White Matter Tract Integrity in Alzheimer's Disease vs. Late Onset Bipolar Disorder and Its Correlation with Systemic Inflammation and Oxidative Stress Biomarkers

Abstract

Background: Late Onset Bipolar Disorder (LOBD) is the development of Bipolar Disorder (BD) at an age above 50 years old. It is often difficult to differentiate from other aging dementias, such as Alzheimer's Disease (AD), because they share cognitive and behavioral impairment symptoms. Objectives: We look for WM tract voxel clusters showing significant differences when comparing of AD vs. LOBD, and its correlations with systemic blood plasma biomarkers (inflammatory, neurotrophic factors, and oxidative stress). Materials: A sample of healthy controls (HC) (n = 19), AD patients (n = 35), and LOBD patients (n = 24) was recruited at the Alava University Hospital. Blood plasma samples were obtained at recruitment time and analyzed to extract the inflammatory, oxidative stress, and neurotrophic factors. Several modalities of MRI were acquired for each subject, Methods: Fractional anisotropy (FA) coefficients are obtained from diffusion weighted imaging (DWI). Tract based spatial statistics (TBSS) finds FA skeleton clusters of WM tract voxels showing significant differences for all possible contrasts between HC, AD, and LOBD. An ANOVA F-test over all contrasts is carried out. Results of F-test are used to mask TBSS detected clusters for the AD > LOBD and LOBD > AD contrast to select the image clusters used for correlation analysis. Finally, Pearson's correlation coefficients between FA values at cluster sites and systemic blood plasma biomarker values are computed. Results: The TBSS contrasts with by ANOVA F-test has identified strongly significant clusters in the forceps minor, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum gyrus. The correlation analysis of these tract clusters found strong negative correlation of AD with the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) blood biomarkers. Negative correlation of AD and positive correlation of LOBD with inflammation biomarker IL6 was also found. Conclusion: TBSS voxel clusters tract atlas localizations are consistent with greater behavioral impairment and mood disorders in LOBD than in AD. Correlation analysis confirms that neurotrophic factors (i.e., NGF, BDNF) play a great role in AD while are absent in LOBD pathophysiology. Also, correlation results of IL1 and IL6 suggest stronger inflammatory effects in LOBD than in AD.

Keywords: Alzheimer disease; inflammatory biomarkers; late onset bipolar disorder; multimodal brain data analysis; nerve growth factors; tract based spatial statistics.

Figure 1

Size of FA skeleton clusters found by each contrast (HC > AD, AD > LOBD, HC > LOBD, AD > HC, LOBD > AD,LOBD > HC, F-test) of the permutation test followed by TFCE cluster inference for each tract identified by the JHU White-Matter Tractography Atlas. R, Right; L, left; ATR, hemispheres of anterior thalamic radiation; CT, corticospinal tract; C_CG, cingulum (cingulate gyrus); CH, Cingulum (hippocampus); FMi, forceps minor; FMa, forceps major; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; SFL, superior longitudinal fasciculus; UF, uncinate fasciculus; SLFT, temporal part of SLF.

Figure 2

Visualization TBSS detection results masked by the F-test overlaid on the mean of registered FA volumes. (A) Mean skeleton (green). (B) F statistics (red-yelow) over the mean skeleton (green). (C) Clusters detected from contrast AD > LOBD masked by F-test clusters (blue) overlaying the mean skeleton (green). (D) Clusters detected from contrast LOBD > AD masked by F-test clusters (red) overlaying the mean skeleton (green).

Figure 3

Significant correlation (p < 0.01) between blood plasma biomarkers (ellipses up) and FA values at the TBSS clusters for AD > LOBD (up) and LOBD > AD contrasts, masked by the F-test, identified by the atlasquery tool (rectangles below). We report separate values for AD and LOBD populations (requested by reviewer). Red lines correspond to negative correlations, green lines correspond to positive correlations. Line width is proportional to the magnitude of correlation. R, Right; L, left; ATR, hemispheres of anterior thalamic radiation; C_CG, cingulum (cingulate gyrus); FMi, forceps minor; FMa, forceps major; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; SFL, superior longitudinal fasciculus; and UF, uncinate fasciculus.