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Cherie Strikwerda-Brown,1–3 Siddharth Ramanan,1–3 Muireann Irish1–3 1The University of Sydney, Brain and Mind Centre, Sydney, NSW, Australia; 2The University of Sydney, School of Psychology, Sydney, NSW, Australia; 3ARC Centre of Excellence in Cognition and its Disorders, Sydney, NSW, Australia Abstract: 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 specialized 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. Keywords: prefrontal cortex, social cognition, mentalizing, executive function, dementia, empathy

Epidemiological studies show that modifiable risk factors account for approximately 40% of the population variability in risk of developing dementia, including sporadic Alzheimer's disease (AD). Recent findings suggest that these factors may also modify disease trajectories of people with autosomal-dominant AD. With positron emission tomography imaging, it is now possible to study the disease many years before its clinical onset. Such studies can provide key knowledge regarding pathways for either the prevention of pathology or the postponement of its clinical expression. The former "resistance pathway" suggests that modifiable risk factors could affect amyloid and tau burden decades before the appearance of cognitive impairment. Alternatively, the resilience pathway suggests that modifiable risk factors may mitigate the symptomatic expression of AD pathology on cognition. These pathways are not mutually exclusive and may appear at different disease stages. Here, in a narrative review, we present neuroimaging evidence that supports both pathways in sporadic AD and autosomal-dominant AD. We then propose mechanisms for their protective effect. Among possible mechanisms, we examine neural and vascular mechanisms for the resistance pathway. We also describe brain maintenance and functional compensation as bases for the resilience pathway. Improved mechanistic understanding of both pathways may suggest new interventions., (Copyright © 2023 Society of Biological Psychiatry. All rights reserved.)

Introduction: We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset., Methods: We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties., Results: Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks., Discussion: White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties., Highlights: Aβ and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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: Aβ 42/40 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. Aβ 42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Systematic changes have been observed in the functional architecture of the human brain with advancing age. However, functional connectivity (FC) is also a powerful feature to detect unique "connectome fingerprints," allowing identification of individuals among their peers. Although fingerprinting has been robustly observed in samples of young adults, the reliability of this approach has not been demonstrated across the lifespan. We applied the fingerprinting framework to the Cambridge Centre for Ageing and Neuroscience cohort ( n = 483 aged 18 to 89 years). We found that individuals are "fingerprintable" (i.e., identifiable) across independent functional MRI scans throughout the lifespan. We observed a U-shape distribution in the strength of "self-identifiability" (within-individual correlation across modalities), and "others-identifiability" (between-individual correlation across modalities), with a decrease from early adulthood into middle age, before improving in older age. FC edges contributing to self-identifiability were not restricted to specific brain networks and were different between individuals across the lifespan sample. Self-identifiability was additionally associated with regional brain volume. These findings indicate that individual participant-level identification is preserved across the lifespan despite the fact that its components are changing nonlinearly., (© 2023 Massachusetts Institute of Technology.)

Importance: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD)., Objective: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD., Design, Setting, and Participants: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years., Exposures: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness., Main Outcomes and Measures: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups., Results: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable., Conclusions and Relevance: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.

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., (© 2021. The Psychonomic Society, Inc.)

Objective: The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aβ 40 and Aβ 42 assays as indicators of tau and Aβ pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults., Methods: In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aβ 40 and Aβ 42 with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-β ( 18 F-NAV4694) and tau ( 18 F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aβ and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection of Aβ-PET positivity. We also investigated associations with 8-year cognitive change., Results: Plasma p-tau biomarkers correlated with flortaucipir binding in medial temporal, parietal, and inferior temporal regions. P-tau231 showed further associations in lateral parietal and occipital cortices. Plasma Aβ 42/40 explained more variance in global Aβ-PET binding than Aβ 42 alone. P-tau231 also showed strong and widespread associations with cortical Aβ-PET binding. Combining Aβ 42/40 with p-tau231 or p-tau181 allowed for good distinction between Aβ-negative and -positive participants (area under the receiver operating characteristic curve [AUC] range = 0.81-0.86). Individuals with low plasma Aβ 42/40 and high p-tau experienced faster cognitive decline., Interpretation: Plasma p-tau231 showed more robust associations with PET biomarkers than p-tau181 in presymptomatic individuals. The combination of p-tau and Aβ 42/40 biomarkers detected early AD pathology and cognitive decline. Such markers could be used as prescreening tools to reduce the cost of prevention trials. ANN NEUROL 2022;91:548-560., (© 2022 American Neurological Association.)

