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This study aimed to clarify associations of clinical and neuropsychological features and change in regional cerebral blood flow (rCBF) on 123I-IMP-SPECT in patients with Parkinson's disease (PD) who developed dementia. Sixty-one PD patients (mean age, 65.9 ± 8.6 years; mean disease duration, 11.0 ± 11.0 years) were recruited and followed-up for two years. Clinical and neuropsychological characteristics, and rCBF from SPECT were compared between PD patients who developed dementia (PDD+) and those who remained undemented (PDD-). Thirty-eight PD patients (62.3%) were diagnosed with PD-MCI at baseline. During follow-up, 22 PD patients (36%) developed dementia (PDD+). Univariate logistic regression models showed that Hoehn and Yahr scale 4 (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.35-30.75]), visual hallucination (OR 5.95; 95%CI 1.67-25.4]), and PD-MCI (OR 6.47; 95%CI 1.57-39.63]) represented a significant risk factor for PDD+. Among neuropsychological parameters, WAIS (Wechsler Adult Intelligence Scale)-III block design (OR 6.55; 95%CI 1.66-29.84), letter number sequencing (OR 7.01; 95%CI 1.65-36.64), digit-symbol coding (OR 3.90; 95%CI 1.13-14.2), Wechsler Memory Scale, revised (WMS-R) visual paired associates II (delayed recall) (OR 4.68; 95%CI 1.36-17.36), Logical memory I (immediate recall) (OR 8.30; 95%CI 1.37-90.89), Logical memory II (delayed recall) (OR 6.61; 95%CI 1.35-44.33), Visual reproduction I (immediate recall) (OR 7.67; 95%CI 2.11-31.40), and Visual reproduction II (delayed recall) (OR 5.64; 95%CI 1.62-21.47) were significant risk factors. Decreased rCBF assessed using the general linear model (two-sample t-test) by SPM8 was observed in the left precuneus (0, -66, 16), right cuneus (6, -76, 30), and left angular gyrus (-46, -74, 32) in PDD+ compared with PDD- patients. Collectively, we have here shown that clinical and neuropsychological characteristics as well as changes to rCBF in PD patients who converted to PDD+. These features should be carefully monitored to detect the development of dementia in PD patients.
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Objectives: Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP). Methods: Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses. Results: The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected. Discussion: These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.
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This study aimed to clarify associations between neuropsychological scales and regional cerebral blood flow (rCBF) of on |123I-IMP-SPECT in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). Forty-two participants (mean age, 65.5 ± 8.9 years; mean disease duration, 11.1 ±5.7 years) were evaluated using the Wechsler Adult Intelligence Scale, third edition (WAIS-III), Wechsler Memory Scale, revised (WMS-R), Stroop test, Category word fluency, Auditory verbal learning test, Raven colored progressive matrices, Trail Making Test-B, and Clock drawing test. Participants were classified into PD-MCI and PD non-demented (PD-ND) using ten of these scales or its subtests. The rCBF of the posterior cingulate gyrus, precuneus, and parietal lobes was evaluated by |123I-IMP-SPECT using the easy Z-|score imaging system (eZIS analysis). Extent was the extent index of voxels showing z-score > 2, and Severity was mean z-score in those regions on eZIS analysis. Cingulate island sign score (CIScore) was the ratio of integrated z-scores of the posterior cingulate gyrus to those of the posterior cortex.Twenty-three participants were diagnosed with PD-MCI (55%). The rCBF indices were significantly increased in the PD-MCI group compared to the PD-ND group (Extent: P = 0.047; CIScore: P = 0.006). These indices were significantly correlated with WAIS-III Processing Speed (Extent: P = 0.041, R = -0.317; Severity: P = 0.047, R = -0.309), Stroop effect (Extent: P = 0.003, R = 0.443; Severity: P = 0.004, R = 0.437), WMS-R Visual memory (Extent: P = 0.019, R = -0.361; Severity: P = 0.014, R = -0.375), and Delayed memory score (Extent: P = 0.005, R = -0.423; Severity: P = 0.044, R = -0.312). The rCBF indices showed no correlations with the number of impaired cognitive domains. Collectively, decreased posterior parietal area rCBF and lower scores on selective neuropsychological scales might be helpful to detect a transition period from PD-MCI to PD-D.
