Leveraging myelin-sensitive imaging to predict early lesion pathogenesis in cerebral adrenoleukodystrophy

点击翻译按钮获取中文摘要

ABSTRACT X-linked Adrenoleukodystrophy (ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene. The estimated incidence of disease is 1/17,000, however the recent institution of newborn screening has revealed significantly higher rates. The majority of patients will develop cerebral ALD (CALD), with the highest incidence occurring in childhood. Most patients undergo inflammatory demyelination followed by neurodegeneration and death in 2 to 3 years. Hematopoietic Stem Cell Transplant (HSCT) is most effective when initiated in the narrow window prior to the onset of neurological symptoms. There is an explicitly stated need for more sensitive measures to detect lesion onset and progression. Early diagnosis of CALD will widen the treatment window, provide lead-time for possible preventative strategies, and thereby help maximize neurological outcomes. Decreased overall lipid content, increase in myelin very long chain fatty acid lipid fractions, and decrease in myelin water content are the earliest pathological changes in CALD, prior to demyelination. Diffusion Tensor (DTI) and Myelin Water Fraction (MWF) Imaging are advanced, in vivo modalities specific to local fiber architecture and myelin water content. Dr. Mallack hypothesizes that abnormal microstructural changes in early CALD during myelin development can be detected by DTI and MWF prior to the onset and/or progression of demyelination. Dr. Mallack will test this hypothesis by investigating individual white matter tract development (Aim 1), and lesion onset and progression (Aim 2), in pediatric patients who developed CALD, asymptomatic hemizygotes, and controls. If his hypotheses are validated by this study, the approach will (1) confirm normal myelin development in patients with CALD, (2) reframe early CALD as a regional, tract-specific, divergence from the expected white matter tract maturational curve, (3) provide a sensitive modality for early disease monitoring, and (4) aid in prediction of patients appropriate for therapy. By achieving these aims, Dr. Mallack will undergo rich inter-institutional mentorship by Dr. Florian Eichler, a world expert in the leukodystrophies, at Massachusetts General Hospital and Dr. Sumit Niogi, a leader in advanced neuroimaging, at Weill Cornell Medical College. Additionally, Dr. Mallack will be guided by a team with complementary expertise in neurogenetic disorders, advanced imaging biomarker development and investigation, and biostatistics. In addition to his career development activities, Dr. Mallack's committee of mentors, collaborators, and advisors will promote his development and transition to an independent investigator. This will address his goals of (1) using advanced imaging techniques to probe the underlying biology of genetic white matter disease, and (2) translate cutting-edge image analyses into clinical applications, thereby advancing the care of patients affected by these devastating disorders.