Default mode network connectivity in stable vs progressive mild cognitive impairment

Abstract

Objective: Dysfunction of the default mode network (DMN) has been identified in prior cross-sectional fMRI studies of Alzheimer disease (AD) and mild cognitive impairment (MCI); however, no studies have examined its utility in predicting future cognitive decline.

Methods: fMRI scans during a face-name memory task were acquired from a cohort of 68 subjects (25 normal control, 31 MCI, and 12 AD). Subjects with MCI were followed for 2.4 years (±0.8) to determine progression to AD. Maps of DMN connectivity were compared with a template DMN map constructed from elderly normal controls to obtain goodness-of-fit (GOF) indices of DMN expression. Indices were compared between groups and correlated with cognitive decline.

Results: GOF indices were highest in normal controls, intermediate in MCI, and lowest in AD (p < 0.0001). In a predictive model (that included baseline GOF indices, age, education, Mini-Mental State Examination score, and an index of DMN gray matter volume), the effect of GOF index on progression from MCI to dementia was significant. In MCI, baseline GOF indices were correlated with change from baseline in functional status (Clinical Dementia Rating-sum of boxes) (r = -0.40, p < 0.04). However, there was no additional predictive value for DMN connectivity when baseline delayed recall was included in the models.

Conclusions: fMRI connectivity indices distinguish patients with MCI who undergo cognitive decline and conversion to AD from those who remain stable over a 2- to 3-year follow-up period. Our data support the notion of different functional brain connectivity endophenotypes for "early" vs "late" MCI, which are associated with different baseline memory scores and different rates of progression and conversion.

Figure 1. Default mode network (DMN) template

The template mask used for the goodness-of-fit index. Color overlay created from DMN component in normal control subjects based on a one-sample t test corrected for multiple comparisons using a family-wise error correction (p < 0.05) and cluster size threshold of 10 voxels. Notice significant clusters of DMN expression in the posterior cingulate/precuneus, ventromedial frontal, and inferior parietal lobule regions.

Figure 2. Box whisker plot of goodness-of-fit (GOF) index

Box whisker plot of GOF index for subjects with Alzheimer disease (AD), mild cognitive impairment converters (MCIc), mild cognitive impairment nonconverters (MCInc), and normal control (NC) groups. Plot depicts the median, interquartile range, and range of values for each group.

Figure 3. Mild cognitive impairment nonconverters (MCInc) and mild cognitive impairment converters (MCIc) default mode networks (DMN)

(A) MCInc DMN. (B) MCIc DMN. Cover overlays display the results of one-sample t tests in SPM8 corrected for multiple comparisons using a family-wise error correction (p < 0.05). Note significant clusters of DMN expression in the posterior cingulate/precuneus and bilateral inferior parietal lobules in the MCInc (A), and in the posterior cingulate/precuneus and left inferior parietal lobule in the MCIc (B).