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Transtornos Cognitivos , Disfunção Cognitiva , Neocórtex , Doença de Parkinson , Idoso , Humanos , Pessoa de Meia-Idade , Circulação Cerebrovascular/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagemRESUMO
Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.
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Disfunção Cognitiva , Estado Nutricional , Idoso , Aminoácidos , Biomarcadores/metabolismo , Disfunção Cognitiva/metabolismo , Estudos Transversais , HumanosRESUMO
Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α-synuclein-identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism-related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long-term follow up followed by postmortem neuropathological evaluation.
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Degeneração Corticobasal , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Diagnóstico Diferencial , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Paralisia Supranuclear Progressiva/diagnósticoRESUMO
A questionnaire survey was conducted on 8,402 members of the Japanese Neurological Society to examine the current status and countermeasures for physician burnout, and 1,261 respondents (15.0%) responded. In this paper, we report the results of a comparison between male and female physicians. There was a significant difference in working and living conditions only for married people. It was confirmed that men work under stricter conditions in terms of working hours, and that the burden on women is heavier in the division of housework. Analysis using the Japanese Burnout Scale revealed no gender differences in overall scores, but as for factors related to burnout, in addition to factors common to both men and women, factors specific to men or women were clarified.
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Esgotamento Profissional/etiologia , Neurologistas/psicologia , Adulto , Povo Asiático , Esgotamento Profissional/epidemiologia , Feminino , Humanos , Internet , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
To identify factors associated with burnout among Japanese physician and to use them in future measures, the Japanese Society of Neurology conducted a survey of neurologists on burnout using a web-based questionnaire in October 2019. A total of 1,261 respondents, 15.0% of the 8,402 members, responded to the survey. The mean of the subscales of the Japanese Burnout Scale was 2.86/5 points for emotional exhaustion, 2.21/5 points for depersonalization, and 3.17/5 points for lack of personal accomplishment. In addition, the burnout of our country's neurologists is not related to workloads such as working hours and the number of patients in charge, but also to a decreased meaningfulness and professional accomplishment. Therefore, it is necessary to take comprehensive measures to improve these issues at the individual, hospital, academic and national levels.
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Logro , Esgotamento Profissional/prevenção & controle , Esgotamento Profissional/psicologia , Satisfação no Emprego , Neurologistas/psicologia , Inquéritos e Questionários , Adulto , Povo Asiático , Esgotamento Profissional/epidemiologia , Despersonalização , Emoções , Feminino , Felicidade , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-IdadeRESUMO
Cancer stem cells (CSCs) reside in a supportive niche, constituting a microenvironment comprised of adjacent stromal cells, vessels, and extracellular matrix. The ability of CSCs to participate in the development of endothelium constitutes an important characteristic that directly contributes to the general understanding of the mechanisms of tumorigenesis and tumor metastasis. The purpose of this work is to establish a reproducible methodology to investigate the tumor-initiation capability of ovarian cancer stem cells (OCSCs). Herein, we examined the neovascularization mechanism between endothelial cells and OCSCs along with the morphological changes of endothelial cells using the in vitro co-culture model NICO-1. This protocol allows visualization of the neovascularization step surrounding the OCSCs in a time course manner. The technique can provide insight regarding the angiogenetic properties of OCSCs in tumor metastasis.
