Introduction
Apathy is highly prevalent in neurocognitive disorders, such as Alzheimer's Disease (AD) and has been found in up to 72% of patients with AD (Mega et al., Reference Mega, Cummings, Fiorello and Gornbein1996). Defined primarily as diminished motivation (Marin, Reference Marin1990), apathy is a commonly reported neuropsychiatric symptom (NPS). In addition, apathy may arise as a secondary symptom as a result of the inability to plan due to cognitive deficits (Stanton and Carson, Reference Stanton and Carson2016).
Diagnostic criteria, initially proposed by Marin and collaborators consists of a three-dimensional model of purposeful behavior, emotional responsiveness, and goal directed cognitions (Marin et al., Reference Marin, Biedrzycki and Firinciogullari1991). More recently, Robert et al. (Reference Robert2009) revised the criteria for apathy, emphasizing diminished motivation as the core principle. Subsequently, they defined the domains of apathy to be a reduction in goal-directed behavior, cognitive activity and emotion as well as the notion of apathy as a persistent state. A variety of scales is frequently used in the literature to assess one's degree of apathy (Radakovic et al., Reference Radakovic, Harley, Abrahams and Starr2015). Radakovic et al. conducted a systematic review of the psychometric properties of commonly utilized apathy scales; including the Apathy Inventory (Robert et al., Reference Robert2002), the Apathy Evaluation Scale (AES) (Marin et al., Reference Marin, Biedrzycki and Firinciogullari1991), and the apathy subcategory of the Neuropsychiatric Inventory (NPI), used to assess severity and frequency of behavioral disturbances in patients with dementia (Cummings et al., Reference Cummings, Mega, Gray, Rosenberg-Thompson, Carusi and Gornbein1994).
However, less is known about apathy in pre-dementia states, such as mild cognitive impairment (MCI) and mild behavioral impairment (MBI). Defined by the National Institute on Aging-Alzheimer's Association, MCI includes a change in cognition as reported by a patient, client, or clinician, objective evidence of impairment in one or more domains, preservation in functional abilities, and not demented (Sachs-Ericsson and Blazer, Reference Sachs-Ericsson and Blazer2015). MBI criteria, proposed by the International Society to Advance Alzheimer's Research and Treatment, includes changes in behavior or personality observed by the patient, informant, or clinician starting in later life (age ≥50 years) and persisting at least intermittently for a minimum of six months (Ismail et al., Reference Ismail2016). There must also be a clear change from the person's usual behavior or personality as evidenced by at least one of the following five domains: decreased motivation (i.e. apathy), affective dysregulation, impulse control, social inappropriateness, and abnormal perception or thought content (Ismail et al., Reference Ismail2016). Moreover, impairments in social, occupational, or interpersonal function must be attributable to NPS, and not to cognitive decline in MBI (Ismail et al., Reference Ismail2016).
As apathy is associated with a more rapid progression from prodromal states, such as MCI to AD (Feldman et al., Reference Feldman2007), recognizing apathy as early as possible may have implications for improved quality of life for these patient groups. The aim of this review is to examine the prevalence, neurobiology, and treatments for apathy in prodromal dementia, and to discuss implications for future research.
Methods
We conducted a comprehensive literature search using the Medical Literature Analysis and Retrieval System Online (MEDLINE; National Library of Medicine, Bethesda, MD), Excerpta Medica Database (Embase; Elsevier, Amsterdam, the Netherlands), and PsycINFO (American Psychological Association, Washington, DC) for data on the prevalence and neurobiology of apathy specific to prodromal dementia as well as for both pharmacological and non-pharmacological management of apathy. Search terms included “MCI,” “MBI,” “pre-dementia syndromes,” “prodromal dementia,” “apathy,” and “decreased motivation.” Data from meta-analyses, review papers, preclinical, and clinical studies up to January 18th 2017 were examined and all publications in the current review were published in the English language.
