Cognitive and neural mechanisms of sense of self in neurodegenerative disorders

The ability to maintain a coherent and continuous ‘sense of self’ is a fundamental component of being human, enabling us to interact and function successfully in everyday life. While a sense of self is commonly accepted to involve both ‘extended’ (i.e., memories) and ‘interpersonal’ (i.e., social) elements, the precise cognitive and neural mechanisms underlying these aspects of the self remain poorly understood. This thesis draws upon theory and methods from contemporary cognitive neuroscience to examine the neurocognitive underpinnings of the extended and interpersonal self in Alzheimer’s disease (AD), semantic dementia (SD), and the behavioural variant of frontotemporal dementia (bvFTD): neurodegenerative disorders involving progressive cognitive and behavioural change as the result of degeneration to distinct brain networks. Employing a novel experimental method (the ‘NExt’ taxonomy), Part 1 of the thesis (Chapters 3 and 4) reveals how a full spectrum of episodic and semantic memory representations may be drawn upon to support one’s past and future life stories, giving rise to a sense of continuity of the extended self. Part 2 (Chapters 5 and 6) illustrates how the complex social interactions that comprise the interpersonal self may be deconstructed into several distinct, yet interacting, psychological components. Furthermore, neuroimaging analyses uncover widespread neural regions to be associated with both the extended and interpersonal aspects of the self, incorporating brain networks beyond those typically implicated in self-related processing. The improved neurocognitive characterisation of the self provided by this thesis highlights the complex, multifaceted nature of this construct. Moreover, from a clinical perspective, distinct profiles of the self unveiled across AD, SD, and bvFTD reveal how ultimately, ‘all is not lost’ in neurodegeneration

Neurocognitive mechanisms of theory of mind impairment in neurodegeneration: a transdiagnostic approach

Much of human interaction is predicated upon our innate capacity to infer the thoughts, beliefs, emotions, and perspectives of others, in short, to possess a “theory of mind” (ToM). While the term has evolved considerably since its inception, ToM encompasses our unique ability to apprehend the mental states of others, enabling us to anticipate and predict subsequent behavior. From a developmental perspective, ToM has been a topic of keen research interest, with numerous studies seeking to explicate the origins of this fundamental capacity and its disruption in developmental disorders such as autism. The study of ToM at the opposite end of the lifespan, however, is paradoxically new born, emerging as a topic of interest in its own right comparatively recently. Here, we consider the unique insights afforded by studying ToM capacity in neurodegenerative disorders. Arguing from a novel, transdiagnostic perspective, we consider how ToM vulnerability reflects the progressive degradation of neural circuits special- ized for an array of higher-order cognitive processes. This mechanistic approach enables us to consider the common and unique neurocognitive mechanisms that underpin ToM dysfunction across neurodegenerative disorders and for the first time examine its relation to behavioral disturbances across social, intimate, legal, and criminal settings. As such, we aim to provide a comprehensive overview of ToM research in neurodegeneration, the resultant challenges for family members, clinicians, and the legal profession, and future directions worthy of exploration

Trait Mindfulness Is Associated With Less Amyloid, Tau, and Cognitive Decline in Individuals at Risk for Alzheimer's Disease

BACKGROUND: Mindfulness, defined as nonjudgmental awareness of the present moment, has been associated with an array of mental and physical health benefits. Mindfulness may also represent a protective factor for Alzheimer's disease (AD). Here, we tested the potential protective effect of trait mindfulness on cognitive decline and AD pathology in older adults at risk for AD dementia. METHODS: Measures of trait mindfulness, longitudinal cognitive assessments, and amyloid-β (Aβ) and tau positron emission tomography scans were collected in 261 nondemented older adults with a family history of AD dementia from the PREVENT-AD (Pre-symptomatic Evaluation of Experimental or Novel Treatments for AD) observational cohort study. Multivariate partial least squares analyses were used to examine relationships between combinations of different facets of trait mindfulness and 1) cognitive decline, 2) Aβ, and 3) tau. RESULTS: Higher levels of mindful nonjudgment, describing, and nonreactivity were associated with less cognitive decline in attention, global cognition, and immediate and delayed memory. Higher levels of mindful nonjudgment and nonreactivity were related to less Aβ positron emission tomography signal in bilateral medial and lateral temporoparietal and frontal regions. Higher levels of mindful acting with awareness, describing, nonjudgment, and nonreactivity were associated with less tau positron emission tomography signal in bilateral medial and lateral temporal regions. CONCLUSIONS: Trait mindfulness was associated with less cognitive decline and less Aβ and tau in the brain in older adults at risk for AD dementia. Longitudinal studies examining the temporal relationship between trait mindfulness and AD markers, along with mindfulness intervention studies, will be important for further clarifying the potential protective benefits of mindfulness on AD risk

Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease

INTRODUCTION: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. METHODS: We measured longitudinal changes in plasma amyloid-beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. RESULTS: Aβ42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. DISCUSSION: Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. HIGHLIGHTS: Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aβ42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden

Examining the episodic-semantic interplay during future thinking – A reanalysis of external details

Traditional analyses of autobiographical construction have tended to focus on the ‘internal’ or episodic details of the narrative. Contemporary studies employing fine-grained scoring measures, however, reveal the ‘external’ component of autobiographical narratives to contain important information relevant to the individual’s life story. Here, we used the recently developed NExt scoring protocol to explore profiles of external details generated by patients with Alzheimer’s disease (AD) (n = 11) and semantic dementia (SD) (n = 13) on a future thinking task. Voxel-based morphometry analyses of structural MRI were used to determine the neural correlates of external detail profiles in each patient group. Overall, distinct NExt profiles were observed across past and future temporal contexts in AD and SD groups, which involved elevations in external details, in the context of reduced internal details, relative to healthy Controls. Specifically, AD patients provided significantly more General Semantic details compared with Controls during past retrieval, whereas Specific Episode external details were elevated during future simulation. These increased external details within future narratives related to grey matter integrity in medial and lateral frontal regions in AD. By contrast, SD patients displayed an elevation of Specific Episode, Extended Episode, and General Semantic details exclusively during future simulation relative to Controls, which related to integrity of medial and lateral parietal regions. Our findings suggest that the compensatory external details generated during future simulation comprise an array of episodic and semantic details that vary in terms of specificity and self-relevance. Moreover, these profiles appear to be differentially affected depending on the locus of underlying neuropathology in dementia. Adopting a fine-grained approach to external details provides important information regarding the interplay between episodic and semantic content during future stimulation and highlights the differential vulnerability and preservation of distinct components of the constructed narrative in clinical disorders

Try to see it my way – Examining the relationship between visual perspective taking and theory of mind in frontotemporal dementia

The behavioural variant of frontotemporal dementia (bvFTD) is characterised by pronounced alterations in social functioning, including the understanding of others’ thoughts and feelings via theory of mind. The emergence of such impairments in other social disorders such as autism and schizophrenia is suggested to reflect an inability to imagine the other person’s visual perspective of the world. To our knowledge, this hypothesis is yet to be explored in bvFTD. Here, we sought to examine the capacity for different forms of perspective taking, including visual perspective taking and theory of mind in bvFTD, and to establish their inter-relationships and underlying neural correlates. Fifteen bvFTD patients and 15 healthy Controls completed a comprehensive battery of perspective taking measures, comprising Level 1 (‘what’) and Level 2 (‘how’) visual perspective taking tasks, a cartoon task capturing theory of mind, and a questionnaire assessing perspective taking in daily life. Compared with Controls, bvFTD patients displayed significant impairments across all perspective taking measures. These perspective taking impairments, however, were not correlated with one another in bvFTD. Moreover, controlling for visual perspective taking performance did not ameliorate the deficits in theory of mind or real-world perspective taking. Region-of-interest voxel-based morphometry analyses suggested distinct neural correlates for visual perspective taking (inferior frontal gyrus) versus theory of mind (medial prefrontal cortex, precuneus), which appeared to partially overlap with those implicated in real-world perspective taking (inferior frontal gyrus, precuneus, temporoparietal junction). Despite pervasive impairments in all aspects of perspective taking in bvFTD, our findings suggest that these deficits may reflect distinct underlying processes. Future studies manipulating discrete aspects of the tasks will help to clarify the neurocognitive mechanisms of, and relationships between different forms of perspective taking in bvFTD, along with their real-world implications

