Concepts and opportunities for repair in cerebral microvascular disease and white matter stroke

Diffuse changes in white matter resulting from cerebral microvascular disease contribute to cognitive impairment (Jokinen et al., 2011), declines in global functionality (Inzitari et al., 2009), and even death (Debette and Markus, 2010). Twenty years ago, estimations of the clinical incidence of cerebral microvascular disease approached 11 million per year in the US alone (Leary and Saver, 2003). More recent estimations suggest the prevalence of diffuse white matter disease and silent brain infarction approaches 20% and increases dramatically in the presence of cardiovascular risk factors (Fanning et al., 2014). Two common clinical presentations of cerebral microvascular disease include diffuse lesions resulting in T2/FLAIR signal abnormality on MRI scans throughout the white matter. Highly related to this diffuse form, is the classic lacunar infarction, with imaging evidence suggesting that new infarcts occur at the leading edge of prior T2/FLAIR signal abnormality (Duering et al., 2013), with subtle changes in axonal diffusivity occurring in the same region (Maillard et al., 2011). Cellular events within this white matter penumbral region are therefore a likely contributor to the progressive nature of white matter disease. Despite the growing prevalence of cerebral microvascular disease, there are no known efficacious treatment strategies to prevent the progression or repair the injury burden of ischemic white matter lesions. In part, this results from a comparative lack of understanding about the precise pathophysiology of cerebral microvascular disease nor the resultant cellular biology that underlies diffuse or focal changes in white matter. This lack of understanding exists because of limitations on the ability to appropriately model white matter lesions in an easily accessible animal model such as the mouse. With the recent development of several variations in a mouse model of focal white matter stroke (Nunez et al., 2016), the field is poised for significant advances in understanding the cellular mechanisms underlying white matter lesions resulting from cerebral microvascular disease and to identify leading strategies to repair ischemic white matter lesions. Here, we outline the neurobiologic concepts and major strategies for repair of diffuse cerebral microvascular disease and white matter stroke (Figure 1).