B.1. MAGNETIC RESONANCE IMAGING: PRE-MANIFEST HUMAN HUNTINGTON’S DISEASE AND POTENTIAL FOR PRECLINICAL THERAPEUTIC TRIALS IN HUNTINGTON’S DISEASE MOUSE MODELS

¹W Duan, ¹S Mori, ¹S Reading, ²E Aylward. ¹Johns Hopkins University, Baltimore, Maryland, USA, ²Universtiy of Washington, Seattle, Washington, USA

Background: Magnetic resonance imaging (MRI) measures may have potential as biomarkers for clinical trials in both premanifest and manifest Huntington’s disease (HD).

Methods and Results: Structural MRI imaging studies at Johns Hopkins in HD indicate that striatal volumes begin to atrophy at least 11–12 years before expected onset and then continue to shrink predictably with disease course—and may prove a marker with greater power than motor ratings to detect change. Data from the PREDICT–HD study are corroborating and extending these findings. We have also found changes in functional MRI and DTI measures, which may begin even before detectable volumetric changes. Validation as outcome measures for clinical trials will require a demonstration that they change with treatment. We have therefore begun detailed MRI studies in several HD mouse models in which we are conducting treatment trials. Using T2-weighted MRI scans combined with large deformation diffeomorphic mapping, significant brain atrophy was present as early as 4 weeks of age in R6/2 mice and then continued in parallel with motor behavioural deficits. Striatum and cortex changes correlate best with motor changes. These studies suggest that R6/2 mice develop brain atrophy and behavioural changes very early, so that it may be difficult to study alterations in disease onset in this model. Preliminary studies in N171-82Q mice indicate that there is little or no significant brain regional atrophy at 6 weeks, but progressive atrophy after that. Our data suggest that N171-82Q mice might make it possible to track both the onset and progression of disease by MRI. Therapeutic trials in both R6/2 and N171-82Q mice are in progress.

Conclusions: MRI measures may thus have potential as biomarkers for preclinical …