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Técnicas de Cocultura/métodos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Células Endoteliais/patologia , Feminino , Humanos , Neoplasias Ovarianas/patologia , Microambiente TumoralRESUMO
The ubiquitin-proteasome pathway plays an important role in the regulation of cellular proteins. As an alternative to the proteasome itself, recent research has focused on methods to modulate the regulation of deubiquitinating enzymes (DUBs) upstream of the proteasome, identifying DUBs as novel therapeutic targets in breast, endometrial, and prostate cancers, along with multiple myeloma. bAP15, an inhibitor of the 19S proteasome DUBs UCHL5 and USP14, results in cell growth inhibition in several human cancers; however, the mechanism remains poorly understood in ovarian cancer. Here, we found that aberrant UCHL5 expression predicted shorter progression-free survival (PFS) in a cohort of 1435 patients with ovarian cancer described in the Gene Expression Omnibus and The Cancer Genome Atlas databases. The subgroup of patients with TP53 mutations was significantly more likely to exhibit poor PFS (p <0.001). Moreover, we found bAP15 could suppress TP53-mutant ovarian cancer cell survival by regulating TGF-ß signaling through inhibiting UCHL5 expression and dephosphorylating Smad2, consequently inducing apoptosis. bAP15 (2.5 and 5.0 mg/kg) also exerted significant anti-tumor effect on nude mice bearing subcutaneous SKOV3 xenografts. As activated TGF-ß signaling is involved in ovarian cancer progression, these findings suggest that UCHL5 inhibition offers potential opportunities for a novel targeted therapy against TGF-ß-activated ovarian cancer.
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BACKGROUND: Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. METHODS: Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. RESULTS: The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). CONCLUSIONS: As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Variações do Número de Cópias de DNA/genética , Linfonodos/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/mortalidade , Aberrações Cromossômicas , Análise por Conglomerados , Hibridização Genômica Comparativa , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
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Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Repetições de Microssatélites , Proteínas do Tecido Nervoso/genética , Motivo Estéril alfa/genética , Adulto , Idade de Início , Autoantígenos/genética , Sequência de Bases , Epilepsias Mioclônicas/etiologia , Epilepsias Mioclônicas/patologia , Feminino , Instabilidade Genômica , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Íntrons , Masculino , Linhagem , Células de Purkinje/patologia , Proteínas de Ligação a RNA/genética , Análise de Sequência de DNARESUMO
PURPOSE: The characteristics and pathogenesis of spinopelvic alignment in Parkinsons's disease (PD) patients-including differences compared to non-PD subjects and their relationships with the severity of PD-have not been clarified. The aim of this study was to investigate the characteristics of spinopelvic alignment in patients with PD. METHODS: Forty-eight PD patients complaining of chronic low back pain were included (PD group). The PD condition, determined using the Hoehn and Yahr (H&Y) stage and Unified Parkinson Disease Rating Scale (UPDRS) score; radiographic spinopelvic alignment; lumbar range of motion (ROM); and low back pain-related quality of life assessments were evaluated. Fifty age- and sex-matched patients with adult spinal deformities were included as controls (ASD group). RESULTS: The spinopelvic alignments of the PD/ASD groups demonstrated sagittal vertical axes of 120.9/106.3 mm and pelvic incidences of 49.7/52.9°, with no significant differences. Conversely, there were significant differences in the thoracic kyphosis (TK; 27.6/16.7°), lumbar lordosis (-22.7/-7.9°), and pelvic tilt (25.3/34.4°) (all, p < 0.05). With regard to correlations with the PD condition, the H&Y stage demonstrated significant correlations with the sagittal vertical axis, thoracolumbar kyphosis, and lumbar ROM (all, p < 0.05), and the UPDRS score tended to correlate with the TK and thoracolumbar kyphosis (both, p < 0.01). CONCLUSION: Characteristic spinal conditions in PD exist, with progressed PD condition causing stooped posture with increased thoracic or thoracolumbar kyphosis and decreased lumbar ROM; moreover, global sagittal malalignment progresses without sufficient compensatory mechanisms such as loss of TK and pelvic retroversion.
