Mild cognitive impairment and cognitive impairment, no dementia: Part B, therapy

Alzheimer’s & Dementia 3 (2007) 283–291

Mild cognitive impairment and cognitive impairment, no dementia: Part B, therapy Fadi Massouda,**, Sylvie Bellevilleb,c, Howard Bergmand,e, John Kirkd, Howard Chertkowb,d,e,f,*, Ziad Nasreddineg, Yves Joanetteb,h, Morris Freedmani a

Service de Gériatrie, Centre Hospitalier de l’Université de Montréal, and Département de Médecine, Université de Montréal, Montreal, Quebec, Canada b Centre de recherche, Institut Universitaire de Gériatrie de Montréal, Montreal, Quebec, Canada c Department de Psychologie, Université de Montréal, Montreal, Quebec, Canada d Division of Geriatric Medicine, Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada e Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada f Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada g Département de médecine, service de neurologie, Hôpital Charles LeMoyne and Université de Sherbrooke, Montreal, Quebec, Canada h Faculté de Médicine, Université de Montréal, Montreal, Quebec, Canada i Department of Medicine (Neurology), University of Toronto, and Behavioural Neurology Program, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada

Abstract

Mild cognitive impairment (MCI) and cognitive impairment, no dementia (CIND) might be the optimum stage at which to intervene with preventative therapies. This article reviews recent work on the possible treatment and presents evidence-based recommendations approved at the meeting of the Third Consensus Conference on the Diagnosis and Treatment of Dementia held in Montreal in March, 2006. A number of promising nonpharmacologic interventions have been examined. Associations exist with both cognitive and physical activity that suggest that both of these, together or separately, can delay progression to dementia. Similarly, case control studies as well as prospective long-term studies suggest a number of low toxicity interventions and supplements that might significantly impact on MCI progression; folate, B6, and B12 to lower homocysteine levels, omega-fatty acids, and anti-oxidants (fruit juices or red wine) are good examples. In selected genotypes such as individuals with APOE e4, therapy with donepezil might slow progression. The concern, however, is that none of these therapies (including cholinesterase inhibitors) have demonstrated a clinically meaningful effect with randomized, placebo-controlled studies. Just as randomized controlled studies have failed to support primary prevention of dementia by using estrogen or nonsteroidal anti-inflammatory drugs (NSAIDs), there exists the possibility that well-designed randomized controlled trials might fail to definitively demonstrate putative or promising mild cognitive impairment interventions. Pharmacologic interventions and nonpharmacologic therapies, while tantalizing, are currently for the most part insufficiently proven to allow serious consideration by physicians. Recommendation were supported for a general “healthy lifestyle” including physical exercise, healthy nutrition, smoking cessation, and mental stimulation. Close monitoring and treatment of vascular risk factors are justified and were also supported. © 2007 The Alzheimer’s Association. All rights reserved.

Keywords:

MCI; CIND; Cognitive impairment; Psychosocial intervention; Cognitive intervention; Exercise

*Corresponding author. Tel.: (514) 340-8260; Fax: (514) 340-8925. E-mail address: [email protected] **Additional Corresponding author. Tel.: (514) 890-8000 26769; Fax: (514) 412-7506. E-mail address: [email protected] 1552-5260/07/$ – see front matter © 2007 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2007.07.002

