The neural substrates of transdiagnostic cognitive-linguistic heterogeneity in primary progressive aphasia.

BACKGROUND: Clinical variants of primary progressive aphasia (PPA) are diagnosed based on characteristic patterns of language deficits, supported by corresponding neural changes on brain imaging. However, there is (i) considerable phenotypic variability within and between each diagnostic category with partially overlapping profiles of language performance between variants and (ii) accompanying non-linguistic cognitive impairments that may be independent of aphasia magnitude and disease severity. The neurobiological basis of this cognitive-linguistic heterogeneity remains unclear. Understanding the relationship between these variables would improve PPA clinical/research characterisation and strengthen clinical trial and symptomatic treatment design. We address these knowledge gaps using a data-driven transdiagnostic approach to chart cognitive-linguistic differences and their associations with grey/white matter degeneration across multiple PPA variants. METHODS: Forty-seven patients (13 semantic, 15 non-fluent, and 19 logopenic variant PPA) underwent assessment of general cognition, errors on language performance, and structural and diffusion magnetic resonance imaging to index whole-brain grey and white matter changes. Behavioural data were entered into varimax-rotated principal component analyses to derive orthogonal dimensions explaining the majority of cognitive variance. To uncover neural correlates of cognitive heterogeneity, derived components were used as covariates in neuroimaging analyses of grey matter (voxel-based morphometry) and white matter (network-based statistics of structural connectomes). RESULTS: Four behavioural components emerged: general cognition, semantic memory, working memory, and motor speech/phonology. Performance patterns on the latter three principal components were in keeping with each variant's characteristic profile, but with a spectrum rather than categorical distribution across the cohort. General cognitive changes were most marked in logopenic variant PPA. Regardless of clinical diagnosis, general cognitive impairment was associated with inferior/posterior parietal grey/white matter involvement, semantic memory deficits with bilateral anterior temporal grey/white matter changes, working memory impairment with temporoparietal and frontostriatal grey/white matter involvement, and motor speech/phonology deficits with inferior/middle frontal grey matter alterations. CONCLUSIONS: Cognitive-linguistic heterogeneity in PPA closely relates to individual-level variations on multiple behavioural dimensions and grey/white matter degeneration of regions within and beyond the language network. We further show that employment of transdiagnostic approaches may help to understand clinical symptom boundaries and reveal clinical and neural profiles that are shared across categorically defined variants of PPA.

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.

Mapping behavioural, cognitive and affective transdiagnostic dimensions in frontotemporal dementia.

Two common clinical variants of frontotemporal dementia are the behavioural variant frontotemporal dementia, presenting with behavioural and personality changes attributable to prefrontal atrophy, and semantic dementia, displaying early semantic dysfunction primarily due to anterior temporal degeneration. Despite representing independent diagnostic entities, mounting evidence indicates overlapping cognitive-behavioural profiles in these syndromes, particularly with disease progression. Why such overlap occurs remains unclear. Understanding the nature of this overlap, however, is essential to improve early diagnosis, characterization and management of those affected. Here, we explored common cognitive-behavioural and neural mechanisms contributing to heterogeneous frontotemporal dementia presentations, irrespective of clinical diagnosis. This transdiagnostic approach allowed us to ascertain whether symptoms not currently considered core to these two syndromes are present in a significant proportion of cases and to explore the neural basis of clinical heterogeneity. Sixty-two frontotemporal dementia patients (31 behavioural variant frontotemporal dementia and 31 semantic dementia) underwent comprehensive neuropsychological, behavioural and structural neuroimaging assessments. Orthogonally rotated principal component analysis of neuropsychological and behavioural data uncovered eight statistically independent factors explaining the majority of cognitive-behavioural performance variation in behavioural variant frontotemporal dementia and semantic dementia. These factors included Behavioural changes, Semantic dysfunction, General Cognition, Executive function, Initiation, Disinhibition, Visuospatial function and Affective changes. Marked individual-level overlap between behavioural variant frontotemporal dementia and semantic dementia was evident on the Behavioural changes, General Cognition, Initiation, Disinhibition and Affective changes factors. Compared to behavioural variant frontotemporal dementia, semantic dementia patients displayed disproportionate impairment on the Semantic dysfunction factor, whereas greater impairment on Executive and Visuospatial function factors was noted in behavioural variant frontotemporal dementia. Both patient groups showed comparable magnitude of atrophy to frontal regions, whereas severe temporal lobe atrophy was characteristic of semantic dementia. Whole-brain voxel-based morphometry correlations with emergent factors revealed associations between fronto-insular and striatal grey matter changes with Behavioural, Executive and Initiation factor performance, bilateral temporal atrophy with Semantic dysfunction factor scores, parietal-subcortical regions with General Cognitive performance and ventral temporal atrophy associated with Visuospatial factor scores. Together, these findings indicate that cognitive-behavioural overlap (i) occurs systematically in frontotemporal dementia; (ii) varies in a graded manner between individuals and (iii) is associated with degeneration of different neural systems. Our findings suggest that phenotypic heterogeneity in frontotemporal dementia syndromes can be captured along continuous, multidimensional spectra of cognitive-behavioural changes. This has implications for the diagnosis of both syndromes amidst overlapping features as well as the design of symptomatic treatments applicable to multiple syndromes.

