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Restless Legs Syndrome and Cognitive Function: A Population-based Cross-sectional Study
CLINICAL RESEARCH STUDY
Restless Legs Syndrome and Cognitive Function: A Population-based Cross-sectional Study Pamela M. Rist, ScD,a,b Alexis Elbaz, MD, PhD,c,d Carole Dufouil, PhD,e,f Christophe Tzourio, MD, PhD,e,f,1 Tobias Kurth, MD, ScDa,b,e,f,1 a
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Mass; cSocial and Occupational Determinants of Health, INSERM Centre for Research in Epidemiology and Population Health, Villejuif, France; dUniversité de Versailles St-Quentin, UMRS 1018, Versailles, France; eTeam Neuroepidemiology, INSERM Research Center for Epidemiology and Biostatistics, Bordeaux, France; fCollege of Health Sciences, University of Bordeaux, Bordeaux, France. b
ABSTRACT BACKGROUND: Restless legs syndrome has been speculated to be linked to cognitive impairment through vascular risk factors or through its effect on sleep deprivation. Previous studies on the association between restless legs syndrome and cognitive function have been inconclusive. We performed a cross-sectional analysis of the association between restless legs syndrome and cognitive function using data from a large population-based study of elderly individuals residing in France. METHODS: We used information from 2070 individuals from the Dijon, France center of the Three-City study who had available information on restless legs syndrome and cognitive functioning measures. Restless legs syndrome was assessed using the 4 minimal diagnostic criteria of the International Restless Legs Study Group. During the same wave in which restless legs syndrome status was assessed, cognitive functions also were assessed using 4 tests: Isaacs’ test of verbal/category fluency, the Benton Visual Retention Test, the Trail Making Test B, and the Mini-Mental State Examination. We created a summary global cognitive score by summing the z scores for the 4 tests and used analysis of covariance to explore the association between restless legs syndrome and cognitive function. RESULTS: We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. The mean global z-score after multivariate adjustment was 0.003 (SE 0.173) for those with restless legs syndrome and 0.007 (SE 0.129) for those without restless legs syndrome (P-value ¼ .98). CONCLUSION: Data from this large, population-based study do not suggest that restless legs syndrome is associated with prevalent cognitive deficits in elderly individuals. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) -, --KEYWORDS: Cognitive function; Epidemiology; Restless legs syndrome
Restless legs syndrome is a neurological disorder characterized by an urge to move the legs and unpleasant leg sensations, which usually are experienced in the evening or Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Tobias Kurth, MD, ScD, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, University of Bordeaux, 146 rue Léo Saignat CS61292, Bordeaux 33076, France. E-mail address: [email protected] 1 These authors contributed equally to this manuscript. 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.04.011
at night while the individual is at rest. Population-based studies using the minimal diagnostic criteria developed by the International Restless Legs Syndrome Study Group found the prevalence of restless legs syndrome to range from 4% to 29% (average of 14.5%).1-3 The prevalence of the disease is approximately twice as high in women as it is in men, and increases with age.4 Previous studies have shown associations between restless legs syndrome and many cardiovascular risk factors including smoking,5-9 diabetes,6,8,10 hypercholerolemia,8,10 exercise,10 body mass index (BMI)5,10-12 and hypertension.6,13,14 Many of these factors are also risk factors for cognitive impairment or
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dementia, which has led to speculation that restless legs Response options were “yes” or “no.” If the participant syndrome may also be associated with cognitive function. In responded “yes,” he or she was asked further: “Do these addition to the potential link between restless legs syndrome unpleasant sensations occur solely or mainly at rest (when and cognition through vascular pathways, the sleep depriyou are sitting or lying down, without moving your legs) vation and poor quality sleep experienced by individuals and do they improve with movement?” and “Are these unwith restless legs syndrome also may be associated with pleasant sensations more intense in the evening or at night poor cognitive performance. than in the morning?” Response Previous studies have examined options for these questions were CLINICAL SIGNIFICANCE the association between restless legs “yes” or “no.” If the participant syndrome and cognitive perforresponded “yes” to all 3 questions, Restless legs syndrome may be linked to mance and have provided conflicthe or she was considered as havcognitive impairment through vascular ing results. Some have observed ing restless legs syndrome. For risk factors or through its effect on sleep deficits in some cognitive dothose respondents who experideprivation. 15-18 mains, but others have found no enced restless legs syndrome Using a population-based cohort of association between restless legs within the past 12 months, we also syndrome and any cognitive funcasked about the frequency of elderly individuals, we examined the tion measure.19,20 Most previous symptoms. Possible response opcross-sectional association between studies were small, with only one tions were: at least once a year but restless legs syndrome prevalence and study having more than 100 particless than once a month, once a cognitive function. ipants with restless legs synmonth, 2 to 4 times per month, 2 This large population-based study does drome.16 Given the discrepant to 3 times per week, 4 to 5 times not support any association between per week, and 6 to 7 times per results and small size of previous week. We collapsed these studies, we performed a crossrestless legs syndrome and existing response options into 2 categories: sectional analysis of the associacognitive deficits across a wide range of 4 or fewer times per month (low tion between restless legs syndrome cognitive domains. frequency) and 2 or more times and cognitive function using data per week (high frequency). from a large population-based study of elderly individuals residing in France.
Cognitive Assessment METHODS The Three-City (3C) Study is a longitudinal cohort study designed to estimate the risk of dementia and cognitive impairment attributable to vascular risk factors.21 The study enrolled (1999-2001) subjects living in 3 French cities (Bordeaux, Dijon, and Montpellier). The present analysis uses data only from subjects living in Dijon, where information about restless legs syndrome status and cognitive function are available. Individuals aged 65 years or older who were living in Dijon, registered on the electoral rolls in 1999, and not institutionalized, were eligible to be included in the study. Each subject provided informed consent and the Ethical Committee of the University Hospital of Kremlin-Bicêtre approved the methods and procedures of the 3C study.
Restless Legs Syndrome Assessment Information on restless legs status was first assessed during the fifth (2008-2009) and sixth (2010-2012) waves of the study. Participants were asked to report the 4 minimal diagnostic criteria of the International Restless Legs Study Group, which have been established and validated in previous studies.22,23 The first question was: “Have you ever felt unpleasant sensation in the legs (restlessness, tingling, tension, annoyances, contractions, twitching, numbness, electricity, etc.) with the irresistible need or want to move?”
