The contributions of hippocampal subfields to the age- and fitness-dependent effects on cognition

Gardner, Jennie Carolina

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https://hdl.handle.net/2142/129485 Copy

Description

Title

The contributions of hippocampal subfields to the age- and fitness-dependent effects on cognition

Author(s)

Gardner, Jennie Carolina

Issue Date

2025-01-28

Director of Research (if dissertation) or Advisor (if thesis)

• Fabiani, Monica
• Gratton, Gabriele

Doctoral Committee Chair(s)

• Fabiani, Monica
• Gratton, Gabriele

Committee Member(s)

• Sutton, Bradley P.
• Cohen, Neal J.
• Goense, Jozien
• Daugherty, Ana M.

Department of Study

Psychology

Discipline

Psychology

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• aging
• fitness
• cognition
• memory
• MRI
• optical imaging
• pulse-DOT
• hippocampus
• hippocampal subfields
• entorhinal cortex
• EC
• subiculum
• SUB
• cornu ammonis sectors 1 and 2
• CA1-2
• dentate gyrus and cornu ammonis sector 3
• DG-CA3
• automatic segmentation of hippocampal subfields
• ASHS
• posterior cerebral artery
• mediation
• moderation

Abstract

Aging is associated with a marked increase in the risk of cognitive decline, mild cognitive impairment (MCI) and eventually Alzheimer’s disease (AD) (Grundman et al., 2004). The risk for cognitive decline is also tied to age-related vascular changes in the brain, such as arterial stiffening (Clark et al., 2009; Firth et al., 2018; Maass, Düzel, et al., 2015; E. C. Smith et al., 2021; Van Praag et al., 2005; Van Praag, 2008; Weiss et al., 2016). When cerebrovascular functioning deteriorates, brain regions associated with memory, such as the hippocampus (Rigdon & Loprinzi, 2019), no longer receive the necessary blood flow to support normal cognitive function (Zimmerman et al., 2021). Although hippocampal volume and memory also decrease with age (Barry et al., 2021; Bender et al., 2013; Broadhouse et al., 2019; Carr et al., 2017; De Flores et al., 2015; Malykhin et al., 2017; Mueller et al., 2007; Nadal et al., 2020; Pereira et al., 2014; Raz et al., 2015; Salthouse, 2003; Shing et al., 2011; Wisse et al., 2014; Zammit et al., 2017), these negative effects can be mitigated with fitness interventions, which also ameliorate risk to cardio- and cerebrovascular health (Broadhouse et al., 2020; Kern et al., 2021; Maass, Düzel, et al., 2015; Nauer et al., 2020; Suwabe et al., 2018). In fact, improvements in fitness are associated with hippocampal adaptations (Broadhouse et al., 2020; Kern et al., 2021; Maass, Düzel, et al., 2015), which are linked to improvements in memory (Rigdon & Loprinzi, 2019). However, the hippocampus is per se a complex structure, and individual hippocampal subfields are linked to different aspects of cognition (Raz et al., 2008; Zhu et al., 2017) and memory (Barry et al., 2021; Bender et al., 2013; Broadhouse et al., 2019; Carr et al., 2017; Delgorio et al., 2022; Shing et al., 2011; Zammit et al., 2017). Additionally, hippocampal subfields may also be differentially related to cerebrovascular health (Bender et al., 2013). Variability in the atrophy of individual hippocampal subfields (De Flores et al., 2015; Malykhin et al., 2017; Mueller et al., 2007; Nadal et al., 2020; Pereira et al., 2014; Raz et al., 2015; Wisse et al., 2014) may account for the mixed patterns of cognitive and memory decline that are common in aging (Baltes et al., 1999; Barry et al., 2021; Bender et al., 2013; Broadhouse et al., 2019; Carr et al., 2017; Cattell, 1971; Gray et al., 2003; Kyllonen & Kell, 2017; Lindenberger, 2001; Shing et al., 2011; Sternberg, 2000; Tucker-Drob et al., 2022; Walker et al., 2017; J. J. Wang & Kaufman, 1993; Zammit et al., 2017). Therefore, the primary goal of this dissertation is to investigate some of the mechanisms underlying the age and fitness effects on hippocampal subfield volumes, which may be modulated by cerebrovascular health and, in turn, result in changes to cognition and memory. The studies described in this dissertation supply some of the groundwork for future research, which will eventually provide the information necessary for improving prevention and treatment strategies for age-related neurodegeneration. Chapter 1 provides a brief overview of the age- and fitness-related effects on brain health and cognition, specifically related to the hippocampus. This includes a discussion of both the animal and human literature related to these topics. The literature discussed in this introductory chapter supports the idea that the hippocampus is a key factor in mediating the relationships between age and fitness on behavior and suggests the need for further research clarifying the roles of individual hippocampal subfields in these relationships. In Chapter 2, we attempt to replicate findings from the existing literature in our sample regarding the associations between age and