Language dysfunction and related amyloid-β in Alzheimer's disease mediated by brain functional connectivity changes

Language dysfunction occurs early in Alzheimer's disease (AD) and whether amyloid-β pathology is related to language dysfunction remains unclear. Functional connectivity (FC) in language networks is critical for language function. We hypothesize that altered FCs in fronto-temporal regions (core language areas) mediate the association between amyloid-β burden and language impairment.

A total of 110 individuals were recruited including 44 cognitively unimpaired individuals, 24 mild cognitive impairment patients and 42 AD patients. The acoustic features and semantic content were extracted from speech recordings of cookie-theft picture description for language assessment. Resting-state functional magnetic resonance imaging and 18F-florbetapir positron emission tomography were conducted to estimate fronto-temporal FCs and amyloid-β burden.

The acoustic features of average duration of silence segments, percentage of silence duration and ratio of hesitation/speech counts were significantly longer in AD patients, which were correlated with the semantic content. Among them, the average duration of silence segments was positively correlated with global amyloid-β burden (r = 0.30, p = 0.015). The fronto-temporal FCs decreased in AD patients. Mediation analysis revealed that the reduced FC between the left rostroposterior superior temporal sulcus (rpSTS) and the right dorsal inferior frontal gyrus mediated the association between global amyloid-β burden and average duration of silence segments (a*b = 0.19, p = 0.026). Additionally, it also mediated the effect of amyloid-β burden in the left rpSTS region on average duration of silence segments (a*b = 0.15, p = 0.030).

Our findings showed that reduced fronto-temporal FCs mediated the association between amyloid-β burden and language dysfunction and further demonstrated the vulnerability of the left rpSTS in response to amyloid-β burden, which might lead to decreased FC with other regions.