During the same study waves in which restless legs syndrome status was assessed, cognitive function also was assessed using a neuropsychological battery that included 4 tests: the Isaacs’ test of verbal/category fluency (Isaac),24 the Benton Visual Retention Test (BVRT),25 the Trail Making Test B (TMTB)26 and the Mini-Mental State Examination (MMSE).27 We calculated TMTB scores by calculating the ratio of time to task completion divided by the number of correct connections. Additionally, we capped time at 300 seconds and total score at 35 (99th percentile at baseline) to reduce the influence of outlying scores. All test results were converted to z-scores using the mean and SD of the original scores of the participants eligible for this study. Because higher times imply worse performance, we multiplied z-scores for TMTB by 1. Additionally, we created a summary global cognitive score by summing the z-scores for the Isaac, BVRT, TMTB, and MMSE tests.
Covariates Trained psychologists collected sociodemographic and medical data on participants during home visits at baseline and during study examination center visits or home visits at the fifth and sixth waves of the study. Information from the baseline and fifth and sixth wave questionnaires were used to determine the participant’s medical history.
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History of cardiovascular disease was defined as a history of myocardial infarction, stroke, angina, percutaneous transluminal coronary angioplasty, or coronary artery bypass surgery. History of diabetes was defined as glycemia 7 mmol/L or use of antidiabetic treatment.28 History of hypertension was defined as measured systolic blood pressure 140 mm Hg or measured diastolic blood pressure 90 mm Hg or antihypertensive treatment. History of high cholesterol was defined as treatment with cholesterollowering medication or having a total cholesterol level of 6.2 mmol/L. History of depression symptoms was defined using the Center for Epidemiological Studies-Depression scale29 with a cutoff of 17 points for men and 23 points for women, as has been done previously.30 For BMI, smoking status, alcohol consumption, and physical activity, we used values from the follow-up wave in which restless legs syndrome was assessed. In the event that this value was missing, we used values from baseline. BMI was calculated from measured height and weight and was categorized as normal weight (<25 kg/m2), overweight (25 to <30 kg/m2), and obese (30 kg/m2). Smoking status was reported as never, past, or current. Alcohol consumption was categorized as no drinking, drinking >0 to 12 grams/day, drinking >12 to 24 grams/day, or drinking >24 grams/day. Physical activity was defined as active vs nonactive because changes in the questionnaires on physical activity precluded more detailed physical activity categorization. Education was assessed at baseline and categorized as low (no education or primary school), medium low (middle school or technical or professional short degree), medium high (secondary level without diploma or technical or professional long degree or baccalaureate), or high (university level).
and high frequency of restless legs syndrome symptoms to those with no history of restless legs syndrome. Most subjects were not missing information on any covariates. Only 2 subjects were missing information on history of high cholesterol and were assigned to having high cholesterol (the most common category). Only one person was missing information on depression status and was classified as not depressed (the most common category). Because over 100 subjects were missing information on migraine status, we created a separate category for missing migraine information. All analyses were performed in SAS
Statistical Analyses We used analysis of covariance (ANCOVA) to explore the association between restless legs syndrome and cognitive function (outcome). Our first model (Model 1) adjusted for age at restless legs syndrome and cognitive assessment and sex. Our second set of models (Model 2) adjusted for age, sex, smoking status, alcohol consumption, physical activity, BMI categories, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, and education. Because it has been hypothesized that restless legs syndrome may impact cognitive function through its effects on sleep, we performed a sensitivity analysis in which we adjusted for self-reported difficulty sleeping (never, rarely, regularly, often), quality of sleep (good, medium, or mediocre/bad), and intake of sleep medication (yes/no), as well as all variables in Model 2. Restless legs syndrome may also impact cognitive function through its association with depression,31 so we performed another sensitivity analysis in which we adjusted for history of depression (yes/no) in addition to all variables in Model 2. We performed another sensitivity analysis in which we compared those with low
Table 1
Characteristics of Participants by Restless Legs Status
Characteristic Age at restless legs assessment and cognitive interview (mean, SD) Sex (% female) Smoking status (%) Never Past Current Alcohol consumption (%) Nondrinker 0 to 12 g/day 12 to 24 g/day >24 g/day Physically active (%) Body mass index <25 kg/m2 25 to <30 kg/m2 30 kg/m2 History of high blood pressure (%) History of high cholesterol (%) History of diabetes (%) History of cardiovascular disease (%) Education Low Medium low Medium high High History of depression Global cognitive score*, mean SD Isaac,* mean SD Benton,* mean SD MMSE,* mean SD Trail Making B,* mean SD
No History of Restless Legs Syndrome (n ¼ 1653)
History of Restless Legs Syndrome (n ¼ 417)
82.7 (4.4)
81.7 (4.6)
63.2
72.4
63.1 33.3 3.6
66.7 30.2 3.1
39.0 41.3 14.0 5.8 16.5
40.3 45.1 10.8 3.8 14.4
43.0 40.7 16.3 89.4
41.7 42.9 15.4 87.1
65.7
63.2
13.5 17.7
11.0 19.7
17.8 42.8 19.7 19.7 18.87 0.01 (2.92)
18.7 45.6 18.9 16.8 26.2 0.05 (2.77)
12.2 (2.7) 11.5 (2.4) 26.8 (2.2) 7.9 (6.3)
12.3 (2.5) 11.7 (2.1) 26.8 (2.1) 8.1 (6.6)
Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Scores are measured in standardized units.
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9.3 (SAS Institute Inc., Cary, NC), and the 2-tailed P-value of <.05 was considered statistically significant.
