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Article first published online: 20 FEB 2013
Nonpharmacological enhancement of cognitive function in Parkinson's disease: A systematic review
Authors: John V. Hindle MBBS, FRCP, FRCPsych1,2,*, Annette Petrelli MSc3,4, Linda Clare MA, MSc, PhD5, Elke Kalbe PhD3,4
1 School of Medical Sciences, Bangor University, Bangor, United Kingdom
2 Department of Care of the Elderly, Betsi Cadwaladr University Health Board, Llandudno Hospital, Conwy, United Kingdom
3 Institute of Gerontology and Center for Neuropsychological Diagnostics and Intervention, University of Vechta, Vechta, Germany
4 Department of Neurology, University Hospital Cologne, Cologne, Germany
5 School of Psychology, Bangor University, Bangor, United Kingdom
*Correspondence to: Dr. Hindle, Llandudno Hospital, Llandudno, Conwy LL30 1LB, UK; firstname.lastname@example.org.UK
The first two authors contributed equally to this article.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
Funding agencies: John V. Hindle was funded in Wales as a Research Fellow by a grant from Academic Health Science Collaboration-National Institute for Social Care and Health Research.
Cognitive decline and dementia are frequent in patients with Parkinson's disease (PD). The evidence for nonpharmacological therapies in Alzheimer's disease and other dementias has been studied systematically, but the evidence is unclear for their efficacy in cognition and dementia in PD. An international collaboration produced a comprehensive, systematic review of the effectiveness and of nonpharmacological and noninvasive therapies in cognitively intact, cognitively impaired, and PD dementia groups. The interventions included cognitive rehabilitation, physical rehabilitation, exercise, and brain stimulation techniques but excluded invasive treatments, such as surgery and deep brain stimulation. The potential biases and evidence levels for controlled trials (CTs) were analyzed based on Cochrane and National Institute for Health and Clinical Excellence criteria. After exclusions, 18 studies were reviewed, including 5 studies of cognitive training, 4 of exercise and physical therapies, 4 of combined cognitive and physical interventions, and 5 of brain stimulation techniques. The methodology, study populations, interventions, outcomes, control groups, analyses, results, limitations, biases, and evidence levels of all reviewed studies were described. There were 9 CTs, including 6 randomized CTs (RCTs). Although 5 trials showed positive results, only 1 study of cognitive training achieved evidence grading of 1+ with a low risk of bias. There were no studies on PD dementia. Current research on nonpharmacological therapies for cognitive dysfunction and dementia in PD is very limited in quantity and quality. There is an urgent need for rigorous RCTs of nonpharmacological treatments for cognitive impairment and dementia in PD.
© 2013 Movement Disorder Society
There is increasing interest in the effects of nonpharmacological interventions on cognitive functions in neurological and psychiatric conditions. The efficacy of nonpharmacological therapies in Alzheimer's disease (AD) and other dementias has been studied, systematically but the evidence is unclear regarding the efficacy of such therapies for cognition and dementia in Parkinson's disease (PD).
Cognitive Impairment and Dementia in PD
Neuropsychiatric symptoms predominate as PD progresses, including cognitive impairment and dementia.[2, 3] Up to 25% of nondemented PD patients will have mild cognitive impairment (MCI) and increased risk of developing PD dementia (PDD). Criteria for the diagnosis of MCI in PD have been published but require validation. Cognitive impairments in PD include frontostriatal executive deficits, which progress as a function of disease duration but are not related to dementia. Dementia is predicted by more posterior cortical deficits of visuospatial function, memory, and language. After 20 years, dementia affects at least 80% of people with PD, occurring most often after the age of 70 years.[7, 8] It has been suggested that cognition-focused intervention may play a role in preventing or delaying the onset of cognitive impairment and PDD[8, 9] by promoting cognitive reserve. Cognitive reserve, which helps explain the mismatch between the extent of pathology and clinical manifestations, may reduce the rates of decline in executive function and conversion from MCI to dementia, providing the substrate for cognitive training and rehabilitation.
Interventions to Prevent or Delay Dementia
Cognitive training, physical activity, and noncognitive, nonphysical leisure activities may reduce the risk for cognitive decline and AD. Cognitive training involves regular guided practice on standard tasks focused on particular aspects of cognitive function. Performance gains from cognitive interventions such as cognitive training cannot be attributed solely to the intervention, because they do not exceed those produced by active control treatment.[15, 16] Computerized brain training has been shown to improve only the cognitive tasks that are trained without evidence for a transfer effect to untrained tasks. Exercise promotes brain function through a number of mechanisms, including cardiorespiratory fitness associated with improved motor function, auditory attention, and cognitive speed. Combining exercise with cognitive interventions may enhance benefits. The effects of physical activity during middle and later life in preventing dementia remain controversial. An early open-label pilot study of the effects of exercise on motor disability, mood, and well being in PD showed no change in Mini-Mental State Examination (MMSE) scores.
Interventions for Existing Cognitive Impairment and Dementia
Group-based cognitive stimulation therapy, which includes structured discussions with trained staff, is well established and cost effective in mild-to-moderate dementia, but individual therapy is less well established. Cognitive rehabilitation is a more individualized approach in which strategies to address personally relevant goals are devised.[14, 25] Activities may be targeted at improving individual cognitive deficits, compensating for the deficits, or developing adaptive methods to promote independence in activities of daily living. In a systematic review of efficacy of nonpharmacological therapies for AD, grade B recommendations were made for cognitive training, cognitive stimulation, and multi-component interventions. In early AD and vascular dementia, there is limited evidence for efficacy of cognitive interventions. In PD, 1 small review, which identified only 4 studies of cognitive training, stated that research remained inconclusive.
Combined physical activity and cognitive exercise may improve memory and executive function in MCI. Vigorous exercise has been suggested to have a neuroprotective effect in PD, although a systematic review of exercise in PD did not include the effects on cognition.
Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Most studies of rTMS or tDCS in AD induce short-duration beneficial cognitive effects and are not adequately powered to establish therapeutic efficacy. There is interest in combining cognitive training with rTMS to produce an enhanced effect.
Aims of the Review
The first aim of this review was to examine the evidence for the effectiveness of all nonpharmacological (cognitive rehabilitation, physical rehabilitation, physical therapies, exercise, and combined approaches) and noninvasive (brain stimulation techniques) interventions to improve cognition in cognitively intact and cognitively impaired people with PD and in PDD. The second aim of the review was to identify all controlled trials (CTs) and particularly randomized CTs (RCTs) of nonpharmacological interventions to improve cognition in cognitively intact and cognitively impaired people with PD and in PDD and to rate the potential biases and quality of those trials.
Patients and Methods
A review was performed using systematic review principles through collaboration between teams in the United Kingdom and Germany who developed complementary search strategies. The results of 2 search strategies form a single systematic review.
Review Strategy 1: United Kingdom
Searches were conducted using the databases PsychInfo, PubMed, CINAHL, and Cochrane and manual searches of references in relevant papers. The review period was from 2000 to December 2011. Studies of nonpharmacological interventions not limited to randomized trials were included if they used cognitive outcomes in cognitively intact, cognitively impaired, and PDD groups and were explicit about the diagnosis of PD. Case reports and series were included only when these provided added information about the effects of a relevant intervention. Laboratory-based experimental studies with no intervention were excluded. Studies had to be published in English, and reports published only in abstract form were excluded. Search terms were based on a systematic review of nonpharmacological interventions in AD (cognitive training, behavioral interventions, cognitive stimulation, transcutaneous electrical stimulation, physical exercise, use of music, reminiscence, activities of daily living training, massage and touch, recreation therapy, use of light, multisensory stimulation, support and psychotherapy, validation, transcranial magnetic stimulation, muscle relaxation, multicomponent). The search terms used were “Parkinson's disease” [title] AND “cognitive rehabilitation” or “cognitive training” OR “cognitive stimulation therapy,” “Parkinson's disease” [title or abstract] AND “cognition,” OR “dementia” AND “exercise” OR “music” OR “dance” OR “light” OR “acupuncture” OR “reminiscence” OR “recreation” OR “relaxation” OR “diet” OR “food” OR “nutrition” OR “supplements” OR “conductive education” OR “transcranial electrical stimulation” OR “transcranial magnetic stimulation.” Abstracts were screened for suitability, and potentially relevant papers were reviewed in full, selected for inclusion, and independently reviewed by 2 authors (J.V.H., L.C.).
Review Strategy 2: Germany
Searches were conducted using the databases PsychInfo, PubMed, MEDLINE, and Google Scholar. The review period was from January 1985 to June 2012. Studies of nonpharmacological interventions over multiple sessions were included that used patients with PD as the study population, had a controlled study design, had cognitive parameters as outcome variables, and were published in English. Search terms [all fields] were “Parkinson's disease or Parkinson” AND “nonpharmacological” OR “neuropsychological” OR “cognitive “ OR “memory” OR “attention” OR “concentration” OR “executive” OR “visuo-spatial” OR “language” OR “ reality orientation” OR “reminiscence” OR “multidisciplinary” OR “physical activity” OR “ exercise” OR “motor” AND “training” OR “treatment” OR “rehabilitation” OR “stimulation.” Studies comprising brain stimulation techniques were only included in review 1. All steps of the review were conducted independently by 2 authors with checks on consistency and inconsistency resolved (A.P., E.K.). An additional review was conducted and agreed (J.V.H., A.P.) using review strategy 1 to update to October 2012.
Within-Study Bias, Quality, and Evidence Level
Two authors (A.P., E.K.) used a modified domain-based assessment of bias of the CTs suggested by Cochrane, including reporting bias. For this purpose, the following domains, which the authors considered relevant for this area of research, were defined: selection, randomization; performance, blinding of participants and personnel; detection, blinding of assessor; attrition, withdrawals and dropouts described, follow-up included; and other, parallel tests, medication, affect assessed. The assessments of bias were independently reviewed and agreed by a third author (J.V.H.).
All studies were allocated an evidence level in accordance with National Institute for Health and Clinical Excellence (NICE) guidelines with 2 authors using the bias assessment to allocate levels for the CTs (A.P., E.K.). All 4 authors then agreed on the final bias assessments for the CTs and evidence levels for all studies in the review, also taking into account the study methodology, interventions, and control interventions.
The results of the collaborative search strategies are summarized in Figure 1. There were insufficient data from RCTs to perform a meta-analysis. The study characteristics have been divided into cognitive training, exercise and physical interventions (any form of physical rehabilitation), combined cognitive and physical interventions, and brain stimulation techniques, as shown in Table 1, which includes study limitations, NICE classifications, and evidence levels. Noncontrolled and controlled studies are reported separately.
