Table 6.
Cognitive outcomes – Efficacy.
| Study | Country | Cognition tools to diagnose for study inclusion, assessment measures to prescribe treatment | Cognitive efficacy measures, global cognitive function, executive function & attention, memory | Pre-test/Baseline IG mean (SD) CG mean (SD) | Post-test(s) IG mean (SD) CG mean (SD) | Control group activity | Outcomes |
|---|---|---|---|---|---|---|---|
| Arkin (2007) | USA | MMSE; CERAD (7 tests); structured clinical interview; dementia stage determined via CDR; WAIS-R (Picture Completion, Comprehension, and Similarities). Confirmatory diagnostic neurological exam by head of the University of Arizona, Department of Neurology. | CERAD (60 Second Verbal Fluency –category animals; 15-Item Boston Naming, MMSE, Sum of Boxes, Word List Memory, Word List Recall, Constructional Praxis, Word List Recognition); WAIS-R (Picture Completion, Comprehension, and Similarities) | 1 Year Completers – AD Rehab: MMSE (N = 4) IG 23.4 (4.0) CERAD CG MMSE values not given | 1 Year Completers: AD Rehab: MMSE (N = 4) IG 20.5 (5.3) CERAD CG MMSE values not given | Comparison group was a matched group from the CERAD database of untreated AD patients from 1986–1994. | Significant annual decline on MMSE occurred for all cohorts except 4-yr completers; Mean annual decline: 2.9 points for 1-yr completers (n = 24), 2.5 for 2-yr, 2.0 for 3-yr, and 1.0 for 4-yr. Only 42% of the CERAD group (n = 245) had an average annual rate of decline of less than 3 points on the MMSE. This 8% difference was statistically significant (p = .02). There was no significant between-yr decline on 5 or 6 tests of global and cognitive functioning after 2 or more semesters of participation. |
| Bredesen et al. (2016) | USA | MMSE, MoCA, MRI, FDG PET scan, ApoE genotype, online quantitative neuropsychological testing (Brain HQ); extensive metabolic testing such as fasting insulin, haemoglobin A1c, HLADR/DQ, C4a and TGF-β1, anti-thyroglobulin antibodies, anti-thyroid peroxidase antibodies, homocysteine. | MMSE, MRI, MoCA, FDG PET scan, quantitative neuropsychological testing w Neuroquant & Neuroreader, California Verbal Learning Test, Stroop colour test, immediate and delayed recall, semantic knowledge, executive function, processing speed, MFI (phagocytosis index) | P2 FDG PET: Early AD; CVLT-IIB 3rd percentileP6 MMSE 23 MFI = 230P7 MMSE 22P9 MoCA 19 | P2 FDG PET: Early AD; CVLT-IIB 84th percentileP6 MMSE 30MFI >1000P7 MMSE 29P9 MoCA 21 | No control group | P2 – Marked subjective and quantitative neuropsychological testing improvement, decline halted; business reinvigorated, a new business site was added (follow-up 24 mos) P6 – Subjective improvement, MMSE 23->30; MFI >1000 (12 mos) P7 – Subjective improvement, MMSE 22->29 (10 mos) P9 – Clear subjective improvement, modest objective improvement MoCA 19->21 (3 mos) |
| Burgener et al. (2008) | USA | Confirmed diagnosis of irreversible dementia (AZD, Lewy body, vascular, frontal lobe, or mixed dementia); a score <2.0 on the CDR indicating an early to early-middle disease stage. | MMSE; Baseline, 20 and 40 wks. | BaselineIG 24.8 (3.5) CG 22.9 (5.2) | 20 wksIG 25.2 (3.1) CG 22.4 (7.6) 40 wksIG 25.2 (2.4) | Attention-controleducational programmes; delayed 20 wks treatment | Treatment group showed improved cognitive functioning following the 20 wks intervention; Significant differences in MMSE scores was evident for treatment group subjects (+0.4), whereas for control group subjects the scores declined over the first 20 wks of the intervention (−0.5). |
