Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer's disease

Abstract

Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aβ), in clinically-normal older adults.The default-mode network (DMN), a prominent intrinsic network, is heavily implicated in AD due to its spatial overlap with AD atrophy patterns and tau deposition. We investigated the influence of baseline Aβ positron emission tomography (PET) signal and intrinsic DMN connectivity on DMN-specific cortical thinning in 120 clinically-normal older adults from the Harvard Aging Brain Study (73 ± 6 years, 58% Female, CDR = 0). Participants underwent¹¹C Pittsburgh Compound-B (PiB) PET, ¹⁸F flortaucipir (FTP) PET, and resting-state MRI scans at baselineand longitudinal MRI (3.6 ± 0.96 scans; 5.04 ± 0.8 years). Linear mixed models tested relationships between baseline PiB and DMN connectivity on cortical thinning in a composite of DMN regions. Lower DMN connectivity was associated with faster cortical thinning, but only in those with elevated baseline PiB-PET signal. This relationship was network specific, in that the frontoparietal control network did not account for the observed association. Additionally, the relationship was independent of inferior temporal lobe FTP-PET signal. Our findings provide evidence that compromised DMN connectivity, in the context of preclinical AD, foreshadows neurodegeneration in DMN regions.

Keywords: Alzheimer’s disease; Amyloid; Default mode network; Functional connectivity.

Fig. 1

Network template maps – Network template maps used for connectivity measures and cortical composites based on TBR methods (adapted from Schultz et al., 2014). DMN = Default Mode Network; FPCN = Frontoparietal Control Network.

Fig. 2

Network composite volumetric maps – Overlap of the TBR-derived DMN (in white) and FPCN (in black) network composites over the Desikan-Killany atlas (Desikan et al., 2006). The full list of atlas brain regions is listed on the left. DMN = Default Mode Network; FPCN = Frontoparietal Control Network.

Fig. 3

DMN composite thinning by baseline DMN and PiB: Predicted values from LME model analyzing the effect of baseline DMN and PiB signal on thinning in the DMN over time. Note: DMN and PiB signal values were median split in this diagram. We observed faster rates of thinning in the DMN composite in individuals with lower baseline DMN connectivity, but primarily in individuals who also have higher baseline PiB signal (solid red line). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Spaghetti plots of raw data by PiB group: Each line depicts a single participant and the demeaned DMN composite thickness over time. Line aesthetics have continuous thickness and transparency values based on their continuous baseline DMN connectivity measure. Darker, thicker lines indicate lower baseline DMN values, while thinner, lighter lines indicate higher baseline DMN values. The panels are split by PiB- group (N = 87) and PiB + group (N = 33).