APPENDIX B
Apathy in the setting of Alzheimer’s disease and related
disorders: overview and research recommendations
Lanctôt, K.L.1,2, Rosenberg, P.B.3, Sultzer, D.L.4, Francis, P.T.5, Brodaty, H.6, Padala, P.R.7,8,
Onyike, C.U.3, Agüera Ortiz, L.9,10, Geda, Y.E.11
for the Neuropsychiatric Syndromes Professional Interest Area of ISTAART
1Senior
Scientist, Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON; 2Departments of Psychiatry and
Pharmacology/Toxicology, University of Toronto
3Division
of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD
4Department
5 Wolfson
of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA
Centre for Age Related Diseases, King's College London, England
6Dementia
Collaborative Research Centre, University of New South Wales, Sydney, Australia
7Geriatric
Research Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR; 8
Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR
9
Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM; 10University Hospital Doce de Octubre, Madrid,
Spain
11Departments
of Psychiatry, Neurology and Health Sciences Research Mayo Clinic, Scottsdale, AZ
1
Abstract
An international panel of experts in apathy in Alzheimer’s disease (AD) was brought together to form a
workgroup to outline a future research agenda for this neuropsychiatric symptom (NPS). The high
prevalence and negative impact of apathy was acknowledged. While apathy is reasonably well-defined,
the need for refinement in its definition and measurement, with particular attention to subdomains was
recognized. Current knowledge includes neuroimaging research and studies focusing on neurobiological
and neurochemical bases of apathy. A focus on brain-behavior relationships, interrelationships between
NPS, and evaluating the neurobiologic basis of the distinct components using multimodal imaging
techniques was recommended. Animal models and genetic studies are lacking. Clinical trials that target
apathy, taking advantage of advances in neuroimaging and biomarkers, and individually tailored nonpharmacological interventions are key. The ultimate goal is to alleviate apathy by identifying treatment
targets and neurobiological factors that mediate successful treatment response and by well
designed clinical trials.
2
[8]. These figures contrasted to a prevalence of
3.2% among cognitively normal persons in the
Cache County Study [9]. The Mayo Clinic Study
of Aging (MCSA) [10] measured NPIQ apathy
in a countywide probability sample and reported
prevalence rates of 18.5% in MCI and 4.8%
among cognitively normal persons. The
population-based Kungsholmen project and
others have also reported that apathy is common
in AD and may be a predictor of disease
progression [11]. The association of apathy with
cognitive progression among normal elders was
also suggested by in findings in the Cache
County Study[12]. The prevalence of apathy in
AD and related conditions is customarily
reported in crude frequency rates. However,
these rates could be driven by demographic
variables such as age [13]. Therefore, future
studies should report by age, sex and other
traditional confounder variables.
Introduction
Apathy is a syndrome primarily characterized by
a marked loss of motivation [1, 2]. It is common
throughout the spectrum of cognitive disorders
from mild cognitive impairment to severe
Alzheimer’s disease (AD), as well as in a variety
of other neuropsychiatric disorders. In the last
20 years, considerable progress has been made
describing
the
phenomenology
and
epidemiology,
developing
measurements,
formulating diagnostic criteria, exploring
neurophysiological substrates, and proposing
and testing interventions for apathy. There is still
much to learn about the boundaries of apathy
and its etiology, so that effective pharmacologic
and behavioral interventions can be developed.
In this paper the Neuropsychiatric Syndromes
Professional Interest Area (NPS-PIA) apathy
workgroup (comprised of specialists and
investigators from the fields of geriatric
medicine,
neuropsychiatry,
behavioural
neurology and neuropsychology) reviews
progress to date and makes recommendations for
future research.
Impact
In addition to a high prevalence, research has
documented the negative impact of apathy on
both patients and caregivers. AD patients with
apathy are 2.8 times more likely than nonapathetic patients to be impaired in one of the
activities of daily living (ADLs), and 3.2 times
more likely to be impaired in all six activities
[14]. In another study of AD patients, apathy
was the only behavioral problem that was
significantly associated with both Instrumental
Activities of Daily Living (IADL) and ADL
impairment. Apathy independently accounted
for 27% of the variance in IADL [15].
Consistent with its association with decreased
function, apathy has a negative impact on
caregiver burden. Caregivers of patients with
AD complain more frequently of apathy than
any other patient behavior and their distress
correlates significantly with apathy [16]; [17]. In
addition, caregivers of apathetic AD patients
report significant levels of caregiver burden and
fewer positive experiences with caregiving.
Apathy is also associated with lower cognitive
and functional performance in normal elders and
those with MCI [12].
Prevalence
The high prevalence of apathy has been well
documented in both clinical and community
samples, and throughout the spectrum of
severity of neurodegenerative conditions. The
frequency of apathy is generally higher in
tertiary settings than in population-based
samples due to referral bias [3];[4]. In AD, a one
month prevalence of 72% among 50 outpatients
with mild to severe AD has been reported based
on the apathy subscale of the Neuropsychiatric
inventory (NPI) [5]. Extending these findings to
Mild Cognitive Impairment (MCI), the same
group reported the prevalence of apathy to be
51% in mild AD (n = 124), 39% in MCI (n = 28)
and 2% in cognitively normal persons (n = 50)
[6]. Similarly, Copeland and colleagues [7]
observed a 41% prevalence of ‘passivity’ in a
clinic sample of elders suffering a mild cognitive
disorder. In contrast, the Cardiovascular Heart
Study (CHS), found a 15% prevalence of NPI
defined apathy among MCI subjects, and a
prevalence of 35.8% in subjects with dementia
Beyond the associations with decreased
cognition and function, apathy is a marker for
3
poor prognosis. In MCI, apathy has consistently
been linked to higher rates of conversion to
dementia. For example, among 131 patients,
those with both amnestic-MCI and apathy had
an almost sevenfold greater risk of progressing
to AD than amnestic-MCI patients without
apathy (HR=6.9; 2.3-20.6). Furthermore, in
another MCI group, the risk of developing AD
increased 30% per point on the NPI apathy item
(HR=1.3; 1.1-1.4) [18]. In 1821 MCI patients
followed for a median of 1.6 years, the risk of
developing AD increased 16% per point on the
NPI apathy item (HR=1.16; 1.01-1.30) [19]. In
those with AD, the presence of apathy has been
associated with treatment response and the speed
of progression. The presence of apathy was a
predictor of poor behavioral response to
donepezil in patients with AD [20]. In addition,
apathy at baseline was associated with faster
cognitive (p = 0.0007) and functional decline (p
= 0.006) in a cohort of 354 AD patients [21].
What remains to be seen is whether treatment of
apathy can modify its association with poor
prognosis.
apathy using three dimensions as a composite of
reductions in emotional response, goal-directed
cognitive activity, and purposeful behavior.
These dimensions are consistent with previous
neurobiological models [25, 26] where three
subtypes of disrupted processing are defined
based on specific underlying lesions: emotionalaffective, cognitive, and auto-activation.
Measurement of Severity. Scales for apathy
assessment include: the Apathy Evaluation Scale
(AES) [27] the Structured Clinical Interview for
Apathy (SCIA) [28], the Apathy Scale (AS)
[29], the Apathy Inventory (AI) [30], the
Dementia Apathy Interview and Rating (DAIR)
[31], and the Lille Apathy Rating Scale (LARS)
[32]. These assessments are largely based on
Marin’s model, which is focused on lack of
motivation. The recently published APADEM
scale [33] has shown good measurement
properties in those with moderate to severe
dementia, where ceiling effects are often
problematic. Investigators from the American
Psychiatric Association and their collaborators
examined the psychometric properties of 15
scales that measure apathy across various
disorders including schizophrenia, depression,
traumatic brain injury, stroke, Parkinson’s
disease etc. They concluded that the apathy
subscale of Neuropsychiatric inventory (NPI),
and AES [27] are the two most psychometrically
robust measures for assessing apathy across
various disease conditions [34].
Measurement of Apathy
The last two decades have witnessed growing
interest in the investigation of apathy. This is in
part fuelled by three measurement advances.
First a practical step was taken to operationalize
the definition of apathy, and subsequently,
measure it using a validated scale [1, 2]. Second,
investigators developed additional scales to
measure apathy and related neuropsychiatric
symptoms in the context of dementia [22, 23].
Third, diagnostic criteria for apathy associated
with primary dementia have been proposed.
Diagnostic Criteria. In 2009, an international
workgroup [35] proposed Consensus Diagnostic
Criteria for apathy using a contemporary
concept, definition and construct (shown in
Table 1). These criteria 1) define apathy in
terms of its core feature of diminished
motivation, 2) introduce additional cognitive,
affective and behavioral requirements, 3) assert
a time criterion (symptoms must be present for
at least 4 weeks) and 4) require demonstrable
functional impairment attributable to apathy.
They also stipulate exclusion criteria for
discounting entities that mimic apathy [36]. The
criteria operationalize present-day concepts of
apathy, denoting persistent declines in
motivation, self-directed action and emotional
vitality in a format that facilitates bedside
ascertainment. By incorporating affective
Operationalization of the Definition. Apathy
is associated with varied concepts including
indifference, lack
of
motivation,
and
procrastination. The syndrome has cognitive,
affective, and behavioral dimensions leading to
difficulties in operationalization and lack of
consistency of use of the term in the literature.
Further complicating assessment is the overlap
of symptoms between apathy and other
syndromes such as depression, anxiety and
motor retardation. Marin’s model [24] defined
4
indicators (i.e., diminished feelings and
reactiveness) and noting persistency, the criteria
extend earlier work [37]; [38] that highlighted
cognitive and behavioral indicators.
High
reliability (Kappa, κ, = 0.93) was demonstrated
in a study of 306 patients with dementia of the
Alzheimer type (DAT), mixed dementia, MCI,
Parkinson’s disease, schizophrenia and major
depression. Reliability was solid for each
criterion (κ = 0.9−1 for A, C and D, and 0.6-0.8
for B1−3)[39].
with specific brain physiologies in distinct brain
regions.
Structural. Studies using MRI to measure
regional cortical volume reported that apathy in
AD was associated with smaller volumes of the
anterior cingulate gyrus, orbitofrontal cortex, or
other regions in the frontal cortex or basal
ganglia. In addition, apathy was associated with
either presence of white matter lesions overall
[41] or volume of frontal white matter
hyperintensities [42]. Diffusion tensor imaging
showed that white matter microstructural
integrity was disrupted in the left anterior
cingulate among AD patients with apathy [43].
While progress has been made defining and
measuring apathy, more refinement is needed.
In particular subdomains of apathy should be
defined and modified as understanding
improves, e.g. scales that sort symptoms into
cognitive, behavioural, and emotional domains,
with adequate validity and reliability for these
domains. Adoption of diagnostic criteria
facilitates communication and collaboration, as
well as compilation and comparison of findings.
Thus promotion of the new diagnostic criteria is
a high priority requiring replication of their
validation in larger samples, and in diverse
clinical populations and settings. It is also of
vital importance to establish the sensitivity and
specificity of these criteria, using for comparison
diagnoses derived from specialist examination
and diagnostic consensus, so as to determine if
refinements are needed. In addition, the field
might develop physiologic markers of apathy
using neuroimaging, neurobiological, genetic
and other (e.g., actigraphy [40]) methods as
outlined below. These markers can be used to
validate clinical diagnosis and serve as
quantitative surrogate measures Ultimately, the
usefulness of diagnostic criteria will be
demonstrated by their ability to define an
endophenotype that is linked to specific
neurobiologic substrates and treatment response.
Functional. Studies using PET imaging to
measure cortical metabolic activity or perfusion
found that apathy in AD was associated with low
metabolism or perfusion in anterior cingulate or
orbitofrontal cortex (e.g. Marshall et al. [44]).
Hypoperfusion of other regions in frontal cortex
or basal ganglia was inconsistently reported.
One study found particular aspects of the apathy
syndrome were associated with hypoperfusion of
individual cortical regions [45]. Ligand
neuroimaging measures of neuroreceptor sites in
AD have demonstrated lower dopamine
transporter binding in the bilateral putamen
associated with poor initiative [46], and lower
cholinergic receptor binding in the left frontal
cortex associated with blunted affect, emotional
withdrawal, and motor slowing [47].
