P.3.23 Disrupted connectivity of the locus coeruleus in healthy adults with parental history of Alzheimer's disease

INÉS DEL CERRO; MIRTA F. VILLARREAL; CAROLINA ABULAFIA; BÁRBARA DUARTE-ABRITTA; STELLA M. SÁNCHEZ; MARIANA N. CASTRO; HERNÁN BOCACCIO; ISIDRO FERRER; JOSÉ M. MENCHÓN; GUSTAVO SEVLEVER; CARLES SORIANO-MAS; SALVADOR M. GUINJOAN

Congreso; 31st European College of Neuropsychopharmacology Congress; 2018

Background: Neurodegenerative disorders are the most incapacitating and prevalent diseases in the elderly, and the first cause of dementia [1]. Previous studies have associated initial pathological changes with Abnormalities in the Locus Coeruleus (LC) [2], a small pontine noradrenergicnucleus involved in attentional function [3], targeting widespread cortical and subcortical brain regions [4]. Structural alterations in the LC have previously been reported in neurodegenerative processes [5]. However, no studies, todate, have evaluated its functional alterations in individuals at a high risk of developing Alzheimer?s disease (AD).Aim of the study: Based on previous evidence concerning alterations of the LC in early AD stages, we used functional magnetic resonance imaging (fMRI) to assess the functional connectivity (FC) of the LC in a large sample of asymptomatic middle-aged adults with a parental history of AD in comparison with an equivalent group of subjects without parental history of AD.Methods: Thirty-one offspring of late-onset AD (O-LOAD) (mean age ± SD=50.36 ± 8.32, 22 females) and 28 healthy controls (HC) (mean age ± SD=53.90 ± 8.44, 20 females) were assessed. All participants underwent a complete neuropsychological evaluation and a fMRI assessment. Neurocognitive measurements were analyzed with SPSS v25, while images were preprocessed, denoised and analyzed with the MATLAB-based CONN toolbox v17. Specifically, weperformed a global connectivity voxel-to-voxel (V2V) analyses to detect regions of altered FC within the pons, which was followed by a seed-based FC analysis using the V2V result as a seed. All analyses were family-wise error (FWE) corrected for multiple comparisons by means of the thresholdfree cluster enhancement (TFCE) non-parametric test.Results: HC and O-LOAD showed significant differences in the Mini-Mental State Examination (MMSE) (t= 2.921; p=0.005); the Rey Auditory-Verbal Learning Test (RAVLT) Recognition measure (t=2.547; p=0.014), and the RAVLT Delayed Recall score (t=2.699, p=0.009).The O-LOAD group, in comparison with HC, showed a decreased global connectivity degree in a cluster encompassing the left locus coeruleus (peak at x= - 4, y= -34, z= -32 (kE= 8, pFWE= 0.047, TFCE= 168.36)). Moreover, global connectivity of the left LC correlated positively with MMSE total score (r= 0.397, p= 0.002), RAVLT total score (r= 0.364, p= 0.005) and RAVLT delayed recall (r= 0.411, p= 0.003).In seed-to-voxel analysis O-LOAD individuals showed a decreased connectivity between left LC and the bilateral cerebellar Crus I (left; pFWE= 0.018; TFCE= 418.86, right; pFWE= 0.033; TFCE= 354.19), the left lobule VI of the cerebellum (pFWE= 0.025; TFCE= 383.04), the left cerebellar IX lobule (pFWE= 0.026; TFCE= 380.41), and the right cerebellar lobule X (pFWE= 0.047; TFCE= 310.13).Finally, MMSE and RAVLT Delayed Recall scores correlated positively with LC ? right cerebellum connectivity pattern in O-LOAD patients.Conclusions: Decreased FC between the LC and the cerebellum during resting state seems to characterize the OLOAD group. Moreover, the positive correlations between LC-cerebellum FC patterns and neuropsychological scorescould be suggesting the existence of a continuum in LC function in this pre-symptomatic population, since O-LOAD participants performing worse in cognitive measurements showed larger alterations in LC-cerebellum FC patterns.