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Apathy may be one of the most common behavioural complications of neurodegenerative disorders such as Alzheimer’s and Parkinson’s (PD) disease and can occur in about a third of those affected by these conditions. Apathy is one of the most underrecognised, underdiagnosed and poorly managed aspects of these diseases. It is defined as a clustering of behavioural, emotional and cognitive symptoms that manifests as diminished initiation and interest and diminished responsiveness to stimuli. Apathy is increasingly being considered as a core symptom of PD and results from underlying disease-related pathological changes. This article outlines various aspects of apathy in PD, particularly focusing on diagnostic criteria, apathy rating scales, underlying pathology, the negative impact of apathy and management strategies.

The term ‘apathy’ refers to a loss of motivation and was first used in ancient Greece by the Stoics (απαθής, meaning ‘without feeling or suffering’) to describe a state of indifference or lack of concern towards the external world. However, in the clinical context, apathy has a more specific meaning and instead refers to a clustering of behavioural and emotional symptoms that manifest as diminished interest and involvement in normal purposeful behaviour, flattened affect, diminished emotional responsivity, lack of initiation of non-routine activity and diminished drive to complete activities once started [1]. Apathy may be one of the most common behavioural complications of neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) disease, and it is one of the most underrecognised, underdiagnosed and poorly managed aspects of these diseases [2, 3]. The consequences of apathy may be significant and may have a negative impact on prognosis, quality of life, level of disability, and carer burden and distress. Management strategies have not been extensively investigated. This chapter provides an outline of various aspects of apathy in PD, including its epidemiology, definitions, method of diagnosis and rating, underlying pathology and the impact that it has on PD sufferers and their carers.

In treated and untreated PD, apathy has been reported with prevalence estimates between 17 and 42% [1]. In a study using a Norwegian PD database, the rates of apathy in 139 PD sufferers using the Neuropsychiatric Inventory (NPI) was found to be 17% [4]. A more recent study, using an apathy scale specifically designed for PD, the Lille Apathy Rating Scale (LARS), found that 51 of 159 (32%) patients scored above the cut-off for apathy [2]. These figures are slightly lower than in AD, where apathy, as detected by the NPI has been reported in 55-80% [5], and has been described in up to 93% of one sample [6]. In a recent cross-sectional study of 306 patients with various psychiatric diagnoses, revised diagnostic criteria for apathy were validated and revealed an apathy frequency of 27% of the subgroup with PD [7].

Apathy has been defined as a lack of goal-directed behaviour, which can be divided into: (1) diminished or blunted emotions, (2) loss of or diminished initiative, and (3) loss of or diminished interest [8]. Another, but similar, definition is that apathy represents a lack of goal-directed behaviour, cognition or emotion [9]. Other formal definitions generally support the notion of apathy as a multi-dimensional construct, rather than merely a symptom secondary to other medical, psychiatric or neurologic conditions [reviewed in 10].

Initially outlined by Marin et al. [11] and modified and operationalised for PD by Starkstein et al. [12], more recently revised diagnostic criteria proposed by a task force from Europe, Australia and North America [13] have been validated in a series of patients with different types of dementia, as well as major depression and schizophrenia [7, 13]. These criteria are based on loss of motivation that persists over time (at least 4 weeks) as well as the presence of at least two of three dimensions of apathy: reduced goal-directed behaviour, goal-directed cognitive activity, and emotions. Evidence for change in each of the three dimensions is derived from observed reduction in either self-initiation of behaviour within the dimension or response to an external stimulus that taps into the dimension. Symptoms should cause clinically significant impairment in various functional domains and should not be due to another condition that may resemble apathy. In the validation study, the NPI apathy domain score with a cut-off of 3 [14] was used as a reference point, and inter-rater reliability was found to be high. The most commonly observed domains in those with apathy were a reduction in goal-directed cognitive activity, followed by goal-directed behaviour. As in the other diagnostic groups, ‘initiation’ symptoms were more frequent in PD, compared with the ‘responsiveness’ symptoms. In a study examining PD alone, there was a high percentage of agreement between the diagnosis of apathy using the criteria of Robert et al. [13] and the cut-off score for apathy on both the LARS (81%) and the NPI apathy sub-score (86%) [15]. Diagnostic criteria of apathy are outlined in table 1.