While still speculative, these studies collectively
suggest that apathy in AD is associated with
atrophy and dysfunction of medial and inferior
frontal regions that mediate behavioral initiation,
motivation, and reward mechanisms. Reduced
dopaminergic input to these regions and low
frontal cholinergic binding may be relevant.
Dysfunction of additional regions in frontal
heteromodal association cortex or interconnected
basal ganglia structures may also contribute to
the expression of apathy.
Neuroimaging
Several research approaches using neuroimaging
can improve understanding of apathy in AD and
contribute to treatment development. Steps
forward include the assessment of brainbehavior relationships in larger samples with
well-characterized apathy symptoms and other
behavioral syndromes. Interrelationships among
Structural and functional neuroimaging can
reveal relationships between regional brain
structure or function and the presence or extent
of clinical apathy. Neuroimaging can illuminate
such relationships in vivo, address state or trait
expressions, and explore relevant relationships
5
behavioral
syndromes
and
relevant
neurobiological factors can thus be examined.
Neuroimaging studies should evaluate the brain
basis of distinct components of the apathy
syndrome
(cognitive,
emotional,
and
behavioral). Different biologic contributions to
each component may be revealed, with heuristic
value and treatment implications. Longitudinal
studies can demonstrate relationships over the
course of the neurodegenerative process, and can
address
causal
factors
more
directly.
Multimodality imaging studies (e.g., structure,
metabolism, neuroreceptor, and/or amyloid) can
reveal
relationships
among
multiple
pathophysiological
processes.
Finally,
neuroimaging studies in preclinical or clinical
treatment studies can identify treatment targets
and neurobiological factors that mediate
successful treatment response.
reduction in a particular neurotransmitter will
produce benefit, these data appear to confirm the
hypothesis that dopaminergic circuits linking the
basal ganglia with the anterior cingulate and
frontal cortices, normally involved in motivation
and reward, are dysfunctional in people with AD
and apathy [55]. Further neurochemical indices
have not been explored as biomarkers. For
example, for dopaminergic neurotransmission,
potential biomarkers include the precursor l-3,4dihydroxyphenylalanine (L-DOPA), dopamine
(DA) and metabolite 3,4-dihydroxyphenylacetic
acid (DOPAC). There are reports of increased
CSF DOPAC in AD vs. controls [56] but no
difference in plasma DA [57]. Urine levels of LDOPA, DA, and DOPA are 2-3X higher in
controls than AD [58]. CSF levels of dopamine
transporter are quantified by Western blot [59].
Amyloid and tau. Higher NPI apathy scores
were associated with higher CSF tau and
phosphorylated tau, suggesting increased tangle
formation, in 32 AD patients [60]. No such
associations were observed between CSF
amyloid, and NPI depression or psychosis
scores.
Neurobiology and Biomarkers
Imaging data suggest that regional substrates of
apathy include structural and functional
alterations in the anterior cingulate, orbitofrontal
cortex, or other components of frontal circuits
such as the dorsolateral frontal cortex, frontal
white matter, or basal ganglia. From a
neuropathological perspective, apathy may result
from atrophy and white matter tract changes
(described above), likely indicating loss of
neurons and synapses innervating and
connecting these particular regions [48, 49]. A
biomarker is a biological test or marker of
disease state or disease mechanism. Biomarkers
are intertwined with an understanding of the
biological mechanisms that may underlie apathy
in AD.
Inflammatory markers. Both mood disorders
and AD may be associated with inflammation
[61, 62] with specific increases in blood levels
of Interleukin-6 (IL-6) and Tumor Necrosis
Factor alpha (TNF-α) [63, 64]. Given the
overlap of symptoms between depression and
apathy, it is possible that apathy is associated
with an altered inflammatory state in AD. Other
potential biomarkers of inflammation include
CSF antimicroglial antibodies [65], serum
neopterin
[66]
and
macrophage-colony
stimulating factor [67].
