{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T22:08:03Z","timestamp":1783721283051,"version":"3.55.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T00:00:00Z","timestamp":1672617600000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001543","name":"Neurological Foundation of New Zealand","doi-asserted-by":"crossref","award":["#1814"],"award-info":[{"award-number":["#1814"]}],"id":[{"id":"10.13039\/501100001543","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Neurogene Inc"},{"name":"Batten Disease Support and Research Association"},{"DOI":"10.13039\/501100001530","name":"Canterbury Medical Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001530","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Lincoln University post-doctoral fellowship,"},{"name":"University of Otago Health Sciences Post-doctoral fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited lysosomal storage disorders characterized by progressive neurodegeneration leading to motor and cognitive dysfunction, seizure activity and blindness. The disease can be caused by mutations in 1 of 13 ceroid lipofuscinosis neuronal (CLN) genes. Naturally occurring sheep models of the CLN5 and CLN6 neuronal ceroid lipofuscinoses recapitulate the clinical disease progression and post-mortem pathology of the human disease. We used longitudinal MRI to assess global and regional brain volume changes in CLN5 and CLN6 affected sheep compared to age-matched controls over 18 months. In both models, grey matter volume progressively decreased over time, while cerebrospinal fluid volume increased in affected sheep compared with controls. Total grey matter volume showed a strong positive correlation with clinical scores, while cerebrospinal fluid volume was negatively correlated with clinical scores. Cortical regions in affected animals showed significant atrophy at baseline (5 months of age) and progressively declined over the disease course. Subcortical regions were relatively spared with the exception of the caudate nucleus in CLN5 affected animals that degenerated rapidly at end-stage disease. Our results, which indicate selective vulnerability and provide a timeline of degeneration of specific brain regions in two sheep models of neuronal ceroid lipofuscinoses, will provide a clinically relevant benchmark for assessing therapeutic efficacy in subsequent trials of gene therapy for CLN5 and CLN6 disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac339","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T14:41:58Z","timestamp":1672670518000},"source":"Crossref","is-referenced-by-count":9,"title":["Progressive MRI brain volume changes in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinosis"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4847-2205","authenticated-orcid":false,"given":"Samantha J","family":"Murray","sequence":"first","affiliation":[{"name":"Faculty of Agriculture and Life Sciences, Lincoln University , Lincoln 7647 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa M","family":"Almuqbel","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group , Christchurch 8014 , New Zealand"},{"name":"New Zealand Brain Research Institute , Christchurch 8011 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A","family":"Felton","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group , Christchurch 8014 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolas J","family":"Palmer","sequence":"additional","affiliation":[{"name":"Pacific Radiology Group , Christchurch 8014 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Myall","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute , Christchurch 8011 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Shoorangiz","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute , Christchurch 8011 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ars\u00e8ne","family":"Ella","sequence":"additional","affiliation":[{"name":"UMR Physiologie de la Reproduction & des Comportements, INRAE\/CNRS\/University of Tours , F-37380 Nouzilly , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Keller","sequence":"additional","affiliation":[{"name":"UMR Physiologie de la Reproduction & des Comportements, INRAE\/CNRS\/University of Tours , F-37380 Nouzilly , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David N","family":"Palmer","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences , Lincoln University, Lincoln 7647 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy R","family":"Melzer","sequence":"additional","affiliation":[{"name":"New Zealand Brain Research Institute , Christchurch 8011 , New Zealand"},{"name":"Department of Medicine, University of Otago , Christchurch 8011 , New Zealand"},{"name":"School of Psychology, Speech and Hearing, University of Canterbury , Christchurch 8041 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia L","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture and Life Sciences, Lincoln University , Lincoln 7647 , New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,2]]},"reference":[{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/humu.21624","article-title":"Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses","volume":"33","author":"Kousi","year":"2012","journal-title":"Hum Mutat"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1016\/j.bbadis.2015.05.014","article-title":"Towards a new understanding of NCL pathogenesis","volume":"1852","author":"Cooper","year":"2015","journal-title":"BBA-Mol Basis Dis"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1016\/j.bbadis.2015.06.014","article-title":"The relevance of the storage