Background

Apathy is increasingly recognized to be a common, disabling syndrome characterized by impairments of motivation and associated with poor prognosis (Husain & Roiser, 2018; Starkstein & Leentjens, 2008). It is now considered a major neuropsychiatric manifestation of many brain disorders, including neurodegenerative and neuroinflammatory conditions, both common and rare. For example in Parkinson’s disease (PD), reported prevalence ranges from 17 to 70%, depending on assessment tools and comorbid symptoms (Brok et al., 2015), and higher apathy is predictive of cognitive decline over time (Martin, McDonald, Allsop, Diggle, & Leroi, 2020). In Alzheimer’s disease (AD), apathy is the most commonly observed and earliest behavioural change, present in 49% of patients, on the basis of pooled prevalence data (Zhao et al., 2016). In neuroinflammatory disorders such as multiple sclerosis apathy is present in ˜40% of cases (Raimo, Spitaleri, Trojano, & Santangelo, 2020), while in a form of auotimmune encephalitis known as Anti-LGI1 limbic encephalitis (LE), it has been documented in 53% of individuals (van Sonderen et al., 2016).

Additionally, it is increasingly recognized that apathy is prevalent amongst people at risk of developing dementia, such as those with mild cognitive impairment (MCI: with cognitive impairment apparent on cognitive screening) or subjective cognitive impairment (SCI: with subjective complaints but no apparent impairment on cognitive screening). SCI can precede MCI, which in turn can progress to AD (Jessen et al., 2014, 2020; Reisberg et al., 2008; Slot et al., 2018). In these groups, the reported prevalence ranges from 2.2 to 75%, with apathy being associated with a two-fold increased risk of dementia (van Dalen et al., 2018).

Two important issues have emerged from investigations of apathy. The first concerns whether there are different, dissociable dimensions of the syndrome and how best to capture these when assessing a patient. The second, related issue is how best to measure apathy. Should the assessment rely on self-report by the patient, the evaluation of a person who knows them well, such as a caregiver, or on independent interview of either the patient or the caregiver? All of these different types of assessment have been used with instruments that seek to dissociate different dimensions of the syndrome.

Apathy has been considered to have several different dimensions or dissociable domains. However, there is no consensus on how many domains there might be. Marin et al.’s triadic theory proposed three different axes of apathy: diminished productivity (behavioural apathy), diminished goals (cognitive apathy) and diminished emotional responses (affective apathy; Marin, Biedrzycki, & Firinciogullari, 1991). However, the Apathy Evaluation Scale (AES), developed to measure these hypothesized domains, instead supported three factors that the authors described as general apathy, curiosity or novelty seeking, and a third factor that contained items on insight, need for help with planning and lack of concern for problems (Marin et al., 1991).

Subsequent scales also tried to measure different dimensions of apathy, finding evidence for cognitive and behavioural (Pedersen et al., 2012; Starkstein, Petracca, Chemerinski, & Kremer, 2001) as well as emotional aspects of apathy (Robert et al., 2002). Other influential approaches have reframed the components or suggested additional ones. For example the Dimensional Apathy Scale (Radakovic & Abrahams, 2014) recovered four factors: executive, emotional, behavioural initiation and cognitive initiation while the Lille Apathy Rating Scale (LARS, Sockeel et al., 2006), reported four distinct factors including a new component of self-awareness in PD. Finally, the Apathy Motivation Index (AMI) demonstrated behavioural and emotional factors, and a new factor that could best be described as social apathy which has been confirmed in healthy people and Parkinson’s disease (Ang, Lockwood, Apps, Muhammed, & Husain, 2017; Ang et al., 2018).

The variability of symptoms, across different domains and measured by different scales, renders assessing apathy a challenge. Moreover, there is no absolute ground truth as to whether a patient suffers from apathy and in which subdomain it manifests. Rather, the evidence suggests that this varies depending upon who reports on the patient’s symptoms. For example Clarke et al. (2007) examined apathy in dementia including patients with AD and dementia with Lewy bodies using three different versions of the AES and found two factors for the self-report (general and other) and two factors using the caregiver and clinician versions (general and interest).

