Web viewTotal word count: 4,139. Corresponding author: Jashelle Caga. ... 1.Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011; 377

Running title: APATHY AND PROGNOSIS 1

Apathy is Associated with Poor Prognosis in Amyotrophic Lateral Sclerosis

J. Caga, MPsych(Health)1,2; M.R. Turner, FRCP3;S. Hsieh, PhD1; R.M. Ahmed, MBBS4; E. Devenney, MRCP4; E. Ramsey, BPsych (Hons)1; M.C. Zoing, BN1; E. Mioshi, PhD5; M.C. Kiernan, FRACP1,2

1Brain & Mind Centre, University of Sydney, Camperdown, NSW, Australia2Sydney Medical School, University of Sydney, Camperdown, NSW, Australia3Nuffield Department of Clinical Neurosciences, Oxford University, UK4Neuroscience Research Australia, Randwick, NSW, Australia5Department of Psychiatry, University of Cambridge, Cambridge, UK

Institution:Brain & Mind CentreUniversity of Sydney94 Mallett Street Camperdown, NSW 2050Australia

Total word count: 4,139

Corresponding author: Jashelle CagaBrain & Mind CentreUniversity of Sydney94 Mallett Street Camperdown, NSW 2050AustraliaTelephone:+61 (2) 9114 4250

Fax:+61 (2) 9114 4254

Email address: [email protected]

Keywords: amyotrophic lateral sclerosis, apathy, depression, prognosis, mortality, survival

Disclosures: This work was supported by a National Health and Medical Research Council of Australia Postgraduate Research Scholarship (APP1092891) (Ms Caga); a Motor Neurone Disease Research Institute of Australia Graham Linford Postdoctoral Fellowship (Dr Hsieh); a Royal Australian College of Physicians Fellows Research Entry PhD Scholarship and Motor Neurone Disease Research Institute of Australia PhD Top-up Scholarship (Dr Ahmed), an University of New South Wales Postgraduate Research Scholarship (Dr Devenney), an Alzheimer’s Association USA New Investigator Research Grant (NIRP-12-258380) and Alzheimer’s Society UK Senior Fellowship (Dr Mioshi) and a National Health and Medical Research Council of Australia program grant (1037746) (Professor Kiernan). Dr Mioshi is on the Dementia and Geriatric Cognitive Disorders and BMC Neurology Editorial Boards; Professor Kiernan is the Editor-in-Chief of the Journal of Neurology, Neurosurgery & Psychiatry Editor-in-Chief and an Associate Editor in Neurology for the Journal of Clinical Neuroscience.


Abstract

Background: Apathy is the most commonly reported behavioural change in amyotrophic

lateral sclerosis (ALS). However, the degree to which it affects prognosis and overlaps with

depression in this population is unknown. The present study examined the relationship

between level of apathy, mortality and survival time and whether apathy was linked to

specific symptom clusters of depression.

Methods: A cohort of 76 consecutive ALS patients attending specialised multidisciplinary

clinics were classified according to level of apathy. The effect of clinical factors and apathy

on survival time were analysed using univariate and multivariate methods.

Results: The majority of patients with moderate-severe apathy died during the study (P =

0.003) and had a median survival time of 21.7 months, considerably shorter than patients

with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001). Apathy remained

a significant predictor of survival even after controlling for clinical factors and symptom

duration at the time of study entry (hazard ratio 3.8, 95% confidence interval 1.9-7.5, P =

0.0001). Depression with demoralisation was not associated with level of apathy (P = 0.172)

whereas depression with anhedonia was more common in patients with apathy than in those

without apathy (P = 0.006).

Conclusions: The presence of severe apathy is an independent, negative prognostic factor in

ALS.


Background

The clinical presentation of amyotrophic lateral sclerosis (ALS) may vary greatly between

individuals [1]. Older age, a short diagnostic interval, bulbar onset disease, and greater

disability at presentation typically carries a poor prognosis [2]. In recent years, there has been

increased understanding about the impact of frontotemporal dysfunction in ALS [3, 4], such

that ALS patients with comorbid frontotemporal dementia (FTD) survive one year less than

patients with “motor only” symptoms [5]. Consistent across studies is the negative effect of

cognitive impairment on survival [5-7]. The prognostic significance of specific changes in

behaviour is much less well understood.

