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

Motivational disturbances are prominent in frontotemporal dementia (FTD), leading to social withdrawal and disengagement from previously enjoyed activities [1]. Loss of motivation in the form of apathy represents a core clinical feature of the behavioral variant of FTD [bvFTD; 2] and is increasingly recognized in language variants of FTD [3, 4]. Apathy is inherently multidimensional and can be deconstructed in terms of its impact on goal-oriented behavior, cognitive engagement, or emotional responsiveness [5, 6]. Unsurprisingly, apathy is a strong predictor of functional decline in FTD [7, 8], compromising the organization, planning, and initiation of basic activities of daily living including cooking, managing medication, and maintaining personal hygiene [8‐10]. Beyond its impact on the individual, apathy has downstream negative effects on the social and emotional wellbeing of the carer [1, 11, 12].

While apathy has tended to take center stage, recent studies suggest that many of the negative behavioral symptoms of FTD (e.g., social withdrawal, lack of engagement, loss of interest) might be better conceptualized in terms of alterations in hedonic processing [13‐15]. Anhedonia refers to the loss of interest in previously enjoyable pursuits, such as food, sex, hobbies, and social interactions, and is pervasive in neuropsychiatric disorders, such as depression and bipolar disorder [16]. Several recent studies demonstrate the presence of marked anhedonia in bvFTD and semantic dementia (SD), representing a significant departure from pre-morbid functioning [16‐18]. Importantly, while anhedonia and apathy co-occur in FTD, their neural substrates are dissociable, suggesting that anhedonia should be considered a standalone clinical symptom in FTD [16]. These observations have prompted calls for a more targeted approach to identifying distinct motivational phenotypes in FTD [18, 19].

Despite growing awareness that apathy and anhedonia co-occur in FTD, their differential impact on functional impairment in FTD syndromes remains unclear. Studies in psychiatric disorders, such as major depressive disorder, schizophrenia, and bipolar disorder, suggest a close coupling between anhedonia, negative functional outcomes, and disease severity [20, 21]. However, no study to date has explored the impact of anhedonia on functional outcomes in FTD. The objective of the present study therefore was to: (1) characterize the nature of multidimensional motivational impairments in bvFTD and SD compared to Alzheimer’s disease (AD) participants; and (2) explore the relative contributions of multidimensional apathy and anhedonia to functional impairment in each diagnostic group.

Demographic, cognitive, and clinical characteristics of the study sample are presented in Table 1. Groups were not statistically significantly different in terms of age [F(3,207) = 2.4, p = 0.07, \({\eta }_{{\text{p}}}^{2}\) = 0.03] but differed for sex distribution (χ² = 13.93, p = 0.003) driven by significantly more males in the bvFTD group and females in the control group (both p’s < 0.05). Groups also differed for years of education [F(3,207) = 4.5, p = 0.005, \({\eta }_{{\text{p}}}^{2}\) = 0.06] as the bvFTD group had, on average, 1.9 fewer years of education relative to Controls (p = 0.004; all other p’s > 0.08). Patient groups had comparable disease duration (years elapsed since onset of symptoms; p = 0.09) but differed in terms of functional impairment on the FRS [FRS Logit score: F(2,127) = 3.9, p = 0.02, \({\eta }_{{\text{p}}}^{2}\) = 0.06], with bvFTD patients showing greater functional impairment relative to SD (p = 0.04). Importantly, using the FRS classification for disease staging, all dementia groups were categorized as being at the same level of disease severity (i.e., “moderate”). No other significant differences were observed on the FRS (all p’s > 0.09).

Group differences were evident on the DASS-D [F(3,185) = 13.7, p < 0.001, \({\eta }_{{\text{p}}}^{2}\)=0.19] with patients self-reporting higher levels of depression relative to Controls (all p’s < 0.008). However, patient groups did not differ for self-rated depression (all p’s > 0.72) or carer-rated behavioral change on the CBI-R (all p’s > 0.09). Significant group differences were evident on the ACE-III [F(3,206) = 105.1, p < 0.001, \({\eta }_{{\text{p}}}^{2}\)=0.61], driven by marked cognitive impairment in patients relative to Controls (all p’s < 0.001). Post hoc tests indicated that AD and SD patients were disproportionately impaired relative to the bvFTD group (both p’s < 0.001) with no difference between AD and SD (p = 0.99). These cognitive and behavioral changes are in keeping with previous studies.

Loss of motivation is a prominent feature of FTD, yet systematic characterization of multidimensional changes in apathy and anhedonia has been lacking. Here, we provide a fine-grained profiling of phenotypic motivational disturbances and their respective contributions to functional impairment in FTD. Overall, we found distinct motivational profiles independent of disease severity in each dementia syndrome; a domain-general dampening of motivation in bvFTD, a predominantly anhedonic profile in SD, and an apathetic profile driven by pronounced initiation and executive apathy in AD. Importantly, dimensions of apathy and anhedonia were differentially related to functional outcomes in each patient group suggesting the need for targeted interventions geared toward the specific motivational profile of the individual.

