A caregiver's perspective on clinically relevant symptoms in behavioural variant frontotemporal dementia: tools for disease management and trial design

ABSTRACT

Background

Adequate detection of symptoms and disease progression in behavioural variant frontotemporal dementia (bvFTD) is complex. Dementia cohorts usually utilize cognitive and functional measures, which fail to detect dominant behavioural and social cognitive deficits in bvFTD. Moreover, since patients typically have a loss of insight, caregivers are important informants. This is the first qualitative study to investigate caregiver relevant symptoms during the disease course of bvFTD, aiming to improve tools for diagnosis, progression, and future clinical trials.

Methods

Informal caregivers of patients in different disease stages of bvFTD (N = 20) were recruited from the neurology outpatient clinic of the Amsterdam UMC and a patient organization for peer support in the Netherlands. Their perspectives on clinical relevance were thoroughly explored during individual semi‐structured interviews. Inductive content analysis with open coding was performed by two researchers independently to establish overarching themes and patterns.

Results

Caregivers reported a variety of symptoms, in which (i) loss of emotional connection, (ii) preoccupation and restlessness, and (iii) apathy and dependency compose major themes of relevance for diagnosis and treatment. Within heterogeneous disease trajectories, symptom presence differed between stages and among individuals, which is relevant in the context of progression and outcome measures. Significant socio‐emotional changes dominated in early stages, while severe cognitive, behavioural, and physical deterioration shifted focus from predominant personality change to quality of life in later stages.

Conclusions

Caregiver perspectives on target symptoms in bvFTD differ according to clinical stage and patient‐caregiver characteristics, with significant socio‐emotional changes characterizing early stages. These findings call for more appropriate tools and symptomatic treatments, as well as a personalized approach in treatment of bvFTD and a focus on early stage interventions in clinical trial design.

INTRODUCTION

Behavioural variant frontotemporal dementia (bvFTD) is one of the most common causes of young‐onset dementia. ¹ Characterized by insidious changes in personality and behaviour, bvFTD has a major impact on the lives of patients and their families. ² Caregiver burden in bvFTD is higher than in Alzheimer's disease (AD) and in other clinical variants of FTD, ³ emphasizing the urgency of improvement in disease management of the behavioural variant. In addition to the core features including disinhibition, apathy, loss of empathy, stereotypy, hyperorality, and executive dysfunction, ⁴ impaired insight is an important hallmark of bvFTD. ⁵ Although this concept is not as well defined as other characteristics, patients are known to be less aware and less concerned of the impact of their disorder on themselves and others. ⁶ Due to this fact, the reported symptoms used in diagnostics and evaluation of progression are predominantly provided by informal caregivers.

Both clinical practice and the research field of bvFTD face many challenges. Since there is no curative therapy for bvFTD at this time, ⁷ symptom management and (non‐)pharmacological treatment during the disease course are important. ⁸ Currently, clinical measures used for diagnosis and progression are often derived from the field of AD. Most general dementia screeners heavily depend on cognitive or daily functioning, and are therefore less appropriate for the dominant behavioural and social cognitive disturbances in bvFTD. Other measures are adapted versions of coarse instruments, such as the Frontotemporal Lobar Degeneration (FTLD)‐Modified Clinical Dementia Rating scale, ⁹ which may be less sensitive for subtle progression and less specific for the behavioural variant. Given the impaired insight of patients with bvFTD, observations of their caregivers during disease course may be essential in finding clinically relevant measures. The few studies investigating caregiver perspectives in bvFTD are primarily focused on caregiver burden, rather than their observations of the patient. From early stages, families' endure confusion and frustration, ¹⁰ in which caregivers experience changes in interpersonal relationship, ¹¹ loss of emotional attachment, ¹² difficulty of communicating, and a decrease in coping style and social support. ¹⁰ , ¹³

