Relationship of Movement Disorders Society–Unified Parkinson's Disease Rating Scale Nonmotor Symptoms to Cognitive Functioning in Patients with Parkinson's Disease

ABSTRACT

Background

Few studies assess the relationships between nonmotor aspects of experiences of daily living and cognitive functioning in Parkinson's disease (PD).

Objective

To evaluate the relationships among the Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) part I items and neuropsychological tests in PD.Methods: We assessed 151 PD patients with the MDS‐UPDRS part I and a battery of cognitive tests focused on the following 5 cognitive domains: attention/working memory, executive functioning, recent memory, language, visuoperception. Raw scores for individual cognitive tests were transformed to z scores, and cognitive domain scores were calculated by averaging z scores within each domain. Individual items from the MDS‐UPDRS part I were entered in a stepwise linear regression analysis assessing item contribution to cognitive domain scores.

Results

The MDS‐UPDRS part I item scores for hallucinations and psychosis and light headedness on standing predicted attention/working memory domain scores (P = 0.004). These same item scores, along with apathy, depressed mood, and dopamine dysregulation syndrome, predicted executive functioning (P = 0.044). The apathy and dopamine dysregulation syndrome items predicted language (P = 0.006). In addition, the cognitive impairment and sleep items were predictors of recent memory (P = 0.031). None of the items were predictors of visuoperception (P = 0.006). Other part I items were not significantly related to cognitive domain scores.

Conclusions

Specific nonmotor MDS‐UPDRS part I items, particularly mood, behavior, and autonomic‐related items, exhibited significant relationships with cognitive domains. The highest number of items were predictive of the executive functioning domain, which is the hallmark cognitive dysfunction in PD.

Nonmotor symptoms are a common complication of Parkinson's disease (PD), although they are not well recognized in clinical practice.1 However, nonmotor symptoms can significantly impact disability and quality of life.1, 2 The Movement Disorders Society–Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) has been shown to be a reliable and valid clinical rating scale in the assessment of PD.3 Part I comprises the nonmotor aspects of experiences of daily living (nM‐EDL). The first 6 questions (1A) are administered by an examiner, and 7 nM‐EDL questions are completed by the patient and/or caregiver (1B). There are few studies assessing the relationship between nM‐EDL on the MDS‐UPDRS and measures of cognitive functioning. Gallagher and colleagues4 found a strong relationship between the MDS‐UPDRS part I total score and composite scores of other nonmotor scales often used in PD. However, the 1 cognitive item from part IA (item 1.1, cognitive impairment) was only weakly correlated with 3 separate cognitive scales used in this study (Addenbrooke's Cognitive Examination,5 Scales for Outcome of Parkinson's Disease,6 Frontal Assessment Battery7, 8). The r values for the 3 cognitive scales in Gallagher's study all fell below 0.40, suggesting there is variability in what these tests measure. In another study, Lang and colleagues9 found moderate correlations (between −0.25 and − 0.34) between the nM‐EDL and motor aspects of experiences of daily living total scores and 3 measures of memory and executive functions (Hopkins Verbal Learning Test,10 verbal fluency,11 and Letter Number Sequencing12). The current study, using regression analysis, assesses the relationship between the nM‐EDL individual item scores and multiple domains of cognitive functioning as commonly grouped in PD according to MDS Task Force recommendations.13

Methods

Participants

PD patients were recruited from the Rush University Medical Center Movement Disorders Clinic, a university‐based tertiary care practice seeing new consultations and follow‐up patients for management. Patients with cognitive concerns, expressed by themselves, caregivers, or a neurologist, receive a battery of neuropsychological tests. All patients were examined by a movement disorders specialist and met the United Kingdom PD Society Brain Bank criteria.14 Consecutive cases with clinically diagnosed PD who completed the MDS‐UPDRS part I and a battery of cognitive testing were included in the study. Patients were excluded if it was deemed by the interviewer's clinical judgment that they were unable to provide valid responses to the MDS‐UPDRS part I because of dementia. A total of 151 patients were recruited and comprised the sample. This study was approved by the Rush University Institutional Review Board, Office of Research Affairs (ORA): 15080605‐IRB02. The patients gave informed consent for this database study by signing the Rush Movement Disorders Repository Consent Form.