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1. Treatment for mild cognitive impairment The preceding article reviewed the concepts and diagnosis of mild cognitive impairment (MCI) and cognitive impairment, no dementia (CIND), reviewed our approach to an evidence-based review of the literature, and presented the recommendations that received consensus at the Third Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD3) held in Montreal in March 2006.This second part will use the same approach to review therapy for MCI and CIND. The treatment of MCI has been the subject of a number of recent chapters and reviews [1,2]. There have been relatively few randomized controlled trials of any therapy sufficient to rank as Level 1 evidence. Nevertheless, there are a number of potential interventions both pharmacologic and nonpharmacologic that deserve to be addressed. 2. Nonpharmacologic treatment for MCI 2.1. Cognitive intervention in MCI There have been several relevant studies in this area. We will first review those carried out in normal elderly and then in MCI. A full listing of these studies is seen in Table 1. Longitudinal cohort studies of healthy elderly persons show that engagement in stimulating cognitive activities (engaged lifestyle; novel and intellectually challenging activities) is associated with better memory and verbal abilities [3]. In a case-control study, participation in intellectually stimulating and social activities in midlife has been associated with reduced risk of developing Alzheimer’s disease (AD) [4]. In a longitudinal cohort study of healthy elderly persons (average follow-up, 4.5 years), a participant’s frequency of participation in common cognitive activities at baseline was associated with reduced risk of clinical diagnosis of AD and reduced cognitive decline (annualized change on global cognition, working memory, and perceptual speed) during the follow-up period [5]. However, the methodology in these studies is based on association; therefore, the direction of causality remains to be clarified. For example, it is unclear whether cognitive activities have a protective effect on the development of cognitive deficits in aging, or whether reduced engagement in cognitive activities is an early sign of AD. Verhaeghen et al [6] conducted a quantitative review of studies measuring the efficacy of memory intervention studies in healthy aging. They reported that memory training improved performance on targeted memory tasks and that the effect sizes for the training effect were in the moderate range. One large scale randomized controlled trial on cognitive interventions (memory, speed, or reasoning vs no training) was completed in a sample of 2,832 healthy older adults [7]. The results indicated improved performance after training on the cognitive domains that were targeted by the interventions. The positive effects were sustained during a

2-year follow-up, and the effect sizes were moderate to large. Thus there is good evidence that cognitive training increases cognitive efficacy on target measures in healthy older adults. Two nonrandomized studies and two randomized controlled trials (RCTs) have been reported on the effect of cognitive training in MCI. With an RCT design, Olazaran et al [8] reported decreased depression and improved cognition (cognitive subscale of the Alzheimer’s Disease Assessment Scale, cognitive portion) in a mixed group comprising 72 AD and 12 MCI patients after a 1-year program of cognitive-motor stimulation plus psychosocial compared with psychosocial support. In a small-scale (n ⫽ 18) RCT trial, Rapp et al [9] compared cognitive intervention with no treatment. They reported improved subjective memory and long-term maintenance during a 6-month period but no effect on objective tests of memory. Gunther et al [10] reported long-term improvement in cognitive performance (working memory and verbal episodic memory) in a prepost comparison study of computer-assisted cognitive training in persons with MCI. Finally, Belleville et al [11] compared the effect of a multifactorial memory training program with a no-training condition (28 MCI participants) and reported larger memory improvement on post-test in the trained MCI participants compared with the untrained ones. Moderate to large effect sizes were obtained for the training effect on target episodic memory measures. Thus, studies investigating the effect of cognitive intervention in MCI provide encouraging findings. However, the effort required to implement such therapeutic measures is not trivial, and large scale cognitive intervention for MCI would require considerable resources. Before widespread recommendation of this therapy can occur, more replication studies are required with properly controlled RCT designs, larger sample sizes, and analyses that control for type 1 error. In conclusion, longitudinal cohort studies of healthy older adults indicate that engagement in intellectually stimulating activities is associated with decreased risk of AD and decreased cognitive decline. However, the evidence at the present time is insufficient to conclude that organized cognitive intervention is beneficial to preventing progression in MCI or warrants prescription. On the other hand, given that there is little or no “downside” to cognitive activity, it is not unreasonable for physicians and therapists to promote engagement in cognitive activity as part of an overall healthy lifestyle formulation for elderly individuals with and without memory loss. 2.2. Physical training in MCI Several longitudinal cohort studies carried out in normal elderly individuals indicated that physical exercise is associated with reduced cognitive decline and reduced risk of dementia. These studies looked at outcomes such as a change score on the Mini-Mental State Examination

Table 1 Studies of non-pharmacological treatment of MCI Authors

Year

Type

Population

Outcome Measures

Results

Notes Not MCI; controlled intervention: ?? Heterogeneous group; 9 with mild impairment; controlled intervention: ??

