Clinical Validity of the Mattis Dementia Rating Scale in Differentiating Mild Cognitive Impairment in Parkinson s Disease and Normative Data

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1 Accepted: January 17, 2015 Published online: March 18, /15/ $39.50/0 Original Research Article Clinical Validity of the Mattis Dementia Rating Scale in Differentiating Mild Cognitive Impairment in Parkinson s Disease and Normative Data Ondrej Bezdicek a Jiri Michalec b Tomas Nikolai a Petra Havránková a Jan Roth a Robert Jech a Evžen Růžička a a Department of Neurology and Centre of Clinical Neuroscience, and b Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic Key Words Dementia rating scale Mild cognitive impairment Normative data Parkinson s disease Validity Abstract Background/Aims: The aim of the present study was to provide normative data and determine the validity of the Czech version of the Mattis Dementia Rating Scale 2 (czdrs-2) in screening for mild cognitive impairment in Parkinson s disease (PD-MCI) based on the Movement Disorder Society (MDS) Level II criteria. Methods: For validation purposes, 41 healthy controls (HC), 46 patients with PD-NI (Parkinson s disease, no impairment) and 41 patients with PD-MCI (all groups assessed by the MDS Level II criteria for PD-MCI) were matched according to age and. Results: With screening and diagnostic cutoff s determined at 139 points, the czdrs-2 showed a sensitivity of 78% and a specificity of 88% in the detection of PD-MCI versus HC and a sensitivity of 78% and a specificity of 76% in the detection of PD-MCI versus PD-NI. The AUC (95% confidence interval) for the czdrs-2 was 84% (75 93) and 82% (73 91), respectively. We report percentile values for 286 subjects from the Czech population stratified by level. Conclusion: Our results show that the czdrs-2 is a valid instrument at Level I for screening PD-MCI and support its construct validity and diagnostic equivalence in a cross-cultural setting. Ondrej Bezdicek, PhD Department of Neurology and Centre of Clinical Neuroscience First Faculty of Medicine, Charles University and General University Hospital in Prague Kateřinská 30, CZ Praha 2 (Czech Republic) gmail.com

2 304 Introduction Normative data are of critical importance for the meaningful interpretation of test s [1, 2]. The cross-cultural comparison of standardized mental status instruments is greatly needed as it may bring information about construct equivalence and diagnostic validity in different cultural settings [3]. The Dementia Rating Scale 2 (DRS-2), formerly the Mattis Dementia Rating Scale [4, 5], is used to assess the general cognitive function in subjects at risk of dementia. A revised version with normative data and the new DRS-2 Alternate Form were published in 2001 without changes to the DRS test material [6, 7]. The DRS is a standard instrument in the cognitive research of neurodegenerative diseases and in Parkinson s disease (PD) in particular [8] (referred to as a generic and non-pd-specific cognitive screening measure) [9]. The DRS has been recommended by the Movement Disorder Society (MDS) for the standard assessment of PD dementia at Level I (PD-D) [10] and, more recently, for mild cognitive impairment in PD at Level I (PD-MCI) [11]. Dubois et al. [10] suggested that a total ( 135) should be used in the estimation of cognitive impairment in PD-D; however, they recommend the use of age- and -based normative values. A cutoff value of <138 on the DRS-2 is suggested in the case of PD-MCI [11], with a sensitivity of 72%, a specificity of 86% and an AUC of 80% [8]. Since this pioneering study on the DRS and PD-MCI, more recent studies have shown similar results [12] which confirm that the DRS-2 has sufficient discriminatory potential in differentiating patients with PD-MCI from healthy controls (HC). For diagnostic purposes, the most recent study recommends a cutoff value of 140 for screening and of 137 in the detection of PD-MCI. However, the former study [12] did not use the current PD-MCI Level II MDS criteria for the diagnosis of PD-MCI, while the latter study [13] did not use a control sample. The principal goals of the present study were to (1) provide a normative data set for the Czech version of the DRS-2 (czdrs-2) in the Czech population stratified by age and [10], (2) to show the discriminatory potential of the czdrs-2 in PD-MCI based on Level II MDS criteria in comparison to HC and patients with PD-NI (PD with no cognitive impairment at Level II) [11], and (3) to determine the sensitivity, specificity and optimal cutoff s in the diagnosis of PD-MCI in the Czech population, thus delimitating the construct equivalence of the method and its diagnostic validity in a different cultural setting [3]. Patients and Methods Study 1: Normative Study Participants Normative participants were recruited from the general community through advertisements, and a brief medical history for each subject was obtained via telephone. A cohort of 286 healthy subjects was included. After the interviews, all participants with a history of head trauma with loss of consciousness, cerebrovascular accident, abuse of alcohol or other psychoactive substances as well as individuals with a history of neurological or psychiatric disease (e.g., epilepsy, multiple sclerosis, schizophrenia or ongoing delirium) were excluded. Participants meeting the above criteria were then tested for cognitive efficiency using the Mini-Mental State Examination (MMSE) [14] and for manifestations of depression. To exclude subjects with cognitive impairment, limits for enrollment were set at 1.5 standard deviation (SD) on the MMSE in comparison to the Czech normative MMSE data, resulting in an MMSE of 28 (mean) ± 1 (SD) [15]. To exclude subjects with a higher level of depression, the Beck Depression Inventory-II was limited to <13 [16]. Finally, participants underwent the czdrs-2. Demographic and other cohort characteristics are presented in table 1. Study 2: Clinical Study Participants The clinical sample consisted of 41 patients with PD-MCI, 46 patients with PD-NI and 41 HC paired according to age and (HC paired with PD-MCI). We also evaluated all PD-NI patients in our clinical sample and compared them (without pairing) to PD-MCI patients ( table 2 ). All subjects were recruited from the Movement Disorders Center, Department of Neurology, First Faculty of Medicine, Charles University and

3 305 Table 1. Demographic characteristics of the czdrs-2 normative sample (n = 286) n % Age years years years years Education Lower Higher Sex Male Female Handedness Right handed Other Lower = Level of formal (8 12 years); higher = college level or higher ( 13 years); handedness, other = left handed, ambidextrous or left handed by birth (instructed systematically to write with the nondominant right hand). Table 2. Demographic characteristics of the clinical study participants: HC (n = 41) versus PD-MCI (n = 41) and PD-NI (n = 46) versus PD-MCI (n = 41) HC PD-MCI p value PD-NI p value Age, years (7.70) (8.37) 0.74 a (9.40) 0.11 a Education, years (2.47) (2.64) 0.84 a (2.84) 0.15 a Gender, % males b b Handedness, % right handed b b Ethnicity, % Caucasians Language, % Czech Duration of PD, years (6.36) (5.09) UPDRS-III (12.23) (6.41) Hoehn/Yahr stage 2 (1 3) 1.95 (0.68) Medication, mg LED 958 (552) 1,029 (606) Data represent the means and SDs in parentheses or percentages; in the case of the Hoehn/Yahr stage, SD is replaced by the range. UPDRS-III = Unified Parkinson Disease Rating Scale III; LED = total daily levodopa equivalent dose. a Independent-samples t test; b χ 2 test. General University Hospital in Prague, Prague, Czech Republic. All PD patients were examined by a neurologist specialized in movement disorders and met the United Kingdom PD Society Brain Bank criteria [17]. Exclusion criteria were as follows: PD-D according to MDS criteria, atypical or secondary parkinsonism, severe or unstable depression, anticholinergic medications and other medical or neurological conditions potentially causing cognitive impairment (e.g., seizure, stroke or head trauma). All PD patients were examined in the on motor state. The study was approved by the Ethics Committee of the General University Hospital in Prague, and all participants provided signed, informed consent. All tests were administered under standard neuropsychological laboratory conditions and were conducted by trained psychologists (O.B. and T.N.). Materials/Test Construction and Evaluations The czdrs-2 was translated from the original [6] and adapted according to guidelines for cross-cultural adaptation [18] in 2010.