| Christofoletti et al. (2008) | Brazil | MMSE, Brief Cognitive Screening Battery; primary diagnosis of dementia based on ICD-1011 Classification of Mental and Behavioral Disorders; Katz Activities Daily Living Scale | Baseline and 6 mos – MMSE, Brief Cognitive Screening Battery including the Semantic Verbal Fluency Test and the Clock Drawing Test. | IG:1 MMSE18.7 ± 1.7IG:2 MMSE12.7 ± 2.1CG MMSE14.6 ± 1.2 | IG:1 MMSE20.2 ± 1.6IG:2 MMSE14.9 ± 2.2CG MMSE14.8 ± 1.3 | IG:2 – only physiotherapy CG: No motor intervention | MANOVA did not indicate benefits on the cognitive functions between IG:1 and CG (F = 1.1, p > 0.05) and groups IG:2 and CG (F = 1.6, p > 0.05). Univariate analysis indicated some benefits of IG:1 on two specific domains measured by the BCSB (F = 26.5, p < 0.05; F = 4.4, p < 0.05). Global cognition did not improve through treatment, but an attenuation in the decline was observed on two specific cognitive domains. |
| Coelho et al. (2013) | Brazil | Diagnosis of AD according to international criteria Diagnostic and Statistical Manual of Mental Disorders 4th edition APA; a clinical and neuropsychological evaluation carried out by a trained team; CDR was used for the classification of dementia severity; MMSE. | MMSE (IG 19.5 ± 4.1; CG 19.0 ± 2.9) Frontal Assessment Battery, Clock Drawing Test, Symbol Search Subtest | IG FAB total8.6 ± 3.6CG FAB total9.9 ± 3.8 | IG FAB total13.3 ± 3.5CG FAB total8.6 ± 4.4 | Kept to their samedaily routine and did not participate in any regular orstructured exercise programs | Favourable effects on frontal cognitive function in AD patients after the 16-wks period. Frontal Assessment Battery (p < .001) and Symbol Search Subtest (p < .001); significant improvements in abstraction, organization, motor sequencing and attention. The control group worsened significantly in frontal cognitive functions, particularly in planning, organization and motor sequencing. The control group decreased the scores in the Clock Drawing Test (p = .001) and increased the number of counting errors during the dual task (p = .008) after the same period. |
| Graessel et al. (2011) | Germany | Primary degenerative dementia according to ICD-10; <24 on MMSE; confirmed by physician. | Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog); Baseline and 12 mos | ADAS-Cog subscale IG 32.6 ± 11.5CG 35.6 ± 14.8 | 12 mos IG 32.5 ± 15.3CG 40.8 ± 17.0 | Treatment as usual | Cognitive function and the ability to carry out activities of daily living had remained stable in the intervention group but had decreased in the control patients (ADAS-Cog: adjusted mean difference: −7.7, 95% CI −14.0 to −1.4, p = .018, Cohen’s d = 0.45; E-ADL test: adjusted meandifference: 3.6, 95% CI 0.7 to 6.4, p = .015, Cohen’s d = 0.50). The effect sizes for the intervention were greater in the subgroup of patients (n = 50) with mild to moderate disease (ADAS-Cog: Cohen’s d = 0.67; E-ADL test: Cohen’s d = 0.69). |
| Han et al. (2017) | Korea | Diagnosed with DSM-IV criteria; all patients had a Clinical Dementia Rating (CDR) of 0.5 or 1. | MMSE and ADAS-Cog assessed treatment effects on cognitive function; all outcome measures administered at weeks 0, 9 and 21. | MMSE20.18 ± 4.75ADAS-Cog21.85 ± 9.51 | MMSE20.89 ± 5.36ADAS-Cog20.41 ± 9.66 Change within-group: MMSE0.71 ± 2.27ADAS-Cog−1.44 ± 3.73 | MT – Mock Therapy: health videos, gymnastics exercises, conversing, recreation | In the MCET group, 58.3% and 70.0% of subjects showed improvement in MMSE (effect size = 0.47, p = .013) and ADAS-Cog scores (effect size = 0.35, p = .045), respectively, whereas, in the Mock Therapy group, significantly fewer subjects showed improvement. For the dementia subgroup MCET was more beneficial than MT in global cognitive function measures: the effect between MCET versus MT was 0.71 ± 2.27 versus −0.03 ± 2.78 for the MMSE and −1.44 ± 3.73 vs. −0.21 ± 3.92 for the ADAS-Cog. |