Table 1.
Diagnostic criteria for apathy validated in PD [13, 15]

The measurement of apathy in PD first became properly validated following the proposal of Marin et al. [11] of diagnostic criteria for apathy as a ‘pure’ syndrome. These criteria were later expanded by Starkstein et al. [12] to apply to various neurodegenerative disorders, including PD, and were informally accepted in PD research as well as in the clinical setting. Two apathy scales were subsequently designed specifically for use in PD populations. The first is the Apathy Inventory (AI) [10], which is an informant-rated scale that is scored in a similar manner to the Neuropsychiatry Inventory [16], i.e. frequency x severity; it assesses three components of apathy: emotional blunting, lack of initiative and lack of interest. The LARS [17] is the most recent scale developed for assessing apathy in PD. Gallagher et al. [18] used the LARS to determine the usefulness of the Unified Parkinson’s Disease Rating Scale (UPDRS), part I [19], as an apathy screening and diagnostic instrument by rating both scales in 74 PD sufferers. Using the LARS cut-off, 20% of the sample had apathy. The apathy item on part I of the UPDRS was sensitive (73%) in detecting apathy symptoms in PD, but was not sufficient to make a diagnosis of a full apathy syndrome.

In 2008, the Movement Disorder Society undertook a comprehensive critique of all apathy scales relevant to PD and proposed recommendations, based on scale properties [20]. Only Starkstein's Apathy Scale (AS) [21], which is an abbreviated version of Marin's original Apathy Evaluation Scale (AES) [11], was recommended by the consensus group to assess apathy in PD. Selected apathy rating scales are outlined in more detail in table 2. More recently, a review of 15 apathy scales, not specific to PD, was undertaken. This review found that the most psychometrically robust measure for assessing apathy across any disease population was the AES as well as the apathy subscale of the NPI [22].

In 1973, Singer [23] concluded that the apathy syndrome in PD was an example of ‘premature social aging’. However, subsequent studies, such as that of Pluck and Brown [1], which found that high levels of apathy in PD compared with their age- and disability-matched osteoarthritis sample, supported the notion that apathy is most likely part of the disease process, in particular, disruptions to the frontal-subcortical circuit, and not a psychological response to disability or loss of role. Studies in non-PD patients with apathy, who have had basal ganglia lesions, have highlighted the potential underlying pathophysiology of apathy in PD. For example, in a case series of 16 patients with bilateral focal lesions of the putamen, caudate nucleus or pallidum, a syndrome of ‘auto-activation deficit’ (AAD) was observed. AAD is a term initially used to describe a particular type of apathy related to basal ganglia lesions [24]. The Alexander and De Jong neural loop most likely to be involved is the limbic loop, including the anterior cingulate cortex (ACC), to ventral striatum, globus pallidus and thalamus, and returning to the ACC [25]. The ACC may also have a role in depression, reward, executive function and goal-directed behaviour and is therefore a plausible substrate for apathy [13, 26]. As apathy and anhedonia are closely linked, and pleasure and reward seeking are associated with ventral tegmental area and nucleus accumbens activity in PD, apathy too may be caused by disruption of these pathways. A few functional imaging studies have investigated apathy and the dimensions of diminished interest or initiative in AD. Key findings are summarised in table 3.

Table 2.
Selected apathy rating scales relevant to PD
Table 3.
Main neuroimaging studies investigating cerebral metabolism in apathy in AD

Dopamine, a key neurotransmitter involved in motivation and reward and the core neurochemical lesion in PD, is likely to have a significant role in apathy. Apathy varies according to the extent of motor fluctuation in PD patients, consistent with a contribution of dopamine [27]. The importance of dopamine is documented in non- PD apathy as well. For example, in subjects diagnosed with AD and dementia with Lewy bodies, those with apathy (according to the NPI) and AD had lower striatal levels of dopamine transporter (DAT) [28]. Similarly, serotonin (5-HT) may have a role in apathy, particularly in PD depression [29]. Interestingly, apathy may be a result of depression treatment due to the interplay between 5-HT and dopamine. This may result in the so-called ‘SSRI-induced apathy’ syndrome [30, 31], which may be taken as a model for the role of 5-HT in PD apathy. Finally, various lines of converging evidence have suggested that the cholinergic deficit in PD, and particularly dementia in PD (PDD), may be even more marked than they are in AD. This deficit has been demonstrated in the ACC, suggesting a link with apathy, as well as by the evidence that cholinesterase inhibitors have a beneficial effect on apathy [32].

