Cognitive dysfunction in rapid eye movement sleep behavior disorder

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1 bs_bs_banner Sleep and Biological Rhythms 2013; 11 (Suppl. 1): doi: /j x REVIEW ARTICLEsbr_547 Cognitive dysfunction in rapid eye movement sleep behavior disorder Josie-Anne BERTRAND, 1,2 Daphné GÉNIER MARCHAND, 1,3 Ronald B POSTUMA 1,4 and Jean-François GAGNON 1,3 1 Center for Advanced Research in Sleep Medicine, Hôpital du Sacré-Cœur de Montréal, 2 Department of Psychology, Université de Montréal, 3 Department of Psychology, Université du Québec à Montréal, and 4 Department of Neurology, Montreal General Hospital, Montreal, Quebec, Canada Abstract Cognitive impairment is a frequent feature of rapid eye movement sleep behavior disorder (RBD). The cognitive profile of RBD patients is heterogeneous, with impairments in attention, executive functions, episodic memory, and visuospatial abilities. Moreover, over 50% of RBD patients meet the diagnostic criteria for mild cognitive impairment (MCI). Although a comprehensive neuropsychological assessment remains the most sensitive way to detect MCI, three cognitive screening tests have been validated in RBD. The Montreal Cognitive Assessment was found to be the most appropriate screening test for detecting MCI in RBD. In addition, RBD in Parkinson s disease may be a risk factor for MCI and dementia. Key words: dementia with Lewy bodies, mild cognitive impairment, Parkinson s disease, REM sleep behavior disorder. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia that is considered a risk factor for synucleinopathies, a category of neurodegenerative diseases including Parkinson s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. 1 Several markers of synucleinopathies have been identified in idiopathic RBD. 2 4 This review focuses on cognitive impairment in RBD. POOR COGNITIVE PERFORMANCE IN IDIOPATHIC RBD Although many cognitive domains have been defined, the main ones are learning and memory, language, atten- Correspondence: Dr Jean-François Gagnon, Centre d Études Avancées en Médecine du Sommeil, Hôpital du Sacré-Cœur de Montréal, 5400 boul. Gouin ouest, Montréal, Québec, Canada, H4J 1C5. gagnon.jean-francois.2@uqam.ca Accepted 17 February tion, executive functions, visuospatial abilities, and praxis. Attention and executive functions are often considered together. A significant proportion of idiopathic RBD patients complain about reduced cognitive abilities. 5 To our knowledge, six controlled studies have assessed cognitive performance in idiopathic RBD patients Table 1 presents the sociodemographic and neuropsychological variables. To facilitate betweenstudy comparison on cognitive tasks, a P-value < 0.05 was used. Note that studies by the Montreal group 5,6 share common participants as well as studies by the Milan group. 7,8 All studies found that idiopathic RBD patients show poorer performance than healthy subjects on neuropsychological tests. However, studies are not consistent on the specific cognitive domains impaired. Several factors may explain these discrepancies. First, because most of these studies have relatively small sample sizes, the results may be affected by low statistical power. Second, there is population heterogeneity between studies on sociodemographic variables. For 2013 The Authors 21

2 J-A Bertrand et al. Table 1 Controlled studies on cognitive performance in idiopathic rapid eye movement sleep behavior disorder Terzaghi et al. Massicotte-Marquez Gagnon et al. Marques et al. Ferini-Strambi Fantini et al. (2008) 10 et al. (2008) 6 (2009) 5 (2010) 9 et al. (2004) 8 (2011) 7 irbd CTRL irbd CTRL irbd CTRL irbd CTRL irbd CTRL irbd CTRL Number of participants Age Education Gender, % men Cognitive tasks Attention/executive functions Digit span NS <0.05 NS NS NS Word span <0.001 Corsi NS NS Attentive matrices NS NS NS TMT, part B <0.03 <0.05 NS NS SCWT <0.05 NS NS NS NS Verbal fluency Semantic NS <0.03 <0.001 NS NS NS Letter NS NS < NS NS WCST 0.05 Symbol digit NS NS Episodic memory Logical memory RAVLT Sum of trials 1 5 <0.02 <0.005 Immediate recall NS <0.03 <0.005 Delayed recall NS <0.05 Recognition <0.03 NS Grober and Buschke Total NS Free recall Corsi supraspan < Rey-O figure, delayed recall NS Visuospatial abilities Rey-O figure, copy NS NS NS < Block Design NS NS Bells test NS or share common participants. Flexibility condition only. CTRL, controls; irbd, idiopathic rapid eye movement sleep behavior disorder; NS, not significant; RAVLT, Rey Auditory Verbal Learning Test; SCWT, Stroop Color Word Test; TMT, Trail Making Test; WCST, Wisconsin Card Sorting Test The Authors

