Melbourne School of Psychological Sciences

Diagnosing Alzheimer’s disease (AD) early in the disease process can be challenging. Incorporating biomarkers into the diagnostic evaluation for AD has been recommended to increase diagnostic accuracy. Structural magnetic resonance imaging (MRI) is a particularly appealing biomarker because it is a widely available and noninvasive procedure. In view of the early pathological involvement of the entorhinal and transentorhinal cortices in the disease process, MRI-based volume measurements of these regions are promising candidate markers for early AD. Whilst significant advances have been achieved in automated segmentation of brain MRI in recent years, the entorhinal and transentorhinal cortices have been shown to be particularly challenging regions for automated segmentation. The current dissertation sought to examine the role of entorhinal and transentorhinal cortical MRI volumetric analysis to enhance the early detection of AD. Chapter 2 presented a systematic review and meta-analysis of studies comparing automated and manual regional brain volume measurements across healthy controls (HCs), individuals with amnestic mild cognitive impairment (aMCI), and individuals with AD dementia. There was no significant difference in automatic and manual volume measurements for the hippocampus, lateral ventricles, and parahippocampal gyrus. There was, however, significant heterogeneity in the effect estimates across the studies. Chapter 3 comprised an investigation into the effect of MRI scan orientation on the reliability of entorhinal and transentorhinal cortical volume measurement in order to establish a standard protocol for segmentation for subsequent Chapters. Aligning MRI scans to a common orientation improved the reliability of entorhinal and transentorhinal cortical volume measurement. Chapter 4 described an independent validation of a recently developed automated segmentation method, Automatic Segmentation of Hippocampal Subfields-T1 (ASHS-T1), for the measurement of entorhinal and transentorhinal cortical volumes in HCs, individuals with aMCI, and individuals with AD dementia. Despite differences between the volumes obtained from ASHS-T1 and those obtained from manual segmentation, ASHS-T1 was sensitive to AD-related entorhinal and transentorhinal cortical atrophy. Chapter 5 contained an examination of the contribution of selected mesial temporal lobe volumes obtained from ASHS-T1 alongside test scores derived from comprehensive neuropsychological assessment to aid identification of individuals with aMCI and individuals with AD dementia in a memory clinic cohort. Volumes of the entorhinal cortex, transentorhinal cortex, and hippocampus performed no better than chance and offered no utility over and above valid and reliable neuropsychological measures for identifying individuals with AD. Chapter 6 introduced a novel, deep learning-based automated segmentation method, TransEntorhinal Segmentation by Deep Learning (TES-DL), to segment the entorhinal and transentorhinal cortices. Despite suboptimal segmentation accuracy, TES-DL showed mostly medium to large effect sizes for the differences in entorhinal and transentorhinal cortical volumes between HC, aMCI, and AD groups in two AD cohorts. Taken together, the findings from the current dissertation highlight the difficulty of accurate automated segmentation of the entorhinal and transentorhinal cortices and challenge the clinical utility of the volumes of these regions in the early detection of AD. Importantly, whilst advances in automated neuroimaging methods promise exciting new possibilities, it is essential that these methods are thoroughly validated prior to widespread clinical application.

