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However, the link between neurodegenerative processes induced by lysosomal pathophysiology and the clinical phenotype remains unclear. This study investigated the longitudinal association of gray matter atrophy on MRI with in\u2010depth clinical phenotyping in 27 patients receiving intraventricular enzyme therapy (\n                    <jats:italic>n<\/jats:italic>\n                    <jats:sub>timepoints<\/jats:sub>\n                    \u2009=\u2009170; biannual clinical assessments and MRIs). Longitudinal changes in cortical thickness and subcortical volumes were modeled via linear mixed effects regression. We used linear regression to correlate 24\u2010week (\u039424) changes in clinical assessments with global cortical thickness and applied multivariate data\u2010driven statistics to model how specific brain regions are associated with clinical domains. Our analysis revealed a significant reduction in the mean cortical thickness over time (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22120.002,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.021), corresponding to an annual loss of 4.2%, compared to natural history controls with 12.5%, respectively. Regional analysis revealed a widespread pattern of cortical and subcortical gray matter atrophy. Global cortical thickness reductions over 24\u2009weeks (\u039424) were significantly associated with changes in the Hamburg motor and language scale \u039424, Weill Cornell scale \u039424, and Movement Disorder Inventory \u039424. Multivariate statistics identified a significant latent dimension relating regional morphometric abnormalities to worse clinical outcomes, accounting for 82% of the shared variance. Leveraging connectome data, we demonstrated that atrophy was linked to brain network architecture. Given their strong associations with clinical outcomes, MRI\u2010based brain morphometric measures are promising CLN2 disease biomarkers to aid diagnosis, monitor disease progression, and guide therapy.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70202","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T07:25:39Z","timestamp":1779521139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping Clinical Progression to Brain Atrophy in\n                    <scp>CLN2<\/scp>\n                    Patients Under Cerliponase Alfa Treatment: A Prospective Neuroimaging Study"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6426-7167","authenticated-orcid":false,"given":"Marvin","family":"Petersen","sequence":"first","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena Marie","family":"Westermann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Hagenah","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Nickel","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-1575","authenticated-orcid":false,"given":"Christoph","family":"Schwering","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Wibbeler","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3774-6765","authenticated-orcid":false,"given":"Felix L.","family":"Naegele","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils\u2010Ole","family":"Gloyer","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Flottmann","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Fiehler","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6tz","family":"Thomalla","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bastian","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurology University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University Medical Center Hamburg\u2010Eppendorf  Hamburg Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Hamburg  Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.04.008"},{"issue":"1","key":"e_1_2_14_3_1","first-page":"682","article-title":"CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis)","volume":"13","author":"Kohlsch\u00fctter A.","year":"2016","journal-title":"Pediatric Endocrinology 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