Neurochemical. Neurochemical correlates of
apathy include reduced indices of dopamine in
the putamen [50], reduced acetylcholine in
lateral frontal cortex [51] and lower plasma
GABA [52]. Pharmacologic challenge has
shown that AD patients with apathy have a
blunted subjective reward after administration of
the dopaminergic agent dextroamphetamine[53].
These changes provide a rational basis for the
success in some trials of both cholinergic [54]
and dopaminergic agents [55] in reducing apathy
in people with dementia. Whilst it does not
always follow that simply correcting a perceived
Genetics. There are few data on genetic
associations of apathy in AD. There are reports
of null associations with polymorphisms of
ApoE, COMT, and the 5HT promoter [68-70]
but no reports on associations with AD
susceptibility genes recently identified in
genome-wide association studies [71] [72]
Key steps forward to aid our understanding of
the neurobiology of apathy in dementia should
include a hypothesis-generating autopsy
investigation of biochemical correlates of apathy
in people with dementia, controlling for other
6
neuropsychiatric disturbances. Such studies can
provide opportunities for focused imaging
studies in well-chosen patient populations and
will drive experimental medicine studies of
licensed drugs in the first instance, and stimulate
industry to undertake drug development based
on these new targets.
placebo-controlled trial in moderate-to-severe
[81, 82] AD patients supported donepezil
treatment for apathy. A randomized, placebocontrolled trial in mild-to-moderate AD suggests
efficacy in delaying the emergence of apathy
[83]. Improvements in apathy were reported
with galantamine treatment for mild-to-moderate
AD in a randomized, placebo-controlled trial
[84]. Similar results were reported in an open
label galantamine study [85] and with
rivastigmine in moderate-to-severe AD patients
[86]. Double-blind, placebo-controlled trials
with metrifonate, [87, 88] and an open-label
study with tacrine [89] found a significant
reduction in NPI apathy scores in AD patients.
However, it should be noted that data supporting
cholinesterase inhibitors for treating apathy in
AD have evaluated apathy as a secondary
outcome only. Furthermore, patients were not
recruited because of apathy.
There is much need for investigation of apathy
biomarkers in AD, such as tau/phosphorylated
tau, DA, and
pro-inflammatory cytokines.
While these are unlikely to be solely associated
with apathy, regional distribution of biomarkers
for AD may be important. More specific
biomarkers for apathy will emerge with greater
understanding of the neurobiology and may
include
those
related
to
specific
neurotransmitters. In addition, such data are
subject to marked variance, and CSF levels of
amyloid and cytokines vary with time of day,
sleep, and lumbar puncture itself [73-75] and
clearly there is significant need for validation.
For off-label use, a case report of modafinil
(without a formal diagnosis of AD) [90] and a
randomized controlled trial for nefiracetam
(without AD) [91] provide suggestions of
effectiveness warranting additional study. Two
randomized, controlled studies, subject to the
same limitations as with the cholinesterase trials,
found significant improvements in apathy for
patients with AD or vascular dementia (VaD)
treated with memantine [92]; [93]. A series of
small studies with mixed results suggest possible
effectiveness of dopaminergic agents including
amantadine [94]; [95], bupropion [96] and
ropinirole [97] for apathy in patients with a
range of cognitive impairments.
Animal models
While there have been few investigations of
animal models of apathy, there are promising
clues in models of mood disorders and addiction.
For example, chronic mild stress and
psychosocial stress rodent models of
“depression” exhibit behaviours that are similar
to apathy in humans, namely decreased
motivation evidenced by decreased desire to
consume sucrose solution, or decreased
socialization and sexual behavior [76]. Another
mechanism for inducing apathy in rodents is
dopamine receptor antagonism by exogenous
antipsychotics [77].
The progressive-ratio
schedule of reinforcement is widely used in
animal models of reinforcement including
cocaine [78] and food administration [79], and
may be a viable tool for assessment of
motivation. Both these approaches might be
applied to the AD transgenic mouse models or to
the development of a novel model of apathy in
AD which would represent an important
advance.
