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
1 Senior Scientist, Brain Sciences Program, Sunnybrook Research Institute, Toronto, ON; 2 Departments of Psychiatry and
Pharmacology/Toxicology, University of Toronto
3 Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD
4 Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA
5 Wolfson Centre for Age Related Diseases, King's College London, England
6 Dementia Collaborative Research Centre, University of New South Wales, Sydney, Australia
7 Geriatric 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; 10 University Hospital Doce de Octubre, Madrid,
Spain
11 Departments of Psychiatry, Neurology and Health Sciences Research Mayo Clinic, Scottsdale, AZ
1

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

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.
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
3
[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.
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 ( ADL s), 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].
Beyond the associations with decreased cognition and function, apathy is a marker for

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.
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.
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 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].
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
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].
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.
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 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].
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.
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
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.
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.
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 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 L-
DOPA, 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.
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].
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.
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.
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.
There are few data to guide clinicians in treating apathy in AD. Results from a randomized withdrawal study [80] as well a randomized,
7 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.
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.
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

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.
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.
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.
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 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.
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.
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

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

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).
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
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 self-initiated behavior
(e.g., in
starting conversation, doing basic tasks of day-to-day living, seeking social activities, communicating choices)
Loss of environmentstimulated behavior (e.g., in responding to conversation, participating in social activities)
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 environmentstimulated ideas and curiosity for routine and new events
(i.e., in the person’s residence, neighborhood or community).
Domain B3 – Emotion
Loss of, or diminished, emotion as evidenced by at least one of the following:
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 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)
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