Cerebrovascular reactivity to carbon dioxide in Alzheimer's disease.

Vasoreactivity is a vasodilatory or constrictor reaction of a blood vessel to a stimulus. In neuroscience, the often-studied measure of cerebrovascular reactivity is the response of brain vessels to changing arterial tension of carbon dioxide: the CVRCO2 which is a topic of this review. Carbon dioxide elevation causes vasodilatation and an increase in cerebral blood flow (CBF), while CO2 reduction results in vasoconstriction and CBF decrease. This process is crucial for maintaining pH and respiratory drive [1]. The response of the cerebral circulation to a changing arterial CO2 concentration is not linear: the circulatory response to hypercapnia is greater than the reaction to hypocapnia [2–4]. The percentage of CBF increase in the human brain is estimated at about 6% per 1 mm Hg rise in arterial tension of CO2 (PaCO2); hypocapnia decreases CBF by approximately 3% per 1 mm Hg change in PaCO2 [5]. With end-tidal CO2 (PetCO2), the effects are 5% CBF increase per 1 mmHg rise in PetCO2, and 2% CBF reduction per 1 mm Hg PetCO2 decrease [6]. PetCO2 measurements are often used instead of PaCO2 to avoid invasive sampling. However, despite the tight relationship between the two, relying on PetCO2 leads to overestimation of PaCO2 in hypercapnic conditions [7] and underestimation of CVRCO2 in hypercapnia [8]. Although commonly studied, the mechanisms behind CVRCO2 are not completely understood (Figure 1). The effect of increased CO2 on vessels is most likely mediated through the increase in perivascular pH, activation of potassium ATP [9] and non-ATP channels [10], influx of potassium, hyperpolarization of the endothelial cell [1], and subsequent decrease in intracellular calcium levels in vascular smooth muscles leading to their relaxation (for review [10]). There is growing evidence that nitric oxide (NO) is an important mediator of CO2-related vessel dilatation [1,10–12], and that it is released by the brain during hypercapnic challenge [2]. The sources of this NO increase are still debated: some argue that neurons are possible NO suppliers (reviewed in [10]), while others suggest that the endothelium may play an important role, and that endothelial dysfunction compromises CVRCO2 [12]. The response to hypocapnia likely involves a pH –related rise in inositol triphosphate leading to increased calcium concentration in vascular smooth muscle cells and vasoconstriction [13]. Altogether, the mechanisms involved in hypercapnic vasodilatation are much better described than the pathways of hypocapnic vasoconstriction. It has been suggested that vessels react more strongly to the vasodilators released during hypercapnia than to the constrictors acting during hypocapnia [14]. Figure 1 Schematic representation of proposed mechanisms involved in hypercapnic vasodilatation and hypocapnic vasoconstriction. Increase in CO2 results in increased pH and activation of potassium channels. Endothelial cells become hyperpolarized due to the rise ... Vasoreactivity is also referred to as cerebrovascular reserve [15], emphasizing the capability of the vascular system to increase its performance above resting blood flow in response to a challenge. Thus CVRCO2 can be considered a measure of vascular health. There is indeed a body of data showing that CVRCO2 is impaired in conditions affecting cerebral vasculature [16–20]. Interestingly, there is also growing evidence that CVRCO2 may be impaired in neurodegenerative diseases like Alzheimer’s disease (AD). It should be noted that CVRCO2 is a different phenomenon from the vascular response to changes in blood pressure (autoregulation) [4,11]. There is also evidence that CVRCO2 is distinct from neurovascular coupling (the increase in blood flow in response to increased brain activation) [21]. In this review, we will first outline data from preclinical experiments that may illuminate possible causes of impaired CVRCO2 in AD, even though it will not be possible to encompass all the mechanisms at play. Second, we will present clinical studies that examined CVRCO2 in subjects with normal cognition, mild cognitive impairment, (MCI), and AD dementia. They are presented by method and, when possible, in chronological order.