Apathy frequently occurs with other psychiatric diagnoses in PD. For example, in the Norwegian PD database, factor analysis of the NPI revealed that apathy covaried with anxiety [4], as it did with anxiety and depression in other studies [1, 21, 33]. In PD, the overlap of depression and apathy may be particularly high or even exclusive compared with other neurodegenerative conditions [34]. It may be related to the shared role that serotonin has in mediating both depression and apathy [29].

The nature of the co-occurrence of depression with apathy has frequently been debated. Indeed, apathy was initially attributed to being a symptom of depression in the same way that anhedonia is a symptom of depression [34]. Diagnostically, it can be difficult to distinguish an apathy syndrome from depression. In spite of this, it has also been demonstrated that if using carefully validated rating scales for apathy and depression and excluding items of overlap, it is possible to discriminate the entities [2, 36]. Furthermore, there are a handful of studies that have shown a significant level of discrepancy between apathy and depression. For example, in AD, a longitudinal study of 65 patients found that apathy and depression had different natural histories and that it is clearly possible to discriminate between them [37].

In 1922, Naville [38] described a clinical profile in PD consistent with what today would be considered ‘bradyphrenia’, or slowness of thinking. This consisted of a constellation of symptoms including fatigue, lack of initiative, slowness of thinking, poor persistence in tasks, mild memory problems and deficits in attention and interest. This syndrome is most likely a combination of the effects of motor impairment, or bradykinesia, and the underlying cognitive deficits and apathy syndrome that are well recognised as being part of PD today. In examining the cognitive profile in apathy, it is tempting to speculate on the direction of causality. That is, does the cognitive profile, which is most often described as being a ‘dysexecutive syndrome’ inform and drive the behavioural syndrome of apathy, or vice versa? According to some authors, apathy is only one of several behavioural signs of executive dysfunction [39]. With impairment in executive function, problems typical of an apathy syndrome, such as with initiation and task completion, may emerge and have significant impact on the ability to function successfully and independently in situations lacking a clear structure. However, with the current state of knowledge, this relationship can at best be described as being ‘bidirectional’.

A handful of studies have explored the associated cognitive profile in apathy, although few studies have done this specifically in the context of PD. The majority of non-PD studies have used rather blunt and non-specific global instruments such as the Mini-mental State Exam (MMSE), and this has led to some conflicting results. In spite of this, the consensus is emerging that global cognitive impairment is more commonly observed in those with apathy compared with those without [33]. In PD specifically, the few studies in the area have had generally consistent findings. Starkstein et al. [21] used a relatively extensive neuropsychological battery in 50 PD sufferers, 21 of whom scored above the cut-off on the AS (15 also had depression). They found no effect of apathy on the MMSE, but lexical fluency and time to complete Trails B were significantly worse in those with apathy. There were no differences found in tests of visuomotor tracking, set shift, concept acquisition, or auditory attention. Interestingly, those with apathy performed overall worse in time-dependent tasks (FAS and Trails B), but if this was corrected for, performance was equivalent to non-apathetic PD sufferers. The authors suggested that this finding supported a link between apathy and bradyphrenia. Pluck and Brown [1] compared the cognitive profile of PD sufferers with ‘high’ apathy (n = 17) with those with ‘low’ apathy (n = 28) as determined by a cut-off score of 38 on the AES-C. Of the high apathy group, only 13 did not have dementia, but the group was analysed as a whole. The key findings supported the notion of executive function being differentially impaired in the high apathy group. Specifically, slowness in performance was seen in the Stroop test, but also on executive tasks less dependent on speed of visual processing. Studies in AD have revealed that those with apathy had significantly worse word list learning, verbal fluency, set shifting and naming than a comparable group without apathy [40, 41].

