{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:50:49Z","timestamp":1787028649337,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T00:00:00Z","timestamp":1716768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CM18\/00106"],"award-info":[{"award-number":["CM18\/00106"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["RH-0135-2020"],"award-info":[{"award-number":["RH-0135-2020"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Consejer\u00eda de Salud y Familias","award":["CM18\/00106"],"award-info":[{"award-number":["CM18\/00106"]}]},{"name":"Consejer\u00eda de Salud y Familias","award":["RH-0135-2020"],"award-info":[{"award-number":["RH-0135-2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods: We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares\u2013Discriminant Analysis (PLS-DA), differential expression with moderated t-test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results: Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p &lt; 0.05), while PPY showed downregulation (p &lt; 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A\/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene (p &lt; 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions: Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression.<\/jats:p>","DOI":"10.3390\/jcm13113138","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T09:33:31Z","timestamp":1716802411000},"page":"3138","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research"],"prefix":"10.3390","volume":"13","author":[{"given":"Paloma","family":"Men\u00e9ndez-Valladares","sequence":"first","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"},{"name":"Department of Clinical Biochemistry, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Commission of Neurochemistry and Neurological Diseases, Spanish Society of Laboratory Medicine, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Acevedo Aguilera","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"N\u00fa\u00f1ez-Jurado","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"},{"name":"Department of Clinical Biochemistry, Virgen Macarena University Hospital, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"L\u00f3pez Azc\u00e1rate","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Dom\u00ednguez Mayoral","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Fern\u00e1ndez-Vega","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8940-9763","authenticated-orcid":false,"given":"Soledad","family":"P\u00e9rez-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Lamana Vallverd\u00fa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Isabel","family":"Garc\u00eda-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Virgen Macarena Hospital Biobank, Biobank of the Public Health System of Andalusia, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Morales Bravo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Busquier","sequence":"additional","affiliation":[{"name":"Department of Radiology, Virgen Macarena University Hospital, 41009 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-2279","authenticated-orcid":false,"given":"Joan","family":"Montaner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Virgen Macarena University Hospital, 41009 Seville, Spain"},{"name":"Department of Neurology, Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/S1474-4422(23)00318-6","article-title":"Advancing our knowledge about cerebral small vessel diseases","volume":"22","author":"Gorelick","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/jcbfm.2015.62","article-title":"Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain?","volume":"36","author":"Joutel","year":"2016","journal-title":"J. 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