Several apathy scales now have different versions that allow patient, caregiver or clinician perspectives. Each of these has its drawbacks, but at the same time may highlight important details that the others fail to detect. For example, a shortcoming of the patient report is that they may have become habituated to their apathy or may lack the necessary insight or awareness, particularly relevant in populations with cognitive impairment. While clinician ratings based on patient interviews might be better, they are dependent on the patient’s cooperation – as well as insight and memory – and take time as well as trained personnel. In everyday clinical experience, many clinicians effectively rely on taking a history from a caregiver or informant, so this might seem a viable alternative to relying on self-report, provided the caregiver report is reliable.

However, current formal assessment using instruments to assess and quantify caregiver ratings either fail to capture the range of apathy domains or take a long time to administer. One of the most widely used assessments in clinical settings is the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) which has a brief clinical version, the Neuropsychiatric Inventory Questionnaire (NPI-Q; Kaufer et al., 2000). The informant-based interview assessment screens for neuropsychiatric symptoms including apathy, but does not distinguish between apathy subtypes and attempts to divide its questions into domains have failed to detect a factor structure in frontotemporal dementia and Alzheimer's disease (Chow et al., 2009). Moreover, if the caregiver responds with a negative response to the screening question for apathy, further detailed questioning is not pursued, or scored, thereby risking false negatives. The informant version of the LARS (LARS-i), on the other hand, consists of four distinct factors (Dujardin, Sockeel, Delliaux, Destée, & Defebvre, 2008), but the assessment is interview-based and takes at least 15 min to administer. Furthermore, it does not provide an assessment of social apathy which was found to be a separate domain (Ang et al., 2018) and is recognized in revised diagnostic criteria for apathy (Robert et al., 2018).

A brief but detailed caregiver assessment of apathy that is clinically practical and also provides sufficient information on different domains of apathy, including the social domain, is currently not available. Here, we present an investigation of a caregiver version of the AMI (AMI-CG). As in the original self-report AMI, the questions attempt to distinguish between behavioural, emotional and social dimensions of apathy (Ang et al., 2018). Our aim was to provide a sensitive caregiver questionnaire that would assess these dimensions, but in contrast to interview-based assessments, take less than 5 min to complete by a caregiver without independent clinician input and time. Apathy and related constructs, such as anhedonia and depression, were assessed in a sample of patients with diverse neurological conditions. The factorial structure was determined and internal reliability and external validity established. Then, we assessed whether it would provide sufficient diagnostic accuracy using the LARS-i as gold standard. Finally, we explored whether discrepancies between self-report and caregiver report are related to the patient’s cognitive ability or caregiver burden.

Methods Participants

One hundred and thirty-four patients with four different diagnosed neurological conditions and their caregivers were recruited from Neurology clinics participating in this study: AD (N = 28), Parkinson’s disease (PD, N = 48), SCI (N = 28) and autoimmune LE (N = 30; LGI1 or Caspr2 cases; Table 1). Of caregivers, 110 were spouses or partners, seven children, six siblings or other family members, seven friends and four not otherwise specified. In order to be included as a caregiver in the study, the participant needed to know the patient well enough to inform us about the impact of their condition. We deemed this given when they were either a spouse or partner (82% of the sample) or had known the patient for at least 3 years. Caregivers knew patients for an average of 39 years (SD = 15.7 years, see group-wise statistics in Table 1). In cases where the caregiver was the spouse, they were of the opposite gender and a similar age. All participants, including caregivers, gave written informed consent; the study was approved by a local NHS ethics committee (REC number 18/SC/0448).

