{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:44:41Z","timestamp":1789764281552,"version":"4.0.1"},"reference-count":63,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,3,27]],"date-time":"2021-03-27T00:00:00Z","timestamp":1616803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS104480"],"award-info":[{"award-number":["R21NS104480"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"publisher","award":["R01NS082338"],"award-info":[{"award-number":["R01NS082338"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Huntington\u2019s disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period.<\/jats:p>\n               <jats:p>An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington\u2019s disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington\u2019s disease.<\/jats:p>\n               <jats:p>Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington\u2019s disease. CRISPR\/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology.<\/jats:p>\n               <jats:p>This study\u2014for the first time\u2014shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awab190","type":"journal-article","created":{"date-parts":[[2021,5,26]],"date-time":"2021-05-26T19:21:09Z","timestamp":1622056869000},"page":"3101-3113","source":"Crossref","is-referenced-by-count":41,"title":["Huntingtin silencing delays onset and slows progression of Huntington\u2019s disease: a biomarker study"],"prefix":"10.1093","volume":"144","author":[{"given":"Hongshuai","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangchuang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiadi","family":"Xu","sequence":"additional","affiliation":[{"name":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA"},{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1508-8036","authenticated-orcid":false,"given":"Jing","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Miao","sequence":"additional","affiliation":[{"name":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA"},{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiliang","family":"Wei","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiying","family":"Liu","sequence":"additional","affiliation":[{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhang","family":"Lu","sequence":"additional","affiliation":[{"name":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA"},{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"name":"Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C M","family":"van Zijl","sequence":"additional","affiliation":[{"name":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA"},{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"Ross","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-7380","authenticated-orcid":false,"given":"Jun","family":"Hua","sequence":"additional","affiliation":[{"name":"F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA"},{"name":"The Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-6308","authenticated-orcid":false,"given":"Wenzhen","family":"Duan","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"name":"Solomon H. 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