The Venular Side of Cerebral Amyloid Angiopathy: Proof of Concept of a Neglected Issue

Abstract

Small vessel diseases (SVD) is an umbrella term including several entities affecting small arteries, arterioles, capillaries, and venules in the brain. One of the most relevant and prevalent SVDs is cerebral amyloid angiopathy (CAA), whose pathological hallmark is the deposition of amyloid fragments in the walls of small cortical and leptomeningeal vessels. CAA frequently coexists with Alzheimer’s Disease (AD), and both are associated with cerebrovascular events, cognitive impairment, and dementia. CAA and AD share pathophysiological, histopathological and neuroimaging issues. The venular involvement in both diseases has been neglected, although both animal models and human histopathological studies found a deposition of amyloid beta in cortical venules. This review aimed to summarize the available information about venular involvement in CAA, starting from the biological level with the putative pathomechanisms of cerebral damage, passing through the definition of the peculiar angioarchitecture of the human cortex with the functional organization and consequences of cortical arteriolar and venular occlusion, and ending to the hypothesized links between cortical venular involvement and the main neuroimaging markers of the disease.

A Closer Look at the Perivascular Unit in the Development of Enlarged Perivascular Spaces in Obesity, Metabolic Syndrome, and Type 2 Diabetes Mellitus

“…Notably, Hartmann et al [107] and Duvernoy et al [117] have previously described how penetrating venules formed "units" that were surrounded by rings of penetrating arterioles [107]. Exact ratios were not specified in their studies; however, a typical penetrating venule appeared to drain blood supplied by ~4-5 penetrating arterioles (Figure 21) [63,103].…”

“…However, EPVS have also been identified in the midbrain (Type III), and they have been identified in the hippocampus and more recently characterized in the subcortical white matter of the anterior superior temporal lobe, cerebellum at the dentate nucleus, and brain stem [62]. With the use of newer more high-intensity 7T MRIs and increased interest in the glymphatic system and EPVS, we will undoubtedly come to learn of even more areas as the venular system is explored and studied more carefully [63]. The EPVS that result from the multicellular crosstalk and aberrant remodeling are most commonly identified in either the basal ganglia (BG) or the centrum semiovale (CSO) on MRI T2 weighted images.…”

“…Additionally, with the newer use of algorithm-based identification of EPV, we may find new regional variation in other clinical diseases as we perform more refined studies with higher-intensity MRI machines such as 3 and 7T MRIs in this field of study. Over time, we have found that this aberrant remodeling and development of EPVS may be also found to be associated with the venular systems [63] within the brain, since we are learning more and more about the glymphatic system at an exponential rate [72].…”

“…All small vessels including the postcapillary venules, venules, and veins are almost completely covered by astrocytic endfeet that provide for a relative barrier, since there are known to be up to 20 nm clefts/gaps between some pvACef [102]. pvACef ensheathment of cortical postcapillary venules, venules, and veins play an essential role in the transcellular trafficking of metabolic solutes, ions, and water as they diffuse bidirectionally into and out of the interstitial neuronal parenchymal spaces at the level of the PVS within the PVUs and subsequently empty into the SAS and CSF to the systemic circulation (Figure 2) [63,102,103]. Also, the polarized AQP4 water channels located at the plasmalemma of pvACef/psACef are responsible for bidirectional water flow and are essential for proper water and volume homeostasis including the ISF within the PVS and the interstitial spaces of the parenchyma, CNS, CSF, PVS within the PVU, and the astrocyte itself [9,89].…”

Tumor-like Lesions in Primary Angiitis of the Central Nervous System: The Role of Magnetic Resonance Imaging in Differential Diagnosis

“…This issue is still open to etiological hypotheses, because the differential effect of SV-PACNS and LV-PACNS on this appearance in t-PACNS is not fully convincing. A more convincing hypothesis could be the venular involvement, a debated issue also in CAA [ 22 ], but it needs further investigations, considering the role of perivenular inflammation in other neurological diseases [ 23 ]. Another common finding is the presence of punctate or linear microhemorrhages within the lesions on GRE-T2* or SWI sequences [ 10 ], probably due to the alteration of vessel wall permeability induced by a vessel wall inflammatory infiltrate.…”