Table 1. Participant demographics Diagnosis Gender (F:M)a Age (years)b Age range Education (years)c ACE Length of patient-caregiver relationship AD (n = 28) 13:13 72.78 ± 9.18 53–89 15.58 ± 5.4 71.93 ± 12.8 45.25 ± 11.22 LE (n = 30) 7:23 67 ± 9.66 47–87 12.38 ± 2.73 90.07 ± 7.98 38.45 ± 15.13 PD (n = 48) 18:27 70.13 ± 7.52 50–87 15.11 ± 3.47 91.78 ± 7.95 41.17 ± 16.17 SCI (n = 28) 14:14 58.29 ± 9.11 34–81 15.09 ± 4.09 92.04 ± 7.37 29.33 ± 15.48 Total (n = 134) 52:77 67.25 ± 10.06 34–89 14.49 ± 4.09 87.13 ± 12.13 39.02 ± 15.67 Note AD, Alzheimer's disease; LE, Limbic encephalitis; PD, Parkinson's disease; SCI, Subjective cognitive impairment; ACE, Addenbrooke's Cognitive Examination III a n = 5 missing. b n = 6 missing. c n = 31 missing. Measures

Patients completed:

Apathy-Motivation Index (AMI) (Ang et al., 2017; N = 134). This 18-item self-report questionnaire assesses apathy in terms of Behavioural Activation (tendency to self-initiate goal-directed behaviour), Social Motivation (level of engagement in social interactions) and Emotional Sensitivity (affective responses) using a 5-point Likert scale. Item scores are averaged to yield scores for subscales and a total score with higher scores indicating greater apathy (range 0–4).

Snaith–Hamilton Pleasure Scale (SHAPS) (Snaith et al., 1995; N = 133). This self-report questionnaire assesses hedonic tone, that is, the degree to which a person is able to experience or anticipate pleasure. It covers four domains: interest/pastimes, social interaction, sensory experience and food/drink, using 14 items and a four-point scale (strongly disagree = 1/disagree = 2/agree = 3/definitely agree = 4). We used the original dichotomous scoring (agree = 1/disagree = 0) to determine which patients could be classified as anhedonic and a four-point scoring system for more dispersion in the data (following Franken, Rassin, & Muris, 2007). Higher scores indicate greater anhedonia.

Geriatric Depression Scale Short Form (GDS-15) (Yesavage & Sheikh, 1986; N = 133). This 15-item, two-point scale self-report screening assesses depressive symptoms in older adults with the exception of somatic symptoms, providing a more robust measure in people with medical illness (yes/no, scores range 0–15 with higher scores indicated more severe depression).

Beck Depression Inventory II (BDI-II) (Beck, Ward, Mendelson, Mock, & Erbaugh, 1961; N = 134). The longstanding self-report inventory describes the varying degrees of depression using a four-point scale with higher scores indicating more severe depression (Scores range 0–63).

Addenbrooke’s Cognitive Examination-III (ACE-III) (N = 128). This screening to assess cognitive functioning in five domains: attention, memory, verbal fluency, language and visuospatial skills. Scores range from 0 to 100 with lower scores indicating higher cognitive impairment.

Caregivers reported on patients’ apathy using:

Apathy-Motivation Index caregiver version (AMI-CG) (N = 134). Our new questionnaire developed using the original AMI, covers apathy in terms of Behavioural Activation, Social Motivation and Emotional Sensitivity domains. Table 3 shows items. Item scores are averaged to yield scores for subscales and a total score with higher scores indicating greater apathy (range 0–4).

Lille Apathy Rating Scale caregiver version (LARS-i) (Dujardin et al., 2008; N = 129). The interview-based caregiver version of LARS assesses apathy in four domains: Intellectual curiosity, emotion, action initiation, self-awareness. Total scores range from −36 to 36 (least apathetic to most apathetic).

Neuropsychiatric Inventory Questionnaire (NPI-Q) (Kaufer et al., 2000; N = 130). This interview screens for symptoms of psychopathology common in dementia, including apathy. It includes one screening question followed by eight yes/no questions if the screening is answered with yes and does not distinguish between domains.

Caregivers also reported on:

Bayer Activities of Daily Living Scale (B-ADL) (Hindmarch, Lehfeld, Jongh, & Erzigkeit, 1998; N = 133). This questionnaire assesses patients’ deficits in performance of everyday activities, such as taking medication or using transportation using 25 items and a 10-point response scale. Item scores are averaged to yield a total score ranging from 0 to 10 with higher scores indicating greater difficulty completing everyday tasks independently.

