Blind randomized controlled study of the efficacy of cognitive training in Parkinson's disease

Blind randomized controlled study of the efficacy of cognitive training in Parkinson's disease
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  Blind Randomized Controlled Study of the Efficacy of CognitiveTraining in Parkinson’s Disease  Anna Prats Parı´ s, MS, PhDc, 1,2 Heidi Guerra Saleta, PhDc, 3 Maria de la Cruz Crespo Maraver, PhDc, 1,4 Emmanuel Silvestre, PhD, 5 Maite Garolera Freixa, PhD, 6 Cristina Petit Torrellas, BA, 1 Silvia Alonso Pont, BA, 1 Marc Fabra Nadal, MS, 1 Sheila Alcaine Garcia, BA, 1 Maria Victoria Perea Bartolome´ , MD, 3  Valentina Ladera Ferna´ ndez, PhD, 3 and A  `ngels Baye´ s Rusin ˜ ol, MD, PhD 1 * 1 Unitat de Parkinson i Trastorns del Moviment, Centro Me´ dico Teknon. Barcelona, Spain  2 Universidad Auto`  noma de Barcelona, Dpto. Biologı´a Celular, Fisiologı´a e Inmunologı´a, Instituto de Neurociencias (INc), Barcelona, Spain 3 Universidad de Salamanca, Facultad de Psicologı´  a, Dpto. Psicologı´  a Ba´ sica, Psicobiologı´  a y Metodologı´  a. Salamanca, Spain 4 Divisio´  de Salut Mental, Fundacio´  Althaia, Manresa, Spain 5 Silvestre Hispanic Market Research & Services, Rocky Hill, Connecticut, USA 6 Consorci Sanitari de Terrasa Hospital, Terrasa, Spain  ABSTRACT:  The aim of this study was to analyzethe efficacy of a cognitive training program on cognitiveperformance and quality of life in nondemented Parkin-son’s disease patients. Participants who met UK BrainBank diagnosis criteria for Parkinson’s disease, with I–IIIHoehn & Yahr, aged 50–80, and nondemented (Mini-Men-tal State Examination    23) were recruited. Patient’s cog-nitive performance and functional and quality-of-lifemeasures were assessed with standardized neuropsycho-logical tests and scales at baseline and after 4 weeks.Subjects were randomly and blindly allocated by age andpremorbid intelligence (Vocabulary, Wechsler Adult Intelli-gence Scale-III) into 2 groups: an experimental group anda control group. The experimental group received 4weeks of 3 weekly 45-minute sessions using multimediasoftware and paper-and-pencil cognitive exercises, andthe control group received speech therapy. A total of 28patients were analyzed. Compared with the control groupparticipants (n  5  12), the experimental group participants(n  5  16) demonstrated improved performance in tests of attention, information processing speed, memory, visuo-spatial and visuoconstructive abilities, semantic verbal flu-ency, and executive functions. There were no observablebenefits in self-reported quality of life or cognitive difficul-ties in activities of daily living. We concluded that intensivecognitive training may be a useful tool in the managementof cognitive functions in Parkinson’s disease.  V C  2011 Movement   Disorder Society Key Words:  Parkinson’s disease; cognition; cognitivetraining neuropsychology; cognitive impairment Cognitive impairment is now recognized as a com-mon feature of Parkinson’s disease (PD). 1 The preva-lence of dementia in PD is close to 30% and is 6times higher than that in the general population. 2 Inaddition, approximately 19%–53% of nondementedPD patients suffer from mild cognitive impairment(MCI). 3–5 Cognitive impairment in PD is characterized by defi-cits in executive functions, attention/working memory,speed of information processing, visuospatial abilities,and memory 6 and has important clinical consequencesfor patient management. MCI and dementia inPD have been linked to difficulties in activities of daily living (ADLs). 7,8 Dementia has also been associ-ated with rapid motor and functional decline, 9,10 increased mortality, 11,12 caregiver stress, 13 and risk of institutionalization. 14 Because of the strong impact of cognitive disorderson the quality of life (QOL) of patients and theircaregivers, it is important to find the necessary toolsto manage cognitive decline. Complementary to ------------------------------------------------------------  Anna Prats Parı´s and Heidi Guerra Saleta contributed equally to thiswork. *Correspondence to:  A  ` ngels Baye´ s Rusin ˜ ol, Unidad de Parkinson y Trastornos del Movimiento, Centro Me´ dico Teknon, Pso. Bonanova 26,Barcelona, Spain. 