Results
Prevalence of apathy
Cognitively normal elderly population
Although an abundance of literature has reported on prevalence rates of NPS in those with AD, there have also been studies that have investigated the prevalence of NPS among cognitively normal older adults. The population-based Cache County study used the NPI to evaluate apathy and reported a prevalence of 3.1% in participants without dementia (Lyketsos et al., Reference Lyketsos, Steinberg, Tschanz, Norton, Steffens and Breitner2000). Subsequently, Onyike et al. (Reference Onyike2007) described apathy in 1.4% of cognitively normal individuals using the Cache County population. Among a population-based cohort study, 4.8% of elderly with normal cognition were found to have apathy based on the NPI (Geda et al., Reference Geda2008). Hwang et al. (Reference Hwang, Masterman, Ortiz, Fairbanks and Cummings2004) examined cognitively normal elderly from a California retirement community, while Fernandez-Martinez et al. (Reference Fernandez-Martinez, Molano, Castro and Zarranz2010) studied a control group from a hospital memory unit and found an apathy prevalence of 2% and 6%, respectively, using the NPI. Additionally, a cross-sectional study evaluating NPS in Chinese elderly controls found an apathy prevalence of 7.6% using the Chinese version of the NPI (Chan et al., Reference Chan2010).
MCI population
Apathy in MCI can be a particularly difficult symptom to identify and diagnose due to varying definitions and scales of both apathy and MCI (Panza et al., Reference Panza2005). The prevalence of apathy in patients with MCI has ranged from 11% to 50.5% (Geda et al., Reference Geda2004; Hwang et al., Reference Hwang, Masterman, Ortiz, Fairbanks and Cummings2004; Geda et al., Reference Geda2008; Fernandez-Martinez et al., Reference Fernandez-Martinez, Molano, Castro and Zarranz2010) in studies using the apathy subscale of the NPI. Results from the Cache County Study found clinically significant apathy in 3.1% of patients with cognitive impairment no dementia (Onyike et al., Reference Onyike2007). Using the Apathy Inventory, Robert et al. (Reference Robert2006b) found the prevalence to be 39.8%; however, apathy was defined as the presence of a single symptom. Using the NPI and structured interviews at a memory clinic in Hong Kong, and the NPI at a memory clinic in Italy, apathy was diagnosed in 9.4% and 6.9% of outpatients, respectively (Di Iulio et al., Reference Di Iulio2010; Choi, Reference Choi2013). A study of outpatients by Taragano et al. (Reference Taragano2009) revealed an apathy prevalence of 11.7% as assessed by the NPI. Forrester et al. (Reference Forrester, Gallo, Smith and Leoutsakos2016) found that apathy was prevalent among 12% of individuals, recruited from the National Alzheimer's Coordinating Centre. Moreover, a systematic review revealed that apathy was found to be higher in amnestic compared to non-amnestic MCI participants (Kohler et al., Reference Kohler2016). Thus, prevalence rates for apathy in MCI have ranged from 3.1% to 50.5% depending on the chosen population and scale.
MBI population
Taragano et al. (Reference Taragano2009) reported an apathy prevalence of 29.4% among geriatric outpatients. The presence of apathy in MBI was found in 39.2% of elderly participants from a community-based sample (Barcelos-Ferreira et al., Reference Barcelos-Ferreira, Folquitto, Dos Santos Tascone and Bottino2015). The above-mentioned apathy prevalence rates were assessed via the apathy subscale of the NPI.