Zarit Burden Interview (ZBI) (Zarit, Todd, & Zarit, 1986; N = 133). This questionnaire assesses the burden caregivers experience from caring for their relative in 22 items using a 5-point response scale Scores range from 0 to 88 with higher scores indicating greater caregiver burden.

Statistical analyses

For the main analyses, data from patients and caregivers were collapsed across patient groups and analysed using R v3.6.1 (R Core Team, 2019). Correlational analyses used pairwise Spearman correlations and corrected for multiple inference using Holm’s method (Holm, 1979). Exploratory factor analysis and reliability analyses were conducted using R packages psych (Revelle, 2018) and paran (Dinno, 2018).

Results Prevalence rates of cognitive impairment, apathy, depression and anhedonia

In order to assess prevalence rates of apathy and relevant neuropsychiatric features in our patient groups, we classified participants according to standard cut-off values. Patients were classified as apathetic if either the AMI or the LARS-CG indicated apathy, as depressed if either the BDI or the GDS indicated depression, as anhedonic based on the SHAPS, and cognitively impaired if the ACE. Absolute values and overlap between symptoms can be found in Figure 1; cut-off values and prevalence rates are reported in Table 2. The AD group showed the highest rates of apathy (78.57%), followed by LE (46.28%), PD (34.78%) and SCI (32%). Similarly, the AD group showed the highest overlap between apathy and cognitive impairment (67.86), likely due to the high prevalence of cognitive impairment (89.3%). The highest overlap between apathy with depression (30.8%) and with anhedonia (15.4%) was found in LE.

Overlap between neuropsychiatric symptoms. Circles show absolute numbers of cases of apathy, depression and anhedonia as well as the intersection of cases by patient group. AD, Alzheimer's disease; LE, Limbic encephalitis; PD, Parkinson's disease; SCI, Subjective cognitive impairment.

Table 2. Prevalence of neuropsychiatric symptoms by patient group AD (n = 28) LE (n = 30) PD (n = 48) SCI (n = 28) Impaireda 25/28 (89.29%) 10/27 (37.04%) 11/45 (24.44%) 5/28 (17.86%) Apatheticb 22/28 (78.57%) 14/29 (48.28%) 16/46 (34.78%) 8/25 (32%) Depressedd 4/28 (14.29%) 17/29 (58.62%) 13/47 (27.66%) 15/28 (53.57%) Anhedonicd 2/28 (7.14%) 6/30 (20%) 2/47 (4.26%) 6/28 (21.43%) Apathetic & Impaired 19/28 (67.86%) 6/26 (23.08%) 8/41 (19.51%) 2/25 (8%) Apathetic & Depressed 3/28 (10.71%) 8/26 (30.77%) 8/41 (19.51%) 4/25 (16%) Apathetic & Anhedonic 2/28 (7.14%) 4/26 (15.38%) 1/41 (2.44%) 1/25 (4%) Note AD, Alzheimer's disease; LE, Limbic encephalitis; PD, Parkinson's disease; SCI, Subjective cognitive impairment. a Cognitive impairment indicated by a score smaller than 88 on the ACE. Missing data: 3 LE, 3 PD. b Apathy, indicated either by a score greater than 1.91 on the AMI (moderate apathy) or by a score greater than −16 on the LARS-i. Missing observations: 1 LE, 2 PD, 3 SCI. c Depression, indicated either by a score greater than 17 (moderate depression) or by a score greater than 5 on the GDS. Missing data: 1 LE, 1 PD. d Anhedonia, indicated by a score greater than 2 on the SHAPS. Missing data: 1 PD. Factorial structures are similar for AMI Caregiver and AMI

Since the items of the AMI-CG were adapted from the AMI, we expected them to map onto similar subscales of Behavioural Activation, Emotional Sensitivity and Social Motivation. In order to assess the factorial structure of the AMI-CG, an exploratory factor analysis was first conducted. The Kaiser–Meyer–Olkin Test (Kaiser, 1974) which measures the proportion of shared variance among the data, indicated sampling was adequate for factor analysis (KMO = 0.82). Horn’s Parallel Analysis (Horn, 1965) for component retention determined that three factors should be retained based on 2,000 iterations. Thus, we conducted an exploratory factor analysis with three factors and Promax rotation, allowing factors to be correlated.

