REVIEW ARTICLE
Apathy and Dementia. Nosology, Assessment and Management Gabriele Cipriani, MD, Claudio Lucetti, MD, Sabrina Danti, PsyD, and Angelo Nuti, MD Abstract: Apathy, characterized by lack of motivation and loss of initiative, is a non-cognitive symptom that affects a high proportion, but not all, of patients with all forms of dementia. To explore the phenomenon of apathy in people with dementia, we searched the PubMed and Google Scholar electronic databases for original research and review articles on apathetic behaviors in patients with dementia using the search terms “apathy, behavioral and psychological symptoms, dementia, Alzheimer’s disease, Frontotemporal dementia, Dementia associated with Parkinson’s disease, Huntington’s disease, Vascular dementia”. Some nosological aspects, neurobiological basis, and assessment of, as well as, potential benefits of non-pharmacologic and pharmacologic interventions for apathy in dementia are discussed. Greater understanding of apathy will improve the identification, intervention, and treatment of this ubiquitous and pernicious syndrome. Key Words: Apathy, behavioral and psychological symptoms, dementia, Alzheimer’s disease, frontotemporal dementia, dementia associated with Parkinson’s disease, Huntington’s disease, vascular dementia (J Nerv Ment Dis 2014;202: 718–724)
T
he word apathy stems from the Greek apathya derived from apathes, “a” (without) plus “pathos” (passion, feeling), and was originally coined by the Greek Stoic philosophers more than 2000 years ago to refer to the condition of being free from emotions and passions. In the conception of the Stoic philosophers only a state of true apathy would release the human mind from emotional constraints (Starkstein et al., 2005). The semantic confusion related to shifts in meaning is one of the problems that have confounded the study of apathy; even today, confusion remains regarding the essential features of apathy and its boundaries with constructs such as aboulia, anhedonia, depression and learned helplessness (Robert et al., 2009). Apathy is common across various neurological and psychiatric disorders and it was also described in association with other medical conditions. There is wide acknowledgement that it is an important behavioral symptom in Alzheimer’s disease (AD) and other dementias.
METHODS Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published since 1980. Search terms used included apathy, behavioral and psychological symptoms (BPSD), dementia, AD, Frontotemporal dementia, Dementia associated with Parkinson disease (PDD), Huntington’s disease (HD), Vascular dementia (VaD). Publications found through this indexed search were reviewed for further relevant references.
Some Nosological Aspects of Apathy Evidence does not provide a clear view of the nosological position of apathy. The ambiguity of the evidence may be attributed in large part to a lack of clarity in definition and etiology, clinical criteria and assessment
Neurology Unit, Hospital of Viareggio, Lido di Camaiore, Lucca (Lu), Italy. Send reprint requests to Gabriele Cipriani, MD, Hospital of Viareggio, via Aurelia, 55043, Lido di Camaiore, Lucca (Lu), Italy. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0022-3018/14/20210–0718 DOI: 10.1097/NMD.0000000000000190
718
www.jonmd.com
overlap (Mortby et al., 2012). The International Classification of Disease (ICD)-10 (WHO, 1992) make no mention of apathy and Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 (APA, 2013) uses the term to refer to a subtype of personality change due to a medical general condition, but not specific definition is provided. The definition of this behavioral symptom has been matter of debate. Cutting (1995) argued that, although regarded as the psychopathological counterpart of the motivational component of emotion, apathy must be better regarded as a manifestation of impaired will. Marin (1991) defined apathy as “a lack of motivation not attributable to diminished level of conscience, cognitive impairment or emotional distress”. Motivation denotes that aspect of behavior concerned with the initiation, direction, and intensity of goal-directed behavior (Marin, 1990). This construct was slightly modified and operationalized into applicable diagnostic criteria by Starkstein (2000) (Table 1). More recently, a task force including experts from Europe, Australia and North America has developed new diagnostic criteria for apathy (Robert et al., 2009). In them, it is defined as a disorder of motivation that persists over time and should meet all the following requirements. Firstly, the core feature of apathy, i.e. diminished motivation, must be present for at least 4 weeks; secondly, impairment in at least 2 among the three dimensions of apathy (i.e. reduced goaldirected behavior, goal-directed cognitive activity and emotions) must also be present; thirdly, there should be identifiable functional impairments attributable to apathy. Finally, exclusion criteria are specified to exclude symptoms and conditions mimicking apathy. In a comprehensive review on the mechanism of apathy, Levy and Dubois (2006) emphasized that apathy should not be defined as “lack of motivation” (considered a obscure psychological concept), “but as an observable behavioural syndrome consisting in a quantitative reduction of voluntary (or goal-directed) behaviours”. One of the main diagnostic dilemmas is how to separate apathy from depression. The differentiation is difficult because of substantial overlap in key symptoms sharing manifestations, such as a lack of interest, anergia, psychomotor slowing, and fatigue. In fact, it is often misinterpreted, with carers describing it as a depressive state even though a lack of sadness, desperation, crying, and a depressive mood distinguish apathy from depression. According to Levy et al. (1998) the typical apathetic patient usually lacks the negative thoughts, emotional distress, sadness, vegetative symptoms and somatic complaints frequently observed in mood disorders.
Neurobiological Basis of Apathy The neurobiology of apathy is not well understood, and we do not know whether it is different in different disorders. It is considered to result from lesions in brain areas that mediate drive and motivation and that participate in the elaboration of plans for actions, and it is associated with both neuropathologic and neurochemical alterations to fronto-subcortical circuits (Moretti et al., 2002; Mega and Cummings, 1994). Because there are several anatomical-functional prefrontalbasal ganglia circuits, the underlying mechanisms responsible for apathy may differ according to which prefrontal-basal ganglia circuit is affect. Lesions or dysfunctions of the limbic territories of the frontal lobes (the orbital-mesial prefrontal cortex) and the basal ganglia (e.g., the ventral striatum) lead to apathy through difficulties to provide the affective value of a given behavioral context; lesions or dysfunctions of the associative (“cognitive”) territories of the frontal lobes (the dorsal
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Apathy and Dementia
TABLE 1. Diagnostic Criteria for Apathy (Starkstein, 2000) A Lack of motivation relative to the patient’s previous level of functioning, or the standards of his or her age and culture, as indicated either by subjective account or observation by others. B Presence for at least 6 weeks, during most of the day, of at least 1 symptom belonging to each of the following three domains: 1. Diminished goal-director behavior • Lack of effort or energy to perform everyday activities • Dependency on prompts from others to structure everyday activities 2. Diminished goal-directed cognition • Lack of interest in learning new things, or in new experience • Lack of concern about one’s personal problems 3. Diminished concomitants of goal-directed behavior • Unchanging or flat affect • Lack of emotional responsivity to positive or negative events C The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D The symptoms are not due diminished level of consciousness or the direct physiological effects of a substance.
prefrontal cortex) and the basal ganglia (e.g., the dorsal caudate) contribute to apathy via a “cognitive inertia”, an inability to generate or activate strategies required to successfully complete a given program of actions (Levy, 2012). The most severe forms of apathy is characterized by difficulties in self-initiating actions or thoughts, contrasting with relatively spared, externally driven response. This pattern is the so called “auto-activation deficit”, and consists in a loss of spontaneous activations that seems to affect both cognitive and emotional responses. It may be due to bilateral lesions in the prefrontal-basal ganglia circuits that can be explained either by the addition of lesions in the cognitive and limbic territories or by a more general and elementary impairment that mirrored the presumed normal functions of the prefrontal-basal ganglia circuits, that is to selectively amplified the behavior that one considers as the most adapted to one’s personal needs or environmental demands (Levy, 2012).
Assessment in Demented Patients Assessment of apathy in dementia is complicated by the need to distinguish between diminished behavior due to loss of motivation and loss of ability secondary to cognitive impairment, and by the overlap in symptoms between depression and apathy (Tagariello et al., 2009; Landes et al., 2001). Furthermore, the use of antipsychotic, antidepressant, and neuroleptic medications can induce side effects such as fatigue, lethargy, listlessness, and reduced response to stimuli, can initiate, maintain, or imitate apathetic behaviors (Colling, 1999). A number of instruments have been developed for assessing neuropsychiatric symptoms in individual with dementia. Some instruments were specifically designed to measure apathy, whereas others were designed to provide broader neuropsychiatric assessment. These include the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) that is the most widely used multidimensional instrument for assessing neuropsychiatric functioning in patients with dementia. It is a valid and reliable instrument involving a caregiver interview designed to assess the presence and severity of 10 symptoms: apathy, irritability/lability, dysphoria, delusions, hallucinations, anxiety, agitation/aggression, euphoria, disinhibition and aberrant motor activity. Moreover, the NPI includes apathy and depression items, which can help clinicians distinguish apathy from depression. The Apathy Inventory is an instrument that generates scores for emotional blunting, lack of initiation and lack of interest, in addition to a global apathy score (Robert et al., 2002). It was validated in AD, mild cognitive impairment and Parkinson’s disease (PD). Strauss and Sperry (2002) developed the Dementia Apathy Interview and Rating to assess dementia related changes in motivation, emotional responsiveness and engagement. It is a 16-item structured interview with the primary caregiver. Each interview question consists of © 2014 Lippincott Williams & Wilkins
two parts. First, the interviewer asks how often a specific behavior was observed over the past month. Second, caregivers are asked whether behavior questioned in the item had changed from the time prior to the memory loss. Starkstein et al. (2005) published the validity and reliability of the Structured Clinical Interview for Apathy. This instrument includes questions assessing the domains of lack of motivation relative to the individual’s previous level of functioning, lack of effort to perform every day activities, dependency on others to structure activities, lack of interest in learning new things or in new experiences, lack of concern about one’s personal problems, unchanging or flat affect, and lack of emotional response to positive or negative personal events.
Apathy and Dementia Subtypes: Results BPSD is the term used to describe a heterogeneous range of psychological reactions, psychiatric symptoms and behaviors occurring in people with dementia of any etiology (Finkel and Burns, 2000). Although memory and other cognitive impairments are considered the hallmark features of most dementia, BPSD occur in the majority of such patients and, between these symptoms, apathy is common in AD and in other dementing illnesses, and may occur in patients with mild cognitive impairment. Cognitive deficits are not sufficient to produce apathy, given that in some studies about half of the individuals with moderate or severe dementia did not suffer from apathy (Starkstein et al., 2001). Whether the syndrome of apathy associated with overt dementia has a different phenomenology than the syndrome of apathy in other neurological disorders (eg, stroke, traumatic brain injury, Parkinson’s disease or frontal lobe lesions) or psychiatric disorders (eg, depression or schizophrenia) has not been examined. We try to provide insights into the structure of the aforementioned behavioral disturbances in different types of dementia.