Understanding the multidimensional cognitive deficits of logopenic variant primary progressive aphasia.

The logopenic variant of primary progressive aphasia is characterized by early deficits in language production and phonological short-term memory, attributed to left-lateralized temporoparietal, inferior parietal and posterior temporal neurodegeneration. Despite patients primarily complaining of language difficulties, emerging evidence points to performance deficits in non-linguistic domains. Temporoparietal cortex, and functional brain networks anchored to this region, are implicated as putative neural substrates of non-linguistic cognitive deficits in logopenic variant primary progressive aphasia, suggesting that degeneration of a shared set of brain regions may result in co-occurring linguistic and non-linguistic dysfunction early in the disease course. Here, we provide a Review aimed at broadening the understanding of logopenic variant primary progressive aphasia beyond the lens of an exclusive language disorder. By considering behavioural and neuroimaging research on non-linguistic dysfunction in logopenic variant primary progressive aphasia, we propose that a significant portion of multidimensional cognitive features can be explained by degeneration of temporal/inferior parietal cortices and connected regions. Drawing on insights from normative cognitive neuroscience, we propose that these regions underpin a combination of domain-general and domain-selective cognitive processes, whose disruption results in multifaceted cognitive deficits including aphasia. This account explains the common emergence of linguistic and non-linguistic cognitive difficulties in logopenic variant primary progressive aphasia, and predicts phenotypic diversification associated with progression of pathology in posterior neocortex.

Outcomes and predictors of failure of arteriovenous fistulae for hemodialysis.

PURPOSE: Arteriovenous fistula(AVF) is preferred vascular access for hemodialysis but has primary failure in 20-60%. Studying predictors of AVF failure would help plan appropriate management.We studied AVF outcomes, clinical and vascular factors predicting their failure in patients requiring hemodialysis. METHODS: Retrospective study of patients with AVF creation from January 2017 to December 2018. Outcomes studied were immediate (< 72 h), primary (3 months) AVF failure, six-month/one-year patency, analyzed for predictive clinical, vascular factors as assessed using Pre-operative Doppler Ultrasound(DUS). RESULTS: Of 530 AVFs in 460 patients, DUS was done in 426/530 (80.4%), 349/460 (75.8%) were males, mean age was 53.10 ± 14.54 (18-91), 215/460(46.7%) had Diabetes mellitus(DM), 423/460(92%) hypertension. AVFs were radiocephalic in 79/530 (14.9%), brachiocephalic 418/530 (78.9%), brachiobasilic 33/530 (6.2%). AVF Immediate/Primary failure was seen in 64/530 (12.1%), 90/352 (25.6%); Patency at six months/one year in 253/352(71.8%),191/305 (62.6%), respectively. Older age had less immediate failures (AOR 0.97, CI 0.95-0.99, p 0.03). Feeding arterial diameter predicted immediate and primary failure on univariate analysis [OR 0.64 (95% CI 0.49-0.83), 0.62 (95% CI 0.47-0.89), respectively], but not multivariate. Artery diameter of > 4.0 mm had less failures [immediate (p 0.01), primary (p 0.02)], < 2.0 mm had specificity 95.9% and 95.4% for immediate, primary failure respectively. CONCLUSION: AVF failure is 12.1%, immediately; 25.6% three months after construction, Patency at 6 months is 71.8%, one year 62.6%. Immediate failures decrease with age. Artery diameters > 4.0 mm had less, < 2.0 mm had more failures.