Caregiver perspectives on target symptoms will be highly relevant in developing adequate scales for diagnosis, progression, and outcome measures in future clinical trials. Signalling the need for caregiver perspectives, the American patient and caregiver organization, the Association for Frontotemporal Degeneration (AFTD), initiated an Externally Led Patient‐Focused Drug Development Meeting, pointing to communication, independence, higher‐quality relationships, and controlled emotions and behaviour, as general targets for drug treatment across the entire spectrum of FTD. ¹⁴ In the current study, we are the first to investigate relevant target symptoms of the behavioural variant of FTD in a systematic and qualitative research design. By conducting semi‐structured interviews with informal caregivers of patients with bvFTD, we ensured a versatile and flexible approach to explore caregiver perspectives in more richness and detail, aiming to improve tools for diagnosis, progression and clinical trial design.

METHODS

Study design

The study employed a qualitative research methodology aimed to gain insights in caregiver relevant symptoms during the disease course in bvFTD. Initially, the study design involved a series of focus groups with informal caregivers, but due to restrictions in the COVID‐19 pandemic it was impossible to organize in‐person gatherings. Therefore, the original design was adjusted to individual in‐depth telephone interviews following a similar structure. The number of included participants was determined by data saturation, the point at which no new information was observed in the data, which generally occurs within 12 interviews. ¹⁵ Because of the known clinical variability in bvFTD, ¹⁶ we decided inclusion ended when the last three interviews provided no additional information regarding the conceptual themes.

Participants

A total of 20 informal caregivers were recruited during consultation at the neurology outpatient clinic of the Amsterdam University Medical Center and via the Dutch patient organization for peer support ‘FTD Lotgenoten’. The sample consisted of 15 partners and 5 adult children of patients with a clinical diagnosis of probable or definite bvFTD ⁴ in a variety of disease stages (n = 8 recently diagnosed and/or living at home, n = 5 progressed and/or in need of extra care, n = 3 institutionalized, and n = 4 deceased). Of deceased patients, in one case autopsy was performed, confirming FTLD with TDP‐43‐immunoreactive pathology (FTLD‐TDP). Caregivers of advanced or deceased patients shared their past experiences. The study protocol is in accordance with the ethical standards of the Declaration of Helsinki and was approved by the Medical Ethical Committee of the Amsterdam UMC (2019.745). All participants provided informed consent to use their data for research purposes and explicit consent to record the telephone conversations.

Interviews

Semi‐structured interviews of approximately 45 min were conducted independently by telephone by two authors (JF, GD). The interview was framed by several neutral and open‐ended questions, which served as a general guideline and could be elaborated on by follow‐up questions. ¹⁷ Following a three‐stage diamond model, ¹⁸ the structure of the interview was divided in three stages: diverging of topics, clustering into categories, and converging into themes. All input from caregivers was used for analysis, including additional remarks and comments. The general questions included:

• With your expertise, what are the hallmarks of bvFTD?

• What did you notice when disease progressed?

• Which of these symptoms belong together?

• If you would have a magic wand, which symptom would you like to remove and why?

• Imagine a drug, which would stabilize (not cure) the most troublesome symptom, would this be desired and why?

Content analysis

The interviews were audio recorded, transcribed, and entered into Atlas.ti 8 (Scientific Software Development, Berlin) for ease in coding and theme development. Open and in vivo coding was used and resulted in 100+ codes on categorical, subcategorical, dimension, or concept level. This way, multiple codes could be assigned to particular quotes, e.g. regarding singular symptoms, associated clusters, presence in disease course, subsequent effects, and conceptual themes. Coding and clustering was done in consensus by two authors (JF, GD). In inductive content analysis, all data were searched for overarching themes and patterns within the interviews. During data gathering and processing, considerations and (preliminary) analyses were thoroughly discussed among the research team (JF, GD, BR, EV, YP, ME, SB) to enhance mutual sense‐making and discuss interpretations.

