Functional and Neurovascular Biomarkers for Huntington’s disease using MRI at 7T

Principal Investigator: Jun Hua

Oxidative stress and metabolic disturbances in the brain are believed to be involved in HD pathogenesis. Functional and neurovascular brain changes may represent altered neuronal physiology and metabolism.  These changes may be detectable prior to anatomical changes.  Early detection of such changes through the development of functional and physiological imaging markers would allow earlier onset of treatment, and better monitoring of treatment efficacy. 

Early motor system dysfunction in HD may involve impairment in the cortico-striatal pathways in the brain. These functional changes can be detected by the BOLD functional MRI (fMRI) method. Different from most prior task-based fMRI studies in HD, resting state fMRI can measure alterations in functional connectivity (i.e. BOLD fMRI signal synchrony between gray matter regions), and may be a promising biomarker for HD.  Our initial study demonstrated reduced functional connectivity between caudate nucleus and premotor cortex in prodromal-HD patients.

BOLD fMRI signals are strongly modulated by neurovascular function. Perturbations in cerebral perfusion and cerebrovasculature have been reported in HD. Therefore, measurement of neurovascular parameters not only allows better interpretation of the BOLD signals, but also facilitates the discovery of novel potential biomarkers.  Cerebral blood volume (CBV) is an important parameter sensitive to brain physiology.  Recent studies using optical imaging indicate that arteriolar CBV (CBVa) is most responsive to changes in metabolism.  Therefore, measurement of CBVa may provide additional and possibly more sensitive information that is not obtainable from total CBV and CBF measures. In our preliminary study at 7T, we applied our recently developed iVASO MRI method, and found that cortical CBVa was significantly elevated in prodromal-HD patients, which correlated with genetic measures, while brain atrophy was still subtle. 

In this project, we propose to perform functional (resting state BOLD functional connectivity) and neurovascular (CBVa) measurements at ultrahigh field strength (7T) in prodromal and early affected HD patients and age-matched healthy controls. Brain atrophy will be measured with structural MRI, and compared with these measures, and both will be correlated with clinical features. This will refine our understanding of functional abnormalities in prodromal and early HD populations, and have the potential for treatment monitoring in future human therapeutic trials.