AD Apathy appears to be the most common behavioral symptom in AD, occurring with a reported frequency range from 19% to 92% of patients (Starkstein et al., 2006; Mega et al., 1996). Apathetic patients are more impaired in their ability to perform basic activities of daily living (ADL) than their cognitive status would suggest (Freels et al., 1992; Devanand et al., 1992), and their caregivers report significantly higher levels of distress as compared to AD patients without apathy (Landes et al., 2001). Apathy appears early in the course of the disease (Piccininni et al., 2005), tends to persist (Hart et al., 2003), is associated with longer illness duration (Devanand et al., 1992), and increases with dementia severity (Turró-Garriga et al., 2009; Gilley et al., 2004 ). Not all researchers agree with this last two statements: some studies tend to www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
719
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
deny systematic relationship between apathy and progressive cognitive impairment (Ott et al., 1996), or increased age (Levy et al., 1998). It was emphasized that apathy is associated with increasing parkinsonism (Starkstein et al., 2009), which can be a poor prognostic factor of AD. Tagariello et al.(2009) suggested that apathy may be a behavioral marker of a more severe type of AD, by characterizing more severe behavioral problems than their cognitive status would suggest. According to Ott et al. (1996) apathetic patients will need more aggressive behavioral management because apathy has been found to be highly related to other problem behaviors. Apathy without symptoms of depressive affect is a separate construct and is associated with an increased risk of progression from MCI to dementia; symptoms of apathy in the context of symptoms of depressive affect or symptoms of depressive affect alone do not increase this risk (Richard et al., 2012). Since AD patients have been reported to underrate their own cognitive deficits and behavioral, Starkstein and colleagues (2001) studied an interesting association between apathy and less awareness of behavioral and cognitive changes. Their finding demonstrated that AD patients with apathy have only partial awareness of their cognitive and behavioral changes and may provide unreliable answers. Research shows apathy in AD to be strongly associated with neuropathology in areas that are components of the anterior cingulate cortex and orbitofrontal cortex. Single-photon emission tomography (SPECT) (Benoit et al., 2002), and positron emission tomography (PET) (Marshall et al., 2007) studies confirmed these findings showing that reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex may be associated with reduced activity in the medial thalamus. A crucial function of the anterior cingulate cortex relates to the initiation and motivational drivers for goal directed activities, particularly when these are effortful, and damage to this cortical structure would likely, therefore, lead to a degree of behavioral and cognitive inertia (Allman et al., 2001).Atrophy of elements of the limbic circuit, including the cingulate gyrus, together with the more prominent atrophy in mediotemporal structures, is observed early in AD (Bruen et al., 2008). The association of apathy with atrophy in these regions is in accord with the temporal coincidence between the early appearance of this symptom and the first stages of regional neuropathology in AD (Tekin et al., 2001). Holthoff et al. (2005) suggest that in early Alzheimer’s disease it is possible to first detect functional deficits in the orbitofrontal areas, since left orbitofrontal structures have revealed hypometabolism in AD patients with apathy in comparison with patients without this syndrome: these authors explain that these brain regions represent a convergence zone for exteroceptive sensory inputs from association cortices and interoceptive inputs from limbic structures linked to emotional processing and cognition.
FTD FTD is the term now preferred over Picks disease to describe the spectrum of non-Alzheimers dementias characterized by focal atrophy of the frontal and anterior temporal regions of the brain. This spectrum of dementia can present in a variety of phenotypes. Clinical variants have arisen: a behavioral variant of frontotemporal dementia (bvFTD) with changes in personality and behavioral problems, and temporal variants with language problems. Apathy is the most common behavioral symptom of bvFTD, with reported prevalence ranging from 62 to 89% of patients (Mendez et al., 2008). As opposed to prior work proposing that apathy and disinhibition in FTD patients are mutually exclusive (Snowden et al., 2001), Chow et colleagues (2009) indicated that apathy is not a benign behavioral disturbance in dementia: when present, it is more likely for a patient to also manifest behaviors that are difficult to manage, whether impulsivity, socially embarrassing behaviors or irritability, lability, and resistance to care. Eslinger et al. (2012) extended other findings (Boone et al., 2003) that reported that the increased negative symptoms detected in FTD were inversely correlated 720
www.jonmd.com
with executive functions and add the new findings that apathy is also inversely correlated with social cognitive measures of theory of mind and empathy in bvFTD cases. Patients suffering from bvFTD exhibit not only significant social cognitive, emotional empathic, and motivational alterations, but also the loss of self-awareness of such dramatic changes, which is a key domain for adaptive social executive functions (Eslinger et al., 1995). Voxel-based morphometry revealed that apathy in bvFTD is related to prominent atrophy in the right caudate (including the ventral striatum), the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region (Eslinger et al., 2012). Massimo and collaborators (2009) performed a study in which identified individual patients with a relatively selective disorder of apathy, i.e., patients with minimal behavioral abnormalities in other domains, showed atrophy in the dorsal anterior cingulate cortex and right dorsolateral prefrontal cortex (dlPFC) regions. Functional MRI studies implicate the dlPFC in attentional and organizational aspects of social functioning (Moll et al., 2005).
HD HD is an inherited neurodegenerative disorder resulting from an expanded trinucleotide cytosine-adenine-guanine coding for the mutant protein huntingtin on the short arm of chromosome 4 (4p16.3) (Walker, 2007), characterized by a combination of motor, cognitive and psychiatric symptoms progressing eventually to a state of severe hypokinesia and dementia. Apathy has received more attention in the disease in recent years: in three original studies, prevalences of apathy in HD patients varied from 34% to 76% (Kulisevsky et al., 2001; Paulsen et al., 2001; Anderson et al., 2001). Apathy and depression are independent entities with apathy being more prevalent in HD patients (Marques and Januário, 2012). It was found that apathy is linked to other clinical characteristics such as cognitive deterioration and functional decline, whereas depression was not (Naarding et al., 2009). In early HD patients, the presence of apathy is associated with more severe deficits of attention, executive function and episodic memory (Baudic et al., 2006). It becomes more severe with advancing disease (Naarding et al., 2009). Apathy causes a great burden of disease and distress in caregivers, also after adjusting for the presence of motor and cognitive deficits (Hamilton et al., 2003). Some researchers (van Duijn et al., 2010) supposed that apathy may be a sign of disease progression in HD, including progressive motor and cognitive impairments, and worse global functioning, but longitudinal studies are needed to investigate precise relationships
PDD Idiopathic PD is one of the most common neurodegenerative disorders, and it has become increasingly apparent that patients with PD can have impairment of certain cognitive functions and develop dementia. PDD has been increasingly better recognized, probably because patients with PD survive for longer than before thanks to modern treatment. The proto-typical PDD has characteristic clinical features, which can be best summarized as a dysexecutive syndrome, with prominent impairment of attention, visual–spatial dysfunction, moderately impaired memory and accompanying behavioural symptoms such as apathy. According to Leroi et al. (2012), apathy is closely linked to cognitive impairment and may even be a harbinger of conversion to dementia, a finding that has previously been observed. For example, a longitudinal study of a PD cohort without dementia found that after a median period of 18 months, the proportion of those who converted to dementia was significantly higher in those with apathy (Dujardin et al., 2009). In PDD, apathy had been reported with a frequency of 23 to 24% (Aarsland et al., 2001a), although a more recent study analyzing a large sample of mild-moderate PDD patients reported a higher figure (54%) (Aarsland et al., 2007), compared to 17% in nondemented patients (Aarsland et al., 2001b). Dujardin et al. (2009) suggest © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
the possible involvement of a cholinergic mechanism in apathy. As stated above, bilateral basal ganglia lesions have been reported to induce a particular form of apathy, termed auto-activation deficit, principally defined as a loss of self-driven behavior that is reversible with external stimulation. Schmidt et al. (2008) proposed that bilateral striato-pallidal damage, observed in PD, specifically disconnects motor output from affective evaluation of potential rewards.
VaD Several vascular pathologies can lead to dementia. The term VaD is used for dementia syndromes likely to be the consequences of ischemic, hemorrhagic, or ipossic lesions of the brain. In patients with stroke or VaD, the frequency of apathy was found to vary between 15% and 93% (Fuh et al., 2005; Brodaty et al., 2005). Apathy is unrelated to the severity of dementia and cognitive dysfunction in VaD patients (Aharon-Peretz et al., 2000), but there is strong association between apathy and patients’ abilities to complete basic and instrumental activities of daily living (IADL) (Zawacki et al., 2002). Cortical lesions in VaD likewise commonly involve frontal regions and may induce changes in the neural networks that generate and control goal-directed actions, which are mostly represented within the prefrontal cortex connections to basal ganglia, thalamus and limbic system structures mediating motivational behaviour. (Fuh et al., 2005; Levy and Dubois, 2006). A study in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) demonstrated that CADASIL patients with apathy had a higher white-matter hyperintensities burden and more lacunes than patients without apathy (Reyes et al., 2009). Staekenborg et al. (2010) demonstrated that patients with small-vessel and large-vessel VaD show different profiles of symptoms, with especially more apathy in small-vessel VaD (prevalence 64%) than in large-vessel VaD (prevalence 54%). The highest prevalence for apathy, noted in this finding, followed by depressive symptoms, irritability and agitation/aggression confirms previous findings in populations of VaD patients (Caputo et al., 2008; Fuh et al., 2005).
