Neurocognitive and neuroimaging markers of emerging cerebral adrenoleukodystrophy

点击翻译按钮获取中文摘要

Project Summary/Abstract Adrenoleukodystrophy (ALD) is a progressive X-linked neurological disorder with unpredictable variation in expression. During childhood, about 1 in 3 boys develop rapidly progressing cerebral ALD with brain inflammation and myelin destruction. Although existing treatments stop progression of cerebral ALD when detected at an early stage, no current assessments can identify which boys will develop cerebral ALD or when it will begin. Newborn screening programs that identify ALD at birth offer an opportunity to provide earlier treatment that avoids irreversible neurocognitive decline while new treatments may present safer alternatives to standard stem cell therapy. This K23 Career Development Award aims to provide the PI with the necessary training to become an independent investigator proficient in cross-modal methodologies to measure subtle brain changes in children with ALD and apply those methods in clinical research protocols. With mentorship from a team of experts at the University of Minnesota, the applicant proposes the following training objectives: (1) to obtain knowledge and experience in acquisition and analysis of neuroimaging data; (2) to learn statistical and computational methods for validation of novel neurocognitive tests; and (3) to acquire the expertise to design and execute clinical trials. The overall research objectives are designed to identify early neurocognitive and neuroimaging markers of cerebral demyelination and enhance the capacity of clinical trials of newer therapies to define robust endpoints for boys who receive early treatment. The central hypothesis is that deterioration in white matter fiber integrity and associated loss of interhemispheric function involving the corpus callosum mark the onset of cerebral ALD, and begin prior to the appearance of a lesion on MRI. To test this hypothesis, the PI will test several methods designed to measure changes associated with demyelination. The specific aims will use longitudinal neurocognitive testing (Aim 1) and longitudinal diffusion MRI studies (Aim 2) to identify functional and microstructural markers of cerebral ALD in boys with early stage disease, and test for presence of these markers during the critical pre-emergent stage in at-risk boys. The neurocognitive findings will also be compared to MRI metrics of disease progression. The successful completion of these Aims will identify reliable indicators of disease onset and early progression. The proposed research is significant because detection and quantification of subtle progressive brain changes in boys with ALD will allow earlier and more effective intervention to reduce the neurocognitive morbidity. The training objectives will support the applicant's career goals to lead a long-term program of research to identify sensitive markers of brain dysfunction in neurodevelopmental and neurodegenerative diseases, with the goal of informing timing and efficacy of interventions to achieve better patient outcomes.