A randomised pilot study to assess the efficacy of
an interactive, multimedia tool of cognitive

stimulation in Alzheimer’s disease
L Tárraga, M Boada, G Modinos, A Espinosa, S Diego, A Morera, M Guitart, JBalcells, O L López and J T Becker 2006;77;1116-1121; originally published online 4 J. Neurol. Neurosurg. PsychiatryJul 2006; doi:10.1136/jnnp.2005.086074 Updated information and services can be found at: Data supplement
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J Neurol Neurosurg Psychiatry 2006;77:1116–1121. doi: 10.1136/jnnp.2005.086074 Objective: To determine the usefulness of an interactive multimedia internet-based system (IMIS) for the cognitive stimulation of Alzheimer’s disease.
Methods: This is a 24-week, single-blind, randomised pilot study conducted on 46 mildly impaired . . . . . . . . . . . . . . . . . . . . . . .
patients suspected of having Alzheimer’s disease receiving stable treatment with cholinesterase inhibitors (ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20-min sessions of IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcome measures were: Mini- Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the Rivermead Behavioral Memory Test story recall subtest.
Results: After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the ADAS-Cog and MMSE, which was maintained through 24 weeks of follow-up. The patients treated with IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after 24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of Accepted 20 June 2006Published Online First Conclusion: Although both the IPP and IMIS improved cognition in patients with Alzheimer’s disease, the IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for . . . . . . . . . . . . . . . . . . . . . . .
Alzheimer’s disease is the most frequent form of Despitetheprogressivenatureofthedegenerativeprocess, dementia in elderly people,1 2 and its current treatment patients with Alzheimer’s disease also seem to retain the includes cholinesterase inhibitors (ChEIs),3–5 and N- physiological capacity to alter brain structure and function.
methyl-D-aspartate receptor blockers (eg, memantine).6 Recent studies have shown cognitive plasticity and learning However, symptomatic treatment often entails non-pharma- potential not only in patients with Alzheimer’s disease but cological treatments as well, and adequate dementia manage- also in healthy elders.22 23 Positron emission tomography ment requires a wide range of intervention to help maximise studies that used activation paradigms24 25 have found that the patient’s independence, increase their self-confidence people with Alzheimer’s disease have a greater activation and relieve burden to the care giver.
than those without dementia in the brain regions usually Current symptomatic treatment of Alzheimer’s disease can associated with memory tasks, as well as in the frontal lobes improve cognition and functionality.3–6 However, before the that were activated only with increasing difficulty of tasks.
emergence of these drugs, non-pharmacological treatments Pathological studies conducted on biopsy specimens of had already been evaluated and cognitive stimulation had patients with Alzheimer’s disease with mild or moderate been found to be potentially beneficial for patients with dementia have shown increased synaptic contact size.26 Thus, dementia.7–9 Although these non-pharmacological treatments the brain may be able to compensate during the early stages do not always seem efficacious, methodological problems of Alzheimer’s disease, suggesting that there may be some may limit the validity of some studies.10 A recent Cochrane utility to non-pharmacological adjunctive interventions.
review11 emphasised caution when interpreting the results of Although studies on cognitive stimulation show that it is non-pharmacological treatments, but suggested that certain possible to stimulate the memory of patients with Alzheimer’s cognitive domains could, in fact, benefit from these types of disease, the results are often modest. Because of methodolo- gical limitations, there is a need to conduct more randomised- Clinical and laboratory studies have shown that mental controlled trials with larger samples to validate this therapeutic and physical activity can positively influence cognition in approach. Computerised systems27 and internet-based distance normal elderly people and people with dementia. Education12 programs offer one potential mechanism by which non- and lifestyle choices (eg, occupation and leisure activities)13–15 pharmacological cognitive stimulation can be conducted in can modulate the risk of developing dementia, and psycho-motor stimulation improves cognition in patients withAlzheimer’s disease.16 17 Environmental enrichment can Abbreviations: ADAS-Cog, Alzheimer’s Disease Assessment Scale- Cognitive; BNT, Boston Naming Test; ChEIs, cholinesterase inhibitors; improve cognition in transgenic mice.18 19 Despite the GDS, Global Deterioration Scale; IMIS, interactive multimedia internet- continued deposition of b-amyloid, exercise can increase based system; IPP, integrated psychostimulation program; MMSE, Mini- the levels of brain-derived neurotrophic factor20 and may Mental State Examination; RBMT, Rivermead Behavioral Memory Test; Multimedia tool of cognitive stimulation in Alzheimer’s disease patients with dementia. In this study, we evaluated an N Experimental group: These patients received the IMIS, as interactive multimedia internet-based system (IMIS) as an adjunct to ChEI treatment and classic psychostimulation N IPP control: These patients received IPP and ChEIs.
