Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease
Abstract
Background and Objectives
A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques.
Methods
People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated.
Results
Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28–1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50–5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48–0.90], HR [depression] = 1.45 [1.04–2.02], HR [motor severity] = 1.37 [1.01–1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44–0.76], OR [depression] = 1.43 [1.04–1.97], OR [female sex] = 0.45 [0.22–0.92], and OR [levodopa equivalent dose] = 0.78 [0.59–1.04].
Discussion
Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.
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References
1.
den Brok MGHE, van Dalen JW, van Gool WA, Moll van Charante EP, de Bie RMA, Richard E. Apathy in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2015;30(6):759-769.
2.
Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson's disease. Mov Disord. 2009;24(11):1641-1649.
3.
Marinus J, Zhu K, Marras C, Aarsland D, van Hilten JJ. Risk factors for non-motor symptoms in Parkinson's disease. Lancet Neurol. 2018;17(6):559-568.
4.
Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in Parkinson's disease: clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 2015;14(5):518-531.
5.
Pedersen KF, Larsen JP, Alves G, Aarsland D. Prevalence and clinical correlates of apathy in Parkinson's disease: a community-based study. Parkinsonism Relat Disord. 2009;15(4):295-299.
6.
Aarsland D, Brønnick K, Alves G, et al. The spectrum of neuropsychiatric symptoms in patients with early untreated Parkinson's disease. J Neurol Neurosurg Psychiatry. 2009;80(8):928-930.
7.
Santangelo G, Barone P, Cuoco S, et al. Apathy in untreated, de novo patients with Parkinson's disease: validation study of Apathy Evaluation Scale. J Neurol. 2014;261(12):2319-2328.
8.
Dujardin K, Langlois C, Plomhause L, et al. Apathy in untreated early-stage Parkinson disease: relationship with other non-motor symptoms. Mov Disord. 2014;29(14):1796-1801.
9.
Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primer. 2017;3(1):17013.
10.
Pedersen KF, Alves G, Aarsland D, Larsen JP. Occurrence and risk factors for apathy in Parkinson disease: a 4-year prospective longitudinal study. J Neurol Neurosurg Psychiatry. 2009;80(11):1279-1282.
11.
Santangelo G, Vitale C, Trojano L, et al. Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study. Eur J Neurol. 2015;22(2):253-260.
12.
Ou R, Lin J, Liu K, et al. Evolution of apathy in early Parkinson's disease: a 4-years prospective cohort study. Front Aging Neurosci. 2020;12:620762.
13.
Zahodne LB, Marsiske M, Okun MS, Rodriguez RL, Malaty I, Bowers D. Mood and motor trajectories in Parkinson's disease: multivariate latent growth curve modeling. Neuropsychology. 2012;26(1):71-80.
14.
Wee N, Kandiah N, Acharyya S, et al. Baseline predictors of worsening apathy in Parkinson's disease: a prospective longitudinal study. Parkinsonism Relat Disord. 2016;23:95-98.
15.
Dujardin K, Sockeel P, Delliaux M, Destée A, Defebvre L. Apathy may herald cognitive decline and dementia in Parkinson's disease. Mov Disord. 2009;24(16):2391-2397.
16.
Weintraub D, Moberg PJ, Culbertson WC, Duda JE, Katz IR, Stern MB. Dimensions of executive function in Parkinson's disease. Dement Geriatr Cogn Disord. 2005;20(2-3):140-144.
17.
Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex–basal ganglia circuits. Cereb Cortex. 2006;16(7):916-928.
18.
Le Heron C, Holroyd CB, Salamone J, Husain M. Brain mechanisms underlying apathy. J Neurol Neurosurg Psychiatry. 2019;90(3):302-312.
19.
Ziropadja L, Stefanova E, Petrovic M, Stojkovic T, Kostic VS. Apathy and depression in Parkinson's disease: the Belgrade PD study report. Parkinsonism Relat Disord. 2012;18(4):339-342.
20.
Skorvanek M, Rosenberger J, Gdovinova Z, et al. Apathy in elderly nondemented patients with Parkinson's disease: clinical determinants and relationship to quality of life. J Geriatr Psychiatry Neurol. 2013;26(4):237-243.
21.
MacAskill MR, Pitcher TL, Melzer TR, et al. The New Zealand Parkinson's progression programme. J R Soc N Z. 2022;53(4):466-488.
22.
Frässle S, Aponte EA, Bollmann S, et al. TAPAS: an open-source software package for translational neuromodeling and computational psychiatry. Front Psychiatry. 2021;12:680811.