Table 1. Studies Included in the Review
|Study (year)||Method||Intervention||Sample PD (control)||Cognitive status||Follow-up||Cognition assessments||Statistical analyses||Results||Limitations||NICE classi-
fication and evidence level a
|A. Cognitive training|
|Mohlman et al. (2011)||Feasibility and acceptability of a nonphar-
macological cognitive remediation program; recruited from a number of sources
|Four 90-min sessions: Attention process training; APT-II audio CD, work sheets; by prior definition, established that training should be fatigue<4, effort fall between 1 and 4, progress between 1 and 5, and enjoyment 1–5||16 PD, 0 controls; exclude dementia; final sample 14 due to 2 dropping out before training||Not demented||None||Six-point Likert scale to rate levels of fatigue, effort, progress, enjoyment; APT scores: 0=none, 1=a little, 2=some, 3=much, 4=very much, 5=extreme; BNT, MMSE, executive function-digit backwards, COWAT, Stroop color/word, TMT-B||Relation between sets of ratings examined using zero order correlation method; repeated ANOVAs to compare across tasks; sex differences using t test; relation of ratings to indices of outcome using correlation methods||Average Likert scores (mean±SD) across participants: Perception of progress, 2.03±0.56, some to much progress; Enjoyment, 2.18±0.84, some to much enjoyment; Effort, 2.74±0.51, some to much effort; Fatigue, 1.88±0.51, little to some fatigue; feasibility criteria met; fatigue negative correlation with effort (r=−0.644) and a near significant negative relation with enjoyment (r=−0.529; P<0.10); improved executive function correlated to perception of progress (r=0.685; P<0.05)||Feasibility and accepta-
|Case series, level 3|
|Disbrow et al. (2012)||Uncontrolled, non-
randomized study of computer-
based cognitive rehabilitation program designed to improve motor related executive function
based trials of externally and internally generated number sequencing—measures sequence initiation, completion time, and error rate
|PD, 30; controls, 21 without PD||“Impaired” and “unimpaired” groups based on motor paradigm but also “impaired” group had worse performance on TMT-B-A||None||TMT-A and B; D-KEFS verbal fluency (the primary outcome was performance on the computerized motor task)||Mixed design ANOVA (2 × 3) with 2 within subject levels (before and after training); Tukey's honesty test and Bonferroni correction applied||Training-impaired PD group greater improvement in sequence initiation, completion time, and error rate for internally represented sequences; all groups improved on TMT-B-A (P=0.02); pretraining TMT-B predicted best training improvement on internally generated sequencing||Case series, level 3|
|Nombela et al. (2011)||Non-RCT study of the effect of daily Sudoku; cortical activation assessed using fMRI||One easy level Sudoku (4-by-4 grid with 2-by-2 blocks) per day for 6 mo||10 PD and 10 controls. 5 in each group voluntarily did daily Sudoku for 6 mo; inclusion criteria very strict to enable fMRI||MMSE mean score: 26.0 trained, 25.8 untrained.||None||UPDRS, MMSE, MADRS, and modified Stroop in fMRI scanner||Complex analysis of fMRI data, statistical images entered into a 1-sample t test (trained, untrained and controls); behavioral analysis, t tests for first and second evaluation for groups trained, untrained, and controls||Stroop reaction times (P<0.01; Cohen's d=1.03), correct answers (P<0.05), and missing answers (P<0.01) improved in trained vs untrained PD; Sudoku also improved (P<0.05); cortical activation patterns in trained PD reduced to be comparable with controls b||Possible unrepre-
sentative sample, no active control, nonrandom-
ized, assessors not blind.
|CT, level 2+|
|Sammer et al. (2006)||RCT of 10-session (30 min each) cognitive training; clinic recruitment but interventions during a 3- to 4-week hospital stay||Ten sessions of 30 min; working memory tasks requiring executive function; executive tasks of BADS not used for baseline scoring; Ravens matrices||Total 26: 12 executive treatment, 14 normal treatment||Not stated||Three to 4 weeks during stay; no further follow-up||Executive-
BADS, cognitive estimates, working memory, GNL, AKT, ZVT, test for verbal intelligence, MWT
|Repeated-measurement ANOVA, no correction for multiple variables||Executive treatment group better in both tasks on the BADS shift task (F1,24 =4.28; P<0.35); both groups improved on 6-element task (F1,24=20.08; P<0.0002), but executive treatment tended to improve more (F1,24=2.53; P<0.12); no effect on AKT, GNL, ZVT||No active control; random-
ization unclear, assessors not blinded
|RCT, level 1−|
|Paris et al. (2011)||Blind multicenter RCT of the efficacy of cognitive training in PD; recruited from 2 Parkinson's clinics; cognitive training (CTG) vs control group (CG) speech therapy group sessions||Three 45-minute sessions per week; targeted at attention, working memory, psychomotor speed, executive functions, visuospatial, language, calculation, and culture||Total 46 PD but 13 not eligible for CTG; 33 patients randomized; completers: 16 in CTG group (2 drop-outs) and 12 in CG (3 dropouts)||MMSE>22||Four weeks during study; no follow-up||UPDRS, H&Y, PDQ-39, cognitive difficulties scale, GDS-15, MMSE, ACE, FAS, animals, CVLT-II, ROCFT, SDMT, Stroop, TMT-A & B, line-orientation form RBANS, TOL, WAIS-III digit subtest, WAIS-III vocabulary, WMS-III logical memory||Demo-
graphics and clinical data were compared using 2-tailed t tests and 2-sided chi squared tests; effects of CTG on neuro-
psychology and functional performance, repeated-measures ANOVAs (time × treatment interaction) to determine effect of MCI on dependent variables used 2-way ANOVA; standardized effect sizes on CTG (Cohen's d); tabulated raw scores and P values from ANOVA and d values from Cohen; no correction for multiple variables
|Repeated-measures ANOVA significant time × treatment interaction in favor of CTG for several variables; Improve-
