{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T17:03:31Z","timestamp":1788023011851,"version":"build-2784847793"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background and objectives<\/jats:title>\n                    <jats:p>Cerebral small vessel disease (CSVD) represents a major contributor to both cerebral ischemic events and the development of vascular cognitive decline. Based on preclinical evidence, phosphodiesterase-5 inhibitors (PDE5-Is) may benefit neurovascular function, this systematic review and meta-analysis evaluated their effects on cerebral hemodynamics, cognitive function, and safety in patients with cerebral small vessel disease (CSVD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically searched four major databases from January 1990 to October 2025 for randomized controlled trials investigating sildenafil or tadalafil in adults with CSVD. Primary outcomes included changes in cerebral blood flow in white matter hyperintensity regions, mean flow velocity in the middle cerebral artery, and performance on standardized cognitive assessments. Data were synthesized using random-effects models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four studies involving 236 patients were included. Meta-analysis showed that PDE5-Is significantly increased cerebral blood flow in white matter hyperintensity regions (MD\u202f=\u202f1.31\u202fmL\/100\u202fg\/min, 95% CI: 0.46\u20132.15,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.002) compared to placebo, but the overall effect of PDE5-Is inhibitors on cerebral blood flow velocity was not statistically significant (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;gt;\u202f0.05). A modest reduction in diastolic blood pressure was also observed (MD\u202f=\u202f\u22124.65\u202fmmHg, 95% CI: \u22125.96 to \u22123.34,\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt;\u202f0.00001). The overall risk of adverse events was increased (RR\u202f=\u202f2.36, 95% CI: 1.53\u20133.65,\n                      <jats:italic>p<\/jats:italic>\n                      =\u202f0.0001), but no severe adverse events were reported. No significant cognitive improvements were found across any domain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>PDE5-Is significantly improve cerebral hemodynamic parameters in patients with CSVD, alongside a modest reduction in diastolic blood pressure. But current evidence does not support a significant beneficial effect on cognitive function. Treatment is generally well-tolerated, though the increased risk of adverse events warrants attention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>Identifier CRD420261360008.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1776589","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:46:59Z","timestamp":1776055619000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphodiesterase-5 inhibitors for cerebral small vessel disease-related ischemic stroke and cognitive decline: systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Lingwan","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linkun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxin","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luo","family":"Man","sequence":"additional","affiliation":[{"name":"Department of Neurology, First Affiliated Hospital of Guangxi Medical University","place":["Nanning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1016\/S1474-4422(19)30079-1","article-title":"Small vessel disease: mechanisms and clinical implications","volume":"18","author":"Wardlaw","year":"2019","journal-title":"Lancet Neurol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3326","DOI":"10.1016\/j.jacc.2019.04.034","article-title":"Vascular cognitive impairment and dementia: JACC scientific expert panel","volume":"73","author":"Iadecola","year":"2019","journal-title":"J Am Coll 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Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.brainresbull.2012.08.010","article-title":"Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion\/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats","volume":"90","author":"Dias Fiuza Ferreira","year":"2013","journal-title":"Brain Res Bull"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e4814","DOI":"10.1371\/journal.pone.0048141","article-title":"Sildenafil enhances neurogenesis and oligodendrogenesis in ischemic brain of middle-aged mouse","volume":"7","author":"Zhang","year":"2012","journal-title":"PLoS One"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e6601","DOI":"10.1590\/1414-431x20176601","article-title":"Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition","volume":"51","author":"Verri","year":"2018","journal-title":"Braz J Med Biol Res"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41582-018-0014-y","article-title":"Cerebral small vessel disease: from a focal to a global perspective","volume":"14","author":"Ter Telgte","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1159\/000522213","article-title":"Cerebral small-vessel diseases: a look back from 1991 to today","volume":"51","author":"Grosset","year":"2022","journal-title":"Cerebrovasc Dis"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1161\/01.STR.0000237236.88823.47","article-title":"National Institute of Neurological Disorders and Stroke-Canadian stroke network vascular cognitive impairment harmonization standards","volume":"37","author":"Hachinski","year":"2006","journal-title":"Stroke"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.bbadis.2016.01.015","article-title":"Stroke injury, cognitive impairment and vascular dementia","volume":"1862","author":"Kalaria","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1038\/jcbfm.2015.45","article-title":"Targeting neutrophils in ischemic stroke: translational insights from experimental studies","volume":"35","author":"Jickling","year":"2015","journal-title":"J Cereb Blood Flow Metab"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2160","DOI":"10.1111\/j.1743-6109.2008.00935.x","article-title":"Long-term safety and efficacy of tadalafil 5 mg dosed once daily in men with erectile dysfunction","volume":"5","author":"Porst","year":"2008","journal-title":"J Sex Med"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"113818","DOI":"10.1016\/j.bcp.2020.113818","article-title":"Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease","volume":"176","author":"Zuccarello","year":"2020","journal-title":"Biochem Pharmacol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1042\/CS20160380","article-title":"Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms","volume":"131","author":"Joutel","year":"2017","journal-title":"Clin Sci"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1776589\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:47:15Z","timestamp":1776055635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1776589\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,13]]},"references-count":29,"alternative-id":["10.3389\/fneur.2026.1776589"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1776589","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,13]]},"article-number":"1776589"}}