RESULTS Of the 2139 participants in the Dijon center of the 3C study with available information on restless legs syndrome status at waves 5 or 6, we excluded 69 individuals who had information missing on all measures of cognitive function, leaving 2070 individuals eligible for inclusion in our analyses. Characteristics of the study participants by restless legs syndrome and cognitive assessment can be seen in Table 1. Four hundred seventeen individuals were classified as having a history of restless legs syndrome. The characteristics and cognitive z-scores were similar between the 2 groups, although those with a history of restless legs syndrome were more likely to be female and more likely to be depressed. Table 2 shows the age- and sex- and multivariableadjusted z-scores for each cognitive test by restless legs syndrome status and the P-value from ANCOVA tests. We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. For example, the mean global z-score after multivariate adjustment was 0.003 (SE 0.173) for those with restless legs syndrome and 0.007 (SE 0.129) for those without restless legs syndrome. The P-value from the ANCOVA test was 0.98. Further adjustments on sleep quality, difficulty sleeping, and taking sleep medication or depression also showed no significant differences in cognitive scores between those with restless legs syndrome and those without restless legs syndrome (see Appendix, available
Table 2
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online). Of the participants who provided information on the frequency of restless legs syndrome symptoms, 193 reported low frequency and 174 reported high frequency. We observed no statistically significant associations between the frequency of restless legs syndrome symptoms and cognitive function.
DISCUSSION Results of this large, population-based cross-sectional study on restless legs syndrome and cognitive function do not suggest that restless legs syndrome is associated with lower cognitive function across a broad range of cognitive domains. Previous studies have examined the association between restless legs syndrome and cognitive performance, but results from these studies are conflicting. A study in elderly Korean individuals observed lower performance on the MMSE among those with restless legs syndrome compared with those without restless legs syndrome.17 Some studies have observed deficits in areas of attention and verbal fluency,15 in verbal fluency and trail making tests,18 or in the Stroop and verbal fluency tests,16 but not in other tests or domains of cognitive functioning. However, some of these studies were performed in clinic-based populations.15,18 These populations may exhibit more severe disease phenotypes than the general population, which may limit the generalizability of their results to those with less severe disease. Other studies using a wide range of cognitive tests have found no association between restless legs syndrome and any cognitive measure.19,20 However, the small size of these studies may limit their ability to detect differences in
Age- and Sex-adjusted and Multivariable-adjusted Cognitive Scores by Restless Legs Syndrome Status
Age- and sex-adjusted Global Score† Isaac† Benton† MMSE† Trail Making B† Multivariable-adjusted* Global Score† Isaac† Benton† MMSE† Trail Making B†
No History of Restless Legs Syndrome
History of Restless Legs Syndrome
No. of Subjects
Adjusted Mean Score (SE)
No. of Subjects
Adjusted Mean Score (SE)
Overall P-Value From ANCOVA
1653 1653 1653 1653 1601
0.013 0.004 0.008 0.007 0.010
(0.069) (0.024) (0.024) (0.025) (0.025)
417 417 417 417 411
0.051 0.015 0.031 0.029 0.038
(0.137) (0.048) (0.048) (0.049) (0.049)
.68 .72 .47 .52 .38
1653 1653 1653 1653 1601
0.007 0.044 0.011 0.002 0.042
(0.129) (0.046) (0.047) (0.048) (0.047)
417 417 417 417 411
0.003 0.047 0.043 0.024 0.071
(0.173) (0.062) (0.062) (0.064) (0.063)
.98 .95 .31 .67 .58
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, and education. †Scores are measured in standardized units.
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cognitive function between participants with restless legs syndrome and those without restless legs syndrome. Compared with prior studies, the current study was much larger and included many more individuals with restless legs syndrome, which improves the ability to detect small differences in cognitive function. While many previous studies controlled for age, sex, and perhaps education, they did not adjust for other potential confounders, including lifestyle factors and history of cardiovascular disease. Many also could not evaluate the role of potential mediators, for example, depression and sleep quality, which may be consequences of restless legs syndrome and also associated with cognition, on the association between restless legs syndrome and cognitive performance. One previous study that adjusted for a range of potential confounders was population-based and larger than many prior studies.16 In univariate analyses, they found no differences in mean cognitive scores between those with restless legs syndrome and those without restless legs syndrome. In multivariable analyses they observed that those with restless legs syndrome demonstrated lower cognitive performance. However, these analyses were performed using logistic regression, which does not provide multivariable-adjusted cognitive scores. Additionally, it is unclear whether cognitive function or restless legs syndrome was the outcome in their analyses. Therefore, it is difficult to compare the results of their analyses to the results presented in this article. While it has been suggested that restless legs syndrome may be linked to cognitive function through sleep deprivation, a study comparing the cognitive function of restless legs syndrome subjects to sleep-restricted controls found that the restless legs syndrome subjects performed better on Letter Fluency and Category Fluency tasks, which suggests that restless legs syndrome subjects may adapt to sleep loss.32 After adjusting for sleep quality, difficulty sleeping, and taking sleep medications, we did not observe differences between those with restless legs syndrome and those without restless legs syndrome.
We also did not have information on sleep-disordered breathing. We also were unable to explore whether specific restless legs syndrome treatments may be related to cognitive function. Finally, to be included in this study, the participants in the 3C Study needed to survive until restless legs syndrome assessment in the fifth and sixth waves. They therefore may be healthier and have better cognitive function than individuals who died or dropped out before restless legs syndrome assessment.
Strengths and Limitations Strengths of this study include the use of a large populationbased cohort with information available on many potential covariates and restless legs syndrome status using standardized assessment criteria from the International Restless Legs Study Group.1,2 One limitation to this study is its cross-sectional design, which prevents us from examining whether rates of cognitive change are different amongst those with restless legs syndrome compared with those without restless legs syndrome. While we used a standard questionnaire for population-level assessment of restless legs syndrome that has been validated in previous cohorts,22,23 misclassification of restless legs syndrome status is still possible. Additionally, we did not have information on kidney disease or iron deficiency, which may be related to restless legs syndrome.
CONCLUSIONS This large population-based study does not support any association between restless legs syndrome and existing cognitive deficits across a wide range of cognitive domains.
