Understanding brain function through small vessel disease

So goes the adage attributed to Dr. Theodore Woodward of the University of Maryland. But perhaps considering the habits of zebras could teach us about their more common equine cousins. Traditionally, our knowledge about the correlation of normal structure and function in the brain has relied, to a large extent, on studying the disruption wrought by disease processes on normal function, whether this disrupted structure was detected at autopsy or more recently by CT and MRI. This led to the common dictum that neurology was learned “stroke by stroke” (lesion-symptom mapping). In the last 5 years, higher-resolution MRI scanners (3T and 7T machines) and innovative scanning protocols and analytic methods have exponentially expanded our ability to “see” subtle details of brain structure in living persons.¹ In parallel, genetic studies have shown that mildly damaging genetic variants located within genes associated with severe monogenic disorders (“the diagnostic zebras”) may explain a larger proportion of common disease (“the horses”) than had been previously suspected. One example is NOTCH3, the gene underlying cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), variants within which are associated with greater white matter lesion load in healthy adults in the community.²