08022; 11741abr@comb.es Relevant conflicts of interest/financial disclosures:  Nothing to report.Full financial disclosures and author roles may be found in the onlineversion of this article. Received:  22 June 2010;  Revised:  25 January 2011;  Accepted:  28January 2011 Published online 25 March 2011 in Wiley Online Library(wileyonlinelibrary.com). DOI: 10.1002/mds.23688 R E S E A R C H A R T I C L E Movement   Disorders, Vol. 26, No. 7, 2011  1251  pharmacological treatment, cognitive intervention pro-grams have been shown to be useful in various patho-logical conditions such as traumatic brain injury, 15 schizophrenia, 16–18 Alzheimer’s disease and demen-tia, 19 and, more recently, MCI. 20,21 To our knowledge, only 2 studies have assessed theeffects of cognitive training (CT) in PD. Results of both studies showed that this therapy had a positiveeffect on the evolution of cognitive impairment. 22,23 The first study on CT in PD patients (Sinforianiet al 22 ) included a sample of 20 early-stage nonde-mented PD patients with mild cognitive deficits whounderwent a 6-week rehabilitation program (12 one-hour sessions), received CT (performed by neuropsy-chological training software TNP), and motor rehabili-tation. This descriptive study with no control groupshowed a significant improvement in cognitive meas-ures at the end of the training and after 6 months.Sammer and colleagues 23 randomized (controlledbut not blind) 26 idiopathic PD patients. Twelve sub-jects participated in a CT regimen (10- to 30-minutesessions) that consisted of working memory tasksrequiring executive functions. Fourteen patientsreceived standard treatment, which included occupa-tional therapy, physiotherapy, and physical treatment.The outcome showed improved performance of thegroup with cognitive treatment in 2 executive tasks,whereas no improvement was seen in the standard-treatment group.We aimed to overcome previous methodologicallimitations, conducting a blind, controlled study on ahomogeneous group of nondemented PD patients. Weperformed an intensive CT program 24,25 (three 45-mi-nute sessions per week for 4 weeks) to achieve moreclinical and cost-effective results. 20 An extensive anddetailed neuropsychological assessment, including mood,QOL, and functional measures commonly used in PD,was obtained at baseline and at the end of training.The main objective of the present study was todetermine the efficacy of a CT program in a 4-weekrandomized, controlled study of cognitive performanceand QOL in nondemented PD patients. Patients and Methods Subjects This study recruited 46 patients from 2 centers inBarcelona province: the Unit of Parkinson and Move-ment Disorders from the Centro Me ´dico Teknon andthe Parkinson’s Association of Mataro ´. The investiga-tion was conducted in accordance with the HelsinkiDeclaration of 1964 (2008 revision) and Good Clini-cal Practice guidelines. All participants gave writteninformed consent. Subjects were men and women aged50–80 years diagnosed with PD according to UK PDSociety Brain Bank Criteria, 26 with disease severity of Hoehn and Yahr (H&Y) stages I–III, 27 and not receiv-ing any other cognitive, psychological, speech therapy,or physical treatment during the study.Participants were excluded if they had significantcognitive impairment (Mini-Mental State Examination <  23), below average premorbid intelligence (vocabu-lary subtest, Wechsler Adult Intelligence Scale-III[WAIS-III] typical score  <  40) that would interfere inlearning or comprehension of the program, were oncholinesterase inhibitors or had changes in their medi-cation during the study, did not complete 75% of thetraining program, had major depression (GDS-15  > 10), or had severe auditory or visual deficits oranother psychiatric/neurological condition. Design and Procedures This was a blind multicenter randomized, controlledtrial divided into 5 principal stages (Fig. 1). The firststage was based on the recruitment of the subjects forthe study. Sociodemographic data, neurological data,and written informed consent were collected from allsubjects enrolled in the study. During the secondstage, an expert evaluator, blinded to