Longitudinal changes in behaviour, mood and functional capacity in the primary progressive aphasia variants.

Primary progressive aphasia (PPA) is a neurodegenerative clinical syndrome characterised by a progressive decline in speech and language functions. Deficits in behaviour, mood and functional capacity are reported in PPA but are less well understood. This study examined the PPA variants' profiles on these domains at initial presentation and over time and evaluated their relations to overall cognitive ability. Behaviour, mood and functional capacity were measured annually (over ~6 years) in 145 individuals diagnosed with PPA (41 logopenic [lv-PPA], 44 non-fluent [nfv-PPA] and 60 semantic variants [sv-PPA]) using the Cambridge Behavioural Inventory-Revised (CBI-R) carer questionnaire. Overall cognition was assessed annually with the Addenbrooke's Cognitive Examination-III. Distinct profiles were observed across PPA syndromes. Notably, sv-PPA carers reported greater behavioural, eating and motivational disturbances than the other PPA variants throughout the disease course. Reported memory problems were also greater in sv-PPA and lv-PPA than in nfv-PPA across all time points. These disturbances occurred in the context of the sv-PPA group demonstrating a slower rate of cognitive decline than the lv-PPA group and a parallel rate to that found in the nfv-PPA group. Associations between overall cognition and the CBI-R domains were trivial at baseline assessment; however, distinct profiles emerged when mapping each syndrome's overall cognitive decline with their behavioural, mood and functional trajectories. Our findings demonstrate that the evolving behaviour, mood and functional capacity profiles of the PPA variants are distinct and extend beyond the primary disorder of language. These findings have important implications for clinical management and caregiver education in PPA.

Evidence for a pervasive autobiographical memory impairment in Logopenic Progressive Aphasia.

Although characterized primarily as a language disorder, mounting evidence indicates episodic amnesia in Logopenic Progressive Aphasia (LPA). Whether such memory disturbances extend to information encoded pre-disease onset remains unclear. To address this question, we examined autobiographical memory in 10 LPA patients, contrasted with 18 typical amnestic Alzheimer's disease and 16 healthy Control participants. A validated assessment, the Autobiographical Interview, was employed to explore autobiographical memory performance across the lifespan under free and probed recall conditions. Relative to Controls, LPA patients showed global impairments across all time periods for free recall, scoring at the same level as disease-matched cases of Alzheimer's disease. Importantly, these retrieval deficits persisted in LPA, even when structured probing was provided, and could not be explained by overall level of language disruption or amount of information generated during autobiographical narration. Autobiographical memory impairments in LPA related to gray matter intensity decrease in predominantly posterior parietal brain regions implicated in memory retrieval. Together, our results suggest that episodic memory disturbances may be an under-appreciated clinical feature of LPA.

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.

"More than words" - Longitudinal linguistic changes in the works of a writer diagnosed with semantic dementia.

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.

The interplay of emotional and social conceptual processes during moral reasoning in frontotemporal dementia.

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.

Establishing two principal dimensions of cognitive variation in logopenic progressive aphasia.

Logopenic progressive aphasia is a neurodegenerative syndrome characterized by sentence repetition and naming difficulties arising from left-lateralized temporoparietal atrophy. Clinical descriptions of logopenic progressive aphasia 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 logopenic progressive aphasia 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 the individual-level variation in cognitive performance in 43 well-characterized logopenic progressive aphasia 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 logopenic progressive aphasia. 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-lateralized temporoparietal, middle frontal regions and their underlying white matter connectivity. Importantly, logopenic progressive aphasia patients with poorer visuospatial and executive factor scores demonstrated greater right-lateralized temporoparietal and frontal atrophy. Our findings demonstrate the inherent variation in cognitive performance at an individual- and group-level in logopenic progressive aphasia, suggesting the presence of a genuine co-occurring cognitive impairment that is statistically independent of language function and disease severity.

Understanding the neural basis of episodic amnesia in logopenic progressive aphasia: A multimodal neuroimaging study.