ments: Attention and working memory, WAIS-III digit span forward (P=0.026; d=0.95), no effect digit span, digit span backwards, CVLT-II list; Information processing speed, Stroop word subtest (P=0.000; d=0.99), no effect TMT-A, SDMT; Verbal memory, no effect CVLT-II short and long delay, WMS-II; Learning, no effect CVLT-II list total; Visual working memory, ROCF immediate recall (P=0.014; d=0.05) and delayed recall (P=0.048; d=0.14), Visuo-
constructive, copy ROCF (P=0.006; d=0.03); Visuospatial abilities, RBANS line orientation subtest (P=0.003; d=0.35); Verbal fluency, semantic animals (P=0.005; d=1.28), no effect phonemic; executive function, TMT-B (P =0.018; d=0.46), TOL-moves (P=0.002; d=1.11), TOL-correct (P=0.002; d=1.15); no effect TOL rules and Stroop interference
|RCT, level 1+|
|B. Exercise and physical therapies|
|Nocera et al. (2010)||Case study; aerobic exercise||Aerobic exercise, 8 weeks, 20 min per session||1||MMSE 30||8 weeks||Some tests done outside exercise: single task MMSE, Stroop; others performed as well during exercise: dual task, FAS, digit span, picture completion||Raw data presented||Performance on Stroop color X's and color words; verbal fluency animals: improved dual task performance||Case report||Noncom-
parative case study, level 3
|Ridgel et al. (2011)||Uncontrolled study; passive exercise||Passive cycling for 30 min, 60/70/80 pedals per min, counter-
balanced order; 3 sessions 1 week apart
|19 (Within subject)||Not stated||N/A||Trail making A and B, Trail making B-A||Dependent variables were dwell time, inter-target time, total time; for each variable, a 2 (pre and post) × 3 (60/70/80) repeated-measures ANOVA looked at interactions||Improved executive function with a main effect of time on TMT-B (P=0.005), TMT dwell time (P=0.021), and reduced TMT B-A (P=0.006); no improvement in TMT-A; therefore, not a motor effect.||Nonblinded, no controls||Noncom-
parative case series, level 3
|Tanaka et al. (2009)||Controlled non-
randomized study of the influence of multimodal exercise program on executive function
|Group exercise, mainly aerobic administered in groups of 10 60-minute sessions 3 × per week for 10 mo||10 PD (10 controls, but they were a control group from a previous study)||Not demented||6 Mo||Executive, WCST; concentrated attention symbol search; WAIS-III; State Trait Anxiety Inventory; HADS||Two-way ANOVA||Exercise improved executive function as measured by the WCST; interaction between groups and time (pre and post intervention) for categories completed (F=4.595; P<0.05; d=1.24) and for perseverative errors (F=4.716; P<0.05; d=0.46); no effect on maintaining set; no interaction with confounding variables, including symbol search||Non-RCT; controls from another study||CT, level 2−|
|Cruise et al. (2011)||Controlled trial of exercise; recruitment from Parkinson's Association||The EIP group had twice-weekly 60-min sessions mixed aerobic and resistance training; controls had no activity||Allocated 17 to EIP: 16 completed and 15 analyzed; controls: allocated 17, 13 allocated and 13 analyzed||MMSE>23||12 Weeks||MMSE, AusNART, FAS, semantic fluency, CANTAB-
eclipse; pattern recognition (PRM) and spatial recognition memory (SRM), spatial working memory (SWM); Stockings of Cambridge (SOC), GDS, PDQ-39
|Mean, SD, and % change for each group; because of small numbers, used method of Hopkins: paired sample t test for pre-post comparison; the resulting P values and mean % change were used to calculate 90% CI and clinical inferences (% chance that the %change scores are beneficial, trivial, or harmful); verbal descriptors most unlikely, very unlikely, unlikely, possibly, likely, very likely. or most likely; no correction for multiple variables||Exercise “likely benefit” for improving performance on verbal fluency and for reducing SWM errors (d=0.96); “possible benefit” for category or semantic fluency (d=0.31); both groups improve on SOC, and no effect on PRM or SRM||Random-
ization by a convenient sample method of allocation to groups; not blinded assessments
|CT, level 2−|
|C. Combined therapies|
|Sinfiorini et al. (2004)||Effects of a 6-week motor and cognitive training in early PD with MCI no dementia||12 Sessions, twice per week for 6 weeks; TNP software developed for neuro-
|20 PD, no control||Not demented or depressed||6 Weeks during study; testing repeated after 6 mo||MMSE, digit span, Corsi's test, FAS, Babcock's story, Ravens matrices, WCST, Stroop||Used t test for paired data||Significant improvement in Babcock (P<0.05), FAS (P<0.005), Raven's matrices (P<0.04) maintained over 6 mo; no effect MMSE, digit span, Corsi's test, WCST score errors, perseverative, and Stroop test||No controls||Case series, level 3|
|Mirelman et al. (2010)||Virtual reality gait training.||Virtual reality stimulation designed for the study; treadmill walking with simultaneous processing of multiple stimuli- obstacle negotiation in 2 planes with distracters, such as change lighting, moving objects, adjustment in frequency and size of objects; demanded attention, response selection, processing of visual stimuli||20 PD (14 men, 6 women); H&Y 2–3 with gait difficulties as defined by UPDRS but able to walk independently for 5 minutes; mean age, 67.1 y||Not demented and no major depression||Post training 6 weeks; follow-up 1 mo later||MOCA baseline; dual task (gait plus serial subtractions); TMT-A&B main outcome; PDQ-39 cognitive measures; gait measures||Repeated-measures analysis with Bonferroni correction for multiple comparisons; significance set at P<0.05||Improved gait speed (P=0.006) similar to normal treadmill; dual task costs improved (p=0.027 post training and 0.05 overall at follow-up); improve-
ments in TMT-A (P=0.003) and TMT-B (P=0.05) post training; association between TMT-A&B and gait speed (P=0.013) and obstacle negotiation (P=0.002)
|Not randomized or controlled||Noncom-
parative case series, level 3
|Pompeu et al, (2012)||Parallel, single blind randomized trial of Nintendo Wii cognitive stimulation and balance exercises||One-hour training sessions for 7 weeks; “global” and balance exercises compared with “global” and balance exercises with cognitive stimulation using Ninendo Wii-based games||Total, 32 (16 in each group; 17 men, 15 women)||MMSE>23||Primary outcome UPDRS-11; secondary- Berg balance scale, unipedal stance test; cognition-
