Imaging Biomarkers for Clinical Trials: Magnetic Resonance Imaging White Matter Hyperintensity Progression
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*Lisa C Silbert, Oregon Health & Science University 

Keywords: MRI, White Matter Hyperintensities

White matter integrity disruption, observed as T2-weighted white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI), are commonly observed with advanced age, and are associated with increased risk of stroke, dementia, and death. Besides age, the main risk factors for WMHs are vascular, particularly high blood pressure. Those with greater amounts of WMH volume on initial imaging are more likely to show progression of such lesions over time. Progression of WMH burden has been associated with decline in cognitive function and may be a more sensitive predictor of conversion to cognitive impairment than baseline WMH volume alone. An acceleration in the rate of WMH expansion occurs early in the presymptomatic phase leading to mild cognitive impairment (MCI) compared with other brain changes. Pathologically, WMHs have been associated largely with small vessel arteriolosclerotic disease, but WMH progression may also be indicative of underlying Alzheimers Disease pathology.

One previous clinical trial demonstrated significantly decreased WMH progression in subjects randomized to an active blood pressure lowering regimen. Current studies support the use of WMH burden as a primary outcome in a newly funded NIH/NIA clinical trial of Omega-3 polyunsaturated fatty acids (pufas) for the vascular component of age-related cognitive decline. Greater plasma pufas is associated with lower WMH burden at baseline and decreased progression of WMH lesions over time. In addition, lower plasma pufas are related to greater decline in executive function, a cognitive domain known to be preferentially affected by white matter disruption. In dementia-free elderly, lower plasma pufas are associated with greater plasma soluble adhesion molecule ICAM-1, an inflammatory protein associated with endothelial function and WMH progression.

In summary, MRI WMH lesions, a likely marker of small vessel ischemic disease and vascular endothelial dysfunction, are extremely common with advanced age and confer increased risk of cognitive impairment and other morbidities. Recent data support the use of MRI WMH volume progression as a primary outcome in clinical trials targeting vascular mechanisms to improve cerebrovascular health in older individuals, prior to dementia onset.