RESULTS

Twenty informal caregivers of bvFTD patients were questioned concerning relevant symptoms and disease progression (75% female), of which were 15 partners and 5 adult children (Table 1). At the time of participation, the patients had a mean age of 64.8 ± 8.7 years and disease‐related symptoms were present for a mean of 7.0 ± 5.4 years. The majority of patients lived at home with their relatives (65%), three patients were admitted in a nursing home (15%), and four patients were deceased (20%) at the time their caregivers participated.

Table 1.

Characteristics of informal caregivers and bvFTD patients

Cases (N)	20 (100)
Informal caregiver, partner/child	15 (75)/5 (25)
Sex of informal caregiver, female/male	15 (75)/5 (25)
Age of patient, years	64.80 ± 8.70 (range 41–80)
Sex of patient, female/male	7 (35)/13 (65)
Disease duration, years	7.03 ± 5.44 (range 2–20)
Status, home/extra care/institutionalized/deceased	8 (40) /5 (25)/3 (15)/4 (20)

Note: Data are presented as n (%); mean ± SD.

From multiple topics to major themes

When describing the variety of symptoms in bvFTD, caregivers mentioned numerous and diverging topics, partly highlighting known characteristics in current bvFTD criteria regarding disinhibition, apathy, loss of empathy, stereotypy, hyperorality, and executive dysfunction. Various additional topics revealed by caregivers included social–emotional changes (e.g. less involvement and reactivity); decreased communication (less spontaneous and more superficial); impaired insight; cognitive disturbances in language, memory, and daily living activities; psychological symptoms (e.g. delusions and mood alterations); and physical changes (e.g. posture or incontinence). However, the presence, severity, and course of these symptoms varied widely among the cases that were described.

Clustering these topics in categorical groups, based on similarity and associations, established a range of nine domains covering known core features (e.g. disinhibition) and additional concepts (e.g. emotional involvement). When evaluating topics on clinical relevance, caregivers designated matters on an abstract level (e.g. loss of ‘one's old self’), as well as more concrete issues (e.g. problems due to executive dysfunction or incontinence). Nevertheless, many individual topics seemed to contribute to larger concepts, such as personality change, egocentricity, challenging behaviour, or dependency.

By converging content of all domains in underlying concepts and context, three overarching themes of caregiver relevance were identified. These major themes encompassed (i) loss of emotional connection, (ii) preoccupation and restlessness, and (iii) apathy and dependency, and will be elucidated in the following paragraphs. The process of divergence, clustering, and convergence into caregiver relevant themes is illustrated in Fig. 1.

Figure 1.

Inductive content analysis from multiple topics to main themes of caregiver relevance in bvFTD.

Loss of emotional connection

A significant overarching theme expressed by nearly all caregivers encompassed the loss of emotional connection and involvement. One caregiver described, ‘You are emotionally connected, and that continues to crumble. As if you are on a boat and you see something floating away, further and further’. Prominent changes stated by the caregivers were an increased disinterest in others, decreased empathy, and emotional indifference. Unsurprisingly, these social‐emotional changes negatively affected the interaction, relationship, and sense of partnership between patient and caregiver, commonly experienced as loss of a deeper connection with one another, unequal contact, and changing roles. In some cases, caregivers associated the emotional detachment with altered communication, e.g. the inability to share former mutual thoughts on events and views on life in all its complexity. In other words, communication was experienced to be unidirectional and more superficial. Caregivers expressed their need for meaningful interaction, e.g. ‘I wish I could talk to him again. A real conversation, meaningful, not just whether the food is good’, or ‘I would prefer to regain the involvement and verbal sparring, having a full‐fledged partner’. An explicit focus inward of the patient, experienced by caregivers, was often at odds with premorbid personality traits, regarding social skills, sensitivity, and communicative behaviour. One caregiver concluded, ‘Most of all, I wish to undo the personality change—from extrovert to introvert—because that has such an impact on who he is right now’. Taken together, caregivers mostly attributed the explicit personality change characterized in bvFTD to these social–emotional symptoms, as one caregiver pinpointed: ‘It would be great if you could influence social cognition and retain interest in others.… But perhaps, you are not talking about FTD anymore, if you could cure that part’.