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6 16. Celle S, Roche F, Kerleroux J, et al. Prevalence and clinical correlates of restless legs syndrome in an elderly French population: the synapse study. J Gerontol A Biol Sci Med Sci. 2009;65(2):167-173. 17. Kim KW, Yoon I-Y, Chung S, et al. Prevalence, comorbidities and risk factors of restless legs syndrome in the Korean elderly population e results from the Korean Longitudinal Study on Health and Aging. J Sleep Res. 2010;19(1-Part-I):87-92. 18. Pearson VE, Allen RP, Dean T, Gamaldo CE, Lesage SR, Earley CJ. Cognitive deficits associated with restless legs syndrome (RLS). Sleep Med. 2005;7(1):25-30. 19. Lee HB, Ramsey CM, Spira AP, Vachon J, Allen R, Munro CA. Comparison of cognitive functioning among individuals with treated restless legs syndrome (RLS), untreated RLS, and no RLS. J Neuropsychiatry. Clin Neurosci. 2014;26(1):87-91. 20. Driver-Dunckley E, Connor D, Hentz J, et al. No evidence for cognitive dysfunction or depression in patients with mild restless legs syndrome. Mov Disord. 2009;24(12):1840-1842. 21. 3C Study Group. Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology. 2003;22:316-325. 22. Berger K, von Eckardstein A, Trenkwalder C, Rothdach A, Junker R, Weiland SK. Iron metabolism and the risk of restless legs syndrome in an elderly general population—the MEMO-Study. J Neurol. 2002;249: 1195-1199. 23. Hogl B, Kiechl S, Willeit J, et al. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology. 2005;64:1920-1924. 24. Isaacs B, Kennie AT. The Set test as an aid to the detection of dementia in old people. Br J Psychiatry. 1973;123(575):467-470. 25. Benton AL. Manuel pour l’application du test de rétention visuelle: applications cliniques et expérimentales. Paris: Centre de Psychologie Appliquee; 1965. 26. Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8(3):271-276. 27. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. 28. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-1197. 29. Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1: 385-401. 30. Godin O, Dufouil C, Maillard P, et al. White matter lesions as a predictor of depression in the elderly: the 3C-Dijon study. Biol Psychiatry. 2008;63:663-669. 31. Hornyak M. Depressive disorders in restless legs syndrome: epidemiology, pathophysiology and management. CNS Drugs. 2010;24(2): 89-98.
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32. Gamaldo CE, Benbrook AR, Allen RP, Oguntimein O, Earley CJ. A further evaluation of the cognitive deficits associated with restless legs syndrome (RLS). Sleep Med. 2007;9(5):500-505.
Funding: The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor SegaleneBordeaux II University, and the Sanofi-Synthélabo Company. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The Three-City Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Haute Autorité de la Santé, Institut National de Prévention et d’Education pour la Santé, Conseils Régionaux of Bourgogne, Fondation de France, Ministry of Research-INSERM Program “Cohortes et collections de données biologiques,” Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseil Général de la Côte d’or. Pamela M. Rist was supported by the Rose Traveling Fellowship Program in Chronic Disease Epidemiology and Biostatistics from the Harvard School of Public Health. Conflict of Interest: PMR has received, within the last 2 years, funding from the Rose Traveling Fellowship Program in Chronic Disease Epidemiology and Biostatistics from the Harvard School of Public Health. AE has received, within the last 2 years, investigator-initiated research funding unrelated to this project from the French National Research Agency, EU Joint ProgrammeeNeurodegenerative Disease Research (JPND), the French Agency for Drug Security (ANSM), and the French Institute for Research in Public Health (IRESP). CD has received honoraria from the American Academy of Neurology for educational lectures and from Eisai, Inc. for providing methodological expertise. CT has received fees from the Fondation Plan Alzheimer, the Fondation de Recherche sur l’Hypertension Artérielle, and ABBOTT for participating in scientific committees. He has also received investigator-initiated research funding from the French National Research Agency (ANR) and the Fondation Plan Alzheimer for the Three-City study. TK has received, within the last 2 years, investigatorinitiated research funding from the French National Research Agency, and the US National Institutes of Health. Further, he has received honoraria from the American Academy of Neurology for educational lectures and from the BMJ and Cephalalgia for editorial services. Authorship: All authors had access to the data and a role in writing the manuscript.
APPENDIX Supplemental tables accompanying this article can be found in the online version at 10.1016/j.amjmed.2015.04.011.
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APPENDIX Supplementary Table 1
Multivariable- and Depression Status-adjusted Cognitive Scores by Restless Legs Syndrome Status
No History of Restless Legs Syndrome
Global Score† Isaac† Benton† MMSE† Trail Making B†
History of Restless Legs Syndrome
No. of Subjects
Multivariable-adjusted Mean* (SE)
No. of Subjects
Multivariable-adjusted Mean* (SE)
Overall P-Value From ANCOVA*
1653 1653 1653 1653 1601
0.014 0.051 0.006 0.004 0.038
417 417 417 417 411
0.094 0.077 0.065 0.002 0.054
.58 .60 .17 .97 .77
(0.128) (0.046) (0.046) (0.048) (0.047)
(0.171) (0.061) (0.062) (0.064) (0.063)
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, education, and depression. †Scores are measured in standardized units.
Supplementary Table 2 Multivariable-adjusted (Including Sleep Quality, Difficulty Sleeping, and Medications for Sleep) Cognitive Scores by Restless Legs Syndrome Status No History of Restless Legs Syndrome
Global Score† Isaac† Benton† MMSE† Trail Making B†
History of Restless Legs Syndrome
No. of Subjects
Multivariable-adjusted Mean* (SE)
No. of Subjects
Multivariable-adjusted Mean* (SE)
Overall P-Value From ANCOVA*
1653 1653 1653 1653 1601
0.029 0.060 0.018 0.005 0.020
417 417 417 417 411
0.074 0.070 0.048 0.001 0.043
.76 .85 .22 .92 .68
(0.138) (0.049) (0.050) (0.051) (0.051)
(0.176) (0.063) (0.064) (0.065) (0.065)
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, education, sleep quality, difficulty sleeping, and sleep medication. †Scores are measured in standardized units.
