Chih-Hsien Tseng1, Yin-Hsiu Chien2, Ni-Chung Lee2, Yung-Chin Hsu3, Shinn-Forng Peng3, Wen-Yih I Tseng3,4, Wuh-Liang Hwu2. 1. Institute of Biomedical Engineering, National Taiwan University College of Medicine, Taipei, Taiwan. 2. Department of Pediatrics and Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 3. Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan. 4. Institute of Medical Device and Imaging, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
OBJECTIVE: Children with aromatic l-amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients. METHODS: Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity. RESULTS: In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = -0.0136; 95% confidence interval [CI] [-0.0319, -0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = -0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy. INTERPRETATION: Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644-652.
OBJECTIVE:Children with aromatic l-amino acid decarboxylase (AADC) deficiency suffer from severe motor dysfunction. Restoration of dopamine levels in the putamen by gene therapy has led to significant improvement in motor function. This study explored brain structure changes in patients. METHODS: Brain diffusion tensor imaging (DTI) was performed before and 12 months after gene therapy. Whole-brain tract-specific analysis was performed to assess white matter microstructural integrity. RESULTS: In the 8 patients (aged 1.67-8.42 years) enrolled in the study, gene therapy did not affect macroscopic structure. DTI before gene therapy revealed lower total mean fractional anisotropy (FA) values in patients than in the age-matched pretreatment controls (p = 0.017; median difference = -0.0136; 95% confidence interval [CI] [-0.0319, -0.0126]). After gene therapy, total mean FA increased (p = 0.012, median difference = 0.0211, 95% CI [0.0094, 0.0456]), and the values in the patients were not different from the age-matched posttreatment controls. Increase in total mean FA after gene therapy in patients was correlated with their increase in motor score (r = 0.846; p = 0.008), but was inversely correlated with their ages at the time of gene therapy (r = -0.754; p = 0.031). Corticospinal tracts, and the thalamic radiation and callosal fibers involving motor function, improved after gene therapy. INTERPRETATION: Improvement in the microstructural integrity of white matter tracts is associated with the improvement in motor function following gene therapy. Ann Neurol 2019;85:644-652.
Authors: Joseph O'Neill; Mary J O'Connor; Guldamla Kalender; Ronald Ly; Andrea Ng; Andrea Dillon; Katherine L Narr; Sandra K Loo; Jeffry R Alger; Jennifer G Levitt Journal: Brain Imaging Behav Date: 2021-06-05 Impact factor: 3.978