3 Cognition and RBD example, the mean educational level varied from 6 to 14 years, and the mean age varied from 64 to 70 years. Finally, the studies used different cognitive tasks, which differ in their sensitivity to detect deficits. Caution should also be taken when linking a cognitive test to a specific cognitive function, as neuropsychological tests used in clinical settings often address more than one cognitive function. For example, good visuospatial abilities as well as good planning, organization, and motor execution capacities are needed to perform well on the Rey-O figure copy test. Therefore, it would be difficult to differentiate or isolate which specific cognitive process is affected when poor performance is recorded on a given task. In general, the most affected domains in idiopathic RBD are attention, executive functions, and episodic memory (characterized by impaired free recall) Additionally, some studies found impaired visuospatial and/or visuoperceptive abilities, 7 9 but others did not. 5,6,10 In fact, impaired visuospatial or nonverbal learning abilities in idiopathic RBD appear to be related to the extent of cognitive decline. 7,11 13 Impaired visuospatial abilities have also been reported in neurodegenerative diseases associated with RBD, such as DLB and PD. 5,14 Although little studied, language and praxis appear to be well preserved in idiopathic RBD. These studies focused on group differences on cognitive tests between idiopathic RBD patients and healthy subjects. What is missing is the most relevant clinical variable the proportion of idiopathic RBD patients who have significant cognitive impairment. MILD COGNITIVE IMPAIRMENT IN IDIOPATHIC RBD Mild cognitive impairment (MCI) is a syndrome characterized by an objectively assessed cognitive decline that is greater than expected for age and education and that does not interfere significantly with daily life activities. 15 MCI refers to an intermediate state between normal cognitive functioning and dementia. 15 Proposed MCI diagnostic criteria includes (i) subjective cognitive complaints reported by patients or informants at a structured interview; (ii) cognitive decline on neuropsychological assessment compared with age- and education-equivalent individuals; and (iii) preserved daily life activities based on previous and actual capacities. 15,16 In addition, medication use and other medical or psychiatric conditions responsible for cognitive deficits should be excluded. MCI subtypes have been identified based on the nature (amnestic vs nonamnestic) Cognitive functioning Single-domain MCI Multiple-domain MCI Dementia Normal functioning Age Figure 1 Various progression patterns in patients with mild cognitive impairment (MCI). and number (single-domain vs multiple-domain) of the cognitive domains alteration. 17 In idiopathic RBD patients referred to a sleep disorders center, MCI frequency has been estimated at up to 50% (16/32) compared to 8% (3/40) in healthy individuals. 5 The proportion of idiopathic RBD patients with MCI is also considerably higher than the proportion of MCI in the general elderly population, at 3 19%. 15 Single-domain MCI with predominant attention and executive dysfunctions was the main MCI subtype observed in our cohort of idiopathic RBD patients. 5 Individuals with MCI are at higher risk for dementia, particularly dementia associated with Alzheimer s disease, vascular dementia, and DLB. 15,18 MCI progression usually follows a predictable pattern: from normal functioning to single-domain MCI and thence to multiple-domain MCI and finally dementia. Studies suggest that individuals with multiple-domain MCI are at higher risk for progressing to dementia. 19,20 However, MCI progression can also be highly heterogeneous (Fig. 1). A substantial proportion of MCI patients, particularly those with single-domain MCI, return to normal cognitive functioning, whereas some remain with mild cognitive deficits for many years. 15,19,21 Moreover, cognition in the elderly may be altered by many factors, including vascular diseases, respiratory disorders, psychiatric symptoms, and medication sideeffects. Consequently, researchers and clinicians should be aware of the variety of progression patterns and avoid directly linking MCI to the future development of a neurodegenerative disease. In idiopathic RBD, the risk for patients with concomitant MCI to develop dementia has not been 2013 The Authors 23

