RESUMO
Mitochondrial tRNAs are indispensable for the intra-mitochondrial translation of genes related to respiratory subunits, and mutations in mitochondrial tRNA genes have been identified in various disease patients. However, the molecular mechanism underlying pathogenesis remains unclear due to the lack of animal models. Here, we established a mouse model, designated 'mito-mice tRNALeu(UUR)2748', that carries a pathogenic A2748G mutation in the tRNALeu(UUR) gene of mitochondrial DNA (mtDNA). The A2748G mutation is orthologous to the human A3302G mutation found in patients with mitochondrial diseases and diabetes. A2748G mtDNA was maternally inherited, equally distributed among tissues in individual mice, and its abundance did not change with age. At the molecular level, A2748G mutation is associated with aberrant processing of precursor mRNA containing tRNALeu(UUR) and mt-ND1, leading to a marked decrease in the steady-levels of ND1 protein and Complex I activity in tissues. Mito-mice tRNALeu(UUR)2748 with ≥50% A2748G mtDNA exhibited age-dependent metabolic defects including hyperglycemia, insulin insensitivity, and hepatic steatosis, resembling symptoms of patients carrying the A3302G mutation. This work demonstrates a valuable mouse model with an inheritable pathological A2748G mutation in mt-tRNALeu(UUR) that shows metabolic syndrome-like phenotypes at high heteroplasmy level. Furthermore, our findings provide molecular basis for understanding A3302G mutation-mediated mitochondrial disorders.
Assuntos
Doenças Mitocondriais , RNA de Transferência de Leucina , Humanos , Animais , Camundongos , RNA de Transferência de Leucina/metabolismo , Doenças Mitocondriais/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Mutação , Processamento Pós-Transcricional do RNARESUMO
BACKGROUND: The beneficial effects of the combination therapy of low-frequency repetitive transcranial magnetic stimulation of nonlesional hemisphere and intensive occupational therapy (LF-rTMS/OT) on upper limb hemiparesis have been well established in poststroke patients. However, there is no information on the effect of brain activity on LF-rTMS/OT treatment outcome. METHOD: A total of 59 poststroke patients with upper limb hemiparesis received 15-day LF-rTMS/OT. Motor function of the affected upper limb was evaluated before and after the treatment. We also conducted functional near-infrared spectroscopy (fNIRS) before the treatment and calculated the laterality index (LI) based on the change in oxy-hemoglobin in the primary sensorimotor cortex and supplementary motor cortex. The correlation between LI before LF-rTMS/OT and observed improvement in upper limb motor function was analyzed. RESULTS: Motor recovery was significantly more pronounced in patients with unaffected hemisphere dominance in both hemispheres (LI of -1 to 0) than in those with affected hemisphere dominance in the lesional hemisphere (LI of 0 to 1). There was a significant negative correlation between LI and improvement in upper limb motor function. DISCUSSION: The results demonstrated that patients with a shift in brain activity to the noninjured cerebral cortex exhibited better motor recovery following LF-rTMS/OT. The findings suggest that evaluation of brain asymmetry before LF-rTMS/OT with fNIRS can help predict the response to LF-rTMS/OT.
Assuntos
Lateralidade Funcional/fisiologia , Terapia Ocupacional/métodos , Avaliação de Resultados em Cuidados de Saúde , Paresia/terapia , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/fisiopatologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Estimulação Magnética Transcraniana/métodos , Extremidade Superior/fisiopatologia , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Motor/diagnóstico por imagem , Córtex Motor/fisiopatologia , Paresia/etiologia , Paresia/fisiopatologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologiaRESUMO
OBJECTIVE: This study was designed to determine the association between motor functional recovery and interhemispheric imbalance in cortical brain activity in sub-cortical stroke patients with moderate-to-severe upper limb hemiparesis admitted to the convalescent rehabilitation ward. SUBJECTS AND METHODS: The study included first-ever stroke patients with moderate-to-severe upper limb hemiparesis who received multidisciplinary rehabilitation therapy in the rehabilitation ward. Motor function of the affected upper extremity was evaluated by the Fugl-Meyer assessment and action research arm test at 1 (T1) and 3 months (T2) after stroke onset. We also conducted serial functional near-infrared spectroscopy at the same time points and calculated the laterality index, which is based on changes in oxyhaemoglobin in primary sensorimotor cortex (Brodmann Area 4), pre-motor cortex and supplementary motor cortex (PMC + SMA, BA6). RESULTS: The study included eight patients (seven females, mean age: 68.8). Both the Fugl-Meyer assessment and action research arm test scores improved significantly during the study. Laterality index did not change significantly from T1 to T2. There was a no significant correlation between changes in laterality index in each region and improvement in Fugl-Meyer assessment score. In contrast, a significant and negative correlation was noted between ΔLI in Brodmann Area 4 and improvement in action research arm test score. CONCLUSION: Our results suggested that activation of the non-lesional hemisphere in sub-acute stroke associated with motor recovery in moderate-to-severe upper limb hemiparesis. A multidisciplinary rehabilitation of stroke patients with moderate-to-severe upper limb hemiparesis might enhance the compensatory movements and pre-existing motor network from the non-lesional motor cortex.