Impact of apathy
Apathy in MCI is closely correlated with additional NPS, predominantly agitation and depression (Mehta et al., Reference Mehta2008). However, apathy in particular, is the only NPS that has been found to independently predict poorer functional performance in MCI patients (Tam et al., Reference Tam2008). Apathy in MCI patients has been shown to be significantly associated with reduced daytime activity (Kuhlmei et al., Reference Kuhlmei, Walther, Becker, Muller and Nikolaus2013), greater weight loss (Volicer et al., Reference Volicer, Frijters and van der Steen2013), and increased caregiver burden (George et al., Reference George, Whitfield and Walker2013). Studies have also shown that apathy in MCI is associated with greater cognitive decline (Robert et al., Reference Robert2006a; Zahodne and Tremont, Reference Zahodne and Tremont2013). In a study of 245 MCI patients, individuals with apathy had significantly lower cognitive scores on free and cued selective reminding tests compared to those without apathy (Robert et al., Reference Robert2006a). Apathy was also shown to be independently associated with poorer letter fluency as measured by the FAS test in a study with 90 amnestic MCI patients (Zahodne and Tremont, Reference Zahodne and Tremont2013).
NPS are also associated with a greater risk of conversion to dementia. However, apathy in particular, has been shown to be an independent risk factor for the progression of MCI to AD (Richard et al., Reference Richard2012; Somme et al., Reference Somme, Fernandez-Martinez, Molano and Zarranz2013). Individuals with MCI and apathy have a greater rate of conversion to dementia (60%) compared to MCI patients with depression (7.9%), depression-apathy (16.9%), and MCI patients without apathy or depression (24%) (Vicini Chilovi et al., Reference Vicini Chilovi, Conti, Zanetti, Mazzu, Rozzini and Padovani2009). While apathy is primarily characterized by diminished motivation for a minimum four-week period (Robert et al., Reference Robert2009), depression is defined by the DSM-5 as a depressed mood or loss of interest for more than two weeks as well as a minimum of five additional symptoms, which cause clinically significant distress and are not attributable to another medical condition (American Psychiatric Association, 2013). Depressive symptoms typically reflect a negative effect, whereas apathy is perceived as lacking in emotional affect (Radakovic et al., Reference Radakovic, Harley, Abrahams and Starr2015).
A similar study found that patients with both amnestic-MCI and apathy had an almost seven-fold risk of AD progression compared to amnestic-MCI patients without apathy (HR = 6.9; 2.3–20.6) (Palmer et al., Reference Palmer2010). In a recent study, apathy progression over time was shown to predict the transition from MCI to dementia using the AES-Clinician subscale (Guercio et al., Reference Guercio2015a). Similarly, MCI patients who developed AD had a significantly higher prevalence of apathetic symptoms (91.7%) compared to patients who did not develop AD (26.9%) after one year (Robert et al., Reference Robert2006a). Greater apathy in MCI patients has also been associated with a faster progression to dementia (Somme et al., Reference Somme, Fernandez-Martinez, Molano and Zarranz2013).
According to Taragano et al. (Reference Taragano2009) elderly with MBI may confer a higher risk of conversion to dementia compared to patients with MCI. Risk of onset was evaluated to be 43% higher in individuals with MBI compared to those with MCI. This distinction may be explained by a significant difference in apathy symptoms as Taragano et al. (Reference Taragano2009) reported apathy in 11.7% of patients with MCI in contrast to 29.4% of patients with MBI. While not all patients who experience MBI or MCI will progress to a dementia disease state, apathy may have a significant negative impact on MBI and MCI patients, including decreased functional and cognitive abilities as well as a greater and faster rate of progression.
Neurobiology of apathy
Although several brain regions are affected by MCI, neuroimaging studies have revealed consistent abnormalities within regions responsible for motivation such as the anterior cingulate and frontal regions (Grambaite et al., Reference Grambaite2011). Evidence suggests that MCI patients, compared to healthy controls, have smaller volumes of the anterior cingulate gyrus and frontal cortex, and exhibit disrupted white matter microstructural integrity (Cacciari et al., Reference Cacciari2010). Apathy has also been associated with reduced fronto-parietal control network connectivity (Munro et al., Reference Munro2015), lower inferior temporal cortical thickness (Guercio et al., Reference Guercio2015b), significantly decreased metabolism in the posterior cingulate cortex (Delrieu et al., Reference Delrieu2014), and greater amyloid burden (Marshall et al., Reference Marshall2013) in MCI patients. In a longitudinal study with 429 MCI patients, researchers reported that amyloid pathology was also a significant risk factor for developing apathy, among other NPS including agitation, irritability, and depression (Apostolova et al., Reference Apostolova, Goukasian, Do, Grotts, Ringman and Elashoff2016). Thus, these neurobiological abnormalities have been postulated to contribute to the apathetic manifestations observed in MCI patients, including loss of motivation, diminished goal-directed behavior, and emotional blunting (Stella et al., Reference Stella, Radanovic, Aprahamian, Canineu, de Andrade and Forlenza2014).