of subunit c of ATP synthase in different forms and models of batten disease (NCLs)","volume":"1852","author":"Palmer","year":"2015","journal-title":"BBA-Mol Basis Dis"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jnen\/62.1.1","article-title":"The neuronal ceroid-lipofuscinoses","volume":"62","author":"Haltia","year":"2003","journal-title":"J Neuropathol Exp Neurol"},{"issue":"2","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.nbd.2007.09.006","article-title":"A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571 + 1G &gt; A) leading to excision of exon 3","volume":"29","author":"Frugier","year":"2008","journal-title":"Neurobiol Dis"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.bbadis.2006.09.004","article-title":"A missense mutation (c.184C &gt; T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA","volume":"1762","author":"Tammen","year":"2006","journal-title":"BBA-Mol Basis Dis"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1016\/j.ymthe.2018.07.015","article-title":"Longitudinal in vivo monitoring of the CNS demonstrates the efficacy of gene therapy in a sheep model of CLN5 Batten disease","volume":"26","author":"Mitchell","year":"2018","journal-title":"Mol Ther"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1038\/s41598-022-07612-7","article-title":"Natural history of retinal degeneration in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses","volume":"12","author":"Murray","year":"2022","journal-title":"Sci Rep"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.nbd.2005.01.025","article-title":"Glial activation spreads from specific cerebral foci and precedes neurodegeneration in presymptomatic ovine neuronal ceroid lipofuscinosis (CLN6)","volume":"20","author":"Oswald","year":"2005","journal-title":"Neurobiol Dis"},{"issue":"5","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/00480169.2002.36311","article-title":"Neuronal ceroid-lipofuscinosis in Borderdale sheep","volume":"50","author":"Jolly","year":"2002","journal-title":"New Zeal Vet J"},{"issue":"4","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/j.1365-2990.1989.tb01236.x","article-title":"Ceroid\u2013lipofuscinosis (Batten\u2019s disease): Pathogenesis and sequential neuropathological changes in the ovine model","volume":"15","author":"Jolly","year":"1989","journal-title":"Neuropath Appl Neuro"},{"issue":"4","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1111\/j.1365-2990.1985.tb00025.x","article-title":"Ceroid-lipofuscinosis (Batten\u2019s disease): Pathogenesis of blindness in the ovine model","volume":"11","author":"Mayhew","year":"1985","journal-title":"Neuropath Appl Neuro"},{"key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"107188","DOI":"10.1016\/j.dib.2021.107188","article-title":"Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses","volume":"37","author":"Russell","year":"2021","journal-title":"Data Brief"},{"issue":"9","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"e01096","DOI":"10.1002\/brb3.1096","article-title":"Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses","volume":"8","author":"Russell","year":"2018","journal-title":"Brain Behav"},{"issue":"2","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"376","DOI":"10.3174\/ajnr.A4978","article-title":"MRI brain volume measurements in infantile neuronal ceroid lipofuscinosis","volume":"38","author":"Baker","year":"2017","journal-title":"Am J Neuroradiol"},{"issue":"6","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.3174\/ajnr.A4669","article-title":"Brain region\u2013specific degeneration with disease progression in late infantile neuronal ceroid lipofuscinosis (CLN2 disease)","volume":"37","author":"Dyke","year":"2016","journal-title":"Am J Neuroradiol"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.pediatrneurol.2013.08.008","article-title":"Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes","volume":"50","author":"Jadav","year":"2014","journal-title":"Pediatr Neurol"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.3174\/ajnr.A4816","article-title":"Volumetric description of brain atrophy in neuronal ceroid lipofuscinosis 2: Supratentorial gray matter shows uniform disease progression","volume":"37","author":"L\u00f6bel","year":"2016","journal-title":"Am J Neuroradiol"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.3174\/ajnr.A6726","article-title":"Expanding the neuroimaging phenotype of neuronal ceroid lipofuscinoses","volume":"41","author":"Biswas","year":"2020","journal-title":"Am J Neuroradiol"},{"key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1007\/s00234-022-02988-9","article-title":"Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: A sensitive imaging biomarker","volume":"64","author":"Hochstein","year":"2022","journal-title":"Neuroradiology"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"9891","DOI":"10.1038\/s41598-019-45859-9","article-title":"CRISPR\/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease)","volume":"9","author":"Eaton","year":"2019","journal-title":"Sci Rep"},{"issue":"3","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/af\/vfz024","article-title":"The development of brain magnetic resonance approaches in large animal models for preclinical research","volume":"9","author":"Ella","year":"2019","journal-title":"Animal Frontiers"},{"issue":"7","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"e0132331","DOI":"10.1371\/journal.pone.0132331","article-title":"Rapid and progressive regional brain atrophy in CLN6 Batten disease affected sheep measured with longitudinal magnetic resonance imaging","volume":"10","author":"Sawiak","year":"2015","journal-title":"PLoS