HHS Public Access Author manuscript Author Manuscript
J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01. Published in final edited form as:
J Neuropsychiatry Clin Neurosci. 2016 ; 28(3): 211–216. doi:10.1176/appi.neuropsych.15090221.
Mood Differences among Parkinson’s Disease Patients with Mild Cognitive Impairment Jacob D. Jones, M.S.1,3, Paul Mangal, M.S.1,3, Jacob Lafo, M.S.1,3, Michael S. Okunm, M.D2,3, and Dawn Bowers, Ph.D.1,2,3 1Department
of Clinical and Health Psychology, McKnight Brain Institute, University of Florida, Gainesville, FL
Author Manuscript
2Department
of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL
3Center
for Movement Disorders and Neurorestoration, McKnight Brain Institute, University of Florida, Gainesville, FL
Abstract Objective—Studies with healthy elderly adults suggest apathy, depression and anxiety are more common among individuals with mild cognitive impairment (MCI). We examined differences in mood/amotivational symptoms among Parkinson’s patients with and without MCI.
Author Manuscript
Methods—Parkinson patients (N=214) underwent neurocognitive evaluations including assessment of apathy (Apathy Scale; AS), depression (Beck Depression Inventory-II; BDI-II) and trait anxiety (State-Trait Anxiety Inventory-Trait scale; STAI-T). Results—Trait anxiety and depression were more severe in PDs with MCI. Delineation of MCI into amnestic vs non-amnestic subtypes revealed greater depression, apathy and anxiety among amnestic MCI relative to cognitively-intact PD patients. Conclusion—Parkinson patients with MCI report greater mood symptoms compared to Parkinson patients who are cognitively intact. Keywords Neuropsychology; Parkinson’s disease; Depression; Mild Cognitive Impairment
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Introduction Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor impairments, as well as mood and cognitive disturbances. The wide-range of symptoms is due in part to dopamine depletion in the substantia nigra and disruption of subcorticalthalamo-cortical circuits {1}.
Corresponding Author: Jacob D. Jones M.S. Clinical & Health Psychology, College of Public Health & Health Professions, 101 S. Newell Drive. PO Box 100165, University of Florida, Gainesville, FL 32601. Phone (352) 392-3450, Fax: (352) 265-0096; [email protected]. Mr. Jones reports no disclosures.
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Cognitive impairments in PD primarily consist of slowed processing speed, multi-tasking/ working memory difficulties and increased forgetfulness; however the pattern of cognitive impairment, as well as the course/trajectory of cognitive decline, can vary across patients {2}. For almost a decade, the concept of identifying individuals with mild cognitive impairment (MCI), who are at-risk for future dementia, has been investigated as a possible meaningful concept among PD {3}. Indeed, a MCI stage has been viewed as an “intermediate” stage between cognitively intact PD patients and those with Parkinson’s disease dementia (PDD) {2,4}. Amnestic and non-amnestic MCI subtypes may also be useful in learning whether certain cognitive profiles represent increased risk for PDD. A non-amnestic, executive dysfunction profile has been primarily associated with frontalstriatal dysfunction involving the dorsolateral prefrontal cortex (DLPFC), while an amnestic profile may reflect a “posterior” profile with additional dysfunction in cholinergic systems and/or the beginning stages of co-morbid Alzheimer’s pathology {5–6}. Evidence has been mixed regarding which MCI-subtype is indicative of future PDD {4,6,7}. The clinical and research utility of MCI relates to its potential to identify individuals at risk for dementia, ideally leading to early interventions that can delay the onset of dementia. However, MCI status has also been shown to relate to other meaningful outcomes. Within PD, MCI status has been linked to worse motor symptoms and stage severity, postural instability, and depression {4,8}. In normal elderly, not only is depression linked to MCI status, but also apathy and anxiety {9}. Identification of mood symptoms in cognitively impaired individuals is important because mood symptoms are strong predictors of quality of life that may be responsive to interventions {9,10}. Furthermore, due to the negative influence of mood symptoms on cognition, treatments targeting depression, apathy and anxiety may lead to better cognitive functioning {11,12}.
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Apathy (disorder of motivation/goal-directed behavior), depression, and anxiety are common, but dissociable, mood symptoms in PD {13}. The high occurrence of mood symptoms in PD may be partly due to the reaction of being diagnosed with a serious medical condition; however there is a direct relationship between PD pathology and emotional dysfunction (particularly apathy). Striatal dopamine depletion leads to a disruption of frontal-subcortical circuits. These circuits include cortical prefrontal regions important for emotional processing, such as the anterior cingulate cortex (ACC) and orbital-frontal cortex (OFC) {1}. In addition to dopamine depletion, high rates of mood symptoms might also be linked to dysregulation of separate neurotransmitters such as serotonin, norepinephrine and possibly acetylcholine {14}.