MDS‐UPDRS Part I and Cognitive Testing

The 6 items from the MDS‐UPDRS part IA nM‐EDL, which are examiner rated, are the following: cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, and features of dopamine dysregulation syndrome. The 7 items from the MDS‐UPDRS part IB nM‐EDL items, which are patient and/or caregiver reports, are the following: sleep problems, daytime sleepiness, pain and other sensations, urinary problems, constipation problems, light headedness on standing, and fatigue. The items are scored from 0 to 4 points on a Likert scale, with 0 being absent and 4 being severe. The total range is 0 to 54. The mean MDS‐UPDRS part I total score for this sample is 9.09 (standard deviation [SD] ± 5.1)

All patients were administered the Mini‐Mental State Exam (MMSE)15 and the following individual tests grouped into 5 cognitive domains as suggested by the MDS Parkinson's Disease‐Mild Cognitive Impairment Task Force recommendations and previous research at our center16, 17: (1) for attention/working memory, the Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) Digit Span Forward,12 Symbol Digit Modalities Test,18 and MMSE WORLD15; (2) for executive functioning, Animal Fluency,19 Digit Span Backward,12 Digit Span Sequencing,12 and the Frontal Assessment Battery7, 8; (3) for language, the Boston Naming Test (15 items)19 and Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) Similarities12; (4) for recent memory, the Consortium to Establish a Registry for Alzheimer's Disease Word List Memory (immediate, delay, recognition)19; (5) for visuoperception, the Judgment of Line Orientation (15 items)20 and MMSE Pentagons.15 MMSE WORLD was scored according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines,19, 21 and the MMSE Pentagons was scored using a 6‐point ordinal scale.22

Raw scores for individual cognitive tests were transformed to z scores based on normative data from healthy controls examined at our center.23, 24 The 5 cognitive domain scores were calculated by averaging z scores for the cognitive tests within each of the specific domains.

Statistical Analysis

All statistical analyses were conducted using SPSS (version 26, IBM Corp., Armonk, NY). Individual items from the MDS‐UPDRS part IA and part IB were entered into a stepwise linear regression to identify which items predicted the 5 cognitive domains assessed.

Results

A total of 151 patients were recruited who had a mean age of 72.5 years (SD ± 7.9), mean education of 15.6 years (SD ± 2.9), and mean disease duration of 29.9 months (SD ± 7.9). Of the sample, 52% were men. The mean MMSE score was 28.3 (SD ± 1.7). Of the 151 patients, 63 (41.7%) were determined to have normal cognition, 79 (52.3%) were determined to have mild cognitive impairment, and 9 (6.0%) were determined to have PD dementia.

The relationships among the MDS‐UPDRS items and cognitive domains are presented in Table 1. Using age as a covariate, the light headedness on standing and hallucinations and psychosis items were significant predictors of performance on the attention/working memory domain (F = 8.386; df = 1, 140; P = 0.004; r ² = 0.202). The hallucinations and psychosis, light headedness on standing, apathy, depressed mood, and features of dopamine dysregulation syndrome items were significant predictors of performance on the executive functioning domain (F = 4.128; df = 1, 137; P = 0.044; r ² = 0.279). The cognitive impairment and sleep problems items were significant predictors of the recent memory domain (F = 4.739; df = 1, 140; P = 0.031; r ² = 0.180). The apathy and features of dopamine dysregulation syndrome items were significant predictors of the language domain (F = 4.830; df = 1, 140; P = 0.030; r ² = 0.167). After controlling for age, there were no items that predicted the visuoperceptual domain (F = 7.837; df = 1, 142; P = 0.006; r ² = 0.052). All other items from the MDS‐UPDRS part I (ie, daytime sleepiness, pain and other sensations, urinary problems, constipation problems) did not predict scores on any of the 5 cognitive domains.

Table 1.

Regressions of Movement Disorders Society–Unified Parkinson's Disease Rating Scale part I items on cognitive domains

Dependent Variable	r 2	F	df	Significance of F	β Coefficient
Attention/working memory	0.202	8.386	1, 140	0.004
Lightheadedness on standing					−0.247
Hallucinations/psychosis					−0.300
Executive functioning	0.279	4.128	1, 137	0.044
Hallucination/psychosis					−0.442
Apathy					−0.375
DDS					−0.705
Depressed mood					0.413
Lightheadedness on standing					−0.212
Recent memory	0.180	4.739	1, 140	0.031
Cognitive impairment					−0.285
Sleep problems					0.160
Language	0.167	4.830	1, 140	0.030
Apathy					−0.530
DDS					−0.915
Visuoperception	0.052	7.837	1, 142	0.006

DDS, Dopamine Dysregulation Syndrome.

Discussion

Several key nonmotor symptoms predominantly affecting mood, behavior, and autonomic functioning from the MDS‐UPDRS related to performance in different cognitive domains in our PD sample. After adjusting for age, the cognitive impairment item was predictive of the recent memory domain. The greatest number of items, hallucinations and psychosis, lightheadedness on standing, apathy, depressed mood, and features of dopamine dysregulation syndrome were predictive of the executive functioning domain, which is the hallmark of the cognitive dysfunction in PD.

Our findings are similar to those of Gallagher and colleagues4 in that we found that the cognitive impairment item was related to the recent memory domain. The former study looked at the correlation between the individual cognitive impairment item and 3 commonly used cognitive tests used in PD and found only a weak relationship. In the current study, multiple MDS‐UPDRS part I items were entered into a stepwise linear regression, showing that the broader nonmotor features of PD are related to cognitive functioning. In addition, in the current study we were able to separate the cognitive tests into different domains for analysis.

