Longitudinal changes in the brain language system as amyloid accumulates

Abstract

AbstractBackgroundLanguage dysfunction is common in Alzheimer disease (AD). There is increasing interest in the preclinical phase of AD. Here we tested longitudinally how activity in the associative‐semantic language network, measured with task‐based fMRI, changes in relation to increases in amyloid load, measured with 18F‐flutemetamol and 11C‐PIB. The main hypothesis was that an increase in amyloid would be associated with changes in activity in left or right posterior superior temporal sulcus (STS) and/or medial temporal gyrus (GTm).MethodA cohort of 35 cognitively intact older adults (mean age=65.4; range: 52‐78 years, 54.3% APOE‐ε4) participated who all received a task‐based fMRI and amyloid PET in 2009‐2011 and a repeat scan for both modalities in 2016‐2017. As primary analysis, we examined how longitudinal change in amyloid, measured using Centiloids (CL), relates to longitudinal activation change in the posterior temporal nodes of the associative‐semantic language network. The left and right posterior STS and GTm were defined as regions of prior interest using the Fan Brainnetome atlas, based on prior studies in amnestic mild cognitive impairment (MCI) and clinically probable AD using the same functional paradigm (Nelissen et al., 2007; Vandenbulcke et al., 2007; Adamczuk et al., 2016). Within this VOI, significance was determined based on SPM12 small volume correction. As a secondary analysis, we also performed a voxelwise whole‐brain analysis with a FWE whole‐brain corrected threshold <0.05. We also examined how the change in amyloid and the change in fMRI activation related to changes in offline language measures.ResultIn the right posterior STS, the change in response amplitude during the associative‐semantic versus the visuoperceptual task showed a positive correlation with the change in amyloid load (x=51 mm, y=‐31 mm, z=5 mm; Z=3.47, Pcorr=0.010; Fig. 1). The change in response amplitude also correlated with longer offline confrontation naming reaction times (RT; r=0.42, P=0.035; Fig. 2). In addition, in the whole‐brain analysis we observed a decrease in response in the right inferior frontal sulcus with increasing amyloid load (x=3 mm, y=20 mm, z=56 mm; Z=4.64, Pcorr=0.021).ConclusionThis study confirms the central role of the posterior STS as area of predilection in the earliest stages of AD.