Introduction

My non-consensual relationship with Parkinson’s disease (PD) officially began in June 2016. I was diagnosed by a great doctor who seemed genuinely concerned that he was about to tell me, at 35, that I had an incurable brain disease. He took his time to explain the motor symptoms of PD and I left his office feeling like I understood the changes my body would undergo over time – my tremors would get worse, my muscles more rigid, and my movements slower. Simple. Difficult prognosis, yes; but relatively simple to understand. I honestly wasn’t too bothered, partly because my doctor had also taken the time to discuss the different treatment options, and I felt equipped to handle whatever lay ahead. If only… When I think about it now, I don’t recall him talking about the non-motor symptoms of PD or how drastically they would affect not just me, but everyone around me. Three and a half years into my diagnosis, I am only just beginning to understand how incredibly challenging these non-motor symptoms can get and how ill-prepared I was to deal with them." (Thomas 2019)1

This is from a blog by a patient with PD sharing his experience with the disease. He explains that despite exceptional efforts made by his doctor to prepare him for the motor symptoms of PD, regrettably, no efforts were made to prepare him for the non-motor symptoms, especially apathy. 

Dr James Parkinson first described PD based on the motor symptoms; he called it ‘Shaking palsy’. To date, the motor symptoms of PD are the main targets for disease identification and for counselling patients and caregivers, and the therapeutic research that aimed at alleviating  effect of motor symptoms on patients’ quality of life.

Non-motor symptoms, such as apathy, anxiety and depression tend to be ignored, although they have a great impact on a patient’s quality of life and wellbeing.2 Apathy may present alone in PD or, more commonly, is associated with dementia, or cognitive impairment, or both.3 As I will discuss later, the prevalence of apathy in PD varies widely based on the characteristics of the study population and the diagnostic criteria.4

Clarke and his associates reviewed 15 apathy scales for validity and reliability and found that the Apathy score (AS), the Apathy evaluation scale (AES) and the Neuropsychiatric Inventory (NPI)-apathy subscale are reliable and valid for various neuropsychiatry disorders. PD specific scales such as the Unified Parkinson's Disease rating scale (UPDRS) do exist; however, its reliability has not yet been established (at time of this review), while the Lille Apathy Rating Scale (LARS) has been reported to be reliable and valid.5  Dimensional Apathy Scale (DAS) was proved to be valid and reliable for patients with  PD by Radakovic et al.6 Despite many studies on apathy in PD, the diagnostic criteria and rating scales used in them are not uniform.

‘I started to notice that for depression I … feel that …you feel down, you feel teary. But apathy is totally different, apathy just is, you just don’t really want to get involved and really there’s nothing in my life that’s horrible so I couldn’t really understand why I felt so …you know disengaged, definitely disengaged.’ 2

This is an explanation by a PD patient about one of the most challenging symptoms in PD: Apathy, which is very common2 and very demanding.7

In this paper, the definition of apathy is investigated in more detail, as well as its prevalence in patients with PD, and its effect on patients and caregivers. Biomarkers that show diagnostic potential for apathy in patients with PD are also emphasised. Many direct quotes from patients are used in this paper since they are the best ones to describe the amount they suffer owing to this symptom.

What is apathy?

The first challenge regarding apathy is the absence of a consistent definition.7 Recently, Mele and his colleagues reviewed 362 scientific papers about apathy in patients with PD, two-third of which were published between the year 2010 and 2019. They reported 20 screening tools, some of which, including the AS and LARS, were validated for use in patients with PD; however, the majority were not. 64% of the included studies used non-recommended apathy screening tools, therefore, they openly stated that the recommendation based on these studies could be questionable.