Assuntos
Lateralidade Funcional/fisiologia , Córtex Motor/fisiopatologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paresia/etiologia , Paresia/fisiopatologia , Espectroscopia de Luz Próxima ao Infravermelho , Acidente Vascular Cerebral/complicações , Reabilitação do Acidente Vascular Cerebral , Extremidade SuperiorRESUMO
There is still no agreement on the most suitable time and modality for application of repetitive transcranial magnetic stimulation (rTMS) to improve motor recovery in subacute stroke patients. The underlying mechanism of motor recovery following low-frequency rTMS is considered to be modulation of the interhemispheric asymmetry. On the other hand, the cortical balance of brain activity during the acute to chronic phase of stroke is reported to be unstable. Therefore, we conducted this study to clarify the time course of the interhemispheric asymmetry and the effect of application of low-frequency rTMS combined with occupational therapy on motor recovery and cortical imbalance of brain activity in a subacute stroke patient. The interhemispheric asymmetry in this patient with new-onset subcortical cerebral infarction and upper limb hemiparesis was evaluated longitudinally using functional near-infrared spectroscopy with finger tasks. A nonlesional hemisphere-dominant activation pattern was observed on day 28 after onset. On day 56 after onset, a bilaterally eminent activation pattern was observed. Low-frequency rTMS was applied on day 109 after stroke onset when the cortical activity shifted to the nonlesional hemisphere. The treatment resulted in improvement in motor function of the affected upper limb and a shift in brain activation to the lesional hemisphere. Our report is the first to describe the therapeutic benefits of low-frequency rTMS as assessed by longitudinal neuroimaging for functional recovery and interhemispheric asymmetry in a subacute stroke patient.
RESUMO
BACKGROUND: Both low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) and intensive occupational therapy (OT) are clinically beneficial for post-stroke patients with upper-limb hemiparesis. However, the usefulness of LF-rTMS and intensive OT for ataxic hemiparesis (AH) is unknown. METHODS: The study subjects included 7 patients with AH. All patients had ataxia and mild hemiparesis without a sensory disturbance that was due to thalamic hemorrhage. Each patient was scheduled to receive 20-min rTMS at 1 Hz at the contralesional cerebral hemisphere followed by 120-min intensive OT, daily for 21 sessions. The primary outcome was the motor function of the affected upper limb that was evaluated by using the Fugl-Meyer Assessment (FMA). In addition, the International Cooperative Ataxia Rating Scale (ICARS) score was determined to assess the severity of ataxia. RESULTS: All patients completed the protocol without any adverse effects. The FMA score significantly increased after treatment. Notably, the ICARS score also significantly decreased. CONCLUSIONS: Our proposed combination treatment is a safe and feasible neurorehabilitative intervention for patients with AH due to thalamic hemorrhage. Our results demonstrate the possibility that rTMS in combination with intensive OT could improve motor function and alleviated ataxia in patients with AH.
RESUMO
BACKGROUND AND AIM: The study aim was to investigate the validity and reliability of the Functional Independence Measure and Functional Assessment Measure (FIM + FAM), which is unfamiliar in Japan, by using its Japanese version (FIM + FAM-j) in patients with cerebrovascular accident (CVA). MATERIAL AND METHODS: Forty-two CVA patients participated. Criterion validity was examined by correlating the full scale and subscales of FIM + FAM-j with several well-established measurements using Spearman's correlation coefficient. Reliability was evaluated by internal consistency (tested by Cronbach's alpha coefficient) and intra-rater reliability (tested by Kendall's tau correlation coefficient). RESULTS: Good-to-excellent criterion validity was found between the full scale and motor subscales of the FIM + FAM-j and the Barthel Index, National Institutes of Health Stroke Scale, modified Rankin Scale, and lower extremity Brunnstrom Recovery Stage. High internal consistency was observed within the full-scale FIM + FAM-j and the motor and cognitive subscales (Cronbach's alphas were 0.968, 0.954, and 0.948, respectively). Additionally, good intra-rater reliability was observed within the full scale and motor subscales, and excellent reliability for the cognitive subscales (taus were 0.83, 0.80, and 0.98, respectively). CONCLUSION AND SIGNIFICANCE: This study showed that the FIM + FAM-j demonstrated acceptable levels of validity and reliability when used for CVA as a measure of disability.