N ChEIs control: These patients received only ChEIs.
The ChEIs group comprised of patients who were diagnosed with Alzheimer’s disease, but who were living at Forty six patients suspected of having Alzheimer’s disease28 home, and never received the IPP or the IMIS. These patients were recruited for the study through a referral clinic and either did not want to come to the daycare centre, although they agree to be followed clinically, or were on a waiting list `ncies Aplicades, Barcelona, Spain). The Institut for admission to the daycare centre. The experimental and `ncies Aplicades is a referral diagnostic the IPP control groups were participants in the daycare clinic for community-dwelling people with dementia, and centre, and the only difference between these two groups was also provides adult daycare services to these patients. All of that the experiment group received the IMIS. Written the patients had been treated with ChEIs for at least 1 year informed consent was obtained from all the participants before inclusion to the study. The inclusion criteria were: enrolled in the study and their legal representative before the Three patients in the experimental group dropped out of the study: one because of rapid progression of the disease and a Mini-Mental State Examination (MMSE)29 30 score two because of institutionalisation. Consequently, from the initial sample of 46, 43 patients completed the study: 15 in N a Global Deterioration Scale (GDS)31 score of 3 or 4; the experimental group, 16 in the IPP control group and 12 in N absence of uncontrolled disruptive behaviours (eg, aggres- sion, delusions, hallucinations and agitation) that couldinterfere with program administration and/or neuro- These patients received the IMIS, IPP and ChEIs.
N absence of major depression, current or partial remission32;N absence of structural lesions in the computed tomogram or These patients received IPP and ChEIs.
N absence of history of alcohol or other substance abuse; and N absence of severe auditory, visual or motor deficits that may interfere with cognitive testing.
No significant differences were observed between the groups in terms of age (F2,41 = 0.72) or level of education None of the participants had previous experience with a (x2 = 5.513, df = 4, p = 0.239). There was a tendency for a personal computer and all attended the daycare centre difference in the proportion of male patients, primarily 5 days/week. Participants were allowed to be on stable doses because all the patients in the ChEI group were female; however, the difference was not significant (x2 = 5.70, df = 2,p = 0.06).
Patients were assessed at study entry, and after 12 and The IMIS was conducted using Smartbrain (http://www.
24 weeks of treatment. The primary outcome measure was, an interactive multimedia tool that allows the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS- patients to carry out a variety of different stimulation Cog) section.33 This is a standardised measure of cognitive programs, at different levels of difficulty and at various function that examines components of memory, language, times during the day. Briefly, the IMIS program consists of 19 visuoconstructional and ideational praxis, and orientation.
separate ‘‘tasks’’ or stimulation exercises across the domains High ADAS-Cog scores indicate worse performance. The of attention, calculation, gnosis, language, memory and orientation. All participants began at the lowest level of N MMSE: This is a global measure of cognitive function that difficulty (first of 15 levels) and the program monitored examines orientation to time and place, immediate and activity at each level. Difficulty increased automatically after delayed recall of three words, attention and calculation, three consecutive performances within a single task without language and visuoconstructional functions.
error, or when a patient was 80% correct over six consecutive N Syndrom Kurztest (SKT)34: This is a short cognitive perfor- sessions. A patient’s level of difficulty decreased when his or mance test that examines memory and attentional her performance fell below 15% correct for three consecutive sessions or ,20% correct for six consecutive sessions. All patients were trained before the study with the use of the Boston Naming Test (BNT)35: Patients must name 60 large computer mouse, especially on how to ‘‘click and drag’’.
ink drawings that are presented to them by the examiner.
