{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:57:01Z","timestamp":1791194221379,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Pediatrics","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Intramural Research Program of the NIH","award":["1. Z1A HD009001 to Dr. An Dang Do"],"award-info":[{"award-number":["1. Z1A HD009001 to Dr. An Dang Do"]}]},{"name":"Intramural Research Program of the NIH","award":["2. ZEB000088-10 to Dr. Carlo Pierpaoli"],"award-info":[{"award-number":["2. ZEB000088-10 to Dr. Carlo Pierpaoli"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objective<\/jats:title>\n                  <jats:p>For their acceptance as endpoints in clinical trials, biomarkers and clinical outcome assessment (COA) measures should show reliability by being reproducible (precise) and responsive to change. We evaluated precision and responsiveness of MRI-derived brain volume metrics and various COAs in ceroid-lipofuscinosis, neuronal-3 (CLN3) disease.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    This longitudinal observational study (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03307304\">NCT03307304<\/jats:ext-link>\n                    ) included 44 individuals with CLN3-related disease (ages 0.5\u201329.1 years, 48% female). Brain volumetric measures were computed using SynthSeg-v2.0 from T1-weighted 3D MPRAGE images acquired at 3T (Median [Q1, Q3] total MRI follow-up duration from baseline: 2.04 [0.00, 3.69] years). Compartmental tissue volumes were normalized to a model-adjusted total intracranial volume and scaled to the tissue-specific volume fraction expected in healthy adolescent brains to extract measures of brain atrophy. COAs included the Vineland Adaptive Behavior Scales, verbal IQ, and the Unified Batten Disease Rating Scale (UBDRS). Analysis of linear mixed-effects models included only CLN3 participants with syndromic presentation, having three or more visits per measurement to estimate slope, its relative standard error (RSE), and the minimum inter-visit interval (\n                    <jats:italic>\n                      T\n                      <jats:sub>min<\/jats:sub>\n                    <\/jats:italic>\n                    ) for statistically significant progression for each participant.\n                    <jats:italic>\n                      T\n                      <jats:sub>min<\/jats:sub>\n                    <\/jats:italic>\n                    to detect progression in 75% of the population (\n                    <jats:italic>\n                      T\n                      <jats:sub>min,75%<\/jats:sub>\n                    <\/jats:italic>\n                    ) was computed for each metric.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Among brain volumetric measures, brain parenchyma volume (BPV) and gray matter volume (GMV) were the most precise and responsive metrics. BPV showed an overall\n                    <jats:italic>intra<\/jats:italic>\n                    -individual decline with age of \u22121.32%\/year (95% CI: \u22121.64% to \u22120.99%), low RSE of 12.5%, and short\n                    <jats:italic>\n                      T\n                      <jats:sub>min,75%<\/jats:sub>\n                    <\/jats:italic>\n                    of 0.85 years (95% CI: 0.47\u20131.24). Amongst COAs, the UBDRS Clinical Global Impression (CGI) score was the most precise and responsive with an overall\n                    <jats:italic>intra<\/jats:italic>\n                    -individual increase of 1.26 units\/year (95% CI: 1.03\u20131.49), RSE of 24.10%, and\n                    <jats:italic>\n                      T\n                      <jats:sub>min,75%<\/jats:sub>\n                    <\/jats:italic>\n                    of 2.56 years (95% CI: 1.73\u20133.46), though with lower precision (RSE higher) and lower responsiveness (\n                    <jats:italic>\n                      T\n                      <jats:sub>min,75%<\/jats:sub>\n                    <\/jats:italic>\n                    longer) than BPV.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>MRI-derived metrics, in particular BPV and GMV, detected change in brain atrophy with high precision and responsiveness suggesting that they would be informative for evaluating potential neuroprotective therapies in CLN3 disease. These findings support incorporating MRI-derived volumetric measurements alongside clinical assessments in future clinical trials in CLN3.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.29.26363931","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:25:22Z","timestamp":1790796322000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluating Precision and Responsiveness of MRI-derived Brain Volumetric and Clinical Outcome Measures in CLN3 Disease"],"prefix":"10.64898","author":[{"given":"Rakibul","family":"Hafiz","sequence":"first","affiliation":[{"name":"Laboratory on Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD (R.H., A.N., C.P.)"},{"name":"Military Traumatic Brain Injury Initiative (MTBI2-formerly known as the Center for Neuroscience and Regenerative Medicine [CNRM]), Bethesda, Maryland, USA. (R.H.)"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA. (R.H.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristan","family":"Farmer","sequence":"additional","affiliation":[{"name":"Neurodevelopmental and Behavioral Phenotyping Service, NIMH, NIH"},{"name":"Office of Clinical Director, NIMH, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Joseph","sequence":"additional","affiliation":[{"name":"Neurodevelopmental and Behavioral Phenotyping Service, NIMH, NIH"},{"name":"Office of Clinical Director, NIMH, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane","family":"Soldatos","sequence":"additional","affiliation":[{"name":"Office of Clinical Director, NINDS, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amritha","family":"Nayak","sequence":"additional","affiliation":[{"name":"Laboratory on Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD (R.H., A.N., C.