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, relationships between visual perspective taking and theory of mind have not previously been explored in bvFTD. Here, we sought to examine the capacity for 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 subjective 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. 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 subjective perspective taking (inferior frontal gyrus, precuneus, temporoparietal junction). Despite pervasive impairments in all aspects of perspective taking in bvFTD, these did not appear to relate to one another at the behavioural or neural level in our study. Future large-scale studies manipulating discrete aspects of the tasks will help to clarify the neurocognitive mechanisms of, and relationships between, visual perspective taking and theory of mind in bvFTD, along with their real-world implications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022 The Authors.)

Older adults display impairments in accessing episodic, but not semantic details, when specifically requested to construct autobiographical events. How aging affects access to autobiographical information under conditions of low retrieval constraint remains unclear. We examined the production of episodic and "non-episodic" details in young ( n  = 25) and older ( n  = 24) adults on a novel autobiographical narrative task free from constraints on the type of information to be retrieved (Thoughts task), compared with the standard autobiographical memory and picture description tasks. Older adults generated fewer episodic and more non-episodic details on the memory task than young adults, however there was no age difference in detail profiles on the Thoughts task. Under these conditions of low retrieval constraint, narratives of young and older adults consisted of mostly personal and general semantic content. Young adults also provided less episodic and more semantic details on the Thoughts than the memory task, while older adults provided similar amounts of details across tasks. These results reveal that both young and older adults retrieve semantic autobiographical content under minimally constrained retrieval conditions. Moreover, aging may impact upon the ability to shift the detail types (episodic, semantic) provided in response to changing demands of different autobiographical narrative tasks.

Leveraging recent advances in automated language analysis and anovel statistical approach utilizing an independent control group, we explored changes in lexical output across two published works of a man diagnosed with semantic dementia. We found significant increase in adverb usage and decline in familiarity, meaningfulness, age of acquisition and co-occurrence probability over 2 years. Collectively, these indices suggest that WR's narrative structure became progressively simpler, lexically less sophisticated, and that words commonly associated together no longer appeared in close proximity. Our study illustrates how degeneration of the semantic knowledge base impacts the production, content, and quality of literary works.

Cooperative social behaviour in humans hinges upon our unique ability to make appropriate moral decisions in accordance with our ethical values. The complexity of the neurocognitive mechanisms underlying moral reasoning is revealed when this capacity breaks down. Patients with the behavioural variant of frontotemporal dementia (bvFTD) display striking moral transgressions in the context of atrophy to frontotemporal regions supporting affective and social conceptual processing. Developmental studies have highlighted the importance of social knowledge to moral decision making in children, yet the role of social knowledge in relation to moral reasoning impairments in neurodegeneration has largely been overlooked. Here, we sought to examine the role of affective and social conceptual processes in personal moral reasoning in bvFTD, and their relationship to the integrity and structural connectivity of frontotemporal brain regions. Personal moral reasoning across varying degrees of conflict was assessed in 26 bvFTD patients and compared with demographically matched Alzheimer's disease patients (n = 14), and healthy older adults (n = 22). Following each moral decision, we directly probed participants' subjective emotional experience as an index of their affective response, while social norm knowledge was assessed via an independent task. While groups did not differ significantly in terms of their moral decisions, bvFTD patients reported feeling 'better' about their decisions than healthy control subjects. In other words, although bvFTD patients could adjudicate between different courses of action in the moral scenarios, their affective responses to these decisions were highly irregular. This blunted emotional reaction was exclusive to the personal high-conflict condition, with 61.5% of bvFTD patients reporting feeling 'extremely good' about their decisions, and was correlated with reduced knowledge of socially acceptable behaviour. Voxel-based morphometry analyses revealed a distributed network of frontal, subcortical, and lateral temporal grey matter regions involved in the attenuated affective response to moral conflict in bvFTD. Crucially, diffusion-tensor imaging implicated the uncinate fasciculus as the pathway by which social conceptual knowledge may influence emotional reactions to personal high-conflict moral dilemmas in bvFTD. Our findings suggest that altered moral behaviour in bvFTD reflects the dynamic interplay between degraded social conceptual knowledge and blunted affective responsiveness, attributable to atrophy of, and impaired information transfer between, frontal and temporal cortices. Delineating the mechanisms of impaired morality in bvFTD provides crucial clinical information for understanding and treating this challenging symptom, which may help pave the way for targeted behavioural interventions., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD)., Methods: Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale., Results: In the ALS-FTD group, 41 (69%) patients were categorized as having an initial cognitive presentation and 18 (31%) a motor presentation. Patients with motor presentation experienced a significantly shorter median survival of 2.7 years compared to 4.4 years ( p < 0.001) in those with a cognitive presentation. No differences between motor vs cognitive onset ALS-FTD were found on cognitive testing. When compared to bvFTD, ALS-FTD-cognitive presentation was characterized by reduced language function ( p < 0.001), verbal fluency ( p = 0.001), and naming ( p = 0.007). Both motor and cognitive onset ALS-FTD showed reduced emotion processing ( p = 0.01) and exhibited greater motor cortex and dorsal lateral prefrontal cortex atrophy than bvFTD. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival., Conclusions: Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes., (© 2020 American Academy of Neurology.)