| Ibarria et al. (2016) | Spain | Diagnosis of Probable or Possible AD according to the (NINCDS-ADRDA) criteria; mild to moderate severity of dementia, with a Clinical Dementia Rating (CDR) staging of 1 to 2 and a Global Deterioration Scale (GDS) staging of 4 to 5 | MMSE and ADAS-Cog Baseline, 3, 6, 9 and 12 mos follow-ups | MMSE19.60 (.33 SE) ADAS-Cog25.63 (.59 SE) | MMSE3 mos 19.66 (.30 SE) 6 mos 19.19 (.31 SE) 9 mos 18.63 (.34 SE) 12 mos 17.54 (.35 SE) ADAS-Cog3 mos 25.48 (.58 SE) 6 mos 26.03 (.62 SE) 9 mos 27.18 (.60 SE) p < .0512 mos 29.19 (.67 SE) p < .05 | No control group | Patients remained cognitively stable (MMSE/ADAS-Cog) for at least 6 mos and significantly worsened at 9 and 12 mos follow-ups. The mean annual changes were MMSE (2.06) and ADAS-Cog (3.56) points. 42.7% of patients maintained or improved global cognitive scores between baseline and 12-mo follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 vs. 74.7 yrs). |
| Kang et al. (2010) | Korea | Researchers and RAs conducted cognitive function tests on participants and chose those with MMSE-K ≤23. | Korean MMSE | IG MMSE-K17.78 (14–23) CG MMSE-K21.42 (15–26) | IG MMSE-K22.03 (17–29) CG MMSE-K16.69 (16–25) Change within group: MMSE-KIG 3.00 (0–7) CG −1.00 (−5–7) | Dementia prevention education & consultations | Median cognitive function score in the IG increased from 17 at pre-test to 23 post-test. Cognitive function is greater in the control group and drops over time (21–16), experimental group is lower at the start and increases (17–23) |
| Kim et al. (2016) | Korea | Diagnosis of AD by a neurologist; moderate to severe AD as determined by a baseline MMSE score of ≤20 | ADAS-K; MMSE; CDT; Baseline and 6 mos | MMSEIG 13.4 (±4.2) CG 16.6 (±4.0) (Post-test MMSE scores not given) | Graph Figure 2. P 228. Change scores – MMSE did not show significant improvementbetween groups (F = 0.00, p = .98) | No placebo control, this comparator group received only the MCP (essentially 2 IGs) | There were significant within-group differences for the ADAS-Cog score but not for the MMSE. No cognitive measures improved significantly after 6 mos in the KEP + MCP group compared to MCP group however the ADAS-Cog score was significantly lower between the two groups in secondary analysis adjusted for baseline value, age, sex, and education yr. ADAS-Cog score was significantly lower after 6 mos in the KEP+MCP group than in the MCP group (F = 5.20, p = .03). |
| La Rue et al. (2015) | USA | Physician’s diagnosis of ADRD or Dementia Questionnaire results consistent with probable ADRD and GDS ratings of 3 (mild cognitive impairment to very mild dementia) or 4 (mild dementia). | MMSE, CERAD, WAIS-R, ABCD at baseline and 1st follow-up (11 mos) & 2nd (20 mos) | MMSE N = 28 with 1 follow-up (11 mos): 22.46 (5.07) N = 7 with 2 follow-ups: 23.57 (4.08) | N = 28 1st follow-up: 22.64 (5.48); (71% Same or improved) N = 7 1st follow-up: 25.43 (2.51) N = 7 2nd follow-up: 22.57 (4.79) | No control group | Participants generally remained stable in cognitive function through 1st follow-up (11 mos.) The modal change in the MMSE was a 1-point improvement, and there was no significant change in mean MMSEscores (t = 0.35, df = 27, p = .731, 95% CI = −0.99 to 1.23). N = 7 completed 2nd follow-up (avg 20 mos) performing near baseline levels for cognition – relative stability at nearly 2 yrs. No statistically significant differences between baseline scores and 2nd follow-up on measures of cognition (physical fitness, or well-being) (p ≥ .15). |