Examining the episodic-semantic interaction during future thinking – A reanalysis of external details

While traditional analyses of autobiographical construction tend to focus on the ‘internal’ or episodic details of the narrative, contemporary studies employing fine-grained scoring measures reveal the ‘external’ component to contain important information relevant to the individual’s life story. Here, we used the recently developed NExt scoring protocol to explore profiles of external details generated by patients with Alzheimer’s disease (AD) (n = 11) and semantic dementia (SD) (n = 13) on a future thinking task. Overall, distinct NExt profiles were observed for future events in AD and SD. Specifically, AD patients provided significantly more Specific Episode external details compared with Controls. Using voxel-based morphometry, these increased external details within future narratives related to grey matter intensity in medial and lateral frontal regions in AD. By contrast, SD patients displayed an elevation of Specific Episode, Extended Episode, and General Semantic details during future simulation relative to Controls, which related to grey matter intensity of medial and lateral parietal regions. Our findings suggest that the compensatory external details generated during future simulation comprise an array of episodic and semantic details that vary in terms of specificity and self-relevance, which may be differentially affected depending on the locus of underlying neuropathology in dementia. Adopting a fine-grained approach to external details helps to characterise the interplay between episodic and semantic content during future stimulation and suggests potentially differential vulnerability and preservation of distinct components of the constructed narrative in clinical disorders

"All is not lost" - Rethinking the nature of memory and the self in dementia

Memory and the self have long been considered intertwined, leading to the common assumption that without memory, there can be no self. This line of reasoning has led to the common misconception that a loss of memory in dementia necessarily results in a diminished sense of self. Here, we challenge this assumption by considering discrete facets of the self, and their relative profiles of loss and sparing, across three neurodegenerative disorders: Alzheimer’s disease, semantic dementia, and frontotemporal dementia. By exploring canonical expressions of the self across past, present, and future contexts in dementia, relative to healthy ageing, we reconcile previous accounts of loss of self in dementia, and propose a new framework for understanding and managing everyday functioning and behaviour. Notably, our approach highlights the multifaceted and dynamic nature in which the self is likely to change in healthy and pathological ageing, with important ramifications for development of person-centred care. Collectively, we aim to promote a cohesive sense of self in dementia across past, present, and future contexts, by demonstrating how, ultimately, ‘All is not lost’

Fronto-parietal contributions to episodic retrieval – evidence from neurodegenerative disorders

Converging evidence suggests a critical role for the parietal cortices in episodic memory retrieval. Here, we examined episodic memory performance in Corticobasal Syndrome (CBS), a rare neurodegenerative disorder presenting with early parietal atrophy in the context of variable medial temporal lobe damage. Forty-four CBS patients were contrasted with 29 typical Alzheimer’s disease (AD), 29 healthy Controls, and 20 progressive supranuclear palsy patients presenting with brainstem atrophy as a disease control group. Participants completed standardised assessments of verbal episodic memory (learning, delayed recall, and recognition), and underwent structural and diffusion-weighted MRI. Selective delayed recall deficits were evident in the CBS group relative to Controls, at an intermediate level to the stark amnesia displayed by AD, and Control-level performance noted in progressive supranuclear palsy. Considerable variability within the CBS group on delayed recall performance led to the identification of memory-spared (N = 19) and memory-impaired (N = 25) subgroups. Whereas CBS-Spared showed no significant memory deficits, the CBS-Impaired subgroup were indistinguishable from typical AD across all episodic memory measures. Whole-brain voxel-based morphometry analyses implicated fronto-parietal and medial temporal regions in delayed recall performance in both the CBS-Impaired and AD groups. Furthermore, diffusion tensor imaging analyses revealed correlations between delayed recall performance and altered structural connectivity between fronto-parietal and fronto-temporal regions in the CBS-Impaired group. Our findings underscore the importance of a distributed brain network including frontal, medial temporal and parietal brain regions in supporting the capacity for successful episodic memory retrieval