Increased medial temporal lobe functional connectivity is critical in Alzheimer’s disease: evidences from longitudinal analyses across the whole cognitive continuum

Abstract

AbstractBackgroundThe medial temporal lobe is extensively connected to the whole brain through two functional networks: the anterior‐temporal (AT) and posterior‐medial (PM) systems. While both increased and decreased functional connectivity (FC) have been reported in Alzheimer’s disease (AD), the specific changes in each network and their clinical relevance throughout AD stages remain to be elucidated. To fill this gap, we aimed to provide a comprehensive overview of AT‐ and PM‐FC changes, and links with AD imaging‐biomarkers, clinical severity and dementia onset, using longitudinal data covering the whole cognitive continuum.MethodLongitudinal data were acquired in 209 cognitively unimpaired (CU) adults aged 19‐85 (n = 56 Aβ‐ over 60), 26 Aβ+ patients with mild cognitive impairment (MCI) (n = 18 AD‐converters), and 26 Aβ+ AD‐demented patients, all followed up to 4 years. All underwent resting‐state (rs)‐fMRI, T1‐w MRI, Florbetapir‐ and FDG‐PET. Connectivity maps were generated from seed‐to‐voxels analyses applied to rs‐fMRI using individual ROIs (AT = perirhinal cortex, PM = parahippocampal cortex). The networks were defined by comparing baseline CU Aβ‐ AT to PM maps (and vice‐versa) using paired permutation t‐tests with FWE correction. Mean FC was then extracted from these masks for each participant. Generalized additive and linear mixed models were run to assess AT‐ and PM‐FC changes across the whole cognitive continuum, and their relationships with i)‐amyloid uptake, ii)‐glucose metabolism, iii)‐hippocampal volume and iv)‐cognitive deficit within participants>60yo, and v)‐AD‐conversion time in MCI patients.ResultResults showed that AT‐FC linearly increased from younger to Aβ+ AD‐demented adults while PM‐FC decreased along the healthy lifespan and then remained stable across the AD continuum (Aβ+ individuals). Higher AT‐FC was associated with i)‐higher amyloid uptake, ii)‐lower glucose metabolism, iii)‐smaller hippocampal volume, iv)‐lower MMSE/Mattis scores and v)‐faster AD‐dementia onset. No such relationships were found with PM‐FC.ConclusionBy encompassing the whole cognitive continuum and assessing longitudinal changes, we highlighted that AT‐ and PM‐FC alterations differ in aging and AD. While reduced PM connectivity seems restricted to age‐related processes (corroborated by no correlation with AD‐signature changes), increased AT connectivity seems to result from specific AD‐related mechanisms. Importantly, we evidenced that AT hyper‐connectivity appears critical in AD and might predict clinical and pathological outcomes.