Author Manuscript
Both mood and cognitive symptoms are important predictors of patient-centered outcomes, however the relationship between mood disturbances and MCI status in PD has received little attention {11,15}. The aim of the current study was to examine, in Parkinson patients, the relationship between MCI and common mood and motivation dysfunctions. The overall hypothesis is that due similar neural circuitry (frontal-striatal circuits) underlying both emotional and cognitive processes, mood symptoms will be greater among Parkinson patients with MCI, with apathy being particularly more severe among PD patients with MCI.
J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01.
Jones et al.
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Methods Design & Participants This cross-sectional design included a convenience sample of 214 patients with idiopathic PD according to UK Brain Bank criteria. The Institutional Review Board at the University of Florida (UF) approved the study and consent was attained prior to patient participation. All patients underwent a detailed neuropsychological assessment, including completion of mood questionnaires as part of their routine clinical care through the UF Center for Movement Disorders and Neurorestoration. Patients were excluded based on the following criteria: 1) previous brain surgery such as deep brain stimulation, 2) severe psychiatric disturbance (e.g. schizophrenia), or 3) severe cognitive impairment defined as a score on the Dementia Rating Scale-II (DRS-II) below the 5th percentile.
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Mood and Clinical Measures
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Mild Cognitive Impairment Classifications
Patients completed standard questionnaires assessing apathy, depression and trait anxiety. Apathy was measured with the Starkstein Apathy Scale (AS) {16}. The Beck Depression Inventory-II (BDI-II) measured depressive symptoms {17}. The Trait scale on the StateTrait Anxiety Inventory assessed long-standing anxiety {18}. For all measures, higher scores represent higher levels of severity for their respective construct. Data pertaining to demographics (age and education) and PD-related severity (duration of motor symptoms and ratings of motor symptoms) were collected by a movement disorder neurologist or trained fellow. Motor symptom severity was determined by the Unified Parkinson Disease Rating Scale Part III (UPDRS motor score) and was taken while patients were “on” medication {19}.
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All patients completed neuropsychological measures of executive functioning, delayed verbal memory, attention/working memory, processing speed, language and visuospatial abilities as part of a neuropsychological examination. The attention/working memory tests consisted of the Forward Span and Backward Span scores of the Digit Span subtest from the Wechsler Adult Intelligence Scale-III. Verbal memory measures included the 20 minute delay recall score from the Hopkins Verbal Learning Test-R and the 30 minute delayed recall of the Logical Memory Stories-II from the Wechsler Memory Scale-III. The Boston Naming Test (total correct without cues) and an Animal Fluency test comprised the language domain. Tests of executive functioning included the Trail Making Test-Part B, the color-word interference trial of the Stroop Color-Word Test, and the letter fluency test of the Controlled Oral Word Association test. Visuospatial tests included the Benton Facial Recognition Test and the Judgment of Line Orientation test. Lastly, the processing speed domain included the Trail Making Test-Part A, and the Word reading trial of the Stroop Color-Word task. All tests were normed for age, education and gender based on test-specific manuals or previously published norms and then converted into a Z-score metric. Mild cognitive impairment was defined according to the Movement Disorder Society (MDS) criteria. The MDS Level II criteria were used as it is appropriate for assessments that include at least two tests within each cognitive domain: attention, executive functioning, processing
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speed, language, memory and visuospatial {12}. Individuals were classified as MCI if they performed 1.5 standard deviations (SD) below the mean on at least two tests. Of note, tests can be within the same domain or in separate domains. Individuals with MCI were further classified into an Amnestic or non-amnestic MCI subtype. Individuals were classified into the amnestic group if either of the memory tests (HVLT-R delayed recall or Stories delayed recall) scored less than 1.5 SD below the normed average (i.e. a Z score less than −1.5). Statistical Analyses A series of independent t-tests were computed to assess group differences. Initial analyses separated groups dichotomously (i.e. cognitively intact vs. MCI) and examined differences in apathy, anxiety and depression. Subsequent analyses separated individuals into three groups: cognitively intact, amnestic-MCI and non-amnestic MCI. Indicators of normality were appropriate for mood variables (skewness and kurtosis values < 1).
