Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.
BackgroundThe medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks which are particularly affected in Alzheimer’s disease (AD): the anterior‐temporal (AT) and posterior‐medial (PM) systems. As the specific and respective effects of age and sex on the functional integrity of these networks are still largely unknown, we sought to fill this gap using longitudinal data spanning the entire adult life.MethodLongitudinal data from 215 cognitively unimpaired adults (aged 19‐85, including 113 females, followed‐up up to 47 months, 419 scans) were analysed. Seed‐based analyses were applied to resting‐state functional magnetic resonance imaging to generate connectivity maps (seeds: the perirhinal cortex for AT and the parahippocampal cortex for PM). The AT and PM networks were defined by comparing baseline maps from adults younger than 40 using a paired permutation t‐test with threshold‐free cluster enhancement (TFCE) and familywise error (FWE) correction (p<.05) (Figure 1). These masks were then used to extract the mean functional connectivity (FC) for each participant. The interaction effects between network, age and sex were investigated using linear mixed models.ResultThere was a significant interaction between age and networks (p<.001), with a decrease of FC with age in PM and an increase in AT (Figure 2). Sex differences were also observed within these two systems (p<.001), with males exhibiting higher FC than females in AT but lower FC in PM (Figure 3). Age‐related trajectories were not modulated by sex differences (p>.05) and were best described by a linear relationship according to model comparison testing different polynomials.ConclusionBy encompassing the entire adult lifespan and assessing longitudinal changes, our study provides strong support that the two MTL networks display differential alterations in the context of aging, as well as sex differences. Since MTL connectivity has been described as particularly affected in the early stages of AD, and age and sex are risk factors, these findings may be helpful to enhance the clinical utility of such biomarkers for the early detection of AD‐related changes.
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