Gliovascular Mechanisms and White Matter Injury in Vascular Cognitive Impairment and Dementia

Introduction

Cerebrovascular factors are significant contributors to cognitive decline during aging. Vascular cognitive impairment and dementia (VCID) is defined as cognitive decline related to impairment of blood supply to the brain ( Fig. 13.1 ). VCID comprises a broad spectrum of disease, including strokes in strategic brain areas, multi-infarct dementia, and subcortical ischemic vascular disease (SIVD). ^, Vascular dysregulation is also an important component of Alzheimer disease pathophysiology. ^,

Although neuronal perturbations in gray matter should ultimately underlie the development of cognitive decline, it is increasingly recognized that white matter mechanisms play a significant role within the broad spectrum of VCID. In SIVD, one of the most common subtypes of VCID, ^, there is a progressive arteriolosclerosis and fibrohyalinosis in small blood vessels supplying deep white matter, thus resulting in chronic cerebral hypoperfusion that leads to accumulating damage within subcortical and periventricular areas. When damage to the white matter is extensive, the term Binswanger disease is used to define this category of vascular demyelination. ^,

White matter vulnerability is based on distribution of the major arteries supplying the deep white matter. End arteries from the base of the brain and the surface supply the periventricular region, forming a watershed. Other vulnerable regions with limited blood flow are gray-white junction beneath the cortex and centrum semiovale. When the cerebral blood flow or oxygen levels are compromised, these regions are impacted. Hypertension, diabetes, and hyperlipidemia predispose the small blood vessels to narrowing of the lumen with thickening of the outer layers by fibrosis. Sleep apnea leads to intermittent hypoxia. Damage to the white matter is visualized as attenuation on computed tomography and hyperintense regions on magnetic resonance imaging (MRI) on the fluid-attenuated inversion recovery (FLAIR) sequences. Because FLAIR white matter hyperintensities can be seen in normal elderly, the diffusion tensor image (DTI) is better for showing damaged fiber tracts. Patients with microstructural injury on DTI have a clinical syndrome involving impaired executive function, increased reflexes, imbalance, and urinary problems. They may have small or lacunar strokes in the white matter and psychiatric symptoms including apathy and depression. These patients differ from patients with Alzheimer disease who have mainly memory and language deficits. Dual pathology of Alzheimer disease and vascular disease accelerates the cognitive decline, suggesting a synergistic effect of inflammation caused by both conditions in many patients with mixed dementia. ^, The reader is referred to the later sections of this book for detailed clinical and neuroimaging discussions of vascular dementia ( Chapters 18 and 41 ).

In this chapter, we will focus on mechanisms of white matter injury in VCID, and the neurovascular unit will be used as a conceptual framework for dissecting gliovascular signaling in normal and diseased conditions. We begin by surveying the wide range of animal models available for investigating VCID. Then we discuss the molecular and cellular mechanisms underlying the coordinated responses in blood-brain barrier (BBB), extracellular matrix, and crosstalk between oligodendrocyte lineage cells and other components in the neurovascular unit. Finally, we introduce the emerging field of gliome and vasculome mapping as a systematic approach for discovering novel mechanisms and targets for VCID pathophysiology.