Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression

Abstract

Bipolar disorder affects approximately 2% of the population and is typically characterized by recurrent episodes of mania and depression. While some patients achieve remission using mood-stabilizing treatments, a significant proportion of patients show progressive changes in symptomatology over time. Bipolar progression is diverse in nature and may include a treatment-resistant increase in the frequency and severity of episodes, worse psychiatric and functional outcomes, and a greater risk of suicide. The mechanisms underlying bipolar disorder progression remain poorly understood and there are currently no biomarkers for identifying patients at risk. The objective of this study was to explore the potential of blood-brain barrier (BBB) imaging as such a biomarker, by acquiring the first imaging data of BBB leakage in bipolar patients, and evaluating the potential association between BBB dysfunction and bipolar symptoms. To this end, a cohort of 36 bipolar patients was recruited through the Mood Disorders Clinic (Nova Scotia Health Authority, Canada). All patients, along with 14 control subjects (matched for sex, age and metabolic status), underwent contrast-enhanced dynamic MRI scanning for quantitative assessment of BBB leakage as well as clinical and psychiatric evaluations. Outlier analysis has identified a group of 10 subjects with significantly higher percentages of brain volume with BBB leakage (labeled the "extensive BBB leakage" group). This group consisted exclusively of bipolar patients, while the "normal BBB leakage" group included the entire control cohort and the remaining 26 bipolar subjects. Among the bipolar cohort, patients with extensive BBB leakage were found to have more severe depression and anxiety, and a more chronic course of illness. Furthermore, all bipolar patients within this group were also found to have co-morbid insulin resistance, suggesting that insulin resistance may increase the risk of BBB dysfunction in bipolar patients. Our findings demonstrate a clear link between BBB leakage and greater psychiatric morbidity in bipolar patients and highlight the potential of BBB imaging as a mechanism-based biomarker for bipolar disorder progression.

Keywords: Anxiety; Bipolar disorder; Blood-brain barrier; Depression; Dynamic contrast-enhanced MRI; Insulin resistance.

Fig. 1

A sub-group of bipolar patients have extensive BBB leakage. A. The rate of BBB leakage was quantified for every brain voxel, with shades of blue representing tissue with non-permeable BBB and shades of red representing contrast agent accumulation due to BBB leakage. Representative leakage maps of five bipolar patients showcase the different extents of leakage among the bipolar cohort (displayed slices were selected to represent maximal BBB leakage in each subject). B. The overall percent of brain tissue with pathological leakage was calculated for all patients and controls, revealing a high variability of values among the bipolar cohort. C. Outlier analysis of all 50 subjects has identified a group with “extensive BBB leakage”, consisting of ten bipolar patients, and a group with “normal BBB leakage”, consisting of 26 patients and 14 controls (p < 0.0001). D. Compared to bipolar patients with normal BBB leakage, the “extensive BBB leakage” group had significantly higher levels of leakage in 112 of the 126 regions (Wilcoxon rank sum test with a false discovery rate correction for multiple comparisons).

Fig. 2

Extensive BBB leakage in bipolar patients is associated with a worse neuropsychiatric status. A. Representative courses of illness show an episodic course in patients with normal BBB leakage (patients I and II, red pixels representing tissue with leaky BBB), and a progression towards a chronic course in patients with extensive BBB leakage (patients III and IV). B. Quantitative analysis confirmed the higher incidence of a chronic (vs episodic) course of illness among patients with extensive BBB leakage. Extensive BBB leakage was also associated with a greater severity of depression (Montgomery–Åsberg Depression Rating Scale, MADRS), elevated anxiety (Hamilton Anxiety Rating Scale, HAM-A), and worse socio/occupational functioning (Global Assessment of Functioning, GAF). The Wilcoxon rank sum test and the Chi square test were used for comparisons of continuous and categorical variables, respectively. Error bars denote standard error of the mean. Asterisks denote level of significance, with * for p ≤ 0.05, ** for p ≤ 0.01, and *** for p ≤ 0.001.

Fig. 3

Extensive BBB leakage is associated with metabolic dysregulation. Bipolar patients with extensive BBB leakage were found to have higher body mass indices, increased risk of cardiovascular disease, advanced heart age, and higher levels of insulin resistance. Statistical comparisons were conducted using the Wilcoxon rank sum test. Error bars denote standard error of the mean. Asterisks denote p ≤ 0.05. HOMA-IR, homeostatic model assessment of insulin resistance.