Restless Legs Syndrome and Cognitive Function: A Population-based Cross-sectional Study Pamela M. Rist, ScD,a,b Alexis Elbaz, MD, PhD,c,d Carole Dufouil, PhD,e,f Christophe Tzourio, MD, PhD,e,f,1 Tobias Kurth, MD, ScDa,b,e,f,1 a
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Mass; cSocial and Occupational Determinants of Health, INSERM Centre for Research in Epidemiology and Population Health, Villejuif, France; dUniversité de Versailles St-Quentin, UMRS 1018, Versailles, France; eTeam Neuroepidemiology, INSERM Research Center for Epidemiology and Biostatistics, Bordeaux, France; fCollege of Health Sciences, University of Bordeaux, Bordeaux, France. b
ABSTRACT BACKGROUND: Restless legs syndrome has been speculated to be linked to cognitive impairment through vascular risk factors or through its effect on sleep deprivation. Previous studies on the association between restless legs syndrome and cognitive function have been inconclusive. We performed a cross-sectional analysis of the association between restless legs syndrome and cognitive function using data from a large population-based study of elderly individuals residing in France. METHODS: We used information from 2070 individuals from the Dijon, France center of the Three-City study who had available information on restless legs syndrome and cognitive functioning measures. Restless legs syndrome was assessed using the 4 minimal diagnostic criteria of the International Restless Legs Study Group. During the same wave in which restless legs syndrome status was assessed, cognitive functions also were assessed using 4 tests: Isaacs’ test of verbal/category fluency, the Benton Visual Retention Test, the Trail Making Test B, and the Mini-Mental State Examination. We created a summary global cognitive score by summing the z scores for the 4 tests and used analysis of covariance to explore the association between restless legs syndrome and cognitive function. RESULTS: We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. The mean global z-score after multivariate adjustment was 0.003 (SE 0.173) for those with restless legs syndrome and 0.007 (SE 0.129) for those without restless legs syndrome (P-value ¼ .98). CONCLUSION: Data from this large, population-based study do not suggest that restless legs syndrome is associated with prevalent cognitive deficits in elderly individuals. Ó 2015 Elsevier Inc. All rights reserved. The American Journal of Medicine (2015) -, --KEYWORDS: Cognitive function; Epidemiology; Restless legs syndrome
Restless legs syndrome is a neurological disorder characterized by an urge to move the legs and unpleasant leg sensations, which usually are experienced in the evening or Funding: See last page of article. Conflict of Interest: See last page of article. Authorship: See last page of article. Requests for reprints should be addressed to Tobias Kurth, MD, ScD, INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, University of Bordeaux, 146 rue Léo Saignat CS61292, Bordeaux 33076, France. E-mail address: [email protected] 1 These authors contributed equally to this manuscript. 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.04.011
at night while the individual is at rest. Population-based studies using the minimal diagnostic criteria developed by the International Restless Legs Syndrome Study Group found the prevalence of restless legs syndrome to range from 4% to 29% (average of 14.5%).1-3 The prevalence of the disease is approximately twice as high in women as it is in men, and increases with age.4 Previous studies have shown associations between restless legs syndrome and many cardiovascular risk factors including smoking,5-9 diabetes,6,8,10 hypercholerolemia,8,10 exercise,10 body mass index (BMI)5,10-12 and hypertension.6,13,14 Many of these factors are also risk factors for cognitive impairment or
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dementia, which has led to speculation that restless legs Response options were “yes” or “no.” If the participant syndrome may also be associated with cognitive function. In responded “yes,” he or she was asked further: “Do these addition to the potential link between restless legs syndrome unpleasant sensations occur solely or mainly at rest (when and cognition through vascular pathways, the sleep depriyou are sitting or lying down, without moving your legs) vation and poor quality sleep experienced by individuals and do they improve with movement?” and “Are these unwith restless legs syndrome also may be associated with pleasant sensations more intense in the evening or at night poor cognitive performance. than in the morning?” Response Previous studies have examined options for these questions were CLINICAL SIGNIFICANCE the association between restless legs “yes” or “no.” If the participant syndrome and cognitive perforresponded “yes” to all 3 questions, Restless legs syndrome may be linked to mance and have provided conflicthe or she was considered as havcognitive impairment through vascular ing results. Some have observed ing restless legs syndrome. For risk factors or through its effect on sleep deficits in some cognitive dothose respondents who experideprivation. 15-18 mains, but others have found no enced restless legs syndrome Using a population-based cohort of association between restless legs within the past 12 months, we also syndrome and any cognitive funcasked about the frequency of elderly individuals, we examined the tion measure.19,20 Most previous symptoms. Possible response opcross-sectional association between studies were small, with only one tions were: at least once a year but restless legs syndrome prevalence and study having more than 100 particless than once a month, once a cognitive function. ipants with restless legs synmonth, 2 to 4 times per month, 2 This large population-based study does drome.16 Given the discrepant to 3 times per week, 4 to 5 times not support any association between per week, and 6 to 7 times per results and small size of previous week. We collapsed these studies, we performed a crossrestless legs syndrome and existing response options into 2 categories: sectional analysis of the associacognitive deficits across a wide range of 4 or fewer times per month (low tion between restless legs syndrome cognitive domains. frequency) and 2 or more times and cognitive function using data per week (high frequency). from a large population-based study of elderly individuals residing in France.
Cognitive Assessment METHODS The Three-City (3C) Study is a longitudinal cohort study designed to estimate the risk of dementia and cognitive impairment attributable to vascular risk factors.21 The study enrolled (1999-2001) subjects living in 3 French cities (Bordeaux, Dijon, and Montpellier). The present analysis uses data only from subjects living in Dijon, where information about restless legs syndrome status and cognitive function are available. Individuals aged 65 years or older who were living in Dijon, registered on the electoral rolls in 1999, and not institutionalized, were eligible to be included in the study. Each subject provided informed consent and the Ethical Committee of the University Hospital of Kremlin-Bicêtre approved the methods and procedures of the 3C study.
Restless Legs Syndrome Assessment Information on restless legs status was first assessed during the fifth (2008-2009) and sixth (2010-2012) waves of the study. Participants were asked to report the 4 minimal diagnostic criteria of the International Restless Legs Study Group, which have been established and validated in previous studies.22,23 The first question was: “Have you ever felt unpleasant sensation in the legs (restlessness, tingling, tension, annoyances, contractions, twitching, numbness, electricity, etc.) with the irresistible need or want to move?”