Meta-analysis (18 RCTs)

Healthy and clinical aged

Cognitive tests

ES, .478; largest on executive

2004

Meta-analysis (30 RCTs)

Demented

Physical, functional, behavioral, and cognitive measures

ES, .62; large effect on most components

Kramer et al [13]

2004

Healthy aged

Cognitive tests

Improves executive functions

Lytle et al [12]

2004

Literature review of RCT and prospective studies Prospective study

Community sample

Laurin et al [13]

2001

Prospective

Community sample

Decline on MMSE over a 2-year time Cognitive impairment

Protects against severe decline Physical activity reduces risk of cognitive impairment, AD, and dementia 5 y later

Psychosocial intervention Ishizaki et al [45]

2002

Prospective study

Mild AD (CDR .05) and controls

Cognitive intervention Kramer et al [3]

2004

Healthy aging

Cognitive tests

Improves targeted cognitive functions (cognition)

Wilson et al [5]

2002

Longitudinal cohort

Diagnosis of AD after a mean follow-up of 4.5 yrs

Lindstrom et al [4]

2005

Literature review of RCTs and prospective studies; cognitive intervention and effect of leisure and environment Prospective study; cognitively stimulating activities Retrospective study of leisure activity (TV viewing in midlife)

AD and controls

Diagnosis of AD

Reduces the risk of AD and the decline on global cognition, WM and speed. TV viewing increases risk of AD; intellectual and social activities reduce it

Verhagen et al [6]

1992

Healthy aging

Memory

Ball et al [7]

2002

Literature review of intervention studies RCT

Healthy aging

Cognition

Poon et al [46]

2005

MCI and early AD

Cognition

Olazaran et al [8]

2005

RCT of videoconference of cognitive and psychosocial intervention RCT of cognitive stimulation (1yr program)

MCI and AD

Cognition, depression, functional impact

Improvement on cognition and affective measures

Improved performance (ES, 0.7; 0.2 in controls) Improves targeted cognitive functions; long-standing effect (2 years); no generalisation. Equivalent effect of VC and Face to face training

Positive effect on cognitive and depression

Small N; a specific intervention (eg, reminiscence); no placebo

Limitations: association direction unclear; retrospective; based on questionnaire in surrogate respondents Negative effect of lower mental status High quality study; follow-up to appear soon

Small N; no placebo

No distinction between MCI and AD; no control of type 1 error 285

2003

F. Massoud et al. / Alzheimer’s & Dementia 3 (2007) 283–291

Physical training Colcombe and Kramer [15] Heyn et al [16]

Cognition MCI 2003

2006

Belleville et al [11] Gunther et al [10]

NOTES. For fitness: more studies are needed to assess modality, safety, intensity. Problems: blinding, small N; long-term; appropriate control; to target MCI. For psychosocial intervention: more studies are needed in MCI to assess potential efficacy, feasibility, safety. For cognitive intervention: encouraging results but more RCT studies are needed in MCI with larger N.

Not randomized; no treatment as control; small N (26 MCI) No group of untrained participants Cognition and well-being

RCT of memory intervention 2002 Rapp et al [9]

Clinical trial of cognitive intervention Pre-post study of cognitive intervention

MCI and controls

Positive effect on subjective measure and long-term maintenance but no effect on objective measures Positive effect on cognitive and well-being Pre-post training effect Cognition MCI

Results Outcome Measures Population Type Year Authors

Table 1 Continued

No-treatment group as control; small N (9 MCI)