Management Apathetic patients require more support, management, and resource utilization and place higher levels of burden on caregivers. They easily descend into a downward spiral of lack of activity, with those affected responding poorly to rehabilitation, due to absent motivation (Galynker et al., 1997). In light of its importance and difficult handling, various different pharmacological and nonpharmacological treatment strategies have been proposed, but in spite of the strong negative impact of apathy in dementia, treatment studies for this frequent behavioral condition are surprisingly few, and recognized guidelines for the management of apathy do not exist (Van Reekum et al., 2005). Brodaty and Burns (2012) performed a systematic review on nonpharmacological intervention studies with outcomes relevant to apathy in dementia. In their opinion, from the literature reviewed, the only intervention with sufficient quality studies, was Therapeutic Activities; this heterogeneous group includes stimulation, creative activities, cooking, Montessori methods, and behavioral elements, often individually tailored. Some positive results, although even less impressive, were reported for music, exercise, multisensory stimulation, pet therapy, and special care units. According to Ferrero-Arias et al. (2011), a structured occupational therapeutic intervention for even a short period of time improves apathy in dementia patients and is much more beneficial than free use of the same amount of time by the patients in a nonstructured environment, but the effect is only useful in patient with mild or moderate dementia, and the effect in patients with severe apathy is even less important. The pharmacological strategies have produced varying results. One problem is that apathy is a secondary outcome rather than a primary outcome measure in most studies. Lee and coworkers (2003) have © 2014 Lippincott Williams & Wilkins
Apathy and Dementia
reviewed the pharmacological treatment: psychostimulants (e.g., methylphenidate, dextroamphetamine -Plenger et al., 1996; Herrmann et al., 2008-) and dopaminergicagonists (e.g., pergolide and bromocriptine) may modestly improve arousal and speed of information processing, reduce distractibility, and improve some aspects of motivation and executive function (Zafonte et al., 2001). Primarily used for treating cognitive symptoms in dementia, more recent findings indicate that acetylcholinesterase inhibitors (AchIs), donepezil, rivastigmine, galantamine, have beneficial effects on noncognitive symptoms such as apathy (Weiner et al., 2000; Holmes et al., 2004; Tanaka et al., 2004; Rockwood et al., 2007; Gauthier et al., 2006; Potkin et al., 2006; Aupperle et al., 2004; McKeith et al., 2000; Erkinjuntti et al., 2002; Cummings et al., 2004). Overall, there is Level II (15 studies supportive versus three showing no benefit) plus a preponderance of various Level III evidences (11 positive and 7 negative studies) that AChIs are beneficial in the treatment for apathy. There is no clear indication that any one AChI is superior (Berman et al., 2012). However, the majority of these studies were poorly run and the benefits observed mild, or of uncertain clinical relevance, therefore they need to be replicated in larger, adequately powered clinical trials. There is no evidence of benefit with rivastigmine in apathy patients with FTD (Moretti et al., 2004). Memantine is a specific N-methyl-D-aspartate receptor antagonist. Two studies of memantine alone (Winblad and Poritis, 1999; Pantev et al., 1993) were randomized, and double-blind, placebo-controlled trials indicated significant improvements in apathy levels for those in the treatment group. A small open-label study of memantine in patients with FTD showed no improvement in apathy (Diehl-Schmid et al., 2008). Corcoran et al. (2004) reported the case of three subjects with amotivational syndromes of varying aetiology, who were unresponsive to conventional treatments, that responded to treatment with bupropion. It a is a 5-HT1A antagonist that, in addition, increases dopamine levels in the ventral tegmental area projecting to frontal cortex by blocking noradrenaline transporters in the frontal cortex. This effect has evoked interest, as this pathway has been implicated in reward mechanisms and motivation, which seem to be central to apathy. There is good evidence that antidepressants do not significantly improve apathy in people with dementia (Berman et al., 2012). Moreover, selective serotonin reuptake inhibitor (SSRIs) have been associated with indifference, both in behavioral terms as well as emotional terms (Sansone and Sansone, 2010; Sato and Asada, 2011). There is evidence demonstrating that atypical antipsychotics may have some beneficial effect, although it is not possible to differentiate improvement in apathy directly from the medication versus as a secondary phenomenon to improvement in neuropsychiatric comorbidity (Berman et al., 2012).
CONCLUSIONS Apathy is an under-recognized syndrome that affects over 70% of individuals with dementia and is associated with functional impairment and caregiver distress at all levels of disease severity. It reflects a syndrome of primary motivational loss as manifested by reduced goal oriented behaviors, whereas depression reflects a primary mood disturbance. Research into apathy has been plagued by variability in definitions and terminology and by a lack of consensus on diagnostic criteria. The mechanism of apathy in neuropsychiatric disorders remains unknown, but studies suggest that disruption of frontal cortical-basal ganglia circuits and executive dysfunction may both play an important role. Several rating scales have been performed to measure severity of apathy, but proper validation is limited by the lack of standard criteria. There are few randomized controlled trials of pharmacological or non-pharmacological treatments for apathy in dementia. On the other hand, there is a growing literature consisting of case reports and small series of patients that were treated for apathy with a variety of psychoactive agents. A combination of pharmacologic and psychosocial treatment would be ideally placed to give a good effect size in intervention trials. Greater understanding of apathy will improve www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
721
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
the identification, intervention, and treatment of this ubiquitous and pernicious syndrome.
DISCLOSURE The authors declare no conflict of interest. REFERENCES Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, Cummings JL (2007) Neuropsychiatric symptoms in patients with PD and dementia: frequency, profile and associated caregiver stress. J Neurol Neurosurg Psychiatry. 78:36–42. Aarsland D, Cummings JL, Larsen JP (2001a) Neuropsychiatric differences between Parkinson’s disease with dementia and Alzheimer’s disease. Int J Geriatr Psychiatry. 16:184–191. Aarsland D, Litvan I, Larsen JP (2001b) Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 13:42–49. Aharon-Peretz J, Kliot D, Tomer R (2000) Behavioral differences between white matter lacunar dementia and Alzheimer’s disease: a comparison on the Neuropsychiatric Inventory. Dement Geriatr Cogn Disord. 11:294–298. Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P (2001) The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci. 935:107–117. American Psychiatric Association (Ed) (2013) Diagnostic and Statistical Manual of Mental Disorders, DSM-5 ed. Washington, DC: American Psychiatric Association. Anderson KE, Louis ED, Stern Y, Marder KS (2001) Cognitive correlates of obsessive and compulsive symptoms in Huntington’s disease. Am J Psychiatry. 158: 799–801. Aupperle PM, Koumaras B, Chen M, Rabinowicz A, Mirski D (2004) Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer’s disease: results of a 52-week open-label study. Currm Med Res Opin. 20:1605–1612. Baudic S, Maison P, Dolbeau G, Boissé MF, Bartolomeo P, Dalla Barba G, Traykov L, Bachoud-Lévi AC (2006) Cognitive impairment related to apathy in early Huntington’s disease. Dement Geriatr Cogn Disord. 21:316–321. Benoit M, Koulibaly PM, Migneco O, Darcourt J, Pringuey DJ, Robert PH (2002) Brain perfusion in Alzheimer’s disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Psychiatry Res. 114:103–111. Berman K, Brodaty H, Withall A, Seeher K (2012) Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 20:104–122. Boone KB, Miller BL, Swartz R, Lu P, Lee A (2003) Relationship between positive and negative symptoms and neuropsychological scores in frontotemporal dementia and Alzheimer’s disease. J Int Neuropsychol Soc. 9:698–709.
Corcoran C, Wong ML, O’Keane V (2004) Bupropion in the management of apathy. J Psychopharmacol. 18:133–135. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994) The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 44:2308–2314. Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W (2004) Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry. 161:532–538. Cutting J (1995) Descriptive psychopathology. In Hirsch SR, Weinberger DR (Eds), Schizophrenia (pp 15–27). Oxford: Blackwell Science. Devanand DP, Brockington CD, Moody BJ, Brown RP, Mayeux R, Endicott J, Sackeim HA (1992) Behavioral syndromes in Azheimer’s disease. Int Psychogeriatr. 4(suppl 2):161–184. Diehl-Schmid J, Förstl H, Perneczky R, Pohl C, Kurz A (2008) A 6-month, openlabel study of memantine in patients with frontotemporal dementia. Int J Geriatr Psychiatry. 23:754–759. Dujardin K, Sockeel P, Delliaux M, Destée A, Defebvre L (2009) Apathy may herald cognitive decline and dementia in Parkinson’s disease. Movement Disorders 24:2391–2397. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 359: 1283–1290. Eslinger PJ, Grattan LM, Geder LM (1995) Impact of frontal lobe lesions on rehabilitation and recovery from acute brain injury. NeuroRehabilitation. 5:161–182. Eslinger PJ, Moore P, Antani S, Anderson C, Grossman M (2012) Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. Behav Neurol. 25:127–136. Ferrero-Arias J, Goñi-Imízcoz M, González-Bernal J, Lara-Ortega F, da SilvaGonzález A, Díez-Lopez M (2011) The efficacy of nonpharmacological treatment for dementia-related apathy. Alzheimer Dis Assoc Disord. 25:213–219. Finkel SI, Burns A (2000) Introduction. Behavioral and psychological symptoms of dementia (BPSD): a clinical and research update. Int Psychogeriatr. 12(suppl 1):9–12. Freels S, Cohen D, Eisdorfer C, Paveza G, Gorelick P, Luchins DJ, Hirschman R, Ashford JW, Levy P, Semla T (1992) Functional status and clinical findings in patients with Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 47: M177–M182. Fuh JL, Wang SJ, Cummings JL (2005) Neuropsychiatric profiles in patients with Alzheimer’s disease and vascular dementia. J Neurol Neurosurg Psychiatry. 276:1337–1341. Galynker I, Prikhojan A, Phillips E, Focseneanu M, Ieronimo C, Rosenthal R (1997) Negative symptoms in stroke patients and length of hospital stay. J Nerv Ment Dis. 185:616–621.
Brodaty H, Burns K (2012) Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry. 20:549–564.
Gauthier S, Juby A, Morelli L, Rehel B, Schecter R; EXTEND Investigators (2006) A large, naturalistic, community-based study of rivastigmine in mildto-moderate AD: the EXTEND Study. Curr Med Res Opin. 22:2251–2265.
Brodaty H, Sachdev PS, Withall A, Altendorf A, Valenzuela MJ, Lorentz L (2005 ) Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke: the Sydney Stroke Study. Psychol Med. 35:1707–1716.
Gilley DW, Wilson RS, Bienias JL, Bennett DA, Evans DA (2004) Predictors of depressive symptoms in persons with Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci. 59:P75–P83.
Bruen PD, McGeown WJ, Shanks MF, Venneri A (2008) Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain. 131:2455–2463.
Hamilton JM, Salmon DP, Corey-Bloom J, Gamst A, Paulsen JS, Jerkins S, Jacobson MW, Peavy G (2003) Behavioral abnormalities contribute to functional decline in Huntington’s disease. J Neurol Neurosurg Psychiatry. 74:120–122.
Caputo M, Monastero R, Mariani E, Santucci A, Mangialasche F, Camarda R, Senin U, Mecocci P (2008) Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types. Acta Psychiatr Scand. 117:455e64.
Hart DJ, Craig D, Compton SA, Critchlow S, Kerrigan BM, McIlroy SP, Passmore AP (2003) A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer’s disease. Int J Geriatr Psychiatry. 18:1037–1042.
Chow TW, Binns MA, Cummings JL, Lam I, Black SE, Miller BL, Freedman M, Stuss DT, van Reekum R (2009) Apathy symptom profile and behavioral associations in frontotemporal dementia vs dementia of Alzheimer type. Arch Neurol. 66:888–893.
Herrmann N, Rothenburg LS, Black SE, Ryan M, Liu BA, Busto UE, Lanctôt KL (2008) Methylphenidate for the Treatment of Apathy in Alzheimer Disease. Prediction of Response Using Dextroamphetamine Challenge. J Clin Psychopharmacol. 28:296–301.
Colling KB (1999) Passive behaviors in dementia. Clinical application of the needdriven dementia-compromised behavior model. J Gerontol Nurs. 25:27–32.
Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, PanditaGunawardena ND, Hogg F, Clare C, Damms J (2004) The efficacy of donepezil in
722
www.jonmd.com
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 63:214–219. Holthoff VA, Beuthien-Baumann B, Kalbe E, Lüdecke S, Lenz O, Zündorf G, Spirling S, Schierz K, Winiecki P, Sorbi S, Herholz K (2005) Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression. Biol Psychiatry. 57:412–421. Kulisevsky J, Litvan I, Berthier ML, Pascual-Sedano B, Paulsen JS, Cummings JL (2001) Neuropsychiatric assessment of Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders. Mov Disorders. 16:1098–1104. Landes AM, Sperry SD, Strauss ME, Geldmacher DS (2001). Apathy in Alzheimer’s disease. J Am Geriatr Soc. 49:1700–1707. Lee HB, Lyketsos CG, Rao V (2003) Pharmacological management of the psychiatric aspects of traumatic brain injury. Int Rev Psychiatry. 15:359–370. Leroi I, Pantula H, McDonald K, Harbishettar V (2012) Neuropsychiatric symptoms in Parkinson’s disease with mild cognitive impairment and dementia. Parkinson’s Disease. 2012:308097. Levy ML, Cummings JL, Fairbanks LA, Masterman D, Miller BL, Craig AH, Paulsen JS, Litvan I (1998) Apathy is not depression. J Neuropsychiatry Clin Neurosci. 10:314–319. Levy R (2012) Apathy: a pathology of goal-directed behaviour: a new concept of the clinic and pathophysiology of apathy. Rev Neurol. 168:585–589. Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortexbasal ganglia circuits. Cereb Cortex. 16:916–928. Marin RS (1990) Differential diagnosis and classification of apathy. Am J Psychiatry. 147:22–30. Marin RS (1991) Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 3:243–254. Marques FJ, Januário C (2012) J17Apathy prevalence and clinical correlations in Huntington’s disease. J Neurol Neurosurg Psychiatry. 83:A41. Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL (2007) Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Arch Neurol. 64:1015–1020. Massimo L, Powers C, Moore P, Vesely L, Avants B, Gee J, Libon DJ, Grossman M (2009) Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord. 27:96–104. McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK (2000) Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int J Geriatr Psychiatry. 15:387–392. Mega MS, Cummings JL (1994) Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci. 6:358–370. Mega MS, Cummings JL, Fiorello T, Gornbein J (1996) The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 46:130–135. Mendez MF, Lauterbach EC, Sampson SM; ANPA Committee on Research (2008) An evidence-based review of the psychopathology of frontotemporal dementia: a report of the ANPA Committee on Research. J Neuropsychiatry Clin Neurosci. 20:130–149. Moll J, Zahn R, Oliveira-Souza R, Krueger F, Grafman JH (2005) The neural basis of human moral cognition. Nat Rev Neurosci. 6:799–809. Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A (2004) Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging. 21:931–937.
Apathy and Dementia
Pantev M, Ritter R, Gortelmeyer R (1993) Clinical and behavioural eveluation in long-term care patients with mild to modertae dementia under memantine treatment. Zeitschrt fur Gerontopsychologie Und-Psychiatrie. 6:S103–S117. Paulsen JS, Ready RE, Hamilton JM, Mega M, Cummings J (2001) Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry. 71:310–314. Piccininni M, Di Carlo A, Baldereschi M, Zaccara G, Inzitari D (2005) Behavioral and psychological symptoms in Alzheimer’s disease: frequency and relationship with duration and severity of the disease. Dement Geriatr Cogn Disord. 19:276–281. Plenger PM, Dixon CE, Castillo RM, Frankowski RF, Yablon SA, Levin HS (1996) Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil. 1996 77:536–540. Potkin SG, Alva G, Gunay I, Koumaras B, Chen M, Mirski D (2006) A pilot study evaluating the efficacy and safety of rivastigmine in patients with mixed dementia. Drugs Aging. 23:241–249. Reyes S, Viswanathan A, Godin O, Dufouil C, Benisty S, Hernandez K, Kurtz A, Jouvent E, O’Sullivan M, Czernecki V, Bousser MG, Dichgans M, Chabriat H (2009) Apathy: a major symptom in CADASIL. Neurology. 72:905–910. Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart SA, Moll van Charante EP, van Gool WA (2012) Alzheimer’s Disease Neuroimaging Initiative. Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer’s disease in non-depressed subjects. Dement Geriatr Cogn Disord. 33:204–209. Robert P, Onyike CU, Leentjens AF, Dujardin K, Aalten P, Starkstein S, Verhey FR, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, Gauthier S, Grossberg G, Vellas B, Byrne J (2009) Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. European Psychiaty. 2009;24:98–104. Robert PH, Clairet S, Benoit M, Koutaich J, Bertogliati C, Tible O, Caci H, Borg M, Brocker P, Bedoucha P (2002) The apathy inventory: assessment of apathy and awareness in Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment. Int J Geriatr Psychiatry. 17:1099–1105. Rockwood K, Black S, Bedard MA, Tran T, Lussier I; TOPS Study Investigators (2007) Specific symptomatic changes following donepezil treatment of Alzheimer’s disease: a multicentre, primary care, open label study. Int J Geriatr Psychiatry. 22:312–319. Sansone RA, Sansone LA (2010) SSRI-Induced Indifference. Psychiatry (Edgmont). 7:14–18. Sato S, Asada T (2011) Sertraline-induced apathy syndrome. J Neuropsychiatry Clin Neurosci. 23:E19. Schmidt L, d’Arc BF, Lafargue G, Galanaud D, Czernecki V, Grabli D, Schüpbach M, Hartmann A, Lévy R, Dubois B, Pessiglione M (2008) Disconnecting force from money: effects of basal ganglia damage on incentive motivation. Brain. 131:1303–1310. Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D (2001) Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70:323– 332. Staekenborg SS, Su T, van Straaten EC, Lane R, Scheltens P, Barkhof F, van der Flier WM. Behavioural and psychological symptoms in vascular dementia; differences between small- and large-vessel disease (2010). J Neurol Neurosurg Psychiatry. 81:547–551 Starkstein SE (2000) Apathy and withdrawal. Int Psychogeriatr. 12(suppl 1): 135–138.
Moretti R, Torre P, Antonello RM, Cazzato G, Bava A (2002) Depression and Alzheimer’s disease: symptom or comorbidity? Am J Alzheimer’s Dis Other Dement. 17:338–344.
Starkstein SE, Ingram L, Garau ML, Mizrahi R (2005) On the overlap between apathy and depression in dementia. J Neurol Neurosurg Psychiatry. 2005 76: 1070–1074.
Mortby ME, Maercker A, Forstmeier S (2012) Apathy: a separate syndrome from depression in dementia? A critical review. Aging Clin Exp Res. 24: 305–316.
Starkstein SE, Jorge R, Mizrahi R, Robinson RG (2006) A prospective longitudinal study of apathy in Alzheimer’s disease J Neurol Neurosurg Psychiatry. 2006 77:8–11.
Naarding P, Janzing JG, Eling P, van der Werf S, Kremer B (2009) Apathy is not depression in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 21: 266–270. Ott BR, Noto RB, Fogel BS (1996) Apathy and loss of insight in Alzheimer’s disease: A SPECT imaging study. J Neuropsychiatry Clin Neurosci. 8:41–46.
© 2014 Lippincott Williams & Wilkins
Starkstein SE, Merello M, Brockman S, Bruce D, Petracca G, Power BD (2009) Apathy predicts more severe parkinsonism in Alzheimer’s disease. Am J Geriatr Psychiatry. 17:291–298.
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
723
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
Starkstein SE, Petracca G, Chemerinski E, Kremer J (2001) Syndromic validity of apathy in Alzheimer’s disease. Am J Psychiatry. 158:872–877.
Van Reekum R, Stuss DT, Ostrander L (2005) Apathy: why care? J Neuropsychiatry Clin Neurosci. 17:7–19.
Strauss ME, Sperry SD (2002) An informant-based assessment of apathy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol. 15:176–183.
Walker FO (2007) Huntington’s disease. Lancet. 369:218–228.
Tagariello P, Girardi P, Amore M (2009) Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch Gerontol Geriatr. 49:246–249.
Weiner MF, Martin-Cook K, Foster BM, Saine K, Fontaine CS, Svetlik DA (2000) Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 61:487–492.
Tanaka M, Namiki C, Thuy DH, Yoshida H, Kawasaki K, Hashikawa K, Fukuyama H, Kita T (2004) Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer’s disease. J Neurol Sci. 225:135–141.
Winblad B, Poritis N (1999) Memantine in severe dementia: results of the 9 M-Best Study (Benefit and efficacy in severely demented patients during treatmentwith memantine). Int J Geriatr Psychiatry. 14:135–146.
Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, Cummings JL (2001) Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol. 49:355–361.
World Health Organisation (Ed) (1992) The ICD-10 classification of mental and behavioural disorders. Clinical description and diagnostic guidelines. Geneva.
Turró-Garriga O, López-Pousa S, Vilalta-Franch J, Turón-Estrada A, Pericot-Nierga I, Lozano-Gallego M, Hernández- Ferràndiz M, Soler-Cors O, Planas-Pujol X, Monserrat-Vila S, Garre-Olmo J (2009) A longitudinal study of apathy in patients with Alzheimer’s disease. Rev Neurol. 48:7–13.
Zafonte RD, Lexell J, Cullen N (2001) Possible applications for dopaminergic agents following traumatic brain injury: part 2. J Head Trauma Rehabil. 16:112–116.
van Duijn E, Reedeker N, Giltay EJ, Roos RA, van der Mast RC (2010) Correlates of apathy in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 22:287–294.
724
www.jonmd.com
Zawacki TM, Grace J, Paul R, Moser DJ, Ott BR, Gordon N, Cohen RA (2002) Behavioral problems as predictors of functional abilities of vascular dementia patients. J Neuropsychiatry Clin Neuosci. 14:296–302.
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Apathy and Dementia. Nosology, Assessment and Management Gabriele Cipriani, MD, Claudio Lucetti, MD, Sabrina Danti, PsyD, and Angelo Nuti, MD Abstract: Apathy, characterized by lack of motivation and loss of initiative, is a non-cognitive symptom that affects a high proportion, but not all, of patients with all forms of dementia. To explore the phenomenon of apathy in people with dementia, we searched the PubMed and Google Scholar electronic databases for original research and review articles on apathetic behaviors in patients with dementia using the search terms “apathy, behavioral and psychological symptoms, dementia, Alzheimer’s disease, Frontotemporal dementia, Dementia associated with Parkinson’s disease, Huntington’s disease, Vascular dementia”. Some nosological aspects, neurobiological basis, and assessment of, as well as, potential benefits of non-pharmacologic and pharmacologic interventions for apathy in dementia are discussed. Greater understanding of apathy will improve the identification, intervention, and treatment of this ubiquitous and pernicious syndrome. Key Words: Apathy, behavioral and psychological symptoms, dementia, Alzheimer’s disease, frontotemporal dementia, dementia associated with Parkinson’s disease, Huntington’s disease, vascular dementia (J Nerv Ment Dis 2014;202: 718–724)
T
he word apathy stems from the Greek apathya derived from apathes, “a” (without) plus “pathos” (passion, feeling), and was originally coined by the Greek Stoic philosophers more than 2000 years ago to refer to the condition of being free from emotions and passions. In the conception of the Stoic philosophers only a state of true apathy would release the human mind from emotional constraints (Starkstein et al., 2005). The semantic confusion related to shifts in meaning is one of the problems that have confounded the study of apathy; even today, confusion remains regarding the essential features of apathy and its boundaries with constructs such as aboulia, anhedonia, depression and learned helplessness (Robert et al., 2009). Apathy is common across various neurological and psychiatric disorders and it was also described in association with other medical conditions. There is wide acknowledgement that it is an important behavioral symptom in Alzheimer’s disease (AD) and other dementias.