the patients’group allocation, assessed the cognitive, mood, QOL,and functional status of the participants. In the thirdstage, subjects were randomly assigned to 2 groups:control (CG) and experimental (CTG). A matched-pairs design was created in which participants wereblindly allocated to these 2 groups taking the variablesage and vocabulary (WAIS-III) into consideration. Inthe fourth stage, 2 trained professionals administeredthe training program to both groups. The treatmentgroup received an individualized CT program, and theCG received speech therapy group sessions. Finally, atthe end of the 4-week training, subjects from bothgroups were administered a blind evaluation, using thesame protocol of neuropsychological, mood, QOL,and functional tests. Both evaluations and trainingwere performed during the ON period. Clinical Assessment Patients’ full clinical histories were collected. Stand-ardized neurological assessment included the UnifiedParkinson’s Disease Rating Scale (UPDRS) 28 togetherwith the H&Y Staging of Parkinson’s Disease. 27 Aspects of functioning and well-being were assessedusing the Parkinson’s Disease Questionnaire (PDQ-39), 29 and cognitive difficulties in ADLs were eval-uated using the Cognitive Difficulties Scale (CDS). 30 To control the possible influence of mood on cognitiveperformance, all patients completed the 15-item Yes-avage Geriatric Depression Scale (GDS-15). 31 Neuropsychological Testing The battery of neuropsychological tests at baselineand retest included cognitive screening assessed by the P R A T S E T A L . 1252  Movement   Disorders, Vol. 26, No. 7, 2011  30-item Mini Mental State Examination 32 and theAddenbrooke Cognitive Examination. 33 Premorbidintelligence was determined by the Vocabulary subtestof the WAIS-III. 34 Attention and working memorywere assessed by the Digits subtest (WAIS-III) 34 andthe first trial of the California Verbal Learning Test(CVLT-II). 35 Information processing speed was meas-ured using the written modality of the Symbol-DigitModalities Test (SDMT), 36 Trail Making Test–A(TMT-A), 37 and the Word subtest (Stroop Test). 38 Verbal memory was evaluated using the CVLT-II 35 and the Logical Memory subtest (WMS-III). 39 Learn-ing was also assessed by the CVLT-II. 35 The ReyOsterrieth Complex Figure Test (ROCFT) 40 measuredvisual memory and visuoconstructive abilities. Visualspatial abilities were measured by the Line Orientationsubtest from the Repeatable Battery for the Assess-ment of Neuropsychological Status (RBANS). 41 Twoverbal fluency tasks were administered: phonemic,using FAS, and semantic, using animals. 42 Frontallobe–sensitive tasks were also included and wereassessed by the Tower of London (TOL), 43 Trail Mak-ing Test–B (TMT-B) , 37 and the Interference subtest of the Stroop Test. 38 Treatment Both groups underwent the same rehabilitation pro-gram methodology: with a duration of 45 minutes, 3times a week for 4 weeks (a total of 12 sessions) and,in addition, exercises to do at home, 1 per week, withindividual tutored sessions once a week.CT was performed using different therapeuticmodalities, including interactive multimedia softwareand paper-and-pencil exercises. Computer-aided train-ing was supervised by a trained clinical psychologistusing the SmartBrain tool. 44 A platform with 28 activ-ities was designed based on stimulating specific cogni-tive domains known to be impaired in PD (attention/ working memory, memory, psychomotor speed, execu-tive functions, and visuospatial abilities) and nonspe-cific cognitive exercises (language, simple calculationsskills, and culture). Initially, all patients were startedat a medium difficulty level (level 7). The softwaremonitored each participant’s performance automati-cally after each correct/incorrect response. Combinedwith computer-aided training, each week CTG partici-pants received a pack with 20 cognitive homeworkexercises designed to stimulate specific and nonspecificcognitive areas. The speech therapy received by theCG aimed to make participants’ aware of their speechand communication difficulties. Statistical Analysis Demographic and clinical characteristics at baselinewere compared using a 2-tailed  t   test for independentsamples or a 2-sided chi-square test when appropriate.The effect of the CT treatment on neuropsychologicalperformances and daily functional scales was analyzedwith repeated-measures ANOVAs (time    treatmentinteraction), with treatment groups as the between-subject factor and the 2 evaluations (pretest and postt-est) as the within-subject factor. To determine theeffect of MCI on the dependent variables, we used a2-way ANOVA (MCI    group) on gain scores of thesubjects (posttest/pretest). The level of statistical sig-nificance was set at .05. FIG. 1.  