So, what is apathy? The word originates from the Greek word  ‘pathos’, which means passion.8 In his 1991 article, Marin proposed that apathy is a syndrome. He defined it as a lack of motivation, determined based on the patient’s age, culture, and previous motivation level, and which is not caused by any impairment in cognition, level of consciousness, or emotional distress. He described the following three diagnostic criteria:

  • A:Motivation is absent in goal-directed behavior, goal-directed cognition, and reduction in emotions that accompany goal-directed behavior.
  • B: Criteria A not due to cognitive impairment or emotional distress or decreased level of consciousness.
  • C: Seems like a repetition of B. He emphasises again that the absence of motivation is not due to emotional distress.

Ten years later, Starkstein and his colleagues modified Marin criteria into the 14-items AS, where A and B of the Marin criteria are almost the same; however, they added that the absence of motivation causes remarkable deterioration in different aspects of a patient’s life (social,  occupational, and others). The 14-items  AS can be used by clients and their caregivers.9 This definition and diagnostic score have been used by many researchers.10-12

The Starkstein Criteria were modified further in 2009, and were the first diagnostic criteria launched and agreed upon by three Associations in Europe: the French Association for Biological Psychiatry, the European Psychiatric Association, and the European Alzheimer Disease Consortium.13 In the new criteria, there are four sections A-D, to be fulfilled to diagnose apathy. In 2018, the criteria were revised again with little modification and endorsed by the international consensus group.14 This is the diagnostic criteria for apathy that was published in 2018:

  • A: there is a quantitative reduction in goal-directive activity, compared to the patient’s previous level, in four dimensions of apathy: cognition, behavior, emotion, and social. It can be reported by patients or their caregivers.
  • B: The presence of two out of three of the following for at least one month and most of the time.
    • B1: reduction in goal-directed activity in behavior or cognition
    • B2: Lack of or reduced emotion
    • B3: Lack or reduced social interaction.
  • C: There is a substantial negative effect on a different aspect of a patient’s life due to A and B
  • D: A and B are not caused by physical incapability, substance abuse, level of consciousness, or dramatic change in the patient’s environment.

In 2020, Chong and his panel provided a more comprehensive and accurate interpretation of the above diagnostic criteria. Apathy was defined  as ‘a clinical syndrome characterised by a reduction in self-initiated, goal-directed activity, which is not driven by a primary motor or sensory impairments, or other comorbidities such as drug intoxication or intercurrent illness.’15 They supported the notion that Apathy is a result of not appreciating the value and rewards of a particular act. They described four types of apathy:

  • Behavioural apathy: It describes the desire in regards to the activity of daily living or/and goal-directed behaviour when it is reduced or not maintained.
  • Cognitive apathy: The reduction in curiosity for knowledge or/and production of ideas. It is manifested as a decreased interest in solving a problem or participation in an activity that challenges cognition.
  • Emotional apathy: A reduction in emotional expression and reaction. It is also called emotional blunting.
  • Social apathy: a noticeable decline in the previous level of interaction and participation in social activities.

It is still not clear whether patients with apathy will have all the four types or they may have one type without the others .

How common is apathy in Parkinson's disease?

In 2009, Oguru and his colleagues from Japan studied 150 patients with idiopathic PD. They used Starkstein’s criteria and Beck Depression Inventory-II to diagnose apathy and depression, respectively. They found that 17%, 43%, and 13% of the patients had apathy without depression, both depression and apathy, and depression without apathy, respectively.16 They concluded that apathy must be distinguished from depression to avoid unnecessary prescription of anti-depression medication.

One meta-analysis of 23 studies from the year 1992 to 2014 with 5,388 patients with PD demonstrated that the pooled prevalence of apathy in patients with PD was approximately 40%; however, 22% of them have apathy without depression or cognitive decline.17 All the included studies used one of the apathy scales that was found to be valid and reliable (as mentioned in the study by Clarke et al).

Interestingly, they found that apathy rate diminishes with increasing disease duration. The prevalence of depression among apathetic patients was 50%, which corresponds to the finding by Oguru et al.  in 2009; that is, most apathetic PD patients have depression. However, both studies proved that apathy is a separate symptom, and not a feature of depression.  

