Vascular contributions to Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology underlying AD is paramount for the management of individuals at risk of and suffering from AD. The vascular hypothesis stipulates a relationship between cardiovascular disease and AD-related changes although the nature of this relationship remains unknown. In this review, we discuss several potential pathological pathways of vascular involvement in AD that have been described including dysregulation of neurovascular coupling, disruption of the blood brain barrier, and reduced clearance of metabolite waste such as beta-amyloid, a toxic peptide considered the hallmark of AD. We will also discuss the two-hit hypothesis which proposes a 2-step positive feedback loop in which microvascular insults precede the accumulation of Aß and are thought to be at the origin of the disease development. At neuroimaging, signs of vascular dysfunction such as chronic cerebral hypoperfusion have been demonstrated, appearing early in AD, even before cognitive decline and alteration of traditional biomarkers. Cerebral small vessel disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes, or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the intracranial vasculature and longitudinal studies in individuals at risk for or in the early stages of the AD continuum could be critical in disentangling this complex relationship between vascular disease and AD.

Figure 1-. Summary of the two prevailing hypotheses for the development of dementia.

The Vascular Cognitive Impairment and Dementia (VCID) hypothesis postulates that peripheral etiologies, such as cardiovascular factors, result in direct cerebral damage via strokes or cerebral hypoperfusion. Other peripheral etiologies that result in arterial stiffening are thought to lead to endothelial damage, BBB dysfunction, pericyte injury, and ultimately increased Aß accumulation and disruption in neuronal activity, leading to dementia. On the other hand, the Vascular Hypothesis for Alzheimer’s Dementia (VHAD) hypothesis proposes that underlying cardiovascular and cerebrovascular causes result in dementia. However, is unclear if both of these factors result in or are a consequence of the dementia. (Adapted from : Zlokovic BV, Gottesman RF, Bernstein KE, Seshadri S, McKee A, Snyder H, et al. Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop.

Figure 2-. Structure of the neurovascular unit.

Penetrating cerebral arteries arise from pial arteries and dive into the brain parenchyma. They further divide into smaller arterioles that in turn give rise to brain capillaries, the smallest vascular component ensuring blood supply. Arterioles and capillaries interact with local cells of the central nervous system to form a complex functional system called the neurovascular unit (NVU). Structurally, the NVU is composed of neurons, astrocytes (in particular the end-feet), endothelial cells, basement membrane, and either vascular smooth muscle cells (in arterioles) or pericytes (in capillaries). All these elements are linked together to form a coherent unit that regulates closely the interactions between the vascular and nervous systems. The two primary roles of the NVU are to ensure the integrity of the blood brain barrier (BBB) and to regulate the cerebral blood flow (CBF). The blood brain barrier is an essential part of the NVU and plays a critical role in brain homeostasis. It is a semi-permeable, continuous, dynamic interface that separates the brain parenchyma from the circulating blood. In the brain, endothelial cells are non-fenestrated unlike in peripheral capillaries. They are also connected by tight junctions and adherens junctions, two important structural parts of the BBB that prevent undesirable exchanges of large molecules between bloodstream and brain parenchyma. Additionally, astrocytic end-feet cover the circumference of the luminal surface of vessels, where they act as an additional barrier and help in signaling pathways between local neurons and vascular structures. Vascular smooth muscle cells are only found in arterioles, whereas pericytes are found in capillaries. Both present contractile properties by which they contribute to the regulation of CBF and the phenomenon of neurovascular coupling. Pericytes also play a role in metabolite clearance and structural integrity of tight junctions.

Figure 3-. Summary of the two-hit hypothesis.

The two-hit hypothesis proposes to explain the relationship between cardiovascular disease and Alzheimer’s disease (AD). It claims that there is a two-step positive feedback loop involving beta-amyloid (Aß) and attempts to explain how it plays a role in AD pathogenesis and progression. The first step (hit 1) is Aß-independent and consists of microvascular insults, such as blood brain barrier (BBB) disruption and cerebral blood flow (CBF) reduction, resulting in vascular-mediated neuronal dysfunction, hypoxic lesions, and leakage of deleterious waste metabolites such as Aß. The second step (hit 2) is Aß-dependent and starts with the pathological accumulation of Aß, as a result of hit 1. The toxic effect of Aß on brain tissue results in neurodegeneration, translated clinically in progressive cognitive decline and eventually, dementia. In addition, since Aß also exhibits vasculotoxic properties, its pathological accumulation in the brain and the vascular system leads to more microvascular insults. This positive feedback loop therefore leads to more vascular dysfunction, itself causing more Aß accumulation, and so forth.

Figure 4-. Example of cerebral hypoperfusion.

Reduction of the cerebral blood flow (CBF), also called hypoperfusion, is one of the most prominent and earliest signs of vascular dysregulation in Alzheimer’s disease (AD). In this patient with AD-related dementia, arterial spin labeling (ASL) magnetic resonance imaging (MRI) shows bilateral occipital hypoperfusion (arrows).

Figure 5-. White matter hyperintensities.

In this patient, periventricular white matter hyperintensities (WMH) are visible as bilateral, symmetrical hyperintense lesions on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging. Compared to grey matter, white matter is more vulnerable to the ischemic conditions related to hypoperfusion, especially at advanced age. WMH are associated with multiple causes of cognitive decline, including vascular dementia and Alzheimer’s disease. Pathological changes associated with WMH include gliosis, demyelination, and axonal loss. Non-vascular causes of WMH are also described, such as inflammatory (e.g., multiple sclerosis), infectious (e.g., human immunodeficiency virus, Lyme encephalitis), or toxic (e.g., chronic alcohol abuse) etiologies. Several classifications aim to quantify the burden of WMH, for instance the Fazekas score, the WMH volume (absolute volume of WMH calculated with (semi-)automated imaging tools), and the WMH ratio (relative to total intracranial volume).

Figure 6-. Microbleeds in cerebral amyloid angiopathy.

In this patient with cerebral amyloid angiopathy (CAA), susceptibility-weighted angiography (SWAN) was used to illustrate the extent of peripherally located microbleeds. SWAN is a high-resolution 3D magnetic resonance imaging (MRI) sequence that is highly sensitive to the presence of blood products. Although they represent a hallmark of CAA, their association with cognitive decline remains debated.

Figure 7-. Cerebral small vessel disease.

In both vascular dementia and Alzheimer’s disease (AD), cerebral small vessel disease (CSVD) is highly prevalent and is thought to contribute to cognitive impairment. In this example, this subject with diagnosed AD dementia has extensive, confluent white matter hyperintensities in addition to hippocampal volume loss. There is one microhemorrhage on SWI that is more centrally located in the white matter, more consistent with a microhemorrhage associated with hypertension than the peripherally located microhemorrhages more commonly seen in cerebral amyloid angiopathy.