Interventions
Pharmacological
Feldman et al. (Reference Feldman2007) examined the effects of rivastigmine in an aging population with MCI to identify whether treatment with rivastigmine would delay the conversion of MCI to AD. NPS including apathy were evaluated, however there was no significant reduction in apathy compared to baseline in either the rivastigmine group (n = 312) or the placebo group (n = 346).
In a randomized, open-label trial, individuals with diagnoses of probable dementia (88%) or MCI (12%) were recruited from a memory clinic to investigate the effects of galantamine and risperidone on overall NPS and global function (Freund-Levi et al., Reference Freund-Levi, Jedenius, Tysen-Backstrom, Larksater, Wahlund and Eriksdotter2014). Although this trial did not recruit for apathy specifically in MCI patients, both galantamine and risperidone treatments resulted in a small non-significant reduction of apathetic behaviors, as measured by the NPI-Apathy subscale. There was no statistically significant difference in changes to apathy over time between treatment groups. However, there was a significant reduction noted in overall NPS in dementia patients as assessed by the NPI. Patients treated with galantamine experienced fewer adverse events compared to those in the risperidone treatment group (Freund-Levi et al., Reference Freund-Levi, Jedenius, Tysen-Backstrom, Larksater, Wahlund and Eriksdotter2014). The authors subsequently conclude that risperidone should only be utilized to treat symptoms of agitation and irritation.
Due to the high comorbidity of apathy and AD, various research studies have focused on identifying pharmacological interventions that primarily target apathy in AD. Treatment with donepezil has showed an improvement in apathy symptoms for patients with mild–severe AD (Drijgers et al., Reference Drijgers, Aalten, Winogrodzka, Verhey and Leentjens2009). Furthermore, trials assessing the safety and efficacy of methylphenidate for the treatment of apathy have seen moderate improvements in AD patients (Rosenberg et al., Reference Rosenberg2013; Lanctot et al., Reference Lanctot2014). However, despite promising results in an AD population, neither donepezil or methylphenidate treatment have yet to be investigated in individuals with MCI or MBI.
Non-pharmacological
There are limited non-pharmacological treatment options available for individuals with apathy in pre-dementia states. Currently, there is a randomized, double-blind, crossover, phase IV clinical trial (NCT02190019) investigating the effects of transcranial magnetic stimulation for apathy in MCI patients.
Additionally, virtual reality (VR) has recently been investigated as a useful therapy tool in patients with MCI. A study with 30 MCI participants performed attentional tasks in either a VR condition or a control condition. Results from a self-report questionnaire revealed greater satisfaction levels among those with apathy in the VR condition compared to the paper control condition with regard to the task. Participants indicated that they found the VR condition to be more engaging and motivating (Manera et al., Reference Manera2016). Another study by Manera et al. investigated the effects of a game adaptation called “Kitchen and Cooking” in patients with MCI or AD, with or without apathy. Participants with apathy rated the game to be as satisfying, motivating, and interesting as non-apathetic participants. Results also showed that apathetic patients played the game more often over the duration of the study compared to their non-apathetic counterparts (Manera et al., Reference Manera2015). Thus, VR and game-based exercises may be considered as a tool to improve interest in MCI or MBI patients with apathy.
