and practical approaches to central nervous system tumor taxonomy (cIMPACT-NOW update 4), our case is also compatible with diffuse glioma with the mitogen-activated protein kinase (MAPK) pathway alteration. Thorough immunohistochemical and molecular studies are necessary for diagnosis of epilepsy-associated, diffuse gliomas. Partial resemblance in histopathological and molecular genetic features to diffuse astrocytoma also calls for attention.
Subject(s)
Brain Neoplasms/genetics , Epilepsy, Temporal Lobe/complications , Glioma/genetics , Proto-Oncogene Proteins B-raf/genetics , Adolescent , Brain Neoplasms/complications , Brain Neoplasms/pathology , Glioma/complications , Glioma/pathology , Histones , Humans , Isocitrate Dehydrogenase , Male , MutationABSTRACT
Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.
Subject(s)
Fibroblast Growth Factor 2/metabolism , Immunotherapy , Lysosomal Storage Diseases/metabolism , Lysosomal Storage Diseases/therapy , Mucins/metabolism , Muscular Diseases/metabolism , Muscular Diseases/therapy , Scleromyxedema/metabolism , Scleromyxedema/therapy , Female , Humans , Lysosomal Storage Diseases/immunology , Lysosomal Storage Diseases/pathology , Middle Aged , Muscular Diseases/immunology , Muscular Diseases/pathology , Scleromyxedema/immunology , Scleromyxedema/pathologyABSTRACT
Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.
Subject(s)
Facial Hemiatrophy/complications , Facial Hemiatrophy/diagnostic imaging , Scleroderma, Localized/complications , Scleroderma, Localized/diagnostic imaging , Adult , Diagnosis, Differential , Facial Hemiatrophy/blood , Female , Humans , Scleroderma, Localized/bloodABSTRACT
Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis.
Subject(s)
Cerebral Cortex/pathology , DNA-Binding Proteins/metabolism , Huntington Disease/metabolism , Intranuclear Inclusion Bodies/metabolism , RNA-Binding Protein FUS/metabolism , RNA-Binding Proteins/metabolism , Aged , Female , Humans , Huntingtin Protein , Huntington Disease/pathology , Intranuclear Inclusion Bodies/pathology , Male , Middle Aged , Peptides , Protein Transport/physiology , RNA Processing, Post-Transcriptional/physiologyABSTRACT
Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.
Subject(s)
Antiviral Agents/adverse effects , Hepatitis B, Chronic/drug therapy , Mitochondrial Myopathies/chemically induced , Mitochondrial Myopathies/pathology , Adenine/adverse effects , Adenine/analogs & derivatives , Administration, Oral , Aged , DNA, Mitochondrial , Female , Gene Deletion , Hepatitis B, Chronic/complications , Humans , Lamivudine/adverse effects , Mitochondrial Myopathies/complications , Mitochondrial Myopathies/genetics , Muscle, Skeletal/pathology , Organophosphonates/adverse effectsABSTRACT
OBJECTIVES: ASL is useful in evaluating tumour blood flow and in detecting hypervascular tumours. The purpose of this study was to assess the additive value of ASL to non-contrast and contrast-enhanced (NC/CE)-T1WI for diagnosing residual or recurrent meningiomas. METHODS: This retrospective study included 25 postoperative patients (20 women, 5 men; median age, 65 [32-85] years) with and 25 gender- and age-matched postoperative patients without residual or recurrent meningiomas. ASL was performed using a pseudocontinuous method. Seven independent observers (two radiology residents, two general radiologists and three neuroradiologists) participated in two reading sessions consisting of only NC/CE-T1WI (first session) or NC/CE-T1WI with ASL (second session). We evaluated the sensitivity and diagnostic performance for the detection of residual or recurrent meningiomas. The diagnostic performance was assessed using a figure of merit (FOM) calculated via jackknife free-response receiver-operating characteristics. Statistical analysis was performed with paired t tests, with a significance level of p < .05. RESULTS: The sensitivities were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (62.1% vs. 70.7%), general radiologists (75.9% vs. 87.9%), neuroradiologists (97.7% vs. 100%) and all observers (81.3% vs. 88.2%). The FOMs were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (0.76 vs. 0.83), general radiologists (0.83 vs. 0.93), neuroradiologists (0.95 vs. 0.99) and all observers (0.86 vs. 0.93). The addition of ASL significantly improved the diagnostic parameters for all observers except neuroradiologists (p <. 05). CONCLUSIONS: ASL improved the detection rate of residual or recurrent meningiomas on NC/CE-T1WI among both radiology residents and general radiologists. KEY POINTS: ⢠ASL improved diagnostic performance for residual/recurrent meningioma compare to NC/CE-T1WI alone. ⢠Diagnostic sensitivity was increased after adding ASL compared with NC/CE-T1WI. ⢠FOM was increased after adding ASL compared with NC/CE-T1WI.
Subject(s)
Magnetic Resonance Angiography/methods , Meningeal Neoplasms/diagnostic imaging , Meningioma/diagnostic imaging , Neoplasm Recurrence, Local/diagnostic imaging , Spin Labels , Adult , Aged , Aged, 80 and over , Arteries/diagnostic imaging , Arteries/pathology , Contrast Media , Female , Humans , Male , Meningeal Neoplasms/pathology , Meningioma/pathology , Middle Aged , Neoplasm Recurrence, Local/pathology , ROC Curve , Retrospective StudiesABSTRACT
Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA.
ABSTRACT
Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology.