14/12/21 10:05 MDS SIC Blog: Apathy in Parkinson's Disease

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Apathy in Parkinson's Disease

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About the Authors

Javier Pagonabarraga, MD, PhD

Unit of Movement Disorders, Department of Neurology

Hospital Sant Pau, Barcelona

Autonomous University of Barcelona, Spain

Tanya Harlow, MD

Director, Movement Disorders Unit

Department of Neurology, University of North Dakota School of Medicine & Health

Science

Department of Neurology, Sanford Health, USA

About the Author/Contributor

 
Prepared by SIC Member:

Jau-Shin Lou, MD, PhD, MBA

Professor and Chair, Roger Gilbertson Endowed Chair in Neurology

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Department of Neurology, University of North Dakota School of

Medicine & Health Science

Chair, Department of Neurology, Sanford Health, USA

Date: April 2019

Prepared by SIC Member: Jau-Shin Lou, MD, PhD, MBA

Authors: Javier Pagonabarraga, MD, PhD; Tanya Harlow, MD; Jau-Shin Lou, MD, PhD, MBA

Blog Editor: Stella M. Papa, MD

Apathy is a common non-motor symptom in Parkinson’s disease (PD), but is often under-
recognized.  Apathy is defined as a lack of motivation characterized by reduced emotional
expression and diminished goal-oriented behavior.  The prevalence of apathy differs greatly
between studies, most likely due to diverse population characteristics and the instruments
used to assess apathy.  Apathy has negative implications for the quality of life of patients and
the long-term outcome. In addition, apathy contributes significantly to caregiver burden. 
Therefore, recognition and understanding of apathy is crucial for the treatment and care of
patients with PD.  In this blog, we invited Dr. Javier Pagonabarraga and Dr. Tanya Harlow to
discuss key clinical aspects of the presentation and treatment of apathy in PD.

What is the relationship between apathy and depression in PD?

Dr. Pagonabarraga
The extended limbic system including hippocampal and parahippocampal cortices, and the
executive areas of the lateral prefrontal cortex help to store and manipulate perceived
emotions, generating more complex feelings and mood states that influence new incoming
stimuli and experiences. Through different regions of the anterior cingulate cortex (ACC), the
constant flow of past and incoming information within the amygdala and ventral striatum
(nucleus accumbens and anteromedial striatal territories) is transferred to the medial and
lateral prefrontal cortex, and finally to motor preparatory areas (SMA, PMC). Considering all
these intricate complex functional circuits, apathy, defined as a state of diminished goal-
directed behaviors, can be the consequence of either executive dysfunction, depressive
mood state or reward deficiency syndrome.

In patients with depression, the feelings of sadness, hopelessness, or the increased presence
of negative ruminations, negative automatic thoughts, or recurrent negative emotions have
been directly linked to increased activity of the subgenual ACC (sgACC) and decreased
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activity in lateral prefrontal regions. In these patients, the frequent concurrence of apathetic
behaviors is more associated with decreased activity in medial prefrontal regions and
decreased excitability of nucleus accumbens (NAcc) and other regions of the limbic system.
This functional dissociation is much more evident in some neurodegenerative diseases such
as Parkinson’s disease (PD), progressive supranuclear palsy (PSP), Huntington disease (HD)
or frontotemporal dementia (FTD). When symptoms related to sadness and hopelessness are
explored along with symptoms of decreased motivation or reward-induced experience, it is
possible to diagnose patients with depression and associated apathetic symptoms, or
patients with isolated apathy and no depressive feelings or thoughts.

Isolated apathy without depression is common in PD, and it is the most frequent mood
disorder in PSP, HD and FTD patients. The clinical differentiation between these two
nosological entities is crucial since potentials treatments differ. While serotonin and/or
norepinephrine reuptake inhibitors improve depression, they are not efficacious in patients
with isolated apathy, and selective serotonin reuptake inhibitors may even worsen it.
 Conversely, isolated apathy (or even apathetic symptoms in patients with depression) can
improve with psychostimulants like methylphenidate or dopamine agonists, although formal
studies are needed to measure the clinical impact of these drugs in patients with
neurodegenerative diseases.

How to differentiate apathy from depression in PD?

Dr. Pagonabarraga

Differentiation of apathy from depression is mainly based on a well-structured clinical

interview. The diagnosis of depression is based on the presence of cognitive and emotional
symptoms of depression, while the diagnosis of apathy (associated with or independent from
depression) will be based on the presence of diminished activities, interests, and emotions.
While the emotional symptoms of depression are characterized by the enhancement of
negative thoughts, beliefs and emotions, apathy refers to a state of decreased self-generated
activities as a consequence of decreased rewarding experiences, which is verbally explained
as a spontaneous reduction of interests. It is noteworthy that while in depression patients are
able to explain sadness as the source of their inactivity, apathetic patients are no longer able
to understand which is the origin of that progressive development of decreased interest in
the world around them.