There is increasing evidence that changes in behaviour may play a contributory role in

disease progression. Hu and colleagues suggested that, among ALS patients with cognitive

dysfunction satisfying dementia criteria, only those with concomitant behavioural changes,

such as apathy and disinhibition had worse survival [8]. This was understood to reflect more

extensive neuropathological involvement, and suggested behaviour was a key predictor of

survival, more so than the diagnosis of ALS with dementia or ALS with cognitive

impairment per se [8]. Such findings highlight the pattern of cognitive and behavioural

deficits observed in ALSFTD and their impact on survival [9]. However, the extent of

behavioural changes among ALS patients without dementia may not necessarily affect

survival [10].

Although it is widely recognised that behavioural changes in ALS can vary in severity [11],

the degree to which prognosis may be affected remains unknown. Given that symptoms of

apathy can affect 40% to 80% of ALS patients [12-15], certainly a prominent feature of non-

motor manifestations of the disease, it remains to be established whether apathy presents as

an independent factor that influences survival. Emerging evidence suggests that apathy may


precede motor symptoms [10] and may even be the earliest symptom discriminating

ALSFTD from frank FTD [16]. As such, identification of apathy may provide a window of

opportunity for early intervention [17, 18], in addition to a better understanding of this

construct and how it may be different from frequently overlapping symptoms such as

depression. With these issues in mind, the present study aimed to compare survival across

ALS patient cohorts exhibiting different levels of apathy and to explore whether apathy

manifested independently of specific symptom clusters of depression.

Methods

Participants

Seventy-six consecutive patients and their caregivers attending two specialised ALS clinics

coordinated through the University of Sydney Brain and Mind Centre between April 2011

and January 2015 were included. Patients with a confirmed diagnosis of ALS according to

current diagnostic criteria [19], with a caregiver who could provide information about their

behaviour, and separately who did not have a diagnosis of ALSFTD at initial presentation,

were eligible to participate in the study. All ALS phenotypes were included. Six patients with

a confirmed diagnosis ALS with co-morbid FTD were excluded (Figure 1).

Participants underwent a detailed clinical evaluation consisting of a neurological examination

and assessment of function, cognitive status and behavioral changes. These data were

supplemented by information obtained from standardised tests and questionnaires that

assessed physical status [20], global cognitive function [21], apathy [22] and depression [23].

Dates of symptom onset, diagnosis and death were obtained from patient medical records and

confirmed using the Ryerson Index [24], an online catalogue of death notices from Australian

newspapers. All participants provided written informed consent. This study was approved by


the South Eastern Sydney Local Health District and the University of Sydney Human

Research Ethics Committees.

– Insert Figure 1 here –

Measures

Disease status was assessed using the Amyotrophic Lateral Sclerosis Functional Rating

Scale - Revised (ALSFRS–R) [20], a 12-item measure of bulbar, fine motor, gross motor and

respiratory function. Each item was rated on a 4-point scale ranging from 0 (no function) to 4

(normal function) with a total score of 48 indicating normal function.

Apathy was assessed using the apathy domain of the revised version of the Cambridge

Behavioral Inventory (CBI-R) [22], a 45-item informant–completed questionnaire that

assessed psychopathology in ALS [25, 26]. Informants were required to rate the frequency of

behavioral symptoms from the onset of disease, using a scale from 0 (never) to 4 (constantly).

The total score for the apathy sub-scale was turned into a percentage of impairment based on

a previous ALS study [14]. The cutoff scores that defined level of apathy were: 0-25%

(mild), 26-50% (moderate), 51-75% (severe) and 76%+ (very severe).

Global cognitive status was evaluated with the Addenbrooke’s Cognitive Examination–

Revised (ACE–R) [21], a brief multi-domain cognitive assessment designed to identify early

cognitive symptoms in dementia. The ACE–R utilised five subscales: orientation, memory,

fluency, language, and visuospatial. A total score below 88/100 indicated suspected

dementia. Raw ACE-R scores were converted into percentages to account for items not

administered due to motor impairment.

Depression was assessed with the Depression, Anxiety, and Stress Scales–21 (DASS–21)

[23] a self-report measure with 21 items, each rated from 0 (did not apply to me at all) to 3

(applied to me very much, or most of the time). To accurately evaluate the relationship


between apathy and symptoms of depression, each item on the depression subscale was

categorised into specific symptom clusters of depression referred to as depression with

demoralisation (sum of DASS-21 items 10, 13, 17 and 21 = ≥ 1 indicated the presence of

symptoms) or depression with anhedonia (sum of DASS-21 items 3, 5 and 16 ≥ 1 indicated

the presence of symptoms) according to a previous ALS study [27] (Table 1).