The syndrome of semantic dementia represents the "other side of the coin" to Alzheimer's disease, offering convergent evidence to help refine Bastin et al.'s integrative memory model. By considering the integrative memory model through the lens of semantic dementia, we propose a number of important extensions to the framework, to help clarify the complex neurocognitive mechanisms underlying recollection and familiarity.

Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival. Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD 
cohorts. Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale. Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months ( p <0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function ( p <0.001), verbal fluency ( p  = 0.001), and naming ( p  = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing ( p  = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival. Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.

Background: Frontotemporal dementia (FTD) is associated with complex changes in eating behavior and metabolism, which potentially affect disease pathogenesis and survival. It is currently not known if body composition changes and changes in fat deposition also exist in FTD, the relationship of these changes in eating behavior and appetite, and whether these changes are centrally mediated., Methods: Body composition was measured in 28 people with behavioral-variant frontotemporal dementia (bvFTD), 16 with Alzheimer's disease (AD), and 19 healthy controls, using dual energy x-ray absorptiometry. Changes in body composition were correlated to brain grey matter atrophy using voxel-based morphometry on high-resolution magnetic resonance imaging., Results: Behavioral-variant FTD was characterized by changes in body composition, with increased total fat mass, visceral adipose tissue area (VAT area), and android: gynoid ratio compared to control and AD participants (all P values < 0.05). Changes in body composition correlated to abnormal eating behavior and behavioral change (P < 0.01) and functional decline (P < 0.01). Changes in body composition also correlated to grey matter atrophy involving a distributed neural network that included the hippocampus, amygdala, nucleus accumbens, insula, cingulate, and cerebellum - structures known to be central to autonomic control - as well as the thalamus, putamen, accumbens, and caudate, which are involved in reward processing., Conclusions: Changes in body composition and fat deposition extend the clinical phenomenology in bvFTD beyond cognition and behavior, with changes associated with changes in reward and autonomic processing suggesting that these deficits may be central in FTD., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Memory and the self have long been considered intertwined, leading to the assumption that without memory, there can be no self. This line of reasoning has led to the 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 self-referential memory, 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 temporally-extended 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'., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Autobiographical memory (ABM) is typically held to comprise episodic and semantic elements, with the vast majority of studies to date focusing on profiles of episodic details in health and disease. In this context, 'non-episodic' elements are often considered to reflect semantic processing or are discounted from analyses entirely. Mounting evidence suggests that rather than reflecting one unitary entity, semantic autobiographical information may contain discrete subcomponents, which vary in their relative degree of semantic or episodic content. This study aimed to (1) review the existing literature to formally characterize the variability in analysis of 'non-episodic' content (i.e., external details) on the Autobiographical Interview and (2) use these findings to create a theoretically grounded framework for coding external details. Our review exposed discrepancies in the reporting and interpretation of external details across studies, reinforcing the need for a new, consistent approach. We validated our new external details scoring protocol (the 'NExt' taxonomy) in patients with Alzheimer's disease (n = 18) and semantic dementia (n = 13), and 20 healthy older Control participants and compared profiles of the NExt subcategories across groups and time periods. Our results revealed increased sensitivity of the NExt taxonomy in discriminating between ABM profiles of patient groups, when compared to traditionally used internal and external detail metrics. Further, remote and recent autobiographical memories displayed distinct compositions of the NExt detail types. This study is the first to provide a fine-grained and comprehensive taxonomy to parse external details into intuitive subcategories and to validate this protocol in neurodegenerative disorders., (© 2018 The British Psychological Society.)

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 standardized 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 frontotemporal 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., (© 2019 Ramanan et al.; Published by Cold Spring Harbor Laboratory Press.)