METHODS Medline and Google Scholar searches were conducted for relevant articles, chapters, and books published since 1980. Search terms used included apathy, behavioral and psychological symptoms (BPSD), dementia, AD, Frontotemporal dementia, Dementia associated with Parkinson disease (PDD), Huntington’s disease (HD), Vascular dementia (VaD). Publications found through this indexed search were reviewed for further relevant references.
Some Nosological Aspects of Apathy Evidence does not provide a clear view of the nosological position of apathy. The ambiguity of the evidence may be attributed in large part to a lack of clarity in definition and etiology, clinical criteria and assessment
Neurology Unit, Hospital of Viareggio, Lido di Camaiore, Lucca (Lu), Italy. Send reprint requests to Gabriele Cipriani, MD, Hospital of Viareggio, via Aurelia, 55043, Lido di Camaiore, Lucca (Lu), Italy. E-mail: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0022-3018/14/20210–0718 DOI: 10.1097/NMD.0000000000000190
718
www.jonmd.com
overlap (Mortby et al., 2012). The International Classification of Disease (ICD)-10 (WHO, 1992) make no mention of apathy and Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 (APA, 2013) uses the term to refer to a subtype of personality change due to a medical general condition, but not specific definition is provided. The definition of this behavioral symptom has been matter of debate. Cutting (1995) argued that, although regarded as the psychopathological counterpart of the motivational component of emotion, apathy must be better regarded as a manifestation of impaired will. Marin (1991) defined apathy as “a lack of motivation not attributable to diminished level of conscience, cognitive impairment or emotional distress”. Motivation denotes that aspect of behavior concerned with the initiation, direction, and intensity of goal-directed behavior (Marin, 1990). This construct was slightly modified and operationalized into applicable diagnostic criteria by Starkstein (2000) (Table 1). More recently, a task force including experts from Europe, Australia and North America has developed new diagnostic criteria for apathy (Robert et al., 2009). In them, it is defined as a disorder of motivation that persists over time and should meet all the following requirements. Firstly, the core feature of apathy, i.e. diminished motivation, must be present for at least 4 weeks; secondly, impairment in at least 2 among the three dimensions of apathy (i.e. reduced goaldirected behavior, goal-directed cognitive activity and emotions) must also be present; thirdly, there should be identifiable functional impairments attributable to apathy. Finally, exclusion criteria are specified to exclude symptoms and conditions mimicking apathy. In a comprehensive review on the mechanism of apathy, Levy and Dubois (2006) emphasized that apathy should not be defined as “lack of motivation” (considered a obscure psychological concept), “but as an observable behavioural syndrome consisting in a quantitative reduction of voluntary (or goal-directed) behaviours”. One of the main diagnostic dilemmas is how to separate apathy from depression. The differentiation is difficult because of substantial overlap in key symptoms sharing manifestations, such as a lack of interest, anergia, psychomotor slowing, and fatigue. In fact, it is often misinterpreted, with carers describing it as a depressive state even though a lack of sadness, desperation, crying, and a depressive mood distinguish apathy from depression. According to Levy et al. (1998) the typical apathetic patient usually lacks the negative thoughts, emotional distress, sadness, vegetative symptoms and somatic complaints frequently observed in mood disorders.
Neurobiological Basis of Apathy The neurobiology of apathy is not well understood, and we do not know whether it is different in different disorders. It is considered to result from lesions in brain areas that mediate drive and motivation and that participate in the elaboration of plans for actions, and it is associated with both neuropathologic and neurochemical alterations to fronto-subcortical circuits (Moretti et al., 2002; Mega and Cummings, 1994). Because there are several anatomical-functional prefrontalbasal ganglia circuits, the underlying mechanisms responsible for apathy may differ according to which prefrontal-basal ganglia circuit is affect. Lesions or dysfunctions of the limbic territories of the frontal lobes (the orbital-mesial prefrontal cortex) and the basal ganglia (e.g., the ventral striatum) lead to apathy through difficulties to provide the affective value of a given behavioral context; lesions or dysfunctions of the associative (“cognitive”) territories of the frontal lobes (the dorsal
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Apathy and Dementia
TABLE 1. Diagnostic Criteria for Apathy (Starkstein, 2000) A Lack of motivation relative to the patient’s previous level of functioning, or the standards of his or her age and culture, as indicated either by subjective account or observation by others. B Presence for at least 6 weeks, during most of the day, of at least 1 symptom belonging to each of the following three domains: 1. Diminished goal-director behavior • Lack of effort or energy to perform everyday activities • Dependency on prompts from others to structure everyday activities 2. Diminished goal-directed cognition • Lack of interest in learning new things, or in new experience • Lack of concern about one’s personal problems 3. Diminished concomitants of goal-directed behavior • Unchanging or flat affect • Lack of emotional responsivity to positive or negative events C The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D The symptoms are not due diminished level of consciousness or the direct physiological effects of a substance.
prefrontal cortex) and the basal ganglia (e.g., the dorsal caudate) contribute to apathy via a “cognitive inertia”, an inability to generate or activate strategies required to successfully complete a given program of actions (Levy, 2012). The most severe forms of apathy is characterized by difficulties in self-initiating actions or thoughts, contrasting with relatively spared, externally driven response. This pattern is the so called “auto-activation deficit”, and consists in a loss of spontaneous activations that seems to affect both cognitive and emotional responses. It may be due to bilateral lesions in the prefrontal-basal ganglia circuits that can be explained either by the addition of lesions in the cognitive and limbic territories or by a more general and elementary impairment that mirrored the presumed normal functions of the prefrontal-basal ganglia circuits, that is to selectively amplified the behavior that one considers as the most adapted to one’s personal needs or environmental demands (Levy, 2012).
Assessment in Demented Patients Assessment of apathy in dementia is complicated by the need to distinguish between diminished behavior due to loss of motivation and loss of ability secondary to cognitive impairment, and by the overlap in symptoms between depression and apathy (Tagariello et al., 2009; Landes et al., 2001). Furthermore, the use of antipsychotic, antidepressant, and neuroleptic medications can induce side effects such as fatigue, lethargy, listlessness, and reduced response to stimuli, can initiate, maintain, or imitate apathetic behaviors (Colling, 1999). A number of instruments have been developed for assessing neuropsychiatric symptoms in individual with dementia. Some instruments were specifically designed to measure apathy, whereas others were designed to provide broader neuropsychiatric assessment. These include the Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) that is the most widely used multidimensional instrument for assessing neuropsychiatric functioning in patients with dementia. It is a valid and reliable instrument involving a caregiver interview designed to assess the presence and severity of 10 symptoms: apathy, irritability/lability, dysphoria, delusions, hallucinations, anxiety, agitation/aggression, euphoria, disinhibition and aberrant motor activity. Moreover, the NPI includes apathy and depression items, which can help clinicians distinguish apathy from depression. The Apathy Inventory is an instrument that generates scores for emotional blunting, lack of initiation and lack of interest, in addition to a global apathy score (Robert et al., 2002). It was validated in AD, mild cognitive impairment and Parkinson’s disease (PD). Strauss and Sperry (2002) developed the Dementia Apathy Interview and Rating to assess dementia related changes in motivation, emotional responsiveness and engagement. It is a 16-item structured interview with the primary caregiver. Each interview question consists of © 2014 Lippincott Williams & Wilkins
two parts. First, the interviewer asks how often a specific behavior was observed over the past month. Second, caregivers are asked whether behavior questioned in the item had changed from the time prior to the memory loss. Starkstein et al. (2005) published the validity and reliability of the Structured Clinical Interview for Apathy. This instrument includes questions assessing the domains of lack of motivation relative to the individual’s previous level of functioning, lack of effort to perform every day activities, dependency on others to structure activities, lack of interest in learning new things or in new experiences, lack of concern about one’s personal problems, unchanging or flat affect, and lack of emotional response to positive or negative personal events.
Apathy and Dementia Subtypes: Results BPSD is the term used to describe a heterogeneous range of psychological reactions, psychiatric symptoms and behaviors occurring in people with dementia of any etiology (Finkel and Burns, 2000). Although memory and other cognitive impairments are considered the hallmark features of most dementia, BPSD occur in the majority of such patients and, between these symptoms, apathy is common in AD and in other dementing illnesses, and may occur in patients with mild cognitive impairment. Cognitive deficits are not sufficient to produce apathy, given that in some studies about half of the individuals with moderate or severe dementia did not suffer from apathy (Starkstein et al., 2001). Whether the syndrome of apathy associated with overt dementia has a different phenomenology than the syndrome of apathy in other neurological disorders (eg, stroke, traumatic brain injury, Parkinson’s disease or frontal lobe lesions) or psychiatric disorders (eg, depression or schizophrenia) has not been examined. We try to provide insights into the structure of the aforementioned behavioral disturbances in different types of dementia.
