Apathy and Huntington’s Disease: A Literature Review Based on PRISMA

Apathy was first conceptualized by Marin in 1990 (17). According to Marin, apathy is characterized by a reduction in goal-directed cognition, associated with a lack of motivation in the following three dimensions: emotional (flat affect and emotional indifference), cognitive (decreased interest and lack of plans and goals), and behavioral (lack of effort, initiative, and productivity). This definition makes clear that apathy is a multifactorial concept with a variety of underlying mechanisms (10). Marin distinguished between apathy as a syndrome and apathy as a symptom of another syndrome. By doing so, he established a set of criteria for diagnosing apathy syndrome.

In 1994, Cummings et al. (18) suggested that apathy should be conceived as a loss of interest and motivation, with loss of initiative and flat affect. However, there is still no consensus on the conception of apathy. For example, Stuss et al. (19) stated that apathy cannot simply be attributed to a lack of motivation, because this is complicated to assess and requires observation and quantification of behaviors and affects. The authors therefore defined apathy as “an absence of responsiveness to stimuli internal or external as demonstrated by a lack of self-initiated action” (19). Here, apathy revolves around one key notion: initiation. For these authors, apathy is a set of related but separate states, and the clinical manifestations depend on the neural substrate and functional processes involved (cognitive, behavioral, and affective).

Based on Marin’s definition, Starkstein et al. (20) developed a set of diagnostic criteria for apathy in Alzheimer’s disease in order to distinguish clearly between depression and apathy, with a special emphasis on lack of motivation. The criteria were as follows: lack of motivation relative to the patient’s previous level of functioning or the standards of his or her age and culture as indicated by subjective account or observation by others; presence for at least 4 weeks during most of the day of at least one symptom belonging to each of the following three domains: diminished goal-directed behavior, diminished goal-directed cognition, and diminished concomitants of goal-directed behavior; the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning; and the symptoms are not due to diminished level of consciousness or the direct physiological effects of a substance (20).

Levy and Dubois (21) put forward an alternative conception of apathy based on a cognitive model of behavior. Given that clinical manifestations of apathy are specific to lesions in the prefrontal cortex and basal ganglia, they deemed that apathy is a “behavioral observable syndrome” that manifests itself in a “quantitative reduction of self-generated, voluntary and purposeful behaviors.” They suggested that there are three underlying processes of apathy: emotional/affective (inability to associate affective/emotional signals with ongoing and forthcoming behaviors), caused by lesions in the orbital and medial prefrontal cortex or basal ganglia; cognitive (inability to elaborate a plan of action needed for ongoing and forthcoming behaviors), caused by lesions in the dorsolateral prefrontal cortex and caudate nucleus; and auto-activation (inability to activate thoughts or initiate actions). These authors suggested that there are many forms of apathy syndrome, the most severe corresponding to disturbance of the auto-activation process, which frequently results from lesions in the limbic and associative areas of the internal globus pallidus.

In line with Marin’s conception, Starkstein and Leentjens (22) focused on lack of motivation, linked to a reduction in goal-directed behaviors, and they included a temporal element in their diagnostic criteria. In order to establish a consensus in research and clinical practice, a new set of diagnostic criteria of apathy was developed (23, 24) (Box 1). These criteria had the same general structure as those of Starkstein et al. (25) based on Marin’s conception (26), and not only allowed apathy to be clearly distinguished from other concepts, but also considered all its dimensions (24).