graphics, unpaired t test; outcomes, repeated-measures ANOVA
|Both groups improved on UPDRS-II1 (P<0.001), but no difference between the groups; both groups improved on the MOCA (P<0.001) but no difference between groups; no additional benefit of the Ninendo Wii cognitive training||Two treatment arms compared, no other active or inactive control||RCT, level 1−|
|Reuter et al. (2012)||RCT inpatient followed by home multimodal cognitive rehabilitation program including physical exercise||Three active treatment arms: A) individualized cognitive training- paper and pencil and multimedia, e.g. executive tasks from BADS; B) as a plus, individualized transfer training; competence in tasks of daily routines; C) A+B plus individualized psychomotor training. e.g., motor sequencing, dual tasking, spatial orientation, Nordic walking; groups A and B had relaxation training and occupational therapy to compensate for the time spent in training by group C||240 PD, 222 completed programs: 71 in group A, n=75 in group B, n=76 in group C||The presence of MCI was required for inclusion; Mean±SD MMSE score: group A, 27.4±1.8; group B, 27.6±1.9; group C, 28.1±1.8||After 6 mo of home training||PANDA, MMSE; Primary outcome: ADAS-COG; secondary outcomes: SCOPA-COG, PASAT, BADS rule shift, zoo map, modified 6 elements; MWT-B, HADS, PDQ-39||Ordinal demographic data: non-
parametric test, Kruskall-Wallis; continuous data: 1-way ANOVA; linear model for repeated measures used for outcomes; significance set at P=0.05; Bonferroni correction used
|All groups, linear trend of improvement on ADAS-COG (P<0.001); group C improved the most—
significant interaction between groups and assessments (P<0.001) and group difference (P<0.001; Cohen's d: A/C, d =1.33; B/C, d=0.11); group B and especially group C maintained improvement better than group A over 6 mo with a higher proportion that had further improvement; secondary outcomes: SCOPA-COG; all groups improved (P<0.001), group C improved the most with significant difference between groups (P<0.001; A/C, d=3.69; B/C, d=2.56); BADS improvement second and final assessments favor group C rule shift (P<0.03 and P<0.01, respectively), zoo map (P<0.03 and P<0.001, respectively), and 6-element (P<0.001 and P<0.001, respectively); PASAT: linear trend favored group C (P<0.001)
|Three treatment arms with no other active or inactive control; inpatients for 4 weeks||RCT, level 1−|
|D. Brain stimulation techniques|
|Boggio et al. (2006)||tDCS||Off medication 12 hours; single sessions to left DLPFC, primary motor cortex (M1) or sham tDCS 20 minutes; either 1-mA or 2-mA; sessions 48 hours apart, order counter-
|18 (within-patient control using sham stimulation)||Not demented||Evaluation at the end of stimulation||3 Back-working memory tasks; scores for correct, errors, time||ANOVA, 2 tailed- significance P=0.05||1 mA: correct, P=0.61; errors, P=0.29; time, P=0.29; 2 mA: correct, P<0.05, errors<0.05, time, P=0.08||Single treatment||Case series, level 3|
|Sedlackova et al. (2009)||rTMS||Off medication 12 hours; rTMS (3 blocks, 15 × 30 trains, 10-s intervals, 10 Hz, intensity 100% resting motor threshold) to left PMd and DLPFC; control rTMS to left OCC; single 30-minute session||10||Not depressed||Single session tests immediately after procedure||Choice reaction time (noise-compatibility paradigm); verbal fluency, TMT A&B, digit span||Two-way ANOVA||Raw scores given; no significant effects of either procedure on any of the measures||Single session||Case series, level 3|
|Srovnalova et al. (2011)||rTMS||Off medication; sequential rTMS (600 pulses, 10 × 30 trains, intervals 11.7 s, 25 Hz, intensity 80% resting motor threshold) to left and right inferior frontal gyri in sequence; sham rTMS in random order||10||Not demented||Single session, tests immediately after procedures||Stroop, FAB||Wilcoxon's matched-pair test (P<0.05) corrected for 4 multiple comparisons (P<0.0125)||All components of Stroop improved; after Bonferroni correction, Stroop word and color word remain positive (P<0.004 and P<0.006, respectively); no effect on FAB or color or interference in Stroop||Single session||Case series, level 3|
|Boggio et al. (2005)||rTMS||Training 10 days in 2 weeks (40 trains of 5-s rTMS, 15 Hz, intensity 110% resting motor threshold) to left DLPFC combined with 8 weeks of placebo tablets (n=13), 2 weeks of sham rTMS combined with 8 weeks fluoxetine 20 mg (n=12)||25||Depression minor/ major DSM-IV and not demented||2 weeks and 8 weeks||WCST, Stroop, Hooper, TMT-B, Raven matrices, digit span, FAS||Factorial 3 × 2 ANOVA (P=0.05); using Bonferroni correction, P=0.005; post hoc analysis, Tukey's honest significant difference test||ANOVA; no difference between treatments; both rTMS and fluoxetine improved cognition independent of mood; WCST perseverative; Hooper, Stroop colored words and interference, P<0.05; Bonferroni correction, Stroop interference became non-
significant; Tukey's: at 2 weeks, Stroop colored words, P=0.002; interference, P=0.033; Hooper, P=0.015; at 8 weeks, Hooper, P=0.010; WCST perseverative, P=0.003
|Primary outcome depression, no placebo control; method of random-
|RCT, level 1−|
|Pal et al. (2010)||rTMS||10 days (600 pulses per day 12 trains of 10 s, 20-s intervals, 5 Hz intensity 90% resting motor threshold) rTMS 5 Hz to left DLPFC compared with sham rTMS||12 (10 sham rTMS)||Mild-to-moderate depression DSM-IV and not demented||1 Day and 30 days||MMSE, Stroop, TMT A&B||SPSS software version 17; Mann–
Whitney, Wilcoxon's, and Friedman tests
|Accuracy of Stroop test improved at 1 and 30 days from 78.1% to 90.6% (P<0.01); no effect on MMSE or TMT A&B||Primary outcome, depression; method of random-
|RCT, level 1−|
A small, open study using very broad definitions of feasibility demonstrated that cognitive training in PD without dementia was both feasible and acceptable (Table 1A, cognitive training). In a nonrandomized study of computer-based cognitive training using number sequencing aimed at improving “motor executive function,” participants were divided into impaired and unimpaired groups based on motor and cognitive tasks. The results showed a greater benefit of training for those who were impaired.