Discussion
Despite evidence that apathy is associated with cognitive, behavioral, and functional decline, there remains a substantial knowledge gap pertaining to the prevalence, neurobiological underpinnings, and treatment of apathy in pre-dementia syndromes, such as MCI and MBI. As there are several scales used for measuring the degree of apathy, each with their respective clinical cut-off, the prevalence rate of apathy in MCI patients greatly varies. The scales most frequently used to assess apathy prevalence rates in the reviewed literature include the NPI and the apathy inventory. While the NPI is one of the most commonly utilized scales for assessing apathetic symptoms, it has been validated for the assessment of NPS in a dementia population (Cummings et al., Reference Cummings, Mega, Gray, Rosenberg-Thompson, Carusi and Gornbein1994), not for individuals with prodromal dementia. There is a great need for novel scales specifically tailored toward a pre-dementia population. There are also diagnostic criteria for apathy (Robert et al., Reference Robert2009), which have been validated in a variety of populations (Mulin et al., Reference Mulin2011), but not in prodromal dementia. Recently, Ismail et al. (Reference Ismail2017) have put forth the MBI checklist (MBI-C), a rating scale for NPS in pre-dementia populations, allowing for identification of NPS, prior to the onset of cognitive decline (Ismail et al., Reference Ismail2017). The MBI-C, tailored to an MBI population, will enable clinicians to exclusively assess NPS in patients without comorbid dementia in the manner they appear in pre-dementia states, rather than as they typically appear in dementia states. The apathy domain of the MBI-C consists of six questions pertaining to cognitive (e.g. does the person lack curiosity in topics that usually would have attracted their interest), behavioral (e.g. has the person become less spontaneous and active), and emotional (e.g. is the person less affectionate and/or lacking in emotions compared to their usual self) apathy, and severity is ranked from 1 to 3. Further research into the validity and reliability of the MBI-C as a novel rating scale is required for a population without clinically significant cognitive decline.
There is also a significant lack of information available for apathy in other pre-dementia states such as Parkinson's disease (PD) MCI (PD–MCI) and vascular MCI (vMCI). Various studies have shown apathy to be a prevalent symptom in PD–MCI, but evidence on prevalence rates and treatment options are limited. Among patients with PD in a cross-sectional study, apathy was not significantly greater in patients with PD-MCI compared to those with PD without MCI. However, when patients with PD–MCI were separated into subcategories of amnestic and non-amnestic PD–MCI, those with amnestic PD–MCI had significantly greater apathy (Jones et al., Reference Jones, Mangal, Lafo, Okun and Bowers2016). A study conducted by Nakamura et al. (Reference Nakamura2013) examined apathy prevalence in an elderly Japanese community using the clinical assessment for spontaneity (CAS), validated by the AES. Results found apathy to be most severe among vMCI, compared to those with amnestic MCI for one of the CAS subcategories, caregiver assessment. Unfortunately, this is one of few studies found to specifically report on prevalence rates for apathy in vMCI. Due to varying diagnostic criteria and definitions, establishing the epidemiological constructs for apathy in vMCI remains a challenge.
Neurochemical and neuropathological correlates of apathy, such as inflammation, abnormal dopaminergic, and cholinergic processes, as well as greater amyloid burden, have been implicated in AD pathology (David et al., Reference David2008; Skogseth et al., Reference Skogseth2008). However, there is still limited information on how these processes are involved in apathy in pre-dementia states. As apathy is significantly associated with a greater rate of conversion from MCI to AD (Robert et al., Reference Robert2009; Palmer et al., Reference Palmer2010), a better understanding of the neurochemical and neuropathological underpinnings of apathy in prodromal dementia is essential in mitigating disease progression and in identifying effective treatments.