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Multiple hierarchical regressions were additionally computed in order to covary for potential confounder variables. Mood variables (depression, apathy and anxiety) were entered as the dependent variable for each regression. Predictor variables included MCI status, age, education and motor symptoms severity (on medication UPDRS motor subscale). Mild cognitive impairment status was forced entered into the model and additional covariates (age, education, motor symptom severity) were entered in step-wise fashion so only predictors that significantly contributed to the model were included. Additional regression analyses were repeated to examine MCI subtypes (i.e. amnestic versus non-amnestic). Dummy coded MCI status variables were forced entered into each model with additional covariates entered in stepwise fashion.
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Results Sample Characteristics Table 1 shows the sample characteristics of the 214 Parkinson patients. Briefly, the sample had a mean age of 64 years, was primarily Caucasian (95.8%) and male (70.6%). Tremor was the dominant symptom in 80.8% of patients, and average duration of symptoms was 10 years. Average UPDRS motor scores while patients were “on medication” was 26.1. Compared to cognitively intact PD patients, those with MCI had longer duration of motor symptoms (t (212) = 2.27, p = .024) and worse UPDRS motor scores (t (212) = 4.70, p < . 001). The two groups did not differ in terms of age, education or levodopa equivalency dose (LED; all p values > .05).
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Almost half (47.2%) of our sample met criteria for MCI. Of the individuals with MCI, 59% were categorized as amnestic MCI and 41% met criteria for non-amnestic MCI. The amnestic and non-amnestic groups did not differ in terms of age, education, UPDRS motor scores, duration of motor symptoms or LED (all p values > .05). Mood Differences among Parkinson Patients with and without MCI Independent samples t-tests were conducted to examine differences in mood scales between MCI and cognitively intact PD patients. Results revealed that PD patients with MCI reported
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more severe depression (t(212)=2.23, p=0.027) and trait anxiety (t(212)=2.27, p=0.024) compared to cognitively intact PD patients. Apathy was not significantly greater in MCI than non-MCI patients (p=.053).
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In order to control for possible confounding variables, three follow-up hierarchical regressions were conducted controlling for age, education and severity of motor symptoms. Results revealed that the overall regression models significantly predicted depression (F(2,211) = 12.80, p = .05).
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In order to control for possible confounding variables, follow-up hierarchical regressions were conducted controlling for age, education and severity of motor symptoms. The overall models significantly predicted depression (F(2,211) = 9.36, p = 60 months has received no support from industry. Dr. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books $Patients, and Cambridge (movement disorders books). Dr. Okun is an associate editor for New England Journal of Medicine Journal Watch Neurology. Dr. Okun has participated in CME and educational activities on movement disorders (in the last 36) months sponsored by PeerView, Prime, Quantia, Henry Stewart, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic, Abbvie, and ANS/St. Jude, and the PI has no financial interest in these grants. Dr. Okun has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria.
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Dr. Bowers was supported by NIH R21-NS079767, R03-MH109336, and Sante Fe Avmed. She has received research support from the NIH, Michael J. Fox Foundation, the National Parkinson Foundation, and the McKnight Research Foundation.