4 306 Table 3. MDS PD-MCI battery at Level II for the differentiation of PD-MCI (n = 41) from HC (n = 41) and of PD-MCI (n = 41) from PD-NI (n = 46) HC PD-MCI p value M Md SD min. max. M Md SD min. max. TMT-A ** DS back ** Letter fluency VST-C * Semantic fluency ** WAIS-R Sim RAVLT-DR ** WMS-III FP-DR ** JoL CLOX I * PD-NI PD-MCI M Md SD min. max. M Md SD min. max. p value TMT-A (54) ** DS backwards (5) ** Letter fluency (46) * VST-C (30) ** Semantic fluency (61) ** WAIS-R Sim (26) * RAVLT-DR (3) ** WMS-III FP-DR (22) ** JoL (27) CLOX I (14) MDS PD-MCI battery domains: s for the neuropsychological tests are provided. TMT-A = Trail Making Test Part A (attention and working memory); DS back = Digit Span backwards (attention and working memory); letter fluency (N + K + P; executive function); VST-C = Victoria Stroop Test Interference Score (executive function); semantic fluency (animals + clothes + shopping); WAIS-R Sim = Wechsler Adult Intelligence Scale Revised, similarities; RAVLT-DR = Rey Auditory Verbal Learning Test Delayed Recall; WMS-III FP-DR = Wechsler Memory Scale Third Revision Family Pictures Delayed Recall; JoL = Judgment of Line Orientation; CLOX I = Royall s Clock Ding Task; M = mean; Md = median; SD = standard deviation; min. = minimal value; max. = maximal value. * p < 0.05, ** p < 0.001, Mann-Whitney U test. Participants (patients and paired controls) underwent a comprehensive clinical evaluation that included the medical history, evaluation of subjective cognitive decline, functional abilities, medication, motor state Unified Parkinson s Disease Rating Scale Part III and the standard MDS Level II neuropsychological assessment for the diagnosis of PD-MCI [11]. The neuropsychological battery at Level II consisted of 10 tests in 5 cognitive domains, and one measure from each test was derived as recommended [11]. We transformed s to z-s for each of the 10 measures. Patients that d 1.5 SD below the average z- derived from the control group were classified as PD-MCI [19]. These subjects satisfied impairment on at least two neuropsychological tests, represented by either two impaired tests in one cognitive domain or one impaired test in two different cognitive domains ( table 3 ) [11]. Statistical Analyses All analyses were performed using IBM SPSS 20.0 for Windows. Continuous variables are expressed as means, SDs and ranges, categorical variables as percentages and ordinal variables as medians. Normality was evaluated by visual inspection and the Q-Q plot. The Spearman correlation coefficient was used to evaluate the relationship between different test measures. Group differences in neuropsychological and motor characteristics were analyzed using the nonparametric Mann-Whitney U test. Sensitivity, specificity, likelihood ratios, positive and negative predictive values, receiver operating characteristic (ROC) curves with AUC and

5 307 Table 4. Percentile range of the czdrs-2 normative sample (n = 286) DRS total Att. I/P Const. Concept. Mem Percentiles were estimated as quantiles and rounded to an integer. Education 12 years = Level of formal (8 12 years); 13 years = college level or higher; DRS total = DRS total (0 144 points); Att. = Attention DRS subscale (0 37 points); I/P = Initiation/Perseveration DRS subscale (0 37 points); Const. = Construction DRS subscale (0 6 points); Concept. = Conceptualization DRS subscale (0 39 points); Mem. = Memory DRS subscale (0 25 points). 