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BACKGROUND: Coupling between neuronal activity and blood perfusion is termed neurovascular coupling (NVC), and it provides a potentially new mechanistic perspective into understanding numerous brain diseases. Although abnormal brain activity and blood supply have been separately reported in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), whether anomalous NVC would be present is unclear.
OBJECTIVE: To investigate NVC changes and potential neural basis in MELAS by combining resting-state functional MRI (rs-fMRI) and arterial spin labeling (ASL).
METHODS: Prospective.
METHODS: Twenty-four patients with MELAS (age: 29.8 ± 7.3 years) in the acute stage and 24 healthy controls (HCs, age: 26.4 ± 8.1 years). Additionally, 12 patients in the chronic stage were followed up.
UNASSIGNED: 3.0 T, resting-state gradient-recalled echo-planar imaging and pseudo-continuous 3D ASL sequences.
RESULTS: Amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and functional connectivity strength (FCS) were calculated from rs-fMRI, and cerebral blood flow (CBF) was computed from ASL. Global NVC was assessed by correlation coefficients of CBF-ALFF, CBF-fALFF, CBF-ReHo, and CBF-FCS. Regional NVC was also evaluated by voxel-wise and lesion-wise ratios of CBF/ALFF, CBF/fALFF, CBF/ReHo, and CBF/FCS.
METHODS: Two-sample t-test, paired-sample t-test, Gaussian random fields correction. A P value <0.05 was considered statistically significant.
RESULTS: Compared with HC, MELAS patients in acute stage showed significantly reduced global CBF-ALFF, CBF-fALFF, CBF-ReHo, and CBF-FCS coupling (P < 0.001). Altered CBF/ALFF, CBF/fALFF, CBF/ReHo, and CBF/FCS ratios were found mainly distributed in the middle cerebral artery territory in MELAS patients. In addition, significantly increased NVC ratios were found in the acute stroke-like lesions in acute stage (P < 0.001), with a recovery trend in chronic stage.
CONCLUSIONS: This study showed dynamic alterations in NVC in MELAS patients from acute to chronic stage, which may provide a novel insight for understanding the pathogenesis of MELAS.
METHODS: 2 TECHNICAL EFFICACY: Stage 1.

BACKGROUND: The mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a matrilineal hereditary multisystem disease caused by mutations in the mitochondrial DNA. Although the initial diagnostic criteria correlate with a range of clinical phenotypes, including clinical onset after the age of 40, there is still lack of a unified single diagnostic standard for MELAS.
METHODS: A 71-year-old female patient with recurrent stroke was reported. Magnetic resonance imaging showed a cerebral gyrus-like diffusion weighted imaging high signal lesion in the parietal-occipital lobe and the area of this lesion expanded with disease progression. The MRS result showed significantly inverted Lac/Lip peaks. The nucleic acid sequencing result displayed a MT-TWm.5541C>T mutation, and a 12.86% mutation rate in the blood sample. The patient had a 6-year history of type 2 diabetes.
CONCLUSIONS: Patients with the MELAS syndrome may present with a variety of clinical manifestations. Our data demonstrated that, for patients with atypical cerebral infarction and suspected MELAS syndrome, gene sequencing and muscle biopsy should be performed in time. This case provides a reference for the diagnostic criteria of MELAS syndrome.

The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately.
After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial.
The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine.
The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS.
UMIN000011908.

OBJECTIVE: The aims of the study were to analyze the conventional and diffusion-weighted MRI (DWI) of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and to investigate underlying mechanisms.
METHODS: Features of 58 acute and 68 chronic stroke-like lesions as well as global brain abnormalities of 40 Chinese MELAS patients were analyzed.
RESULTS: Gyriform DWI hyperintensity with decreased apparent diffusion coefficient (ADC) and patchy DWI hyperintensity with normal ADC were noted in 56 of 58 and 2 of 58 cortical regions of acute lesions, respectively. High ADC and mix of low and high ADC were observed in 51 of 58 and 5 of 58 affected subcortical white matters, respectively. Lacunar infarcts existed in 23 of 40 patients. Among 17 patients who have been followed, recurrence, progression, and progressive atrophy were noted in 8, 9, and 4 cases, respectively.
CONCLUSIONS: This study demonstrates the conventional and diffusional MRI features of MELAS, suggesting a model of acute stroke-like lesions in which the cortex manifest with cytotoxic edema and the subcortical area with vasogenic edema.

Ultrastructural changes in skeletal muscle biopsy in a 24-year-old female patient with clinically suspected mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) syndrome are presented. We observed proliferation and/or pleomorphism of mitochondria in skeletal muscle and smooth muscle cells of arterioles, as well as in pericytes of capillaries. Paracrystalline inclusions were found only in damaged mitochondria of skeletal muscle. Genetic testing revealed a point mutation in A3243G tRNALeu(UUR) typical for MELAS syndrome. We conclude that differentiated pathological changes of mitochondria in the studied types of cells may be associated with the different energy requirements of these cells.

The aim of this study was to investigate the clinically latent brain atrophy of patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) harboring a mitochondrial DNA A3243G mutation (A3243G) and A3243G carriers without stroke-like episodes (SEs).
We used voxel-based morphometry (VBM) with magnetic resonance imaging to investigate gray matter (GM) and white matter (WM) volume reductions in four MELAS patients and in five A3243G carriers compared to 16 healthy controls. In addition, we investigated the regions of previous SEs using conventional MRI.
All four MELAS patients showed significant GM volume reductions in the left superior parietal lobule (SPL), right precuneus, right middle temporal gyrus (MTG), and bilateral posterior lobes of the cerebellum. These areas of GM volume reduction were beyond the regions of previous SEs. As for A3243G carriers, GM volume reductions in the left SPL, right precuneus, right MTG, and bilateral posterior lobes of the cerebellum were detected in three, one, two, and five subjects, respectively. All four MELAS patients showed significant WM volume reductions in the bilateral or unilateral temporal sub-gyral regions, which were included in the regions of previous SEs. No A3243G carriers showed WM volume reductions.
The distribution patterns of GM volume reductions in VBM may reflect a common vulnerability of the brains among MELAS patients and A3243G carriers.

Myopathy-lactic acidosis-sideroblastic anemia (MLASA) syndrome is a rare autosomal recessive disease. We studied a 43-year-old female presenting since childhood with mild cognitive impairment and sideroblastic anemia. She later developed hepatopathy, cardiomyopathy, and insulin-dependent diabetes. Muscle weakness appeared in adolescence and, at age 43, she was unable to walk. Two novel different mutations in the PUS1 gene were identified: c.487delA (p.I163Lfs*4) and c.884 G>A (p.R295Q). Quantitative analysis of DNA from skeletal muscle biopsies showed a significant increase in mitochondrial DNA (mtDNA) content in the patient compared to controls. Clinical and molecular findings of this patient widen the genotype-phenotype spectrum in MLASA syndrome.