{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:04:24Z","timestamp":1791201864964,"version":"4.2.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age-related accumulation of neuromelanin (NM) has been implicated in the intrinsic vulnerability of catecholaminergic neurons in Parkinson\u2019s disease. Postmortem studies in Parkinson\u2019s disease patients have revealed elevated intracellular and extracellular NM in the substantia nigra pars compacta, whereas experimental enhancement of NM synthesis in animal models disrupts neuronal homeostasis and accelerates neurodegeneration. Low-intensity focused ultrasound combined with microbubbles (LIFU-MB) induces focal opening of the blood\u2013brain barrier. It has been shown to influence protein aggregation and modulate pigment-related processes, thereby raising the possibility that it may also impact NM dynamics in the brain.<\/jats:p>\n                  <jats:p>Here, we investigated the possibility that repeated LIFU-MB\u2013mediated blood\u2013brain barrier opening could modify NM accumulation in a non-human primate model that overexpresses human tyrosinase, leading to elevated NM accumulation in the substantia nigra pars compacta.<\/jats:p>\n                  <jats:p>Comprehensive characterization revealed that these animals exhibit several features compatible with early pathological changes in Parkinson\u2019s disease including extracellular NM release, increased iron accumulation, nigral inflammatory changes, and intracellular inclusion formation. Importantly, these alterations occur in the absence of substantial dopaminergic cell loss and behavioral deficits. LIFU-MB\u2013treated animals showed a marked reduction in both intracellular and extracellular NM, accompanied by a trend toward decreased free ferric iron.<\/jats:p>\n                  <jats:p>These results indicate that early, non-invasive LIFU-MB intervention can counteract mechanisms linked to excessive NM accumulation. Moreover, this approach provides a translational framework to explore the broader feasibility of reducing intracellular pigments and pathological aggregates in the brain. Given its clinical safety, capacity to reach deep brain structures, and non-invasive nature, LIFU-MB warrants further investigation as a possible therapeutic approach in Parkinson\u00b4s disease and other neurodegenerative disorders.<\/jats:p>","DOI":"10.1093\/brain\/awag343","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:44:59Z","timestamp":1790941499000},"source":"Crossref","is-referenced-by-count":0,"title":["Blood\u2013brain barrier opening with focused ultrasound reduces neuromelanin in a non-human primate model"],"prefix":"10.1093","author":[{"given":"Noelia","family":"Esteban-Garc\u00eda","sequence":"first","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"PhD Program in Neuroscience, Universidad Aut\u00f3noma de Madrid-Cajal Institute , Madrid, 28029 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Mart\u00edn-Fl\u00f3rez","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"PhD Program of Biochemistry, Molecular Biology and Biomedicine, Faculty of Medicine, Complutense University of Madrid , Madrid, 28040 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-0031","authenticated-orcid":false,"given":"Jos\u00e9 A","family":"Pineda-Pardo","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"L\u00f3pez-Aguirre","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Carrillo","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Rodr\u00edguez-Rojas","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"Facultad de Tecnolog\u00eda y Ciencia, Universidad Camilo Jos\u00e9 Cela , Madrid, 28036 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Trigo-Damas","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"Centro Universitario HM Hospitales de Ciencias de la Salud (CUHMED), Universidad Camilo Jos\u00e9 Cela. Madrid , 28660 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2301-5419","authenticated-orcid":false,"given":"Jos\u00e9 L","family":"Lanciego","sequence":"additional","affiliation":[{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"CNS Gene Therapy Program, Center for Applied Medical Research (CIMA), University of Navarra , Pamplona, 31008 ,","place":["Spain"]},{"name":"CIEN Foundation, Instituto de Salud Carlos III , Madrid, 28031 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7376-7470","authenticated-orcid":false,"given":"Miquel","family":"Vila","sequence":"additional","affiliation":[{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"Neurodegenerative Diseases Research Group, Vall d\u2019Hebron Research Institute (VHIR) , Barcelona, 08035 ,","place":["Spain"]},{"name":"Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona (UAB) , Barcelona, 08193 ,","place":["Spain"]},{"name":"Catalan Institution for Research and Advanced Studies (ICREA) , Barcelona, 08010 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 A","family":"Obeso","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"Centro Universitario HM Hospitales de Ciencias de la Salud (CUHMED), Universidad Camilo Jos\u00e9 Cela. Madrid , 28660 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4257-1325","authenticated-orcid":false,"given":"Javier","family":"Blesa","sequence":"additional","affiliation":[{"name":"HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales , Madrid, 28938 ,","place":["Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria HM Hospitales , Madrid, 28015 ,","place":["Spain"]},{"name":"Network Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos III , Madrid, 28031 ,","place":["Spain"]},{"name":"Centro Universitario HM Hospitales de Ciencias de la Salud (CUHMED), Universidad Camilo Jos\u00e9 Cela. Madrid , 28660 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,5]]},"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag343\/71601472\/awag343.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awag343\/71601472\/awag343.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:45:06Z","timestamp":1791200706000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/advance-article\/doi\/10.1093\/brain\/awag343\/8864851"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1093\/brain\/awag343","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"awag343"}}