23.
Radakovic R, Harley C, Abrahams S, Starr JM. “A systematic review of the validity and reliability of apathy scales in neurodegenerative conditions”: Corrigendum. Int Psychogeriatr. 2015;27(6):925.
24.
Robert P, Lanctôt KL, Agüera-Ortiz L, et al. Is it time to revise the diagnostic criteria for apathy in brain disorders? The 2018 international consensus group. Eur Psychiatry. 2018;54:71-76.
25.
Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry. 2009;24(2):98-104.
26.
Kulisevsky J, Pagonabarraga J, Pascual-Sedano B, García-Sánchez C, Gironell A, Trapecio Group Study. Prevalence and correlates of neuropsychiatric symptoms in Parkinson's disease without dementia. Mov Disord. 2008;23(13):1889-1896.
27.
Thompson N, MacAskill M, Pascoe MJ, Anderson T, Heron CL. Dimensions of apathy in Parkinson's disease. Brain Behav. 2023;13(6):e2862.
28.
Goetz CG, Stebbins GT, Tilley BC. Calibration of unified Parkinson's disease rating scale scores to Movement Disorder Society-unified Parkinson's disease rating scale scores. Mov Disord. 2012;27(10):1239-1242.
29.
Nasreddine ZS, Phillips NA, Bédirian V, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-699.
30.
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370.
31.
Bürkner PC. brms: an R package for Bayesian multilevel models using stan. J Stat Softw. 2017;80(1):1-28.
32.
Friedman J, Hastie T, Tibshirani R. Regularization paths for generalized linear models via coordinate descent. J Stat Softw. 2010;33(1):1-22.
33.
Rubin DB. Multiple imputation after 18+ years. J Am Stat Assoc. 1996;91(434):473-489.
34.
Hamilton CA, Matthews FE, Donaghy PC, et al. Progression to dementia in mild cognitive impairment with Lewy bodies or Alzheimer disease. Neurology. 2021;96(22):e2685–e2693.
35.
Jackson C. Multi-state models for panel data: the msm package for R. J Stat Softw. 2011;38(8):1-28.
36.
Starkstein SE, Ingram L, Garau ML, Mizrahi R. On the overlap between apathy and depression in dementia. J Neurol Neurosurg Psychiatry. 2005;76(8):1070-1074.
37.
Costello H, Berry AJ, Reeves S, et al. Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2022;93(5):555-562.
38.
Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011;35(3):537-555.
39.
Salamone JD, Yohn SE, López-Cruz L, San Miguel N, Correa M. Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. Brain. 2016;139(Pt 5):1325-1347.
40.
Kolling N, Behrens T, Wittmann MK, Rushworth M. Multiple signals in anterior cingulate cortex. Curr Opin Neurobiol. 2016;37:36-43.
41.
Klein-Flügge MC, Kennerley SW, Friston K, Bestmann S. Neural signatures of value comparison in human cingulate cortex during decisions requiring an effort-reward trade-off. J Neurosci. 2016;36(39):10002-10015.
42.
Le Heron C, Apps MAJ, Husain M. The anatomy of apathy: a neurocognitive framework for amotivated behaviour. Neuropsychologia. 2018;118(Pt B):54-67.
43.
Holroyd CB, Umemoto A. The research domain criteria framework: the case for anterior cingulate cortex. Neurosci Biobehav Rev. 2016;71:418-443.
44.
Pardo JV, Pardo PJ, Janer KW, Raichle ME. The anterior cingulate cortex mediates processing selection in the Stroop attentional conflict paradigm. Proc Natl Acad Sci U S A. 1990;87(1):256-259.
45.
Devos D, Moreau C, Maltête D, et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry. 2014;85(6):668-674.
46.
Eurelings LS, van Dalen JW, Ter Riet G, et al. Apathy and depressive symptoms in older people and incident myocardial infarction, stroke, and mortality: a systematic review and meta-analysis of individual participant data. Clin Epidemiol. 2018;10:363-379.
47.
de Figueiredo JM, Zhu B, Patel A, Kohn R, Koo BB, Louis ED. From perceived stress to demoralization in Parkinson disease: a path analysis. Front Psychiatry. 2022;13:876445.
48.
Thompson JC, Harris J, Sollom AC, et al. Longitudinal evaluation of neuropsychiatric symptoms in Huntington's disease. J Neuropsychiatry Clin Neurosci. 2012;24(1):53-60.
49.
Hoogland J, van Wanrooij LL, Boel JA, et al. Detecting mild cognitive deficits in Parkinson's disease: comparison of neuropsychological tests. Mov Disord. 2018;33(11):1750-1759.