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Mau Alinhamento Ósseo/diagnóstico por imagem , Dor Lombar/fisiopatologia , Doença de Parkinson/fisiopatologia , Pelve/fisiopatologia , Doenças da Coluna Vertebral/diagnóstico por imagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Cifose/diagnóstico por imagem , Cifose/epidemiologia , Lordose/diagnóstico por imagem , Lordose/epidemiologia , Dor Lombar/etiologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Pelve/diagnóstico por imagem , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores Sexuais , Doenças da Coluna Vertebral/fisiopatologia , Estatísticas não ParamétricasRESUMO
OBJECTIVE: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals. METHODS: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. RESULTS: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation. CONCLUSIONS: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.
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Alopecia/enzimologia , Alopecia/genética , Infarto Cerebral/enzimologia , Infarto Cerebral/genética , Heterozigoto , Leucoencefalopatias/enzimologia , Leucoencefalopatias/genética , Mutação de Sentido Incorreto , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Doenças da Coluna Vertebral/enzimologia , Doenças da Coluna Vertebral/genética , Alopecia/diagnóstico por imagem , Alopecia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/enzimologia , Encéfalo/patologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/patologia , Cromatografia em Gel , Dimerização , Família , Serina Peptidase 1 de Requerimento de Alta Temperatura A , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Análise de Sequência de DNA , Doenças da Coluna Vertebral/diagnóstico por imagem , Doenças da Coluna Vertebral/patologiaRESUMO
BACKGROUND: The aim of this study was to determine the exacerbating factors of chronic low back pain (LBP) and strategic points against LBP in patients with Parkinson's disease (PD). METHODS: Forty-four consecutive PD patients complaining of LBP were included. Clinical characteristics of PD and LBP, spinal musculoskeletal condition, and clinical health status were evaluated. RESULTS: Patient age at PD and LBP onset was contiguous, and LBP time period was mainly described as constant or upon waking up. Exacerbating factors of LBP included modified Hoehn and Yahr stage and motor complications of PD, such as the wearing-off phenomenon and dyskinesia. Bone quality demonstrated osteopenia due to elevated bone resorption, with vitamins K and D insufficiencies. Spinal alignment demonstrated an increased sagittal vertical axis (120.2 ± 65.4 mm) with decreased lumbar lordosis (-24.0 ± 20.6°) and lumbar range of motion (28.7 ± 10.2°), which were significantly related to severity of LBP and quality of life assessments. CONCLUSIONS: This study demonstrated that exacerbating factors of LBP include stage of motor function, motor complications of PD and stooped posture with decreased lumbar lordosis and range of lumbar movement. Therefore, control of PD, including motor complications, active treatment for osteoporosis and therapeutic exercise, are important for treating chronic LBP in patients with PD.
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Dor Lombar/diagnóstico , Dor Lombar/fisiopatologia , Região Lombossacral/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Dor Lombar/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Amplitude de Movimento Articular/fisiologia , Fatores de RiscoRESUMO
We report the case of a 19-year-old woman who had been suffering from general fatigue and exercise intolerance since 15 years old. At 18 years old, she experienced muscle weakness and myalgia of the calves. Six months later, she was admitted to our hospital. She showed muscle weakness of the neck and proximal limbs, and myalgia of the calves was prominent. Serum levels of creatine kinase (CK) and lactic acid were elevated, as was the level of lactic acid in cerebrospinal fluid. T2-weighted and short-inversion-time inversion recovery (STIR) imaging of the lower limbs showed hyperintensity on bilateral gastrocnemius muscles, and the region revealed Gd enhancement. Based on histopathological findings from muscle and identification of a m.3271T>C point mutation, mitochondrial myopathy was diagnosed. Rest and administration of vitamins B1 and B2, coenzyme Q10, and L-carnitine improved serum CK levels; however, exercise intolerance, myalgia, and lactic acidemia remained. Sodium pyruvate was then administered, and lactic acid levels, exercise intolerance, and findings on magnetic resonance imaging improved. Sodium pyruvate could prove effective in addressing both elevated serum lactic acid levels and exercise intolerance in mitochondrial disease.
