Background Alzheimer’s disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. Objective We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. Methods We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2), and cerebrovascular reactivity (CVR) after a single dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2, and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. Results Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p = 0.03, p = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. Conclusion Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD.
Hypercapnia challenge (e.g. inhalation of CO 2 ) has been used in calibrated fMRI as well as in the mapping of vascular reactivity in cerebrovascular diseases. An important assumption underlying these measurements is that CO 2 is a pure vascular challenge but does not alter neural activity. However, recent reports have suggested that CO 2 inhalation may suppress neural activity and brain metabolic rate. Therefore, the goal of this study is to propose and test a gas challenge that is truly ''iso-metabolic,'' by adding a hypoxic component to the hypercapnic challenge, since hypoxia has been shown to enhance cerebral metabolic rate of oxygen (CMRO 2 ). Measurement of global CMRO 2 under various gas challenge conditions revealed that, while hypercapnia (P ¼ 0.002) and hypoxia (P ¼ 0.002) individually altered CMRO 2 (by À7.6 AE 1.7% and 16.7 AE 4.1%, respectively), inhalation of hypercapnic-hypoxia gas (5% CO 2 /13% O 2 ) did not change brain metabolism (CMRO 2 change: 1.5 AE 3.9%, P ¼ 0.92). Moreover, cerebral blood flow response to the hypercapnichypoxia challenge (in terms of % change per mmHg CO 2 change) was even greater than that to hypercapnia alone (P ¼ 0.007). Findings in this study suggest that hypercapnic-hypoxia gas challenge may be a useful maneuver in physiological MRI as it preserves vasodilatory response yet does not alter brain metabolism.
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