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Notes

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(MMSE) 2 years later [12] and risk of dementia 5 years later [13]. However, there are also studies that failed to find a protective effect of physical exercise on cognitive decline and on incident dementia [14]. Two recent meta-analyses have been published regarding the impact of physical exercise programs on the cognitive function of older adults [15,16]. Colcombe and Kramer [15] included 18 RCT studies in their meta-analysis, and Heyn et al [16] included 30 studies. Both meta-analyses reported moderate effect sizes for the exercise training effect on global cognitive scores, with a larger effect on tasks measuring executive control reported by Colcombe and Kramer. There are immense implications of such research in terms of potential public health measures to prevent dementia and cognitive decline. However, more studies, particularly RCTs, are needed to assess the optimal exercise training modalities in older adults, particularly in terms of intensity and duration. Safety issues will also need to be better addressed. Furthermore, there were methodologic limitations in past studies regarding appropriate blinding procedures and sample size. Finally, no studies have been carried out specifically with MCI persons to assess the effect of physical training on their cognitive capacities and cognitive decline. In conclusion, longitudinal cohort studies of healthy older adults indicate that physical training might be protective against cognitive decline. RCTs have provided compelling evidence for a beneficial effect of physical training on the cognitive performance of healthy older adults. However, the evidence is insufficient to conclude that physical training is beneficial to preventing progression in MCI or warrants prescription. Furthermore, safety issues will need to be better addressed. Keeping this in mind, physicians and therapists might promote physical activity at an intensity level that is adapted to the person’s overall physical capacities as part of a healthy lifestyle for older individuals with and without memory loss. 2.3. Psychosocial intervention There are few data in this area, and no suggestions will be reviewed at this time. 2.4. Cognitive intervention in MCI 2.4.1. Recommendation 7 The evidence at the present time is insufficient to conclude that organized cognitive intervention is beneficial to preventing progression in MCI or warrants prescription (Grade C, Level 1). 2.4.2. Recommendation 8 There is fair evidence that physicians and therapists should promote engagement in cognitive activity as part of an overall healthy lifestyle formulation for elderly individuals with and without memory loss (Grade B, Level 2).

F. Massoud et al. / Alzheimer’s & Dementia 3 (2007) 283–291 Table 2 Drugs under investigation to prevent progression to AD CHEIs Anti-inflammatories Estrogen Statins Cholesterol-lowering drugs Anti-amyloid drugs (beta-secretase inhibitors, gamma-secretase inhibitors, GAG mimetics, amyloid immunotherapy) Various anti-oxidants including vitamin E AMPAkines

2.5. Physical training as therapy in MCI 2.5.1. Recommendation 9 There is fair evidence that physicians and therapists should promote physical activity at an intensity level that is adapted to the person’s overall physical capacities as part of a healthy lifestyle for older individuals with and without memory loss (Grade B, Level 2). 2.5.2. Recommendation 10 Current evidence is insufficient to conclude that a specific program of physical training warrants prescription in MCI patients to prevent progression to dementia (Grade C, Level 3). 3. Pharmacologic approaches to MCI Several pharmacologic treatment approaches have been attempted in MCI (Table 2). The formal review of the evidence is presented in Table 3. 3.1. Cholinesterase inhibitors Although evidence suggests the absence of significant cholinergic deficits in MCI [17], several lines of evidence

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suggest early cholinergic “functional” modifications such as choline transport and acetylcholine release at this stage [18]. All three cholinesterase inhibitors (ChEIs) currently available in Canada have been used in clinical trials of MCI. Salloway et al [19] conducted a 24-week, multicenter, randomized, double-blind placebo-controlled study in 270 individuals with MCI, comparing donepezil 10 mg daily with placebo. There were no significant beneficial effects on the two primary outcome measures used, the New York University Paragraph Delayed Recall test and the Alzheimer Disease Cooperative Study Clinician’s Global Impression of Change for MCI (ADCS-CGIC-MCI). Subjects on donepezil exhibited statistically significant benefit on two a priori secondary outcome measures, the Alzheimer’s Disease Assessment Scale– cognitive subscale (ADAS-cog) and the Patient Global Assessment (PGA). More individuals treated with donepezil also had adverse events. The Alzheimer’s Disease Cooperative Study Group (ADCS) led by Petersen conducted a 3-year double-blind study randomizing individuals with amnestic MCI to vitamin E 2000 IU daily, donepezil 10 mg daily, and placebo [20]. In this study, the primary outcome was conversion to possible or probable AD. At the end of the study, there were no differences in the progression to AD between the three groups. However, on preplanned interim analyses, donepeziltreated individuals had a slightly reduced likelihood of progression to AD during the first year of the study. On a priori pharmacogenetic analyses, the study confirmed that possession of the APOE e4 allele is a major predictor of progression to AD and indicated that most of the treatment effect occurred among the APOE e4 carriers. On secondary analysis confined to APOE e4 carriers, the effect of donepezil was significant at 12, 24, and 36 months. “In fact, a closer look at their data reveals no convincing evidence of a difference in treatment effect according to APOE e4 carrier