More recently, a group of 23 experts (researchers, healthcare professionals, etc.) met to revise the diagnostic criteria for apathy in brain disorder. Using the Standard Delphi Methodology, they revised and developed the criteria in a two-step process: web surveys, followed by a consensus meeting (27) (Box 1). The modifications mainly concerned criteria A and B (subcriteria B1 and B3). More specifically, in criterion A, the term motivation was replaced with the term goal-directed behavior. According to Robert et al. (27), goal-directed behavior is a quantifiable term, unlike motivation. The second major modification concerned criterion B. Experts wanted to keep the same three-dimensional structure (behavior, cognition, and emotion). However, it was important to add a social aspect. Behavior and cognition have different underlying brain processes, but in clinical practice, apathy manifests itself in both cases as diminished observable activity (27). Thus, the expert group placed behavior and cognition in the same subcriterion (B1) and added a separate dimension: social interaction (subcriterion B3). According to the authors, this modification improved the assessment of apathy in both clinical research and everyday clinical practice. Another key change concerned criterion D, with the addition of the sentence “the symptoms (criteria A and B) are not exclusively explained or due to major changes in the patient’s environment.” This took account of the fact that some tragic events (e.g., terrorist attack) can lead to changes that may mimic apathy (27). By including a separate social interaction dimension covering spontaneous or stimulated social interaction, this new diagnostic criterion for apathy reflects an awareness of apathy’s multidimensional aspect. It provides as objective an assessment as possible, as it is based on aspects whose impairment can easily be described and observed.

The concept of apathy is also found in DSM, but it is only mentioned as a symptom of other pathologies (e.g., depression). The International Classification of Diseases makes no reference to apathy.

Defining specific criteria is very important. It avoids potential confusion between apathy and other clinical terms like abulia, anhedonia, depression, and learned helplessness. For example, the Oxford English Dictionary defines apathy as a lack of interest (cognitive aspect) or a lack of enthusiasm (affective aspect). However, abulia is defined as an absence of willpower or an inability to act decisively. This confusion has led to diagnostic errors. For example, in psychiatry, abulia is regarded as the severe form of apathy (24).

Many different instruments have been used to examine the presence and severity of apathy in psychiatric, neurological and neurodegenerative pathologies. Box 2 cites the apathy measures most commonly used in HD (5).

As can be seen, there is still only a limited choice of tests. In the majority of studies, apathy is evaluated with nonspecific tools. For example, the short version of the Problem Behaviors Assessment (PBA-s), the Frontal Systems Behavior Scale, and the Neuropsychiatric Inventory (NPI) are general tests for behavioral disorders, with only one or two items devoted to apathy. Other measures can assess apathy, but they are one-dimensional, simply providing an overall score to confirm or refute the presence of apathy (e.g., Apathy Evaluation Scale [AES] and 14-item Apathy Scale) (28). Another tool that is supposed to assess the different substructures of apathy is the Apathy Inventory, which was developed to collect comprehensive information about apathy’s presence in several brain pathologies (29). It takes several components of apathy into account: flat affect, loss of initiative, and loss of interest. This scale comes in three versions: clinician, caregiver, and patient. Its aim is to detect behavioral changes since disease onset. The clinician version takes the form of a semistructured interview (or even observation, in the case of prolonged hospitalization). The Apathy Inventory has consistent psychometric properties (30).

The Lille Apathy Rating Scale (LARS) also assesses different aspects of apathy. It was developed by Sockeel et al. (31), based on Marin’s conception of apathy. This scale includes 33 items covering nine domains: reduction in everyday productivity, lack of interest, lack of initiative, extinction of novelty seeking, motivation, blunting of emotional responses, lack of concern, poor social life, and self-awareness. It is administered in the form of a structured interview. It has a four-factor structure: intellectual curiosity, emotion, action initiation, and self-awareness. However, there has been no confirmatory analysis to validate these four factors (10). Internal consistency (α=0.80) and test–retest reliability (r=0.95) are satisfactory (30). A shortened version was developed and validated by Dujardin et al. (32). This version includes seven of the original nine domains (reduction in everyday productivity, lack of interest, lack of initiative, extinction of novelty seeking, motivation, blunting of emotional responses, and poor social life). The other two (lack of concern and self-awareness) were deleted because of their lack of sensitivity (33). This shortened version has acceptable internal consistency (α=0.73), good interrater reliability (r=0.95), and good test–retest reliability at 4 months (r=0.92) (11).

