{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T19:28:40Z","timestamp":1769455720088,"version":"3.49.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The Neuronal Ceroid Lipofuscinoses (NCLs) may be considered distinct neurodegenerative disorders with separate underlying molecular causes resulting from monogenetic mutations. An alternative hypothesis is to consider the NCLs as related diseases that share lipofuscin pathobiology as the common core feature, but otherwise distinguished by different a) initial anatomic location, and b) disease propagation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We have tested this hypothesis by comparing known differences in symptomatology and pathology of the CLN1 phenotype caused by complete loss of <jats:italic>PPT1<\/jats:italic> function (i.e., the classical infantile form) and of the classical juvenile CLN3 phenotype. These two forms of NCL represent early onset and rapidly progressing vs. late onset and slowly progressing disease modalities respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Despite displaying similar pathological endpoints, the clinical phenotypes and the evidence of imaging and <jats:italic>postmortem<\/jats:italic> studies reveal strikingly different time courses and distributions of disease propagation. Data from CLN1 disease are indicative of disease propagation from the body, with early effects within the spinal cord and subsequently within the brainstem, the cerebral hemispheres, cerebellum and retina. In contrast, the retina appears to be the most vulnerable organ in CLN3, and the site where pathology is first present. Pathology subsequently is present in the occipital connectome of the CLN3 brain, followed by a top-down propagation in which cerebral and cerebellar atrophy in early adolescence is followed by involvement of the peripheral nerves in later adolescence\/early twenties, with the extrapyramidal system also affected during this time course.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The propagation of disease in these two NCLs therefore has much in common with the \u201cBrain-first\u201d vs. \u201cBody-first\u201d models of alpha-synuclein propagation in Parkinson's disease. CLN1 disease represents a \u201cBody-first\u201d or bottom-up disease propagation and CLN3 disease having a \u201cBrain-first\u201d and top-down propagation. It is noteworthy that the varied phenotypes of CLN1 disease, whether it starts in infancy (infantile form) or later in childhood (juvenile form), still fit with our proposed hypothesis of a bottom-up disease propagation in CLN1. Likewise, in protracted CLN3 disease, where both cognitive and motor declines are delayed, the initial manifestations of disease are also seen in the outer retinal layers, i.e., identical to classical Juvenile NCL disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.1061363","type":"journal-article","created":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T07:56:57Z","timestamp":1668153417000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Top-down and bottom-up propagation of disease in the neuronal ceroid lipofuscinoses"],"prefix":"10.3389","volume":"13","author":[{"given":"John R.","family":"Ostergaard","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hemanth R.","family":"Nelvagal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan D.","family":"Cooper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1016\/j.bbadis.2013.04.008","article-title":"NCL diseases-clinical perspectives","volume":"1832","author":"Schulz","year":"2013","journal-title":"Biochim Biophys Acta."},{"key":"B2","doi-asserted-by":"publisher","first-page":"165681","DOI":"10.1016\/j.bbadis.2020.165681","article-title":"Future perspectives: what lies ahead for neuronal ceroid lipofuscinosis research?","volume":"866","author":"Cooper","year":"2020","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/S1474-4422(18)30368-5","article-title":"Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis","volume":"18","author":"Mole","year":"2019","journal-title":"Lancet Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1212\/WNL.0b013e31825f0547","article-title":"New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses","volume":"79","author":"Williams","year":"2012","journal-title":"Neurology."},{"key":"B5","doi-asserted-by":"publisher","first-page":"102715","DOI":"10.1016\/j.nicl.2021.102715","article-title":"Alteration of brain structural connectivity in progression of parkinson's disease: a connectome-wide network analysis","volume":"31","author":"Yang","year":"2021","journal-title":"Neuroimage Clin."},{"key":"B6","doi-asserted-by":"publisher","first-page":"102718","DOI":"10.1016\/j.nicl.2021.102718","article-title":"Functional connectivity of spoken language processing in early-stage Parkinson's disease: an MEG study","volume":"32","author":"Hyder","year":"2021","journal-title":"Neuroimage Clin."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.3174\/ajnr.A5687","article-title":"Global and widespread local white matter abnormalities in juvenile neuronal ceroid lipofuscinosis","volume":"39","author":"Roine","year":"2018","journal-title":"AJNR Am J Neuroradiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.3174\/ajnr.A6306","article-title":"Topological alterations of the structural brain connectivity network in children with juvenile neuronal ceroid lipofuscinosis","volume":"40","author":"Roine","year":"2019","journal-title":"AJNR Am J Neuroradiol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1093\/brain\/awaa238","article-title":"Brain-first vs. body-first Parkinson's disease: a multimodal imaging case-control study","volume":"143","author":"Horsager","year":"2020","journal-title":"Brain."},{"key":"B10","doi-asserted-by":"publisher","first-page":"455","DOI":"10.3233\/JPD-202481","article-title":"The \u03b1-synuclein origin and connectome model (SOC model) of parkinson's disease : explaining motor asymmetry, non-motor phenotypes, and cognitive decline","volume":"11","author":"Borghammer","year":"2021","journal-title":"J Parkinson's Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/0022-510X(73)90075-0","article-title":"Infantile type of so-called neuronal ceroid-lipofuscinosis 1. 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