{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:04:44Z","timestamp":1789416284345,"version":"build-2803163510"},"reference-count":318,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T00:00:00Z","timestamp":1613692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Homocysteine (Hcy) is a sulfur-containing amino acid generated during methionine metabolism, accumulation of which may be caused by genetic defects or the deficit of vitamin B12 and folate. A serum level greater than 15 micro-mols\/L is defined as hyperhomocysteinemia (HHcy). Hcy has many roles, the most important being the active participation in the transmethylation reactions, fundamental for the brain. Many studies focused on the role of homocysteine accumulation in vascular or degenerative neurological diseases, but the results are still undefined. More is known in cardiovascular disease. HHcy is a determinant for the development and progression of inflammation, atherosclerotic plaque formation, endothelium, arteriolar damage, smooth muscle cell proliferation, and altered-oxidative stress response. Conversely, few studies focused on the relationship between HHcy and small vessel disease (SVD), despite the evidence that mice with HHcy showed a significant end-feet disruption of astrocytes with a diffuse SVD. A severe reduction of vascular aquaporin-4-water channels, lower levels of high-functioning potassium channels, and higher metalloproteinases are also observed. HHcy modulates the N-homocysteinylation process, promoting a pro-coagulative state and damage of the cellular protein integrity. This altered process could be directly involved in the altered endothelium activation, typical of SVD and protein quality, inhibiting the ubiquitin-proteasome system control. HHcy also promotes a constant enhancement of microglia activation, inducing the sustained pro-inflammatory status observed in SVD. This review article addresses the possible role of HHcy in small-vessel disease and understands its pathogenic impact.<\/jats:p>","DOI":"10.3390\/ijms22042051","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T09:06:10Z","timestamp":1613725570000},"page":"2051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Homocysteine in Neurology: A Possible Contributing Factor to Small Vessel Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-2697","authenticated-orcid":false,"given":"Rita","family":"Moretti","sequence":"first","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9910-3514","authenticated-orcid":false,"given":"Mauro","family":"Giuffr\u00e9","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Caruso","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9403-3564","authenticated-orcid":false,"given":"Silvia","family":"Gazzin","sequence":"additional","affiliation":[{"name":"Italian Liver Foundation, AREA SCIENCE PARK, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Italian Liver Foundation, AREA SCIENCE PARK, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.jclinepi.2009.06.006","article-title":"The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration","volume":"62","author":"Liberati","year":"2009","journal-title":"J. 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