The control mechanisms of CBF include chemoreceptors and autoregulation, endothelium-mediated signaling, and neurovascular coupling [14, 15]. Cerebrovascular autoregulation (CA) is the mechanism that is responsible for securing CBF over a range of blood pressures [16]. CA can be triggered by a host of stimuli, comprising changes in wall shear stress and chemical stimuli that are detected by endothelial receptors [17]. These stimuli ultimately result in changes in the tone of the smooth muscle cells of cerebral arterioles, leading to changes in arteriolar diameter that affect the brain’s resistance to blood flow. By adapting the flow resistance to local needs or changes of the systemic blood pressure, the brain secures its blood supply. There is evidence that the autonomous nervous system and the neurovascular unit also contribute to CA [18].

Chemoregulation is another mechanism that rules CBF. It involves the strong cerebrovascular responsiveness to changes in the arterial carbon dioxide partial pressure (Pa CO2) in direct relation to the pH [15]. Finally, the increased local metabolic needs that occur during neural activity are met by a powerful local increase in blood flow due to a mechanism called neurovascular coupling, also known as functional hyperemia [19]. Neurovascular coupling is executed at the level of the so-called neurovascular unit (interplay between neurons, vascular cells, and glia), ensuring that the brain’s blood supply matches its energy requirements [20, 21].

However, CA is not always able to compensate for hemodynamic challenges. The most drastic example is acute arrest of CBF, due to cardiac arrest [13], or occlusion of a large cerebral artery, which leads to infarction of brain tissue [22]. Apart from being overwhelmed, the efficacy of the CA can be reduced by microvascular diseases including those affecting the neurovascular unit. Endothelium-dependent responses in the microcirculation may be impaired in atherosclerosis, hypertension, diabetes, and old age (discussed in [1]). Oxidative stress and inflammation may play an important role in dysfunction of the neurovascular unit. Oxidative stress induces endothelial dysfunction, opening of the blood-brain barrier, and cytokine production [23]. Inflammation, in turn, enhances oxidative stress by upregulating the expression of reactive oxygen species-producing enzymes and down-regulating antioxidant defenses [24]. Furthermore, oxidative stress and inflammation compromise the repair mechanism of the damaged white matter, by interfering with proliferation, migration, and differentiation of oligodendrocyte progenitor cells [25–27]. The loss of growth factors produced by the brain, observed in both AD and VCI, further compromises repair mechanisms [28]. Finally, apolipoprotein E .4 genotype seems to have an influence on the neurovascular unit via the pericytes, giving rise to blood-brain barrier breakdown and microvascular flow changes that precede and initiate neurodegenerative changes [29, 30]. All these mechanisms affect cerebral arterioles in particular and can contribute to the development of small vessel diseases such as cerebral amyloid angiopathy and arteriolosclerosis. Diseases affecting the neurovascular unit cause blunting of the cerebral vasomotor reactivity [31, 32]. This, in turn, creates an increased vulnerability to changes in systemic blood pressure. Impaired cognition, stroke-like symptoms, and structural brain changes (white matter lesions, lacunar infarcts, and parenchymal hemorrhages) are the clinical consequences (discussed in [1]).

The amount of blood reaching the cerebral circulation further depends on cardiac function and patency of the cerebropetal arteries. In patients with HF, reduced CBF was observed, and reduced CBF correlated with a rising prevalence (of up to 25%) of cognitive dysfunction [33, 34]. Even a subclinical decrease in cardiac output has been shown to be associated with impaired cognitive functioning [35], while improvement of cardiac function by transplantation or resynchronization improved cognitive functioning [8, 10, 11]. These observations cannot be explained by the limited blood supply due to extracerebral factors beyond normally functioning CA. There is experimental evidence that reduced cardiac output hampers CA efficacy, challenging cerebral perfusion [36]. More evidence for the assumption that insufficient blood supply to the cerebral circulation can lead to cognitive impairment comes from observations in patients with blocked internal carotid arteries [37]. In a well-documented study, about half of these patients were cognitively impaired [37, 38]. Cognitive impairment could not be explained by the presence of structural brain damage, but rather by—potentially reversible—lactate accumulation in non-infarcted brain regions [39].

Apart from the amount of blood reaching the cerebral circulation, the arterial pulse profile, which is influenced by the arterial elasticity, may be an important hemodynamic parameter for the brain. Due to the so-called “Windkessel function”, the wall of a healthy, elastic aorta absorbs the pulsatile energy during systole and releases it during diastole. Due to the lower stiffness of a normal aorta as compared to the carotids (impedance mismatch), a portion of the pulsatile energy is reflected at the origin of the common carotid artery and therefore is not transmitted into the distal vasculature [40]. With increasing age and vascular risk factor exposure aortic stiffness increases, with two important hemodynamic effects [40].

First, the loss of Windkessel function causes an increase of pulsatile energy. Second, due to a decreased impedance mismatch, transmission of the increased pulsatile energy into the cerebral microcirculation is facilitated, leading to microvascular damage and impaired function. Aortic stiffness can be determined noninvasively, using ultrasound or magnetic resonance imaging (MRI), and is reflected by the pulse-wave velocity (PWV). In patients with cognitive impairment, increased PWV has been observed [34]. An inverse relationship between PWV and cognitive performance was reported cross-sectionally [41–43]. PWV was found to be an independent predictor of longitudinal changes in cognitive function in older individuals [43, 44]. Furthermore, correlations have been found between PWV and structural changes on neuroimaging studies, such as white matter lesions, atrophy, and subcortical infarcts [40]. Atherosclerosis can also contribute to the development of VCI by affecting the wall of the carotids and vertebral arteries.

In the Rotterdam Study, intracranial carotid artery calcification measured by CT is present in more than 80% of the participants [45]. Larger calcification volume is associated with smaller brain volumes, higher white matter hyperintensity loads, cerebral infarcts, and loss of microstructural brain integrity on MRI on the one hand, and on the other worse cognitive performance [46, 47]. In addition, there is evidence that atherosclerosis affects the neurovascular unit with consequences for local cerebral perfusion-metabolism (mis)matching [1]. And, finally, atherosclerosis can result in hemodynamic compromise of the brain through steno-occlusive disease and plaque rupture with thrombotic occlusion of large arteries and emboli originating from ruptured plaques [1].