Relation of Apathy to Dementia in Patients with Parkinson’s Disease

Apathy is often defined simply as a general loss of motivation. Marin (1996) added to this definition a reduction in goal-directed behavior and thought with few displays of emotion. Although a consensus within the literature has not been reached regarding whether apathy is a neuropsychiatric syn­drome or if it is a syndrome by itself, this will not be covered in this post. The reader is referred to previous debates of this topic (Starkstein and Leentjens 2008; Marin 1996). Patients with Parkinson’s disease (PD) are not the only clinical group that manifests apathy. Other groups include stroke patients, Alzheimer’s disease patients, patients with dementia, major depression (Marin, Biedrzycki, and Firinciogullari 1991), and other disorders involving the basal ganglia such as parkinsonism (Sockeel et al. 2006′ . The prevalence of apathy in patients with PD is found to vary between 16.5% (Aarsland et al. 1999) to 45% (Isella et al. 2002), with one study even reporting apathy in as many as 51% of their sample of patients with PD (Kirsch-Darrow et al. 2006). In addition, apathy has been found to be the most distressing neuropsychiatric problem to caregivers (Leiknes et al. 2010).

In this post, we will review the neurobiology of PD. Then we will provide a literature review about studies that have previously been con­ducted to evaluate apathy in PD and relate apathy to the development of dementia. We will then describe three subtypes of apathy that have been linked to basal ganglia and fronto-subcortical circuits and how a patient with PD would present with the respective type of apathy. Is one subtype of apathy predictive of progressive dementia over another? Finally, we will explore how these patients ‘ quality of life can be increased through better diagnosis and treatment.

NONMOTOR SYMPTOMS OF PARKINSON’S DISEASE WITH A FOCUS ON APATHY

Parkinson’s disease (PD) is classically regarded as a degenerative move­ment disorder of unknown etiology due to a loss of dopaminergic neurons in the basal ganglia, particularly within an area known as the substantia nigra pars compacta (SNc). The basal ganglia are a set of structures within the midbrain that are responsible for learning and coordinating move­ment such as swinging a baseball bat, walking, initiating, maintaining, or carrying out a particular behavior. The loss of dopamine (DA) within the SNc contributes to a variety of motor and nonmotor problems that are associated with PD. The gamut of such nonmotor problems include changes in personality (Poewe et al. 1983; Menza et al. 1993; Menza 2000; McNamara, Durso, and Harris 2008), sleep disorders (Chaudhuri et al. 2002; Lauterbach 2007; Stavitsky et al. 2008), pain (Chaudhuri, Healy, and Schapira 2005), falls (Chaudhuri et al. 2005), anosmia (Cramer, Friedman, and Amick 2010), impulse control disorders related to gambling, sexual paraphilias, buying addictions, or binge eating (Ferrara and Stacy 2008; Lim, Evans, and Miyasaki 2008; Wolters, van der Werf, and van den Heuvel 2008)   ,  deficits in executive cognitive dysfunction (McNamara, Durso, and Brown 2003), and mood changes including depression (Lew 2007) and apathy ( Lew 2007 ; Simuni and Sethi 2008 ; Aarsland, Marsh, and Schrag 2009)    . More than likely, some of these nonmotor symptoms are present before the actual display of motor symptoms (Siderowf and Stern 2008; Tolosa et al. 2009). In this post, we will focus on apathy.

Clinicians and neurologists are taking the nonmotor symptoms of PD, including apathy, more seriously since the revised Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; Goetz et al. 2008), part 1, which addresses nonmotor aspects of daily living in an interview format between the clinician and the patient. One of the questions is about apathy and assesses if the patient feels indifferent to doing activities or to being with people. The clinician and patient decide what the best response is for the patient, 0 indicating there have been no changes in the last week to 4, there is a complete loss of initiative and the patient is passive and withdrawn. Kirsch-Darrow et al. (2009) evaluated this new apathy question on the UPDRS against the Apathy Scale (AS) used by Starkstein et al. (1992). Kirsch-Darrow and colleagues found that this one apathy item has low specificity if subjects indicate a 1 and it has low sensitivity with a cut-off of 2 or better. As a result, they recommend that users of this apathy screener question exercise prudence when evalu­ating patients as there is a high probability of missing patients who need to be managed for clinical apathy.

