Dataset Information

Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial.

ABSTRACT:

Background

Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain.

Methods

The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study.

Discussion

The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024.

Trial registration

Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021.

SUBMITTER: Olmestig J

PROVIDER: S-EPMC11360322 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial.

Ölmestig Joakim J Mortensen Kristian Nygaard KN Fagerlund Birgitte B Naveed Nadia N Nordling Mette Maria MM Christensen Hanne H Iversen Helle Klingenberg HK Poulsen Mai Bang MB Siebner Hartwig Roman HR Kruuse Christina C

Trials 20240829 1

<h4>Background</h4>Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain.<h4>Methods</h4>The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the f ...[more]

PMID: 39210472

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Project description:New treatments for cerebral small-vessel disease are needed to reduce the risk of small-vessel occlusion stroke and vascular cognitive impairment. We investigated an approach targeted to the signalling molecule cyclic guanosine monophosphate, using the phosphodiesterase 5 inhibitor tadalafil, to explore if it improves cerebral blood flow and endothelial function in patients with cerebral small-vessel disease and stroke. In a randomized, double-blinded, placebo-controlled, cross-over pilot trial (NCT02801032), we included patients who had a previous (>6 months) small-vessel occlusion stroke. They received a single dose of either 20 mg tadalafil or placebo on 2 separate days at least 1 week apart. We measured the following: baseline MRI for lesion load, repeated measurements of blood flow velocity in the middle cerebral artery by transcranial Doppler, blood oxygen saturation in the cortical microvasculature by near-infrared spectroscopy, peripheral endothelial response by EndoPAT and endothelial-specific blood biomarkers. Twenty patients with cerebral small-vessel disease stroke (3 women, 17 men), mean age 67.1 ± 9.6, were included. The baseline mean values ± standard deviations were as follows: blood flow velocity in the middle cerebral artery, 57.4 ± 10.8 cm/s; blood oxygen saturation in the cortical microvasculature, 67.0 ± 8.2%; systolic blood pressure, 145.8 ± 19.5 mmHg; and diastolic blood pressure, 81.3 ± 9.1 mmHg. We found that tadalafil significantly increased blood oxygen saturation in the cortical microvasculature at 180 min post-administration with a mean difference of 1.57 ± 3.02%. However, we saw no significant differences in transcranial Doppler measurements over time. Tadalafil had no effects on peripheral endothelial function assessed by EndoPAT and endothelial biomarker results conflicted. Our findings suggest that tadalafil may improve vascular parameters in patients with cerebral small-vessel disease stroke, although the effect size was small. Increased oxygenation of cerebral microvasculature during tadalafil treatment indicated improved perfusion in the cerebral microvasculature, theoretically presenting an attractive new therapeutic target in cerebral small-vessel disease. Future studies of the effect of long-term tadalafil treatment on cerebrovascular reactivity and endothelial function are needed to evaluate general microvascular changes and effects in cerebral small-vessel disease and stroke.

Project description:Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small-vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess β-index, pressure-strain elastic modulus, and pulse-wave velocity-β. Brain magnetic resonance images were graded for cerebral small-vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that β-index (β=0.69; P=0.002), elastic modulus (β=0.78; P<0.001), and pulse-wave velocity-β (β=0.80; P<0.001) were associated with white matter hyperintensities, and elastic modulus (odds ratio [OR], 1.39 [95% CI, 1.04-1.85]) and pulse-wave velocity-β (OR, 1.47 [95% CI, 1.10-1.98]) were independently associated with lacunes. Similarly, β-index (OR, 2.04 [95% CI, 1.14-4.13]), elastic modulus (OR, 2.22 [95% CI, 1.25-4.42]), and pulse-wave velocity-β (OR, 2.50 [95% CI, 1.36-5.18]) were independently associated with vascular dementia. Carotid stiffness measures were independently associated with worse performance in global cognition, visuomotor speed, visuospatial function, and executive function. These associations became largely nonsignificant after further adjusting for cerebral small-vessel disease markers. Conclusions In memory clinic patients, carotid artery stiffness was associated with white matter hyperintensities and lacunes, impairment in global and domain-specific cognition, and causative subtypes of dementia, particularly vascular. The effects of carotid stiffness on cognition were not independent of, and were partially mediated by, cerebral small-vessel disease.

Dataset Information

Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial.

Background

Methods

Discussion

Trial registration

Publications

Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial.

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