Results indicated that three factors were sufficient (χ2 (102) = 170.26, p < .001), cumulatively explaining 46% variance. This structure had a good model fit (RMSEA = 0.077 with 90% CI of 0.052–0.089, RSMR = 0.05, TLI = 0.88). Furthermore, the factor structure of the original AMI was confirmed in the AMI-CG, with Factor 1, 2 and 3 loading on all items of subscales Behavioural Activation, Emotional Sensitivity and Social Motivation respectively (mean absolute loadings 0.7, 0.64, 0.42). Additionally, Factor 1 had moderately high loadings on items of the Social Motivation subscale (mean absolute loading 0.34; Figure 2). Moreover, factors were intercorrelated, with Factor 2 (associated with Emotional Sensitivity) showing smaller correlations with the other factors (rFactor3/Social Motivation = 0.42, rFactor1/Behavioural Activation = 0.39, p-values < .01) than Factor 3 (predominantly high Social Motivation items) and Factor 1 (predominantly high on Behavioural Activation items; r = .47, p < .01). These findings speak for a social domain of apathy that shares elements with aspects of behavioural apathy.

Factor structure of AMI-CG. Results from the exploratory factor analysis of AMI-CG items. Factors 1, 2 and 3 predominantly load on items from subscales Behavioural Activation (BA), Emotional Sensitivity (ES) and Social Motivation (SM) respectively. This shows that the AMI-CG reproduces the initial structure of the AMI.

AMI-CG shows good reliability and construct validity across subscales

Next, we investigated reliability and construct validity of the new scale. Cronbach’s alpha values for AMI-CG total scores and subscales demonstrated good internal reliability (αoverall = 0.85). Consistency across subscales ranged from good (αBehavioural Activation = 0.85) to acceptable (αEmotional Sensitivity = 0.79, αSocial Motivation = 0.70), providing evidence of reasonable reliability of the AMI-CG. Figure 3 shows the pairwise item correlations of the AMI-CG illustrating that items moderate-to-high correlations between items from the same subscale. Moreover, it shows also found low-to-moderate correlations between items from the Behavioural Activation and Social Motivation subscales (.18 ≤ r ≤ .53) and between Emotional Sensitivity and Social Motivation (.19 ≤ r ≤ .39), as well as low correlations between the Behavioural Activation and Emotional Sensitivity (−.21 ≤ r ≤ .33). Moreover, subscale scores correlated highly with the total score (r = .63–.84, p-values < .01, Table 3).

Correlations between AMI-CG items ordered by subscale. Correlation matrix showing correlations between AMI-CG items. Blank tiles indicate that the correlation did not reach significance at a significance level of p = .05. Orange lines highlight correlations between items within one subscale to illustrate internal consistency. BA, Behavioural Activation; ES, Emotional Sensitivity; SM, Social Motivation. *p < .05, **p < .01.

Table 3. Apathy motivation index caregiver version item scores Subscale Item Statement Mean (SD) Behavioural activation (BA) BA1 Makes decisions firmly and without hesitation 1.91 (1.22) BA2 When he/she decides to do something, he/she is able to make an effort easily 1.43 (1.25) BA3 Doesn't like to laze around 1.84 (1.37) BA4 Gets things done when they need to be done, without requiring reminders from others 2.04 (1.28) BA5 When he/she decides to do something, he/she is motivated to see it through to the end 1.34 (1.18) BA6 When he/she has something they need to do, he/she can do it straightaway 1.61 (1.1) Emotional sensitivity (ES) ES1 Feels sad or upset when they hear bad news 0.91 (0.95) ES2 After making a decision, will wonder if they made the wrong choice 2.27 (1.04) ES3 Seems to care deeply about what their loved ones think of them 1.18 (1.1) ES4 Feels awful if they say something insensitive 1.69 (1.17) ES5 Feels bad when they hear an acquaintance has an accident or illness 0.8 (0.9) ES6 Feels guilty if he/she realizes he/she has been unpleasant to someone 1.26 (1.08) Social motivation (SM) SM1 Starts conversations with random people 2.15 (1.42) SM2 Seems to enjoy doing things with people he/she has just met 2.03 (1.12) SM3 Suggests activities to do 1.99 (1.26) SM4 Goes out with friends on a weekly basis 2.25 (1.51) SM5 Starts conversations without being prompted 1.42 (1.11) SM6 Enjoys choosing what to do from a range of activities 1.76 (1.17)