Table 1 Demographic characteristics of the patients The IPP is a daily program in the daycare centre that includes cognitive stimulation tasks, workshops (eg, music therapy, art and crafts, and physical activity) and reinforcement of instrumental activities of daily living.17 The IPP is integrated into the daycare centre activities, and it takes 2 h in the morning and 1.5 h in the afternoon out of the 8 h that the Each patient was randomly assigned to one of three study ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram.
The test is discontinued after eight consecutive failures.
differed from each other on the MMSE (D-lysergic acid When the patient fails to name the drawing, the examiner diethylamide test, p,0.05). After 24 weeks, group differences provides a semantic cue; if still unable to name the were still apparent on the ADAS-Cog (F2,42 = 3.08, p = 0.06, drawing, a phonemic cue is provided.
N Verbal fluency: This includes letter generation (letter P) and Reanalyses showed that the experimental group was better than the ChEI control group on the ADAS-Cog (p,0.05), N The story recall subtest from the Rivermead Behavioral Memory whereas the experimental and IPP control groups differed Test (RBMT)36: Patients listen to a short passage of a prose from the ChEIs control group on the MMSE (p,0.05; fig 2).
being read aloud and then recall as much as they can.
There was no significant change in SKT scores over 24 weeks Rapid Disability Rating Scale—2 (RDRS-2)37: This is an assessment of three functional and behavioural areas: Measures at week 12 and 24 are shown as compared with (a) help with activities of daily living, (b) degree of disability, and (c) degree of special problems (ie, mental No significant differences were observed in the functional confusion, uncooperativeness and depression). The RDRS-2 assessments, as measured by the RDRS-2 at baseline was administered at baseline and at 24-week follow-up examination (experimental group mean: 26.6 (SD 0.96), IPP control: 27.3 (0.93), ChEI control: 24.4 (1.0); F2,42 = 2.16, GDS31: This is a staging system of seven distinguishable p = 0.12, r = 0.32), or after 24 weeks of follow-up (experi- cognitive and functional stages, ranging from normal mental group: 25.3 (1.1), IPP control: 25.6 (1.0), ChEI (stage 0) to severe dementia (stage 7). All patients in the control: 23.7 (1.2); F2,42 = 0.76, p = 0.47 , r = 0.14). The GDS stage was 4 in all patients at baseline and in all follow-upevaluations.
The primary and secondary outcome measures were Figure 3 shows the mean difficulty level obtained by the administered to all participants in the experimental and IPP patients over the course of the 24 weeks of treatment in each control groups at all visits. Owing to manpower limitations, of the six cognitive domains of the IMIS. Performance in all the BNT, verbal fluency tests and RBMT (all secondary cognitive domains showed an improvement, but most outcome measures) were not administered to the ChEI especially in the measures of attention and memory. In no case did a patient’s performance level for any individualactivity actually decline over the course of the 24 weeks.
INTERACTIVE MULTIMEDIA INTERVENTIONPatients in the experimental group received a total of 72 IMIS sessions, three times a week for 24 weeks. All of the patientsin the experimental group had the same computerised This study shows that both classic cognitive stimulation activities, order of presentation and session length. During treatment and computer-based treatment improved cognition the first 24 sessions, the IMIS sessions lasted only 15 min.
