Blood-brain barrier link to human cognitive impairment and Alzheimer's Disease

Abstract

Vascular dysfunction is frequently seen in disorders associated with cognitive impairment, dementia and Alzheimer's disease (AD). Recent advances in neuroimaging and fluid biomarkers suggest that vascular dysfunction is not an innocent bystander only accompanying neuronal dysfunction. Loss of cerebrovascular integrity, often referred to as breakdown in the blood-brain barrier (BBB), has recently shown to be an early biomarker of human cognitive dysfunction and possibly underlying mechanism of age-related cognitive decline. Damage to the BBB may initiate or further invoke a range of tissue injuries causing synaptic and neuronal dysfunction and cognitive impairment that may contribute to AD. Therefore, better understanding of how vascular dysfunction caused by BBB breakdown interacts with amyloid-β and tau AD biomarkers to confer cognitive impairment may lead to new ways of thinking about pathogenesis, and possibly treatment and prevention of early cognitive impairment, dementia and AD, for which we still do not have effective therapies.

Figure 1.. Blood-brain barrier and the associated cell types.

The brain is amongst the highest vascularized organs in the body. Oxygenated blood, nutrients and regulatory molecules are delivered to the brain via arterial and arteriolar blood vessels that branch out into brain capillaries. Carbon dioxide and metabolic end products are removed from the brain by venous drainage system. Tightly-sealed brain capillary endothelium is the key site of the blood–brain barrier (BBB). The endothelial BBB monolayer extends along the arterioles, small arterial vessels and venules. Middle inset: An arteriole branching out into small capillaries. Vascular smooth muscle cells (pink) and pericytes (green) wrap around the arterioles and capillaries, respectively. Pericytes are embedded into the basement membrane encircling endothelial cells of the capillary vessel wall. Astrocyte endfeet (blue) wrap around the capillary wall, and in places not covered by pericytes are separated from endothelial cells by the basement membrane. Together with perivascular microglia (light brown) and macrophages, and neurons (orange), these different cell types form the neurovascular unit (NVU). Right inset: Capillary cross-section illustrates the cellular composition of the NVU at the level of brain capillary.

Figure 2.. ATv(N) matrix.

The AT(N) system classifies individuals in the Alzheimer’s disease (AD) continuum by monitoring biomarkers for amyloid-β (A), tau (T), and neurodegeneration (N). Recent neuroimaging and fluid biomarker studies suggest that novel candidate biomarkers (X) for additional pathophysiological mechanisms should be incorporated within the AT(N) system. Adding vascular dysfunction caused by an early breakdown in the blood-brain barrier (v) should be helpful when evaluating preclinical decline, and clinical progression from cognitively unimpaired to mild cognitive impairment (MCI), and MCI to dementia both in individuals along the AD continuum and in those with negative AT biomarkers that may develop at a different type of dementia, such as vascular dementia and mixed dementia, and/or convert to AD a later stage. The ‘v’ could be chosen from neuroimaging and/or molecular biomarkers of blood-brain barrier breakdown. The ATv(N) matrix allows for A, T, and v pathways to contribute to early cognitive dysfunction and neurodegeneration independently of each other or acting synergistically. The ‘v’ does not take into account the effects of other comorbid AD vascular pathologies such white matter changes, lacunes, microinfarcts, and/or ischemic changes, and may not apply to late stage progressive AD dementia, as discussed in this Perspective.