References
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1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986; 9:357–381. [PubMed: 3085570] 2. Litvan I, Aarsland D, Adler CH, et al. MDS task force on mild cognitive impairment in Parkinson's disease: Critical review of PD-MCI. Movement Disord. 2011; 26:1814–1824. [PubMed: 21661055] 3. Fernandez HH, Crucian GP, Okun MS, et al. Mild cognitive impairment in Parkinson’s disease: the challenge and the promise. Neuropsychiatr Dis and Treat. 2005; 1:37. 4. Janvin CC, Larsen JP, Aarsland D, et al. Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia. Movement Disord. 2006; 21:1343–1349. [PubMed: 16721732] 5. Hilker R, Thomas AV, Klein JC, et al. Dementia in Parkinson disease functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005; 65:1716–1722. [PubMed: 16344512] 6. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009; 132:2958–2969. [PubMed: 19812213] 7. Woods SP, Tröster AI. Prodromal frontal/executive dysfunction predicts incident dementia in Parkinson's disease. J Int Neuropsychol Soc. 2003; 9:17–24. [PubMed: 12570354] 8. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease A multicenter pooled analysis. Neurology. 2010; 75:1062–1069. [PubMed: 20855849]
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9. Karlsen KH, Larsen JP, Tandberg E, Mæland JG. Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease. J Neurol Neurosur Ps. 1999; 66:431–435. 10. Jones JD, Butterfield LC, Song W, et al. Anxiety and Depression Are Better Correlates of Parkinson’s Disease Quality of Life Than Apathy. J Neuropsychiatry Clin Neurosci. 2014; 27:213–218. [PubMed: 25162776] 11. Butterfield LC, Cimino CR, Oelke LE, et al. The independent influence of apathy and depression on cognitive functioning in Parkinson's disease. Neuropsychology. 2010; 24:721. [PubMed: 20853956] 12. Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Movement Disorders. 2012; 27:349–356. [PubMed: 22275317] 13. Kirsch-Darrow L, Fernandez HF, Marsiske M, et al. Dissociating apathy and depression in Parkinson disease. Neurology. 2006; 67:33–38. [PubMed: 16832074] 14. Poletti M, De Rosa A, Bonuccelli U. Affective symptoms and cognitive functions in Parkinson's disease. Journal of the neurological sciences. 2012; 317:97–102. [PubMed: 22503136] 15. Hanna KK, Cronin-Golomb A. Impact of anxiety on quality of life in Parkinson's disease. Parkinson’s Disease. 2012 16. Starkstein SE, Mayberg HS, Preziosi T, et al. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1992; 4:134–139. [PubMed: 1627973] 17. Beck AT, Steer RA, Ball R, Ranieri WF. Comparison of Beck Depression Inventories-IA and-II in psychiatric outpatients. J Pers Assess. 1996; 67:588–597. [PubMed: 8991972] 18. Spielberger CD, Sydeman SJ, Owen AE, Marsh BJ. Measuring anxiety and anger with the StateTrait Anxiety Inventory(STAI) and the State-Trait Anger Expression Inventory(STAXI). 1990 19. Fahn S, Elton R, members of the UPDRS Development Committee. Fahn S. Recent Developments in Parkinson’s Disease. 1999:153–163. 20. Chaudhuri K, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009; 8:464–474. [PubMed: 19375664] 21. Monastero R, Di Fiore P, Ventimiglia GD, et al. The neuropsychiatric profile of Parkinson’s disease subjects with and without mild cognitive impairment. J Neural Transm. 2013; 120:607– 611. [PubMed: 23400362] 22. Leroi I, Pantula H, McDonald K, Harbishettar V. Neuropsychiatric symptoms in Parkinson's disease with mild cognitive impairment and dementia. Parkinson’s Disease. 2012 23. Owen AM. Cognitive dysfunction in Parkinson’s disease: the role of frontostriatal circuitry. Neuroscientist. 2004; 10:525–537. [PubMed: 15534038] 24. Kish SJ, Shannak K, Hornykiewicz O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. N Engl J Med. 1988; 318:876–880. [PubMed: 3352672] 25. Santangelo G, Vitale C, Trojano L, et al. Relationship between depression and cognitive dysfunctions in Parkinson’s disease without dementia. J Neurol. 2009; 256:632–638. [PubMed: 19370301] 26. Zahodne LB, Marsiske M, Okun MS. Mood and motor trajectories in Parkinson's disease: Multivariate latent growth curve modeling. Neuropsychology. 2012; 26:71. [PubMed: 22142359] 27. Beaudreau SA, O'Hara R. Late-life anxiety and cognitive impairment: a review. Am J Geriatr Psychiatry. 2008; 16:790–803. [PubMed: 18827225] 28. Weintraub D, Newberg AB, Cary MS, et al. Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson’s disease. J Nucl Med. 2005; 46:227–232. [PubMed: 15695780] 29. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th edition. Arlington, VA: American Psychiatric Association; 2013.
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Figure 1.
Raw means scores on measures of apathy, depression and trait anxiety are depicted for each group with higher scores representing greater severity; MCI= mild cognitive impairment; error bars depict the 95% confidence interval; * p≤.05.
