Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Abstract

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.

Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).

Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.

Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

Figure 1. DMN component derived from group ICA

The DMN was readily identified in the study population in one component of the group ICA. Dorsal (A) and ventral (B) portions of this component are shown above. DMN = default mode network; ICA = independent component analysis.

Figure 2. Whole-brain analysis of variance

(A) Whole-brain map depicting regions of significantly altered DMN fcMRI across groups (p < 0.001 threshold). Comparison across groups using a 10-mm sphere region of interest in the PPC (B), mPFC (C), LPC (D), and RPC (E). For post hoc analyses, error bars are SEM. ^a p < 0.05 compared with CDR 0M−; ^b p < 0.001 compared with CDR 0M−; ^c p < 0.001 compared with CDR 0M+; ^d p < 0.005 compared with CDR 0M−; ^e p < 0.05 compared with CDR 0M+. CDR = Clinical Dementia Rating; DMN = default mode network; fcMRI = functional connectivity MRI; LPC = left lateral parietal cortex; mPFC = medial prefrontal cortex; PPC = precuneus/posterior cingulate; RPC = right lateral parietal cortex.

Figure 3. Decreasing DMN connectivity as subjects approach and surpass their expected age of symptom onset

(A) Illustration of the DMN component (a; red); regions within the DMN that show negative correlation with eYO (p < 0.001; b; blue); overlap between the left and middle panels with common regions in green (c). Decreased connectivity within the DMN as measured in a 10-mm sphere based in the PPC (B), mPFC (C), LPC (D), and RPC (E). Solid lines denote linear correlation (with M− in blue and M+ in red) and curved dotted boundaries represent 95% confidence intervals. DMN = default mode network; eYO = estimated years from expected symptom onset; fcMRI = functional connectivity MRI; LPC = left lateral parietal cortex; mPFC = medial prefrontal cortex; PPC = precuneus/posterior cingulate; RPC = right lateral parietal cortex.