In a very small nonrandomized study of functional magnetic resonance imaging (fMRI) and cognitive training, participants voluntarily performed 1 easy-level Sudoku at home every day over 6 months, whereas the control group of PD patients performed none. Both groups were assessed with fMRI during cognitive testing using a modified Stroop test. Positive effects were observed for all reported domains, which were executive functions (inhibition/set shifting) and logical reasoning. The authors suggested that cognitive training induces cortical plasticity; because, after the intervention, cortical activation patterns in patients with PD were comparable to those in healthy controls.
In a CT, cognitive training was administered during a 3-week to 4-week inpatient stay. The intervention, a working memory task that required executive function, was compared with a control group that received unspecified standard treatment without cognitive intervention. The results showed improvement in executive functions in both groups with a greater improvement in the executive training group.
In a small, blinded RCT, cognitive training was provided in 45-minute sessions 3 times a week for 4 weeks that targeted attention, working memory, memory, psychomotor speed, executive functions, visuospatial abilities, language, calculation, and “culture” compared with an active control of speech therapy. Half of the participants in the final analysis in each group had MCI, although the presence of MCI did not contribute to any effects. The results demonstrated a significant benefit for cognitive training in the domains of attention, information processing speed, memory, visuospatial and visuoconstructive abilities, and executive functions (inhibition/set shifting, semantic word fluency, and planning/problem solving). No significant effects were observed for global measures of cognition (MMSE, Addenbrooke's Cognitive Examination). Other nonsignificant results are not reported.
Exercise and Physical Interventions
An unblinded single case study demonstrated that 8 weeks of 20-minute sessions of aerobic exercise on a bicycle ergometer produced some improvement in executive function, working memory, and language (Table 1B, exercise and physical therapies). The study explored dual task performance (combined cognitive and motor tasks), and motor output improved during both single and dual task conditions after training with no apparent benefit in cognitive performance in the dual task condition. This suggests that the effects of dual tasking on cognitive and motor performance require further study.
The effect of exercise on cognition was studied by passive cycling, off medication, using within-patient controls and the Trail Making Test (TMT), parts A and B, as an executive outcome measure. There was an improvement in performance on TMT-B and on TMT-B-A. TMT-A did not improve, suggesting that improvements in cognition are not related to motor function. It was proposed that the effect was due to improved cerebral blood flow.
A study of multimodal group exercise (mostly aerobic) with progressive increments of load and complexity used a single measure of executive function and demonstrated a significant improvement on the Wisconsin Card Sorting Test (WCST) in categories of completed and perseverative errors compared with controls. However, in that study, the control group was not active but was derived from a previous study.
In another controlled study, participants were allocated to an exercise intervention program or to delayed exercise. The active treatment group had twice-weekly, 60-minute sessions for 12 weeks of combined aerobic and resistance exercises compared with a delayed treatment control group. Various cognitive measures were used as outcomes and demonstrated an improvement in the active treatment group compared with controls on tests of verbal fluency, spatial working memory, and possibly semantic fluency. This improvement in cognition was not associated with a benefit for mood or quality of life.
Combined Cognitive and Physical Interventions
An uncontrolled study of a day hospital rehabilitation program of computer-based cognitive (focused on attention, abstract reasoning, and visuospatial abilities) and motor training twice weekly for 6 weeks demonstrated significant improvements in measures of abstract reasoning, visuospatial ability, and verbal fluency that were maintained over 6 months with no improvement in other components of memory, set shifting, or inhibition (Table 1C, combined therapies). There was only limited information on the nature and content of the training intervention and the motor component.
A small study combined treadmill walking with simultaneous processing of virtual reality cognitive challenges using obstacle negotiation in 2 planes and including distracters like changed lighting, moving objects, adjustment in frequency, and size of objects. These tasks demanded a combination of attention, response selection, and processing of visual stimuli. The results showed an improvement in gait speed similar to standard treadmill training with improvement in dual task performance (combined cognitive and motor tasks) and measures of executive function.
A recent RCT compared the effects of Wii-based motor and cognitive training with a control of balance exercises (Wii; Nintendo Company, Ltd., Kyoto, Japan). Both groups received the same amount of timed training, and both received general exercises at the beginning of each session. The primary outcome was the Unified Parkinson's Disease Rating Scale, self-evaluation of activities of daily living (UPDRS-II), and secondary outcomes were balance tests and the Montreal Cognitive Assessment (MOCA). Both groups improved on the UPDRS-II and the MOCA, but there was no difference between groups, indicating no added benefit from the Wii-based training. The nature of the cognitive component of the Wii was not well characterized and difficult to separate from the balance exercises, and there was no other control group.
In a large, complex RCT, the effects of 3 interventions were compared. One group received only cognitive training (intervention A); another group received cognitive training plus transfer training (intervention B); and the third group received a multimodal training consisting of cognitive training, transfer training, and psychomotor training (intervention C). To compensate for the additional training times, interventions A and B included relaxation training and occupational therapy. Cognitive training (intervention A) was individually tailored to cognitive level and deficits at baseline. Training comprised tasks for various cognitive domains with a focus on executive functions. Transfer training (intervention B) included relevant everyday activities (e.g. find the way to the supermarket or prepare a meal). In psychomotor training, aerobic (e.g. Nordic walking) and psychomotor elements (e.g. walking and bouncing or throwing a ball) were combined. The effects of the multimodal intervention C were significantly superior to cognitive training (intervention A) and to cognitive training plus transfer training (intervention B) with regard to overall cognitive functions, verbal long-term memory, tasks of attention, and executive functions (inhibition/set shifting). For planning and problem solving, all intervention groups improved significantly; whereas, in cognitive estimation, only group B and C improved. The multimodal interventions included a very broad spectrum of individualized activities, which were not well standardized, and the compensatory time in relaxation or occupational therapy also was not well standardized. There was no control group without cognitive training.