Methylphenidate for apathy has been explored in
many patient populations including severely
demented nursing home patients, [98] VaD
patients, [99] AD patients [100] and in a small
number of patients with mixed diagnoses in a
series of individual cross-over, double-blind,
randomized “N of 1” trials [101]. A small, crossover randomized controlled trial in outpatients
with mild to moderate AD demonstrated that
methylphenidate was efficacious in the treatment
of apathy [102]. These results were supported by
a randomized placebo controlled parallel group
trial [103]. Currently, a multicentre, doubleblind, placebo-controlled trial is investigating
methylphenidate treatment for apathetic patients
Pharmacotherapy
There are few data to guide clinicians in treating
apathy in AD. Results from a randomized
withdrawal study [80] as well a randomized,
7
with mild-to-moderate AD with results expected
in 2012 [104] Lastly, double-blind, placebocontrolled trials have found improvements in
apathy with ginkgo biloba extract EGb 761 in
AD and VaD [105] as well as probable AD
patients [106] as reported in secondary analyses.
intervention across a broad range of people with
dementia and apathy will not be enough to
demonstrate
clinically
and
statistically
significant outcomes.
Even where such
outcomes can be shown, effects usually wane
once interventions cease unless activities are
continued.
It should be apparent that there is a need for
placebo-controlled trials with apathy as the
primary target and outcome. These studies
should use current diagnostic criteria and take
advantage of advances in neuroimaging and
biomarkers, combined with pharmacologic
challenge, to better understand the relationship
between apathy and treatment response. Trials
should include patients with carefully defined
apathy symptoms, paying particular attention to
delineating subtypes of apathy. Ultimately, the
validity of diagnostic criteria will be related to
whether or not they can identify patients with a
higher probability of responding to specific
treatments.
Future research may be best designed to match
activities to individual interests, personal history
and retained skills to engage persons with
dementia and maintain involvement. Useful
outcome measures are scales to evaluate prespecified goals such as goal attainment scales
[108] or quality of life indicators, as well as
apathy itself. Given the increased prevalence or
worsening of apathy with dementia progression,
delay of emergence, or stabilization of severity
over long periods might be important outcomes.
Alternative strategies may have to be considered
over the broad span of dementia severities.
Confounds that should be accounted for are
depression, medication effects (therapeutic and
adverse), physical problems that cause pain,
lethargy or depletion, premorbid behavioral
dispositions, and environmental factors and
interventions (such as structured activity
programs). Combination of non-pharmacological
and drug treatments such as cholinesterase
inhibitors should be evaluated. Finally, context
is important in demonstrating efficacy and
sustainability. Nursing homes that incorporate
interventions into usual care or family caregivers
that can continue use of individual activities are
more likely to effect lasting improvements. By
its nature, recruitment is difficult in undertaking
apathy trials; proxy consent from family
caregivers and provision of clear information to
institutional ethics review boards are important.
Non-pharmacological management
A systematic review of the literature on nonpharmacological interventions for apathy in
dementia focused on randomized or pseudorandomized trials of interventions grouped for
convenience into six categories. The review
noted many other studies that were small, open
label or qualitative, which reported benefits, but
that could not be captured quantitatively. Only
one category, a heterogeneous group of
interventions, labelled Therapeutic Activities,
contained sufficient, high research quality
studies [107]. Therapeutic Activities included
stimulation, creative activities, cooking,
Montessori methods or incentive based
behavioral approaches, often individually
tailored to patient needs. This category of
interventions was found to be the most effective.
Positive results, although less impressive, were
reported in other categories of intervention,
namely
music,
exercise,
multi-sensory
stimulation, pet therapy and special care units.
However the evidence for efficacy of these
interventions was limited as the standard of
research was generally low.
Immediate Next Steps
Much progress has been made in defining apathy
as a distinct syndrome. Key questions that
should be studied in the next 5 years include:
1) Apathy is recognized as a marker of
poor prognosis. Do the new diagnostic
criteria also predict poor prognosis in
MCI and dementia? Are there valid
subdomains of apathy, and can they be
It may be that individual attention in activities
personally rewarding to recipients is the key
element and that application of a single type of
8
reliably measured? Do subtypes of
apathy confer a greater risk?
2) Neuroimaging
studies
collectively
suggest that apathy in AD is associated
with regions that mediate behavioral
initiation, motivation, and reward
mechanisms.