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Table 1
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Sample Characteristics N=214 Parkinson Patients 151 Males (70.6%); 63 Females (29.4%)
Total
Intact Cognition
MCI
N=113
N=101
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Mean (SD)
Mean (SD)
Mean (SD)
Percent Caucasian
95.8
98.2
93.1
Age in years
64.3 (9.5)
63.7 (9.5)
65.1 (9.5)
Years of Education
14.9 (2.9)
15.0 (2.8)
14.9 (3.0)
Years with Symptoms
10.0 (5.8)
9.1 (4.6)
10.9 (6.6)
UPDRS Motor Score, on medication
26.1 (10.8)
23.0 (9.5)
29.3 (9.6)
Percent Tremor Predominant
80.8
80.5
81.2
Levodopa Equivalency Dose
829.1 (564.3)
816.4 (590.0)
843.3 (536.7)
Percent on Antidepressant Medication
38.6
37.8
39.6
Percent on Anti-anxiety Medication
19.7
21.6
17.5
Dementia Rating Scale-Total
137.25 (4.9)
139.3 (3.4)
135.0 (5.2)
Beck Depression Scale-II
9.4 (6.3)
8.5 (5.9)
10.4 (6.5)
Apathy Scale
10.7 (6.3)
9.9 (5.9)
11.6 (6.5)
State-Trait Anxiety Inventory-Trait Scale
35.4 (9.8)
34.0 (9.6)
37.0 (9.8)
UPDRS= Unified Parkinson’s Disease Rating Scale-Part III; SD= standard deviation; MCI= mild cognitive impairment
Author Manuscript Author Manuscript J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01.
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Author Manuscript −.179 .009
Partial Correlation
p
.076
p
.292 −.123
p
Partial Correlation
−.073
Partial Correlation
.002
−.211
.062
−.130
.083
−.120
Verbal Memory
.444
−.053
.977
−.002
.206
−.034
Attention
Controlling for education and gender; significant correlations appear in bold.
Trait Anxiety
Apathy
Depression
Executive Function
.001
−.231
.016
−.167
.051
−.136
Language
.076
−.123
.072
−.125
.192
−.091
Processing Speed
.107
−.112
.241
−.082
.448
−.053
Visuospatial
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Partial Correlations Between Mood Symptoms and Neurocognitive Domains
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Table 2 Jones et al. Page 12
J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01.
J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01. Published in final edited form as:
J Neuropsychiatry Clin Neurosci. 2016 ; 28(3): 211–216. doi:10.1176/appi.neuropsych.15090221.
Mood Differences among Parkinson’s Disease Patients with Mild Cognitive Impairment Jacob D. Jones, M.S.1,3, Paul Mangal, M.S.1,3, Jacob Lafo, M.S.1,3, Michael S. Okunm, M.D2,3, and Dawn Bowers, Ph.D.1,2,3 1Department
of Clinical and Health Psychology, McKnight Brain Institute, University of Florida, Gainesville, FL
Author Manuscript
2Department
of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL
3Center
for Movement Disorders and Neurorestoration, McKnight Brain Institute, University of Florida, Gainesville, FL
Abstract Objective—Studies with healthy elderly adults suggest apathy, depression and anxiety are more common among individuals with mild cognitive impairment (MCI). We examined differences in mood/amotivational symptoms among Parkinson’s patients with and without MCI.
Author Manuscript
Methods—Parkinson patients (N=214) underwent neurocognitive evaluations including assessment of apathy (Apathy Scale; AS), depression (Beck Depression Inventory-II; BDI-II) and trait anxiety (State-Trait Anxiety Inventory-Trait scale; STAI-T). Results—Trait anxiety and depression were more severe in PDs with MCI. Delineation of MCI into amnestic vs non-amnestic subtypes revealed greater depression, apathy and anxiety among amnestic MCI relative to cognitively-intact PD patients. Conclusion—Parkinson patients with MCI report greater mood symptoms compared to Parkinson patients who are cognitively intact. Keywords Neuropsychology; Parkinson’s disease; Depression; Mild Cognitive Impairment
Author Manuscript
Introduction Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor impairments, as well as mood and cognitive disturbances. The wide-range of symptoms is due in part to dopamine depletion in the substantia nigra and disruption of subcorticalthalamo-cortical circuits {1}.
Corresponding Author: Jacob D. Jones M.S. Clinical & Health Psychology, College of Public Health & Health Professions, 101 S. Newell Drive. PO Box 100165, University of Florida, Gainesville, FL 32601. Phone (352) 392-3450, Fax: (352) 265-0096; [email protected]. Mr. Jones reports no disclosures.