Table 3 Standard evidence table for pharmacologic therapy in MCI Agent

Design

Author, Year

N

Donepezil

RCT

Salloway et al [19], 2004

270

Donepezil

RCT

Petersen et al [20], 2005

769

Rivastigmine (InDDEX) Galantamine Rofecoxib Estrogen

RCT

Feldman et al [23], 2007

1018

RCT RCT RCT

Scheltens et al [24], 2004 Thal et al [26], 2005 Shumaker et al [28], 2003

1457 4532

Ginkgo biloba

RCT

van Dongen et al [30], 2003

214

Statistical Significance

Quality of Study*

Magnitude of Benefit

Absolute Risk Reduction

Numbers Needed to Treat

On secondary outcome measures None in primary outcome; some positive secondary analyses No

4/5

NA

NA

NA

4/5

NA

NA

NA

5/5

NA

NA

NA

No Increased risk of dementia (hazard ratio, 2.1)in treatment group No

5/5 5/5

NA NA

NA NA

NA NA

5/5

NA

NA

NA

Comments

* Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. The quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;1:1–12.

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status; the effect of donepezil was similar among APOE e4 carriers and noncarriers (hazard ratio for progression of 0.66 as compared with 0.80 for the entire cohort, with overlapping confidence intervals). These numbers suggest that the observed difference in significance might have been due to analogous differences in statistical power, because AD developed in about twice as many APOE e4 carriers (who are more likely to be on a course toward AD) as noncarriers within the 3 years after enrolment” [21]. Also, the authors indicate that “ . . . there are insufficient data to warrant recommending APOE e4 genotyping in persons with mild cognitive impairment, and our results cannot be used to make this recommendation, since the study was not statistically powered to determine the effects of treatment in separate groups of APOE e4 carriers and noncarriers.” Results from a 4-year double-blind, placebo-controlled, clinical trial of rivastigmine in MCI individuals (InDDEX) showed no difference in the likelihood of progression to AD between the treatment group and those on placebo [22]. At the time of the CCCDTD3, preliminary data had been published in abstract format only. Although the final published form of the study came out after the CCCDTD3 voting [23], there was no meaningful change in the recommendations based on this study. The overall rate of progression from MCI to AD in this randomized clinical trial was much lower than predicted. Two clinical trials with galantamine in MCI similarly showed no difference in the probability of conversion to AD. However, there was a reduced rate of whole-brain atrophy in patients treated with galantamine [24]. Therapy with galantamine was associated with an increased all-cause mortality risk that might be explained, at least in part, by the very low mortality rate in the placebo groups. These results are published as abstracts only; therefore, there is little information concerning the methodology. 3.1.1. Recommendation 11 There is currently insufficient evidence to recommend for the use of ChEIs in MCI (Grade C, Level 1). 3.2. Anti-inflammatory agents Several large well-conducted epidemiologic studies have shown a negative association between the use of NSAIDs and the development of AD [25]. In the only clinical trial of NSAIDs in MCI, Thal et al [26] randomized patients to rofecoxib 25 mg and placebo daily for up to 4 years. Individuals on rofecoxib did not exhibit significant benefit in terms of clinical conversion to clinical AD, which was the primary outcome measure, or on secondary outcome measures. 3.2.1. Recommendation 12 There is currently fair evidence to recommend against the use of NSAIDs in MCI (Grade D, Level 1).