Another important factor in the loss of emotional connection concerned impaired insight. This impaired insight ranged from failure to evaluate own behaviour, to complete denial of ongoing changes, which affected both patient and caregiver in coping with the consequences of the progressive disease. However, the consequence and relevance of disease insight remained ambiguous. One caregiver explained, ‘They have no insight in their disease, I feel that is the only positive side of FTD. We always kept in mind: what doesn't know, doesn't hurt’, while another caregiver shared an opposite feeling: ‘The most important difference with other forms of dementia is disease insight. As long as this remains missing in bvFTD, it doesn't matter to me at all. Prolonging the process would only mean more misery’. On the one hand, one might say ignorance is bliss, in which decreased awareness and concern about a devastating diagnosis mitigated both agony for the patient as well as associated burden for the caregiver. On the other hand, impaired insight led to decreased consensus between patient and caregiver, widening the gap between both individuals. This discrepancy led to more disconnect, in which feelings of grief could not be shared with one another, accusations led to frustration and conflict, and/or increased feelings of loneliness throughout the disease process. As one caregiver thoughtfully pointed out, ‘I wish to reverse the lack of problem awareness, that is a selfish answer though. It would be in favour of caregivers if disease insight would remain intact a little longer. This way you can communicate with each other and can be connected for a longer period of time, instead of both living in a different world on which you have no consensus. But if mom had realized she no longer felt anything for us, that would hurt. The question is whether you would want this or not, the only advantage is that you can share it together’.

Preoccupation and restlessness

A variety of preoccupations and an overall restlessness were expressed by caregivers and comprised another overarching theme. Numerous intrusive thoughts, stubborn beliefs, and aggressive visualizations were shared, often negative in nature (e.g. regarding adultery, pain, or burglary). These preoccupations led to visible psychological distress according to caregivers, in which patients were not easily comforted or distracted. One caregiver illustrated, ‘She is afraid that she will get killed by our neighbour, or that burglars will enter the house. She lives in constant fear’. Caregivers often associated the observed restlessness with delusions or hallucinations. However, more positive preoccupations were also mentioned, such as amorous fixations, mostly leading to less harmful consequences. Furthermore, caregivers often associated restlessness with forms of compulsivity and agitation, such as tendencies to pace, engage in rituals, or be easily irritated. ‘At this time, the agitation caused by the delusions is hardest to deal with. Because she completely loses balance, as far as there is balance though’ or ‘For her, I wish she would be a little bit happier, and relaxed. If the delusions would disappear, that would probably take away a lot of restlessness’. These unsettling symptoms mainly caused despair and compassion concerning the patient, stressing the effects on well‐being and quality of life of the patient. In other cases, severe behavioural disturbances led to conflict and emotional damage for the caregiver, emphasizing the effects on the patient‐caregiver relationship. One family stated ‘I wish to remove those hateful comments. She wishes you dead and scolds us in the supermarket. That is very hurtful’. A common factor involved the fact that such aimless behaviours were easily misinterpreted by the patient's surroundings and society. For instance, several cases in which impulsivity and disinhibition were present led to theft in supermarkets, wandering alongside highways or (sexual) harassment, often involving intervention by law enforcement.

