Loss of intranetwork and internetwork resting state functional connections with Alzheimer's disease progression

Abstract

Alzheimer's disease (AD) is the most common cause of dementia. Much is known concerning AD pathophysiology but our understanding of the disease at the systems level remains incomplete. Previous AD research has used resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) to assess the integrity of functional networks within the brain. Most studies have focused on the default-mode network (DMN), a primary locus of AD pathology. However, other brain regions are inevitably affected with disease progression. We studied rs-fcMRI in five functionally defined brain networks within a large cohort of human participants of either gender (n = 510) that ranged in AD severity from unaffected [clinical dementia rating (CDR) 0] to very mild (CDR 0.5) to mild (CDR 1). We observed loss of correlations within not only the DMN but other networks at CDR 0.5. Within the salience network (SAL), increases were seen between CDR 0 and CDR 0.5. However, at CDR 1, all networks, including SAL, exhibited reduced correlations. Specific networks were preferentially affected at certain CDR stages. In addition, cross-network relations were consistently lost with increasing AD severity. Our results demonstrate that AD is associated with widespread loss of both intranetwork and internetwork correlations. These results provide insight into AD pathophysiology and reinforce an integrative view of the brain's functional organization.

Figure 1.

Schematic representation of the 36 canonical expanded seed regions used for evaluating composite scores for five brain RSNs. Abbreviations and corresponding Montreal Neurological Institute (MNI) coordinates are listed in Table 2.

Figure 2.

rs-fcMRI maps using the PCC as a seed region projected onto a characteristic brain slice. A–C,C orrelations (orange and red) and anticorrelations (dark blue) with PCC are seen for CDR 0 (A) CDR 0.5 (B), and CDR 1 (C). Reduced correlations (less orange and red) and anticorrelations (blue) were seen with increasing disease severity. D, E, Random effects contrast of CDR 0 versus CDR 0.5 (p < 0.01; D) and CDR 0.5 versus CDR 1 (p < 0.01 (E).

Figure 3.

rs-fcMRI maps for each of the four non-DMN networks obtained in the CDR 0, CDR 0.5, and CDR 1 groups. Each row shows the correlation map obtained for a given network using a representative seed ROI. For these maps, the left MT+ was used as a seed region for the DAN; the dorsal mPFC for the CON; the dorsal anterior cingulate cortex for the SAL; and the supplementary motor area for the SMN.

Figure 4.

A–C, ROI pair correlation matrices for CDR 0 (A), CDR 0.5 (B), and CDR 1 (C). The ROIs are grouped by RSN. Intranetwork correlations appear on diagonal bocks; internetwork correlations appear in off-diagonal blocks. D, CDR 0 − CDR 0.5 difference matrix. E, CDR 0.5 − CDR 1 difference matrix. Colors denote network membership: blue, DMN; red, DAN; green, CON; purple, SAL; teal, SMN. Units are z-transformed correlation coefficients.

Figure 5.

Mean composite z scores for intranetworks and internetworks across CDR status. A, Mean composite scores for the five investigated networks. All network composite scores tended toward 0 with increasing disease severity. A transient increase in functional correlations was seen in the SAL between CDR 0 and CDR 0.5. Thick solid line, DMN; dashed line, DAN; dotted line, CON; dashed and dotted line, SAL; thin solid line, SMN. B, Mean composite scores for internetwork pairs that showed a significant effect of CDR. Note that the anticorrelations for three network pairs also tended to move toward 0. Solid line, DMN–DAN; dashed line, DMN–SMN; dotted line, CON–SMN. C, Mean composite scores for internetwork pairs that did not show a significant effect of CDR. Thick solid line, DMN–CON; thick dashed line, DMN–SAL; thick dotted line, DAN–CON; dashed and dotted line, DAN–SAL; thin solid line, DAN–SMN; thin dashed line, CON–SAL; thin dotted line, SAL–SMN.

Figure 6.

Scatter plots of mean composite z scores versus CDR-SB. Linear fit lines are shown. Both p and r values for each correlation are shown.

Figure 7.

Scatter plots of CDR stage-dependent correlation difference vs correlation mean. Left, CDR 0 and CDR 0.5. Right, CDR 0.5 and CDR 1. Red, DAN; blue, SAL; black, other RSNs. The bottom right quadrant shows positively correlated ROI pairs that are more correlated at more advanced CDR.

Figure 8.

CDR stage-dependent correlation difference versus correlation mean. The plot axes are the same as in Figure 7 but ROI pairs are evaluated at CDR 0 and CDR 0.5 (empty circles) and at CDR 0.5 and CDR 1 (filled circles) and connected by lines. Network composite scores are represented by the larger symbols. Subscripts in the axis labels refer, respectively, to earlier and later CDR stages.