Brain amyloid-β burden is associated with disruption of intrinsic functional connectivity within the medial temporal lobe in cognitively normal elderly

Abstract

The medial temporal lobe is implicated as a key brain region involved in the pathogenesis of Alzheimer's disease (AD) and consequent memory loss. Tau tangle aggregation in this region may develop concurrently with cortical Aβ deposition in preclinical AD, but the pathological relationship between tau and Aβ remains unclear. We used task-free fMRI with a focus on the medical temporal lobe, together with Aβ PET imaging, in cognitively normal elderly human participants. We found that cortical Aβ load was related to disrupted intrinsic functional connectivity of the perirhinal cortex, which is typically the first brain region affected by tauopathies in AD. There was no concurrent association of cortical Aβ load with cognitive performance or brain atrophy. These findings suggest that dysfunction in the medial temporal lobe may represent a very early sign of preclinical AD and may predict future memory loss.

Keywords: Alzheimer's disease; amyloid; hippocampus; perirhinal cortex.

Figure 1.

Mean fMRI volume of one example subject in coronal (A) and sagittal (B) views. L, Left; R, right; A, anterior; P, posterior; HH, hippocampal head; HB, hippocampal body; ERC, entorhinal cortex; PRC, perirhinal cortex; PHC, parahippocampal cortex.

Figure 2.

Scatter plots of functional connectivity between anatomical ROIs of the perirhinal cortex and hippocampal heads against the SUVr. The correlation between the SUVr and the functional connectivity in each subplot was assessed controlling for age, education, and sex. L, Left; R, right; HH, hippocampal head; PRC, perirhinal cortex. #p < 0.1; *p < 0.05; **p < 0.01.

Figure 3.

Overlapped ROI of the right perirhinal cortex that survived the signal loss censoring in the majority of the participants. A, The overlapped ROI was located near the medial portion of the right perirhinal cortex. It is labeled with red color in the sagittal and coronal views of the anatomical template image. B, Scatter plot against the SUVr of the functional connectivity between the overlapped ROIs of the right perirhinal cortex and the right hippocampal head. C, Scatter plot of the functional connectivity between the overlapped ROIs of the right perirhinal cortex and the right hippocampal head against the functional connectivity between the originally censored ROIs (R² = 0.75).

Figure 4.

Direct detection of Aβ effects on functional connectivity of the left perirhinal cortex seed. A, Sagittal and coronal views of the statistical map within the medial temporal lobe defined by the linear regression analysis of functional connectivity to the seed region against the SUVr. B, Sagittal and coronal views of the cluster region in the medial temporal lobe where the SUVr had a significant effect on the functional connectivity to the left perirhinal cortex seed (Table 2). X, Left/right Talairach coordinate; Y, anterior/posterior Talairach coordinate; L, left; R, right; A, anterior; P, posterior.

Figure 5.

Direct detection of Aβ effects on functional connectivity of the right perirhinal cortex seed. A, Sagittal and coronal views of the statistical map within the medial temporal lobe defined by the linear regression analysis of functional connectivity to the seed region against the SUVr. B, Sagittal and coronal views of the cluster regions in the medial temporal lobe where the SUVr had a significant effect on the functional connectivity to the right perirhinal cortex seed (Table 2). Different colors indicate different cluster regions. X, Left/right Talairach coordinate; Y, anterior/posterior Talairach coordinate; L, left; R, right; A, anterior; P, posterior.