High-Definition Brain Network (HDBN) Delineation of CDKL5 Deficiency Disorder (CDD) in Genetically Engineered Mice

Area of Science:

• Neuroscience
• Biomarkers
• Medical Imaging

Background:

• Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficient Disorder (CDD) is a severe neurodevelopmental and epileptic encephalopathy.
• Current anti-seizure medications are often ineffective, and therapeutic development is challenged by clinical heterogeneity and lack of biomarkers.
• Existing mouse models lack seizures, limiting seizure-based outcome measures for therapeutic evaluation.

Purpose of the Study:

• To establish high-definition brain network (HDBN) biomarkers using diffusion MRI in a Cdkl5 knockout mouse model.
• To quantify whole-brain network organization and identify disruptions relevant to CDD.
• To provide a translatable biomarker framework for CDD clinical trials.

Main Methods:

• Utilized advanced diffusion MRI tractography and graph-theoretical analysis to assess brain network organization in Cdkl5 knockout mice.
• Employed high-angular-resolution acquisition to overcome limitations of conventional diffusion tensor imaging.
• Quantified disruptions in specific brain regions implicated in CDD-related functions.

Main Results:

• Identified reproducible, region-specific disruptions in brain network organization in Cdkl5 knockout mice.
• Observed prominent network alterations in the somatosensory/somatomotor cortex, hippocampus, hypothalamus, amygdala, and superior colliculus.
• Found largely preserved network organization within the entorhinal cortex.

Conclusions:

• High-definition brain network (HDBN) metrics serve as sensitive, non-invasive biomarkers for CDD.
• These biomarkers capture clinically relevant, circuit-level abnormalities.
• HDBN biomarkers offer a unified, translatable framework for longitudinal monitoring and therapeutic evaluation across species in CDD research.