One"},{"issue":"3","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1002\/cne.24079","article-title":"Computation of a high-resolution MRI 3D stereotaxic atlas of the sheep brain.","volume":"525","author":"Ella","year":"2017","journal-title":"J Comp Neurol"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1016\/j.mri.2015.09.001","article-title":"Construction of an MRI 3D high resolution sheep brain template","volume":"33","author":"Ella","year":"2015","journal-title":"Magn Reson Imaging"},{"issue":"6","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"e0155974","DOI":"10.1371\/journal.pone.0155974","article-title":"Development and implementation of a Corriedale ovine brain atlas for use in atlas-based segmentation","volume":"11","author":"Liyanage","year":"2016","journal-title":"PLoS One"},{"key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3389\/fnana.2015.00069","article-title":"A stereotaxic, population-averaged T1w ovine brain atlas including cerebral morphology and tissue volumes","volume":"9","author":"Nitzsche","year":"2015","journal-title":"Front Neuroanat"},{"issue":"2","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/j.neuroimage.2011.10.025","article-title":"SPM: A history","volume":"62","author":"Ashburner","year":"2012","journal-title":"Neuroimage"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting linear mixed-effects models using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J Stat Soft"},{"key":"2023022702535743000_","author":"R Core Team"},{"key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3389\/fpsyg.2017.00456","article-title":"Repeated measures correlation","volume":"8","author":"Bakdash","year":"2017","journal-title":"Front Psychol"},{"key":"2023022702535743000_","author":"Grosjean"},{"issue":"5","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s002340050427","article-title":"MRI of neuronal ceroid lipofuscinosis. II. Postmortem MRI and histopathological study of the brain in 16 cases of neuronal ceroid lipofuscinosis of juvenile or late infantile type","volume":"39","author":"Autti","year":"1997","journal-title":"Neuroradiology"},{"issue":"10","key":"2023022702535743000_","doi-asserted-by":"publisher","first-page":"368","DOI":"10.33588\/rn.7310.2021174","article-title":"Neuronal ceroid lipofuscinosis. Type 6 late infantile variant in two compound heterozygous siblings with novel mutations","volume":"73","author":"Bravo-Oro","year":"2021","journal-title":"Rev Neurol"},{"issue":"3","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"S71","DOI":"10.1007\/s100720070043","article-title":"MRI In neuronal ceroid lipofuscinosis","volume":"21","author":"D\u2019Incerti","year":"2000","journal-title":"Neurol Sci"},{"key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"536221","DOI":"10.3389\/fgene.2020.536221","article-title":"Functional analysis of a novel CLN5 mutation identified in a patient with neuronal ceroid lipofuscinosis","volume":"11","author":"Luo","year":"2020","journal-title":"Front Genet"},{"issue":"5","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1111\/j.1751-0813.2002.tb10847.x","article-title":"Neuronal ceroid lipofuscinosis in Merino sheep","volume":"80","author":"Cook","year":"2002","journal-title":"Aus Vet J"},{"issue":"7","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00234-007-0220-6","article-title":"Decreased T2 signal in the thalami may be a sign of lysosomal storage disease","volume":"49","author":"Autti","year":"2007","journal-title":"Neuroradiology"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"e15752","DOI":"10.1371\/journal.pone.0015752","article-title":"Executive decision-making in the domestic sheep","volume":"6","author":"Morton","year":"2011","journal-title":"PLoS One"},{"issue":"6860","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/35102669","article-title":"Sheep don\u2019t forget a face","volume":"414","author":"Kendrick","year":"2001","journal-title":"Nature"},{"issue":"11","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"171228","DOI":"10.1098\/rsos.171228","article-title":"Sheep recognize familiar and unfamiliar human faces from two-dimensional images","volume":"4","author":"Knolle","year":"2017","journal-title":"R Soc Open Sci"},{"issue":"5","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s00429-022-02479-w","article-title":"The orbitofrontal cortex of the sheep. Topography, organization, neurochemistry, digital tensor imaging and comparison with the chimpanzee and human","volume":"227","author":"Gerussi","year":"2022","journal-title":"Brain Struct Funct"},{"issue":"1","key":"2023022702535743000_","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.nbd.2008.06.004","article-title":"Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis","volume":"32","author":"Oswald","year":"2008","journal-title":"Neurobiol Dis"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcac339\/48478474\/fcac339.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/5\/1\/fcac339\/48606533\/fcac339.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/5\/1\/fcac339\/48606533\/fcac339.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,19]],"date-time":"2023-03-19T19:32:48Z","timestamp":1679254368000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcac339\/6967066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,29]]},"references-count":43,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12,29]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcac339","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,2,1]]},"published":{"date-parts":[[2022,12,29]]},"article-number":"fcac339"}}