Pederson et al performed a population-based study in which 232 patients with PD were recruited.18 In this study, they used the UPDRS and found that 38% of patients have apathy, 9% only had apathy without depression or cognitive impairment, 10% had apathy with depression, 11% had both dementia and depression, and the minority had apathy with dementia without depression. Therefore, there was a high prevalence of apathy among patients with PD; however, the rate of coexisting depression was not very high.

Skorvanek et al used the AS and studied 106 elderly patients with PD and they found that the prevalence of apathy was 54%, and only 11% had apathy without depression.19

Aarsland et al. used NPI, and studied 176 patients with early-stage drug-naïve patients with PD and compared the results with that of 166 healthy participants. Apathy was diagnosed in 27% of patients with early untreated PD compared to 1% of the control group.20 Apathy was more common than sleep disturbance and anxiety, which were 18% and 17%, respectively. A higher prevalence of apathy among newly diagnosed PD patients was also found in the AMINO study (52%).21

Why we should not ignore apathy?

The following quote comes from PD patients, explaining how apathy affects their life:

"We no longer enjoy the things we used to and we become more apathetic. It's not that we DON'T care, it's that we CAN'T care."22

"Apathy, brain fog, and chronic pain only begin to scratch the surface of a long list of PD non-motor symptoms, yet these three symptoms alone are enough to sway the decision-making process of many aspects of my life: they influence my desire and ability to exercise, shower, eat healthily, take my medication, articulate my thoughts, rebut an argument, attend social gatherings, walk my dog, cook, do laundry, write this article, and a host of other things. The seemingly simple act of getting through one’s daily activities requires constantly having to drown out the voices of resistance from these symptoms – Apathy shouts out “Please leave me alone, I’m not interested in doing anything today!”; Brain Fog says “That’s a little complex, don’t you think?”; and Chronic Pain snorts “You might want to think twice before you do that!”. The impact is constant. The impact is iterative. The impact is real… very, very real."

Apathy has a significant impact on a patient’s quality of life, as understood from the above statements made by patients with PD. It was mentioned earlier that a significant number of patients with apathy also have depression; however, there are many other negative impacts of apathy on patients and their caregivers.

Apathy decreases functioning and quality of life

A research group recruited 557 newly diagnosed PD patients from 102 outpatients clinics in 82 communities across Spain21 to determine the impact of apathy on health-related quality of life (HRQL). They used the LARS as a diagnostic tool for apathy and the EuroQol-5D questionnaire for assessing HRQL. 52% of the patients were diagnosed with apathy, and these patients showed a EuroQol-5D index score that was remarkably lower than that of the non-apathetic group (0.64 and 0.83, respectively; P<0.001).

Another group of researchers reported similar findings (using different scales) with high disability in patients with apathy in PD.16,23,24 

Apathy and caregiver burden

"It's no wonder we “Parkies” can be seen as lazy, disinterested, or uncaring by friends, family, and even strangers."22

The word ‘ burden’ is defined as the physical, socioeconomic, and emotional load that caregivers have as a result of taking care of someone.25 It cannot be underestimated. This constant  burden must be considered to help them deal with the patient effectively, as their role is vital in stabilizing the patient's quality of life and promoting independence.26

Leroi et al interviewed 22 caregivers of patients with non-demented PD with apathy and 28 non-demented PD patients without apathy. They used the 22-item Zarit Burden Interview questionnaire (ZBI) to measure the burden objectively. A higher score indicates a greater burden on the caregiver. They found that caregivers of patients with non-demented PD with apathy had a higher ZBI score compared to those of patients with non-demented PD without apathy (28 vs. 16, respectively, P= 0.004).