| Li and Li (2017) | China | Screened by researchers using CDR >0.5 and MMSE (cut-off score for cognitive impairment was corrected for education: ≤19 for illiterate, ≤22 for primary education, ≤26 secondary education or higher); Physician-diagnosed dementia | MMSE | MMSE IG 14.58 (±5.59) CG 14.48 (±4.40) | MMSEIG 17.00 (±4.03) CG 13.05 (±5.48) | Routine care without any special intervention | For the experimental group, the scores of MMSE and BI had a statistically significant increase after 16 wks (p < .01). Control group, the mean score of MMSE decreased significantly (p < .01) |
| Maci et al. (2012) | Italy | Diagnosis of AD made according to the diagnostic criteria proposed by NINCDS-ADRDA for probable or possible AD; Inclusion criteria: MMSE score 16–24 Mild to Moderate AD | MMSEFAB – Frontal Assessment Battery assessing executive functions (values corrected for age and education); CDR assessing severity of dementia | MMSEIG 17.5 ± 2.7CG 18.2 ± 2.9FAB IG 8.9 ± 2.8FAB CG 7.9 ± 1.9 | 3 mos: MMSEIG 17.3 ± 3.3CG 17.0 ± 2.7FAB IG 9.9 ± 3.1FAB CG 6.9 ± 1.6 p < .05 | Usual activities at home | No significant changes in cognitive performances were observed; participants submitted for 3 mos to the stimulation protocol exhibited a good stability of their cognitive condition; FAB scores rose 1 point in the IG and dropped 1 point in the CG. The MMSE also lowered 1.2 points in controls who displayed a worsening of cognitive abilities. |
| Onor et al. (2007) | Italy | Diagnoses according to the criteria of the DSM-IV and the NINCDS-ADRDA | Milan Overall Dementia Assessment (MODA) was administered at baseline (T0) and after 4 months (T2) of rehabilitation to assess cognitive function. | MMSE T0 – IG 23.12 ± 4.15T0 – CG 20.00 ± 2.20MODA ΔT0–T2IG –0.28 ± 14.17 CG –2.08 ± 10.72 | MMSE 2 mos/4 mosT1 – IG 23.62 ± 4.92 CG 21.25 ± 3.01T2 – IG 24.37 ± 4.30 CG 21.25 ± 2.76 | 8 patients and 8 caregivers in thecontrol group received no form of intervention | No within group difference in MMSE between T0 and T1 and between T0 and T2. A significant difference was found between T1 and T2 (t = −2.393; p = .048). Comparison between CG & IGs: no differences in MMSE scores. MODA results: Comparison between groups and Δ – cognitive performance remained stationary. Multimodal programme had only limited efficacy, maybe due to short duration of the rehabilitation programme. |
| Oswald et al. (2007) | Germany | No cognitive inclusion criteria for participation in the study. MMSE score of >10 or <10 determined assignment to a specific cognitive activation programme | SISCO SIDAM, MMSE, Subtests of the NAI: Number Connection Test ZVT-G + Memory Span ZN-G; picture Test BT. External rating questionnaire administered to nursing staff on residents cognitive performance; Baseline, 6, 12 mos | IG t0 mean s21.80 (5.60) CG21.53 (5.36) | IG t12mean s 21.18 (7.35) CG 17.77 (9.01) | Treatment as usual | Both the MMSE and the SISCO score, a global measure of cognitive performance/impairment, indicate that the general cognitive status of IG participants remained stable, whereas that of CG members deteriorated significantly (p = .001). There was a significant improvement in memory skills that involve dynamic encoding (picture test) in the IG. Nursing staff perceived residents to be more independent in everyday life and to show higher levels of psychological well-being and mental alertness. |