Apathy mimics some of the symptoms of depression but can be dif­ferentiated from depression (Marin 1996) . Approximately 40% of PD patients evidence some degrees of a depression (Cummings 1992; Cum­mings and Masterman 1999). Depression in patients with PD is differ­ent from depression in psychiatric populations because patients with PD have greater anxiety and less negative self-reflecting, or self-ideation, fewer feelings of guilt, and less suicidal ideation. Moreover, patients with lower levels of 5-HIAA (5-hydroxyindoleacetic acid, a metabolite of serotonin), a past history of depression, and more functional disabil­ity usually have a greater risk for developing depression in PD. Being female, having an early age of onset of PD, and greater left-brain involve­ment may all be risk factors for depression in PD as well (Cummings and Masterman 1999). What is more, those patients who exhibit more bradykinesia and gait instability than tremor are more likely to develop depression (Cummings 1992) whereas the apathy studies have reported there is more tremor and akinesia as the predominant motor symptoms in patients with PD (Kirsch-Darrow et al. 2006). In addition, depressed patients with PD have greater frontal-lobe dysfunction and greater involvement of dopaminergic and noradrenergic systems than nonde­pressed patients ( Cummings 1992 ; Starkstein et al. 1992 ).

NEUROBIOLOGY OF PARKINSON’S DISEASE

In the initial stages of PD, the loss of dopamine within the brain is chiefly localized to either the left or right hemisphere. Depending on which hemisphere has a greater depletion of dopamine, the display of motor symptoms is on the contralateral side of the body (Amick, Grace, and Chou 2006; Djaldetti, Ziv, and Melamed 2006). For example, if there is a greater depletion of dopamine in the left hemisphere, then tremors may first begin in the right hand and vice versa. There are two major dopamin­ergic pathways within the brain that are affected in PD. These include the nigrostriatal—or movement—pathway and the mesolimbic—or reward— pathway. The nigrostriatal pathway sends dopamine from the substantia nigra to the basal ganglia (Bjorklund and Lindvall 1975) and the mesolim­bic pathway sends dopamine from the ventral tegmental area (VTA) to the striatum, the limbic system, and the frontal cortex (Lindvall et al. 1974; Swanson 1982). Apathy can result from lesions to the basal ganglia and to these fronto-subcortical circuits (Levy and Dubois 2006; Dujardin et al. et al. 2007). Understanding the connections and projections of the dop­aminergic neurotransmitter system will help us to learn how these neuro- anatomical areas can be disrupted and produce apathy.

PREVIOUS RESEARCH ON APATHY IN PARKINSON’S DISEASE

As described above, apathy is a behavioral syndrome that is the result of a loss of motivation and incentives, a lack of emotion, and no exhibition of goal-directed behavior or thought, with apathy not being attributable to a loss of consciousness (Marin 1996). Levy and Dubois (2006) extend this definition by stating that apathy is the result of a loss of voluntary and intentional behavior on behalf of the self; this behavior can be measured and observed. What are the signs of a patient who is apathetic? This is the patient who does not comply with medication regimens, who says he is going to show up for appointments but does not, and who, in general, just does not do what he is asked to do (Marin 1996). In addition, patients who display apathy are more likely to not complete questionnaires about themselves and exhibit negative personality traits. These patients may make statements such as “I do not care about being around people” or “I do not have a desire to learn anything new.”

Several types of scales have been developed to measure apathy, but none have been established as the gold standard (van Reekum, Stuss, and Ostrander 2005). One such scale is the Apathy Evaluation Scale (AES; Marin 1996)  with a patient and an informant version. There are four subscales in addition to a Global Severity Score: Cognitive, Behavior, Emotional, and Other. The AES has been validated in Alzheimer’s disease patients, right hemisphere stroke patients, patients with major depression, and healthy elderly controls, with internal consistency reliability ranging from 0.86 to 0.94 and test-retest reliability fluctuating between 0.76 and 0.94. The con­vergent validity coefficients range from 0.43 to 0.72 (Marin, Biedrzycki, and Firinciogullari 1991). Starkstein et al. (1992) evaluated a 14-item ver­sion of the Apathy Scale (a brief form of the AES) in patients with Parkin­son’s disease. They found interrater reliability to be r = 0.81 and internal validity to be alpha = 0.76. Another scale that has been used to measure apathy is the Lille Apathy Rating Scale (LARS; Sockeel et al. 2006). The LARS focuses on four of the core features of apathy including intellectual curiosity, self-awareness, emotion, and action initiation. Between-items reliability was established to be 0.80 whereas between-subscales reliability was 0.74. The test-retest coefficient was found to be 0.95 with split-half reliability at 0.84. Concurrent validity was r = 0.87 (comparing the global scores of the AES and the LARS). Moreover, the Neuropsychiatric Inven­tory (NPI; Cummings 1997) is a tool that is used to measure neuropsy­chiatric behavioral changes in patients with dementia, but there is only one question that assesses global apathy. And finally, Robert et al. (2002) developed the Apathy Inventory (AI) specifically for those patient groups who have suffered brain damage. Like the NPI, it can be used with a care­giver or next-of-kin. The AI is a global measure of apathy that consists of patient and caregiver versions to measure the core features of apathy: lack of emotion, no initiative, and a loss of interest in previous activities and people. Internal consistency for reliability was found to be alpha = 0.84, but this applies only to the caregiver version of the AI. Interrater reliability was high with Kappa coefficient = 0.99.