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Tolerância ao Exercício , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/fisiopatologia , Debilidade Muscular/etiologia , Piruvatos/uso terapêutico , Feminino , Humanos , Adulto JovemRESUMO
Post-polio syndrome (PPS) characterized by new neuromuscular problems can appear many years after acute poliomyelitis in polio survivors. We report a 77-year-old man with antecedent poliomyelitis who newly developed neuromuscular disease with a clinical course of 27 years, the final 10 years of which were characterized by apparent progression, thus raising doubt as to the clinical diagnosis of amyotrophic lateral sclerosis (ALS) following PPS. Pathologically, plaque-like, old poliomyelitis lesions were found almost exclusively in the lumbosacral cord, showing complete neuronal loss and glial scars in the anterior horns. Although less severe, neuronal loss and gliosis were also evident outside the old lesions, including the intermediate zone. Moreover, symmetrical degeneration of the corticospinal tracts, as evidenced by CD68 immunostaining, was a feature of the white matter of the lower spinal cord. In the motor cortex, loss of Betz cells was also confirmed. Synaptophysin immunostaining of the lumbosacral cord also revealed decreased expression outside the old lesions, excluding the posterior horn. Interestingly, decreased expression of synaptophysin was also evident in the cervical anterior horns, where no old lesions were observed. No Bunina bodies, TDP-43 inclusions, or Golgi fragmentation were found. Neurogenic atrophy was evident in the iliopsoas and scalenus muscles, and inclusion body myositis-like changes were also observed in these muscles and the tongue. Was it possible to have diagnosed this patient as having ALS? We consider that the features in this case may have represented the pathology of long-standing and/or fatal PPS itself, and not ALS.
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Esclerose Lateral Amiotrófica/patologia , Encéfalo/patologia , Síndrome Pós-Poliomielite/patologia , Tratos Piramidais/patologia , Medula Espinal/patologia , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Atrofia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Progressão da Doença , Humanos , Masculino , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Síndrome Pós-Poliomielite/metabolismo , Tratos Piramidais/metabolismo , Medula Espinal/metabolismoRESUMO
Primary lateral sclerosis (PLS) is clinically defined as a disorder selectively affecting the upper motor neuron (UMN) system. However, recently it has also been considered that PLS is heterogeneous in its clinical presentation. To elucidate the association of PLS, or disorders mimicking PLS, with 43-kDa TAR DNA-binding protein (TDP-43) abnormality, we examined two adult patients with motor neuron disease, which clinically was limited almost entirely to the UMN system, and was followed by progressive frontotemporal atrophy. In the present study, the distribution and severity, and biochemical profile of phosphorylated TDP-43 (pTDP-43) in the brains and spinal cords were examined immunohistochemically and biochemically. Pathologically, in both cases, frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) was evident, with the most severe degeneration in the motor cortex. An important feature in both cases was the presence of Bunina bodies and/or ubiquitin inclusions, albeit very rarely, in the well preserved lower motor neurons. The amygdala and neostriatum were also affected. pTDP-43 immunohistochemistry revealed the presence of many positively stained neuronal cytoplamic inclusions (NCIs) and dystrophic neurites/neuropil threads in the affected frontotemporal cortex and subcortical gray matter. By contrast, such pTDP-43 lesions, including NCIs, were observed in only a few lower motor neurons. pTDP-43 immunoblotting revealed that fragments of â¼25-kDa were present in the cortices, but not in the spinal cord in both cases. Genetically, neither of the patients had any mutation in the TDP-43 gene. In conclusion, we consider that although PLS may be a clinically significant disease entity, at autopsy, the majority of such clinical cases would present as upper-motor-predominant amyotrophic lateral sclerosis with FTLD-TDP.