Logopenic progressive aphasia (LPA) is a neurodegenerative disorder characterised by profound naming and sentence repetition disturbances, attributable to disproportionately left-sided temporo-parietal atrophy. Accumulating evidence suggests, in addition to language impairments, the presence of stark verbal and nonverbal episodic memory dysfunction in LPA. The neurocognitive bases of such impairments, however, remain to be clarified. Here, we characterised episodic memory disruption and its corresponding grey and white matter correlates in the LPA syndrome. Nineteen LPA patients were contrasted with 23 matched typical Alzheimer's disease (AD) patients and 31 healthy Controls on standardized verbal and nonverbal episodic delayed recall measures. Participants further underwent structural magnetic resonance and diffusion-weighted imaging. Significant verbal memory deficits were evident in both patient groups, with LPA patients performing at an intermediate level to AD and Controls. For nonverbal memory, however, LPA performance was indistinguishable from that of AD, with both groups displaying marked impairments relative to Controls. Whole-brain voxel-based morphometry analyses revealed significant left temporo-parietal and left hippocampal atrophy in the LPA group. Covariate analyses showed that verbal and nonverbal amnesia in LPA correlated with grey matter integrity of bilateral frontoparietal and left medial temporal lobe regions. Notably, the common regions underpinning verbal and nonverbal memory dysfunction in LPA were the left orbitofrontal cortex and bilateral angular gyri in the inferior parietal cortex. The bilateral angular gyri, along with prefrontal and hippocampal regions further emerged as disease-general correlates of verbal and nonverbal memory performance. Alterations in mean diffusivity in structural connections between the left angular gyrus and medial temporal lobes were further associated with verbal memory performance in all participants. Our findings reveal, for the first time, the presence of pervasive memory impairments in LPA mediated by degeneration of a distributed prefrontal-hippocampal-parietal network, and disrupted parieto-hippocampal structural connectivity.

Relationship Between the Gut Microbiome and Systemic Chemotherapy.

The intestinal microbiome encodes vast metabolic potential, and multidisciplinary approaches are enabling a mechanistic understanding of how bacterial enzymes impact the metabolism of diverse pharmaceutical compounds, including chemotherapeutics. Microbiota alter the activity of many drugs and chemotherapeutics via direct and indirect mechanisms; some of these alterations result in changes to the drug's bioactivity and bioavailability, causing toxic gastrointestinal side effects. Gastrointestinal toxicity is one of the leading complications of systemic chemotherapy, with symptoms including nausea, vomiting, diarrhea, and constipation. Patients undergo dose reductions or drug holidays to manage these adverse events, which can significantly harm prognosis, and can result in mortality. Selective and precise targeting of the gut microbiota may alleviate these toxicities. Understanding the composition and function of the microbiota may serve as a biomarker for prognosis, and predict treatment efficacy and potential adverse effects, thereby facilitating personalized medicine strategies for cancer patients.

Scene construction impairments in frontotemporal dementia: Evidence for a primary hippocampal contribution.

The capacity to generate naturalistic three-dimensional and spatially coherent representations of the world, i.e., scene construction, is posited to lie at the heart of a wide range of complex cognitive endeavours. Clinical populations with selective damage to key nodes of a putative scene construction network of the brain have provided important insights regarding the contribution of medial temporal and prefrontal regions in this regard. Here, we explored the capacity for atemporal scene construction, and its associated neural substrates, in the behavioural-variant of frontotemporal dementia (bvFTD); a neurodegenerative brain disorder in which atrophy systematically erodes medial and lateral prefrontal cortices with variable medial temporal lobe involvement. Nineteen bvFTD patients were compared to 18 typical Alzheimer's Disease (AD), and 25 healthy older Control participants on a scene construction task. Relative to Controls, both patient groups displayed marked impairments in generating contextually detailed and spatially coherent scenes, with bvFTD indistinguishable from AD patients across the majority of task metrics. Voxel-based morphometry, based on structural brain MRI, revealed divergent neural substrates of scene construction performance in each patient group. Despite widespread medial and lateral prefrontal atrophy, the capacity to generate richly detailed and spatially coherent scenes in bvFTD was found to rely predominantly upon the integrity of right medial temporal structures, including the hippocampus and parahippocampal gyrus. Scene construction impairments in AD, by contrast, hinged upon the integrity of posterior parietal brain regions. Our findings in bvFTD resonate with a large body of work implicating the right hippocampus in the construction of spatially integrated scene imagery. How these impairments relate to changes in autobiographical memory and prospection in bvFTD will be an important question for future studies to address.

A question of scale.

An fMRI experiment reveals distinct brain regions that respond in a graded manner as humans process distance information across increasing spatial scales.

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 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.

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 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.

Exploring the contribution of visual imagery to scene construction - Evidence from Posterior Cortical Atrophy.

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.

"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.