Apathy and dependency

An extensive theme encompassed apathy and overall dependency on others, which was illustrated by the majority of caregivers. First, loss of initiative was often annotated as a predominant symptom. A range of matters regarding apathy concerned decreased engagement in social life, former interests, usual daily activities, or a general non‐presence. One of the caregivers explained ‘I wish to reverse that terrible absence. That she is back again, you know. The spontaneity, that is what you miss. She is present in the room, but then again she is not’. Many caregivers shared observations that intrinsic motivation declined, in which incentive needed to be offered externally and reliance on one's surroundings grew. As one caregiver elaborated, ‘It feels like a sort of constant shadow over me, which is totally dependent of me, which does not give me any space to move. For me, this oppressing “shadow effect” is the hardest, I do not have freedom anymore. At home, the only place where I can be by myself is on the toilet with the door closed’. Correspondingly, in cases where patients were still intrinsically engaged in a few activities (e.g. daily walks, sports, or drinking coffee in a local bar), caregivers shared feelings of autonomy and resilience in coping with the disease. Second, several caregivers expressed another form of dependency, related to specific consequences of cognitive, behavioural, or physical impairment. One caregiver explained, ‘The executive problems are actually his largest problem, there is no cause‐and‐effect any more. The fact that he does not know how to do certain things. That concerns … basically everything’. Other examples included problems caused by incontinence hindering daily life, memory deficits demanding assistance in everyday tasks, and disinhibited or irresponsible behaviour requiring protection from oneself. In general, caregivers shared that practical or physical care did not weigh up against the mental aspect of losing emotional connection or premorbid personality. One caregiver even acknowledged the fact that nursing created a sense of intimacy and fulfilment. However, at the same time, several caregivers declared that this dependency contributed to the transition to a ‘childlike relationship’, diminishing equality and changing the roles between patient and caregiver.

Caregiver perspectives during disease progression

Concerning the disease course, a significant heterogeneity in presence and severity of symptoms over time complicates specific staging. Yet, in broad perspective, caregivers roughly associated different topics to different phases, serving evidence for a shift in symptom relevance over time. In many cases, early symptoms involved a decreased motivation and/or ability to engage in social interaction, as one caregiver summarized: ‘In short, the “social layer” disappears’. These socio‐emotional symptoms were often subtle, yet substantial, and tended to progress quickly. For caregivers, feelings of grief over the loss of connection and premorbid personality dominated in the early phases and continued throughout the disease course, evidently illustrated as ‘You must say goodbye, while she is still alive’. As opposed to significant personality change, several caregivers explained that mild behavioural or cognitive deficits in the early stages could be easily limited, dissolved, or overcome with strategies or tricks. In addition, minor changes in body posture were described with low clinical relevance, e.g. changes in gait or crooked poses. Illustrating the intermediate stages, a variety of behavioural, cognitive, and physical disturbances affected daily life and dependence of the patient. For caregivers, acceptance and adjustment seemed to be essential in coping with the accumulating changes, and daytime activity care was often arranged. With further progression, the quote ‘Everything that makes us human diminishes’ described a global and scattered deterioration. Severe physical, behavioural, and cognitive symptoms included incontinence, dysphagia, extreme apathy, rigidity, amnesia, apraxia, or mutism, and required institutionalization. Where topics of initial phases often shared an external focus (patient in relation with their environment), later phases seemed to have a common internal focus (patient in relation to survival). In the end stages, quality of life of the patient seemed to become a primary goal. One caregiver defined ‘That slight smile on the face becomes most important’. The main themes of caregiver relevance during disease progression are visualized in Fig. 2.

Figure 2.

Main themes of caregiver relevance during disease progression of bvFTD.