During the same study waves in which restless legs syndrome status was assessed, cognitive function also was assessed using a neuropsychological battery that included 4 tests: the Isaacs’ test of verbal/category fluency (Isaac),24 the Benton Visual Retention Test (BVRT),25 the Trail Making Test B (TMTB)26 and the Mini-Mental State Examination (MMSE).27 We calculated TMTB scores by calculating the ratio of time to task completion divided by the number of correct connections. Additionally, we capped time at 300 seconds and total score at 35 (99th percentile at baseline) to reduce the influence of outlying scores. All test results were converted to z-scores using the mean and SD of the original scores of the participants eligible for this study. Because higher times imply worse performance, we multiplied z-scores for TMTB by 1. Additionally, we created a summary global cognitive score by summing the z-scores for the Isaac, BVRT, TMTB, and MMSE tests.
Covariates Trained psychologists collected sociodemographic and medical data on participants during home visits at baseline and during study examination center visits or home visits at the fifth and sixth waves of the study. Information from the baseline and fifth and sixth wave questionnaires were used to determine the participant’s medical history.
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History of cardiovascular disease was defined as a history of myocardial infarction, stroke, angina, percutaneous transluminal coronary angioplasty, or coronary artery bypass surgery. History of diabetes was defined as glycemia 7 mmol/L or use of antidiabetic treatment.28 History of hypertension was defined as measured systolic blood pressure 140 mm Hg or measured diastolic blood pressure 90 mm Hg or antihypertensive treatment. History of high cholesterol was defined as treatment with cholesterollowering medication or having a total cholesterol level of 6.2 mmol/L. History of depression symptoms was defined using the Center for Epidemiological Studies-Depression scale29 with a cutoff of 17 points for men and 23 points for women, as has been done previously.30 For BMI, smoking status, alcohol consumption, and physical activity, we used values from the follow-up wave in which restless legs syndrome was assessed. In the event that this value was missing, we used values from baseline. BMI was calculated from measured height and weight and was categorized as normal weight (<25 kg/m2), overweight (25 to <30 kg/m2), and obese (30 kg/m2). Smoking status was reported as never, past, or current. Alcohol consumption was categorized as no drinking, drinking >0 to 12 grams/day, drinking >12 to 24 grams/day, or drinking >24 grams/day. Physical activity was defined as active vs nonactive because changes in the questionnaires on physical activity precluded more detailed physical activity categorization. Education was assessed at baseline and categorized as low (no education or primary school), medium low (middle school or technical or professional short degree), medium high (secondary level without diploma or technical or professional long degree or baccalaureate), or high (university level).
and high frequency of restless legs syndrome symptoms to those with no history of restless legs syndrome. Most subjects were not missing information on any covariates. Only 2 subjects were missing information on history of high cholesterol and were assigned to having high cholesterol (the most common category). Only one person was missing information on depression status and was classified as not depressed (the most common category). Because over 100 subjects were missing information on migraine status, we created a separate category for missing migraine information. All analyses were performed in SAS
Statistical Analyses We used analysis of covariance (ANCOVA) to explore the association between restless legs syndrome and cognitive function (outcome). Our first model (Model 1) adjusted for age at restless legs syndrome and cognitive assessment and sex. Our second set of models (Model 2) adjusted for age, sex, smoking status, alcohol consumption, physical activity, BMI categories, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, and education. Because it has been hypothesized that restless legs syndrome may impact cognitive function through its effects on sleep, we performed a sensitivity analysis in which we adjusted for self-reported difficulty sleeping (never, rarely, regularly, often), quality of sleep (good, medium, or mediocre/bad), and intake of sleep medication (yes/no), as well as all variables in Model 2. Restless legs syndrome may also impact cognitive function through its association with depression,31 so we performed another sensitivity analysis in which we adjusted for history of depression (yes/no) in addition to all variables in Model 2. We performed another sensitivity analysis in which we compared those with low
Table 1
Characteristics of Participants by Restless Legs Status
Characteristic Age at restless legs assessment and cognitive interview (mean, SD) Sex (% female) Smoking status (%) Never Past Current Alcohol consumption (%) Nondrinker 0 to 12 g/day 12 to 24 g/day >24 g/day Physically active (%) Body mass index <25 kg/m2 25 to <30 kg/m2 30 kg/m2 History of high blood pressure (%) History of high cholesterol (%) History of diabetes (%) History of cardiovascular disease (%) Education Low Medium low Medium high High History of depression Global cognitive score*, mean SD Isaac,* mean SD Benton,* mean SD MMSE,* mean SD Trail Making B,* mean SD
No History of Restless Legs Syndrome (n ¼ 1653)
History of Restless Legs Syndrome (n ¼ 417)
82.7 (4.4)
81.7 (4.6)
63.2
72.4
63.1 33.3 3.6
66.7 30.2 3.1
39.0 41.3 14.0 5.8 16.5
40.3 45.1 10.8 3.8 14.4
43.0 40.7 16.3 89.4
41.7 42.9 15.4 87.1
65.7
63.2
13.5 17.7
11.0 19.7
17.8 42.8 19.7 19.7 18.87 0.01 (2.92)
18.7 45.6 18.9 16.8 26.2 0.05 (2.77)
12.2 (2.7) 11.5 (2.4) 26.8 (2.2) 7.9 (6.3)
12.3 (2.5) 11.7 (2.1) 26.8 (2.1) 8.1 (6.6)
Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Scores are measured in standardized units.
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9.3 (SAS Institute Inc., Cary, NC), and the 2-tailed P-value of <.05 was considered statistically significant.