Apathetic symptoms to consider in the clinical interview include reduced initiative,

decreased participation in external activities (unless engaged by another person), loss of
interest in social events or everyday activities, decreased interest in starting new activities,
emotional indifference, diminished emotional reactivity, less affection than usual, or lack of
concern for others’ feelings or interests.  The emotional and cognitive symptoms of
depression include an increase or enhancement of sadness, feelings of guilt, recurrent (and
even involuntary intrusion of) negative thoughts and/or feelings, helplessness, hopelessness,
pessimism, self-criticism, anxiety, and even suicidal ideation. If the patient manifests
apathetic symptoms but depressive symptoms are absent, a diagnosis of isolated apathy
(associated with reward deficiency syndrome) can be established.

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A more practical approach is the use of validated scales for depression or apathy. In the field
of neurodegenerative diseases, it has been useful to select scales in which the number of
items assessing somatic symptoms is less important.  The Starkstein Apathy Scale (SAS) and
the Lille Apathy Rating Scale (LARS) are useful for both the screening and assessment of
severity of apathy in neurological disorders. Depression can be accurately screened and
measured by the Montgomery–Åsberg Depression Rating Scale, Geriatric Depression Scale,
and the Hospital Anxiety and Depression scale, although other scales, such as the Hamilton
Depression Scale and the Beck Depression Inventory have also been validated in different
neurological disorders.

References
Pagonabarraga J, Kulisevsky J, Antonio P Strafella AP, Krack P. Apathy in Parkinson’s disease:
clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol 2015;14:518–
31.

Starkstein SE, Brockman S. The neuroimaging basis of apathy: Empirical findings and
conceptual challenges. Neuropsychologia. 2018;118:48-53.

Dujardin K, Sockeel P, Devos D, Delliaux M, Krystkowiak P, Destée A, Defebvre L.

Characteristics of apathy in Parkinson's disease. Mov Disord. 2007;22(6):778-84.

Does apathy affect cognitive function in PD?

Dr. Lou

It is challenging to study the independent effect of apathy on cognitive function because

apathy often coexist with cognitive dysfunction (such as dementia) and depression.  Apathy is
more prevalent in PD patients with depression or cognitive impairment.  For the PD
population in general, apathy is present in about 40% of patients.  However, apathy is present
only in approximately 22% of the patients who do not have coexisting depression or cognitive
impairment.  Apathy is associated with lower MMSE scores  (den Brok et al., 2015).

A meta-analytical study (D’Iorio et al, 2018) demonstrated that there was a strong
association between “pure apathy” (PD patients with apathy but without depression or
dementia) and cognitive dysfunctions, particularly deficits of memory and executive
functions. To minimize the confounding effects of depression or dementia on cognitive status,
this meta-analysis only used eight studies that excluded PD patients with depression or
dementia. The study explored the cognitive correlates of pure apathy, which included the
following outcomes: global cognitive function, memory, executive functions, processing
speed/attention/working memory, visuospatial abilities and language.  Results demonstrated
a strong association between “pure apathy” and cognitive dysfunction, particularly regarding
deficit of memory and executive function, which are related to altered prefronto-subcortical
circuits. Unfortunately, the authors did not address if PD patients with mild cognitive
impairment (MCI) were included in those eight studies used in the meta-analysis.

Apathy by itself, without the presence of MCI, does not affect cognitive performance. Costa
et al. (2018) showed that in a PD group without MCI, the severity of apathy did not impact
cognitive performance.   By contrast, in a PD group with MCI, the AES (Apathy Evaluation
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Scale) scores correlated with the scores of executive tests, especially in relation to planning
and abstract reasoning. These findings suggest that there is a specific association between
apathy severity and reduced efficiency of the executive function in individuals with PD and
MCI.  The authors did not address if the study subjects had coexisting depression.

References
D’Iorio A, Maggi G, Vitale C, Trojano L, Santangelo G. “Pure apathy” and cognitive
dysfunctions in Parkinson’s disease: A meta-analytic study. Neurosci Biobehav Rev.
2018;94:1-10.

den Brok MG, van Dalen JW, van Gool WA, Moll van Charante EP, de Bie  RM, Richard E.
Apathy in Parkinson's disease: A systematic review and meta-analysis.  Mov Disord.
2015;30(6):759-69.

