Poster 6: Cerebrospinal Fluid (CSF) Volume Is the Main Marker of Huntington Disease Progression Severity and Age-at-Onset Prediction

Abstract

Background Searching brain and peripheral biomarkers is a requisite to cure for Huntington's disease (HD). Mutated huntingtin exerts its main pathological effects on brain neurons. Neuronal dysfunction and degeneration cause progressively invalidating extrapyramidal symptoms, cognitive decline, and behavioral changes. Neuropathological studies showed progressive striatal dysfunction and degeneration since the beginning of the disease. Methods We analyzed the cross-sectional and longitudinal rate of brain atrophy, quantitatively measured by fully automated multiparametric magnetic resonance imaging, as fractional gray matter (GM, determining brain cortex volume), white matter (WM, measuring the volume of axonal fibers), and corresponding cerebrospinal fluid (CSF, a measure of global brain atrophy), in 94 gene-positive subjects with pre-symptomatic to advanced HD and age-matched healthy controls. Results and Discussion Each of the three brain compartments we studied (WM, GM, and CSF) had a diverse role, and their time courses differed in the development of HD. GM volume decreased early in life. Its decrease was associated with decreased serum brain derived neurotrophic factor and started even many years before onset symptoms, then decreased slowly in a nonlinear manner during the various symptomatic HD stages. WM volume loss also began in the pre-symptomatic stage of HD, a few years before manifest symptoms appear, rapidly decreasing near to the zone-of-onset. Finally, the CSF volume increase began many years before age at onset. Its volume measured in pre-symptomatic subjects contributed to improving the CAG-based model of age at onset prediction. The progressive CSF increase depended on CAG mutation size and continued linearly until the last stages of HD since the pre-symptomatic life stage, representing the best marker of progression rate and severity in HD ( R 2 = 0.25, p