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

Establishing two principal dimensions of cognitive variation in Logopenic Progressive Aphasia

Logopenic Progressive Aphasia (LPA) is a neurodegenerative syndrome characterised by sentence repetition and naming difficulties arising from left-lateralised temporoparietal atrophy. Clinical descriptions of LPA largely concentrate on profiling language deficits, however, accumulating evidence points to the presence of cognitive deficits, even on tasks with minimal language demands. Although non-linguistic cognitive deficits in LPA are thought to scale with disease severity, patients at discrete stages of language dysfunction display overlapping cognitive profiles, suggesting individual-level variation in cognitive performance, independent of primary language dysfunction. To address this issue, we used principal component analysis to decompose individual-level variation in cognitive performance in 43 well-characterised LPA patients who underwent multi-domain neuropsychological assessments and structural neuroimaging. The principal component analysis solution revealed the presence of two, statistically independent factors, providing stable and clinically intuitive explanations for the majority of variance in cognitive performance in the syndrome. Factor 1 reflected ‘speech production and verbal memory’ deficits which typify LPA. Systematic variations were also confirmed on a second, orthogonal factor mainly comprising visuospatial and executive processes. Adopting a case-comparison approach, we further demonstrate that pairs of patients with comparable Factor 1 scores, regardless of their severity, diverge considerably on visuo-executive test performance, underscoring the inter-individual variability in cognitive profiles in comparably ‘logopenic’ patients. Whole-brain voxel-based morphometry analyses revealed that speech production and verbal memory factor scores correlated with left middle frontal gyrus, while visuospatial and executive factor scores were associated with grey matter intensity of right-lateralised temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, LPA patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralised temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in LPA, suggesting the presence of a genuine co-occurring cognitive impairment that is independent of language function and disease severity.This work was supported in part by funding to Forefront, a collaborative research group specialized to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council (NHMRC) of Australia program grant (APP1037746) and the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders Memory Program (CE110001021). Siddharth Ramanan is supported by a Faculty of Science Ph.D. Research Scholarship from The University of Sydney. Olivier Piguet is supported by an NHMRC Senior Research Fellowship (APP1103258). Muireann Irish is supported by an ARC Future Fellowship (FT160100096) and an ARC Discovery Project (DP180101548). Matthew A. Lambon Ralph is supported by a UKRI-MRC Programme Grant (MR/R023883/1) and an ERC Advanced grant (GAP: 670428 - BRAIN2MIND_NEUROCOMP)

Anhedonia in Semantic Dementia-Exploring Right Hemispheric Contributions to the Loss of Pleasure.

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith-Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer's disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer's patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer's disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.This study was supported in part by funding to ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases, from the National Health and Medical Research Council (NHMRC) Program grant (#1132524) and Dementia Research Team Grant (#1095127), as well as the Australian Research Council (ARC) Centre of Excellence in Cognition and its Disorders (CE11000102) and an NHMRC Project grant (#1121791). The authors acknowledge the technical assistance provided by the Sydney Informatics Hub, a Core Research Facility of the University of Sydney. M.I. is supported by an ARC Future Fellowship (FT160100096). A.E.W. is supported by an NHMRC Fellowship (#1110773). O.P. is supported by an NHMRC Senior Research Fellowship (GNT1103258). These funding sources were not involved in the study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the manuscript for publication

Determinants of Theory of Mind performance in Alzheimer’s disease: A data-mining study

Whether theory of mind (ToM) is preserved in Alzheimer’s disease (AD) remains a controversial subject. Recent studies have showed that performance on some ToM tests might be altered in AD, though to a lesser extent than in behavioural-variant Frontotemporal Dementia (bvFTD). It is however, unclear if this reflects a genuine impairment of ToM or a deficit secondary to the general cognitive decline observed in AD. Aiming to investigate the cognitive determinants of ToM performance in AD, a data-mining study was conducted in 29 AD patients then replicated in an independent age-matched group of 19 AD patients to perform an independent replication of the results. 44 bvFTD patients were included as a comparison group. All patients had an extensive neuropsychological examination. Hierarchical clustering analyses showed that ToM performance clustered with measures of executive functioning in AD. ToM performance was also specifically correlated with the executive component extracted from a principal component analysis. In a final step, automated linear modelling conducted to determine the predictors of ToM performance showed that 48.8% of ToM performance was significantly predicted by executive measures. Similar findings across analyses were observed in the independent group of AD patients, thereby replicating our results. Conversely, ToM impairments in bvFTD appeared independent of other cognitive impairments. These results suggest that difficulties of AD patients on ToM tests do not reflect a genuine ToM deficit, rather mediated by general (and particularly executive) cognitive decline. They also suggest that executive functioning has a key role in mental state attribution, which support interacting models of ToM functioning. Finally, our study highlights the relevancy of data-mining statistical approaches in clinical and cognitive neurosciences

Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: a systematic review

Introduction: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. Methods: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. Results: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. Discussion: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. Highlights: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias

Inferior parietal lobe contributions to recollection and imagination in neurodegenerative dementias

The left angular gyrus (AG) in the inferior parietal lobe is an integral node of the episodic recollection network, as demonstrated by functional neuroimaging evidence, yet its precise contribution to episodic retrieval remains unclear. This thesis investigates the importance of the AG for episodic retrieval from the perspective of neurodegenerative syndromes. First, a novel theoretical model is advanced, proposing a role for the AG in integrating and representing contextual information, in recollective as well as constructive abilities (Chapter 1). Next, the central tenets of this model are tested in three rare neurodegenerative syndromes traditionally characterised as ‘non-amnestic’ disorders, namely Corticobasal Syndrome (CBS), Logopenic Progressive Aphasia (LPA), and Posterior Cortical Atrophy (PCA). Notably, all three syndromes present with early atrophy of the inferior parietal lobe, amidst variable levels of prefrontal and hippocampal involvement, enabling us to examine AG contributions to episodic retrieval. The results from this thesis indicated the presence of significant episodic retrieval difficulties in both CBS and LPA groups (Chapters 3 and 4). Furthermore, LPA patients displayed poor retrieval of episodic event and contextual information from autobiographical memories across the lifespan (Chapter 5). Across these studies, grey and white matter neuroimaging analyses implicate a key role for the AG and its white matter structural connections to parietal, prefrontal, and medial temporal cortices in episodic retrieval performance. Extending these findings to atemporal imagination, patients with PCA demonstrated marked impairment in the mental construction of spatially coherent scenes, which further related to reduced grey matter integrity of posterior parietal regions including the AG (Chapter 6). Taken together, these findings provide important lesion evidence for the central role of the AG in supporting complex recollective and imaginative endeavours

Is forgetting in visual memory best explained by decay, temporal distinctiveness, or interference models of serial order?

Forgetting in short-term memory has generally been attributed to the passage of time or interfering events. Various models tracing patterns of recall over brief periods of time ascribe forgetting to decay of information with time, loss of distinctiveness of information, or interference from other material. This study attempted to choose between the Primacy model, the SIMPLE (scale-independent memory, perception, and learning) model, and the SOB (serial order in-a-box) model that would best explain performance on a visual serial recall task manipulating delay at encoding and retrieval. The results failed to find detrimental effects of decay with longer intervals, refuting predictions of the decay-based Primacy model. In contrast, an interference-based SOB was found to reasonably explain the results obtained. Analysis of error patterns revealed the Primacy model to not best explain the error patterns noted in the data, contrary to popular findings in serial recall literature. The SIMPLE and SOB provided satisfactory explanation for error patterns, with the SOB accommodating error patterns better. It can be concluded that purely temporal models of forgetting cannot offer adequate explanation for forgetting in visual STM

Rethinking the role of the angular gyrus in remembering the past and imagining the future - the Contextual Integration Model

Despite consistent activation on tasks of episodic memory, the precise contribution of the left angular gyrus (AG) to mnemonic functions remains vigorously debated. Mounting evidence suggests that AG activity scales with subjective ratings of vividness and confidence in recollection, with further evidence pointing to its involvement during construction of detailed and coherent future simulations. Lesion studies however, indicate that damage to the AG does not render patients amnesic on standard source and associative memory paradigms. To reconcile these findings, we present the Contextual Integration model as a unifying framework that couches the mnemonic role of the AG in terms of multimodal integration and representation of contextual information across temporal contexts. Irrespective of whether one is remembering the past or constructing future or hypothetical scenarios, the Contextual-Integration model holds that the core elements of an event (i.e., the who, what, when, where) are bound within the medial temporal lobes while the multimodal details which give rise to perceptually rich recollection are integrated and represented in the AG. Building on previous work, the Contextual Integration model therefore provides a comprehensive exposition of the mnemonic and constructive functions of the AG across temporal contexts, offering a novel test-bed for future work

"Truth be told” – Semantic memory as the scaffold for veridical communication

Theoretical accounts placing episodic memory as central to constructive and communicative functions neglect the role of semantic memory. We argue that the decontextualized nature of semantic schemas largely supersedes the computational bottleneck and error-prone nature of episodic memory. Rather, neuroimaging and neuropsychological evidence of episodic-semantic interactions suggest that an integrative framework more accurately captures the mechanisms underpinning social communication