Do the distinct
components of the apathy syndrome
(cognitive, emotional, and behavioral)
differ in this regard? Can they be used
to predict treatment response?
3) There is little understanding of the role
of genetics in presentation and response
to treatment for those with apathy, and
animal models have not been developed.
These areas have the potential to
improve understanding of apathy and as
a result, suggest new treatment targets.
4) Apathy is increasingly being recognized
as a therapeutic target. The first RCTs
have been completed. Do the diagnostic
criteria define a population who
responds to specific interventions? Will
treatment of apathy change its
relationship with poor prognosis?
5) There is a need for both pharmacologic
and nonpharmacologic trials with apathy
as a primary outcome measure. For
nonpharmacologic studies, interventions
may have to be individualized.
Collectively, these studies should use
current diagnostic criteria and take
advantage of advances in neuroimaging
and biomarkers, combined with
pharmacologic challenge to better
understand the relationship between
apathy and treatment response.
9
Acknowledgements
KLL receives research support funding from the National Institutes of Health (5R01AG033032),
Canadian Institute for Health Research (MOP-114913), Alzheimer Society of Canada (#12-74),
Heart and Stroke Foundation (#NA 7220) and the Ontario Mental Health Foundation. PBR
receives support from NIA grants 1R01AG039384, 5K08AG029157, 5R01AG033032 and the
American Foundation for Aging Research. DLS receives support from the Department of
Veterans Affairs (Merit Review Award) and the NIMH (MH56031). PTF receives research
support from the UK charities Alzheimer’s Society and Alzheimer’s Research UK (Brains for
Dementia Research), Alzheimer’s Society and The Edmund J Safra Foundation. PRP receives
research support from the Department of Veterans Affairs and the Alzheimer’s Association.
YEG receives research support funding from the National Institutes of Health (AG06786,
RR024150 (Mayo Clinic CTSA [Career Transition Award]), RWJ Foundation and the European
Union Regional Development Fund (Project FNUSA-ICRC: CZ.1.05/1.1.00/02.0123).
Conflict of Interest
The authors have no conflict of interest to report. The views expressed in this paper are those of
the authors, and do not necessarily represent the official views of their sponsoring agencies.
10
Table 1. Diagnostic criteria for apathy in neurodegenerative disease
Diagnosis requires fulfillment of criteria A, B, C and D
A. Loss of or diminished motivation in comparison to the patient’s previous level of functioning
and which is not consistent with his age or culture. These changes in motivation may be
reported by the patient himself or by the observations of others
B. Presence of at least one symptom in at least two of the three following domains for a period
of at least four weeks and present most of the time
Domain B1 – Behavior
Domain B2 – Cognition
Domain B3 – Emotion
Loss of, or diminished, goaldirected behavior as evidenced
by at least one of the
following:
Loss of, or diminished, goaldirected cognitive activity as
evidenced by at least one of
the following:
Loss of, or diminished,
emotion as evidenced by at
least one of the following:
Loss of self-initiated behavior
(e.g., in
starting
conversation, doing basic
tasks of day-to-day living,
seeking social activities,
communicating choices)
Loss of spontaneous ideas and
curiosity for routine and new
events (i.e., challenging tasks,
recent news, social
opportunities, personal/family
and social affairs).
Loss of spontaneous emotion,
observed or self-reported (e.g.,
subjective feeling of weak or
absent emotions, or
observation by others of a
blunted affect)
Loss of environmentstimulated behavior (e.g., in
responding to conversation,
participating in social
activities)
Loss of environmentstimulated ideas and curiosity
for routine and new events
(i.e., in the person’s residence,
neighborhood or community).
Loss of emotional
responsiveness to positive or
negative stimuli or events
(e.g., observer-reports of
unchanging affect, or of little
emotional reaction to exciting
events, personal loss, serious
illness, emotional-laden news)
C. These symptoms (A & B) cause clinically significant impairment in personal, social,
occupational, or other important areas of functioning
D. The symptoms (A & B) are not exclusively explained or due to physical disabilities (e.g.
blindness and loss of hearing), to motor disabilities, to diminished level of consciousness or
to the direct physiological effects of a substance (e.g. drug of abuse, a medication)
11
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