Intracortical Myelin in Bipolar Disorder and its Relation to Cognitive Function and Peripheral Blood Markers

Abstract

Introduction: White matter abnormalities are routinely implicated in the pathophysiology of Bipolar Disorder (BD). Although the cerebral cortex is primarily composed of gray matter, myelinated axons are present throughout the cortical layers, most abundantly in the deeper layers. This is known as intracortical myelin (ICM). Many prior studies have shown that there are decreased counts and compromised integrity of oligodendrocytes in the prefrontal cortex of individuals with BD, in addition to altered expression of myelin protein genes. We have previously shown loss of ICM in the medial frontal gyrus in BD, using both MRI and histology. We, along with other groups, have also shown that in healthy humans, the development of ICM follows an “inverted-U” trajectory. To our knowledge, no prior studies have investigated whole brain ICM in BD in vivo. The first aim of this thesis was to explore whole-brain age-related ICM maturation over young adulthood in individuals with BD-I in comparison to controls, using T1-weighted MRI, and determine whether this was associated with any clinical variables such as the age of onset, duration of illness, number of mood episodes, lifetime psychosis, and medication use. Due to ICM’s essential function of maintaining neural synchrony and the integrity of local neural connections within the cerebral cortex, its role in preserving cognitive function is becoming increasingly recognized. Although poor cognitive function persists through euthymic states in BD, its neurobiological correlates remain undetermined. The second aim of this thesis is to examine whole-brain ICM content and cognitive function in individuals with BD-I and controls. Lastly, we explore whether the association between ICM and cognition is mediated by peripheral blood markers of the inflammatory response- C-Reactive Protein (CRP) and anti-myelin basic protein (anti-MBP). Results: ICM follows an “inverted –U” pattern over age in healthy controls (p<0.05). In BD, this association with age is lost throughout the cortex, and appears to plateau. These effects are seen throughout cortex, but have the greatest magnitude in motor and premotor regions, followed by prefrontal and parietal regions. Exploratory analyses show that ICM is also associated with duration of illness, age of onset, the number of manic, hypomanic and mixed episodes, and mood stabilizer and antipsychotic use, although this does not survive correction for multiple comparisons. In BD, verbal memory (VM) performance was strongly predicted by ICM throughout a cortical network identified a priori in association with performance. Executive function, processing speed, and reaction time were also predicted by ICM, although this does not survive Bonferroni correction. Serum analysis showed that CRP was only associated with ICM in the right anterior cingulate cortex in BD, but not controls (Chapter 4). Further, CRP was associated with performance on verbal memory and Stoop tasks. anti-MBP levels were associated with ICM in regions of the bilateral visual, parietal, and somatosensory cortices, and left temporal, cingulate, and orbitofrontal cortices in healthy controls. In BD subjects, anti-MBP levels were only associated with ICM in the left caudal medial visual cortex and the right cuneus. Anti-MBP was not associated with cognitive performance in either BD or control subjects. Conclusion: The results from this thesis suggests a deficit in ICM maturation in young adults with BD. Whether this is developmental in origin is unclear. Further, ICM predicts cognitive performance on region-related tasks in BD, particularly verbal memory. Our work provides a novel potential structural correlate of cognitive performance in BD, and has significant implications for the underlying pathophysiology of cognitive dysfunction in the illness. We also identify anti-MBP as a potential marker of myelin maintenance and regenerative potential.