Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. HD preferentially involves the basal ganglia- especially the striatum- but also affects other brain regions and has no cure or disease-modifying treatment yet. Because of its gain-of- function mechanism, strategies to lower mutant HTT are promising as first-ever disease-modifying therapies. Most approaches are currently targeted at manifest HD when clinical outcomes can be used to evaluate the effectiveness. However, as almost 50% of striatal volume has been lost at the time of onset, it would be preferable to begin treatment in the premanifest period before massive loss of striatal volumes. An unmet challenge is how to reliably evaluate therapeutic efficacy in the absence of clinical symptoms as outcome measures. The clinical diagnosis of HD is based on the presence of movement disorders. However, functional changes in the brain can precede motor onset by many years. Neurovascular abnormalities have been reported in premanifest and early HD by us and others. We have reported significantly altered arteriolar CBV (CBVa) in premanifest HD brains, when striatal atrophy was undetectable. We recently found that altered CBVa occurred prior to striatal atrophy in an HD mouse model and that CRISPR/Cas9-mediated mHTT lowering restored CBVa in premanifest HD mice. Collectively, these data suggest reliable measures of neurovascular changes might be valuable biomarkers in premanifest HD. CBV is strongly coupled with brain metabolism, and cerebral metabolic abnormalities are increasingly considered as early neuropathological events in HD. We found impaired response of cerebral metabolism to visual stimulation in premanifest HD patients, correlating with the CAG-Age product (CAP) score, supporting that metabolic disturbances occur at early pathogenic stage and may be another early biomarker for HD. In addition, the recent (re)discovery of brain lymphatic vessels and CSF-lymphatic drainage system illustrates an important brain waste clearance system. Our preliminary data implicate that impairment of elements of this system precedes striatal atrophy and mHTT aggregation in HD mice. The objective of this project is to identify early brain functional changes that rapidly respond to treatment in HD preclinical study by incorporating multimodal advanced MRI measures and to develop sensitive biomarkers translatable to HD clinical trials, particularly in the premanifest period. Aim 1. We will test the hypothesis that mutant HTT impairs cerebral metabolism and alters neurovascular responsivity prior to brain atrophy and behavioral deficits in HD mice. Aim 2. We will assess brain lymphatic flow by monitoring dynamic signal changes in small lymphatic vessels and monitor BBB permeability in HD mice. Aim 3. We will determine the extent to which metabolic, vascular, and lymphatic MRI measures can monitor the effects of premanifest and...