Aging is the leading risk factor for the development of late-onset AD. Investigation of the normal aging brain and age-related changes in vasculature serves as a fundamental template on which to better understand the pathogenesis of AD and its effect on cognition. Evidence from aging and stroke studies suggest that chronic brain hypoperfusion (CBH) leads to tissue pathology and cognitive impairments that are characteristic of AD.
With normal aging, cerebral vasculature undergoes both structural and functional changes that may act as a catalyst for cerebrovascular diseases and subsequent cognitive deficits. For example, changes in vascular ultrastructure, vascular reactivity, resting cerebral blood flow (rCBF) and oxygen metabolism are all associated with age [64
]. There is also evidence that aging, per se, in the absence of other risk factors, promotes thickening and stiffness of the arteries and increases the morbidity and mortality of myocardial infarction and stroke [65
]. Perfusion studies have shown that in normal aging, uncomplicated by the presence of hypertension, diabetes, arteriosclerosis or dementia, there is evidence for decreased CBF, CBV, cerebral metabolic rate for oxygen (CMRO2), and glucose oxidation without significant change in oxygen extraction or blood brain barrier permeability [e.g., 67
]. Also, these changes in CBF and CMRO2 have been found to be largely restricted to discrete brain regions presumed to be associated with cell loss [68
Studies have documented that CBF decreases with age, either globally or in a region specific manner. In an ASL study, Bertsch et al. demonstrated an association between the age-dependent decline in global rCBF and performance in an attention task [69
], but other studies suggest that declines in perfusion may be more region-specific. For example, brain regions critical to higher-cognition, such as the frontal cortex, the medial temporal lobe, and the cingulate gyrus display local age-related decreases in rCBF, even after controlling for partial volume effects [70
In addition to decreasing the volume of blood flow, age-related changes in cerebral vasculature can significantly alter the speed of blood flow during task performance. In a functional transcranial Doppler ultrasound study measuring cerebral blood flow velocities (BFV) in the ACA (anterior cerebral artery) and PCA (posterior cerebral artery), Sorond et al. found differences in BFV in healthy young and old adults during a word stem completion and a visual search task. In the younger subjects, greater activation was observed in the ACA than in the PCA territories during the word task, but older subjects did not show the same pattern. During the visual search task, however, both younger subjects and older subjects showed greater activation in PCA than in the ACA territories [72
]. This suggests that blood flow to frontal areas may be altered in some cognitive tasks as part of the aging process.
Neurovascular and physiological changes associated with normal aging are often reflected in behavioral differences between the young and old. Studies show that older adults tend to display a general slowing in processing speed, a reduction in inhibitory control, and a general decline of attentional resources [73
]. Models of neurocognitive aging based on neuroimaging studies suggest that during task performance, older adults recruit additional brain regions compared to younger adults due to the effects of age on brain integrity and function [76
The relationship between perfusion and cognition in older adults raises the question of whether hyperperfusion can serve as compensatory mechanism against the cognitive decline seen in normal aging. It is known that exercise promotes healthy cognitive aging [78
]. Conversely, Mozolic et al. have recently demonstrated that cognitive training increases rCBF in the rostrolateral PFC in older adults, and that this increase in rCBF correlated with the increase in their attention task [79
]. Interestingly, models of neurocognitive aging suggest that the PFC is the seat of compensatory recruitment in older adults [76
] and sometimes in MCI. In an fMRI study in which MCI patients were divided into two groups based on Mattis Dementia Rating Scale scores, higher-cognition MCI patients activated right ventrolateral and dorsolateral prefrontal cortex during verbal memory tasks while lower-cognition MCI patients and control subjects did not [80
]. This suggests that PFC compensation is present at the beginning of the MCI continuum but eventually breaks down as the symptoms increase in severity. This is similar to the hypothesis that PFC hyperperfusion is compensatory in early stages of AD [14
]. Another interesting connection between perfusion in normal aging and in AD was noted in a study by Lee et al. [81
]. In this study, cognitively normal elderly individuals displayed cortical thinning and hypoperfusion, as measured by ASL, in patterns similar to those observed in AD.
Animal studies have shown that reduced CBF over long durations, or chronic brain hypoperfusion (CBH), leads to neurochemical, metabolic, anatomic [e.g., 33
], and cognitive changes that are very similar to that observed in AD [90
]. Aged rats that were subjected to 1–2 weeks of 2-vessel occlusion showed behavioral, physiological and anatomical changes. A significant finding was that the age of the animal together with the severity of CBH determined whether reperfusion could aid the animals to recover the CBF levels that existed prior to vessel occlusion. Based on evidence from rat CBH studies, de la Torre [85
] suggests that aging combined with a vascular risk factor can lead to CBH which can, upon falling below a certain threshold (i.e., the critically attained threshold of cerebral hypoperfusion [CATCH]), trigger hemodynamic changes in the brain micro-circulature and impair optimal delivery of glucose and oxygen needed for normal brain cell function. Because glucose and oxygen are the crucial substrates in the production of tissue energy, metabolic energy deficits can trigger an intracellular biochemical cascade that effectively compromises brain cells and eventually leads to metabolic, cognitive and tissue pathology that characterize AD [91
There is strong evidence for hypoperfusion and the occurrence of brain ischemia and infarcts. Patients with severe arterial stenosis, or narrowing of the arteries, often show the presence of microemboli that fail to get washed out on account of reduced blood flow [93
]. Hypoperfusion also leads to sub-optimal supply of nutrients to places that may be blocked by the emboli. It has been suggested that the degree of severity of stenosis is accompanied by differential rates of transient ischemic attacks (TIA; an episode of stroke-like symptoms lasting less than 24 hours) and strokes. Stroke patients in the acute and subacute phase show region specific hypoperfusion leading to cognitive deficits [94
]. There is also evidence that chronic stroke patients show hypoperfusion associated with cognitive deficits although without accompanying structural infarcts as indicated by T1- or T2-weighted scans [97
]. This suggests that functional areas receive enough blood supply so that tissue viability is sustained but not enough to support cognitive or neurological functioning [100
]. Twenty to twenty-five percent of ischemic stroke patients go on to develop post-stroke dementia, especially in patients who are 55 years or older [101
]. Patients with post-stroke dementia show changes in cerebral blood flow, white matter hyperintensities, and cortical thinning associated with varying degrees of cognitive impairments.
Although the evidence of a direct relationship between brain hypoperfusion and micro- or macro-structural changes leading to cognitive impairments is still forthcoming, recent studies suggest that the animal model of CBH proposed by de la Tore and colleagues [33
] may very likely hold true in humans too. The thesis that CBH is a key determinant of eventual cognitive impairment is borne out of studies that have demonstrated that reperfusion of hypoperfused but dysfunctional regions leads to better functional outcomes [e.g., 102
]. We therefore suggest that compromised vasculature may be represented on a continuum with mild vasculopathy falling at one end of this continuum (such as the vascular changes seen with aging), followed by moderate vasculopathy (such as those seen in patients with TIA or MCI) and severe vasculopathy (as noted in patients with stroke, VaD, or AD) falling at the other end of this continuum (see ). Chronic brain hypoperfusion may lead to micro- and macro-structural changes that are associated with cognitive impairments and dementia. However, the acuity of onset of these hypoperfusion changes contributes to the varying presentations of clinical disease in these population subsets.
Figure 1 Schematic figure of a perfusion model of chronic brain hypoperfusion (CBH) and micro- and macro-structural changes leading to behavioral deficits and cognitive impairment. The triangle represents a vasculature compromised in varying degrees with accompanying (more ...)