While amyloid-centered etiology remains the leading hypothesis in Alzheimer’s disease (AD), experimental therapies targeting A-beta have been disappointing. Therefore, in recent years, improved cerebrovascular function has become an attractive goal for intervention in AD. Sildenafil, sold under the trademark Viagra, is an inhibitor of cGMP-specific phosphodiesterase and enhances nitric oxide (NO)-mediated vasodilatation. In animal studies, after treatment for 3 weeks, sildenafil has been shown to rescue the memory deficits of transgenic mouse models of AD (1). However, sildenafil has not been investigated in AD patients. The goal of this study is to obtain evidence that a single dose of sildenafil improves cerebral hemodynamic dysfunction in patients with AD.

Participants

A total of 14 early AD patients aged 62-87 years (Mean±SD 71.6±7.5) were studied on a 3T MRI (Philips). The study consisted of two sessions. The first session started in the morning. Blood pressure was measured before they entered into the MRI scanner room. Three brain physiological markers were measured by advanced MRI techniques, including CBF, cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) to CO2. After the first session, participants were taken out of the magnet and given a single 50mg dose of sildenafil. One hour later, the second session started with repeated measurement of CBF, CMRO2 and CVR. Blood pressure was measured one more time before subjects entered into the scanner room.

MRI Experiment

CBF of the participant was assessed with two different techniques. Global CBF was measured with a phase-contrast MRI technique and regional CBF was measured with a Pseudo-Continuous Arterial Spin Labeling (pCASL) technique. CMRO2 reflects the amount of oxygen consumed by the brain. Global CMRO2 (in units of μmol O2/min/100 g brain tissue) was quantified based on Fick principle of arteriovenous difference in oxygen content, in which global CBF is already measured with phase-contrast as described above and global venous oxygenation (Yv) was measured from the superior sagittal sinus (SSS) using a novel T2-relaxation-under-spin-tagging (TRUST) MRI (2) (Figure 1). CVR response to CO2 was measured using hypercapnia (5% CO2 mixed with 21% O2 and 74% N2) challenge, in which the subjects breathed hypercapnic gas and room air via a mouthpiece in an interleaved manner (50 seconds CO2, 70 seconds room air, repeated four times), while BOLD images were acquired continuously during the entire experimental period.

Statistical

Analysis Global changes in CBF, CMRO2 and CVR between the two time-points (before and after administration of sildenafil) were assessed by paired t tests. Correlations between cognitive scores and the MRI markers were assessed.

Participants’ demographic information in all experiments is summarized in Table 1. Blood pressure between two time-points was unchanged.

We first examined whether the administration of sildenafil altered blood supply to the brain. Global CBF as measured by PC-MRI was 55.3 ± 9.6 ml/100g/min (mean±SD) at the baseline and significantly increased (P=0.03) to 59.0 ± 7.9 ml/100g/min after administration of sildenafil (Fig. 2A), an increase of 7.9±12.8%. We then analyzed regional CBF maps measured with ASL MRI to examine which brain region(s) manifests the most pronounced CBF enhancement. Voxel-wise analyses suggested that increases in CBF were most significant in bilateral medial temporal lobes (MTL) (Fig. 2B), an increase by 22.8% after taking the drug.

Next, we examined whether the additional oxygen delivered due to increased blood supply was actually taken up by the brain for its oxidative metabolism. We observed that CMRO2 significantly increased by 5.1±7.9% (P=0.05) (Fig. 3A). Moreover, we found a significant correlation (P=0.04) between baseline MoCA scores and CMRO2 alterations (Fig. 3B), suggesting that physiological effects of sildenafil are more pronounced in patients with more severe cognitive deficit (R=0.59, P=0.04).

CVR is another useful index of cerebral vascular function. We found that whole-brain averaged CVR values showed a trend of lower CVR after taking drugs (paired t test, one tail P=0.05). Voxel-wise comparison revealed that CVR was significantly lower after administration of sildenafil in several brain regions including precuneus, limbic lobe, temporal lobe, and parietal lobe (Fig.4).

The present study assessed brain blood supply and metabolism before and after a single 50mg dose of sildenafil and revealed that sildenafil could improve CBF and CMRO2 in AD patients, especially in the bilateral medial temporal lobes. Furthermore, the enhancing effect seems to be more pronounced in patients with more severe cognitive deficits.