It has not yet been established whether apathy is related to a stage of disease or to greater motor impairment. There also is not a consensus on whether there is an overall decline in Mini-Mental State Examination (MMSE) scores and general cognitive functioning in patients with PD who suffer from apathy (Levy et al. 1998; Pluck and Brown 2002; Starkstein et al. 1992; Starkstein and Leentjens 2008). On the other hand, some studies have shown that degrees of apathy predict risk for dementia, but these studies have not always specified exact subtypes of apathy. Below is a review of apathy studies previously conducted with patients with PD.

Starkstein et al. (1992) assessed apathy in a group of 50 patients with idiopathic PD using the Apathy Scale (AS). They found that only 12% of their sample exhibited apathy without depression whereas 30% had both apathy and depression; patients with apathy exhibited greater difficulty with timed neuropsychological tests and verbal memory tests. Pedersen and colleagues (2009) conducted a longitudinal study with a community- based sample of 139 patients with PD in western Norway. They found that patients with apathy were demented at baseline and often at follow-up (79 patients of the original 139 patients were reassessed four years later). At follow-up, 29.1% of their sample was demented with 63.6% of patients displaying apathy to also be demented. They concluded that apathy may be a result of the natural, biological course of PD for those patients with more advanced disease but that the emergence of dementia may be related to the nondopaminergic circuits and the fact that the patient sample was older.

Pluck and Brown (2002) evaluated apathy in 45 PD patients and in a control group of 17 patients with osteoarthritis. They found that the patients with PD had higher levels of apathy. Those patients with PD
who were classified as having high apathy performed worse on verbal fluency and the Stroop test than those who scored low on apathy. They hypothesized that those patients, 7.1% of the sample, could possibly be demented since they did so poor on the cognitive battery. Cognitive impairment was also found to be related to apathy, but disease progres­sion or stage of disease was found to be unrelated to levels of apathy, possibly indicating a subtype of apathy. Furthermore, apathy was not related to anxiety scores or to depression and was not predicted by stage of disease or duration of disease. Kirsch-Darrow et al. (2006) investi­gated apathy in 80 idiopathic patients with PD and in 20 patients with adult-onset dystonia using the short version of the AES. They found that 51% of patients with PD experienced apathy with almost 29% experi­encing apathy and depression together. None of the patients with dys­tonia experienced apathy. They also found a small positive correlation between age and apathy score, which previous studies have not. They concluded that apathy is more than likely a defining feature of PD and that apathy is not a symptom of depression and occurs independently of depression since the anterior cingulate-mesial frontal cortex is more damaged in PD.

Finally, Cramer, Friedman, and Amick (2010) examined olfaction in apathy in patients with PD by administering the AES. They found that greater apathy indicated greater olfactory impairment. Their reasoning was that smell is intricately tied to emotions and since olfaction areas are anatomically close to limbic areas within the brain, studying the overlap of these areas is important to understanding how apathy can be a part of the physiological changes that emerge during the course of PD. They further recommend that more research be tailored to deciphering the link between dementia and motor-symptom severity to be sure apathy scores or olfactory test scores are not influenced by these factors.

