{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:44:39Z","timestamp":1785422679610,"version":"3.56.0"},"reference-count":196,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015326","name":"NIH","doi-asserted-by":"publisher","award":["R21-EB023507"],"award-info":[{"award-number":["R21-EB023507"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"NIH","doi-asserted-by":"publisher","award":["R21-NS121706"],"award-info":[{"award-number":["R21-NS121706"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015326","name":"NIH","doi-asserted-by":"publisher","award":["R21-NS142555"],"award-info":[{"award-number":["R21-NS142555"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R21-EB023507"],"award-info":[{"award-number":["R21-EB023507"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21-NS121706"],"award-info":[{"award-number":["R21-NS121706"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21-NS142555"],"award-info":[{"award-number":["R21-NS142555"]}],"id":[{"id":"https:\/\/ror.org\/044zkrt47","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["18CDA34140024"],"award-info":[{"award-number":["18CDA34140024"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"award":["18CDA34140024"],"award-info":[{"award-number":["18CDA34140024"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"publisher","award":["W81XWH1810070"],"award-info":[{"award-number":["W81XWH1810070"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-22-1-0221"],"award-info":[{"award-number":["W81XWH-22-1-0221"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"award":["W81XWH1810070"],"award-info":[{"award-number":["W81XWH1810070"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"award":["W81XWH-22-1-0221"],"award-info":[{"award-number":["W81XWH-22-1-0221"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy characterized by early-onset refractory epilepsy, severe neurodevelopmental impairment, and lifelong disability. Although more than thirty anti-seizure medications are available, most CDD patients remain pharmaco-resistant. Gene-based therapies are emerging, but therapeutic development is hindered by marked clinical heterogeneity, small patient populations, and the lack of robust, translatable brain-based biomarkers for clinical trials. Genetically engineered Cdkl5 mouse models recapitulate many cognitive, behavioral, and molecular features of CDD, yet their utility is limited by the absence of overt seizures, precluding seizure-based outcome measures. Here, we establish high-definition brain network (HDBN) biomarkers using advanced diffusion MRI tractography combined with graph-theoretical analysis to quantify whole-brain network organization in Cdkl5 knockout mice. Diffusion MRI enables non-invasive mapping of axonal connectivity by leveraging anisotropic water diffusion, while high-angular-resolution acquisition overcomes key limitations of conventional diffusion tensor imaging in regions with complex fiber architecture. We demonstrate that Cdkl5 knockout mice exhibit reproducible and region-specific disruptions in brain network organization, prominently affecting the somatosensory and somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus\u2014regions implicated in cognition, learning and memory, homeostasis, anxiety, and visual\u2013motor function. In contrast, networks within the entorhinal cortex remain largely preserved. These findings identify HDBN metrics as sensitive, non-invasive biomarkers that capture clinically relevant circuit-level abnormalities in CDD. Because diffusion MRI\u2013based network analyses are directly translatable across species, HDBN biomarkers provide a unified framework for therapeutic evaluation in mouse models, large animals, and human clinical trials, enabling longitudinal monitoring of disease progression and treatment response.<\/jats:p>","DOI":"10.3390\/biom16050652","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High-Definition Brain Network (HDBN) Delineation of CDKL5 Deficiency Disorder (CDD) in Genetically Engineered Mice"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9902-525X","authenticated-orcid":false,"given":"Dalton","family":"West","sequence":"first","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah William","family":"Coulson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8130-8513","authenticated-orcid":false,"given":"Devin Raine Everaldo","family":"Cortes","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Animal Imaging Core, Rangos Research Center, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina Elsa","family":"Schwab","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Animal Imaging Core, Rangos Research Center, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0540-4289","authenticated-orcid":false,"given":"Thomas","family":"Becker-Szurszewski","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Animal Imaging Core, Rangos Research Center, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2474-5623","authenticated-orcid":false,"given":"Sean","family":"Hartwick","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Animal Imaging Core, Rangos Research Center, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1241-045X","authenticated-orcid":false,"given":"Margaret Caroline","family":"Stapleton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella Marie","family":"Saladino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4314-3434","authenticated-orcid":false,"given":"Cecilia Wen-Ya","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0608-8181","authenticated-orcid":false,"given":"Christina M.","family":"Patterson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-1931","authenticated-orcid":false,"given":"Subramanian","family":"Subramanian","sequence":"additional","affiliation":[{"name":"UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"},{"name":"Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa Soundara","family":"Rajan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9509-5417","authenticated-orcid":false,"given":"Yijen Lin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA"},{"name":"Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15261, USA"},{"name":"Animal Imaging Core, Rangos Research Center, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.pediatrneurol.2019.02.015","article-title":"Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review","volume":"97","author":"Olson","year":"2019","journal-title":"Pediatr. 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