Cereb Circ Cogn Behav. 2025 Nov 11;9:100520. doi: 10.1016/j.cccb.2025.100520. eCollection 2025.
ABSTRACT
BACKGROUND: Cerebral small vessel disease (CSVD) is the dominant cause of vascular cognitive impairment and dementia. We aimed to test whether continuous daily treatment with the vasoactive phosphodiesterase 5 inhibitor tadalafil improved cognitive performance in patients with CSVD.
METHODS: This is a pre-registered sub-study on cognitive outcomes from the ETLAS-2 trial, a randomized, placebo-controlled, double-blind, parallel study investigating 3 months of daily tadalafil (20 mg) treatment against placebo in patients with CSVD and previous stroke or transient ischemic attack. Outcomes were assessed twice, at baseline and after 3 months of treatment. The primary outcomes were changes in the cognitive domains of processing speed, attention, memory, and executive functions assessed by the Symbol Digit Modalities test, digit span forward, and tests from the computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB).
RESULTS: The per-protocol sub-study analysis comprised 60 participants, 28 of whom received tadalafil and 32 received placebo. Baseline cognitive impairments involved reduced processing speed and impaired visual learning and memory. At follow-up, we found a slower mean simple reaction time in the tadalafil group compared to placebo (28.8 ± 13.8 ms, p = 0.04). There were no differences between groups in any other primary or secondary outcome.
CONCLUSION: We found no overall difference in cognitive outcomes between groups over 3-month treatment. In the tadalafil group, a slower reaction time in a single test was observed, which may be a spurious finding. A longer treatment time may be required to identify potential effects on cognitive outcomes, which could be secondary to improved blood flow.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov, Unique identifier: NCT05173896.
PMID:41332889 | PMC:PMC12666843 | DOI:10.1016/j.cccb.2025.100520