Of the reviewed treatment options, few have indisputably shown efficacious interventions for apathy in a pre-dementia patient population. A randomized open label trial assessing galantamine and risperidone demonstrated a significant improvement in overall NPS using the NPI. Mild improvements in apathy were indicated by a decrease in the apathy subcategory of the NPI, but these results were not statistically significant (Freund-Levi et al., Reference Freund-Levi, Jedenius, Tysen-Backstrom, Larksater, Wahlund and Eriksdotter2014). Although widely used for various NPS, the NPI should not be used as the sole measure for assessing apathy. Individuals treated with galantamine presented with fewer adverse events compared to those in the risperidone treatment group, suggesting that galantamine may be safer for future trials. Additionally, researchers did not use a placebo control, and had a sample size of 12 individuals, thus limiting the generalizability of the results. Therefore, there is a significant need for additional randomized controlled trials (RCTs) with larger samples. It should be noted that neither galantamine nor risperidone are approved for the treatment of apathy. There are currently no approved drugs for the specific treatment of apathy, but measures are underway to investigate the use of drugs such as methylphenidate or modafinil for the treatment of apathy in AD (Camargos and Quintas, Reference Camargos and Quintas2011; Lanctot et al., Reference Lanctot2014). In mild-to-severe AD, there have been studies that demonstrated improvements in apathy symptoms with donepezil treatment, suggesting a need for additional RCTs with donepezil in apathetic MCI and MBI patients (Drijgers et al., Reference Drijgers, Aalten, Winogrodzka, Verhey and Leentjens2009).
Establishing motivating tools is a key challenge in designing effective rehabilitation programs for this clinical population. With respect to non-pharmacological treatments, VR exhibits potential for increasing adherence to training exercises (Manera et al., Reference Manera2016). If apathetic patients are engaged in VR or game-based interventions on a regular basis, it may help patients maintain a minimum level of motivation. However, these non-pharmacological interventions require further investigation with larger sample sizes and longer follow-up. Another study by Baker et al. (Reference Baker2001) conducted an RCT on multi-sensory stimulation (MSS) in people with dementia. Compared to a general activity group, results from pre, during, and post sessions revealed significant improvements in people with dementia for the following areas: spontaneous speech, relating to others, initiative taking and stimulation level with regard to alertness, boredom, or inactivity. As these conditions are prominent issues in those with apathy, MSS may also be suggested to improve apathy in an MCI population. Verkaik et al. recruited elderly individuals with a Mini-Mental State Examination score ranging between 18 and 23 to participate in a controlled clinical trial, wherein group sessions of reality orientation were administered five times a week for 24 weeks. Apathy was measured using the multidimensional observation scale for elderly participants subscale and found to be significantly reduced following the trial when compared to pretest apathy scores (Verkaik et al., Reference Verkaik, van Weert and Francke2005). Reality orientation may be a promising tool for apathy treatment but has yet to be investigated in a population with prodromal dementia. Additional longitudinal non-pharmacological studies are warranted.
Apathy is a highly prevalent symptom in prodromal dementia. More comprehensive guidelines for diagnosing apathy in prodromal dementia and further research investigating the neurobiological mechanisms of apathy in these patients groups are required in order to effectively treat apathy in MCI and MBI. Treatments currently used to manage apathy in AD should also be considered for the treatment of apathy in prodromal dementia.
Conflict of interest
None.
Description of authors’ roles
The conceptualization of project focus was completed by CS. Data collection and writing structure for introduction, methods, results, and discussion was completed by CS and CL. Further writing and editing conducted by authors NH and KL.
Acknowledgments
Krista L. Lanctôt has received research grants from the National Institute of Aging for “Apathy in Alzheimer's Disease Methylphenidate Trial II (ADMET II)” (award number R01AG046543) Alzheimer Drug Discovery Fund, the Alzheimer Society of Canada, (Grant 15–17) AbbVie, Lundbeck, Pfizer, Sanofi-Aventis, Janssen-Ortho Inc., Roche and Wyeth; honoraria from Abbvie and Lundbeck. Nathan Herrmann has received research grants from the Alzheimer Drug Discovery Fund, the Alzheimer Society of Canada, the National Institute of Health, Canadian Institute of Health Research, Lundbeck, and Roche; consultation fees from Lilly, Merck, and Astellas.
