Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in
Matteo Lenge1, Simona Balestrini1, Antonio Napolitano2
1Child Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital IRCCS, 50139, Florence, Italy.
Insights
Protocadherin-19 (PCDH19) encephalopathy is linked to reduced brain surface area and hippocampal/amygdala atrophy. These structural changes correlate with epilepsy severity and psychiatric comorbidities in patients.
Area of Science:
- Neuroscience
- Genetics
- Radiology
Background:
- Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy presents with early-onset epilepsy, intellectual disability, and psychiatric disorders.
- Previous studies identified abnormal cortical areas and white matter in the limbic formation.
Purpose of the Study:
- To investigate structural brain alterations in PCDH19 encephalopathy using advanced neuroimaging techniques.
- To correlate these structural changes with clinical variables and PCDH19 expression patterns.
Main Methods:
- Employed morphometric, network-based, and multivariate statistical analyses on MRI data from 20 PCDH19-mutated patients.
- Examined cortex, hippocampus, and amygdala substructures.
- Correlated morphometric findings with clinical data and PCDH19 expression.
Main Results:
- Significant reductions in whole-brain cortical surface area and limbic network regions (parahippocampal, entorhinal gyri).
- Bilateral atrophy in amygdala and hippocampus subunits (CA regions), with shape differences in hippocampal structures.
- Greater psychiatric comorbidity correlated with more severe alterations in the entorhinal gyrus and hippocampus.
Conclusions:
- PCDH19 encephalopathy is characterized by specific patterns of cortical and subcortical atrophy.
- Quantitative MRI findings correlate with clinical severity and may have predictive value.
- This condition serves as a model for genetically determined, network-based neuropsychiatric disorders.
Abstract:
Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right pvalue = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri pvalue = 0.230/0.016; left/right entorhinal gyri pvalue = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 pvalue = 0.002; body of the right CA3 pvalue = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (pvalue = 0.013) and body of hippocampus (pvalue = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (rvalue = -0.26, pspin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.