in patients who were treated with a stable dose of ChEI, Sessions 25–28 lasted 20 min, and sessions 29–72 lasted compared with those who were treated only with ChEIs. In 25 min. Because this was the first time that such a addition, the IMIS program provided an improvement above computerised multimedia program was applied for the and beyond that seen with classic cognitive stimulation, with cognitive stimulation of these patients, it was necessary to improvement lasting 24 weeks. Not only did ADAS-Cog and ensure tolerability and adequate dose to avoid fatigue or MMSE scores fail to decline (as was seen in the ChEIs control other possible negative effects that might arise from exposure group) but scores also actually improved, and the improve- to a PC. A minimum requirement was that the participants ment was maintained over the 24 weeks that the IMIS was completed 58 of 72 (80%) sessions, with an interruption of no more than 10 days between sessions; all participants met this The progression of illness observed in the ChEI control group is consistent with what has previously been describedin subjects with prolonged exposure to ChEIs (.1 year).38 Onaverage, this group declined at a rate of approximately 2–3 MMSE points per year, which is slightly slower than is The data were analysed using SPSS V.12. Descriptive typical, but falls within the range of expected decline in mild statistics were prepared at baseline, 12 weeks and 24 weeks.
Outcomes were assessed using one-way analysis of variance These results show that it is possible to augment the effects at each of the three critical time points.
of cholinesterase inhibition using cognitive stimulationprocedures, with the result that patients have improved outcomes. These findings from the experimental group Table 1 shows the characteristics of the groups.
cannot be explained simply by increased social contact or No significant differences were observed between the three interactions, as the experimental group and the IPP control study groups on the ADAS-Cog (F2,42 = 0.67) or SKT group attended the daycare centre. The IMIS greatly (F2,42 = 0.84) at baseline, although the experimental group augmented the traditional psychomotor stimulation, because had slightly lower MMSE scores than the other groups when both treatments were used together efficacy was (F2,42 = 3.33, p = 0.046; table 2). There were no differences extended to 24 weeks. Thus, it seems that an individually between the experimental and the IPP control groups on the constrained cognitive stimulation program such as the IMIS other neuropsychological measures at baseline examination used here is more efficacious than treatment only with drugs, (the ChEI control group did not receive these additional four and at least augments traditional psychostimulation. In regard to the possible effects of IMIS-alone treatment, we After 12 weeks of treatment, the three study groups hypothesise that it would represent an improvement com- differed in terms of the ADAS-Cog (F2,42 = 7.05, p = 0.002, pared with non-treated patients and also with patients r = 0.50) and the MMSE (F2,42 = 10.3, p,0.001, r = 0.57; treated with ChEIs alone, as shown in previous studies.27 40 fig 1). Both experimental and IPP control groups were The degree of difficulty of the problems is individually superior to the ChEI control group on the ADAS-Cog (D- adjusted to maximise success (and increase the challenges) lysergic acid diethylamide test, p,0.05), and all three groups for each patient. Although an understanding of the Multimedia tool of cognitive stimulation in Alzheimer’s disease Table 2 Neuropsychological characteristics at baseline, and at 12 and 24 weeks follow-up examination ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive; BNT, Boston Naming Test; ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram; MMSE, Mini-Mental State Examination; RBMT, Rivermead Behavioral Memory Test; SKT, Syndrom Kurztest.
physiological basis of the efficacy of these individualised other cognitive functions43 or activities of daily living cognitive stimulation programs is beyond the scope of this initial study, our findings and data from others suggest that N training in ADLs (procedural memory stimulation) and its plasticity remains possible in patients with Alzheimer’s disease at the cellular level, and that these changes can N psychosocial intervention programmes (ie, reality orienta- modify disease progression.22–26 Cellular plasticity could thus provide a substrate on which the improvements observed combination of cognitive stimulation and counselling(patients and care givers)47; No functional improvement was noted among the three groups. This may be explained by the fact that these were combination of cognitive rehabilitation with mental mildly impaired patients (mean MMSE was 22.0), who retained the physical or functional ability to participate in a N combination of cognitive enhancers and computerised cognitive or motor stimulation program, and did not exhibit disruptive behaviours. Similarly, the ChEI control group was N comprehensive cognitive and motor stimulation pro- only mildly impaired, and they had sufficient support from their care giver to come to the clinic for frequent evaluations.
