![]() In addition, perfusion deficits have been associated with decreased functional connectivity despite maintained glucose metabolism ( Göttler et al., 2018). Non-invasive functional magnetic-resonance imaging (MRI) has provided strong evidence that CBF can be used to distinguish between at-risk individuals, patients and normal controls ( Johnson et al., 2005). Irrespective of the specific disease mechanism, vascular deficits have been demonstrated as a promising early indicator of AD. Paradoxically, tau pathology has been associated with an increase in regional vascular reactivity ( Wells et al., 2015), a controversy that is still under investigation. The various pathways of vascular dysfunction can lead to increasing vascular tortuosity and decreasing vascular reactivity ( Black et al., 2009), compromising Aβ clearance and eventually lead to neuronal death. Furthermore, Aβ-mediated pericyte degeneration leads to BBB breakdown, increasing the perivascular accumulation of neurotoxins. Moreover, the cholinergic deficit in AD can result in a reduction of cholinergic input to cortical blood vessels ( Claassen and Zhang, 2011). Aβ is known to interact with endothelin-1 ( Kawanabe and Nauli, 2011) and myocardin ( Ramanathan et al., 2015) to promote vascular hypercontractility. Soluble amyloid beta (Aβ), which predates Aβ plaques, deregulates cerebrovascular function by activating a free-radical cascade ( Park et al., 2008), leading to compromised microvascular integrity ( Dorr et al., 2012), and reduced CBF. In brief, the current understanding is that genetic, environmental, and lifestyle factors may all predispose individuals to damage to the NVU (Figure 1). While the □4 allele of the apolipoprotein E (APOE) gene is an acknowledged genetic risk factor found in 40–80% of Alzheimer’s disease (AD) patients ( Strittmatter et al., 1993), and amyloid plaques are a hallmark of AD, an approximated 60–90% of AD patients also exhibit cerebrovascular pathologies ( Bell and Zlokovic, 2009), supporting the vascular theory of AD. Neurovascular dysfunction leads to failure to meet neuronal energy needs, which leads to oxidative stress and eventual neuronal death. Pericytes play a crucial role in the formation and functionality of the selectively permeable space that is the blood–brain barrier (BBB), and BBB disruption is a classic marker of vascular dysfunction. The NVU consists of arterial/arteriolar vascular smooth-muscle cells (VMSCs), endothelial cells, neuroglia (notably astrocytes), and pericytes. The brain’s energy needs are mainly met by neurovascular regulation of cerebral blood flow (CBF) ( Roy and Sherrington, 1890 Duling and Berne, 1970), realized by the neurovascular unit (NVU). It also summarizes the biological basis for the vascular contribution to AD, and provides critical perspective on the choice of CVR-mapping techniques amongst frail populations. This review focuses on the use of MRI to map CVR, paying specific attention to recent developments in MRI methodology and on the emerging stimulus-free approaches to CVR mapping. CVR is a measure that is rooted in clinical practice, and as non-invasive CVR-mapping techniques become more widely available, routine CVR mapping may open up new avenues of investigation into the development of AD. As a result, neuroimaging studies of AD are increasingly aiming to incorporate vascular measures, exemplified by measures of cerebrovascular reactivity (CVR). However, there is growing recognition of the link between cerebrovascular dysfunction and AD, supported by continuous experimental evidence in the animal and human literature. 2Department of Medical Biophysics, University of Toronto, Toronto, ON, CanadaĪlzheimer’s disease (AD) is associated with well-established macrostructural and cellular markers, including localized brain atrophy and deposition of amyloid.1Rotman Research Institute, Baycrest, Toronto, ON, Canada.
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