Another group of researchers used the NPI Caregiver Distress Scale to measure the emotional distress of caregivers of patients with early-diagnosed PD with neuropsychiatric manifestation. They found that most caregivers of patients with apathy reported significant distress in comparison to other symptoms, such as  agitation,  anxiety, and sleep disturbance.27

Apathy and cognitive impairment

A meta-analysis of eight research papers explored the effect of apathy on the cognition in patients with PD without dementia or depression. It revealed that apathy negatively affected all domains of cognition, especially the executive function and memory.28 Den Brok and his colleagues conducted a meta-analysis of 23 studies and found that individuals with apathy  have a lower score on the Mini-Mental State Exam.17 A recent prospective study of 104 PD patients with apathy suggested that apathy could be a marker for future decline of cognitive abilities.29

Apathy and PD motor symptoms

Wang et al. concluded apathy was not related to the severity of PD motor symptoms.24 Hinkle et al. recently found that apathy in patients with newly diagnosed PD patients (not yet receiving treatment) plays an essential role in predicting the occurrence of dyskinesia and motor fluctuation following commencement of administration of  dopaminergic drugs.30 They used data from the Parkinson’s Progression Markers Initiative (PPMI) and included 361 patients; 17% of them were diagnosed with apathy based on the UPDRS over a 6-year follow up.

Are there any Biomarkers for apathy?

A research group from China compared the level of neuroinflammatory agents in the cerebrospinal fluid, including iron, a-synuclein, hydroxyl radical, and hydrogen peroxide in three groups: The first group comprised 25 patients with PD and  pure apathy(no dementia or depression), the second group comprised 30 patients with PD without apathy, and the third group comprised 30 normal controls.24

They found that the level of these agents was significantly higher in patients with PD with pure apathy compared to the other two groups. They concluded that oxidative stress, due to free radicals generated from a-synuclein oligomer and iron overload, plays an important role in PD with pure apathy. This supports the possible theoretical role of antioxidant supplements in the prevention or treatment of apathy and warrants further studies.

Serum uric acid (UA) is another biomarker found to be associated with apathy in early drug naïve patients with PD.31 Picillo and colleagues analysed 49 patients with early-stage drug-naïve PD in whom apathy was diagnosed in 15 candidates using the AES. Patients using medication or having metabolic disorders known to interfere with the UA levels were excluded.

All participants were administered dopaminergic drugs following the initial assessment. They divided the cohort into two groups based on the serum UA level: group 1 = serum UA ≤4.8 mg/dl and group 2 = serum UA level > 4.8 mg/dl. Both the groups were evaluated at baseline and after two years. At baseline, apathy was diagnosed in 44% of group 1 and 16.7% of group 2. The AES total score was significantly higher in group 1 than in group 2 (36.9 vs. 32.7, respectively). After two years, 36% of those in group 1 were diagnosed with apathy and 0% in group 2. They suggested that the resolution of apathy in group 2 was because of dopaminergic medications, while group 1 was resistant to them.

Conclusion

The major challenge associated with the currently available data is the absence of agreement on the diagnostic criteria and rating scales to assess apathy, which questions the validity and reliability of the study findings. Many patients are confused about what is happening to them. It is not part of ageing nor part of their personality, but a syndrome that needs more attention from healthcare providers and caregivers to help them overcome this challenge effectively and safely.

In conclusion, it is time to define PD based on its motor and non-motor symptoms. Apathy is a common neuropsychiatry feature of PD that has a dramatic effect on patients and their caregivers. Failure to understand that apathy is part of the disease, may lead to the assumption that apathy is a personality problem or a sign of depression. There should be regular screening for apathy in patients with PD.

I believe that the diagnostic criteria proposed by Robert et al14 are practical and comprehensive and should be used widely to diagnoses apathy. The subsequent step should be to find out the most sensitive and specific rating scale for apathy to be taken as a gold stander among the scales available. Once we have a unified diagnostic criteria and gold stander rating scale, further studies on the proposed diagnostic biomarkers, neuroimaging and therapeutic intervention trials could be undertaken.

Remember when seeing patients with PD with slowness, question yourself: Is it due to PD, apathy or depression?

For more articles on Parkinson's disease go to our neurology section


Dr R Majdah, Cardiff University


References

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