Statistical analysis

Length of survival time was calculated as the total number of months from diagnosis until

death or census date (March 1, 2015). The effect of apathy on survival time was initially

assessed by Kaplan-Meier survival analysis (log-rank test). To identify individual factors that

may confound the relationship between apathy and survival, the chi-square test (with Yates

Correction for Continuity when appropriate) and the Fisher's exact test for categorical

variables and independent-samples t-tests and one-way between-groups ANOVA with post-

hoc tests (or Kruskal-Wallis Test and Mann-Whitney U Tests with Bonferroni adjustment)

for continuous variables were performed. Factors significantly associated with survival were

subsequently included in a Cox proportional hazards model, adjusted for inflated familywise

error rate. In the Cox model, the four levels of apathy were treated as continuous: (1) mild

apathy, (2) moderate apathy, (3) severe apathy, and (4) very severe apathy. All values are

presented as the mean ± the standard error (SE). A P value of < .05 was considered

statistically significant for all tests, unless otherwise specified.

Results

Demographic and clinical characteristics

Prior to analysis, apathy, symptom duration at study entry and known prognostic factors in

ALS such as age at symptom onset, diagnostic interval length, site of onset and disease status

were examined for the assumptions underlying multivariate analysis [28]. One patient with an


extremely high apathy score, one with a lengthy diagnostic interval, and one with an

exceptionally long history of symptoms before study entry were found to be univariate

outliers based on standardised residual values greater than 3.29; no cases were identified

through Mahalanobis distance as multivariate outliers (P < .001) [29]. All three outliers were

removed from subsequent analyses.

The 73 patients included 39 men (53%) and 34 women (47%) with a mean age of 63.4 ± 1.5

years. Limb onset disease was evident in 50 patients (69%). ALSFRS-R scores ranged from

19 to 47 (37.9 ± 0.9), indicative of moderate disease. Fifty-nine patients had mild apathy

(81%), 11 had moderate apathy (15%) and 3 had severe apathy (4%). There were no patients

with very severe levels of apathy. To reduce the probability of a type II error due to highly

unequal sample sizes, the mild apathy group was divided into patients that exhibited no

apathy (apathy subscale total score = 0) and those previously categorised as having mild

apathy. Finally, the moderate and severe apathy groups were combined. The resulting apathy

groups were: no apathy (n = 24), mild apathy (n = 35) and moderate-severe apathy (n = 14).

Apathy, mortality and survival

Level of apathy was significantly associated with mortality. Nine patients in the no apathy

(38%), 12 in the mild apathy (34%) and 12 in the moderate-severe apathy (86%) group died

during the course of the study (2 (2) = 11.5, P = 0.003). Further subgroup analysis was not

carried out due to the small number of patients with moderate-severe apathy. Patients with

moderate-severe apathy survived for a considerably shorter time (21.7 months) than patients

with mild apathy (46.9 months) and no apathy (51.9 months) (P = 0.0001; Figure 2).

When potential confounding demographic and clinical factors were examined, only cognitive

status differed significantly between the three apathy groups. Approximately half of the

patients with moderate-severe apathy scored below the standard cutoff score for cognitive


impairment on the ACE-R (2 (2) = 6.5, P = 0.039) (Table 2). Although disease status (F (2,

70) = 3.0, P = 0.059) and symptom duration at study entry (F (2, 70) = 0.4, P = 0.663) were

comparable across the three apathy groups, they were considered potential confounders given

that all ALS phenotypes were included resulting in a wide range of clinical presentations at

the outset. After controlling for cognitive status, disease status and symptom duration at study

entry, apathy remained significantly associated with survival time (hazard ratio 3.8, 95%

confidence interval 1.9-7.5, P = 0.0001 using P < .0125 to adjust for inflated familywise error

rate with four covariates). Specifically, for each one-unit change in level of apathy, the risk of

death more than tripled (Table 3).


Apathy and symptom clusters of depression

Depression data were available for 54 patients (74%). This discrepancy was not likely to be

due to demographic and clinical differences between patients who completed the depression

measure and those who did not (supplementary Table 1). There was no significant association

between level of apathy and depression with demoralisation (2 (2) = 3.5, P = 0.172),

suggesting that they were distinct constructs. In contrast, depression with anhedonia was

more common among patients with mild and moderate-severe apathy, highlighting

similarities in symptomatology (2 (2) = 10.1, P = 0.006; Figure 3).


Discussion

The present study has established that apathy is a critical prognostic factor in ALS. As such,

aspects of behavioral impairment may be considered equally important with respect to


prognosis in ALS, with moderate-severe apathy linked to shorter survival. This finding in

ALS patients with moderate-severe apathy was not likely to be due to demoralisation

associated with depression.