Despite its psychometric limitation, the LARS is one of the rare assessment tools to consider the multifactorial and multidimensional aspect of apathy. However, according to Radakovic et al. (34), the Apathy Inventory and LARS are good assessment tools for unidimensional apathy but not for multidimensional apathy. In order to remedy the lack of multidimensional scales, Radakovic and Abrahams (35) created a tool that is well adapted to the multidimensional aspect of apathy. The Dimensional Apathy Scale (DAS) was designed for persons with neurodegenerative diseases who have motor difficulties. To avoid the impact of motor deficits, none of the items rely on physical performances to assess the motor aspect of apathy. The structure of this scale was based on Levy and Dubois’s (21) conception, and it contains items taken from other scales (11). The authors conducted an exploratory factorial analysis based on 311 responses from healthy individuals. There were initially 45 items, but after deleting some items with a low saturation index, they came up with a version featuring 24 items evaluating the executive, emotional, and cognitive/behavioral dimensions of apathy. These items have good internal consistency (α=0.80). No study has yet been conducted with the scale’s target population (11). Although the exclusion of the motor aspect avoids confusion between pure motor difficulties and apathetic behaviors, the total exclusion of the motor dimension deprives users of information about the possible contribution of physical illness to the emergence of apathy (11). In several studies, researchers have argued that motor difficulties can contribute to the development of apathy and that there is a significant link between the two (36, 37). These authors suggested that physical disorders lead to a lack of interest in activities requiring physical performances. In this context, it is important to use scales that take account of the different factors that may contribute to the emergence of apathy (38).

However, the DAS remains one of the few multidimensional scales of apathy. For this reason, it was adapted and translated into French by M’Barek et al. (28). The French version (f-DAS) was validated with 223 healthy participants. Analyses indicated psychometric properties similar to those of the original version (35). The f-DAS has good validity and reliability, good internal consistency, and good discriminant validity against depression. A confirmatory factor analysis corroborated the three-factor model (28) of Radakovic and Abrahams (35).

In essence, the absence of a consensus on the nature of aspects of apathy and the different conceptions of apathy are reflected in several inconsistencies in the psychometric properties of all these assessment tools. To remedy these, we must have a single theoretical and conceptual basis on which to develop reliable and valid tools for measuring apathy (11).

Psychiatric and behavioral disorders are not yet well documented in HD, even though researchers have known about them for a long time. These disorders are known to be responsible, at least in part, for the occupational and social disintegration that accompanies HD (39). They are also known to have a more harmful impact than the cognitive and motor symptoms on functional skills (40) and quality of life (41). In their literature review, van Duijn et al. (42) revealed a high prevalence of depression, anxiety, irritability, and apathy in HD. The frequency of these manifestations varied across studies from 33% to 76%, probably owing to disease progression. Obsessive-compulsive disorder (10%−52%) and psychotic disorder (3%−11%) were less frequent. Other psychobehavioral disorders are also reported in HD, including sexual behavior disorders (25%), which can give rise to everyday conflict (39). Eating disorders have also been reported, such as bulimia, snacking, or refusing food on account of delusions such as fear of poison (39). Furthermore, Snowden et al. (43) identified social behavior disorders such as egocentricity and lack of sympathy or empathy combined with mental toughness in patients with HD. Respect for shared social conventions can be disturbed in this population. For example, people with HD may make crude or obscene comments or engage in offensive behavior (44).

Apathy has always been addressed as a symptom of other pathologies (e.g., depression). Some authors consider apathy to be a symptom of depression. For example, Paoli et al. (45) suggested that depression is the most frequent symptom in HD, and that apathy is one of its clinical manifestations or somatic expressions. Authors sometimes include apathy in the same category as inactivity and weight loss. The boundaries between apathy and depression remained blurred for a long time, because they share common symptoms such as loss of interest and hypersomnia (35, 46). Over time, researchers realized that they are actually two completely different psychological entities: Apathy is a lack of motivation, whereas depression is a mood disorder. Marin (17, 26) noticed that the relation between apathy and depression varies according to the disease profile but also according to the individual’s profile. It should be noted that these two entities can frequently coexist. This confusion can lead to bias when estimating their frequency in different clinical pictures (47).

As discussed above, apathy is one of the most common symptoms of HD. It has been investigated in several studies using different scales (e.g., NPI, PBA for HD [PBA-HD], and AES), as shown in Table 1.

