Altered Dynamic Functional Connectivity in Patients With Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes (MELAS) at Acute and Chronic Stages: Shared and Specific Brain Connectivity Abnormalities.

BACKGROUND: Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare maternally inherited genetic disease; however, little is known about its underlying brain basis. Furthermore, the dynamic functional connectivity (dFC) of brain networks in MELAS has not been explored. PURPOSE: To investigate the abnormalities of dFC in patients with MELAS at the acute and chronic stages, and to determine the possible relations between dynamic connectivity alterations and volumes of stroke-like lesions (SLLs). STUDY TYPE: Prospective. SUBJECTS: Twenty-two MELAS patients at the acute stage, 23 MELAS patients at the chronic stage, and 22 healthy controls. FIELD STRENGTH/SEQUENCE: Single-shot gradient-recalled echo planar imaging (EPI) sequence at 3T. ASSESSMENT: Dynamic FC states were estimated using the sliding window approach and k-means clustering analyses. Combined with graph theory, the topological properties of the dFC network were also accessed. STATISTICAL TESTS: Permutation test, Pearson correlation coefficient, and false discovery rate correction. RESULTS: We identified four dFC states and found that MELAS patients (especially at the acute stage) spent more time in a state with weaker connectivity (state 1) and less time in states with stronger connectivity. In addition, volumes of acute SLLs were positively correlated with mean dwell time in state 1 (r = 0.539, P < 0.05) and negatively correlated with the number of transitions (r = -0.520, P < 0.05). Furthermore, MELAS patients at the acute stage exhibited significantly increased global efficiency (P < 0.01) and decreased local efficiency (P < 0.001) compared to the controls and the patients at the chronic stage. Patients at the chronic stage only showed significantly (P < 0.001) decreased local efficiency compared to the controls. DATA CONCLUSION: Our findings suggest similar and distinct dFC alterations in MELAS patents at the acute and chronic stages, providing novel insights for understanding the neuropathological mechanisms of MELAS. Level of Evidence 2 Technical Efficacy Stage Stage 2 J. MAGN. RESON. IMAGING 2021;53:427-436.

Neurofilament light is a novel biomarker for mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a complicated maternally inherited disorder lacking of sensitive and specific biomarkers. The objective of this study was to investigate the serum neurofilament light chain (NfL) as a novel biomarker of neurological dysfunction in MELAS. Patients with different status of MELAS were enrolled in this study. The Mini-Mental State Examination (MMSE) was given to the participants to evaluate cognition status. Multiple functional MRI was performed on the participants. Blood samples were collected and the serum NfL concentrations were determined by the single-molecule array technology (Simoa). This study enrolled 23 patients with MELAS, 15 people in the acute attack phase of MELAS and 10 people in the remission phase, including 2 patients in both acute attack and remission phase. Sixteen healthy controls (HCs) were also enrolled. Serum NfL level increased significantly in patients with MELAS. Serum NfL level in the acute attack group (146.73 [120.91-411.31] pg/ml, median [IQR]) was higher than in the remission group (40.31 [19.54-151.05] pg/ml, median [IQR]) and HCs group (7.70 [6.13-9.78] pg/ml, median [IQR]) (p < 0.05). The level of NfL in the remission phase group was higher than in HCs group (p < 0.05). A negative correlation was found between the serum NfL level and MMSE (p = 0.006, r = -0.650). The NfL concentration correlated positively with stroke-like lesion volume in the brain (r = 0.740, p < 0.001). Serum NfL may serve as a novel biomarker for the neurological dysfunction in MELAS patients.

Altered spontaneous brain activity at attack and remission stages in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): Beyond stroke-like lesions.

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) may cause whole-brain functional changes due to mitochondrial dysfunction. Our purpose is to comprehensively evaluate the alterations of spontaneous brain activity in MELAS patients at stroke-like episodes (SLE) attack and remission stages using resting-state functional magnetic resonance imaging. Forty MELAS patients at attack stage (n = 20) and remission stage (n = 20) and 22 healthy controls were enrolled in this study. We suggested that MELAS patients presented decreased spontaneous brain activities beyond the areas of stroke-like lesions (SLLs), with a downward trend from SLE attack stage to remission stage. In addition, the regional spontaneous activity of SLL, an inherent change in MELAS, was less than that in unaffected areas. Furthermore, the fractional amplitude of low frequency fluctuations value in left precuneus may be used as a promising neuroimaging biomarker for monitoring the disease status of MELAS.