95% confidence intervals (CIs) were calculated and compared to the diagnostic classification of PD-MCI using the MDS PD-MCI Task Force Level II criteria for each 1.5 SD below average values based on the HC sample. The level of significance was set at α = Results Study 1: Normative Study We analyzed the effects of age, and gender on the czdrs-2 and found a statistically significant relationship between the czdrs-2 total and (r = 0.20, p < 0.01). Neither age (r = 0.01, p = 0.84) nor gender (p = 0.17) showed any significant relationship with the czdrs-2 total. We investigated the effect of age in more detail; however, we did not find any significant correlation with age in any of the older age groups: 56+ years (n = 155; r = 0.08, p = 0.31) or, in particular, years (n = 73; r = 0.08, p = 0.49) and years (n = 82; r = 0.16, p = 0.16). The sample was then split into two groups by. The first group consisted of participants (n = 98) with 9 12 formal, while the second group (n = 188) consisted of participants with a higher level of (13 21 years). No significant relationship between the czdrs-2 and was detected in either subgroup. In table 4, the czdrs-2 total (0 144 points) is presented as percentile with all 5 subscales: Attention, Initiation/Perseveration, Construction, Conceptualization and Memory. Study 2: Clinical Characteristics of PD-MCI in Comparison to HC and of PD-MCI in Comparison to PD-NI Clinical characteristics for all groups are presented in table 2. The results of the MDS PD-MCI battery at Level II that was used in differentiating PD-MCI from HC and PD-MCI from

6 Fig. 1. ROC analysis: PD-MCI versus HC. The ROC curve discloses the diagnostic accuracy of the cz- DRS-2 total and subscales in HC versus PD-MCI. DRS total = DRS total ; Att. = Attention; I/P = Initiation/Perseveration; Const. = Construction; Concept. = Conceptualization; Mem. = Memory. Sensitivity AUC 0.50 DRS total (AUC 0.84) DRS Att. (AUC 0.74) DRS I/P (AUC 0.79) DRS Const. (AUC 0.18) DRS Concept. (AUC 0.57) DRS Mem. (AUC 0.74) Specificity Table 5. czdrs-2 total and subscale discriminatory potential for PD-MCI diagnosis based on Level II MDS PD-MCI criteria DRS s AUC, % 95% CI lower bound PD-MCI versus HC DRS total DRS Att DRS I/P DRS Const DRS Concept DRS Mem PD-MCI versus PD-NI DRS total DRS Att DRS I/P DRS Const DRS Concept DRS Mem upper bound DRS total = DRS total ; Att. = Attention; I/P = Initiation/ Perseveration; Const. = Construction; Concept. = Conceptualization; Mem. = Memory. PD-NI are presented in table 3. After establishing a diagnosis of PD-MCI, we determined the discriminatory potential of the czdrs-2 total and subscales in differentiating PD-MCI from paired HC and concomitantly PD-MCI from PD-NI (following the approach of Pirogovsky et al. [13] ). A ROC curve analysis yielded an AUC of 84% (95% CI 75 93) for the czdrs-2 total (PD-MCI vs. HC) and an AUC of 82% (95% CI 73 91) for the czdrs-2 total (PD-MCI vs. PD-NI). The AUCs and 95% CIs for all 5 czdrs-2 subscales are presented in table 5, and the contribution of these subscales to the classification accuracy of the czdrs-2 for PD-MCI status are depicted in figures 1 and 2. Table 6 presents the sensitivity, specificity, likelihood

7 Fig. 2. ROC analysis: PD-MCI versus PD-NI. The ROC curve discloses the diagnostic accuracy of the czdrs-2 total and subscales in PD-MCI versus PD-NI. DRS total = DRS total ; Att. = Attention; I/P = Initiation/Perseveration; Const. = Construction; Concept. = Conceptualization; Mem. = Memory. Sensitivity AUC 0.50 DRS total (AUC 0.82) DRS Att. (AUC 0.80) DRS I/P (AUC 0.75) DRS Const. (AUC 0.49) DRS Concept. (AUC 0.52) DRS Mem. (AUC 0.72) Specificity Table 6. Discriminative validity of the czdrs-2 total in the detection of PD-MCI Sensitivity, % Specificity, % LR+ LR PPV, % NPV, % Cutoff (PD-MCI vs. HC) 134/ / / / / /140 a / / / / Cutoff (PD-MCI vs. PD-NI) 134/ / / / / /140 a / / / / LR+ = Positive likelihood ratio; LR = negative likelihood ratio; PPV = positive predictive value; NPV = negative predictive value. Positive and negative predictive values are calculated with a prevalence set at 50% in accordance with our sample, allowing the comparison of both values directly without additional calculation (see PPV and NPV formula). Figures in bold indicate the optimal cutoff in the detection of PD-MCI for both screening and diagnostic purposes. a Optimal screening cutoff defined as a cutoff with a sensitivity around 80% and the highest specificity; optimal diagnostic cutoff defined as a cutoff with a specificity around 80% and the highest sensitivity.