Prospective longitudinal studies suggest that the presence of an apathy syndrome can worsen prognosis and is associated with a faster rate of cognitive and functional decline [12, 42, 43]. In a 4-year follow-up of a cohort of over 350 AD patients, the rate of apathy was noted to increase as the disease progressed, and those with apathy declined faster and had a more severe course compared with those without apathy [12]. Robert et al. [43] followed a group of 251 patients with amnestic mild cognitive impairment for a year, and found that those who converted sooner to dementia had initial higher rates of apathy. In a group of non-demented PD patients followed-up at a median period of 18 months, more apathy sufferers had converted to dementia compared with those who did not have apathy at baseline [42]. Furthermore, for the group who had not yet converted to dementia at follow-up, higher apathy was associated with more significant cognitive decline. Thus, it appears that apathy may be associated with more aggressive forms of AD and PD. It is not yet clear whether early intervention and amelioration of apathy will alter this poor prognosis.

Apathy may also have negative effects on physical aspects of AD and PD. Core features of apathy may include lack of initiative and interest, which can manifest in decreased motor behaviour and withdrawal from usual physical activities and hobbies, including activities of daily living. This was elegantly shown by ambulatory monitoring of the extent of motor activity in AD patients with apathy compared with those without apathy, demonstrating significantly less movement in those with apathy [44]. Sedentary behaviour in elderly demented people can lead to secondary physical complications such as deep vein thrombosis, urinary and respiratory infections and increased frailty. Although there is a growing recognition that exercise may be beneficial to those with a neurodegenerative disease, in the context of apathy, such potentially beneficial non-specific interventions as exercise may be difficult to implement. Other physical complications associated with apathy in dementia may be a decline in weight and nutritional status, as demonstrated in a study of over 600 community-dwelling AD sufferers where poor nutritional status was significantly associated with the presence of apathy [45].

The negative impact of apathy on disability levels and overall functional decline in PD can be significant. In a sample of 99 non-demented PD patients with apathy, clinician-rated apathy was strongly and significantly associated with higher levels of disability, as determined by activities of daily living rating scores [46]. In this study, a multivariate regression analysis revealed that apathy, together with later stage of disease and more cognitive impairment, accounted for 56% (p < 0.001) of the variance predicting disability. These findings are consistent with the literature in AD, where numerous studies have found higher levels of impairment in ADLs in those with apathy or depression [8, 45, 47, 48].

The effect of apathy on carers needs to be considered since the role of carers in chronic degenerative diseases such as AD and PD is significant. Psychiatric symptoms such as depression in the PD sufferer have been strongly associated with carer distress [4, 49], and this appears to be the case with apathy as well. However, the impact on carer burden of apathy has not been as well studied other than in those with significant cognitive impairment and dementia [50]. In our own study of 71 non-demented PD sufferers and their carers, a strong correlation between level of self-reported apathy (rho = 0.41; p <0.001) and carer burden, as measured by the Zarit Burden Inventory was found [51].

The cornerstone to managing apathy is recognising its presence, differentiating it from depression or other differential diagnoses, and developing an individualised care plan that is based on multidisciplinary input. Differential diagnoses, other than depression include the undertreatment of motor symptoms of PD, hypoactive delirium, sleep disturbances with excessive daytime sleepiness, medication side effects and disease progression. Other medical conditions, besides PD, may also present with an apathy-like syndrome and need to be ruled out. In particular, these can include systemic conditions common in the elderly such as thyroid disease, B12 or folate deficiency, cardiac conditions and malignancies.