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey E","family":"Thurm","sequence":"additional","affiliation":[{"name":"Neurodevelopmental and Behavioral Phenotyping Service, NIMH, NIH"},{"name":"Office of Clinical Director, NIMH, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An N.","family":"Dang Do","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine, NICHD, NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Pierpaoli","sequence":"additional","affiliation":[{"name":"Laboratory on Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD (R.H., A.N., C.P.)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100502400772000_2026.09.29.26363931v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/62.1.1"},{"key":"2026100502400772000_2026.09.29.26363931v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-005-0218-3"},{"key":"2026100502400772000_2026.09.29.26363931v1.3","doi-asserted-by":"publisher","DOI":"10.1542\/peds.44.4.570"},{"key":"2026100502400772000_2026.09.29.26363931v1.4","doi-asserted-by":"crossref","unstructured":"Whiteman IT , Cook AL , Augustine EF , et al. A timeline of symptom onset and disease progression in CLN3 disease. Orphanet Journal of Rare Diseases 2026;21:38.","DOI":"10.1186\/s13023-025-04174-5"},{"key":"2026100502400772000_2026.09.29.26363931v1.5","doi-asserted-by":"crossref","first-page":"e214110","DOI":"10.1212\/WNL.0000000000214110","article-title":"Long-Term Open-Label Study Evaluating Oral Miglustat Treatment in Patients With Neuronal Ceroid Lipofuscinosis Type 3","volume":"105","year":"2025","journal-title":"Neurology"},{"key":"2026100502400772000_2026.09.29.26363931v1.6","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1177\/08830738251374538","article-title":"Visual Recovery and Neurological Stabilization Following Miglustat Treatment in Pediatric CLN3 Disease","volume":"41","year":"2026","journal-title":"J Child Neurol"},{"key":"2026100502400772000_2026.09.29.26363931v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2447-21.2023"},{"key":"2026100502400772000_2026.09.29.26363931v1.8","unstructured":"Alcyone Therapeutics I. Phase I\/IIa Gene Transfer Clinical Trial for Juvenile Neuronal Ceroid Lipofuscinosis, Delivering the CLN3 Gene by Self-Complementary AAV9. 2018."},{"key":"2026100502400772000_2026.09.29.26363931v1.9","doi-asserted-by":"crossref","unstructured":"Zi\u00f3\u0142kowska EA , Jablonka-Shariff A , Williams LL , et al. Gene therapy ameliorates neuromuscular pathology in CLN3 disease. Acta Neuropathol Commun 2025;13:160.","DOI":"10.1186\/s40478-025-02059-z"},{"key":"2026100502400772000_2026.09.29.26363931v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0986-1"},{"key":"2026100502400772000_2026.09.29.26363931v1.11","doi-asserted-by":"crossref","unstructured":"Stratton MP , Centa JL , Swier VJ , et al. Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease. Nucleic Acids Res 2025;53.","DOI":"10.1093\/nar\/gkaf1141"},{"key":"2026100502400772000_2026.09.29.26363931v1.12","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318237f649"},{"key":"2026100502400772000_2026.09.29.26363931v1.13","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.ejpn.2022.03.005","article-title":"The Unified Batten Disease Rating Scale (UBDRS): Validation and reliability in an independent CLN3 disease sample","volume":"38","year":"2022","journal-title":"Eur J Paediatr Neurol"},{"key":"2026100502400772000_2026.09.29.26363931v1.14","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-018-0143-x"},{"key":"2026100502400772000_2026.09.29.26363931v1.15","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/ajmg.a.62607","article-title":"Use of the Vineland-3, a measure of adaptive functioning, in CLN3","volume":"188","year":"2022","journal-title":"Am J Med Genet A"},{"key":"2026100502400772000_2026.09.29.26363931v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s00234-022-02988-9"},{"key":"2026100502400772000_2026.09.29.26363931v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.pediatrneurol.2013.10.013"},{"key":"2026100502400772000_2026.09.29.26363931v1.18","first-page":"344","article-title":"Which Score for What?","volume":"130","year":"2025","journal-title":"Operationalizing Standardized Cognitive Test Performance for the Assessment of Change. American Journal on Intellectual and Developmental Disabilities"},{"key":"2026100502400772000_2026.09.29.26363931v1.19","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009454"},{"key":"2026100502400772000_2026.09.29.26363931v1.20","doi-asserted-by":"publisher","DOI":"10.32614\/R.manuals"},{"key":"2026100502400772000_2026.09.29.26363931v1.21","doi-asserted-by":"crossref","unstructured":"Brandel MG , Kamel GN , Carbulido K , et al. Intracranial Volumes of Healthy Children in the First 3 Years of Life: An Analysis of 270 Magnetic Resonance Imaging Scans. Plastic and Reconstructive Surgery 2022;150.","DOI":"10.1097\/PRS.0000000000009188"},{"key":"2026100502400772000_2026.09.29.26363931v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/J.DCN.2018.03.001"},{"key":"2026100502400772000_2026.09.29.26363931v1.23","doi-asserted-by":"crossref","unstructured":"Silk TJ , Genc S , Anderson V , et al. Developmental brain trajectories in children with ADHD and controls: a longitudinal neuroimaging study. BMC Psychiatry 2016;16:59.","DOI":"10.1186\/s12888-016-0770-4"},{"key":"2026100502400772000_2026.09.29.26363931v1.24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1177\/0271678X19888967","article-title":"Brain atrophy in cerebral small vessel diseases: Extent, consequences, technical limitations and perspectives: The HARNESS initiative","volume":"40","year":"2020","journal-title":"Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism"},{"key":"2026100502400772000_2026.09.29.26363931v1.25","first-page":"2020","article-title":"Cortical Thickness Estimation in Individuals With Cerebral Small Vessel Disease, Focal Atrophy, and Chronic Stroke Lesions","volume":"14","year":"2020","journal-title":"Frontiers in neuroscience"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.29.26363931","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:40:15Z","timestamp":1791193215000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.09.29.26363931"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.09.29.26363931","relation":{},"subject":[],"published":{"date-parts":[[2026,9,30]]},"subtype":"preprint"}}