Subjective concerns of memory decline (or subjective memory complaints) are a common phenomenon in the normal population, particularly in older adults. Complaints arise from a negative self-appraisal of memory performance, and form the bridge that connects an individual to clinical attention. The experience of memory failure, whether momentary, gradually progressive, or sudden and acute, is universal and inherently subjective. Within this experiential realm lies rich and complex subjective detail. A threshold exists at which point self-appraised memory dysfunction becomes intolerable, and most individuals seek diagnostic resolution for their symptoms. Alzheimer’s disease (AD) is the most common form of dementia, which is characterised by early impairment in objective memory performance, and gradual accrual of in vivo biological markers. The current trend in the literature is to assume a monotonic relationship between memory complaint severity and level of objective memory impairment, but in general studies have been unable to find a consistent association. The relationship between subjective memory complaining and biomarkers of AD, such as neocortical β-amyloid (Aβ) burden, measured via positron emission tomography (PET) imaging, and brain atrophy, measured via magnetic resonance imaging (MRI), is gathering pace. Brain atrophy in the medial temporal lobes (MTL) is consistently related to memory complaining, but the literature relating to neocortical Aβ burden is less clear; recent studies have shown a relationship, but the effect sizes are small. Autobiographical (ABM) and personal semantic memories (PSM), along with their autonoetic re-experiencing, form the foundation of everyday personal memory. An assessment of personal memory impairment does not feature in the mainstream diagnostic approach to mild cognitive impairment (MCI), the clinical transitional stage prior to a diagnosis of AD. ABM, or the highly contextualised details related to a personal event, are consistently found to be impaired in individuals with MCI, but the pattern of impairment of PSM is less understood. As the most ecologically valid form of memory, it is possible that a breakdown in ABM and PSM is the main driver for subsequent memory complaining. To the candidate’s knowledge, there is no literature which has yet examined a possible connection between memory complaining and personal memory function. It is also unclear how markers of AD pathology, such as Aβ burden and brain atrophy, may be related to ABM and PSM, but functional MRI studies of these personal memory systems suggest they are supported by differing functional networks. ABM is related to a core functional network that primarily involves the MTL, frontal, and posterior cingulate regions, while PSM has been attributed to networks in the lateral temporal lobe. The current inquiry is aimed at describing the phenomenological experience of memory change in non-demented older adults in order to elucidate complaints in those at greater risk of AD, such as individuals with evidence of biological markers of AD, or those with MCI. The specific objectives of this these were: 1) to determine cognitive, affective and AD biological marker correlates of SMCs in healthy older adults and individuals with MCI examined via a commonly-used subjective memory complaint questionnaire (SMCQ), 2) to characterise the phenomenological experiences of memory loss in the earliest stages of Alzheimer’s disease, such as healthy older adults with evidence of AD biological markers and those with MCI, and 3) to examine the pattern of ABM and PSM impairment and its relationship with AD biomarkers in healthy memory complainers and individuals with MCI. The first study (Chapter 4), investigated memory, affective and AD biomarker correlates of SMC severity as measured via a commonly-used SMCQ, the Memory Assessment Clinics Questionnaire (MAC-Q), in healthy older adults and individuals with MCI. Participants were healthy controls (n = 674) and individuals with MCI (n = 66) in the Australian Imaging, Biomarker and Lifestyle (AIBL) study of ageing, who responded to the MAC-Q. Scores from measures of new learning and retention, as well as mood (anxiety and depression), age, education and diagnostic category, were regressed onto the total MAC-Q score, to determine whether memory would relate to SMC severity over and above the other variables. Diagnostic category, depressive symptomatology, and age, were the strongest correlates. In healthy older adults, the strongest driver of greater MAC-Q score was depressive symptomatology, while in individuals with MCI, the sole correlate was age. Aβ deposition, grey matter volumes, and APOE ε4 carrier status were regressed onto MAC-Q total score in both diagnostic groups, but no correlates were found. A strong relationship between depression and memory complaint severity in healthy older adults aligns with other studies using SMCQs. The relationship with age in MCI supports the notion of an underlying organic driver of memory complaining, and a transition from affectively-driven phenomena. The second study (Chapter 5), addressed the characterisation of SMCs in different AD-risk groups, such as healthy older adults with high Aβ load, healthy memory complainers (identified by asking “do you have difficulties with your memory, yes or no?”), and individuals with MCI. Healthy control (n = 80) and MCI (n = 43) participants were randomly recruited from the AIBL study for the next three studies. A semi-structured interview was developed by the candidate, in conjunction with supervisor, MS to probe the phenomenological experience of memory loss. A thematic analysis was conducted and meaningful phrases were extracted, and grouped similar phrases into what ultimately became twelve themes. A comparison between healthy individuals with high and low Aβ load showed that greater Aβ deposition was related to greater acknowledgement of a progressive memory decline. Complaint themes in healthy memory complainers closely aligned to those expressed by MCI individuals, suggesting that a single SMC question has the potential to uncover individuals with subjectively similar experiences of memory loss as those with a diagnosed memory dysfunction. Individuals with MCI diverged from healthy memory complainers in their greater acknowledgement of dependency on a significant other, and the implementation of burdensome coping strategies. Thus, an increasing acknowledgement of dysfunction in daily activities may well signify an interim early stage outcome of accumulating memory problems. The pattern of ABM and PSM impairment in healthy memory complainers and those with MCI was examined in the third study (Chapter 6). The Episodic Autobiographical Memory Interview, a validated semi-structured interview, measured the spatiotemporal and emotional details of a recent personal event (ABM) and personally factual knowledge from the recent past (PSM). Individuals with MCI showed a deficit in both ABM and PSM, supporting conceptual notions of a dynamic and interactive overlap between these two memory systems. Healthy memory complainers did not show a deficit compared to non-complaining healthy older adults, raising the question as to whether current measures of memory complaining are sensitive to the subjective experience of memory decline. In the fourth and final study, AD biomarkers were considered in relation to personal memory performance, namely ABM, PSM and the conscious re-experiencing connected with ABM (Chapter 7). Aβ deposition, grey matter volumes and APOE ε4 carrier status were regressed onto each form of personal memory. PSM was negatively associated with neocortical Aβ burden in healthy older adults, but neither ABM nor autonoetic consciousness were related to any AD biomarkers. ABM impairment exerted a large magnitude of effect on MCI unlike PSM, so there are potentially other underlying neurodegenerative processes affecting ABM performance. The prevailing assumption in the literature is to treat subjective memory complaining as a unidimensional proxy for neuropsychological measures of memory impairment. The problem with this assumption is that it does not recognise the complex, and often counter-intuitive, nature of subjective experiences. SMCQs, such as the MAC-Q, are structured as screening tools in that they are non-interactive, non-specific and designed for quick self-administration. This approach provides no diagnostic information over and above a quantified score, and neglects the possibility that phenomenological experiences contain important clinical information. The impairment to both ABM and PSM in MCI, highlighting that both personal memory systems are affected by underlying AD-related neuropathology. Specifically, findings from this thesis suggest that ABM and PSM are affected by differential disease mechanisms, with PSM strongly influenced by neocortical Aβ burden in healthy older adults, and ABM showing a trend towards association with hippocampal volume. Thus, elevated AD biomarkers were found to have an effect on the subjective experience (via complaints) and expression (via autobiographical narratives) of memory, supporting the notion that these phenomena are affected in the early stages of AD. This thesis highlights the subjective experience of memory change in non-demented older adults, which will help to inform future approaches to the clinical evaluation of memory complaints prior to diagnosis.

Melbourne School of Psychological Sciences - Theses

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