We undertook a systematic review, based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This approach was chosen because of the lack of research and the heterogeneous nature of existing studies, as well as the lack of a comprehensive review of the literature on apathy and HD. This systematic review was conducted with two major databases; PubMed and PubMed Central. We manually searched reviews and checked reference lists to identify further relevant citations. We used the following key terms to search the databases: PubMed Central: (huntington[Abstract] AND apathy[Abstract]) and (huntington[Body - Key Terms]) AND apathy[Body - Key Terms]); PubMed: (huntington[Title/Abstract]) AND (apathy[Title/Abstract]) and (huntington[Text Word]) AND (apathy[Text Word]).

The database searches yielded a total of 368 articles, which were reduced to 230 articles after duplicate suppression; removal of posters, letters, and other forms of study apart from original articles; and filtering for English language. Following the screening of titles and abstracts, 65 articles were eligible for review. After screening of the full-text articles, 25 were included in this systematic review (Figure 1).

Our review indicates that apathy is present at every stage of the disease. Studies of apathy in HD that were included are summarized in Table 1 (48–69). It is also the only symptom that gradually progresses, making it an excellent marker of disease progression (48, 57, 70). In their clinical review, McColgan and Tabrizi (71) confirmed that apathy is the most prevalent symptom in HD. According to these authors, this may be due to the absence of treatment for apathy, as other neuropsychiatric symptoms, such as depression and irritability, can be treated medically (antidepressants and antipsychotics).

First of all, as we can see in Table 1, the prevalence of apathy varied from study to study. This may have been due to several factors, such as place of recruitment, inclusion and exclusion criteria, disease severity (stage), and type of assessment tool. Nevertheless, all the authors agreed that apathy is a frequent neuropsychiatric manifestation in HD.

Second, it should be noted that patients rarely complained of apathy, although this does not imply that apathy is not disabling and does not have a negative effect on patients’ quality of life (16). Apathy is considered to be one of the most impactful disorders in terms of the quality of life of patients with HD and their caregivers (67). Patients have fewer social interactions and are less engaged in their activities and hobbies, while caregivers have a sense of isolation and the feeling of missing out on their lives (5). Apathy therefore has a substantial direct negative effect on the quality of life of both patients and caregivers. It also has a negative effect on family relations, as shown in the review by Good et al. (70), although it should not be forgotten that every patient is unique, in terms of the association of symptoms and the implications of the disease at family, social, and occupational levels. By the same token, the assessment of individual patients must take into account the social, cultural, and environmental dimensions of their psychological disorders. Patients each have their own life story, which obviously has an impact on the manifestation and maintenance of their disorders. By considering these different aspects, researchers and clinicians can avoid the neurobiologization of psychological functioning.

The findings of this systematic review show that research on apathy in HD is limited in terms of methods, approaches, and clinical findings. These are discussed below, along with suggestions for a new approach allowing apathy in HD and its underlying mechanisms to be better understood.

Apathy is common to many pathologies (psychiatric, neurological, and neurodegenerative), but regrettably its underlying mechanisms have been relatively unexplored. This has affected the development of apathy assessment scales and their psychometric properties. Apathy clearly has a multidimensional aspect, but its study continues to be based on a categorical and descriptive approach, even if a new multidimensional framework has been developed and applied in some research. For example, Arnould’s (11) study of apathy in patients with severe head trauma highlighted the diversity and heterogeneity of apathy profiles in these patients. Arnould also found that each profile was associated with different psychological processes. For example, the high apathy profile was significantly related to poor psychosocial functioning and a high level of subjective burden reported by caregivers, while the loss of initiative and interest profile was related exclusively to poor psychosocial functioning. This study assumed that apathy has four possible dimensions (cognitive, affective, motivational, and identity) and that each dimension is sustained by a variety of mechanisms (11).

Research needs to adopt this new model based on an integrative and multifactorial approach, thereafter generalizing it to other pathologies, which is what we are planning to do in our next study. At the theoretical level, we will aim to understand apathy, its various mechanisms, and its interrelations with other psychological difficulties in order to redefine and reconsider this symptom in HD. At the clinical level, this research will lead to a better understanding of apathetic behaviors related to HD and thus to more reliable and more sensitive assessments aimed at developing more effective psychological interventions targeting the relevant mechanisms.