| Prokopov (2010) | Spain | MRI, detailed biomedical history and lifestyle investigation; suffered mental decline for about 1 yr; declining memory, low energy, low-quality sleep; loss of interests/motivations; could no longer conduct her usual activities and home chores; could not hear without a hearing aid; past medical history of moderate hypertension. | MRI, ongoing biomedical monitoring, lifestyle monitoring | Brain magnetic resonance imaging (MRI) in February 2008 showed hippocampal and cortical atrophy, enlarged volume of ventricles. | MRI April 2009showed no degenerative changes. | No control group | Improvement in mood and vitality was noticeable after the first 5 IHT sessions. Gradually, the mental and cognitive state recovered. Patient reported increased energy and activity, better memory and cognition, a slight weight loss, improved sleep, and better mood. The patient gradually recovered her healthy mental state; resumed shopping and cooking and began playing piano again, which she was not capable of doing the previous year. Only needs the hearing aid for a few hours a day, compared to the whole-day use several months before. |
| Raggi et al. (2007) | Italy | Patients with probable AD (mild to severe) diagnosed by a senior neurologist (DSM-IV criteria), CDR, cognitive status MMSE, a structured medical history collected from the patient and the primary caregiver, a neurological examination, routine laboratory analyses, a neuropsychological assessment and neuroimaging studies consistent with an AD diagnosis. Basal assessment by a staff nurse, psychologist and education specialist. | MMSE | MMSE at admission16.06 (SD 5.60) | MMSE at discharge17.54 (SD 6.45) | No control group | The mean MMSE scores at admission and discharge were respectively 16.06 and 17.54 (Wilcoxon Ranks Test: p = .005). Authors contribute the beneficial effect to continuous stimulation, positive group feeling secondary to the programme (ROT) development, and socialization. |
| Serdà i Ferrer and del Valle (2014) | Spain | Neuropsychological diagnosis of AD at any stage of the pathology confirmed by a medical practitioner based on the results of the MMSE and in accordance with standard international diagnostic criteria. | MMSE | MMSE14.65 (SD 5.68) | MMSE13.59 (SD 6.60) | No control group | Results show a significant reduction in cognitive capacity (p < .001). |
| Tay et al. (2016) | Singapore | Diagnosis of early dementia in accordance with the DSM-III-R. | Locally validated Chinese Mini-Mental State Examination (CMMSE) for evaluation of cognitive performance at T0 and at the end of each 8-wk cycle. | CMMSE17.2 ± 4.8 | CMMSE After MINDVital – 119.2 ± 3.9After MINDVital – 219.0 ± 4.1 | No control group | Significant improvements in dual-task walking in early dementia, which may be contributed by improvement in cognitive performance, as single-task gait performance remained stable. Improvement in cognitive performance on CMMSE was evident following the first cycle of MINDVital and sustained through the second cycle, with an estimated 0.9 point improvement in the CMMSE score following each MINDVital cycle (random effects coefficient (SE) of MINDVital cycle on CMMSE = +0.90 (0.31), p = .003)). |
| Vicente de Sousa et al. (2017) | Portugal | Outpatients with AD from the geriatric department of a psychiatric hospital were recruited to the IG and CG. A second IG recruited on a convenience basis from an AD day care center is of interest: NSPRG. | Baseline psychomotor performance scores, clock drawing test (CDT) and MMSE; Follow up at 21, 90 and 180 days (6 mos) | MMSENSPRG 19.3 (5.4) CG 20.0 (4.9) | MMSE 21 days: NSPRG 18.0 (6.6) CG 20.0 (4.9) 90 days: NSPRG 18.0 (6.6) CG 20.0 (4.9) 180 days: NSPRG 17.6 (8.4) CG 20.0 (4.9) | Standard dietetic advice | Cognitive status baseline to 21 days a slight decrease in the MMSE score was observed in the NSPRG −1.2 (3.1) and also on the 180th day of follow-up –1.7 (5.1) p < .05. This compares to the control group showing no declines from baseline 20.0 (4.9). The compliance with the ONS and to the psychomotor rehabilitation programme was excellent, without any refusals or dropouts in both intervention groups, the NSG and the NSPRG. |
