Exploring graded profiles of hippocampal atrophy along the anterior-posterior axis in semantic dementia and Alzheimer's disease.

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer's disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior-posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease-specific vulnerability along the anterior-posterior axis of the hippocampus was associated with canonical clinical features of these syndromes.

Implicit bias training can remove bias from subliminal stimuli, restoring choice divergence: A proof-of-concept study.

Subliminal information can influence our conscious life. Subliminal stimuli can influence cognitive tasks, while endogenous subliminal neural information can sway decisions before volition. Are decisions inextricably biased towards subliminal information? Or can they diverge away from subliminal biases via training? We report that implicit bias training can remove biases from subliminal sensory primes. We first show that subliminal stimuli biased an imagery-content decision task. Participants (n = 17) had to choose one of two different patterns to subsequently imagine. Subliminal primes significantly biased decisions towards imagining the primed option. Then, we trained participants (n = 7) to choose the non-primed option, via post choice feedback. This training was successful despite participants being unaware of the purpose or structure of the reward schedule. This implicit bias training persisted up to one week later. Our proof-of-concept study indicates that decisions might not always have to be biased towards non-conscious information, but instead can diverge from subliminal primes through training.

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.

Cognitive and Neural Mechanisms of Social Communication Dysfunction in Primary Progressive Aphasia.

Mounting evidence suggests that, in parallel with well-defined changes in language, primary progressive aphasia (PPA) syndromes display co-occurring social cognitive impairments. Here, we explored multidimensional profiles of carer-rated social communication using the La Trobe Communication Questionnaire (LCQ) in 11 semantic dementia (SD), 12 logopenic progressive aphasia (LPA) and 9 progressive non-fluent aphasia (PNFA) cases and contrasted their performance with 19 Alzheimer's disease (AD) cases, 26 behavioural variant frontotemporal dementia (bvFTD) cases and 31 healthy older controls. Relative to the controls, the majority of patient groups displayed significant overall social communication difficulties, with common and unique profiles of impairment evident on the LCQ subscales. Correlation analyses revealed a differential impact of social communication disturbances on functional outcomes in patient and carer well-being, most pronounced for SD and bvFTD. Finally, voxel-based morphometry analyses based on a structural brain MRI pointed to the degradation of a distributed brain network in mediating social communication dysfunction in dementia. Our findings suggest that social communication difficulties are an important feature of PPA, with significant implications for patient function and carer well-being. The origins of these changes are likely to be multifactorial, reflecting the breakdown of fronto-thalamic brain circuits specialised in the integration of complex information.

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.

Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia.

Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer's disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer's disease, and 51 healthy older control participants. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer's disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular cortices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.