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Cognitive impairments in PD primarily consist of slowed processing speed, multi-tasking/ working memory difficulties and increased forgetfulness; however the pattern of cognitive impairment, as well as the course/trajectory of cognitive decline, can vary across patients {2}. For almost a decade, the concept of identifying individuals with mild cognitive impairment (MCI), who are at-risk for future dementia, has been investigated as a possible meaningful concept among PD {3}. Indeed, a MCI stage has been viewed as an “intermediate” stage between cognitively intact PD patients and those with Parkinson’s disease dementia (PDD) {2,4}. Amnestic and non-amnestic MCI subtypes may also be useful in learning whether certain cognitive profiles represent increased risk for PDD. A non-amnestic, executive dysfunction profile has been primarily associated with frontalstriatal dysfunction involving the dorsolateral prefrontal cortex (DLPFC), while an amnestic profile may reflect a “posterior” profile with additional dysfunction in cholinergic systems and/or the beginning stages of co-morbid Alzheimer’s pathology {5–6}. Evidence has been mixed regarding which MCI-subtype is indicative of future PDD {4,6,7}. The clinical and research utility of MCI relates to its potential to identify individuals at risk for dementia, ideally leading to early interventions that can delay the onset of dementia. However, MCI status has also been shown to relate to other meaningful outcomes. Within PD, MCI status has been linked to worse motor symptoms and stage severity, postural instability, and depression {4,8}. In normal elderly, not only is depression linked to MCI status, but also apathy and anxiety {9}. Identification of mood symptoms in cognitively impaired individuals is important because mood symptoms are strong predictors of quality of life that may be responsive to interventions {9,10}. Furthermore, due to the negative influence of mood symptoms on cognition, treatments targeting depression, apathy and anxiety may lead to better cognitive functioning {11,12}.
Author Manuscript
Apathy (disorder of motivation/goal-directed behavior), depression, and anxiety are common, but dissociable, mood symptoms in PD {13}. The high occurrence of mood symptoms in PD may be partly due to the reaction of being diagnosed with a serious medical condition; however there is a direct relationship between PD pathology and emotional dysfunction (particularly apathy). Striatal dopamine depletion leads to a disruption of frontal-subcortical circuits. These circuits include cortical prefrontal regions important for emotional processing, such as the anterior cingulate cortex (ACC) and orbital-frontal cortex (OFC) {1}. In addition to dopamine depletion, high rates of mood symptoms might also be linked to dysregulation of separate neurotransmitters such as serotonin, norepinephrine and possibly acetylcholine {14}.
Author Manuscript
Both mood and cognitive symptoms are important predictors of patient-centered outcomes, however the relationship between mood disturbances and MCI status in PD has received little attention {11,15}. The aim of the current study was to examine, in Parkinson patients, the relationship between MCI and common mood and motivation dysfunctions. The overall hypothesis is that due similar neural circuitry (frontal-striatal circuits) underlying both emotional and cognitive processes, mood symptoms will be greater among Parkinson patients with MCI, with apathy being particularly more severe among PD patients with MCI.
J Neuropsychiatry Clin Neurosci. Author manuscript; available in PMC 2017 July 01.
Jones et al.
Page 3
Author Manuscript
Methods Design & Participants This cross-sectional design included a convenience sample of 214 patients with idiopathic PD according to UK Brain Bank criteria. The Institutional Review Board at the University of Florida (UF) approved the study and consent was attained prior to patient participation. All patients underwent a detailed neuropsychological assessment, including completion of mood questionnaires as part of their routine clinical care through the UF Center for Movement Disorders and Neurorestoration. Patients were excluded based on the following criteria: 1) previous brain surgery such as deep brain stimulation, 2) severe psychiatric disturbance (e.g. schizophrenia), or 3) severe cognitive impairment defined as a score on the Dementia Rating Scale-II (DRS-II) below the 5th percentile.
Author Manuscript
Mood and Clinical Measures
Author Manuscript
Mild Cognitive Impairment Classifications
Patients completed standard questionnaires assessing apathy, depression and trait anxiety. Apathy was measured with the Starkstein Apathy Scale (AS) {16}. The Beck Depression Inventory-II (BDI-II) measured depressive symptoms {17}. The Trait scale on the StateTrait Anxiety Inventory assessed long-standing anxiety {18}. For all measures, higher scores represent higher levels of severity for their respective construct. Data pertaining to demographics (age and education) and PD-related severity (duration of motor symptoms and ratings of motor symptoms) were collected by a movement disorder neurologist or trained fellow. Motor symptom severity was determined by the Unified Parkinson Disease Rating Scale Part III (UPDRS motor score) and was taken while patients were “on” medication {19}.