Brain Stimulation Techniques
A single session of tDCS to the left dorsolateral prefrontal cortex (DLPFC), compared with tDCS to the primary motor cortex or sham stimulation, produced a positive effect on a working memory task for 2-mA stimulation over both control settings (Table 1D, brain stimulation techniques). Two small studies examined the effects of single-session rTMS on cognition using differing sites. In the first study, rTMS to the left DLPFC or the left dorsolateral premotor cortex was compared with a control of rTMS to the left occipital cortex using choice reaction time, verbal fluency, TMT A&B, and digit span as outcomes. That study did not demonstrate significant effects of either procedure. In contrast, a study that used sequential rTMS to the inferior frontal gyri bilaterally compared with sham rTMS demonstrated a significant improvement in the word and color word components of the Stroop test but no change in scores on the Frontal Assessment Battery.
A trial of serial rTMS in PD and depression examined executive function by comparing 2 weeks of rTMS combined with 8 weeks of placebo medication with sham rTMS combined with fluoxetine 20 mg daily. Both treatment groups improved cognitively after the interventions and at 8 weeks, independent of improvement in mood, and a post hoc analysis demonstrated positive effects on executive tests. A placebo-controlled, randomized, double-blind trial that compared 10 sessions of rTMS to the left DLPFC with sham rTMS among patients who had PD with mild-to-moderate depression demonstrated a significant improvement in depression with treatment and a significant improvement in the accuracy of the Stroop test at 1 day and 30 days after treatment but no improvement in MMSE or TMT scores.
Bias and Quality of the Controlled Trials
The results from a domain-based evaluation of 9 CTs are provided in Table 2. Overall, most studies were subject to several forms of potential bias, with the least bias being attributed to 3 RCTs.[40, 48, 49] Randomization was adequately generated in 3 RCTs, and others used convenience sampling or a control group from another study or provided no detailed information on randomization. Because of the nature of the interventions, performance bias was difficult to assess. A blinded examiner was used in 5 studies.[40, 48, 49, 52, 53] Withdrawals and dropouts and other forms of attrition were not described in 3 studies.[38, 39, 43] Reporting bias was difficult to assess in most studies, because there was no independent publication of the study protocols. Only 2 RCTs examined long-term effects.[47, 48] Parallel tests in pretests and post-tests were used in only 2 studies.[38, 39] With 2 exceptions,[43, 47] all studies provided information about medication, and all studies except 1 reported on the affective state at least at baseline, but this was included as a covariate in only 2 studies.[38, 52]
Table 2. Risk of Bias in the Randomized Trials
|Selection bias||Other bias|
|Detection bias||Attrition bias||Reporting bias||Follow-up was examined||Use of parallel test||Medication status is described||Affect is included in examination||Suitable active control|
|Nombela et al. 2011||−||−||−||−||−||?||−||+||+||+||−|
|Paris et al. 2011||+||+||−||+||+||−||−||−||+||+||+|
|Sammer et al. 2006||?||−||−||−||−||−||−||+||+||+||−|
|Cruise et al. 2011||−||−||−||−||+||?||−||−||+||+||−|
|Tanaka et al. 2009||−||−||−||−||−||?||−||−||−||+||−|
|Pompeu et al. 2012||+||+||−||+||+||+||+||−||−||−||?|
|Reuter et al. 2011||+||+||−||+||+||?||+||−||+||+||−|
|Boggio et al. 2005||?||?||−||+||+||+||−||−||+||+||+|
|Pal et al. 2010||?||?||−||+||+||+||−||−||+||+||+|
The level of evidence was agreed, producing 5 studies rated with level “1−” evidence (RCTs with a high risk of bias),[39, 47, 48, 52, 53] and only 1 had “1+” evidence (RCTs with a low risk of bias). In assessing evidence levels, authors also considered the appropriateness of control group interventions and their contribution to possible bias and interpretation of results, producing a downgrading of 2 studies to level 1−.[47, 48]
Effects on Noncognitive Domains
Although they were not the focus of this review, we also looked for reports regarding effects on noncognitive psychological domains. Some studies examined effects on depression,[40, 43, 44] anxiety, activities of daily living, and quality of life as (secondary) outcome measures. For neuropsychological treatment and exercise training, no effects were reported for depression,[40, 43, 44] anxiety, activities of daily living, or quality of life.[40, 44] In 1 combined approach, the only effect observed was an improved quality of life. There was an improvement in depression scores using rTMS in 2 studies[52, 53] equivalent to the improvement observed with fluoxetine.
This unique, collaborative, systematic review demonstrates that, despite the increasing interest and awareness of nonpharmacological therapies for cognitive impairment in AD, there is a lack of high-quality trial evidence in PD. Many studies appear to have positive results particularly for executive functions. However, this needs cautious interpretation, because there is likely to be significant publication bias. There was only 1 positive, small RCT of cognitive training of sufficient quality to warrant a 1+ grading. Although that trial had positive results, the samples were small (16 received cognitive training, and there were 12 controls), and the results require replication. One study of multimodal therapy compared with cognitive training was a complex, large randomized trial in which a spectrum of individualized combined approaches was used. The major limitation of that study was the lack of an active control group without cognitive training, and this made interpretation of the results difficult. The authors believed it was not possible to withhold treatment, because they had “already shown the superiority of cognitive training compared with standard treatment in a previous study,” which had a significant likelihood of bias; and we rated it 1− here. Although use of the Wii in rehabilitation has grown, the evidence base for its use in PD for cognitive training remains poor. Our current review included 1 small, negative (1−) study on the use of the Wii.