4 J-A Bertrand et al. Table 2 The validity of three cognitive screening tests for detecting mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder MMSE 16 MoCA 22 DRS-2 16 Administration features Maximum score Administration time, min Training Minimal Minimal Specialized Alternative versions No Yes No Free No Yes No Psychometric properties Cut-off scores <30 <29 <27 <26 <141 <139 Sensitivity, % Specificity, % PPV, % NPV, % % correctly diagnosed AUC, 95% CI 0.75 ( ) 0.84 ( ) 0.86 ( ) Optimal screen value: the lowest value with sensitivity and NPV at ~80%. Optimal diagnostic value: the highest value with specificity and PPV at ~80%. Maximum accuracy value according to the Youden index (Y = sensitivity + specificity - 1). For PPV and NPV, estimated population base rates were 58% for MMSE and DRS-2 and 50% for MoCA. AUC, area under the curve; CI, confidence interval; DRS-2, Mattis Dementia Rating Scale, second edition; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; NPV, negative predictive value; PPV, positive predictive value. prospectively studied in a large cohort. Molano et al. studied seven idiopathic RBD patients with MCI who subsequently developed Lewy body disease, confirmed by autopsy. 13 This suggests that idiopathic RBD patients with MCI are at higher risk for developing DLB. However, the time required to progress from idiopathic RBD to MCI and from MCI to dementia may vary greatly. For example, idiopathic RBD patients developed MCI 3 48 years after RBD onset and progressed from MCI to dementia after 1 5 years. 13 Further studies are therefore needed to better understand the progression of cognitive impairment in idiopathic RBD. SCREENING TESTS FOR COGNITIVE IMPAIRMENT IN IDIOPATHIC RBD A comprehensive neuropsychological assessment is the most effective way to detect cognitive impairment, including MCI. However, it is a time-consuming method that requires specialized training, and is often unavailable to idiopathic RBD patients in clinical practice. Efficient MCI screening tests in idiopathic RBD would therefore be useful. Three screening tests have been systematically assessed in idiopathic RBD: 16,22 the Mini-Mental State Examination (MMSE), 23 the Montreal Cognitive Assessment (MoCA), 24 and the Mattis Dementia Rating Scale, second edition (DRS-2). 25 The main administration features of the three tests and their psychometric properties for idiopathic RBD patients are summarized in Table 2. The MoCA and the DRS-2 show superior psychometric properties than the MMSE. However, because of its short administration time, its validated alternative versions (allowing retesting), the fact that it is available free of charge and does not require specialized training, the MoCA ( mocatest.org/) appears to be the most appropriate screening test for detecting MCI in idiopathic RBD. RBD AS A RISK FACTOR FOR MCI AND DEMENTIA IN PD RBD and cognitive impairment are frequently observed features of PD. 26,27 A substantial proportion of PD patients will develop dementia as the disease progresses. 27 RBD in PD patients has been reported to be associated with a higher frequency of cognitive impairment. 5,28,29 Indeed, we found a higher risk of having MCI in PD with concomitant RBD (73% or 16/22) compared with PD without RBD (11% or 2/18) and healthy controls (8% or 3/40). 5 Moreover, we conducted a prospective follow-up study in a cohort of 42 PD patients without dementia at baseline, including 27 with polysomnographically-confirmed RBD and 15 without RBD. 30 Our objective was to assess whether the presence of RBD at baseline predicted the future development of dementia. Over a mean 4-year follow-up, 48% of PD The Authors