Costa A, Peppe A,  Zabberoni S et al.  Apathy in individuals with Parkinson's disease
associated with mild  cognitive impairment. A neuropsychological investigation.
Neuropsychologia 2018; 118: 4–11.

How can we treat apathy?

Dr. Harlow

Currently, there are no approved treatments for apathy.  Apathy has traditionally been very
difficult to treat in patients with Parkinson’s disease (PD).  However, apathy was one of the
four most important determinants of health-related quality of life in a recent study by
Skorvanek et al.  It has also been found to cause greater impairment in the patient’s ability to
perform activities of daily living, and greater caregiver burden (see Leiknes et al., 2010, and
Leroi et al.,2012).  This indicates that treatment for apathy may result in improvement of
quality of life for both the patient and caregiver.

Randomized clinical trials (RCTs) demonstrate that dopaminergic agents and cholinesterase
inhibitors may improve apathy in PD.  In several RCTs, the dopamine agonist rotigotine
improved apathy, Piribedil, a D2 and D3 receptor agonist, improved the apathy developed
after deep brain stimulation, and methylphenidate, a dopamine and norepinephrine reuptake
inhibitor, improved apathy as well.  Rivastigmine, an acetylcholinesterase inhibitor, tested
also in RCTs improved apathy in PD (Liu et al.,2019). 

Treating patients with apathy and coexisting depression requires special consideration. 
Apathy can be associated with depression, and treatment of the associated condition can
sometimes help to improve apathy.  There is some evidence to suggest that patients may have
more apathy when depression is treated with selective serotonin reuptake inhibitors (SSRIs)
(Zahondne  et al.,2012), possibly indicating that treatment with a more activating
antidepressant such as venlafaxine or bupropion may provide more benefit. 

There has also been some consideration that treatment may vary depending on the subtypes
of apathy.  Three subtypes of apathy have been proposed:  emotional-affective (motivation),
cognitive (planning), and auto-activation (initiation) (see Levy and Dubois).  For patients with
both the emotional-affective and the auto-activation subtypes, treatment with dopaminergic

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agents may provide more benefit.  For the cognitive subtype, acetylcholinesterase inhibitors
may provide more benefit (Pagonabarraga et al.,2015). 

A better design of clinical trials using a common, validated scale of apathy is necessary to
assess apathy treatments in the future.  One of the main problems in previous RCTs was that
different scales were used to measure apathy (Liu et al.,2019).  While further studies are
needed, one could certainly consider treating apathy in PD with a dopaminergic agent or an
acetylcholinesterase inhibitor in appropriate clinical settings.  In patients with depression on
SSRIs, a switch to a different class of antidepressants may be warranted.

References
M. Skorvanek, P. Martinez-Martin, N. Kovacs. I. Zezula, M. Rodrigues-Violante, J.C. Corvol, et
al., Relationship between the MDA-UPDS and Quality of Life: a large multicenter study of
3206 patients, Park. Relat. Disord. 2018;52: 83-89.

Leiknes I, Tysnes OB, Aarsland D, Larsen JP. Caregiver distress associated with
neuropsychiatric problems in patients with early Parkinson’s disease:  the Norwegian
ParkWest study, Acta Neurol. Scan. 2010; 122 (6): 418-424

I. Leroi, V. Harbishettar, M. Andrews, K. McDonald, E.J. Byrne, A. Burns, Carer burden in

apathy and impulse control disorders in Parkinson’s disease, Int. J. Geriatr. Psychiatr.
2012;27(2):160-166

J. Liu, C.A. Cooper, D. Weintraub, N. Dahodwala, Pharmacologic treatment of apathy in Lewy

body disorders:  A systematic review, Park. Relat. Disord. 2019;60 (March):14-24

L.B. Zahondne, O. Bernal-Pacheco, D. Bowers, H. Ward, G. Oyama, N. Limotai, et. All, Are
selective serotonin reuptake inhibitors associated with greater apathy in Parkinson’s
disease? J. Neuropsychiatry Clin. Neurosci. 2012;24 (3):326-330

R. Levy, B. Dubois, Apathy and the functional anatomy of the prefrontal cortex-basal ganglia
circuits, Cerebr. Cortex 2006;16 (7): 916-928

J. Pagonabarraga, J. Kulisevsky, A.P. Strafella, P. Krack, Apathy in Parkinson’s disease: clinical

features, neural substrates, diagnosis, and treatment, Lancet Neurol. 2015;14 (5) :518-531

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