Author Manuscript
All patients completed neuropsychological measures of executive functioning, delayed verbal memory, attention/working memory, processing speed, language and visuospatial abilities as part of a neuropsychological examination. The attention/working memory tests consisted of the Forward Span and Backward Span scores of the Digit Span subtest from the Wechsler Adult Intelligence Scale-III. Verbal memory measures included the 20 minute delay recall score from the Hopkins Verbal Learning Test-R and the 30 minute delayed recall of the Logical Memory Stories-II from the Wechsler Memory Scale-III. The Boston Naming Test (total correct without cues) and an Animal Fluency test comprised the language domain. Tests of executive functioning included the Trail Making Test-Part B, the color-word interference trial of the Stroop Color-Word Test, and the letter fluency test of the Controlled Oral Word Association test. Visuospatial tests included the Benton Facial Recognition Test and the Judgment of Line Orientation test. Lastly, the processing speed domain included the Trail Making Test-Part A, and the Word reading trial of the Stroop Color-Word task. All tests were normed for age, education and gender based on test-specific manuals or previously published norms and then converted into a Z-score metric. Mild cognitive impairment was defined according to the Movement Disorder Society (MDS) criteria. The MDS Level II criteria were used as it is appropriate for assessments that include at least two tests within each cognitive domain: attention, executive functioning, processing
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Jones et al.
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speed, language, memory and visuospatial {12}. Individuals were classified as MCI if they performed 1.5 standard deviations (SD) below the mean on at least two tests. Of note, tests can be within the same domain or in separate domains. Individuals with MCI were further classified into an Amnestic or non-amnestic MCI subtype. Individuals were classified into the amnestic group if either of the memory tests (HVLT-R delayed recall or Stories delayed recall) scored less than 1.5 SD below the normed average (i.e. a Z score less than −1.5). Statistical Analyses A series of independent t-tests were computed to assess group differences. Initial analyses separated groups dichotomously (i.e. cognitively intact vs. MCI) and examined differences in apathy, anxiety and depression. Subsequent analyses separated individuals into three groups: cognitively intact, amnestic-MCI and non-amnestic MCI. Indicators of normality were appropriate for mood variables (skewness and kurtosis values < 1).
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Multiple hierarchical regressions were additionally computed in order to covary for potential confounder variables. Mood variables (depression, apathy and anxiety) were entered as the dependent variable for each regression. Predictor variables included MCI status, age, education and motor symptoms severity (on medication UPDRS motor subscale). Mild cognitive impairment status was forced entered into the model and additional covariates (age, education, motor symptom severity) were entered in step-wise fashion so only predictors that significantly contributed to the model were included. Additional regression analyses were repeated to examine MCI subtypes (i.e. amnestic versus non-amnestic). Dummy coded MCI status variables were forced entered into each model with additional covariates entered in stepwise fashion.
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Results Sample Characteristics Table 1 shows the sample characteristics of the 214 Parkinson patients. Briefly, the sample had a mean age of 64 years, was primarily Caucasian (95.8%) and male (70.6%). Tremor was the dominant symptom in 80.8% of patients, and average duration of symptoms was 10 years. Average UPDRS motor scores while patients were “on medication” was 26.1. Compared to cognitively intact PD patients, those with MCI had longer duration of motor symptoms (t (212) = 2.27, p = .024) and worse UPDRS motor scores (t (212) = 4.70, p < . 001). The two groups did not differ in terms of age, education or levodopa equivalency dose (LED; all p values > .05).
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Almost half (47.2%) of our sample met criteria for MCI. Of the individuals with MCI, 59% were categorized as amnestic MCI and 41% met criteria for non-amnestic MCI. The amnestic and non-amnestic groups did not differ in terms of age, education, UPDRS motor scores, duration of motor symptoms or LED (all p values > .05). Mood Differences among Parkinson Patients with and without MCI Independent samples t-tests were conducted to examine differences in mood scales between MCI and cognitively intact PD patients. Results revealed that PD patients with MCI reported
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more severe depression (t(212)=2.23, p=0.027) and trait anxiety (t(212)=2.27, p=0.024) compared to cognitively intact PD patients. Apathy was not significantly greater in MCI than non-MCI patients (p=.053).
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In order to control for possible confounding variables, three follow-up hierarchical regressions were conducted controlling for age, education and severity of motor symptoms. Results revealed that the overall regression models significantly predicted depression (F(2,211) = 12.80, p = .05).
