Medial temporal lobe (MTL) ‐ default‐mode network (DMN) functional connectivity disruption in the progression of Alzheimer’s disease

Abstract

AbstractBackgroundA multi‐modal analysis of resting‐state functional connectivity disruption (fMRI) and morphometric changes characteristic of neurodegeneration (T1 structural MRI) in Alzheimer's disease (AD) was performed to develop biomarkers for the transition from cognitively normal (CN) to significant memory concern (SMC) to early and late mild cognitive impairment (EMCI, LMCI).MethodsFalse Detection Rate (FDR) corrected (q=0.005) parallel group‐level one‐way four‐factor (CN, SMC, EMCI, LMCI) ANOVA and post hoc pairwise t tests of ROI pairs [1]; same‐session functional connectivity (AFNI) and morphometry (FreeSurfer); ADNI‐3 sub‐population with baseline diagnosis CN (N=33), SMC (N=35), EMCI (N=13), and LMCI (N=14) matched for age (p=0.33), education (p=0.63), and gender (p=0.127).ResultsA 3‐mm grid of ROI seeds (r=6mm) in left MTL yielded 435 ROI “anchors”. 3D (Fisher Z‐transformed) correlation maps were computed for each subject for each anchor ROI and input to a group‐level one‐way four‐factor 3D ANOVA. Cluster analysis (N vox 20; p=0.02; P=3.45) of the 3D F Statistic maps yielded 4,185 target ROIs. An r=6mm ROI was placed at the center of mass of each target cluster. ROI anchor‐target pair correlations were input to a group‐level one‐way four‐factor ANOVA and FDR corrected (q=0.005; p*=0.003) (estimated by permutation, N=1000) which identified 2,420 significant tests (ROI pairs). Post hoc pairwise t tests only on the significant ANOVA tests were FDR‐corrected (q=0.005) and yielded 31 significant SMC‐CN tests (p*=6.3x10‐5); 54 EMCI‐CN tests (p*=1.1x10‐4); and 209 LMCI‐CN tests (p*=4.2x10‐4). The spatial distribution of target ROIs included (bilaterally) MTL and DMN‐associated regions. Of the significant SMC‐CN tests, 39% were positive (increased connectivity). In the significant EMCI‐CN tests, 100% were positive. However, in the significant LMCI‐CN comparisons, the pattern reversed and only 5% were positive. An independent analysis of right hemisphere yielded similar results.ConclusionsAn hybrid a priori data‐driven approach identified a population of MTL‐anchored ROI pairs whose spatial distribution of target ROIs included regions associated with DMN and MTL, and whose functional connectivity revealed a striking pattern of change with clinical progression when compared to CN: SMC, a mixture of hyper‐ and hypo‐connectivity; EMCI, widespread hyper‐connectivity; and LMCI, widespread hypo‐connectivity. Reference: (1) Grajski, K. A., Bressler, S., and ADNI. (2019). Neuroimage Clin. 2019;23:101860.