| Viola et al. (2011) | Brazil | Diagnoses according to NINCDS-ADRDA; a score of 0.5 or 1.0 in the CDR, a score of 16 or more in the MMSE and concomitant standard pharmacological treatment for AD (cholinesterase inhibitors and/or memantine in stable therapeutic doses for at least 3 mos). | MMSE, Short Cognitive Test (SKT) pre- and post-treatment | MMSEIG 22.6 (2.9) CG 23.3 (3.9) SKT total scoreIG 14.5 (5.4) CG 12.6 (5.4) | MMSEIG 22.5 (3.8) p = .9CG 22.4 (2.8) p = .1SKT total scoreIG 14.6 (6.1) p = .9CG 13.8 (5.5) p = .05 | Standard outpatient care with monthlyfollow-up visits to the memory clinic. Wait list for future intervention group | Paired-sample t tests addressing within-group differences (baseline vs. endpoint) in test scores showed that patients in the control group had a tendency for cognitive decline, which was indicated by a slight, but significant, increase in total SKT scores and in the attention SKT subscore (i.e., higher scores in the SKT mean worse performance). Conversely, patients in the experimental group remained stable with respect to these cognitive measures of attention and global performance. |
| Yoon et al. (2013) | Korea | MMSE-K | DSF; DSB; 7MS; MMSE-K | MMSECAE 18.0 ± 1.5CA 18.7 ± 1.2 (MMSE post-test not given) | Within group post-preDSF CAE −2.1 ± 1.1 CA −1.2 ± 1.2DSB CAE −0.9 ± 0.5 CA −0.2 ± 0.47MST CAE 10.8 ± 8.4 CA 4.3 ± 5.0 | 2 group design (CA & CAE) no control | Working memory performance (DSF, DSB 7MST scores) improved significantly in the CAE group (p < .05). There were significant beneficial effects of the therapeutic programme on memory performance in the CAE group compared to CA group, and between pre-test and post-test. After the 12-wks intervention, the CAE group showed significant improvement compared to the CA group in all the measures studied. |
ABCD: The Arizona Battery for Communication Disorders of Dementia; ADAS-Cog: Cognitive subscale of the Alzheimer’s Disease Assessment Scale (scoring range 0 to 70, higher scores indicate greater cognitive impairment); ADAS-K: Korean version of Alzheimer’s Disease Assessment Scale; BCSB: Brief Cognitive Screening Battery; CERAD: Consortium to Establish a Registry for Alzheimer’s Disease; CDR: Clinical Dementia Rating; CDT: Clock Drawing Test; CMMSE: Chinese Mini-Mental State Examination; CVLT: California Verbal Learning Test; DSB: Digit Span Backward; DSF: Digit Span Forward; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; GDS: Global Deterioration Scale; KADLS: Katz Activities Daily Living Scale; MDRS: Mattis Dementia Rating Scale; MFI: phagocytosis index; MMSE: Mini Mental State Examination; MMSE-K: Korean version of the Mini Mental State Examination; MoCA: Montreal Cognitive Assessment; MODA: Milan Overall Dementia Assessment; NAI: Neuropsychological Aging Inventory; NINCDS-ADRDA: National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and Related Disorders Association; SISCO SIDAM: a global measure of cognitive performance/impairment; SKT: Short Cognitive Test; TMT: Trail-Making Test; WAIS-R: Logical Memory subtest of the Wechsler Memory Scale – Revised; 7MST: 7-Minute Screening Test; SD: standard deviation (given except where ‘SE’ is specified); SE: standard error.