Therefore, any change in functional capacity could have been Although these approaches show varying degree of benefits more difficult to measure in this cohort than in patients in from non-pharmacological interventions in patients with moderate or severe stages of dementia. In addition, it is Alzheimer’s disease, it is difficult to establish comparisons possible that the functional measures used in this study were among studies, as the outcome measures and duration of the not sensitive enough to detect subtle change.
interventions were not the same, especially when compared There have been multiple methodological approaches to with drug trials. Studies of non-pharmacological interven- explore the benefits of non-pharmacological treatments in tions should, therefore, use the same outcome measures and patients with Alzheimer’s disease. These included studies of: study duration as the pharmacological trials to provide abetter perspective of the effects of non-pharmacological N memory training in one specific task (eg, errorless learning treatments. This study used the ADAS-Cog and MMSE, paradigm) and its effects on memory function,41 42 or on which are the standard cognitive measures used in drugtrials; participants who had cognitive or motor stimulation Figure 1 Mini-Mental State Examination mean change at 12 and Figure 2 Alzheimer’s Disease Assessment Scale-Cognitive mean 24 weeks. ChEI, cholinesterase inhibitor; IPP, integrated change after 12 and 24 weeks. ChEI, cholinesterase inhibitor; IPP, integrated psychostimulation program.
Table 3 Mean change in cognitive measures at 12 and 24 weeks follow-up ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive; BNT, Boston Naming Test; ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram; MMSE, Mini-Mental State Examination; RBMT, Rivermead Behavioral Memory Test; SKT, Syndrom Kurztest; 0, baseline.
*Lower scores indicate cognitive improvement.
treatment had improved scores, and this effect was enhanced Although this was a trial of a non-pharmacological by the use of a computerised program.
intervention, one way to conceptualise the design is to One of the limitations of the study is that we were unable consider that we were able to evaluate ‘‘dose’’ and ‘‘toler- to complete the neuropsychological battery (secondary out- ability’’. In this context, the ‘‘dose’’ refers to the amount of comes) in the ChEI control group. Therefore, we could not time each day that a patient could engage in the IMIS.
further expand our analysis to specific cognitive domains.
Similarly, we could consider the patient’s willingness to The improvement seen with the ADAS-Cog and the MMSE complete the assigned tests on schedule as a measure of was not seen with the SKT. This discrepancy could be ‘‘tolerability’’. Therefore, we started with sessions of 15 min explained by assessing whether these treatments have of duration and increased them to 25 min, and all patients beneficial effects in some cognitive domains, and not in completed the minimum requirement of 58 sessions.
others. However, the limited scope of the cognitive functions Future research is needed to evaluate the efficacy of the assessed by the SKT, and a possible ceiling effect in mildly IMIS-type programs in larger, more diverse populations to impaired patients can also explain these findings.
understand factors that may modify the response, as well as The patients in the experimental and the IPP control to establish its long-term effects (.1 year). The IMIS should groups were in the daycare centre; the only difference be tested outside the controlled clinical environment (ie, between the groups was that the experimental group received home-based) to determine the efficacy of ‘‘distance therapy’’ the IMIS. Patients in these groups were drawn from the same in Alzheimer’s disease. Nevertheless, the results of this study institution, where the IPP program is used in all patients.
suggest that this is a promising avenue of approach to help Therefore, we could not create a group of patients receiving maximise a patient’s cognitive functions in the context of a daycare only, as patients could not be isolated from their progressive degenerative disease, potentially altering the daily stimulation routines (which are an integral part of the effect of the condition on both the patients and the caregivers.
ACKNOWLEDGEMENTThis study was conducted with an unrestricted grant from Fundacio . . . . . . . . . . . . . . . . . . . . .
Authors’ affiliations L Ta´rraga, M Boada, G Modinos, A Espinosa, S Diego, A Morera,M Guitart, J Balcells, Fundacio´ ACE. Institut Catala` de Neurocie`nciesAplicades, Barcelona, SpainO L Lo´pez, J T Becker, Departments of Neurology and Psychiatry,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,USA 1 Ott A, Breteler MM, van Karskamp F, et al. Incidence and risk of dementia.
