Background: Low-grade inflammation has been implicated in the progression of neuropsychiatric disorders including psychosis, unipolar and bipolar II depression (BDII-D) [1-3]. Excess weight /obesity is considered to be a low-grade chronic inflammatory state that may be involved in the pathophysiology of psychiatric disorders [4]. Free water (FW), an imaging technique used to measure extracellular water particularly in white matter (WM) microstructure [5], is closely related to neuroinflammation. The interplay of immuno-metabolic dysregulation with WM integrity and FW has been implicated in the pathogenesis of psychiatric disorders, however, the interrelationship between peripheral inflammatory dysregulation, increased body mass index (BMI), and WM microstructures and FW are not clear in bipolar II depression (BDII-D).
Methods: FW measures including voxel-wise FW and FW corrected fractional anisotropy (FA-t) were compared between 146 BDII-D individuals and 151 health controls (HCs) using Randomise in FSL. Partial correlations with multiple comparison corrections was used to explore associations between BMI, peripheral inflammation, FW measures, and psychiatric symptoms. A low-grade inflammation composite score was created by averaging the standardized z-scores of IL-6, IL-1β, and TNF-α. Moderation analysis was conducted to explore the interrelationships among BMI, peripheral inflammation, and FW measures.
Results: Higher BMI was significantly related to lower global FAt (r = -0.316, q < 0.001), while higher peripheral inflammation of IL-6 (r = 0.361, q < 0.001), TNF-α (r = 0.267, q = 0.003) and low-grade inflammation (r = 0.223, q = 0.01) was significantly associated with higher global FW. Lower FAt in the genu of corpus callosum and higher FW in the body of corpus callosum were significantly related to higher BMI, higher peripheral inflammation, and greater depressive symptoms (all q < 0.05). Higher BMI was significant correlated with higher levels of IL-1β (r = 0.233, q = 0.013), low-grade inflammation (r = 0.236, q = 0.013), and WBC (r = 0.251, q = 0.011). Low-grade inflammation played a moderate role in the relations between BMI and FAt in the genu of corpus callosum.
Conclusions: The findings described herein expand our understanding of the potential relationship between a measure neuroinflammation and measures of peripheral inflammation in BDII-D. It was also shown that BMI contributed more to the disruption of global WM integrity, while peripheral inflammation was associated with elevated global FW. Additionally, alterations in the corpus callosum, both in terms of WM integrity and FW warrant further exploration, as it was simultaneously related to BMI, peripheral inflammation, and depressive symptoms in BDII-D. Furthermore, the high levels of low-grade inflammation moderated the relationship between greater BMI and impaired WM integrity in the genu of the corpus callosum, which implies that inflammation may play a role in the neurological effects associated with obesity, and changes in white matter integrity. Longitudinal studies are imperative to unveil the causal links among these factors.