Sockeel et al. (2006) developed the Lille Apathy Rating Scale (LARS). They found that this new measure is a useful tool in separating apathy from depression in patients with PD. Of 159 patients with probable PD, 32.1% were found to have apathy in a study conducted by Dujardin et al. (2007) to validate the LARS using the same patient sample from the Sockeel group. Dujardin and colleagues found that having a low level of cognitive functioning was the main contributing factor to more severe apathy. Motor-symptom severity did not contribute to apathy, and the occurrence of apathy is not dependent on depression. Overall, the LARS was reliable in differentiating various types of apathy among PD patients, the types of apathy including none, slight, moderate, and severe. Dujar- din et al. (2009) examined dementia in 20 apathetic patients with PD and
in 20 nonapathetic patients with PD using the LARS. They administered various tests of executive function including the Stroop, word generation, a letter and number sequencing test, and the oral version of the Symbol Digit Modalities test. Apathetic patients with PD performed much more poorly on this cognitive battery with reduced response inhibition and action initiation. At 18 months follow-up, dementia was much more com­mon in patients who were apathetic, suggesting that apathy can predict later dementia. Only one case of dementia was seen at follow-up in the nonapathetic group. Dujardin et al. (2009) allude to a subtype of apa­thy known as cognitive-affective apathy (Levy and Dubois 2006) that is present in this sample of patients. More about this subtype of apathy is explained below.

Levy et al. (1998) used the Neuropsychiatric Inventory (NPI) to assess apathy in PD patients. They found that depression and apathy were uncorrelated. PD patients had greater cognitive dysfunction as evidenced by the MMSE and this was correlated with apathy. They also had greater levels of depression. Oguru et al. (2010) found in their study that 60% of Japanese patients with PD exhibited apathy and 56% of these patients exhibited depression. Of their sample, 43% displayed apathy and depres­sion together, and 8% displayed dementia. After removing patients with depression and dementia, they found that only 15% of their sample dis­played apathy as the sole behavioral disorder. They concluded that it is possible that apathy can occur independent of depression in PD. Those patients with apathy had higher levels of depression and worse cognitive functioning. Oguru and colleagues hypothesize as did Kirsch-Darrow et al. (2006) that impairment to the mesial frontal-anterior cingulate circuits underlie the production of apathy.

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Pedersen et al. (2010) administered the NPI to a group of community- dwelling PD patients who had never begun taking medicine for their PD. Of their sample, 25 patients were diagnosed solely with apathy whereas 14 patients were diagnosed with depression and apathy together. Apathy in patients with PD was significantly associated with male gender, worse motor scores, high depression, and impairments in attention/executive deficits. No correlation was found between apathy and increased cogni­tive impairment as has been found in other studies, and no controls were diagnosed with apathy. Newly diagnosed PD patients who had never taken medicine and had apathy indicated that their apathy was more than likely the result of a neurobiological change. Aarsland et al. (1999) found that 4.3% of patients with untreated PD who were assessed with the NPI had apathy and no depression whereas Pedersen et al. (2010) found that 8.3% of untreated patients with PD did.

Finally, Robert et al. (2002) used the AI to rate apathy in Alzheimer’s disease patients, mild cognitive impairment patients, and patients with PD. They found that the patients with PD rated their global apathy higher than the other two neurological groups and showed that they were aware of their apathy. This was not seen in the nonapathetic patient group. Robert et al. (2002) recommend that future research try to unravel the cog­nitive, behavioral, and emotional components of apathy.

In summary, it is inconclusive from this previous research if apathy is a result solely of the disability of PD or if it is a neurobiological problem resulting from PD. Most of the researchers conclude that apathy is a mul­tifactorial neuropsychiatric problem and is probably a result of the under­lying neurobiology in PD. Apathy, furthermore, appears to be a strong predictor for development of a later dementing process. However, PD is a complicated neurodegenerative disease. There are different ages of onset of disease with different disease courses. Even diagnosing the disease can be difficult with up to 25% of patients being misdiagnosed (Tolosa, Wenning, and Poewe 2006). In addition, it is impossible gauge how much loss of dopamine has occurred in the brainstem and progressed to the midbrain and to the cortex. As a result, even though we have these data on apathy, research groups are still trying to establish the best method to measure apathy in addition to consistently detailing the specific subtypes of apathy we would see in patients with PD based on the type of lesion in the basal ganglia and fronto-subcortical circuits and resulting cognitive batteries.