The attitudes towards the relevance of hypothetical interventions differed as well. Unquestionably, intervention with disease modifying therapies was preferred in the early stages, when personality is mostly preserved. Since socio‐emotional symptoms occurred early in the disease and progressed quickly, a ‘window of opportunity’ for future therapies aiming to preserve emotional connection appeared relatively small. In hindsight, one caregiver explained ‘There was a time where I really struggled with the actual loss of my husband, but by now, I have already lost him. Right now, I am living with a patient and that ship has sailed’. With disease progression, potential benefits of stabilizing or prolonging therapies differed between individuals, depending on disease conditions of the patient and (moral) beliefs of the caregiver. Many caregivers attributed any limits of clinical relevance to the quality of life of the patient and/or honouring their partnership: ‘There still are moments where you can see he is enjoying himself, and yes, those moments are my incentive’, or ‘You meet someone, fall in love and spend your lives together. That is what you want to maintain’. Others referred to the impact of personality change as a whole, and the related caregiver burden: ‘The fact remains that they already have the disease, the behaviour remains challenging. I did not choose to grow old with this man’. One caregiver concluded by stressing the relative and individual nature of this issue, ‘As for progression, I do not have a limit like “this far and no further”. The moment you face it, you will probably push that limit again. The moment you think “let's stop”, you adapt anyway. That's just human nature, some will deal with it more easily than others’. These different perspectives stressed the significant role of individual caregiver and patient characteristics with respect to hypothetical interventions, regarding (premorbid) personality, relationship, coping mechanisms, and burden during the disease course of bvFTD.

DISCUSSION

This study examined caregiver perspectives of relevant symptoms and disease course in bvFTD through in‐depth interviews with informal caregivers. Within a variety of topics and clusters, three overarching themes of caregiver relevance arose, comprising (i) loss of emotional connection, (ii) preoccupation and restlessness, and (iii) apathy and dependency. Among heterogeneous disease trajectories, we recognize a shift in symptom presence and relevance during progression. Whereas earlier stages were dominated by socio‐emotional changes contributing to loss of premorbid personality, later stages seemed increasingly influenced by severe cognitive, behavioural, and physical deficits causing dependency and decreased quality of life. Furthermore, individual patient and caregiver characteristics regarding (premorbid) personality and relationship may affect symptom relevance during the disease course.

Our results on caregiver relevant themes add to the scarce literature on caregiver perspectives in bvFTD. Previous studies stated that first symptoms concern subtle changes in interpersonal relationships, ¹¹ communication, closeness, meaningfulness, ¹⁰ and emotional attachment. ¹² Indeed, we found that socio‐emotional involvement, as well as meaningful communication, decline in early stages. As both affect the emotional connection between patient and their surroundings, we underline the relevance of this significant theme. Additionally, we acknowledge a role of impaired insight in the loss of emotional connection. The literature suggests that the lack of insight in bvFTD rather involves a loss of emotional concern than a loss of cognitive awareness. ⁶ In our study, we emphasize a caregiver‐specific relevance of impaired insight in bvFTD. Caregivers described a patient‐caregiver discrepancy in the consequences of impaired insight, in which full awareness and distress were spared for the patient, while at the same time consensus and emotional connection between patient and caregiver further diverged. This paradox in symptom relevance highlights the complexity of neuropsychiatric disorders such as bvFTD, the impact on patients and their families, and their fundamental difference from other neurodegenerative diseases.

Caregiver relevant themes of (ii) preoccupation and restlessness and (iii) apathy and dependence were both supported by a variety of symptoms, corresponding to the diagnostic criteria of bvFTD. ⁴ While psychotic symptoms in bvFTD have been described before, negative symptoms (e.g. social withdrawal, stereotypical thinking) are thought to be more frequently present than positive symptoms (e.g. delusions, suspiciousness). ¹⁹ Based on our findings, we add that positive psychotic symptoms do occur in bvFTD, have a significant impact on the quality of life of the patient, and call for relief. Furthermore, we conclude the caregiver relevant theme of dependence to be associated with either predominating apathy or severe cognitive or physical disturbances. As apathetic behaviour and cognitive deficits required extrinsic motivation and daily assistance, patients' dependence on caregivers increased. These findings are consistent with studies stating that apathy particularly affects emotional distress of the caregiver ²⁰ and contributes to patients’ functional disability, ²¹ as well as the presence of executive, language, and memory deficits in bvFTD. ²² However, caregiver relevance of dependency differed between individuals and may be related to phenomena such as caregiver burden and caregiver adaptation (i.e. psychological adjustment to a situation). While caregiver burden generally increases during disease progression and neuropsychiatric decline in bvFTD, ³ , ²³ adequate caregiver adaptation may maintain quality of life and can be encouraged through effective caregiver support programs. ¹³ , ²⁴ Individual factors regarding personality and coping might explain the variance in attribution of caregiver relevance to dependency, and should be considered when optimizing treatment of bvFTD by means of personalized medicine.