AD Apathy appears to be the most common behavioral symptom in AD, occurring with a reported frequency range from 19% to 92% of patients (Starkstein et al., 2006; Mega et al., 1996). Apathetic patients are more impaired in their ability to perform basic activities of daily living (ADL) than their cognitive status would suggest (Freels et al., 1992; Devanand et al., 1992), and their caregivers report significantly higher levels of distress as compared to AD patients without apathy (Landes et al., 2001). Apathy appears early in the course of the disease (Piccininni et al., 2005), tends to persist (Hart et al., 2003), is associated with longer illness duration (Devanand et al., 1992), and increases with dementia severity (Turró-Garriga et al., 2009; Gilley et al., 2004 ). Not all researchers agree with this last two statements: some studies tend to www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
719
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
deny systematic relationship between apathy and progressive cognitive impairment (Ott et al., 1996), or increased age (Levy et al., 1998). It was emphasized that apathy is associated with increasing parkinsonism (Starkstein et al., 2009), which can be a poor prognostic factor of AD. Tagariello et al.(2009) suggested that apathy may be a behavioral marker of a more severe type of AD, by characterizing more severe behavioral problems than their cognitive status would suggest. According to Ott et al. (1996) apathetic patients will need more aggressive behavioral management because apathy has been found to be highly related to other problem behaviors. Apathy without symptoms of depressive affect is a separate construct and is associated with an increased risk of progression from MCI to dementia; symptoms of apathy in the context of symptoms of depressive affect or symptoms of depressive affect alone do not increase this risk (Richard et al., 2012). Since AD patients have been reported to underrate their own cognitive deficits and behavioral, Starkstein and colleagues (2001) studied an interesting association between apathy and less awareness of behavioral and cognitive changes. Their finding demonstrated that AD patients with apathy have only partial awareness of their cognitive and behavioral changes and may provide unreliable answers. Research shows apathy in AD to be strongly associated with neuropathology in areas that are components of the anterior cingulate cortex and orbitofrontal cortex. Single-photon emission tomography (SPECT) (Benoit et al., 2002), and positron emission tomography (PET) (Marshall et al., 2007) studies confirmed these findings showing that reduced metabolic activity in the bilateral anterior cingulate gyrus and medial orbitofrontal cortex may be associated with reduced activity in the medial thalamus. A crucial function of the anterior cingulate cortex relates to the initiation and motivational drivers for goal directed activities, particularly when these are effortful, and damage to this cortical structure would likely, therefore, lead to a degree of behavioral and cognitive inertia (Allman et al., 2001).Atrophy of elements of the limbic circuit, including the cingulate gyrus, together with the more prominent atrophy in mediotemporal structures, is observed early in AD (Bruen et al., 2008). The association of apathy with atrophy in these regions is in accord with the temporal coincidence between the early appearance of this symptom and the first stages of regional neuropathology in AD (Tekin et al., 2001). Holthoff et al. (2005) suggest that in early Alzheimer’s disease it is possible to first detect functional deficits in the orbitofrontal areas, since left orbitofrontal structures have revealed hypometabolism in AD patients with apathy in comparison with patients without this syndrome: these authors explain that these brain regions represent a convergence zone for exteroceptive sensory inputs from association cortices and interoceptive inputs from limbic structures linked to emotional processing and cognition.
FTD FTD is the term now preferred over Picks disease to describe the spectrum of non-Alzheimers dementias characterized by focal atrophy of the frontal and anterior temporal regions of the brain. This spectrum of dementia can present in a variety of phenotypes. Clinical variants have arisen: a behavioral variant of frontotemporal dementia (bvFTD) with changes in personality and behavioral problems, and temporal variants with language problems. Apathy is the most common behavioral symptom of bvFTD, with reported prevalence ranging from 62 to 89% of patients (Mendez et al., 2008). As opposed to prior work proposing that apathy and disinhibition in FTD patients are mutually exclusive (Snowden et al., 2001), Chow et colleagues (2009) indicated that apathy is not a benign behavioral disturbance in dementia: when present, it is more likely for a patient to also manifest behaviors that are difficult to manage, whether impulsivity, socially embarrassing behaviors or irritability, lability, and resistance to care. Eslinger et al. (2012) extended other findings (Boone et al., 2003) that reported that the increased negative symptoms detected in FTD were inversely correlated 720
www.jonmd.com
with executive functions and add the new findings that apathy is also inversely correlated with social cognitive measures of theory of mind and empathy in bvFTD cases. Patients suffering from bvFTD exhibit not only significant social cognitive, emotional empathic, and motivational alterations, but also the loss of self-awareness of such dramatic changes, which is a key domain for adaptive social executive functions (Eslinger et al., 1995). Voxel-based morphometry revealed that apathy in bvFTD is related to prominent atrophy in the right caudate (including the ventral striatum), the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum-anterior insula region (Eslinger et al., 2012). Massimo and collaborators (2009) performed a study in which identified individual patients with a relatively selective disorder of apathy, i.e., patients with minimal behavioral abnormalities in other domains, showed atrophy in the dorsal anterior cingulate cortex and right dorsolateral prefrontal cortex (dlPFC) regions. Functional MRI studies implicate the dlPFC in attentional and organizational aspects of social functioning (Moll et al., 2005).
HD HD is an inherited neurodegenerative disorder resulting from an expanded trinucleotide cytosine-adenine-guanine coding for the mutant protein huntingtin on the short arm of chromosome 4 (4p16.3) (Walker, 2007), characterized by a combination of motor, cognitive and psychiatric symptoms progressing eventually to a state of severe hypokinesia and dementia. Apathy has received more attention in the disease in recent years: in three original studies, prevalences of apathy in HD patients varied from 34% to 76% (Kulisevsky et al., 2001; Paulsen et al., 2001; Anderson et al., 2001). Apathy and depression are independent entities with apathy being more prevalent in HD patients (Marques and Januário, 2012). It was found that apathy is linked to other clinical characteristics such as cognitive deterioration and functional decline, whereas depression was not (Naarding et al., 2009). In early HD patients, the presence of apathy is associated with more severe deficits of attention, executive function and episodic memory (Baudic et al., 2006). It becomes more severe with advancing disease (Naarding et al., 2009). Apathy causes a great burden of disease and distress in caregivers, also after adjusting for the presence of motor and cognitive deficits (Hamilton et al., 2003). Some researchers (van Duijn et al., 2010) supposed that apathy may be a sign of disease progression in HD, including progressive motor and cognitive impairments, and worse global functioning, but longitudinal studies are needed to investigate precise relationships
PDD Idiopathic PD is one of the most common neurodegenerative disorders, and it has become increasingly apparent that patients with PD can have impairment of certain cognitive functions and develop dementia. PDD has been increasingly better recognized, probably because patients with PD survive for longer than before thanks to modern treatment. The proto-typical PDD has characteristic clinical features, which can be best summarized as a dysexecutive syndrome, with prominent impairment of attention, visual–spatial dysfunction, moderately impaired memory and accompanying behavioural symptoms such as apathy. According to Leroi et al. (2012), apathy is closely linked to cognitive impairment and may even be a harbinger of conversion to dementia, a finding that has previously been observed. For example, a longitudinal study of a PD cohort without dementia found that after a median period of 18 months, the proportion of those who converted to dementia was significantly higher in those with apathy (Dujardin et al., 2009). In PDD, apathy had been reported with a frequency of 23 to 24% (Aarsland et al., 2001a), although a more recent study analyzing a large sample of mild-moderate PDD patients reported a higher figure (54%) (Aarsland et al., 2007), compared to 17% in nondemented patients (Aarsland et al., 2001b). Dujardin et al. (2009) suggest © 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
the possible involvement of a cholinergic mechanism in apathy. As stated above, bilateral basal ganglia lesions have been reported to induce a particular form of apathy, termed auto-activation deficit, principally defined as a loss of self-driven behavior that is reversible with external stimulation. Schmidt et al. (2008) proposed that bilateral striato-pallidal damage, observed in PD, specifically disconnects motor output from affective evaluation of potential rewards.
VaD Several vascular pathologies can lead to dementia. The term VaD is used for dementia syndromes likely to be the consequences of ischemic, hemorrhagic, or ipossic lesions of the brain. In patients with stroke or VaD, the frequency of apathy was found to vary between 15% and 93% (Fuh et al., 2005; Brodaty et al., 2005). Apathy is unrelated to the severity of dementia and cognitive dysfunction in VaD patients (Aharon-Peretz et al., 2000), but there is strong association between apathy and patients’ abilities to complete basic and instrumental activities of daily living (IADL) (Zawacki et al., 2002). Cortical lesions in VaD likewise commonly involve frontal regions and may induce changes in the neural networks that generate and control goal-directed actions, which are mostly represented within the prefrontal cortex connections to basal ganglia, thalamus and limbic system structures mediating motivational behaviour. (Fuh et al., 2005; Levy and Dubois, 2006). A study in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) demonstrated that CADASIL patients with apathy had a higher white-matter hyperintensities burden and more lacunes than patients without apathy (Reyes et al., 2009). Staekenborg et al. (2010) demonstrated that patients with small-vessel and large-vessel VaD show different profiles of symptoms, with especially more apathy in small-vessel VaD (prevalence 64%) than in large-vessel VaD (prevalence 54%). The highest prevalence for apathy, noted in this finding, followed by depressive symptoms, irritability and agitation/aggression confirms previous findings in populations of VaD patients (Caputo et al., 2008; Fuh et al., 2005).
Management Apathetic patients require more support, management, and resource utilization and place higher levels of burden on caregivers. They easily descend into a downward spiral of lack of activity, with those affected responding poorly to rehabilitation, due to absent motivation (Galynker et al., 1997). In light of its importance and difficult handling, various different pharmacological and nonpharmacological treatment strategies have been proposed, but in spite of the strong negative impact of apathy in dementia, treatment studies for this frequent behavioral condition are surprisingly few, and recognized guidelines for the management of apathy do not exist (Van Reekum et al., 2005). Brodaty and Burns (2012) performed a systematic review on nonpharmacological intervention studies with outcomes relevant to apathy in dementia. In their opinion, from the literature reviewed, the only intervention with sufficient quality studies, was Therapeutic Activities; this heterogeneous group includes stimulation, creative activities, cooking, Montessori methods, and behavioral elements, often individually tailored. Some positive results, although even less impressive, were reported for music, exercise, multisensory stimulation, pet therapy, and special care units. According to Ferrero-Arias et al. (2011), a structured occupational therapeutic intervention for even a short period of time improves apathy in dementia patients and is much more beneficial than free use of the same amount of time by the patients in a nonstructured environment, but the effect is only useful in patient with mild or moderate dementia, and the effect in patients with severe apathy is even less important. The pharmacological strategies have produced varying results. One problem is that apathy is a secondary outcome rather than a primary outcome measure in most studies. Lee and coworkers (2003) have © 2014 Lippincott Williams & Wilkins
Apathy and Dementia
reviewed the pharmacological treatment: psychostimulants (e.g., methylphenidate, dextroamphetamine -Plenger et al., 1996; Herrmann et al., 2008-) and dopaminergicagonists (e.g., pergolide and bromocriptine) may modestly improve arousal and speed of information processing, reduce distractibility, and improve some aspects of motivation and executive function (Zafonte et al., 2001). Primarily used for treating cognitive symptoms in dementia, more recent findings indicate that acetylcholinesterase inhibitors (AchIs), donepezil, rivastigmine, galantamine, have beneficial effects on noncognitive symptoms such as apathy (Weiner et al., 2000; Holmes et al., 2004; Tanaka et al., 2004; Rockwood et al., 2007; Gauthier et al., 2006; Potkin et al., 2006; Aupperle et al., 2004; McKeith et al., 2000; Erkinjuntti et al., 2002; Cummings et al., 2004). Overall, there is Level II (15 studies supportive versus three showing no benefit) plus a preponderance of various Level III evidences (11 positive and 7 negative studies) that AChIs are beneficial in the treatment for apathy. There is no clear indication that any one AChI is superior (Berman et al., 2012). However, the majority of these studies were poorly run and the benefits observed mild, or of uncertain clinical relevance, therefore they need to be replicated in larger, adequately powered clinical trials. There is no evidence of benefit with rivastigmine in apathy patients with FTD (Moretti et al., 2004). Memantine is a specific N-methyl-D-aspartate receptor antagonist. Two studies of memantine alone (Winblad and Poritis, 1999; Pantev et al., 1993) were randomized, and double-blind, placebo-controlled trials indicated significant improvements in apathy levels for those in the treatment group. A small open-label study of memantine in patients with FTD showed no improvement in apathy (Diehl-Schmid et al., 2008). Corcoran et al. (2004) reported the case of three subjects with amotivational syndromes of varying aetiology, who were unresponsive to conventional treatments, that responded to treatment with bupropion. It a is a 5-HT1A antagonist that, in addition, increases dopamine levels in the ventral tegmental area projecting to frontal cortex by blocking noradrenaline transporters in the frontal cortex. This effect has evoked interest, as this pathway has been implicated in reward mechanisms and motivation, which seem to be central to apathy. There is good evidence that antidepressants do not significantly improve apathy in people with dementia (Berman et al., 2012). Moreover, selective serotonin reuptake inhibitor (SSRIs) have been associated with indifference, both in behavioral terms as well as emotional terms (Sansone and Sansone, 2010; Sato and Asada, 2011). There is evidence demonstrating that atypical antipsychotics may have some beneficial effect, although it is not possible to differentiate improvement in apathy directly from the medication versus as a secondary phenomenon to improvement in neuropsychiatric comorbidity (Berman et al., 2012).
