Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies

Abstract

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid β-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Keywords: Brain clearance; Cerebral amyloid angiopathy; Cerebrospinal fluid; Glymphatics; IPAD; Perivascular spaces.

Fig. 1

Examples from immunohistochemistry against Aβ in two autopsy cases with a clinical diagnosis of CAA, demonstrating extensive CAA with capillary involvement (A, CAA type I) and predominantly arteriolar involvement (B, CAA type II)

Fig. 2

Traditional MRI markers of CAA include lobar cerebral microbleeds and cortical superficial siderosis (A). Recently, white matter features in the form of severe degree of MRI-visible perivascular spaces (B) and white matter hyperintensities in a subcortical multi-spot pattern (C, arrows) were added to the version 2.0 of the Boston criteria for the clinical diagnosis of CAA during life. SWI: susceptibility-weighted imaging, FLAIR: fluid-attenuated inversion recovery

Fig. 3

Schematic of a human brain arteriole with the proposed entry route for CSF into the brain as well as the location of initial vascular Aβ depositions indicated (A). An example of an (X40 SP8) confocal microscopy image of a cross-section of a human brain arteriole with CAA, stained for Aβ (red), collagen IV (blue), and laminin (green) (B). Note that the Aβ is surrounding the smooth muscle cells in tunica media. SMCs: smooth muscle cells

Fig. 4

The wall and perivascular space of a penetrating arteriole from the MICrONS Cortical MM^3 volume EM dataset (A). Magnified views of the arteriole wall showing the perivascular space diminishing in size and becoming compact layers of different vascular cell types with greater cortical depth (pial surface is toward the top of the image). Specifically, the perivascular space appears to become continuous with the perivascular fibroblast layer and the basement membrane that flanks these cells. EC: endothelial cell, BM: basement membrane, SMC: smooth muscle cell, PVF: perivascular fibroblast, AC: astrocyte. Adapted from [101]. 2D cross-section and volume rendering of penetrating arteriole from mouse cortex showing ultrastructure of perivascular compartment (B). Yellow = one astrocyte. Blue/green = two individual smooth muscle cells

Fig. 5

Visualization of penetrating arteriolar perivascular space bounded by astroglial endfeet and vascular smooth muscle cells in vivo using multiphoton microscopy. Images were taken in an isoflurane anesthetized mouse. Astrocytes (green) are labeled by AAV-GFAP-Lck-GFP and smooth muscle cells (SMCs; red) are endogenous to PDGFRβ-tdTomato mice

Fig. 6

Arterial Spin Labeling (ASL) is a suitable translational MRI technique that non-invasively captures blood-to-CSF water exchange in the rat and human brain. By employing long labeling durations, long post-labeling delay times and a long echo time, the arrival of labeled spins in the CSF can be captured. The long echo time ensures that signal from brain tissue is already nulled, leaving only signal in water-like regions, like ventricular and cortical CSF. Note that exchange is not limited to the ventricles but is also found around the cortex