A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01–0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p < 0.03, α = 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO2. We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD.

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

“…In 10 AD patients, a single 50 mg dose of sildenafil significantly decreased spontaneous neural activity in the right hippocampus as shown by the fractional amplitude of low-frequency fluctuations recorded on functional magnetic resonance imaging of the blood oxygen level-dependent signal, a parameter that had been shown to be aberrantly increased in AD patients' hippocampi and parahippocampal gyri [152]. In 12 elderly patients with AD, a single dosage of 50 mg of sildenafil significantly increased the cerebral metabolic rate of oxygen and cerebral blood flow [127].…”

Phosphodiesterase Inhibitors for Alzheimer’s Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale

“…Caffeine and cilostazol may be associated with a decreased risk of incident dementia, cognitive decline, and AD [213, 313-316, 364, 368-370, 372], suggesting that PDE inhibitors may help prevent AD. The clinical trials of denbufylline and sildenafil are promising but very preliminary [327,328,338,339], so no conclusions can be drawn from them. Clinical trials of PF-04447943 and BI 409,306 have shown a lack of efficacy [341,342], which might be because PDE9 inhibition increases periplasma membrane cGMP (rather than cytoplasmic cGMP) and allows Ca 2+ influx through CNG [68,71,213].…”

“…Single-doses of 50 mg sildenafil have been shown in small groups of AD patients to decrease spontaneous neural activity in the right hippocampus, decrease cerebrovascular reactivity, and increase cerebral blood flow and the cerebral metabolic rate of oxygen [338,339]. Based on this very limited preliminary evidence, clinical trials of sildenafil in AD patients are warranted.…”

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

“…In addition, a pilot study on a small number of AD patients [ 61 ] (5 males and 5 females) reported that a single administration of sildenafil (50 mg) is able to normalize the fractional amplitude of low frequency fluctuations (a measure of spontaneous neural activity) in the right hippocampus and in the left and right parahippocampal regions, although in the two latter cases the effect did not reach statistical significance. This normalization was not related to vascular effects and could help improve cognitive functions.…”