Given common frontal-subcortical circuit dysfunction [30], apathy has often been found to be

associated with executive dysfunction in different types of neurodegenerative diseases [31-

33]. This is particularly relevant in ALS since apathy has been found to be associated with

greater cognitive impairment. A large scale study conducted by Witgert and colleagues that

utilised a comprehensive neuropsychological battery, established that patients with moderate

to severe cognitive impairment had the highest rates of behavioral change, although this was

only statistically significant for apathy [34]. In another study, apathy was predictive of

performance on verbal fluency tests [13], which are considered especially sensitive to

executive dysfunction in ALS [35]. Since approximately half of the patients with moderate-

severe apathy scored below the recommended cut-off point for suspected dementia in the

present study, further research using ALS-specific instruments [36-37] may provide further

insight into the association between extent of cognitive impairment and apathy. Specifically,

whether more severe apathy indeed represents an early manifestation of the ALSFTD

phenotype [16]. This would also help delineate the clinical significance, including treatment

and prognostic implications of common but often more subtle frontotemporal dysfunction in

ALS [4].

While apathy is often described in the context of cognitive impairment in ALS, it may occur

as an isolated behavioural disturbance. In ALS patients without dementia, apathy severity has

been linked to atrophy involving the orbitofrontal cortex and the dorsolateral prefrontal

cortex in voxel-based morphometry, in addition to the right frontal gyrus using voxel-based

analysis of diffusion tensor images [38]. Abnormalities in the right anterior cingulum have


also been observed in ALS patients exhibiting apathy and no signs of executive dysfunction

or depression [39]. Thus, apathy may not necessarily co-exist with cognitive impairment in

ALS, such that apathy may manifest as a specific behavioural syndrome [40] with perhaps a

distinct survival trajectory.

The finding that patients with moderate-severe apathy were not more likely to exhibit

demoralisation supports the notion that apathy and specific symptoms of depression can

occur independently of each other in ALS [14, 39]. As such, demoralization characterised by

feelings of worthlessness and hopelessness may be a key feature [27] that separates apathy

from depression in ALS. Diagnosis of apathy in ALS should therefore be based not just on

impairment in motivation and goal-directed behavior, but also the absence of dysphoria and

devaluation of self and life.

Differentiating between anhedonic symptoms of depression and apathy may be more

complicated. In the present study, patients with mild and moderate-severe apathy were more

likely to report anhedonia compared to patients with no apathy, suggesting that it may be

difficult to separate loss of interest or pleasure associated with apathy from depression, and

vice versa. This finding may be related to similar patterns of frontal- subcortical circuit

dysfunction in both apathy and depression. Specifically, abnormalities in the orbitofrontal

cortex, dorsolateral prefrontal cortex and anterior cingulate circuits have been implicated in

the pathophysiology of both conditions [41, 42].

A potential limitation of the present study relates to the self-report measure of depression

and the caregiver-completed rating scale of apathy. Correlation of apathy with objective

outcome measures such as volumetric MRI may further contribute towards understanding

patterns of brain atrophy associated with different levels of apathy [39]. Separately, patients

recruited from specialised ALS clinics may result in selection bias towards more motivated


patients, compared to a population-based approach as well as its independent survival benefit

[43].

In summary, the present study has identified the importance of assessing the presence of

apathy, and also its severity. In particular, where moderate-severe apathy occurs in the

absence of depression with demoralisation, this behaviour may be indicative of more

aggressive disease which warrants prompt intervention and support for patients and their

caregivers.


Acknowledgments

The authors are grateful to the participants. This work was supported by funding to Forefront,

a collaborative research group dedicated to the study of motor neurone disease and

frontotemporal dementia from the National Health and Medical Research Council of

Australia Program Grant (1037746). Ms Caga is a National Health and Medical Research

Council of Australia Postgraduate Research Scholarship recipient (APP1092891).


Table 1. Categorisation of DASS-21 Depression Subscale Items

DASS-21 Item Number DASS-21 Depression Items Symptom Cluster of Depression

3 Couldn’t experience any positive feeling at all. Anhedonia

5 Difficult to work up the initiative to do things. Anhedonia

16 Unable to become enthusiastic about anything. Anhedonia

10 Nothing to look forward to. Demoralisation

13 Felt down-hearted and blue. Demoralisation

17 Felt that I wasn’t worth much as a person. Demoralisation

21 Felt that life was meaningless. Demoralisation

Abbreviations: DASS-21 = Depression, Anxiety and Stress Scales – 21


Table 2. Demographic and Clinical Characteristics of ALS patients Determined by Level of Apathy

Noapathy(n = 24)

Mildapathy(n = 35)

Moderate-Severe apathy

(n = 14)P

value

Age, mean ± SE, years 62.1 ± 2.6 62.9 ± 2.2 66.9 ± 3.4 0.521

Male, No. (%) 12 (50) 21 (60) 6 (43) 0.509

Total education, mean ± SE, years 12.3 ± 0.7 11.5 ± 0.5 11.3 ± 0.9 0.553

Bulbar onset, No. (%) 7 (29) 11 (31) 5 (36) 0.916

Age at symptom onset, mean ± SE, years 59.4 ± 2.6 60.2 ± 2.3 64.7 ± 3.3 0.443

Diagnostic interval length, mean ± SE, months 17.9 ± 4.4 19.5 ± 3.8 14.1 ± 2.2 0.690

Symptom duration study entry, mean ± SE, months 33.2 ± 5.2 33.0 ± 4.4 26.5 ± 4.0 0.663

ALSFRS-R total score, mean ± SE 39.1 ± 1.3 38.7 ± 1.3 33.6 ± 2.2 0.059

ACE-R total score < 88, No. (%)a 9 (45) 7 (21) 7 (58) 0.039

NIV, No. (%)b 1 (4) 3 (9) 3 (21) 0.414

PEG, No. (%)c 2 (8) 2 (6) 3 (21) 1.000

Abbreviations: ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; ACE-R = Addenbrook’s Cognitive Examination – Revised; NIV = Non-invasive ventilation; PEG = Percutaneous endoscopic gastrostomya89% patients underwent cognitive testing.


bThe proportion of patients using NIV according to level of apathy are presented. The p-value noted was based on the Fisher's exact test (2-sided) comparing no apathy group with mild and moderate-severe apathy group combined as 50% of cells had an expected frequency of five or less. cThe proportion of patients using PEG according to level of apathy are presented. The p-value noted was based on the Fisher's exact test (2-sided) comparing the no apathy group with mild and moderate-severe apathy group combined as 50% of cells had an expected frequency of five or less.


Table 3. Cox Regression Analysis of the Effect of Apathy on Survival Time

Predictors Exp(B) (95% CI) P value

ACE-R total score < 88 1.2 (0.5-2.9) 0.740

ALSFRS-R total score 1.0 (1.0-1.1) 0.375

Symptom duration study entry 0.9 (0.9-1.0) 0.0001

Apathy 3.8 (1.9-7.5) 0.0001

Abbreviations: Exp(B) = Hazard ratio; 95% CI = 95% confidence interval; ACE-R = Addenbrooke’s Cognitive Examination–Revised;

ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised


Supplementary Table 1. Demographic and Clinical Characteristics of Patients who did and did not Complete the Depression Measure

DASS21 not completed

n = 19

DASS21 completed

n = 54 P value

Age, mean ± SE, years 59.3 ± 3.0 64.9 ± 1.7 0.101

Male, No. (%) 12 (63) 27 (50) 0.471

Total education, mean ± SE, years 11.6 ± 0.6 11.7 ± 0.4 0.877

Bulbar onset, No. (%) 6 (32) 17 (32) 1.000

Age at symptom onset, mean ± SE, years 56.6 ± 3.1 62.3 ± 1.7 0.097

Diagnostic interval length, mean ± SE, months 15.1 ± 2.6 19.0 ± 3.0 0.463

Symptom duration at study entry, mean ± SE, months 32.7 ± 4.1 31.5 ± 3.5 0.835

ALSFRS-R total score, mean ± SE 35.7 ± 2.1 38.6 ± 0.9 0.220

ACE-R total score < 88, No. (%)a 4 (25) 19 (39) 0.484

Abbreviations: ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; ACE-R = Addenbrook’s Cognitive Examination – Revised.a91% of patients who completed the depression measure underwent cognitive testing.


Figures

Figure 1. Flowchart of the capture rate and the sequence of participant selection.

Figure 2. Kaplan-Meier survival curves of ALS patients with different levels of apathy. The

survival probability for patients with moderate-severe apathy at any given time was markedly

lower than that for patients with no apathy and mild apathy (P = 0.0001).

Figure 3. Proportion of ALS patients exhibiting specific symptom clusters of depression. A.

Patients with different levels of apathy were equally likely to report depression with

demoralisation (P = 0.172). B. Patients with mild and moderate-severe apathy were more

likely to report depression with anhedonia compared to patients with no apathy (P = 0.006).


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Web viewTotal word count: 4,139. Corresponding author: Jashelle Caga. ... 1.Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011; 377