SUBTYPES OF APATHY IN PATIENTS WITH PARKINSON’S DISEASE

Levy and Dubois (2006) discuss three models of apathy (based on Stuss, van Reekum, and Murphy 2000) including emotional-affective, cognitive-affective and auto-activation deficit, that are linked with pro­files of dysfunction within the basal ganglia and the frontal lobes. Even though these specific subtypes of apathy are described, the occurrence of dementia along with the presentation of apathy in patients with PD is not uniform (Starkstein et al. 1992; Levy and Dubois 2006; Pluck and Brown

2002)      . However, these models can serve as heuristics to evaluate apathy while dementia is concurrently assessed not only in patients with PD but in other patient populations as well. We revisit these models of apathy for two purposes: (1) to redirect the research community to these subtypes, and (2) to begin thinking of ways by which these subtypes of apathy are expressed in patients with PD.

Emotional-Affective Apathy

Emotional-affective apathy is linked with dysfunction in the orbital- medial prefrontal cortex (PFC) and the limbic regions of the basal ganglia including the ventral striatum and ventral pallidum (Levy and Dubois 2006). Lesions to the orbital-medial PFC often result in emotional blunt­ing, poor judgment related to actions and consequences, and the perfor­mance of actions based on feelings and emotions alone. Robert et al. (2002) report that in their study that mild cognitively impaired (MCI) patients differed on the lack of initiative domain, but this could not be adequately investigated due to the small sample size. They suggest that future stud­ies should investigate whether this domain is indicative of a progressive change toward dementia. In patients with PD who exhibit this type of apa­thy, we would see the emergence of impulsive behaviors and a reduction in self-initiated behaviors, possibly increased novelty seeking and a lack of response to rewarding behaviors. There would be a lack of disregard for any consequences of behavior. Many of these types of behaviors are seen after these patients have been medicated with dopamine agonists over a long period of time (Weintraub 2008). The neurotransmitter dop­amine responds to reward, but these patients are less likely to recognize the reward; therefore, there is no recognition of a rewarding and benefi­cial outcome (Daw and Shohamy 2008). When we are surprised by a new outcome and our dopamine receptors respond, it is considered that we have learned from this response. Daw and Shohamy (2008) argue that the striatum is where this learning occurs in the basal ganglia. One type of test that can evaluate this form of apathy is the Gambling Task developed by Bachara (Levy and Dubois 2006). This form of apathy is difficult for caregivers to manage because these patients may perform activities that can be quite embarrassing to the family. In addition, there is also a loss of interaction with the family on behalf of the patient. Activities of daily liv­ing such as maintaining good hygiene are also neglected.

Cognitive-Affective Apathy

Cognitive-affective apathy involves lesions of the dorsolateral PFC and the dorsal caudate nucleus, the internal portion of the globus pallidus, the lateral substantia nigra pars reticulata, and the anterior thalamic nuclei (Levy and Dubois 2006). Patients with PD who suffer from this type of apathy perform poorly on tests of executive cognitive functioning and planning including the Stroop, Trails, categorical verbal fluency, the Tower
of London, and the Wisconsin Card Sorting Test (Levy and Dubois 2006). Each of these tasks requires the patient to plan, to establish a set of rules, to maintain the set of rules, and then be able to shift the rules to exhibit cognitive flexibility. These patients also have difficulties with working memory in that they forget the mini goals they are working towards in these various tasks (Levy and Dubois 2006). An as example, patients with PD who have this type of apathy are those who more than likely exhibit the greatest deficits on the Tower of London (TOL) planning task and who become frustrated because they cannot do it. From personal testing expe­rience, some apathetic patients with PD have not gotten farther than part five of nine of the TOL task and do extremely poor on word-generation tasks. Much of the research as discussed in the literature review indicates that this subtype of apathy is common.

Auto-Activation Deficit

Auto-activation deficit is the most debilitating form of apathy. The lesions are located in the medial PFC and may be large frontal lesions or white-matter lesions and in the cognitive and limbic areas of the basal ganglia, particularly in the internal portion of the globus pallidus (Levy and Dubois 2006). In this form of apathy, whatever information is gleaned from the external environment does not elicit any behavior from the basal ganglia to reach the output systems. The basal ganglia and frontal lobes need input to communicate with each other. When this input cannot reach the desired brain areas, such as the pallidum, there is no feedback loop providing information to the frontal lobes about what behavior to per­form. Patients with this type of apathy remain motionless and respond to needing a “little” push each day or having someone tell them what to do. If they are given some form of external environmental stimuli, they can move and carry out behaviors for a short period of time, but this is not sustained (Levy and Dubois 2006). As a result, there is no voluntary action that is carried out by the patient. Patients with PD who exhibit this type of apathy would exhibit all of these symptoms. It will be especially important to identify those patients who suffer from this type of apathy early, with treatment interventions aimed towards the patient and the caregiver.

