Abstract
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.
Highlights
The hippocampus (HPC), entorhinal cortex (ERC), perirhinal cortex (PRC), and parahippocampal cortex (PHC) are subregions of the medial temporal lobe (MTL) that are critical for several cognitive functions such as declarative memory and spatial navigation (Wixted and Squire, 2011; Raslau et al, 2015; Moscovitch et al, 2016; Baumann and Mattingley, 2021)
All MTL subregions volume were significantly related to age using the best-fitted models [HPC: F(317.89) = 14.58, p < 0.001; aHPC: F(344.43) = 8.05, p < 0.001; pHCP: F(316.73) = 17.49, p < 0.001; ERC: F(309.85) = 16.37, p < 0.001; PRC: F(318.03) = 37.23, p < 0.001; BA35: F(290.60) = 14.11, p < 0.001; BA36: F(339.54) = 35.04, p < 0.001; PHC: F(370.18) = 48.41, p < 0.001)
The Brodmann areas (BA) 35 and 36, PRC, and PHC volumes were linearly associated with age, a quadratic term better described this relationship between volume and age for the aHCP and ERC, and a cubic term better described this relationship for the HPC and pHPC (Supplementary Table 1)
Summary
The hippocampus (HPC), entorhinal cortex (ERC), perirhinal cortex (PRC), and parahippocampal cortex (PHC) are subregions of the medial temporal lobe (MTL) that are critical for several cognitive functions such as declarative memory and spatial navigation (Wixted and Squire, 2011; Raslau et al, 2015; Moscovitch et al, 2016; Baumann and Mattingley, 2021) These subregions are altered early and severely in Alzheimer’s disease (AD), as they are the primary target of neurofibrillary tangles (Braak and Braak, 1991, 1995; Schöll et al, 2016). As neuropathological changes are known to start several years before symptom onset, more and more studies have focused on the preclinical stage of AD—defined as amyloidpositive (Aβ+) cognitively unimpaired (CU) individuals (Jack et al, 2018)—(Miller et al, 2013; Fortea et al, 2014; Pegueroles et al, 2017; Pettigrew et al, 2017); findings are sparse with only a few studies showing medial temporal lobe subregional atrophy in Aβ+ compared to amyloid-negative (Aβ−) CU (Wolk et al, 2017; Xie et al, 2020), while others have found no difference (Xie et al, 2019)
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