Considering first the bvFTD group, we uncovered a profile of profound motivational impairments, spanning all apathy dimensions on the DApS (executive, emotional, initiation). These changes in goal-directed behavior were more severe relative to disease-matched cases of SD and AD, in keeping with previous studies [1]. In addition, anhedonia was prominent in bvFTD, again of a greater magnitude than reported in AD, but comparable with the SD group, consistent with previous findings [16]. Importantly, the magnitude of apathy and anhedonia severity was comparable across all subdomains in bvFTD, indicative of a global motivational impairment in this syndrome. Despite this overall dampening of motivation in bvFTD, correlation analyses suggested that executive apathy was more strongly associated with functional decline compared to emotional apathy and anhedonia, while initiation apathy was as strongly related to functional decline as executive apathy. Several studies in bvFTD have documented the negative impact of apathy, as a global construct, on instrumental activities of daily living, such as managing finances and shopping, as well as more advanced activities, such as playing games, planning, and going on holiday [reviewed by 8, 34]. Crucially, our findings caution against a simple one-to-one mapping between apathy and functional outcomes and suggest that a more fine-grained approach is needed. Notably, behavioral inertia and economy of cognitive effort appear particularly important for poor prognostic outcomes in bvFTD, while hedonic and emotional motivational changes (anhedonia, emotional apathy) do not seem to play as central a role. As such, our findings suggest that a reduction in spontaneous cognitive activities and accompanying behavioral inertia may be critical harbingers of poor functional outcomes in this syndrome [see also 35].

In contrast, SD patients were characterized largely by motivational impairments related to hedonic processing, with significantly higher levels of anhedonia relative to executive and initiation apathy. Importantly, anhedonia, executive apathy, and initiation apathy emerged as significantly associated with poor functional outcomes in SD. Our findings align with previous research linking apathy to functional decline in SD patients [9] but offer increased precision by pinpointing executive and initiation dimensions of apathy as crucial in this context. Moreover, our findings resonate with recent work highlighting changes in hedonic tone as a prominent yet overlooked feature of the SD motivational phenotype [17‐19], and one which has been largely neglected in terms of prognostic outcomes. Recent theoretical frameworks have suggested that loss of hedonic tone in SD might lead to a truncating of interest onto a restricted range of activities that are pursued compulsively, to the neglect of more adaptive behaviors [36]. Our findings of a predominantly anhedonic relative to apathetic profile in SD fit well with this proposal. Rather than displaying a global apathetic profile, carers report SD patients as initiating and executing some aspects of goal-directed behavior, often manifesting in the form of rituals or stereotypical behaviors [36]. Uncovering the nature of these behaviors is an important future direction for this work, ensuring the patient can be supported to remain independent, while also mitigating carer stress and burden. Finally, we note that our current SD sample comprised a mixed group of left- and right-lateralized cases, and it will be important to explore effects of laterality on motivational profiles in SD subtypes, given previous reports of greater anhedonia severity in right SD [17].

Finally, the AD motivational profile was characterized by greater executive and initiation apathy in comparison to anhedonia. This finding resonates with previous reports of less severe emotional apathy [11] and lower levels of anhedonia [16] in AD relative to bvFTD. Importantly, correlation analyses suggested that executive and emotional apathy made the strongest contributions to functional impairment in AD. That executive apathy should be associated with functional decline in AD is not surprising, and potentially reflects widespread difficulties in the cognitive initiating, planning, and implementing of goal-directed actions essential for an array of complex activities of daily living [discussed by 37]. Our finding that emotional apathy is associated with functional decline was somewhat unexpected. It may be that with disease progression, cognitive impairments in AD result in increasing social withdrawal. However, further empirical research will be required to substantiate this proposal. Our findings mesh well with longitudinal studies suggesting that apathy might serve as a behavioral marker of a more aggressive disease course and poorer prognosis in AD [10, 38]. Given that these studies assessed apathy in a unidimensional manner, it will be imperative to chart how the multidimensional nature of apathy changes over the AD disease course and how fluctuations across apathy components relate to different disease trajectories. This is particularly relevant in the context of younger-onset presentations of AD, for whom clinical symptoms may differ from the canonical later-onset presentation [40].

Several methodological considerations warrant discussion. While our emphasis was on multidimensional aspects of motivation, the SHAPS questionnaire provides a somewhat coarse snapshot of anhedonia. Future studies distinguishing between putative dimensions of anhedonia (e.g., anticipatory versus consummatory) will provide important insights in this regard. We acknowledge the need to move beyond traditional carer report questionnaires and to develop objective assays of motivated behaviors as expressed in daily life. This is particularly pertinent given that in the current study we relied on carer report for ratings of patient anhedonia and apathy, while depression symptoms were self-rated by the patient. Notably, early features of anhedonia may be subtle and therefore less amenable to carer report (e.g., loss of interest, decreased pleasure). In addition, there are currently no validated methods for measuring anhedonia in dementia, which highlights the need for multidimensional validated measures in this population. Finally, given all our patient groups were in the “moderate” stage of functional impairment, it will be crucial to systematically track how multidimensional motivational changes vary according to disease staging and dynamically evolve over the disease course. Longitudinal studies with larger sample sizes will enable us to determine whether the phenotypic motivational profiles reported here stabilize or even resolve in each dementia syndrome, with a view to identifying critical periods of transition during which targeted interventions might have optimal efficacy.

In conclusion, this study provides a fine-grained characterization of distinct motivational phenotypes in dementia and their respective impact on functional outcomes. Motivational disturbances in dementia are gaining increasing attention as predictors of early entry to residential care and patient mortality and are reported as some of the most difficult symptoms to manage by carers [39]. Our findings underscore the importance of screening for apathy and anhedonia in younger-onset dementia populations and delineating the specific stages at which such symptoms emerge. This detailed characterization of motivational phenotypes can inform patient stratification for targeted interventions to potentially improve functional outcomes and reduce carer stress.