The Rotterdam Study. Am J Epidemiol 1998;147:574–80.
2 Fratiglioni L, Launer LJ, KA, Breteler MM, et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts.
Neurology 2000;54:S10–S15.
Figure 3 Mean levels of difficulty attained by the experimental group 3 Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with on each cognitive function over a 24-week training period.
Alzheimer’s disease: results of a US multicentre, randomized, double-blind, Multimedia tool of cognitive stimulation in Alzheimer’s disease placebo-controlled trial. The Donepezil Study Group. Dementia 27 Hofmann M, Hock C, Kuhler A, et al. Interactive computer-based cognitive training in patients with Alzheimer’s disease. J Psychiatr Res 4 Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial.
28 McKhann G, Drachman DA, Folstein MF, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the 5 Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD. A six-month, auspices of the Department of Health and Human Services Task Force on randomized, placebo-controlled trial with a six-month extension. Neurology Alzheimer’s disease. Neurology 1984;34:939–44.
29 Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method 6 Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients grading the cognitive state of patients for the clinician. Psychiatr Res with moderate to severe Alzheimer’s disease already receiving donepezil.
30 Blesa R, Pujol M, Aguilar M. Clinical validity of the ‘‘mini-mental state’’ for 7 Breuil V, DeRetrou J, Forette F. Cognitive stimulation of patients with dementia: Spanish speaking communities. Neuropyschologia 2001;39:1150–7.
preliminary results. Int J Geriatr Psychiatry 1994;9:211–17.
31 Reisberg B, Gordon B, McCarthy M, et al. Clinical symptoms accompanying 8 Woods RT. Non-pharmacological techniques. In: Qizilbash N, Schneider LS, progressive cognitive decline and Alzheimer’s disease. In: Melnick VL, Chui H, et al, eds. Evidence-based dementia practice. Oxford: Blackwell, Dubler NN, eds. Alzheimer’s dementia. Clifton, NJ: Humana Press, 9 Douglas S, James I, Ballard C. Non-pharmacological interventions in 32 American Psychiatric Association. DSM-IV: Diagnostic and Statistic Manual dementia. Adv Psychiatr Treat 2004;10:171–9.
of Mental Disorders, 4th edn. Washington, DC: American Psychiatric 10 Grandmaison E, Simard M. A critical review of memory stimulation programs in Alzheimer’s disease. J Neuropsychiatr Clin Neurosci 2003;15:130–44.
33 Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease.
11 Clare L, Woods RT, Moniz-Cook ED, et al. Cognitive rehabilitation and cognitive training for early-stage Alzheimer’s disease and vascular dementia 34 Erzigkeit H. The SKT: a short cognitive performance test as an instrument for [Review]. Cochrane Database Syst Rev 2003;4:CD003260.
the assessment of clinical efficacy of cognitive enhancers. In: Berenger M, 12 Katzman R. Education and the prevalence of dementia and Alzheimer’s Reisberg B, eds. Diagnosis and treatment of senile dementia. Berlin: Springer 13 Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of 35 Goodglass H, Kaplan E, Weintraub S. In: The assessment of aphasia and dementia in the elderly. N Engl J Med 2003;348:2508–16.
related disorders, 2nd edn. Philadelphia: Lea and Febiger, 1987.
14 Wilson RS, Mendes de Leo´n CF, Barnes LL. Participation in cognitively 36 Wilson B, Cockburn J, Baddeley A. The Rivermead Behavioral Memory Test.
stimulating activities and risk of incident Alzheimer’s disease. JAMA Reading: Thames Valley Test Company, 1985.
