It was suggested 20 years ago that vascular defects present in AD may be important in the development of the disease [77
]. More recently, data from clinical imaging, epidemiological and pharmacotherapy studies have indicated that vascular changes play an important role early in AD pathogenesis [21
]. Magnetic resonance imaging (MRI), transcranial doppler measurements, and single photon excitation computed tomography (SPECT) in humans have established that the resting CBF is significantly reduced in AD patients, and this may be an early event in AD pathogenesis. Arterial spin-labeling MRI has demonstrated cerebral hypoperfusion in AD patients [48
]. Functional MRI (fMRI) studies using blood oxygenation level dependent (BOLD) contrast to measure increases in CBF during a task that assess episodic memory have established that there is a delay in the CBF response in patients with mild cognitive impairment (MCI), and that this delay in fMRI-BOLD signal becomes more pronounced in AD patients [70
]. This suggests that CBF reductions are present in the early stages of AD pathogenesis, as MCI is considered a potential transitional state between normal aging and dementia.
Longitudinal data from a large population-based study (1,730 participants of the Rotterdam Study), showed that higher CBF velocity, measured by transcranial doppler flowmetry, was related to a lower prevalence of cognitive decline [72
]. MRI scans showed less hippocampal and amygdalar atrophy in the elderly patients with greater CBF. Furthermore, this study suggested that low CBF may contribute early to the progression of dementia, prior to the cognitive decline and cerebral atrophy. Another longitudinal study examining the conversion of MCI to AD using SPECT imaging showed significant CBF reductions in the parietal lobule, angular gyrus, and precuneous of MCI patients that had a high-predictive value of conversion to AD [41
].These data also suggest that regional reduction in CBF is an early event in AD.
Studies using 2-[18F] fluoro-2-deoxy-d
-glucose (FDG)-PET, which measures cerebral glucose transport across the BBB, have shown reduction in cerebral glucose uptake in individuals with MCI or probable and possible AD prior to conversion to AD [26
]. These studies have indicated that reduced brain glucose uptake is not a result of brain atrophy, but, on the contrary, it may precede neurodegeneration [75
]. A longitudinal FDG-PET study has also suggested hippocampal reductions in glucose uptake during normal aging as a predictive factor of cognitive decline [61
Several epidemiological and pathological studies have demonstrated positive links and overlap between cerebrovascular disorder, such as atherosclerosis and AD. For example, it was found that there is a threefold increase in the risk of developing AD or vascular dementia in people with severe atherosclerosis [42
]. More recently, it was found in a large population-based study (678 participants of the Rotterdam Study) that atherosclerosis, primarily in the carotid arteries, is positively associated with the risk of developing dementia [89
]. Furthermore, postmortem grading of circle of Willis atherosclerotic lesions has showed that atherosclerosis was more severe in cases with AD and vascular dementia than in non-demented controls [6
]. It has been suggested that the atherosclerotic changes in the arteries of the circle of Willis may account for the observed hemodynamic disturbances present in brains of AD individuals [52
Another hypothesis of CBF reductions in AD has suggested that loss or abnormal cholinergic innervations of intracerebral blood vessels may contribute to brain hypoperfusion [29
]. More recently, the upregulation of two transcription factors myocardin (MYOCD) and serum response factor (SRF) in AD cerebral VSMC has been shown to lead to arterial hypercontractility potentiating reduced CBF [15
], as discussed below.
Vascular anatomical defects observed in AD further support the importance of vascular disorder in AD pathogeneses. These are atrophy and irregularities of arterioles and capillaries, swelling and increased number of pinocytic vesicles in endothelial cells, increase in collagen IV, heparan sulfate proteoglycans and laminin deposition in the basement membrane, disruption of the basement membrane, reduced total microvascular density and occasional swelling of astrocytic end feets [5
]. Reduced staining of endothelial markers CD34 and CD31 observed in AD brains suggests that there is an extensive degeneration of the endothelium during the disease progression [50
]. Recent genomic profiling of brain endothelial cells has uncovered that extremely low expression of vascular-restricted mesenchyme homeobox 2 gene in AD individuals leads to aberrant angiogenesis and premature pruning of capillary networks resulting in reductions in cerebral microcirculation [99
]. Thus, it is possible that brain endothelial morphological changes seen in AD are not caused necessarily by direct ischemic vascular injury, but may reflect a state of a failing vascular remodeling in the presence of overwhelming angiogenic stimuli and unresponsive endothelium.
Reduced smooth muscle alpha actin (SMA) expression has been suggested in AD vessels based on the immunostaining studies [28
]. However, more recent quantitative Western blot analysis indicated that SMA expression may in fact be increased in AD VSMC when the SMA protein expression levels in cerebral VSMC were normalized to the levels of proteins whose expression was not altered by AD process [15
Finally, cerebral amyloid angiopathy (CAA) with Aβ deposits in the VSMC layer of small cerebral arteries () is a major pathological insult to the neurovascular unit in AD [85
]. Aβ plaques also accumulate onto and around cerebral capillaries [16
]. Decreased clearance of Aβ across the BBB and by cells of the neurovascular unit may contribute to CAA and parenchymal Aβ deposits, as discussed below. The prevalence of CAA in AD individuals and in the elderly population without AD is >80% and 10–40%, respectively [3
]. A strong association between CAA and cognitive impairment has also been established [4
]. CAA is a significant cause of cerebral hemorrhage in elderly population [46
]. Clinical topographical imaging has shown cerebral microbleedings are present in roughly 30% of AD cases [66
]. On the other hand, lobar cerebral hemorrhage occurs in 7–18% of AD cases [36
], which may be due to a significant loss of the VSMC layer [53
] leading to vessel rupture.
Fig. 1 Cerebral amyloid angiopathy in AD. Immunofluorescent staining of smooth muscle α actin (SMA; red) and amyloid staining (thioflavin S, green) in an AD cerebral vessel from Brodmann area 9. Staining shows significant amyloid accumulation in the (more ...)