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S075-4

Fronto-Amygdala Functional Dysconnectivity as an Endophenotype and
Modulated by Mitochondrial Dna 10398A in Bipolar Disorder

Cheng-Ta Li

Taipei Veterans General Hospital, Taiwan

Background/Objective: Bipolar disorder (BD) is a brain disorder and mitochondrial dysfunction
has been proposed to be critically involved in the pathophysiology of BD. A growing body of
evidence from neuroimaging studies, e.g., 18F-FDG-PET and resting-state fMRI (rsfMRI), reveals a
fronto-limbic dysregulation in BD. In addition, BD is highly heritable and mitochondrial DNA
(mtDNA) 10398A polymorphism is one of the reported BD risk genes. The mtDNA-10398A leads to
deficient glycolytic energy production by affecting mitochondrial matrix pH and intracellular
calcium levels. However, whether mtDNA-10398A has functional effects on the brain and whether
the neuroimaging findings are stable endophenotypes remain elusive. Since siblings carry identical
mtDNA, we hypothesized that certain characteristics co-segregate in BD families.

Method: We compared neuroimaging scans of 18F-FDG-PET and rsfMRI among BD patients, their
unaffected siblings (BD-sib), and a group of matched healthy control subjects. mtDNA gene
polymorphisms, fasting plasma glucose, and cognitive functions were also compared between
groups.

Result: We found that BD-pairs (BD+BDsib) carried more mtDNA-10398A and had higher fasting
glucose, even after controlling for many covariates. BD-pairs had abnormally lower glucose
utilizations in dorsolateral prefrontal cortex (dlPFC), but only BD demonstrated lower glucose
utilizations in medial PFC and cognitive function. BD-pairs also showed function dysconnectivity
between right dlPFC and bilateral amygdala. Subjects carrying mtDNA-10398A had significantly
lower prefrontal-GU (FWE-corrected p<0.05) and worse findings on rsfMRI.

Conclusion: The results suggested bipolar disorder is with a more severe inflammatory
dysregulation than the unipolar disorder, and sTNF-R1 may be a potential biomarker for staging
bipolar disorder.