Sildenafil Improves Vascular and Metabolic Function in Patients with Alzheimer's Disease

Abstract

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.

Keywords: Cerebral blood flow; Montreal Cognitive Assessment; cerebral metabolic rate of oxygen; cerebrovascular reactivity; magnetic resonance imaging; sildenafil.

Fig. 1

Representative MR images in one participant. A) Procedures to measurement of global CBF. Four PC MRI scans, red bars for Internal Carotid Arteries (ICA) and green bars for Vertebral Arteries (VA) are positioned perpendicular to the respective feeding arteries on an angiogram image (shown in black-and-white). B) Measurement of venous T₂ value using T₂ relaxation under spin tagging (TRUST) MRI. Upper panel shows raw images of control and labeled scans. The red boxes illustrate the manually drawn ROI of superior sagittal sinus (SSS). Lower panel shows difference images, i.e., control-labeled. eTE = effective echo time. Red circle highlighted the location of the SSS. C) Monoexponential fitting of the signal intensity in SSS as a function of eTE yields blood T₂ value.

Fig. 2

Comparison of cerebral blood flow (CBF) between two time-points. A) Global CBF comparison using Phase Contrast-MRI technique. The asterisk indicates p < 0.05. B) Voxel-wise analyses demonstrate a higher CBF in the bilateral medial temporal lobes after sildenafil.

Fig. 3

Effect of sildenafil administration on brain metabolic rate. A) Comparison of Cerebral metabolic rate of oxygen (CMRO₂) between two time-points. CMRO₂ increased after administration of sildenafil. B) The degree of CMRO₂ change was significantly correlated with the individual’s baseline Montreal Cognitive Assessment (MoCA) scores (p = 0.04). The error bar is standard error of the mean.

Fig. 4

Voxel based paired t-tests of CVR maps (n = 8) between the pre- and post-sessions. Both rendered review and glass-brain overlay are shown. Red color indicates clusters where CVR significantly decreased after administration of sildenafil.