Journal of Alzheimer’s Disease 46 (2015) 35–53 35 DOI 10.3233/JAD-142976 IOS Press Review CORE Metadata, citation and similar papers at core.ac.uk Provided by SZTE Publicatio Repozitórium - SZTE - Repository of Publications Is Vasomotion in Cerebral Arteries Impaired in Alzheimer’s Disease? Luigi Yuri Di Marcoa,∗, Eszter Farkasb, Chris Martinc, Annalena Vennerid,e and Alejandro F. Frangia aCentre for Computational Imaging and Simulation Technologies in Biomedicine (CISTIB), Department of Electronic and Electrical Engineering, University of Sheffield, Sheffield, UK bDepartment of Medical Physics and Informatics, Faculty of Medicine and Faculty of Science and Informatics, University of Szeged, Szeged, Hungary cDepartment of Psychology, University of Sheffield, Sheffield, UK dDepartment of Neuroscience, University of Sheffield, Sheffield, UK eIRCCS, Fondazione Ospedale S. Camillo, Venice, Italy Handling Associate Editor: Mauro Silvestrini Accepted 11 February 2015 Abstract. A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer’s disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this path- way. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-␤ (A␤) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter dam- age. Vasomotion—the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds including the brain—is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of A␤ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of A␤ clearance. In spite of potential clinical interest, studies address- ing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. A␤ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further A␤ and oxidative stress accumulation. Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebral autoregulation, endothelium, perivascular drainage, vascular smooth muscle cell, vasomotion INTRODUCTION Neurovascular homeostasis in the brain is main- ∗ Correspondence to: Luigi Yuri Di Marco, PhD, Centre for Com- tained through the inherent ability of vascular putational Imaging & Simulation Technologies in Biomedicine (CISTIB), Department of Electronic and Electrical Engineering, resistance to adapt to changes in blood pressure, The University of Sheffield, Sheffield S1 3JD, UK. Tel.: +44 114 thereby preserving an adequate and stable cerebral 2226074; E-mail: [email protected]. blood flow (CBF) [1]. This adaptation mechanism, ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 36 L.Y. Di Marco et al. / Impaired Vasomotion in Alzheimer’s Disease? termed autoregulation, is essential as the brain has a The mechanisms underlying AD pathogenesis are high metabolic demand. not fully understood; however, a substantial body of Cerebral autoregulation is the outcome of a complex evidence supports the hypothesis of a vascular contri- interplay of vascular, neuronal, and metabolic compo- bution to pathophysiology [26–29], in which cerebral nents, in which the vascular tonic response to increased hypoperfusion and blood-brain barrier dysfunction are blood pressure (known as myogenic response [2]) key elements [22, 26], aggravated by impaired cerebral plays an important role in maintaining an adequate microcirculation [30, 31]. level of tissue perfusion. Cerebral autoregulation deteriorates with age Arterial resistance, especially in the arteriolar [32–34], increasing neuronal vulnerability to hypoxia circulation, is also modulated by spontaneous rhyth- and ischemia [32]. In transgenic mice overexpressing mic variations in the vessel lumen resulting from amyloid-␤ protein precursor, impaired endothelium- smooth muscle dilatation and constriction. This intrin- dependent vasodilatation and paradoxical vasocon- sic phenomenon, known as vasomotion [3–5], is striction reduce basal CBF [35], resulting in impaired unrelated to cardiac rhythm, and is observed clin- autoregulation [36]. In contrast with animal models, ically through related flow variations (flowmotion) preliminary data from AD patients show no alter- using non-invasive technologies such as laser Doppler ations of cerebral autoregulation [37]. These reports, flowmetry. however, are currently few and based on very small Vasomotion has been observed in vitro and in vivo in cohorts [38–40]. Furthermore, they rely on trans- various vascular beds including, among others, skele- cranial Doppler (TCD) techniques for noninvasive tal muscles, cutaneous and retinal circulation, coronary quantification of CBF (in the middle cerebral artery). and mesenteric arteries [3, 5], and cerebral arteries These techniques measure relative velocity instead of [6–8]. absolute flow, under the assumption of constant arte- Despite research efforts spanning over 150 years, rial diameter. On the other hand, imaging techniques both the underlying mechanisms and the functional such as single-photon emission computed tomography implications of vasomotion remain to some extent (SPECT), have provided evidence of cerebrovascu- unclear. lar deficit with reduced regional CBF in AD patients It has been suggested that vasomotion can improve [41–44]. perfusion [9, 10] and local tissue oxygenation [11, 12]. Although experimental evidence is currently limited, Cerebral amyloid angiopathy mathematical computational models also support the Cerebral amyloid angiopathy (CAA), a cerebrovas- role of vasomotion in oxygen (O2) delivery [13–15]. cular disorder characterized by the accumulation of A␤ In the current view, vasomotion is the outcome of peptide in the tunica media and adventitia of cerebral multiple and interacting systems, in which the inhibi- blood vessels, is associated with vascular smooth mus- tion of one may unveil the role of another [5], thus cle cell degeneration and loss of vessel wall integrity explaining the heterogeneous manifestation of vaso- [45], resulting in impaired regulation of cerebral cir- motion in different vascular beds within the same culation [46–50], vascular insufficiency and increased organism. This heterogeneous distribution may repre- susceptibility to cerebral ischemia [51], microhemor- sent an adaptation mechanism to meet the dynamically rhages [52], and white matter damage [51]. changing local metabolic demand of the perfused tis- CAA is found in elderly patients without dementia; sues [6, 16, 17]. however, its prevalence significantly increases in spo- radic AD [23, 49], in which it is found in more than Impaired cerebral autoregulation in Alzheimer’s 60% of the cases [53]. CAA has been suggested to disease and cerebral amyloid angiopathy damage the contractile apparatus of cerebral vessels, and disrupt autoregulation [31]. Alzheimer’s disease Alzheimer’s disease (AD) is the most prevalent Focus questions cause of dementia in the older population account- ing for 65–70% of the cases [18–20]. The formation Although vasomotion is thought to play an impor- of amyloid-␤ (A␤) plaques and neurofibrillary tangles tant role in cerebral autoregulation, specific studies are the hallmarks of AD [21]; however, autopsy stud- in the context of AD or CAA in humans are ies also show symptoms of vascular pathology in the limited—possibly owing to the experimental complex- majority of AD cases [22–25]. ity of quantitative measurements. Furthermore, while L.Y. Di Marco et al. / Impaired Vasomotion in Alzheimer’s Disease? 37 experimental techniques for in vivo measurement of surrounding large draining veins. This mechanism has vasomotion in animals are available, their application been reported to depend on the expression of water to animal models of AD or CAA remains largely unex- channel aquaporin-4 in astrocytes [75]. Owing to its plored. functional analogy to peripheral lymph vessels, this This study reviews the current literature on vasomo- pathway has been termed “glymphatic” system [75]. tion, in the attempt to address two questions: A contrasting view suggests that the interstitial Question I: “Is impaired vasomotion in cerebral solutes (including A␤) from the perivascular space arteries implicated in the development or progression enter the basement membranes of capillaries and drain of sporadic Alzheimer’s disease?” along the basement membrane of the arterial tunica This question is motivated by the current view media toward the leptomeningeal arteries, in opposite