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In order to control for possible confounding variables, follow-up hierarchical regressions were conducted controlling for age, education and severity of motor symptoms. The overall models significantly predicted depression (F(2,211) = 9.36, p = 60 months has received no support from industry. Dr. Okun has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books $Patients, and Cambridge (movement disorders books). Dr. Okun is an associate editor for New England Journal of Medicine Journal Watch Neurology. Dr. Okun has participated in CME and educational activities on movement disorders (in the last 36) months sponsored by PeerView, Prime, Quantia, Henry Stewart, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic, Abbvie, and ANS/St. Jude, and the PI has no financial interest in these grants. Dr. Okun has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria.
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Dr. Bowers was supported by NIH R21-NS079767, R03-MH109336, and Sante Fe Avmed. She has received research support from the NIH, Michael J. Fox Foundation, the National Parkinson Foundation, and the McKnight Research Foundation.
References
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1. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986; 9:357–381. [PubMed: 3085570] 2. Litvan I, Aarsland D, Adler CH, et al. MDS task force on mild cognitive impairment in Parkinson's disease: Critical review of PD-MCI. Movement Disord. 2011; 26:1814–1824. [PubMed: 21661055] 3. Fernandez HH, Crucian GP, Okun MS, et al. Mild cognitive impairment in Parkinson’s disease: the challenge and the promise. Neuropsychiatr Dis and Treat. 2005; 1:37. 4. Janvin CC, Larsen JP, Aarsland D, et al. Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia. Movement Disord. 2006; 21:1343–1349. [PubMed: 16721732] 5. Hilker R, Thomas AV, Klein JC, et al. Dementia in Parkinson disease functional imaging of cholinergic and dopaminergic pathways. Neurology. 2005; 65:1716–1722. [PubMed: 16344512] 6. Williams-Gray CH, Evans JR, Goris A, et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009; 132:2958–2969. [PubMed: 19812213] 7. Woods SP, Tröster AI. Prodromal frontal/executive dysfunction predicts incident dementia in Parkinson's disease. J Int Neuropsychol Soc. 2003; 9:17–24. [PubMed: 12570354] 8. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease A multicenter pooled analysis. Neurology. 2010; 75:1062–1069. [PubMed: 20855849]
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Figure 1.
Raw means scores on measures of apathy, depression and trait anxiety are depicted for each group with higher scores representing greater severity; MCI= mild cognitive impairment; error bars depict the 95% confidence interval; * p≤.05.
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Table 1
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Sample Characteristics N=214 Parkinson Patients 151 Males (70.6%); 63 Females (29.4%)
Total
Intact Cognition
MCI
N=113
N=101
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Mean (SD)
Mean (SD)
Mean (SD)
Percent Caucasian
95.8
98.2
93.1
Age in years
64.3 (9.5)
63.7 (9.5)
65.1 (9.5)
Years of Education
14.9 (2.9)
15.0 (2.8)
14.9 (3.0)
Years with Symptoms
10.0 (5.8)
9.1 (4.6)
10.9 (6.6)
UPDRS Motor Score, on medication
26.1 (10.8)
23.0 (9.5)
29.3 (9.6)
Percent Tremor Predominant
80.8
80.5
81.2
Levodopa Equivalency Dose
829.1 (564.3)
816.4 (590.0)
843.3 (536.7)
Percent on Antidepressant Medication
38.6
37.8
39.6
Percent on Anti-anxiety Medication
19.7
21.6
17.5
Dementia Rating Scale-Total
137.25 (4.9)
139.3 (3.4)
135.0 (5.2)
Beck Depression Scale-II
9.4 (6.3)
8.5 (5.9)
10.4 (6.5)
Apathy Scale
10.7 (6.3)
9.9 (5.9)
11.6 (6.5)
State-Trait Anxiety Inventory-Trait Scale
35.4 (9.8)
34.0 (9.6)
37.0 (9.8)
UPDRS= Unified Parkinson’s Disease Rating Scale-Part III; SD= standard deviation; MCI= mild cognitive impairment
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Author Manuscript −.179 .009
Partial Correlation
p
.076
p
.292 −.123
p
Partial Correlation
−.073
Partial Correlation
.002
−.211
.062
−.130
.083
−.120
Verbal Memory
.444
−.053
.977
−.002
.206
−.034
Attention
Controlling for education and gender; significant correlations appear in bold.
Trait Anxiety
Apathy
Depression
Executive Function
.001
−.231
.016
−.167
.051
−.136
Language
.076
−.123
.072
−.125
.192
−.091
Processing Speed
.107
−.112
.241
−.082
.448
−.053
Visuospatial
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Partial Correlations Between Mood Symptoms and Neurocognitive Domains
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Table 2 Jones et al. Page 12
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