Differential annualized rates of hippocampal subfields atrophy in aging and future Alzheimer's clinical syndrome

Abstract

Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of non-demented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality-control. In the one hand, CA4-dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3:-0.68%/year; subiculum:-0.99%/year and CA4-DG:-1.39%/year; p<0.0001). In the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level and ApoE4 genotype (HR=2.0; IC95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years prior to symptom onset.

Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescencein vitroand in the aging human hippocampus

“…The hippocampus is critical for cognitive functions and is one of the most vulnerable brain regions to aging and implicated in age-related cognitive decline (Small et al, 2011). Moreover, emerging evidence has pointed to a differential vulnerability of hippocampal subfields in aging and neurodegenerative diseases (Fu et al, 2018; Morrison and Baxter, 2012; Roussarie et al, 2020), being the dentate gyrus particularly affected during normal aging (Morrison and Baxter, 2012; Nadal et al, 2020). Although most of these studies have focused on neuronal populations, recent findings have suggested that major changes in the gene expression profile of glial cells, especially astrocytes, might predict and/or impact the selective vulnerability of brain regions to aging-associated cognitive decline (Boisvert et al, 2018; Clarke et al, 2018; Soreq et al, 2017).…”

The human hippocampus and its subfield volume across age, sex and APOE e4 status

“…Post-mortem studies provide evidence of neuronal loss of the dentate gyrus, subiculum and CA1 in the range of 32-67% across the lifespan (Simić et al 1997;West et al 1994). Voxel-based morphometry (VBM) analysis of structural MRI has sometimes agreed with this, nding reduced volume in the subiculum in ageing (Chételat et al 2008;La et al 2010;Thomann et al 2013), but the sub elds implicated vary widely across studies (Nadal et al 2020;Olsen et al 2019).…”

“…Advances in MRI spatial resolution and automated segmentation algorithms using ultra-high resolution ex-vivo MRI reference templates (Iglesias et al 2015), have allowed increasingly precise estimation of the volume of the sub elds. It is now evident that sub elds are differentially impacted across neurological diseases (Nadal et al 2020) suggesting selective vulnerabilities to different pathologies with varying phenotypic outcomes. Examination of the effects of age across the entire hippocampus may mask non-linear trajectories that re ect some of the unique properties of hippocampal sub elds.…”

“…Fewer studies have examined the association between APOE e4 status on hippocampal sub eld volume than the effect of AD itself. Where it has been investigated, there are wide variations in the sub elds affected and those that are speci cally associated with APOE e4 status as opposed to general ageing (Nadal et al 2020; de, La, and Chételat 2015).…”

Brainwide functional networks associated with anatomically- and functionally-defined hippocampal subfields using ultrahigh-resolution fMRI

“…Anatomically, the hippocampal formation consists of multiple, lamellar subdivisions organized along the longitudinal axis of hippocampus, including cornu ammonis 1 (CA1), CA3, CA4, dentate gyrus (DG) and subiculum 4 – 6 . Hippocampal subfields have been reported to be differentially vulnerable to a variety of disorders, including autism, Alzheimer’s disease, schizophrenia, and bipolar disorder 7 – 12 , as well as prodromal disease states and in individuals clinically normal, yet at-risk for disease 13 – 15 .…”