RESULTS Of the 2139 participants in the Dijon center of the 3C study with available information on restless legs syndrome status at waves 5 or 6, we excluded 69 individuals who had information missing on all measures of cognitive function, leaving 2070 individuals eligible for inclusion in our analyses. Characteristics of the study participants by restless legs syndrome and cognitive assessment can be seen in Table 1. Four hundred seventeen individuals were classified as having a history of restless legs syndrome. The characteristics and cognitive z-scores were similar between the 2 groups, although those with a history of restless legs syndrome were more likely to be female and more likely to be depressed. Table 2 shows the age- and sex- and multivariableadjusted z-scores for each cognitive test by restless legs syndrome status and the P-value from ANCOVA tests. We did not observe any statistically significant differences in any cognitive z-score between those with restless legs syndrome and those without restless legs syndrome. For example, the mean global z-score after multivariate adjustment was 0.003 (SE 0.173) for those with restless legs syndrome and 0.007 (SE 0.129) for those without restless legs syndrome. The P-value from the ANCOVA test was 0.98. Further adjustments on sleep quality, difficulty sleeping, and taking sleep medication or depression also showed no significant differences in cognitive scores between those with restless legs syndrome and those without restless legs syndrome (see Appendix, available
Table 2
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online). Of the participants who provided information on the frequency of restless legs syndrome symptoms, 193 reported low frequency and 174 reported high frequency. We observed no statistically significant associations between the frequency of restless legs syndrome symptoms and cognitive function.
DISCUSSION Results of this large, population-based cross-sectional study on restless legs syndrome and cognitive function do not suggest that restless legs syndrome is associated with lower cognitive function across a broad range of cognitive domains. Previous studies have examined the association between restless legs syndrome and cognitive performance, but results from these studies are conflicting. A study in elderly Korean individuals observed lower performance on the MMSE among those with restless legs syndrome compared with those without restless legs syndrome.17 Some studies have observed deficits in areas of attention and verbal fluency,15 in verbal fluency and trail making tests,18 or in the Stroop and verbal fluency tests,16 but not in other tests or domains of cognitive functioning. However, some of these studies were performed in clinic-based populations.15,18 These populations may exhibit more severe disease phenotypes than the general population, which may limit the generalizability of their results to those with less severe disease. Other studies using a wide range of cognitive tests have found no association between restless legs syndrome and any cognitive measure.19,20 However, the small size of these studies may limit their ability to detect differences in
Age- and Sex-adjusted and Multivariable-adjusted Cognitive Scores by Restless Legs Syndrome Status
Age- and sex-adjusted Global Score† Isaac† Benton† MMSE† Trail Making B† Multivariable-adjusted* Global Score† Isaac† Benton† MMSE† Trail Making B†
No History of Restless Legs Syndrome
History of Restless Legs Syndrome
No. of Subjects
Adjusted Mean Score (SE)
No. of Subjects
Adjusted Mean Score (SE)
Overall P-Value From ANCOVA
1653 1653 1653 1653 1601
0.013 0.004 0.008 0.007 0.010
(0.069) (0.024) (0.024) (0.025) (0.025)
417 417 417 417 411
0.051 0.015 0.031 0.029 0.038
(0.137) (0.048) (0.048) (0.049) (0.049)
.68 .72 .47 .52 .38
1653 1653 1653 1653 1601
0.007 0.044 0.011 0.002 0.042
(0.129) (0.046) (0.047) (0.048) (0.047)
417 417 417 417 411
0.003 0.047 0.043 0.024 0.071
(0.173) (0.062) (0.062) (0.064) (0.063)
.98 .95 .31 .67 .58
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, and education. †Scores are measured in standardized units.
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cognitive function between participants with restless legs syndrome and those without restless legs syndrome. Compared with prior studies, the current study was much larger and included many more individuals with restless legs syndrome, which improves the ability to detect small differences in cognitive function. While many previous studies controlled for age, sex, and perhaps education, they did not adjust for other potential confounders, including lifestyle factors and history of cardiovascular disease. Many also could not evaluate the role of potential mediators, for example, depression and sleep quality, which may be consequences of restless legs syndrome and also associated with cognition, on the association between restless legs syndrome and cognitive performance. One previous study that adjusted for a range of potential confounders was population-based and larger than many prior studies.16 In univariate analyses, they found no differences in mean cognitive scores between those with restless legs syndrome and those without restless legs syndrome. In multivariable analyses they observed that those with restless legs syndrome demonstrated lower cognitive performance. However, these analyses were performed using logistic regression, which does not provide multivariable-adjusted cognitive scores. Additionally, it is unclear whether cognitive function or restless legs syndrome was the outcome in their analyses. Therefore, it is difficult to compare the results of their analyses to the results presented in this article. While it has been suggested that restless legs syndrome may be linked to cognitive function through sleep deprivation, a study comparing the cognitive function of restless legs syndrome subjects to sleep-restricted controls found that the restless legs syndrome subjects performed better on Letter Fluency and Category Fluency tasks, which suggests that restless legs syndrome subjects may adapt to sleep loss.32 After adjusting for sleep quality, difficulty sleeping, and taking sleep medications, we did not observe differences between those with restless legs syndrome and those without restless legs syndrome.
We also did not have information on sleep-disordered breathing. We also were unable to explore whether specific restless legs syndrome treatments may be related to cognitive function. Finally, to be included in this study, the participants in the 3C Study needed to survive until restless legs syndrome assessment in the fifth and sixth waves. They therefore may be healthier and have better cognitive function than individuals who died or dropped out before restless legs syndrome assessment.
Strengths and Limitations Strengths of this study include the use of a large populationbased cohort with information available on many potential covariates and restless legs syndrome status using standardized assessment criteria from the International Restless Legs Study Group.1,2 One limitation to this study is its cross-sectional design, which prevents us from examining whether rates of cognitive change are different amongst those with restless legs syndrome compared with those without restless legs syndrome. While we used a standard questionnaire for population-level assessment of restless legs syndrome that has been validated in previous cohorts,22,23 misclassification of restless legs syndrome status is still possible. Additionally, we did not have information on kidney disease or iron deficiency, which may be related to restless legs syndrome.
CONCLUSIONS This large population-based study does not support any association between restless legs syndrome and existing cognitive deficits across a wide range of cognitive domains.