Besides the cognitive impairment item, other nM‐EDL items, including hallucinations and psychosis, light headedness on standing, apathy, depressed mood, features of dopamine dysregulation syndrome, and sleep problems, were related to the attention/working memory, executive functioning, and language cognitive domains. Prior studies have linked the presence of hallucinations to greater cognitive impairment, with some studies demonstrating greater executive dysfunction in hallucinators,25 and other studies implicating attentional dysfunction in the pathophysiology of hallucinations in PD.26, 27 Orthostatic hypotension, and the associated symptom of lightheadedness, has been associated with cognitive impairment in PD, possibly as a result of cerebral hypoperfusion or through peripheral noradrenergic dysfunction.28, 29 Apathy has been associated with cognitive impairment, particularly with executive dysfunction, in patients with PD.30, 31, 32 Depressed mood has previously been shown to be associated with cognitive impairment in PD.32, 33 Although dopamine dysregulation syndrome may not be related to cognitive functioning,34 studies suggest that other aspects of impulse control disorder are associated with executive functioning in patients with PD.35, 36 Several studies have found an association between sleep disturbance, including rapid eye movement behavior disorder, and cognitive functioning in patients with PD.37, 38, 39

Although the relationships between MDS‐UPDRS part I items and cognitive functioning in the current study are statistically significant, they may not be clinically pertinent. For example, Horvath and colleagues40 evaluated the minimally clinically important difference for the MDS‐UPDRS motor examination (part III). In that study, they found that improvement larger than 3.25 points or worsening larger than 4.63 points represented minimal but clinically meaningful change. The amount of explained variance in the current study is small. Thus, for each regression analysis for the cognitive domains, the r 2 was modest, and did not improve appreciably as each item was entered. This suggests that other variables may be involved, such as physical disability. The findings of the current study support the use of the MDS‐UPDRS part I as a pertinent composite outcome measure in studies with PD, particularly those focused on cognition and nM‐EDL.

One of the limitations of the current study is that we assessed cognitive tests that are part of the battery used in our clinic, and these tests may not be the most representative measures of each domain. Another limitation of the current study is that we used patients from a university‐based tertiary care center with high education, which may not be representative of community‐based patients.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

B.A.B.: 1A, 1B, 1C, 2C, 3A, 3B

D.C.: 1C, 2C, 3B

G.T.S.: 1A, 1B, 2A, 2B, 2C, 3B

J.G.G.: 1A, 2C, 3A, 3B

C.G.G.: 1A, 1B, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: This study was approved by the Rush University Institutional Review Board, ORA: 15080605‐IRB02. Patients gave informed consent for this data base study by signing the Rush Movement Disorders Repository Consent Form. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: B.A.B. and D.C. have nothing to disclose. G.T.S. has consulting and advisory board membership with honoraria from Acadia, Pharmaceuticals, Adamas Pharmaceuticals, Inc., Biogen, Inc., Ceregene, Inc., CHDI Management, Inc., Cleveland Clinic Foundation, Ingenix Pharmaceutical Services (i3 Research), MedGenesis Therapeutix, Inc., Neurocrine Biosciences, Inc., Pfizer, Inc., Tools‐4‐Patients, Ultragenyx, Inc., and Sunshine Care Foundation. Grants and research funding include the National Institutes of Health, Department of Defense, Michael J. Fox Foundation for Parkinson's Research, Dystonia Coalition, CHDI, Cleveland Clinic Foundation, International Parkinson and Movement Disorder Society, and CBD Solutions. Dr. Stebbins receives honoraria from the International Parkinson and Movement Disorder Society, American Academy of Neurology, Michael J. Fox Foundation for Parkinson's Research, Food and Drug Administration, National Institutes of Health, and the Alzheimer's Association. J.G.G. has received grant and research support from the National Institutes of Health, Michael J. Fox Foundation, Rush University, Acadia, CHDI, and Parkinson's Foundation. Dr. Goldman has received consulting fees from Acadia, Aptinyx, Sunovion, and Worldwide Med and honoraria from the International Parkinson and Movement Disorder Society, American Academy of Neurology, and Parkinson's Foundation. C.G.G. has consulting or advisory board membership with honoraria from Boston Scientific and Oxford Biomedica. Grants and research funding include Rush University Medical Center from the National Institutes of Health and Michael J. Fox Foundation for research conducted by Dr. Goetz. Dr. Goetz directs the Rush Parkinson's Disease Research Center that receives support from the Parkinson's Disease Foundation, and some of these funds support Dr. Goetz's salary as well as his research efforts. He participated in the directorship of the translation program for the Movement Disorders Society–Unified Parkinson's Disease Rating Scale and Unified Dyskinesia Rating Scale and received funds directed to Rush University Medical Center from the International Parkinson and Movement Disorder Society for this effort. He receives honoraria from a Presidential stipend from the International Parkinson and Movement Disorder Society paid to Rush University Medical Center as part of Dr. Goetz's salary and a faculty stipend from the International Parkinson and Movement Disorder Society.