In addition to our research aim, a recurring theme arose based on spontaneous input by our caregivers, stressing a lack of knowledge and awareness of bvFTD in most levels of disease management. Medical professionals, governmental organizations, and financial institutions often failed in early recognition of disease or fell short in providing adequate care and support. Previous studies described a similar lack of acknowledgment, understanding, and sufficient recourses, contributing to caregivers' feelings of loneliness, ¹⁰ , ²⁵ urging the need to raise FTD awareness among essential health care networks and government agencies. ¹¹ Hampering patient and caregiver resilience, it is clear this issue must be addressed. Another additional theme which was repeatedly raised concerned various recommendations of caregivers for managing symptoms in bvFTD and minimizing their consequences, intended to benefit other informal caregivers. These peer recommendations are presented in Fig. 3.

Figure 3.

Peer recommendations for informal caregivers in managing bvFTD.

The findings of this qualitative study have several important implications, which are listed in Fig. 4. First, the identification of our three caregiver relevant themes emphasizes the need for sensitive and specific tools for diagnosis regarding socio‐emotional changes, preoccupied and restless behaviour, and functional decline in bvFTD. Improvement of measures focusing on social cognition should be a priority. Currently, social cognition testing in clinical practice and cohorts mainly consists of single‐level tasks assessing emotion recognition or theory of mind, of which more evidence regarding diagnostic accuracy is preferred. ²⁶ , ²⁷ , ²⁸ As social cognition refers to all processes necessary for adequate social functioning, test batteries may be improved by structural and validated assessment on all levels of social cognition. ²⁹ Furthermore, development of novel tools capturing implicit processes associated with socio‐emotional functioning are promising, such as decreased levels of physiological arousal reflecting typical ‘emotional blunting’ in bvFTD. ³⁰ , ³¹ , ³² , ³³ Regarding adequate assessment of preoccupied, restless, and apathetic behaviour and functional decline in bvFTD, current measures may be optimized as well. Several informant‐rated questionnaires, such as the Frontal Behavioural Inventory, ³⁴ Cambridge Behavioural Inventory‐Revised, ³⁵ , ³⁶ and FTD‐Rating Scale, ³⁷ seem able to detect FTD‐related symptoms and distinguish FTD from other dementias. ²⁷ However, in view of the remaining challenge in differentiating bvFTD from primary psychiatric disorders (PPD), ³⁸ systematic use of (new) scales requires further research. Notwithstanding the fact that there are multiple factors impending early diagnosis (e.g. thresholds to seek early consultation), our findings reflect the view that the development of adequate tools targeting these major themes may be a primary goal.

Figure 4.

Main implications of caregiver perspectives in bvFTD.

Second, identification of our three caregiver relevant themes advocates for improvement of symptomatic treatment of socio‐emotional, and specific behavioural and functional features in bvFTD. Currently, there are no approved pharmacological treatments with specific indication for bvFTD and attempts to alleviate core symptoms are often derived from similar symptoms in PPD. ⁸ , ³⁹ , ⁴⁰ The manifestation of empathy loss, disinhibition, and apathy may involve altered serotoninergic systems, and in line with this thought, treatment with antidepressants (e.g. trazodone, citalopram, paroxetine) have shown improvement in multiple symptoms. ⁸ , ³⁹ Studies on the effects of atypical antipsychotics, anti‐epileptics, cholinesterase inhibitors, and NMDA‐antagonists are less conclusive, or may even worsen behavioural symptoms. ⁸ , ³⁹ Moreover, with adverse effects of increased cardiovascular risk, extrapyramidal side effects and enhanced emotional blunting, caution is urged and more research is needed. Randomized controlled trials on administration of oxytocin showed promising results in improvement of socio‐emotional symptoms, as well as apathy. ⁴¹ , ⁴² Additionally, identification of effective non‐pharmacological interventions, such as tailored activity programs, may further influence engagement and functional abilities of bvFTD patients, and caregivers' strategies. ³⁹ By optimizing clinical guidance of bvFTD through adequate symptom management with (non‐)pharmacological interventions, the quality of life of patient and caregiver may be significantly improved.