8 310 ratios, positive predictive value, negative predictive value and best diagnostic and screening cutoffs for the use with the czdrs-2, which was identical for both a diagnostic/screening cutoff of 139 (a sensitivity of 78% and a specificity of 88% in PD-MCI vs. HC, and a sensitivity of 78% and a specificity of 76% in PD-MCI vs. PD-NI). Discussion The purpose of the present study was to provide normative values for the czdrs-2, one of the most widely used scales in the evaluation of dementia [10] and predementia states [8, 11], especially in PD-MCI research. Percentile values for the czdrs-2 total and all subscales adjusted for are available and can be used as a standard measure in differentiating between normal aging and cognitive impairment. Another principal aim of the present study was to demonstrate the clinical utility of the czdrs-2, a standard Level I screening instrument for PD-MCI proposed by the MDS Task Force [11]. The PD-MCI diagnosis was determined by a Level II neuropsychological battery, currently the gold standard in the diagnosis of PD-MCI. We found a czdrs-2 total of 139 as the optimal cutoff in the detection of PD-MCI for both screening and diagnostic purposes. This cutoff has both a good detection ability (sensitivity 78%) and a high diagnostic certainty (specificity 88%) in PD-MCI versus HC and a still acceptable sensitivity of 78% and specificity of 76% in PD-MCI versus PD-NI. When screening and diagnostic cutoffs are overlapping, the czdrs-2 may be considered as suitable abbreviated assessment tool at Level I. Our results go beyond other comparable studies that have measured the contribution of the DRS to the detection of PD-MCI, as the present study clearly shows a better discriminatory potential of the czdrs-2 in the diagnosis of PD-MCI versus HC [12] and a comparable discriminatory potential for PD-MCI versus PD-NI [13]. Among the czdrs-2 measures, which have the highest accuracy in the diagnosis of PD-MCI, the czdrs-2 total was the best indicator of PD-MCI with an AUC of 84% in comparison to HC and an AUC of 82% in comparison to PD-NI. From the czdrs-2 subscales, Initiation/Perseveration performed best with an AUC of 79%, and, in combination with Attention and Memory, with an AUC of 74%, both have the highest discriminatory potential for PD-MCI diagnosis among the czdrs-2 subscales (in PD-MCI vs. HC). Similar results can be seen in PD-MCI versus PD-NI: Attention with an AUC of 80% followed by Initiation/Perseveration and Memory with an AUC of 75 and 72%, respectively. Even though Level I criteria do not allow complete subtyping of PD-MCI [11], these results show the profile of cognitive impairment in PD-MCI in comparison to both HC and PD-NI, which is one of the great advantages of the DRS over other screening measures (e.g., the Montreal Cognitive Assessment). The following limitations of the present study must be stated. The selection of subjects in our normative data was nonrandom and has a clear age limitation for individuals >87 age. All participants in the current study were Caucasians and generally well educated, which clearly limits the generalizability of the results to different ethnic groups or individuals with substandard levels of [20]. Instead of using semantic verbal fluency as a language domain test, the use of the Boston Naming Test-60 would be better justified because some researchers might classify semantic verbal fluency as an executive function test (see MDS Level II criteria [9] ). In conclusion, the present study shows better results regarding discriminative validity and supports previous studies on the clinical validity of the DRS in PD-MCI. We provide normative data and, with respect to clinical applicability, optimal cutoff values for the diagnosis of PD-MCI at Level I according to the MDS PD-MCI criteria. Moreover, the czdrs-2 provides robust evidence of its construct validity and diagnostic equivalence in a cross-cultural setting with identical or very similar cutoffs, congruent with studies from other language or cultural backgrounds.