Studies have not clarified the role or type of cognitive interventions required and whether interventions should be aimed at those who have no significant impairment, those with MCI, or those with dementia. There is no study on the role of these therapies in PDD. There is a lack of clarity in terminology, and the terms cognitive remediation and cognitive rehabilitation are both used to describe cognitive training. The studies do not consider the wider psychosocial factors or deficits that cause people difficulty in their daily lives. Future studies should clearly describe the active (e.g. cognitive training) and control interventions focused on those cognitive deficits that trouble people with PD.
Studies of exercise in PD have yet to establish the type and dose of exercise required, separate out the social benefits of group therapies, and explore the possible benefits of combining exercise with cognitive training. Future studies should more clearly define the intervention, the dose-response effect, and the type of exercise or training compared with an active control group to control for possible effects of social interaction.
Studies of tDCS and rTMS have reported variable effects on cognition with the RCTs that had mood as the primary outcome. There is no consensus regarding the most suitable format, the number of treatments, stimulation parameters, or site for studying the effects on cognition with tDCS and rTMS in PD. In the future, studies should use standardized interventions and should consider the possibility of combining with other cognitive interventions. These techniques require serial sessions with a qualified technician, and some suggest that the procedure is likely to be burdensome for patients. One small study examined changes in cerebral blood flow as a result of cognitive training, but no study looked at any possible effect of these therapies on disease progression or neuroprotection.
Our review strategy 1 was potentially limited by restricting searches to 10 years, although review strategy 2 was conducted over a longer time and identified no studies outside this period. It is possible that the search terms missed more obscure nonpharmacological interventions, although the terms were based on the best available published evidence in AD. The exclusion of deep brain simulation or surgery may have missed significant treatment effects, but these treatments require separate review. The collaborative approach using 2 search strategies overcame some of the potential individual limitations of each strategy. The use of numerical grading for evidence levels has been criticized by Cochrane, although it is used by NICE; however, we believe that the use of combined bias and evidence levels makes the level of evidence in this field more understandable for clinicians.
Overall, studies lack sufficient numbers and power, clear randomization methods, blinding of assessors, active control groups, clearly defined cognitive outcomes, follow-up of the sustainability of the effect, and translation into everyday function. Analyses often did not include dropouts, and future studies should include an intention-to-treat analysis. Active control groups using noncognitive-based therapies are needed to account for psychosocial effects. It would be useful to separate the effects of interventions on executive function from those on more posterior cortical functions, because the latter may be more predictive of the development of PDD. Future studies should measure executive functions using clear, standardized assessments and interpretations. The possible added and confounding effect of nonpharmacological treatments on depression and anxiety needs to be considered in future studies. Agreed criteria should be used to define MCI for studies. Studies should focus on the cognitive difficulties experienced by people with PD in their daily lives, and studies specifically in PDD are needed. The potential added benefit from combining nonpharmacological and pharmacological interventions, such as cholinesterase inhibitors, requires further study. The possible neuroprotective effect of nonpharmacological therapies, particularly exercise, would be an innovative addition to future trials. Cost effectiveness has not been assessed in any of the studies and must be an outcome in future trials. The structure, conduct, and reporting of future randomized trials in PD should follow the Consolidated Standards of Reporting Trials (CONSORT) statement for trials of nonpharmacological treatments.
In conclusion, although current research on nonpharmacological therapies for cognitive dysfunction in PD is very limited, it is at a point at which further study is highly relevant, given the impact of cognitive dysfunctions on people with PD and caregivers and the costs of care. It is important that enthusiasm for nonpharmacological therapies does not override scientific rigor in constructing future RCTs. Thus, there is an urgent need for rigorous RCTs of nonpharmacological, noninvasive treatments for cognitive impairment and dementia in PD.
We are grateful to the editor Professor Obeso for his constructive feedback. We also are grateful for the comments and advice of our colleagues in Bangor University, UK, Dr. Martyn Bracewell (School of Medical Sciences) and Dr. Jeanette Thom (School of Sports Health and Exercise Science). We thank our colleagues in Cologne, Germany, MSc Psy Julia Rahe, MSc Psy Stephanie Kaesberg, and MSc Psy Jan Rosen (Institute of Gerontology and Center for Neuropsychological Diagnostics and Intervention [CeNDI], University of Vechta) as well as MSc Psy Katrin Müller and Prof. Dr. Josef Kessler (Department of Neurology, University Hospital of Cologne) for their very helpful comments on the manuscript.
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.
J.V.H.: 1A, 1B, 1C, 2A, 3A
A.P.: 1A, 1B, 1C, 2A, 3A
L.C.: 1A, 1B, 1C, 2A, 3B
E.K.: 1A, 1B, 1C, 2A, 3B
Financial Disclosures: John V. Hindle has received honoraria from Teva-Lunbeck, GSK, and Boehringer; research grants from the Economic and Social Research Council, the Biotechnology and Biological Sciences Research Council, National Institute for Health Research, Parkinson's UK, the East Kent National Health Service (NHS) Foundation Trust, North Wales NHS Trust, and the National Institute for Social Care and Health Research; and royalties from Radcliffe and Arnold Publishing. Annette Petrelli serves on the Advisory Board of Novartis Pharmaceuticals. Linda Clare has received research grants from the Economic and Social Research Council, the Medical Research Council, the National Institute for Health Research, and the National Institute for Social Care and Health Research and has received royalties from Pearson, Psychology Press, and Wiley. Elke Kalbe is on the Novartis Advisory Board, has received honoraria from Novartis, and has received research grants from the German Federal Ministry of Education and Research (BMBF).
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