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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.
Running title: APATHY AND PROGNOSIS 2
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.
Running title: APATHY AND PROGNOSIS 3
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
Running title: APATHY AND PROGNOSIS 4
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
Running title: APATHY AND PROGNOSIS 5
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
Running title: APATHY AND PROGNOSIS 6
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
Running title: APATHY AND PROGNOSIS 7
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
Running title: APATHY AND PROGNOSIS 8
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).
– Insert Figure 2 here –
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).
– Insert Figure 3 here –
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
Running title: APATHY AND PROGNOSIS 9
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
Running title: APATHY AND PROGNOSIS 10
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
Running title: APATHY AND PROGNOSIS 11
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.
Running title: APATHY AND PROGNOSIS 12
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).
Running title: APATHY AND PROGNOSIS 13
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
Running title: APATHY AND PROGNOSIS 14
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.
Running title: APATHY AND PROGNOSIS 15
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.
Running title: APATHY AND PROGNOSIS 16
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
Running title: APATHY AND PROGNOSIS 17
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.
Running title: APATHY AND PROGNOSIS 18
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).
Running title: APATHY AND PROGNOSIS 19
References
1. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet
2011;377:942-955.
2. Chio A, Logroscino G, Hardiman O, et al. Prognostic factors in ALS: A critical
review. Amyotrophic lateral sclerosis : official publication of the World Federation of
Neurology Research Group on Motor Neuron Diseases 2009;10:310-323.
3. Murphy JM, Henry RG, Langmore S, Kramer JH, Miller BL, Lomen-Hoerth C.
Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Archives of neurology
2007;64:530-534.
4. Strong MJ. Consensus criteria for the diagnosis of frontotemporal cognitive and
behavioural syndromes in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis :
official publication of the World Federation of Neurology Research Group on Motor Neuron
Diseases 2009;10:131-146.
5. Olney RK, Murphy J, Forshew D, et al. The effects of executive and behavioral
dysfunction on the course of ALS. Neurology 2005;65:1774-1777.
6. Elamin M, Phukan J, Bede P, et al. Executive dysfunction is a negative prognostic
indicator in patients with ALS without dementia. Neurology 2011;76:1263-1269.
7. Hu WT, Seelaar H, Josephs KA, et al. Survival Profiles of Patients With
Frontotemporal Dementia and Motor Neuron Disease. Archives of neurology 2009;66:1359-
1364.
8. Hu WT, Shelnutt M, Wilson A, et al. Behavior matters--cognitive predictors of
survival in amyotrophic lateral sclerosis. PloS one 2013;8:e57584.
9. Rippon GA, Scarmeas N, Gordon PH, et al. An observational study of cognitive
impairment in amyotrophic lateral sclerosis. Archives of neurology 2006;63:345-352.
Running title: APATHY AND PROGNOSIS 20
10. Mioshi E, Caga J, Lillo P, et al. Neuropsychiatric changes precede classic motor
symptoms in ALS and do not affect survival. Neurology 2014;82:149-155.
11. Raaphorst J, Beeldman E, De Visser M, De Haan RJ, Schmand B. A systematic
review of behavioural changes in motor neuron disease. Amyotrophic lateral sclerosis :
official publication of the World Federation of Neurology Research Group on Motor Neuron
Diseases 2012;13:493-501.
12. Chio A, Ilardi A, Cammarosano S, Moglia C, Montuschi A, Calvo A.
Neurobehavioral dysfunction in ALS has a negative effect on outcome and use of PEG and
NIV. Neurology 2012;78:1085-1089.
13. Grossman AB, Woolley-Levine S, Bradley WG, Miller RG. Detecting
neurobehavioral changes in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis :
official publication of the World Federation of Neurology Research Group on Motor Neuron
Diseases 2007;8:56-61.
14. Lillo P, Mioshi E, Zoing MC, Kiernan MC, Hodges JR. How common are
behavioural changes in amyotrophic lateral sclerosis? Amyotrophic lateral sclerosis : official
publication of the World Federation of Neurology Research Group on Motor Neuron
Diseases 2011;12:45-51.
15. Chio A, Vignola A, Mastro E, et al. Neurobehavioral symptoms in ALS are
negatively related to caregivers' burden and quality of life. European journal of neurology :
the official journal of the European Federation of Neurological Societies 2010;17:1298-
1303.
16. Hsieh S, Caga J, Leslie F, et al. Cognitive and behavioural symptoms in ALSFTD:
detection, differentiation and progression. Journal of Geriatric Psychiatry and Neurology
2015;"in press".
Running title: APATHY AND PROGNOSIS 21
17. Brodaty H, Burns K. Nonpharmacological Management of Apathy in Dementia: A
Systematic Review. The American journal of geriatric psychiatry : official journal of the
American Association for Geriatric Psychiatry 2012;20:549-564.
18. Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in
dementia. The American journal of geriatric psychiatry : official journal of the American
Association for Geriatric Psychiatry 2012;20:104-122.
19. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria
for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other
motor neuron disorders : official publication of the World Federation of Neurology,
Research Group on Motor Neuron Diseases 2000;1:293-299.
20. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS
functional rating scale that incorporates assessments of respiratory function. BDNF ALS
Study Group (Phase III). Journal of the neurological sciences 1999;169:13-21.
21. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke's Cognitive
Examination Revised (ACE-R): a brief cognitive test battery for dementia screening.
International journal of geriatric psychiatry 2006;21:1078-1085.
22. Wear HJ, Wedderburn CJ, Mioshi E, et al. The Cambridge Behavioural Inventory
revised. Dementia & Neuropsychologia 2008;2:102-107.
23. Lovibond SH, Lovibond PF. Manual for the depression anxiety stress scales. Sydney:
Psychology Foundation; 1995.
24. The Ryerson Index. The Ryerson Index [updated 18 November 2014].
http://www.ryersonindex.org/index.htm (accessed 01/03/2015).
25. Lillo P, Savage S, Mioshi E, Kiernan MC, Hodges JR. Amyotrophic lateral sclerosis
and frontotemporal dementia: A behavioural and cognitive continuum. Amyotrophic lateral
Running title: APATHY AND PROGNOSIS 22
sclerosis : official publication of the World Federation of Neurology Research Group on
Motor Neuron Diseases 2012;13:102-109.
26. Mioshi E, Lillo P, Yew B, et al. Cortical atrophy in ALS is critically associated with
neuropsychiatric and cognitive changes. Neurology 2013;80:1117-1123.
27. Clarke DM, McLeod JE, Smith GC, Trauer T, Kissane DW. A comparison of
psychosocial and physical functioning in patients with motor neurone disease and metastatic
cancer. Journal of palliative care 2005;21:173-179.
28. IBM Corp. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM
Corp; 2013.
29. Tabachnick BG, Fidell LS. Using Multivariate Statistics. 5th edition ed. Boston,
Massachusetts: Pearson Education; 2006.
30. Cummings JL. Frontal-subcortical circuits and human behavior. Archives of
neurology 1993;50:873-880.
31. Pluck GC, Brown RG. Apathy in Parkinson's disease. Journal of neurology,
neurosurgery, and psychiatry 2002;73:636-642.
32. Baudic S, Maison P, Dolbeau G, et al. Cognitive impairment related to apathy in early
Huntington's disease. Dementia and geriatric cognitive disorders 2006;21:316-321.
33. McPherson S, Fairbanks L, Tiken S, Cummings JL, Back-Madruga C. Apathy and
executive function in Alzheimer's disease. Journal of the International Neuropsychological
Society : JINS 2002;8:373-381.
34. Witgert M, Salamone AR, Strutt AM, et al. Frontal-lobe mediated behavioral
dysfunction in amyotrophic lateral sclerosis. European journal of neurology : the official
journal of the European Federation of Neurological Societies 2010;17:103-110.
Running title: APATHY AND PROGNOSIS 23
35. Abrahams S, Leigh PN, Harvey A, Vythelingum GN, Grise D, Goldstein LH. Verbal
fluency and executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia
2000;38:734-747.
36. Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and
behaviour changes in ALS. Amyotrophic lateral sclerosis & frontotemporal degeneration
2014;15:9-14.
37. Woolley SC, York MK, Moore DH, et al. Detecting frontotemporal dysfunction in
ALS: Utility of the ALS Cognitive Behavioral Screen (ALS-CBS (TM)). Amyotrophic lateral
sclerosis : official publication of the World Federation of Neurology Research Group on
Motor Neuron Diseases 2010;11:303-311.
38. Tsujimoto M, Senda J, Ishihara T, et al. Behavioral changes in early ALS correlate
with voxel-based morphometry and diffusion tensor imaging. Journal of the neurological
sciences 2011;307:34-40.
39. Woolley SC, Zhang Y, Schuff N, Weiner MW, Katz JS. Neuroanatomical correlates
of apathy in ALS using 4 Tesla diffusion tensor MRI. Amyotrophic lateral sclerosis : official
publication of the World Federation of Neurology Research Group on Motor Neuron
Diseases 2011;12:52-58.
40. Marin RS. Apathy: a neuropsychiatric syndrome. The Journal of neuropsychiatry and
clinical neurosciences 1991;3:243-254.
41. Naismith SL, Norrie LM, Mowszowski L, Hickie IB. The neurobiology of depression
in later-life: Clinical, neuropsychological, neuroimaging and pathophysiological features.
Progress in Neurobiology 2012;98:99-143.
42. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal
ganglia circuits. Cerebral Cortex 2006;16:916-928.
Running title: APATHY AND PROGNOSIS 24
43. Rooney J, Byrne S, Heverin M, et al. A multidisciplinary clinic approach improves
survival in ALS: a comparative study of ALS in Ireland and Northern Ireland. Journal of
neurology, neurosurgery, and psychiatry 2015;86:496-501.