Stages in the study design. E F F I C A C Y O F C O G N I T I V E T R A I N I N G I N P D Movement   Disorders, Vol. 26, No. 7, 2011  1253  Furthermore, to compare the magnitude of the treat-ment effects on the CTG, standardized effect sizes(Cohen’s  d  ) were calculated for each variable follow-ing the Thalheimer and Cook 45 methodology. Follow-ing to the recommendation of Wilson et al, 46 wesubtracted the CG posttest score from the CTG postt-est score, and divided this term by the standard devia-tion of the whole sample at retest. The followingcutoff scores applied:   1.10 to  < 1.45, very largeeffect;   0.75 to  < 1.10, large effect;   0.40 to  < 0.75,medium effect;   0.15 to  < 0.40, small effect. Results From the initial sample of 46, a total of 33 subjectswere randomly assigned to treatment. Only 5 partici-pants dropped out (2 in the CTG and 3 in the CG)during the study. Reasons for the dropping out werenot completing the attendance criteria or not partici-pating in the postevaluation. Among completers, 16patients received the CT program (CTG) and 12 thespeech therapy program (CG). The diagram flow of participation can be seen in Figure 2.The sample included participants from both sexes(50% male). Their mean age was 65  6  9.19 years,mean duration of the disease was 7.5 6  6.8 years, andmean years of education was 9  6  2.9 years. Of thestudied sample, 50% (14 of 28 patients) met Petersenet al criteria for MCI. 47,48 Subjects classified as havingMCI demonstrated a decrement of more than 1.5 SDon any cognitive test or subtest. There were no statisti-cally significant differences between groups at baselineobservation for any of the variables studied (Table 1).The repeated-measures ANOVA showed a signifi-cant time    treatment interaction in favor of the CTGfor several neurocognitive variables. The CTG had animproved performance in 1 of the attention and work-ing memory measures, the WAIS-III Digit Span For-ward ( F   ¼  5.58,  P  ¼  .026). Also, 1 of the measures of information processing speed showed this expectedinteraction, the Stroop Word subtest ( F   ¼  16.46,  P  ¼ .000). Both measures of visual memory showed theexpected time    treatment interaction, Immediate ( F  ¼  7.02,  P  ¼  .014) and Delayed ( F   ¼  4.31,  P  ¼  .048)Recall of the ROCFT. The measure of visuoconstruc-tive abilities, the Copy of the ROCFT, also showedour hypothesized interaction ( F   ¼  8.95,  P  ¼  .006), asdid the measure of visuospatial abilities, the RBANS–Line Orientation subtest, ( F   ¼  10.80,  P  ¼  .003).Moreover, 1 of the verbal fluency measures, theSemantic–Animals, showed the expected improvementfor the CTG ( F   ¼  9.53,  P  ¼  .005), as well as 3 of theexecutive function measures, the TMT-B ( F   ¼  6.44,  P ¼  .018), the TOL–Total Moves ( F   ¼  12.17,  P  ¼ .002), and the TOL–Total Correct ( F   ¼  12.21,  P  ¼ .002). However, QOL and functional scales did notshow the expected significant time    treatment inter-action (Table 2).The MCI group did not show any significant effectin the multivariate tests. In the tests of the within-sub-jects effects, we found a significant interaction MCI   group in the dependent variables RBANS–Line Orien-tation ( F   ¼  6.264,  P  <  .05), TOL–Total Movements( F   ¼  4.441,  P  <  .05), and Trail Making Test–B ( F   ¼ 4.323,  P  <  .05). This significant interaction occurredbecause the experimental treatment more improved FIG. 2.  Flow diagram of subject recruitment and participation in the study. (1) The experimental group participated in an individualized cognitivetraining program; (2) the control group received group speech therapy reeducation. Randomization was performed after baseline assessment toblind investigators. P R A T S E T A L . 