No abstract

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI. Methods:In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed.

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test–retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test–retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test–retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015).

BackgroundThis trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely‐used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of vascular cognitive impairment.MethodIn a double‐blinded, placebo‐controlled, cross‐over trial, female and male participants received tadalafil (20mg) and placebo on two visits at least 7 days apart (randomized to order of treatment). The primary endpoint was change in subcortical CBF, with secondary outcome measures including change in cortical CBF and a panel of neuropsychological assays of cognition. The Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease (PASTIS) trial was funded by the ADDF and the UK Alzheimer’s Society (Clinical trial registration: clinicaltrials.gov/ct2/show/NCT02450253; eudract.ema.europa.eu/2015‐001235‐20).ResultTadalafil increased CBF non‐significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = 0.0960). There were incidental treatment effects on systolic and diastolic blood pressure (‐7.8, ‐4.9 mmHg respectively; P<0.001). No serious adverse events were observed.ConclusionThe PASTIS trial did not identify a significant treatment effect of single‐administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.