Objective: Physiological changes potentially influence disease progression and survival along the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum. The peripheral peptides that regulate eating and metabolism may provide diagnostic, metabolic, and progression biomarkers. The current study aimed to examine the relationships and biomarker potential of hormonal peptides., Methods: One hundred and twenty-seven participants (36 ALS, 26 ALS- cognitive, patients with additional cognitive behavioral features, and 35 behavioral variant FTD (bvFTD) and 30 controls) underwent fasting blood analyses of leptin, ghrelin, neuropeptide Y (NPY), peptide YY (PYY), and insulin levels. Relationships between endocrine measures, cognition, eating behaviors, and body mass index (BMI) were investigated. Biomarker potential was evaluated using multinomial logistic regression for diagnosis and correlation to disease duration., Results: Compared to controls, ALS and ALS-cognitive had higher NPY levels and bvFTD had lower NPY levels, while leptin levels were increased in all patient groups. All groups had increased insulin levels and a state of insulin resistance compared to controls. Lower NPY levels correlated with increasing eating behavioral change and BMI, while leptin levels correlated with BMI. On multinomial logistic regression, NPY and leptin levels were found to differentiate between diagnosis. Reduced Neuropeptide Y levels correlated with increasing disease duration, suggesting it may be useful as a potential marker of disease progression., Interpretation: ALS-FTD is characterized by changes in NPY and leptin levels that may impact on the underlying regional neurodegeneration as they were predictive of diagnosis and disease duration, offering the potential as biomarkers and for the development of interventional treatments., Competing Interests: No author reports a conflict of interest.

Posterior Cortical Atrophy (PCA) is a rare neurodegenerative syndrome characterised by profound visuoperceptual processing disturbances, attributable to focal parieto-occipital cortical atrophy. Despite relative sparing of the medial temporal lobes, converging evidence reveals significant autobiographical memory impairments in this syndrome, underscoring the crucial role of visual imagery for episodic memory processes. The contribution of visual imagery to complex constructive endeavours, however, remains unclear. Here, we investigated the capacity for atemporal scene construction in 5 well-characterised cases of PCA and contrasted their performance with 10 typical amnestic Alzheimer's Disease (AD) and 10 healthy older Control participants. Behavioural data were analysed using case-Control statistics comparing each PCA patient's scene construction scores to the mean scores of AD and Control groups. In keeping with their clinical phenotype, PCA patients demonstrated significant visuoperceptual and episodic memory impairments on standard neuropsychological tasks. Scene construction performance was grossly impaired in PCA, at a level comparable to that observed in the AD group, manifesting in impoverished and spatially fragmented scenes. Structural neuroimaging confirmed prominent grey matter intensity decrease predominantly in posterior cortical regions in PCA, in the absence of frank hippocampal atrophy. Using an a priori motivated region-of-interest approach across all participants, scene construction performance was found to correlate with grey matter intensity in the left angular gyrus, right precuneus, and right hippocampus. This study is the first to reveal compromised scene construction capacity in PCA, extending our understanding of the cognitive profile of this rare syndrome and pointing towards the fundamental contribution of visual imagery to atemporal forms of imagination., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Early timing of adrenarche, associated with relatively high levels of Dehydroepiandrosterone (DHEA) in children, has been associated with mental health and behavioral problems. However, little is known about effects of adreneracheal timing on brain function. The aim of this study was to investigate the effects of early adrenarche (defined by high DHEA levels independent of age) on affective brain function and symptoms of psychopathology in late childhood (N = 83, 43 females, M age 9.53 years, s.d. 0.34 years). Results showed that higher DHEA levels were associated with decreased affect-related brain activity (i) in the mid-cingulate cortex in the whole sample, and (ii) in a number of cortical and subcortical regions in female but not male children. Higher DHEA levels were also associated with increased externalizing symptoms in females, an association that was partly mediated by posterior insula activation to happy facial expressions. These results suggest that timing of adrenarche is an important moderator of affect-related brain function, and that this may be one mechanism linking early adrenarche to psychopathology., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Changes in the functional connectivity of the subgenual anterior cingulate cortex (SGC) have been linked with depressive symptoms. The aim of this study was to map this relationship across mid to late adolescence. Employing a longitudinal functional magnetic resonance imaging (fMRI) design, associations between patterns of resting-state SGC functional connectivity and symptoms of depression were examined at two time points in an initial sample of 72 adolescents. Using a region-of-interest approach, these associations were evaluated cross-sectionally and longitudinally. Cross-sectionally, weaker SGC functional connectivity with the posterior cingulate cortex (PCC), angular gyrus and dorsal prefrontal cortex at baseline, and weaker SGC connectivity with the dorsomedial prefrontal cortex (DMPFC) and ventromedial prefrontal cortex at follow-up, were associated with higher depressive symptoms. Longitudinally, a decrease in SGC functional connectivity with DMPFC, PCC, angular gyrus and middle temporal gyrus was associated with higher depressive symptoms at follow-up. The observation of weaker SGC connectivity predicting increased symptoms contrasts with the majority of resting-state fMRI studies in clinically depressed populations. Taken together with these past studies, our findings suggest depression-related changes in SGC functional connectivity may differ across developmental and illness stages., (© The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)