Cerebrospinal fluid Aβ42, phosphorylated Tau181, and resting-state functional connectivity

Abstract

Importance: Resting-state functional connectivity magnetic resonance imaging has great potential for characterizing pathophysiological changes during the preclinical phase of Alzheimer disease.

Objective: To assess the relationship between default mode network integrity and cerebrospinal fluid biomarkers of Alzheimer disease pathology in cognitively normal older individuals.

Design, setting, and participants: Cross-sectional cohort study at The Charles F. and Joanne Knight Alzheimer's Disease Research Center at Washington University in St Louis, St Louis, Missouri, among 207 older adults with normal cognition (Clinical Dementia Rating, 0).

Main outcomes and measures: Resting-state functional connectivity magnetic resonance imaging measures of default mode network integrity.

Results: Decreased cerebrospinal fluid Aβ42 and increased cerebrospinal fluid phosphorylated tau181 were independently associated with reduced default mode network integrity, with the most prominent decreases in functional connectivity observed between the posterior cingulate and medial temporal regions. Observed reductions in functional connectivity were unattributable to age or structural atrophy in the posterior cingulate and medial temporal areas. Similar resting-state functional connectivity magnetic resonance imaging findings in relation to cerebrospinal fluid biomarkers were obtained using region-of-interest analyses and voxelwise correlation mapping.

Conclusions and relevance: Both Aβ and tau pathology affect default mode network integrity before clinical onset of Alzheimer disease.

Figure 1. Voxel-wise analyses assessing functional connectivity of the posterior cingulate cortex (PCC) in cognitively normal individuals with abnormal levels of cerebrospinal fluid (CSF) Aβ₄₂ or ptau₁₈₁

Two-sample t-test assessed decreases (hot color) or increases (cold color) in functional connectivity of the PCC in CSF Aβ₄₂-positive individuals (≤500 pg/ml) compared to CSF Aβ₄₂-negative individuals (>500 pg/ml) (A), and in CSF ptau₁₈₁-positive individuals (≥80 pg/ml) compared to CSF ptau₁₈₁-negative individuals (<80 pg/ml) (B). Maps were displayed at a voxel-level |t| > 2.5 and cluster size > 35 voxels. Solid and dashed circles represent regions reaching a significance level of p < 0.05 and 0.05 < p < 0.1 respectively, corrected at cluster-level. Detailed information about anatomic location and statistics of observed functional connectivity differences are listed in eTable 3.