5 Cognition and RBD patients with RBD developed dementia, according to neuropsychological and neurological assessments. In comparison, none of PD patients without RBD developed dementia. The higher frequency of MCI and dementia in PD patients with concomitant RBD suggests that these patients are affected by a more devastating and widespread neurodegenerative disease than PD patients without RBD symptoms. However, these results remain to be confirmed by independent groups and in larger cohorts of PD patients. ACKNOWLEDGMENTS Our studies have been supported by the Canadian Institutes of Health Research and the Fonds de recherche du Québec Santé. CONFLICTS OF INTEREST The authors declare no potential conflicts of interest. REFERENCES 1 Postuma RB, Gagnon JF, Vendette M, Fantini ML, Massicotte-Marquez J, Montplaisir J. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009; 72: Ferini-Strambi L. Does idiopathic REM sleep behavior disorder (irbd) really exist? What are the potential markers of neurodegeneration in irbd? Sleep Med. 2011; 12: S Postuma RB, Gagnon JF, Montplaisir JY. REM sleep behavior disorder: from dreams to neurodegeneration. Neurobiol. Dis. 2011; doi: /j.nbd Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol. 2006; 5: Gagnon JF, Vendette M, Postuma RB et al. Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson s disease. Ann. Neurol. 2009; 66: Massicotte-Marquez J, Décary A, Gagnon JF et al. Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder. Neurology 2008; 70: Fantini ML, Farini E, Ortelli P et al. Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep 2011; 34: Ferini-Strambi L, Di Gioia MR, Castronovo V, Oldani A, Zucconi M, Cappa SF. Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): does the idiopathic form of RBD really exist? Neurology 2004; 62: Marques A, Dujardin K, Boucart M et al. REM sleep behaviour disorder and visuoperceptive dysfunction: a disorder of the ventral visual stream? J. Neurol. 2010; 257: Terzaghi M, Sinforiani E, Zucchella C et al. Cognitive performance in REM sleep behaviour disorder: a possible early marker of neurodegenerative disease? Sleep Med. 2008; 9: Iranzo A, Isetta V, Molinuevo JL et al. Electroencephalographic slowing heralds mild cognitive impairment in idiopathic REM sleep behavior disorder. Sleep Med. 2010; 11: Iranzo A, Molinuevo JL, Santamaría J et al. Rapid-eyemovement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 2006; 5: Molano J, Boeve B, Ferman T et al. Mild cognitive impairment associated with limbic and neocortical Lewy body disease: a clinicopathological study. Brain 2010; 133: Ferman TJ, Boeve BF, Smith GE et al. Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J. Int. Neuropsychol. Soc. 2002; 8: Gauthier S, Reisberg B, Zaudig M et al. International Psychogeriatric Association Expert Conference on mild cognitive impairment. Mild cognitive impairment. Lancet 2006; 367: Villeneuve S, Rodrigues-Brazète J, Joncas S, Postuma RB, Latreille V, Gagnon JF. Validity of the Mattis Dementia Rating Scale to detect mild cognitive impairment in Parkinson s disease and REM sleep behavior disorder. Dement. Geriatr. Cogn. Disord. 2011; 31: Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch. Neurol. 2005; 62: Dubois B, Albert ML. Amnestic MCI or prodromal Alzheimer s disease? Lancet Neurol. 2004; 3: Nordlund A, Rolstad S, Klang O, Edman A, Hansen S, Wallin A. Two-year outcome of MCI subtypes and aetiologies in the Göteborg MCI study. J. Neurol. Neurosurg. Psychiatry 2010; 81: Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia meta-analysis of 41 robust inception cohort studies. Acta Psychiatr. Scand. 2009; 119: Fischer P, Jungwirth S, Zehetmayer S et al. Conversion from subtypes of mild cognitive impairment to Alzheimer dementia. Neurology 2007; 68: Gagnon JF, Postuma RB, Joncas S, Desjardins C, Latreille V. The Montreal Cognitive Assessment: a screening tool for mild cognitive impairment in idiopathic REM sleep behavior disorder. Mov. Disord. 2010; 25: Folstein MF, Folstein SE, McHugh PR. Mini-mental state. A practical method for grading the cognitive state 2013 The Authors 25

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