cardiorespiratory fitness on cognition, memory, and volumes of the total hippocampus, hippocampal subfields, and entorhinal cortex (EC). Because there is evidence in the existing literature that the associations between brain structure and cognition do not follow a strictly linear trajectory with age (Bowie et al., 2024), we also attempt to identify whether there is a specific age at which point the slope of the line representing the rate of change between age and hippocampal volume, cognition, or memory becomes steeper. As a result, we found that older age was associated with lower fluid cognition, memory, and hippocampal subfield volumes and that the age-related decline in fluid cognition becomes more precipitous in the mid-50s, the age at which arterial stiffening emerges (Bowie et al., 2024). We also found that cardiorespiratory fitness exerted a protective effect, such that that greater cardiorespiratory fitness was associated with higher scores on measures of fluid cognition and memory and larger hippocampal subfield volumes, although the fitness-related effects on subfield volumes were limited to the EC and subiculum (SUB). This result suggests some specificity of the fitness-related effects on subfield volumes. Chapter 3 builds on Chapter 2 by addressing the relationships between age and cardiorespiratory fitness on cerebrovascular health and between cerebrovascular health and cognition, memory, and volumes of the total hippocampus, hippocampal subfields, and EC. Since both age and cardiorespiratory fitness are particularly relevant for predicting cerebrovascular health, these analyses allow us to identify another key element in the cascade of negative effects associated with age, which impacts both brain structure and cognitive function. As a result, we found the expected negative association between age and arterial elasticity, with a steeper decline in this association occurring in the early 50s. We also found a positive relationship between cardiorespiratory fitness and arterial elasticity as well as positive associations between arterial elasticity and fluid cognition, memory, total hippocampal volume, and volumes of the SUB and combined cornu ammonis sectors 1 and 2 (CA1-2) in particular. These results, again, support the idea that individual hippocampal subfields may play specific roles in these relationships, with the volumes of certain subfields being affected more so than others. In Chapter 4, we report exploratory mediation and moderation analyses in an attempt to gain insight into the underlying mechanisms of the age- and fitness-related effects on cognition and memory. As a result, we found that the volume of the SUB and one of our measures of cerebrovascular health, average rise time of the posterior cerebral artery (PCA), are significant mediators of the relationship between age and fluid cognition. We also found that the volume of the CA1-2 was a moderator of the relationship between average rise time of the PCA and memory and that volumes of the EC and SUB were moderators of the relationships between our other measure of cerebrovascular health, the average pulse relaxation function (PReFx) of the PCA, and memory. These results suggest that hippocampal subfield volumes are specific in their relationships to measures of cerebrovascular health, cognition, and memory and that they have significant effects on the nature of these associations. Chapter 5 includes a methodological analysis of the consistency over repeated measures of the atlas we used for semi-automatic segmentation of hippocampal subfields. This analysis will allow us to gain preliminary insights regarding the potential for measurement error resulting from our method of hippocampal segmentation. To assess this, we used intraclass correlation coefficients (ICCs) and established adequate consistency over repeated measures for all subfields except for the right hemisphere of the EC. However, due to our limited sample size for this longitudinal study, further work is required before making any firm conclusions. Finally, Chapter 6 provides relevant context and summarizes the findings from each chapter. Chapter 6 also includes a discussion of future directions that would build upon the work conducted in this dissertation. Despite its limitations, this dissertation suggests specific roles of individual hippocampal subfields and provides the foundation necessary for future work, which has the potential to supply additional insights into the underlying mechanisms relating age and fitness to cognition and memory. These insights would allow researchers to further optimize prevention and treatment plans for neurodegenerative diseases, such as AD.

Graduation Semester

2025-05

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/129485

Copyright and License Information

Copyright 2025 Jennie Gardner

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