CONCLUSIONS Apathy is an under-recognized syndrome that affects over 70% of individuals with dementia and is associated with functional impairment and caregiver distress at all levels of disease severity. It reflects a syndrome of primary motivational loss as manifested by reduced goal oriented behaviors, whereas depression reflects a primary mood disturbance. Research into apathy has been plagued by variability in definitions and terminology and by a lack of consensus on diagnostic criteria. The mechanism of apathy in neuropsychiatric disorders remains unknown, but studies suggest that disruption of frontal cortical-basal ganglia circuits and executive dysfunction may both play an important role. Several rating scales have been performed to measure severity of apathy, but proper validation is limited by the lack of standard criteria. There are few randomized controlled trials of pharmacological or non-pharmacological treatments for apathy in dementia. On the other hand, there is a growing literature consisting of case reports and small series of patients that were treated for apathy with a variety of psychoactive agents. A combination of pharmacologic and psychosocial treatment would be ideally placed to give a good effect size in intervention trials. Greater understanding of apathy will improve www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
721
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
the identification, intervention, and treatment of this ubiquitous and pernicious syndrome.
DISCLOSURE The authors declare no conflict of interest. REFERENCES Aarsland D, Bronnick K, Ehrt U, De Deyn PP, Tekin S, Emre M, Cummings JL (2007) Neuropsychiatric symptoms in patients with PD and dementia: frequency, profile and associated caregiver stress. J Neurol Neurosurg Psychiatry. 78:36–42. Aarsland D, Cummings JL, Larsen JP (2001a) Neuropsychiatric differences between Parkinson’s disease with dementia and Alzheimer’s disease. Int J Geriatr Psychiatry. 16:184–191. Aarsland D, Litvan I, Larsen JP (2001b) Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 13:42–49. Aharon-Peretz J, Kliot D, Tomer R (2000) Behavioral differences between white matter lacunar dementia and Alzheimer’s disease: a comparison on the Neuropsychiatric Inventory. Dement Geriatr Cogn Disord. 11:294–298. Allman JM, Hakeem A, Erwin JM, Nimchinsky E, Hof P (2001) The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci. 935:107–117. American Psychiatric Association (Ed) (2013) Diagnostic and Statistical Manual of Mental Disorders, DSM-5 ed. Washington, DC: American Psychiatric Association. Anderson KE, Louis ED, Stern Y, Marder KS (2001) Cognitive correlates of obsessive and compulsive symptoms in Huntington’s disease. Am J Psychiatry. 158: 799–801. Aupperle PM, Koumaras B, Chen M, Rabinowicz A, Mirski D (2004) Long-term effects of rivastigmine treatment on neuropsychiatric and behavioral disturbances in nursing home residents with moderate to severe Alzheimer’s disease: results of a 52-week open-label study. Currm Med Res Opin. 20:1605–1612. Baudic S, Maison P, Dolbeau G, Boissé MF, Bartolomeo P, Dalla Barba G, Traykov L, Bachoud-Lévi AC (2006) Cognitive impairment related to apathy in early Huntington’s disease. Dement Geriatr Cogn Disord. 21:316–321. Benoit M, Koulibaly PM, Migneco O, Darcourt J, Pringuey DJ, Robert PH (2002) Brain perfusion in Alzheimer’s disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Psychiatry Res. 114:103–111. Berman K, Brodaty H, Withall A, Seeher K (2012) Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry. 20:104–122. Boone KB, Miller BL, Swartz R, Lu P, Lee A (2003) Relationship between positive and negative symptoms and neuropsychological scores in frontotemporal dementia and Alzheimer’s disease. J Int Neuropsychol Soc. 9:698–709.
Corcoran C, Wong ML, O’Keane V (2004) Bupropion in the management of apathy. J Psychopharmacol. 18:133–135. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994) The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 44:2308–2314. Cummings JL, Schneider L, Tariot PN, Kershaw PR, Yuan W (2004) Reduction of behavioral disturbances and caregiver distress by galantamine in patients with Alzheimer’s disease. Am J Psychiatry. 161:532–538. Cutting J (1995) Descriptive psychopathology. In Hirsch SR, Weinberger DR (Eds), Schizophrenia (pp 15–27). Oxford: Blackwell Science. Devanand DP, Brockington CD, Moody BJ, Brown RP, Mayeux R, Endicott J, Sackeim HA (1992) Behavioral syndromes in Azheimer’s disease. Int Psychogeriatr. 4(suppl 2):161–184. Diehl-Schmid J, Förstl H, Perneczky R, Pohl C, Kurz A (2008) A 6-month, openlabel study of memantine in patients with frontotemporal dementia. Int J Geriatr Psychiatry. 23:754–759. Dujardin K, Sockeel P, Delliaux M, Destée A, Defebvre L (2009) Apathy may herald cognitive decline and dementia in Parkinson’s disease. Movement Disorders 24:2391–2397. Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet. 359: 1283–1290. Eslinger PJ, Grattan LM, Geder LM (1995) Impact of frontal lobe lesions on rehabilitation and recovery from acute brain injury. NeuroRehabilitation. 5:161–182. Eslinger PJ, Moore P, Antani S, Anderson C, Grossman M (2012) Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. Behav Neurol. 25:127–136. Ferrero-Arias J, Goñi-Imízcoz M, González-Bernal J, Lara-Ortega F, da SilvaGonzález A, Díez-Lopez M (2011) The efficacy of nonpharmacological treatment for dementia-related apathy. Alzheimer Dis Assoc Disord. 25:213–219. Finkel SI, Burns A (2000) Introduction. Behavioral and psychological symptoms of dementia (BPSD): a clinical and research update. Int Psychogeriatr. 12(suppl 1):9–12. Freels S, Cohen D, Eisdorfer C, Paveza G, Gorelick P, Luchins DJ, Hirschman R, Ashford JW, Levy P, Semla T (1992) Functional status and clinical findings in patients with Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 47: M177–M182. Fuh JL, Wang SJ, Cummings JL (2005) Neuropsychiatric profiles in patients with Alzheimer’s disease and vascular dementia. J Neurol Neurosurg Psychiatry. 276:1337–1341. Galynker I, Prikhojan A, Phillips E, Focseneanu M, Ieronimo C, Rosenthal R (1997) Negative symptoms in stroke patients and length of hospital stay. J Nerv Ment Dis. 185:616–621.
Brodaty H, Burns K (2012) Nonpharmacological management of apathy in dementia: a systematic review. Am J Geriatr Psychiatry. 20:549–564.
Gauthier S, Juby A, Morelli L, Rehel B, Schecter R; EXTEND Investigators (2006) A large, naturalistic, community-based study of rivastigmine in mildto-moderate AD: the EXTEND Study. Curr Med Res Opin. 22:2251–2265.
Brodaty H, Sachdev PS, Withall A, Altendorf A, Valenzuela MJ, Lorentz L (2005 ) Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke: the Sydney Stroke Study. Psychol Med. 35:1707–1716.
Gilley DW, Wilson RS, Bienias JL, Bennett DA, Evans DA (2004) Predictors of depressive symptoms in persons with Alzheimer’s disease. J Gerontol B Psychol Sci Soc Sci. 59:P75–P83.
Bruen PD, McGeown WJ, Shanks MF, Venneri A (2008) Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain. 131:2455–2463.
Hamilton JM, Salmon DP, Corey-Bloom J, Gamst A, Paulsen JS, Jerkins S, Jacobson MW, Peavy G (2003) Behavioral abnormalities contribute to functional decline in Huntington’s disease. J Neurol Neurosurg Psychiatry. 74:120–122.
Caputo M, Monastero R, Mariani E, Santucci A, Mangialasche F, Camarda R, Senin U, Mecocci P (2008) Neuropsychiatric symptoms in 921 elderly subjects with dementia: a comparison between vascular and neurodegenerative types. Acta Psychiatr Scand. 117:455e64.
Hart DJ, Craig D, Compton SA, Critchlow S, Kerrigan BM, McIlroy SP, Passmore AP (2003) A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer’s disease. Int J Geriatr Psychiatry. 18:1037–1042.
Chow TW, Binns MA, Cummings JL, Lam I, Black SE, Miller BL, Freedman M, Stuss DT, van Reekum R (2009) Apathy symptom profile and behavioral associations in frontotemporal dementia vs dementia of Alzheimer type. Arch Neurol. 66:888–893.
Herrmann N, Rothenburg LS, Black SE, Ryan M, Liu BA, Busto UE, Lanctôt KL (2008) Methylphenidate for the Treatment of Apathy in Alzheimer Disease. Prediction of Response Using Dextroamphetamine Challenge. J Clin Psychopharmacol. 28:296–301.
Colling KB (1999) Passive behaviors in dementia. Clinical application of the needdriven dementia-compromised behavior model. J Gerontol Nurs. 25:27–32.