37 Linn MW, Linn BS. The rapid disability rating scale, part 2. J Am Geriatr Soc 15 Stern Y, Alexander GE, Prohovnik I, et al. Relationship between lifetime occupation and parietal flow: implications for a reserve against Alzheimer’s 38 Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 disease pathology. Neurology 1995;44:55–60.
extension study of the safety and efficacy of donepezil in patients with 16 Olazara´n J, Mun˜iz R, Reisberg B, et al. Benefits of cognitive-motor Alzheimer disease. Arch Neurol 2001;58:427–33.
intervention in MCI and mild to moderate Alzheimer disease. Neurology 39 Doody RS, Dunn JK, Clark CM, et al. Chronic donepezil treatment is associated with slowed cognitive decline in Alzheimer’s disease. Dement 17 Ta´rraga L. Soft therapies: the programme of integral psychostimulation.
Geriatr Cogn Disord 2001;12:295–300.
Alternative treatment for persons with Alzheimer’s disease. Rev Neurol 40 Hofmann M, Rosler A, Schwarz W, et al. Interactive computer-training as a therapeutic tool in Alzheimer’s disease. Compr Psychiatry 2003;44:213–19.
18 Jankowsky JL, Melnikova T, Fadale DJ, et al. Environmental enrichment 41 Clare L, Wilson BA, Roth I, et al. Relearning face-name associations in early mitigates cognitive deficits in a mouse model of Alzheimer’s disease.
Alzheimer’s disease. Neuropsychology 2002;16:538–47.
42 Clare L, Wilson BA, Carter G, et al. Cognitive rehabilitation as a component of 19 Arendash GW, Garcı´a MF, Costa DA, et al. Environmental enrichment early intervention in Alzheimer’s disease: a single case study. Aging Ment improves cognition in aged Alzheimer’s transgenic mice despite stable beta- amyloid deposition. NeuroReport 2004;15:1751–4.
43 Davis RN, Massman PJ, Doody RS. Cognitive intervention in Alzheimer 20 Berchtold NC, Chinn G, Chou M, et al. Exercise primes a molecular memory disease: a randomized placebo-controlled study. Alzheimer Dis Assoc Disord for brain-derived neurotrophic factor protein indiction in the rat hippocampus.
44 Cahn-Weiner DA, Malloy PF, Rebok GW, et al. Results of a randomized 21 Adlard PA, Perreau VM, Pop V, et al. Voluntary exercise decreases amyloid placebo-controlled study of memory training for mildly impaired Alzheimer’s load in a transgenic model of Alzheimer’s disease. J Neurosci disease patients. Appl Neuropsychol 2003;10:215–23.
45 Zanetti O, Binetti G, Magni E, et al. Procedural memory stimulation in 22 Kemperman G, Gast D, Gage FH. Neuroplasticity in old age: sustained Alzheimer’s disease: impact of training programme. Acta Neurol Scand fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann Neurol 2002;52:135–43.
46 Metitieri T, Zanetti O, Geroldi C, et al. Reality orientation therapy to delay 23 Ferna´ndez-Ballesteros R, Zamarro´n MD, Ta´rraga L. Learning potential: a new outcomes of progression in patients with dementia. A retrospective study. Clin method for assessing cognitive impairment. Int Psychogeriatr 47 Quayhagen MP, Quayhagen M, Corbeil RR, et al. Coping with dementia: 24 Becker JT, Mintun MA, Aleva K, et al. Compensatory reallocation of brain evaluation of four nonpharmacologic interventions. Int Psychogeriatr resources supporting verbal episodic memory in Alzheimer’s disease.
48 Loewenstein DA, Acevedo A, Czaja SJ, et al. Cognitive rehabilitation of mildly 25 Herbster AN, Nichols T, Wiseman MB, et al. Functional connectivity in impaired Alzheimer disease patients on cholinesterase inhibitors. Am J Geriatr auditory verbal short-term memory in Alzheimer’s disease. Neuroimage 49 Heiss W-D, Kessler J, Mielke R, et al. Long-term effects of phosphatidylserine, 26 Dekosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s pyritinol and cognitive training in Alzheimer’s disease. A neuropsychological, disease: correlation with cognitive severity. Ann Neurol 1990;27:457–64.
EEG, and PET investigation. Dementia 1994;5:88–98.


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