1254  Movement   Disorders, Vol. 26, No. 7, 2011  the performance of the subjects with MCI than thosewithout MCI.Complementary analysis including the center fromwhere the subjects were recruited as a secondbetween-subject factor showed that the differencesbetween the subjects from both centers did not affectthe significant time    treatment interaction found. Effect Sizes of Improvement Table 2 also shows the effect sizes of improvementfor the differences between groups. Cohen’s  d   valueconfirmed the significant interaction found in Seman-tic–Animals, TOL–Total Correct, and TOL–TotalMoves, indicating a very large effect from CT. TheStroop Word subtest, and the WAIS-III Digit SpanForward, which also showed a significant time   treatment interaction, showed a large effect from CT.The significance found with the TMT-B was confirmedby a medium effect size, and the RBANS–Line Orien-tation test only showed a small effect after CT. Discussion Cognitive impairment is frequent in nondementedPD. Similar to in other studies, 3–5 in our sample 50%met criteria for MCI. CT has proved to be a usefuland efficient tool in the management of cognitiveimpairment of other pathological conditions. As veryfew studies have been conducted in PD, we aimed todetermine the efficacy of a CT program on cognitiveperformance and QOL in nondemented PD patients.Our findings suggest that an intensive CT program(3 times a week for 4 weeks) can be a useful tool inimproving cognitive performance in PD patients.Improved cognitive performance was observed in CTGparticipants compared with controls in attention, in-formation processing speed, memory, visuospatial andvisuoconstructive abilities, semantic verbal fluency,and executive functions. Thus, our study supports the-ories that suggest CT may activate mechanisms of cer-ebral plasticity and slow down the progression of cognitive manifestations of the disease. 49,50 Futureinvestigations with functional neuroimaging methodssuch as positron emission tomography and functionalmagnetic resonance should be encouraged. Such stud-ies may be useful in assessing CT effectiveness andexplaining the cerebral consequences of plasticity asso-ciated with PD.Even though classic tests of executive functions, suchas the TMT, have been widely accepted as good predic-tors of functional status, 51–53 the observed cognitivechanges were not shown in a change of functionalmeasures. It is worth noting that specific functionalscales sensitive to detecting subtle cognitive change forPD do not exist. However, a recent study demonstratedhow a functional scale designed for Alzheimer’s diseasecould also be used to assess functional changes in PDwith MCI. 8 Our functional scale was a self-adminis-tered measure designed to assess cognitive difficulties TABLE 1.  Demographic and clinical data at baseline of patientsin the CTG and CG groups VariableGroup StatisticsCTG CG  v 2a P  Sex (male/female), n 7/9 7/5 0.58 .45 t  b P   Age, mean (SD) 64.75 (9.19) 65.42 (9.60)   0.19 .85 Year of diagnosis, mean (SD) 2002.06 (4.58) 2001.17 (9.63) 0.33 .75 Years of evolution, mean (SD) 6.94 (4.58) 8.25 (9.22)   0.50 .62Hoehn & Yahr, mean (SD) 2.37 (0.76) 2.25 (0.78) 0.49 .63 Years of education, mean (SD) 9.88 (2.94) 9.50 (3.09) 0.33 .75WAIS-III Vocabulary, c mean (SD) 58.19 (6.57) 55.33 (8.38) 1.42 .17 v 2a P  Mild cognitive impairment, d n (%) 8 (50%) 6 (50%) 0 1 a Two-sided chi-square test; b 2-tailed  t   for independent samples; c adjusted by age; d according to Petersen’s et al. 45 Criteria: (1) presence of a subjective memory complaint, (2) preserved generalintellectual functioning as estimated by performance on a vocabulary test, (3) decrement of more than 1.5 SD onany cognitive test or subtest, (4) intact ability to perform activities of daily living, and (5) absence of dementia.CTG, cognitive training group; CG, control group; WAIS-III Vocabulary, Wechsler Adult Intelligence Scale–III,Vocabulary subtest.E F F I C A C Y O F C O G N I T I V E T R A I N I N G I N P D Movement   Disorders, Vol. 26, No. 7, 2011  1255
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