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.

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

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

Profiles of motivational impairment and their relationship to functional decline in frontotemporal dementia.

Motivational disturbances are pervasive in frontotemporal dementia (FTD) and impact negatively on everyday functioning. Despite mounting evidence of anhedonia in FTD, it remains unclear how such changes fit within the broader motivational symptom profile of FTD, or how anhedonia relates to functional outcomes. Here we sought to comprehensively characterize motivational disturbances in FTD and their respective relationships with functional impairment. A cross-sectional study design was used including 211 participants-68 behavioral-variant FTD (bvFTD), 32 semantic dementia (SD), 43 Alzheimer's disease (AD), and 68 healthy older control participants. Anhedonia severity was measured using the Snaith-Hamilton Pleasure Scale while severity of apathy was assessed across Emotional, Executive, and Initiation dimensions using the Dimensional Apathy Scale. Functional impairment was established using the FTD Functional Rating Scale (FRS). Distinct motivational profiles emerged in each dementia syndrome: a domain-general motivational impairment in bvFTD; a predominantly anhedonic profile in SD; and more pronounced initiation and executive apathy in AD. Correlation analyses revealed differential associations between motivational symptoms and severity of functional impairment in each group. Executive apathy was associated with functional impairment in bvFTD, while anhedonia was strongly correlated with functional decline in SD. Finally, executive and emotional apathy were associated with functional decline in AD. Our study indicates distinct profiles of apathy and anhedonia in FTD syndromes, which in turn are differentially associated with functional decline. This detailed characterization of motivational phenotypes can inform patient stratification for targeted interventions to improve functional outcomes.

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.