50.
De Pablo-Fernández E, Lees AJ, Holton JL, Warner TT. Prognosis and neuropathologic correlation of clinical subtypes of Parkinson disease. JAMA Neurol. 2019;76(4):470-479.
51.
Willis AW, Schootman M, Kung N, Evanoff BA, Perlmutter JS, Racette BA. Predictors of survival in patients with Parkinson disease. Arch Neurol. 2012;69(5):601-607.
52.
Gonzalez MC, Dalen I, Maple-Grødem J, Tysnes OB, Alves G. Parkinson's disease clinical milestones and mortality. NPJ Parkinson's Dis. 2022;8(1):58.
53.
Morris LA, Harrison SJ, Melzer TR, et al. Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease. Brain. 2023;146(7):2739-2752.
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© 2024 American Academy of Neurology.
Publication History
Received: August 18, 2023
Accepted: February 13, 2024
Published online: June 3, 2024
Published in issue: June 25, 2024
Disclosure
The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.
Study Funding
This study was primarily supported by a Canterbury Medical Research Foundation grant (to CLH), while funding from Health Research Council of New Zealand and Neurologic Foundation, Rangahou Roro Aotearoa, Canterbury Medical Research Foundation, New Zealand Brain Research Institute, Lottery Health Research, and the University of Otago have supported the longitudinal New Zealand Parkinson's Progression Program since 2007.
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Cited By
- Non-motor Symptoms and Treatments in Parkinson’s Disease, Neurologic Clinics, 43, 2, (291-317), (2025).https://doi.org/10.1016/j.ncl.2024.12.008
- Redefining Non-Motor Symptoms in Parkinson’s Disease, Journal of Personalized Medicine, 15, 5, (172), (2025).https://doi.org/10.3390/jpm15050172
- Understanding disrupted motivation in Parkinson’s disease through a value-based decision-making lens, Trends in Neurosciences, 48, 4, (297-311), (2025).https://doi.org/10.1016/j.tins.2025.02.008
- Editors' Note: Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease, Neurology, 104, 5, (2025)./doi/10.1212/WNL.0000000000213339
- Author Response: Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease, Neurology, 104, 5, (2025)./doi/10.1212/WNL.0000000000209958
- Reader Response: Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease, Neurology, 104, 5, (2025)./doi/10.1212/WNL.0000000000209812
- Behavioral disorders in Parkinson disease: current view, Journal of Neural Transmission, (2024).https://doi.org/10.1007/s00702-024-02846-3
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We thank Dr. Zhang and colleagues for their letter regarding our paper.1 We agree that stable group-level rates of apathy across the time course of Parkinson disease (PD) by no means imply stable individual trajectories. However, Figure 1 in our paper illustrates that apathy is an important clinical feature throughout PD, not only later in the disease course. A limitation of these group-level summaries is that the group composition changes over time, with slower-progressing PD dominating the later time points. Indeed, this is exactly why we fitted models that consider, at an individual level, which risk factors signal either the presence or onset of apathy.1
A key result from the multistate incidence model was that apathy itself is a risk factor for early mortality, and that when this risk is accounted for, the relationship between other PD features and apathy varies across the disease course (illustrated in Figure 4 in our paper).1 Clinically and mechanistically, these relationships are important because both the reasons for apathy incidence and the appropriate treatment strategies may be quite different at different disease stages, despite stable group-level prevalence. As Zhang et al. pointed out, more complex models with sufficient data points will likely help further our understanding in this area.
Reference
Author disclosures are available upon request ([email protected]).
We read the recent article by Le Heron et al. with great interest.1 Psychiatric disorders such as depression, anxiety, and apathy are among the most prevalent nonmotor symptoms of Parkinson disease (PD).2 Understanding the trajectory of these psychological symptoms throughout the course of PD is crucial for effective treatment and prognosis.3
In their paper, Le Heron et al. examined the incidence of apathy at various stages of PD and found no significant differences over time.1 This result is unsatisfactory due to the study’s focus on overall levels rather than individual trajectories. A more plausible approach might be using a nonlinear mixed-effects model to capture the trajectory of apathy at the individual level (as shown in Figure 1, the trajectory of apathy is more likely to be nonlinear). This approach would allow for a comparison of the slope and the incidence (symptoms) at each point in the post-diagnostic period.4 We recommend a comprehensive analysis of symptom trajectories to enhance clinicians’ understanding of nonmotor symptoms in PD.
References
Author disclosures are available upon request ([email protected]).