If reversible causes of apathy have been excluded and the diagnosis of apathy is made, both non-pharmacological and pharmacological interventions need to be considered. Non-pharmacological approaches generally depend on motivated carers to activate and interest the affected person and provide external sources of stimulation to overcome the loss of internal drive and motivation. Occupational therapists and activity coordinators may develop specialised programs that can be continued by carers. Fostering physical activity through exercise may be helpful, but this often requires much dedication from carers to undertake such programs: the apathy sufferer may resist such interventions. A current French study examines the effectiveness of staff education in non-pharmacological intervention methods to manage apathy in older people with dementia in nursing home settings. This study involves a trainer providing guidance on structured activities designed to stimulate and involve the residents and is an example of an intervention that can be undertaken at a relatively low cost and with few adverse effects [Robert, pers. commun.].

From a pharmacological perspective, there is little evidence to guide therapeutic choice, although there is some evidence supporting the use of cholinesterase inhibitors in alleviating apathy symptoms in AD. In particular, studies with donepezil, the most commonly prescribed cholinesterase inhibitor, have shown reduction in apathy in AD as measured by the NPI [52, 53] or the AS [54]. Apathy was not specifically examined as an outcome measure in the few small studies of donepezil in PD [e.g. 55]. On the other hand, rivastigmine, the only cholinesterase inhibitor licensed for the treatment of PDD, does appear to be beneficial in this condition, as well as in AD and dementia with Lewy bodies [56-58]. Finally, galantamine, another cholinesterase inhibitor has been shown to be of benefit in improving clusters of behavioural symptoms comprising apathy [59]. There is no evidence in PD specifically. Memantine, an N-methyl D-aspartate receptor antagonist, does not appear to have a role in treating apathy in AD or PDD [60-62].

Evidence to support the use of drugs other than cholinesterase inhibitors is rather limited. Stimulants such as methylphenidate may be effective, but they carry significant risk of precipitating psychosis in PD or causing insomnia or appetite loss, particularly if cognitive impairment or advanced disease is present. Modafinil, a non-stimulant wakefulness-promoting agent, may have a role in treating both excessive daytime sleepiness and apathy [63]. However, robust evidence for its efficacy in PD specifically is lacking.

Dopamine-enhancing medications have long been of interest in alleviating the symptoms of apathy. For example, there is evidence that bupropion, a dopaminergic antidepressant, is effective in enhancing motivation [64]. Amantadine, an N-methyl-D-aspartic acid receptor antagonist, which may indirectly enhance dopaminergic transmission, may have a role in alleviating frontal-type behavioural disturbances in dementia, and is generally well tolerated in elderly patients. It too may have a role in improving apathy; however, the evidence for this in PD and AD is not extensive [65, 66]. Dopamine agonists, particularly pramipexole, which has the most specific D3 receptor activity, may be helpful, and increasing the dose of agonists in apathetic PD sufferers may improve apathy and mood symptoms. A recent meta-analysis of seven randomised controlled trials suggested that of the 70 PD patients with some degree of motivational loss, 63.2% had improvement in motivation with pramipexole compared with 45% of those on placebo (odds ratio = 2.06) [67]. This approach, however, needs to be undertaken cautiously since many apathy sufferers will be older, have advanced disease and therefore may be unable to tolerate the cognitive and psychiatric side effects of higher doses of dopamine agonists. Another approach may be to increase the overall daily dopaminergic load with levodopa and other, better tolerated dopamine replacement therapies. Finally, the role of antidepressants in the treatment of apathy needs to be considered. Since the overlap of depression and apathy is high, and some antidepressants (e.g. sertraline, venlafaxine) are slightly stimulating, PD patients with depression and apathy may benefit from a course of antidepressants. However, since as seen above there is some evidence that SSRIs may cause apathy, patients on SSRIs need to be closely monitored for worsening, or emergence of apathy symptoms. Other antidepressants which may have a role in treating apathy are the monoamine oxidase inhibitors. These are used clinically in some centres, but the evidence supporting their use is very limited.

Another intervention that may be of interest for treating apathy in PD is deep brain stimulation. Current evidence is too conflicting for any clear recommendations to be made [68-70].

We have highlighted various aspects of apathy in neurodegenerative disorders such as PD. The significant negative impact that the presence of apathy can have in AD, as well as in PD, has been outlined. There is a need for more detailed prospective studies to examine these and other apathy-related issues further, as well as trials of pharmacological and non-pharmacological interventions for the management of apathy.

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