SUGGESTIONS FOR TREATMENT AND FUTURE RESEARCH

Any treatments for apathy thus far seem to be targeted only to global apathy and not to any specific subtype of apathy. Dopaminergic agents such as bromocriptine and amantadine, in addition to amphetamines,
atypical antipsychotics, and acetylcholinesterase inhibitors, might be ben­eficial for some patients with apathy. However, which drug is effective for which type of apathy has yet to be described (van Reekum, Stuss, and Ostrander 2005). It could be possible that one type of medication may not be suitable for emotional-affective apathy but is ideal for cognitive-affec­tive apathy and vice versa. As Stuss, van Reekum, and Murphy (2000) point out, until we have a better grasp as to the underlying neurobiologi- cal and neurochemical manifestations of apathy, any pharmacological or behavioral therapy will not be useful.

As several authors recommend ( Kirsch-Darrow et al. 2006 , 2009 ; Stark- stein and Leentjens 2008), better measurement and methodologies of studying apathy can assist pharmaceutical companies in developing bet­ter medications to assist with the problems associated with apathy includ­ing motivation and emotion. What are the risk factors for apathy? How can we better predict those patients who will develop apathy versus those who do not? As we have discussed above, however, there are various sub­types of apathy that patients may endure. It is problematic that there are no specific treatments tailored toward these individual subtypes of apa­thy. Since the definition of apathy is still not ideally defined, what we may be categorizing as apathy within PD may be something entirely different (Starkstein and Leentjens 2008). However, we need to find other avenues of treatment that are nonpharmacologic, especially for patients with PD since they are already taking very detailed medication regimens.

One of the first steps is for clinicians to become better educated about the signs and symptoms of apathy (van Reekum, Stuss, and Ostrander 2005)       . Furthermore, educating caregivers and patients that apathy is a symptom of PD will help them to be better prepared in the event the patient becomes apathetic (Kirsch-Darrow et al. 2006). Better education can then possibly lead to rehabilitative programs of which there currently are none specifically tailored to patients with PD and apathy. Stuss et al. (2000)    report on a study that attempted therapy for apathetic patients who were not patients with PD. Kopelowicz and colleagues (1997) enrolled a total of six subjects with schizophrenia, three with and without deficit syn­drome. In other words, they exhibited the amotivational syndrome that is typically found in schizophrenia. The authors implemented a social-skills training program that lasted for 12 weeks. The schizophrenic patients who did not have the deficit syndrome improved, but those with the deficit syndrome were not influenced by the social-skills training. Other types of rehabilitation that were discussed refer to teaching compensatory strate­gies and training executive cognitive functions (Stuss, van Reekum, and Murphy 2000). The paucity of research on rehabilitation of patients with apathy indicates that better emotional and cognitive therapies need to be developed (Aarsland et al. 1999). In the end, though, it will take dedicated caregivers and clinicians to work with these patients.

One factor not addressed in current studies of apathy in patients with PD is the impact of PD subtype on apathy. Patients with left-onset dis­ease are known to significantly differ along an array of clinical variables from PD patients with right-onset disease. For example, there are differ­ences in language production among left-versus right-onset PD patients. Could the language production among these patients be linked to specific types of apathy (Pluck and Brown 2002)? What type of apathy is seen in patients with left-onset versus right-onset PD? Knowing this information may tell us something special about the various forms of apathy that are seen in these patients. More than likely, there is a different neurobiol­ogy and neurochemical basis depending upon the side of onset exhibit­ing a different presentation of apathy. Additionally, although it is clear that apathy is a strong predictor of later dementia, it is uncertain as to whether any particular subtype of apathy more strongly predicts demen­tia than the other subtypes of apathy. Researchers investigating apathy in patients with PD should report their data with respect to side of onset to provide additional information by which the tangled web of apathy can be addressed.

Although not all patients with PD will have apathy, this neuropsychi­atric symptom is not to be ignored. As Cummings (1997) indicates, those patients who suffer from dementia may be a subgroup with neurobiologi- cal changes occurring at a different rate than those without dementia. This equally applies to our patients with PD who have apathy. They are a spe­cial subgroup of patients with PD who need to be treated as such. These patients are an interesting group to study to learn more about how such symptoms can develop from a neurodegenerative disease and can help us eventually find better ways to treat and to manage apathy in patients with PD and to possibly predict whether apathy definitely predicts later dementia.

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