Functional connectivity changes of the Locus Coeruleus in Alzheimer’s Disease

Abstract

AbstractBackgroundGrowing evidence indicates neurone loss in the Locus Coeruleus(LC) in patients with Alzheimer’s Disease(AD). The widespread projection and rich connectivity of the LC with multiple brain regions and its interaction with different neural networks suggests the importance of investigating the functional connectivity of the LC, an area of research which has been less studied. Aims: The primary aim of this study was to test for differences in functional connectivity of the LC between AD subjects and matched controls using neuromelanin‐sensitive MRI(NM‐MRI). The secondary aim of this study was to test for the effects of AD on the resting state networks.MethodPre‐processing of the fMRI and structural MRI data from 23 AD subjects and 23 controls was completed using the FMRIB Software Library(FSL). The images were skull‐stripped, registered, and normalised to the MNI152_t1_2mm_brain template. LC masks were created from the NM‐MRI scans also using FSL. The subsequent data was processed using the CONN toolbox. Seed‐to‐voxel and ROI‐ROI analysis were used to produce connectivity maps and comparisons were conducted between AD and controls, left and right LC, mild and moderate AD, and resting state networks.ResultAD subjects had connections from the LC to only 43 brain regions, compared to 80 brain regions in the controls. In comparison to controls, AD subjects had reduced LC connectivity in the subcallosal cortex(p‐FDR = 0.016417), increased LC connectivity in the right supramarginal and postcentral gyri(p‐FDR = 0.000002), and reduced connectivity in the default mode network(p‐FDR = 0.000286) and sensorimotor network(p‐FDR = 0.027524). The left LC in the AD subjects had significant connections to only 56 brain regions compared to 81 brain regions in the right LC. In particular, the left LC had decreased number of significant connections to the amygdala and vermis, compared to the right LC. The number of significant LC connections decreased with progression from controls to mild AD to moderate AD.ConclusionThis study provides new evidence of reduced LC functional connectivity in AD patients and asymmetrical reduction in the LC skewed towards the left LC. LC connectivity reduction could indicate pathogenesis and progression of AD, aiding prediction of disease progression and development of novel intervention targets.