3.3. Hormone replacement therapy Estrogen has been shown to have neuroprotective effects in several studies. It is considered a neurotrophic factor for cholinergic neurons; it stimulates cerebral cellular growth, contributes to synaptic reorganization, and decreases betaamyloid production. It is also associated with antioxidant properties and beneficial vascular effects [27]. In a metaanalysis of 12 observational studies, estrogen is associated with a decreased risk of developing AD, with an odds ratio of 0.69 [27]. In the Women’s Health Initiative Memory Study, 4,532 women were randomized to estrogen 0.625 mg daily with medroxyprogesterone 2.5 mg daily and placebo and were followed up between 3 and 4 years [28]. Not only did this study fail to demonstrate any benefit on the risk of developing MCI and dementia, it actually showed a doubling (hazard ratio, 2.05) of the risk of dementia in the hormone-treated group. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, postmenopausal women were randomized to a selective estrogen receptor modulator, raloxifene, at doses of 60 mg and 120 mg daily and placebo [29]. At 3-year follow-up, women taking 120 mg of raloxifene had a 33% decreased risk of developing MCI. This benefit was not observed in the group taking raloxifene 60 mg daily. 3.3.1. Recommendation 13 There is currently fair evidence to recommend against the use of estrogen replacement therapy in MCI (Grade D, Level 1). 3.4. Ginkgo biloba Ginkgo biloba is commonly used for memory impairment because of its presumably beneficial antioxidant, antiplatelet, and neuroprotective properties. The only relevant randomized, placebo-controlled clinical trial of ginkgo biloba was conducted by van Dongen et al [30] in patients with dementia and Age-Associated Memory Impairment (AAMI). This category includes individuals with memory impairment when compared with young controls. At the end of the 36-week-long trial, there were no statistically significant differences between the ginkgo biloba and placebo groups. A Cochrane Database systematic review of ginkgo biloba for cognitive impairment concludes that the three most recent clinical trials, which are methodologically more sound, show inconsistent results [31]. They add that “there is a need for a large trial using modern methodology . . .”. 3.4.1. Recommendation 14 There is currently fair evidence to recommend against the use of ginkgo biloba in MCI (Grade D, Level 1). 3.5. Vitamin E Epidemiologic data suggest a negative association between ingestion of vitamin E from natural [32] and artificial sources [33] and developing AD. The potential neurocog-

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nitive benefit of vitamin E was further supported by a randomized clinical trial showing it delayed reaching significant clinical milestones in patients with AD [34]. The only trial of vitamin E in MCI, discussed in the ChEI section, was negative [20]. Concerns have been raised about the safety of vitamin E since the publication of a metaanalysis of 19 clinical trials that suggested an increased all-cause mortality in individuals ingesting 400 or more IU daily [35]. 3.5.1. Recommendation 15 There is currently fair evidence to recommend against the use of vitamin E in MCI (Grade D, Level 1). 3.6. Treatment of vascular risk factors Several epidemiologic studies have shown the association between vascular risk factors and cognitive impairment [36 –39]. Clinical trials have evaluated the role of primary prevention of vascular risk factors and the risk of cognitive deterioration. In the Systolic Hypertension in EURope Trial (SYST-EUR), 2,418 subjects were randomized to active treatment with nitrendipine with the possible addition of enalapril and hydrochlorothiazide or placebo [40]. In the active treatment group, the incidence of dementia was reduced by 50% at 2 years. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) 6,015 patients with previous stroke or transient ischemic attack were randomized to receive perindopril with or without indapamide or placebo [41]. At the end of the 3.9-year follow-up, the risk of dementia and cognitive decline was significantly reduced in the active treatment group. The risk was reduced even further in subjects with recurring stroke. The two large primary prevention trials with statins have reached somewhat different conclusions; statins do reduce cardiovascular and cerebrovascular events in primary prevention, but they do not provide any benefit on cognitive function [42,43]. These seemingly counterintuitive results can be explained by some of the methodologic limitations of these trials, namely the relatively short duration of follow-up and the limited, and probably incomplete, evaluation of cognitive function. One clinical trial evaluated the role of hypertension treatment in individuals with mild cognitive deficits broadly defined as a MMSE score between 20 and 28 [44]. In this study, captopril was compared with bendrofluazide in 81 subjects with systolodiastolic hypertension for 24 weeks. There were no statistically significant differences between the two drugs, but patients with the best response to treatment in terms of reduction of their diastolic blood pressure significantly improved on two cognitive tests. Interestingly, this study suggests that reduction of blood pressure in elderly hypertensive patients with MCI is not hazardous. 3.6.1. Recommendation 16 Because vascular risk factors and comorbidities impact on the development and expression of dementia, they

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should be screened for and treated optimally in MCI (Grade B, Level 2). Other pharmacologic agents that have been considered in MCI have shown either marginal or inconsistent benefit. These include neurotrophic medications (phosphatidylserine, acetyl-l-carnitine, piracetam), memory stimulants (ampakines, N-methyl-D-aspartate modulators, CREB modulators), antioxidants, vitamin supplements, and omega fatty acids.