Third, recognition of a shift in symptom relevance during disease stages is highly relevant for the development of tools evaluating progression in disease course and/or intervention effects of future clinical trials. During disease course, it is known that initial symptoms can change and new behaviours appear in later stages of bvFTD. ⁴³ , ⁴⁴ , ⁴⁵ , ⁴⁶ This suggests that progression of behavioural disturbances is not linear and not limited to worsening of initial symptoms, complicating prognosis. As longitudinal studies on social cognition in bvFTD are scarce and inconclusive, ²⁷ , ⁴⁷ more research is needed to validate their potential as progression markers or outcome measures in clinical trials. To date, there is no effective disease modifying therapy available to cure or delay progression for bvFTD. ³⁹ , ⁴⁰ , ⁴⁸ Increased understanding of FTLD pathogenesis points to therapies targeting interference of the aggregation process or clearance of FTLD‐related proteins. ⁴⁰ , ⁴⁸ In our study, we conclude that socio‐emotional changes tend to occur early in the disease, progress quickly, and largely contribute to the significant personality change in bvFTD. Therefore, we suggest the window of opportunity for preservation of personality is limited, and stress the value of early stage interventions in future clinical trial design, aiming to precede or minimize socio‐emotional changes. Furthermore, acknowledging the significant heterogeneity in symptom presence between stages, among individuals, and in the associated desire for hypothetical prolonging therapies, current symptom management and future treatment of bvFTD should aim for a personalized approach, in which individual differences in disease, patient, and caregiver characteristics are considered.

Finally, large scale education of professionals in the complete spectrum of disease management should be a priority. Expanding knowledge and awareness of bvFTD among essential care and support networks may aid in the multidimensional challenges faced by patients and their families.

This study has a few limitations. For informal caregivers living with the patient day‐by‐day, gradual neurodegenerative processes seemed challenging to evaluate. Therefore, perspectives on disease progression were integrated in broad stages and specific individual changes were interpreted on a concept level (e.g. socio‐emotional). Also, the proportion of female participants (75%) was relatively high in our sample. As it is not unlikely for sex differences to play a role in caregiver relevance (e.g. regarding appreciation of social interactions), this aspect requires further research. Additionally, since FTD is a heterogeneous disease with different underlying pathologies, future research in pathologically confirmed samples could point out whether differences in clinically relevant symptoms over the disease course exist. Lastly, in recollection of past experiences, recall bias is plausible. However, the individual interviews allowed for enough time and depth to thoroughly elaborate perspectives on a personal level.

This is one of the first studies on informal caregiver perspectives regarding relevant symptomatology and disease course in bvFTD. The qualitative nature of this research design adequately fitted our research aim to grasp caregiver relevance in bvFTD. The choice for individual interviews enabled the interviewers to probe and thoroughly elaborate on the expressed topics and their foundations. To ensure structured analysis, systematic coding was done by two researchers independently and interpretations were meticulously discussed among the research team. By including informal caregivers of patients in different disease stages, the complete disease course of bvFTD was represented. Preferably, these findings may be verified with surveys or studies in larger (e.g. international) samples of caregivers across different pathogenic mutations of bvFTD.

DISCLOSURE

The authors have no potential conflicts of interest to disclose.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.