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6 16. Celle S, Roche F, Kerleroux J, et al. Prevalence and clinical correlates of restless legs syndrome in an elderly French population: the synapse study. J Gerontol A Biol Sci Med Sci. 2009;65(2):167-173. 17. Kim KW, Yoon I-Y, Chung S, et al. Prevalence, comorbidities and risk factors of restless legs syndrome in the Korean elderly population e results from the Korean Longitudinal Study on Health and Aging. J Sleep Res. 2010;19(1-Part-I):87-92. 18. Pearson VE, Allen RP, Dean T, Gamaldo CE, Lesage SR, Earley CJ. Cognitive deficits associated with restless legs syndrome (RLS). Sleep Med. 2005;7(1):25-30. 19. Lee HB, Ramsey CM, Spira AP, Vachon J, Allen R, Munro CA. Comparison of cognitive functioning among individuals with treated restless legs syndrome (RLS), untreated RLS, and no RLS. J Neuropsychiatry. Clin Neurosci. 2014;26(1):87-91. 20. Driver-Dunckley E, Connor D, Hentz J, et al. No evidence for cognitive dysfunction or depression in patients with mild restless legs syndrome. Mov Disord. 2009;24(12):1840-1842. 21. 3C Study Group. Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiology. 2003;22:316-325. 22. Berger K, von Eckardstein A, Trenkwalder C, Rothdach A, Junker R, Weiland SK. Iron metabolism and the risk of restless legs syndrome in an elderly general population—the MEMO-Study. J Neurol. 2002;249: 1195-1199. 23. Hogl B, Kiechl S, Willeit J, et al. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology. 2005;64:1920-1924. 24. Isaacs B, Kennie AT. The Set test as an aid to the detection of dementia in old people. Br J Psychiatry. 1973;123(575):467-470. 25. Benton AL. Manuel pour l’application du test de rétention visuelle: applications cliniques et expérimentales. Paris: Centre de Psychologie Appliquee; 1965. 26. Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8(3):271-276. 27. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. 28. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-1197. 29. Radloff LS. The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1: 385-401. 30. Godin O, Dufouil C, Maillard P, et al. White matter lesions as a predictor of depression in the elderly: the 3C-Dijon study. Biol Psychiatry. 2008;63:663-669. 31. Hornyak M. Depressive disorders in restless legs syndrome: epidemiology, pathophysiology and management. CNS Drugs. 2010;24(2): 89-98.
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32. Gamaldo CE, Benbrook AR, Allen RP, Oguntimein O, Earley CJ. A further evaluation of the cognitive deficits associated with restless legs syndrome (RLS). Sleep Med. 2007;9(5):500-505.
Funding: The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Victor SegaleneBordeaux II University, and the Sanofi-Synthélabo Company. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The Three-City Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Haute Autorité de la Santé, Institut National de Prévention et d’Education pour la Santé, Conseils Régionaux of Bourgogne, Fondation de France, Ministry of Research-INSERM Program “Cohortes et collections de données biologiques,” Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Conseil Général de la Côte d’or. Pamela M. Rist was supported by the Rose Traveling Fellowship Program in Chronic Disease Epidemiology and Biostatistics from the Harvard School of Public Health. Conflict of Interest: PMR has received, within the last 2 years, funding from the Rose Traveling Fellowship Program in Chronic Disease Epidemiology and Biostatistics from the Harvard School of Public Health. AE has received, within the last 2 years, investigator-initiated research funding unrelated to this project from the French National Research Agency, EU Joint ProgrammeeNeurodegenerative Disease Research (JPND), the French Agency for Drug Security (ANSM), and the French Institute for Research in Public Health (IRESP). CD has received honoraria from the American Academy of Neurology for educational lectures and from Eisai, Inc. for providing methodological expertise. CT has received fees from the Fondation Plan Alzheimer, the Fondation de Recherche sur l’Hypertension Artérielle, and ABBOTT for participating in scientific committees. He has also received investigator-initiated research funding from the French National Research Agency (ANR) and the Fondation Plan Alzheimer for the Three-City study. TK has received, within the last 2 years, investigatorinitiated research funding from the French National Research Agency, and the US National Institutes of Health. Further, he has received honoraria from the American Academy of Neurology for educational lectures and from the BMJ and Cephalalgia for editorial services. Authorship: All authors had access to the data and a role in writing the manuscript.
APPENDIX Supplemental tables accompanying this article can be found in the online version at 10.1016/j.amjmed.2015.04.011.
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APPENDIX Supplementary Table 1
Multivariable- and Depression Status-adjusted Cognitive Scores by Restless Legs Syndrome Status
No History of Restless Legs Syndrome
Global Score† Isaac† Benton† MMSE† Trail Making B†
History of Restless Legs Syndrome
No. of Subjects
Multivariable-adjusted Mean* (SE)
No. of Subjects
Multivariable-adjusted Mean* (SE)
Overall P-Value From ANCOVA*
1653 1653 1653 1653 1601
0.014 0.051 0.006 0.004 0.038
417 417 417 417 411
0.094 0.077 0.065 0.002 0.054
.58 .60 .17 .97 .77
(0.128) (0.046) (0.046) (0.048) (0.047)
(0.171) (0.061) (0.062) (0.064) (0.063)
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, education, and depression. †Scores are measured in standardized units.
Supplementary Table 2 Multivariable-adjusted (Including Sleep Quality, Difficulty Sleeping, and Medications for Sleep) Cognitive Scores by Restless Legs Syndrome Status No History of Restless Legs Syndrome
Global Score† Isaac† Benton† MMSE† Trail Making B†
History of Restless Legs Syndrome
No. of Subjects
Multivariable-adjusted Mean* (SE)
No. of Subjects
Multivariable-adjusted Mean* (SE)
Overall P-Value From ANCOVA*
1653 1653 1653 1653 1601
0.029 0.060 0.018 0.005 0.020
417 417 417 417 411
0.074 0.070 0.048 0.001 0.043
.76 .85 .22 .92 .68
(0.138) (0.049) (0.050) (0.051) (0.051)
(0.176) (0.063) (0.064) (0.065) (0.065)
ANCOVA ¼ analysis of covariance; Benton ¼ Benton Visual Retention Test; Isaac ¼ Isaacs’ test of verbal/category fluency; MMSE ¼ Mini-Mental State Examination. *Adjusted for age, sex, smoking status, alcohol consumption, physical activity, body mass index, history of high blood pressure, history of high cholesterol, history of diabetes, history of cardiovascular disease, education, sleep quality, difficulty sleeping, and sleep medication. †Scores are measured in standardized units.