In order to assess construct validity, we examined correlations of all collected measures collapsed across patient groups (Table 4). The AMI-CG total score demonstrated good convergent construct validity, correlating with other measures of apathy. It showed a strong correlation with LARS-i total scores (r = .72, p < .01) and moderate correlations with NPI-Q apathy score (r = .5, p < .01, Figure 4) and the AMI itself (r = .44, p < .01, Figure 4).

Table 4. Correlations between AMI caregiver total score and subscale score with related measures AMI-CG total Behavioural activation Emotional sensitivity Social motivation Apathy measures Apathy Motivation Index Total (AMI) 0.44** 0.31** 0.26** 0.49** Behavioural Activation 0.31** 0.33** 0.13 0.25** Emotional Sensitivity 0.30** 0.14 0.32** 0.27** Social Motivation 0.39** 0.24** 0.19* 0.51** Apathy Motivation Index Caregiver Version Total (AMI-CG) – 0.84** 0.63** 0.81** Behavioural Activation 0.84** – 0.29** 0.55** Emotional Sensitivity 0.63** 0.29** – 0.34** Social Motivation 0.81** 0.55** 0.34** – Lille Apathy Rating Scale Caregiver Version (LARS-i) 0.72** 0.68** 0.44** 0.51** Neuropsychiatric Inventory Apathy Score (NPI-Q) 0.50** 0.49** 0.29** 0.33** Related neuropsychiatric measures Beck's Depression Inventory (BDI) 0.18* 0.26** −0.04 0.19* Geriatric Depression Scale (GDS) 0.1 0.17 −0.08 0.18* Snaith–Hamilton Anhedonia Scale (SHAPS) 0.27** 0.16 0.15 0.33** Related caregiver measures Bayer Activities of Daily Living (B-ADL) 0.52** 0.67** 0.13 0.32** Zarit Burden Interview (ZBI) 0.56** 0.60** 0.31** 0.35**

Correlation of AMI-CG with other apathy measures by patient group. There was a moderate significant correlation between the AMI-CG and the original AMI, a strong significant correlation between AMI-CG and LARS-i and a moderate relationship between the AMI-CG and the NPI-Q. AD, Alzheimer's disease; LE, Limbic encephalitis; PD, Parkinson's disease; SCI, Subjective cognitive impairment. *p < .05, **p < .01.

There was also considerable agreement between the subscales of the AMI and AMI-CG, with the strongest relationship evident in the social domain (rSocial Motivation = 0.51, p < .01; rEmotional Sensitiivty = 0.32, p < .01; rBehavioural Activation = 0.33, p < .01; Figure 5).

Correlation between AMI-CG and AMI subscale scores by patient group. Low correlations between the AMI-CG and AMI Behavioural Activation subscale. Low and moderate correlations between items of the Emotional Sensitivity subscale and moderate. Correlations between subscales did not hold for all patient groups (see text). AD, Alzheimer's disease; LE, Limbic encephalitis; PD, Parkinson's disease; SCI, Subjective cognitive impairment. *p < .05, **p < .01.

Importantly, the total AMI-CG score did not correlate with GDS (r = .1, p = .23) and only weakly with the BDI (r = .18, p = .04). Thus, apathy, as indexed by the AMI-CG, was only weakly associated with established measures of depression, showing good discriminant construct validity. However, the AMI-CG total scores did correlate moderately with the SHAPS index of anhedonia (r = .27, p < .01), perhaps consistent with recognition that some elements of anhedonia and apathy might overlap (Husain & Roiser,