4. Pharmacologic treatment recommendations for MCI (summary) 4.1. Recommendation 11 There is currently insufficient evidence to recommend for the use of ChEIs in MCI (Grade C, Level 1). 4.2. Recommendation 12 There is currently fair evidence to recommend against the use of NSAIDs in MCI (Grade D, Level 1). 4.3. Recommendation 13 There is currently fair evidence to recommend against the use of estrogen replacement therapy in MCI (Grade D, Level 1). 4.4. Recommendation 14 There is currently fair evidence to recommend against the use of ginkgo biloba in MCI (Grade D, Level 1). 4.5. Recommendation 15 There is currently fair evidence to recommend against the use of vitamin E in MCI (Grade D, Level 1). 4.6. Recommendation 16 Because vascular risk factors and comorbidities impact on the development and expression of dementia, they should be screened for and treated optimally in MCI (Grade B, Level 2). In conclusion, an evidence-based review of the literature provides evidence that leisure activities, cognitive stimulation, and physical activity should be promoted as part of a healthy lifestyle in elderly individuals and those with MCI. Vascular risk factors should be treated optimally in these individuals as well. No other specific therapies can yet be recommended or supported as having adequate demonstration of efficacy. There is certainly a need for larger scale trials to demonstrate efficacy of some of the pharmacologic interventions, and our recommendations might have to be altered in the future as such trials are completed.

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Author Disclosures Fadi Massoud has had associations with Janssen Ortho Inc. (Advisory Board, CME Speaker, Research Funds), Lundbeck Canada (Advisory Board, CME Speaker, Research Funds), Novartis (Advisory Board, CME Speaker, Research Funds), and Pfizer (Advisory Board, CME Speaker, Research Funds). Howard Chertkow has had associations with Pfizer Canada (Advisory Board, Speaker, Grant Recipient), Neurochem Inc. (Advisory Board), and Lundbeck Canada (Advisory Board, Speaker). Ziad Nasreddine has had associations with Pfizer (Consultant, Adviser, Program Organizer, Lecturer), Novartis (Lecturer, Drug Trials, Advisor), Janssen Ortho Inc. (Lecturer, Drug Trials, Advisor), Neurochem (Drug Trial), Myriad (Drug Trial), and Sanofi-Aventis (Drug Trial). Howard Bergman has had associations with Pfizer (Drug Trial) and Novartis (Drug Trial). Morris Freedman has had associations with Pfizer (Advisory Board, CME Speaker, Research Funds), JanssenOrtho Inc. (Advisory Board, CME Speaker), Novartis (Advisory Board, CME Speaker), Lundbeck (CME Speaker), Eli Lilly (Research Funds), and Orphan Medical (Research Funds). Acknowledgments This work was supported by grants from a number of agencies. Howard Chertkow is supported by operating grants from the CIHR (Canadian Institutes for Health Research), the Alzheimer Society of Canada, and the Fonds de la recherche en santé du Québec (FRSQ). Howard Chertkow and Sylvie Belleville receive “chercheur national” awards from the FRSQ (Fonds de la Recherche en Santé du Québec). Howard Bergman is supported through the Dr Joseph Kaufmann Chair in Geriatric Medicine at McGill University. Yves Joanette was supported by a grant from the Canadian Institutes of Health Research (MOP-15006). Sylvie Belleville is supported by research grants from the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, Alzheimer’s Society of Canada, CAREC, and NSERC. References [1] Chertkow H. Mild cognitive Impairment and very early stage Alzheimer’s disease. In: Gauthier S, ed. Clinical diagnosis and management of Alzheimer’s disease, third edition. London: Informa UK; 2006. p. 205–21. [2] Chertkow H. Emerging pharmacological therapies for mild cognitive impairment. In: Hultsch IHTaD, ed. Mild cognitive impairment: international perspectives. New York: Taylor & Francis; 2006. p. 217– 43. [3] Kramer AF, Bherer L, Colcombe SJ, Dong W, Greenough WT. Environmental influences on cognitive and brain plasticity during aging. J Gerontol A Biol Sci Med Sci 2004;59:M940 –57.

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