Holmes C, Wilkinson D, Dean C, Vethanayagam S, Olivieri S, Langley A, PanditaGunawardena ND, Hogg F, Clare C, Damms J (2004) The efficacy of donepezil in
722
www.jonmd.com
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
the treatment of neuropsychiatric symptoms in Alzheimer disease. Neurology. 63:214–219. Holthoff VA, Beuthien-Baumann B, Kalbe E, Lüdecke S, Lenz O, Zündorf G, Spirling S, Schierz K, Winiecki P, Sorbi S, Herholz K (2005) Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression. Biol Psychiatry. 57:412–421. Kulisevsky J, Litvan I, Berthier ML, Pascual-Sedano B, Paulsen JS, Cummings JL (2001) Neuropsychiatric assessment of Gilles de la Tourette patients: comparative study with other hyperkinetic and hypokinetic movement disorders. Mov Disorders. 16:1098–1104. Landes AM, Sperry SD, Strauss ME, Geldmacher DS (2001). Apathy in Alzheimer’s disease. J Am Geriatr Soc. 49:1700–1707. Lee HB, Lyketsos CG, Rao V (2003) Pharmacological management of the psychiatric aspects of traumatic brain injury. Int Rev Psychiatry. 15:359–370. Leroi I, Pantula H, McDonald K, Harbishettar V (2012) Neuropsychiatric symptoms in Parkinson’s disease with mild cognitive impairment and dementia. Parkinson’s Disease. 2012:308097. Levy ML, Cummings JL, Fairbanks LA, Masterman D, Miller BL, Craig AH, Paulsen JS, Litvan I (1998) Apathy is not depression. J Neuropsychiatry Clin Neurosci. 10:314–319. Levy R (2012) Apathy: a pathology of goal-directed behaviour: a new concept of the clinic and pathophysiology of apathy. Rev Neurol. 168:585–589. Levy R, Dubois B (2006) Apathy and the functional anatomy of the prefrontal cortexbasal ganglia circuits. Cereb Cortex. 16:916–928. Marin RS (1990) Differential diagnosis and classification of apathy. Am J Psychiatry. 147:22–30. Marin RS (1991) Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci. 3:243–254. Marques FJ, Januário C (2012) J17Apathy prevalence and clinical correlations in Huntington’s disease. J Neurol Neurosurg Psychiatry. 83:A41. Marshall GA, Monserratt L, Harwood D, Mandelkern M, Cummings JL, Sultzer DL (2007) Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Arch Neurol. 64:1015–1020. Massimo L, Powers C, Moore P, Vesely L, Avants B, Gee J, Libon DJ, Grossman M (2009) Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord. 27:96–104. McKeith IG, Grace JB, Walker Z, Byrne EJ, Wilkinson D, Stevens T, Perry EK (2000) Rivastigmine in the treatment of dementia with Lewy bodies: preliminary findings from an open trial. Int J Geriatr Psychiatry. 15:387–392. Mega MS, Cummings JL (1994) Frontal-subcortical circuits and neuropsychiatric disorders. J Neuropsychiatry Clin Neurosci. 6:358–370. Mega MS, Cummings JL, Fiorello T, Gornbein J (1996) The spectrum of behavioral changes in Alzheimer’s disease. Neurology. 46:130–135. Mendez MF, Lauterbach EC, Sampson SM; ANPA Committee on Research (2008) An evidence-based review of the psychopathology of frontotemporal dementia: a report of the ANPA Committee on Research. J Neuropsychiatry Clin Neurosci. 20:130–149. Moll J, Zahn R, Oliveira-Souza R, Krueger F, Grafman JH (2005) The neural basis of human moral cognition. Nat Rev Neurosci. 6:799–809. Moretti R, Torre P, Antonello RM, Cattaruzza T, Cazzato G, Bava A (2004) Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging. 21:931–937.
Apathy and Dementia
Pantev M, Ritter R, Gortelmeyer R (1993) Clinical and behavioural eveluation in long-term care patients with mild to modertae dementia under memantine treatment. Zeitschrt fur Gerontopsychologie Und-Psychiatrie. 6:S103–S117. Paulsen JS, Ready RE, Hamilton JM, Mega M, Cummings J (2001) Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry. 71:310–314. Piccininni M, Di Carlo A, Baldereschi M, Zaccara G, Inzitari D (2005) Behavioral and psychological symptoms in Alzheimer’s disease: frequency and relationship with duration and severity of the disease. Dement Geriatr Cogn Disord. 19:276–281. Plenger PM, Dixon CE, Castillo RM, Frankowski RF, Yablon SA, Levin HS (1996) Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: a preliminary double-blind placebo-controlled study. Arch Phys Med Rehabil. 1996 77:536–540. Potkin SG, Alva G, Gunay I, Koumaras B, Chen M, Mirski D (2006) A pilot study evaluating the efficacy and safety of rivastigmine in patients with mixed dementia. Drugs Aging. 23:241–249. Reyes S, Viswanathan A, Godin O, Dufouil C, Benisty S, Hernandez K, Kurtz A, Jouvent E, O’Sullivan M, Czernecki V, Bousser MG, Dichgans M, Chabriat H (2009) Apathy: a major symptom in CADASIL. Neurology. 72:905–910. Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart SA, Moll van Charante EP, van Gool WA (2012) Alzheimer’s Disease Neuroimaging Initiative. Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer’s disease in non-depressed subjects. Dement Geriatr Cogn Disord. 33:204–209. Robert P, Onyike CU, Leentjens AF, Dujardin K, Aalten P, Starkstein S, Verhey FR, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, Gauthier S, Grossberg G, Vellas B, Byrne J (2009) Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. European Psychiaty. 2009;24:98–104. Robert PH, Clairet S, Benoit M, Koutaich J, Bertogliati C, Tible O, Caci H, Borg M, Brocker P, Bedoucha P (2002) The apathy inventory: assessment of apathy and awareness in Alzheimer’s disease, Parkinson’s disease and mild cognitive impairment. Int J Geriatr Psychiatry. 17:1099–1105. Rockwood K, Black S, Bedard MA, Tran T, Lussier I; TOPS Study Investigators (2007) Specific symptomatic changes following donepezil treatment of Alzheimer’s disease: a multicentre, primary care, open label study. Int J Geriatr Psychiatry. 22:312–319. Sansone RA, Sansone LA (2010) SSRI-Induced Indifference. Psychiatry (Edgmont). 7:14–18. Sato S, Asada T (2011) Sertraline-induced apathy syndrome. J Neuropsychiatry Clin Neurosci. 23:E19. Schmidt L, d’Arc BF, Lafargue G, Galanaud D, Czernecki V, Grabli D, Schüpbach M, Hartmann A, Lévy R, Dubois B, Pessiglione M (2008) Disconnecting force from money: effects of basal ganglia damage on incentive motivation. Brain. 131:1303–1310. Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D (2001) Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 70:323– 332. Staekenborg SS, Su T, van Straaten EC, Lane R, Scheltens P, Barkhof F, van der Flier WM. Behavioural and psychological symptoms in vascular dementia; differences between small- and large-vessel disease (2010). J Neurol Neurosurg Psychiatry. 81:547–551 Starkstein SE (2000) Apathy and withdrawal. Int Psychogeriatr. 12(suppl 1): 135–138.
Moretti R, Torre P, Antonello RM, Cazzato G, Bava A (2002) Depression and Alzheimer’s disease: symptom or comorbidity? Am J Alzheimer’s Dis Other Dement. 17:338–344.
Starkstein SE, Ingram L, Garau ML, Mizrahi R (2005) On the overlap between apathy and depression in dementia. J Neurol Neurosurg Psychiatry. 2005 76: 1070–1074.
Mortby ME, Maercker A, Forstmeier S (2012) Apathy: a separate syndrome from depression in dementia? A critical review. Aging Clin Exp Res. 24: 305–316.
Starkstein SE, Jorge R, Mizrahi R, Robinson RG (2006) A prospective longitudinal study of apathy in Alzheimer’s disease J Neurol Neurosurg Psychiatry. 2006 77:8–11.
Naarding P, Janzing JG, Eling P, van der Werf S, Kremer B (2009) Apathy is not depression in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 21: 266–270. Ott BR, Noto RB, Fogel BS (1996) Apathy and loss of insight in Alzheimer’s disease: A SPECT imaging study. J Neuropsychiatry Clin Neurosci. 8:41–46.
© 2014 Lippincott Williams & Wilkins
Starkstein SE, Merello M, Brockman S, Bruce D, Petracca G, Power BD (2009) Apathy predicts more severe parkinsonism in Alzheimer’s disease. Am J Geriatr Psychiatry. 17:291–298.
www.jonmd.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
723
The Journal of Nervous and Mental Disease • Volume 202, Number 10, October 2014
Cipriani et al.
Starkstein SE, Petracca G, Chemerinski E, Kremer J (2001) Syndromic validity of apathy in Alzheimer’s disease. Am J Psychiatry. 158:872–877.
Van Reekum R, Stuss DT, Ostrander L (2005) Apathy: why care? J Neuropsychiatry Clin Neurosci. 17:7–19.
Strauss ME, Sperry SD (2002) An informant-based assessment of apathy in Alzheimer disease. Neuropsychiatry Neuropsychol Behav Neurol. 15:176–183.
Walker FO (2007) Huntington’s disease. Lancet. 369:218–228.
Tagariello P, Girardi P, Amore M (2009) Depression and apathy in dementia: same syndrome or different constructs? A critical review. Arch Gerontol Geriatr. 49:246–249.
Weiner MF, Martin-Cook K, Foster BM, Saine K, Fontaine CS, Svetlik DA (2000) Effects of donepezil on emotional/behavioral symptoms in Alzheimer’s disease patients. J Clin Psychiatry. 61:487–492.
Tanaka M, Namiki C, Thuy DH, Yoshida H, Kawasaki K, Hashikawa K, Fukuyama H, Kita T (2004) Prediction of psychiatric response to donepezil in patients with mild to moderate Alzheimer’s disease. J Neurol Sci. 225:135–141.
Winblad B, Poritis N (1999) Memantine in severe dementia: results of the 9 M-Best Study (Benefit and efficacy in severely demented patients during treatmentwith memantine). Int J Geriatr Psychiatry. 14:135–146.
Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, Cummings JL (2001) Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol. 49:355–361.
World Health Organisation (Ed) (1992) The ICD-10 classification of mental and behavioural disorders. Clinical description and diagnostic guidelines. Geneva.
Turró-Garriga O, López-Pousa S, Vilalta-Franch J, Turón-Estrada A, Pericot-Nierga I, Lozano-Gallego M, Hernández- Ferràndiz M, Soler-Cors O, Planas-Pujol X, Monserrat-Vila S, Garre-Olmo J (2009) A longitudinal study of apathy in patients with Alzheimer’s disease. Rev Neurol. 48:7–13.
Zafonte RD, Lexell J, Cullen N (2001) Possible applications for dopaminergic agents following traumatic brain injury: part 2. J Head Trauma Rehabil. 16:112–116.
van Duijn E, Reedeker N, Giltay EJ, Roos RA, van der Mast RC (2010) Correlates of apathy in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 22:287–294.
724
www.jonmd.com
Zawacki TM, Grace J, Paul R, Moser DJ, Ott BR, Gordon N, Cohen RA (2002) Behavioral problems as predictors of functional abilities of vascular dementia patients. J Neuropsychiatry Clin Neuosci. 14:296–302.
© 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