9 311 Acknowledgements This work was supported the by the Czech Ministry of Education (grant LH13256; VES13-KontaktII), PRVOUK-P26/LF1/4, by GAUK and by the Alzheimer Foundation Fund. The authors thank all participants for their willingness to take part in the present study and the administrators (Lenka Beláňová, MA, and Hana Žaloudková, MA) for their help with the normative data collection. The authors are grateful to Aaron Rulseh, MD, PhD, for his help with editing the English language and grammar. Disclosure Statement The authors have no financial interests in the czdrs-2 and have nothing to disclose. The czdrs-ii is licensed by Psychological Assessment Resources. References 1 Mitrushina M, Boone KB, Razani J, D Elia LF: Handbook of Normative Data for Neuropsychological Assessment, ed 2. New York, Oxford University Press, Lezak MD, Howieson DB, Bigler ED, Tranel DW: Neuropsychological Assessment, ed 5. New York, Oxford University Press, Pedraza O, Mungas D: Measurement in cross-cultural neuropsychology. Neuropsychol Rev 2008; 18: Mattis S: Mental status examination for organic mental syndrome in the elderly patients; in Bellack L, Karasu TE (eds): Geriatric Psychiatry. New York, Grune and Stratton, 1976, pp Mattis S: Dementia Rating Scale Professional Manual. Odessa, Psychological Assessment Resources, Jurica PJ, Leitten C, Mattis S: DRS-2. Dementia Rating Scale. Professional Manual. Lutz, Psychological Assessment Resources, Schmidt KS, Mattis PJ, Adams J, Nestor P: Test-retest reliability of the dementia rating scale-2: alternate form. Dement Geriatr Cogn Disord 2005; 20: Janvin C, Aarsland D, Larsen JP, Hugdahl K: Neuropsychological profile of patients with Parkinson s disease without dementia. Dement Geriatr Cogn Disord 2003; 15: Marras C, Tröster AI, Kulisevsky J, Stebbins GT: The tools of the trade: a state of the art How to Assess Cognition in the patient with Parkinson s disease. Mov Disord 2014; 29: Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, Dickson D, Duyckaerts C, Cummings J, Gauthier S, Korczyn A, Lees A, Levy R, Litvan I, Mizuno Y, McKeith IG, Olanow CW, Poewe W, Sampaio C, Tolosa E, Emre M: Diagnostic procedures for Parkinson s disease dementia: recommendations from the Movement Disorder Society Task Force. Mov Disord 2007; 22: Litvan I, Goldman JG, Tröster AI, Schmand BA, Weintraub D, Petersen RC, Mollenhauer B, Adler CH, Marder K, Williams-Gray CH, Aarsland D, Kulisevsky J, Rodriguez-Oroz MC, Burn DJ, Barker RA, Emre M: Diagnostic criteria for mild cognitive impairment in Parkinson s disease: Movement Disorder Society Task Force guidelines. Mov Disord 2012; 27: Matteau E, Dupré N, Langlois M, Provencher P, Simard M: Clinical validity of the Mattis Dementia Rating Scale-2 in Parkinson disease with MCI and dementia. J Geriatr Psychiatry Neurol 2012; 25: Pirogovsky E, Schiehser DM, Litvan I, Obtera KM, Burke MM, Lessig SL, Song DD, Liu L, Filoteo JV: The utility of the Mattis Dementia Rating Scale in Parkinson s disease mild cognitive impairment. Parkinsonism Relat Disord 2014; 20: Folstein MF, Folstein SE, Fanjiang G: Mini-Mental State Examination. Clinical Guide. Lutz, Psychological Assessment Resources, Štěpánková H, Nikolai T, Lukavský J, Bezdíček O, Vrajová M, Kopeček M: Mini-Mental State Examination Czech normative data study. Cesk Slov Neurol N, submitted. 16 Beck AT, Steer RA, Brown GK: Beck Depression Inventory, ed 2. San Antonio, Pearson, Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of clinical diagnosis of idiopathic Parkinson s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: Beaton DE, Bombardier C, Guillemin F, Ferraz MB: Guidelines for the process of cross-cultural adaptation of self-report measures. Spine 2000; 25: Petersen RC: Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: Marcopulos BA, Gripshover DL, Broshek DK, McLain CA, Brashear HR: Neuropsychological assessment of psychogeriatric patients with limited. Clin Neuropsychol 1999; 13: