THE IMPACT OF NON-PHARMACOLOGICAL TREATMENT ON SYMPTOM REDUCTION AND PROGRESSION OF MILD COGNITIVE IMPAIRMENT TO DEMENTIA

MILD COGNITIVE IMPAIRMENT(MCI)
Mild cognitive impairment is situated between „normal aging process” and dementia. The Alzheimer Association and National Institute of Aging define MCI as (I) concern regarding a change in cognition from the patient, knowledgeable informant, or from a skilled clinician observing the patient, (II) objective evidence of impairment (from cognitive testing) in one or more cognitive domains, including memory, executive function, attention, language, or visuospatial skills, (III) preservation of independence in functional abilities and (IV) no evidence of a significant impairment in social or occupational functioning (1). MCI differs mainly from dementia because its preservation of independence in functional abilities and lack of significant impairment in social or occupational functioning (2).
The same organisations define MCI due to Alzheimer’s disease as memory impairment, longitudinal decline in cognitive function and lack of evidence for vascular, traumatic, or other medical causes of cognitive decline (1,2).
The DSM-5 refers to it as “mild neurocognitive disorder” with similar criteria as mentioned above (3).
Clinical and population based samples indicate an MCI prevalence of 10-20% for adults over 65 years (4), while the DSM-5 state a prevalence of 2-10% for adults of same age and 5-25% for adults of around 85 years (3). The uncertainty of these estimates exist due to differences in sample characteristics across studies. The prevalence increases with age and appears to be higher in men (5).
Amongst the risk factors for developing MCI are risk factors for dementias such as: lower educational level, vascular risk factors (like diabetes, hypertension), presence of cerebrovascular disease and the presence of APOE E4 allele (6).
The objective evidence of cognitive impairment is obtained through use of validated questionnaires such as MoCA (Montreal Cognitive Assessment) and MMSE (Mini Mental State Examination). There are studies showing that MoCA is a screening tool developed for detecting MCI, having a sensitivity of 80 to 100% and a specificity of 50 to 67% (7) using a cut-off point of 25/26 (In the same study the MMSE had a sensitivity of 45 to 60% and specificity of 65 to 90% for detecting MCI using cut-points of 27 or 28).
One study (8) showed that in the general population the prevalence of MCI was 3.2% with an 11.1% progression rate to dementia within a 3-year period. In another study (9) of 1,435 aged 75 to 95 years 35% progressed to dementia, 21% remained stable, 25% improved and 34% died within a 3-year period. In a study (10) of 305 patients with MCI, 65% progressed to dementia, 28% remained with an MCI diagnosis and 7% had a subsequent diagnosis of being cognitively normal within a 3 year period. The relative risk of progressing to dementia within 3 years was 3.6. This pleads to the heterogeneity of MCI, given that the progression rate to dementia varies between studies. If the person already has a cerebral-vascular disease (11) the rate of progression to dementia is 50% in 5 years. Given the high rate of progression it is highly important to find an early treatment for MCI.
Amongst the treatments used in trying to manage MCI and/or delay progression to dementia are: a c e t y l c h o l i n e s t e r a s e – i n h i b i t o r s ( r i v a s t i g m i n e , galantamine, donepezil), antioxidants (Vitamine E, selegiline, Ginko Biloba), dopamine receptor agonists (piribedil), sex steroid hormones (testosterone injections for men and conjugated equine oestrogen for women), antiinflamatory agents (refecoxib) (12), peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (rosiglitazone and pioglitazone) (13), vitamin B complex (folic acid, cyanocobalamin and pyridoxine) (14), acetyl-L-carnitine (15), intranasal insulin (16), transdermal nicotine (17), melatonin (18), fluoxetine (19), combination of green tea extract and l-theanine (20), Yamabushitake mushroom (21) – thought to have compounds which enhance nerve growth factor synthesis and acupuncture (22). Of the ones mentioned, only fluoxetine showed some promising results as discussed below. In some studies, PPAR-gamma agonists showed some improvements in patients with diabetes and MCI, but it is most likely as a part of controlling metabolic risk factors.
MEDICAL TREATMENT
Currently there is no effective drug for the treatment of MCI. Cholinesterase inhibitors have not been shown to decrease risk of progression from MCI to dementia at 1 and 3 years, they have limited to no significant effects on cognitive function over the short- term (<12 months) and may substantially increase adverse effects based on a meta-analysis of 4 trials (n=1,960) and another of 9 trials (n=5,149) (7,23). Some hypotheses for the lack of sustained benefit of cholinesterase inhibitors are: the compensatory upregulation of central cholinergic activity, lack of sensitivity of the cognitive outcomes of our current measurement tools, and heterogeneity of patients (24). Recent studies show that long-term treatment with SSRI (>4 years) in patients with MCI and previous depression was associated with a 3-year delay in progression from MCI to Alzheimer’s dementia (25) which represent a very promising result worthy for further studies.
A randomised control trial of 45 participants (26) found that lithium treatment (target serum level 0.25–0.5 mmol/l) decreases P-tau concentrations in the cerebrospinal fluid, improves cognition and has good tolerability and adherence. Lithium shows disease modifying potential (26,27) through interaction with enzymatic activity, thus reducing Tau phosphorylation and increasing synaptic plasticity.
Ginko-biloba supplements, widely used supplement in MCI patients, has not been shown in randomized control trials to prevent cognitive decline (28).
A key point in reducing the risk of progression from MCI to dementia is to control the vascular risk factors (29). That can be achieved through blood pressure control, smoking cessation, statin therapy, anti-platelet therapy, and anticoagulation or antithrombotic therapy for atrial fibrillation (30,31).
G i v e n t h e l a c k o f e f f i c i e n c y o f t h e pharmacological treatment, other methods that can stop progression to dementia are essential.
NONPHARMACHOLOGICAL APPROACH
Physical activity lowers the risk of developing cardiovascular disease, diabetes mellitus, cancer (colon and breast), obesity, hypertension, bone and joint diseases and depression (32). Also, it was positively associated with general well-being, low levels of anxiety and depression and overall positive mood (33). In a study (34) of 28 adults with minor depression, running reduced depressive symptoms and it proved to be as effective as psychotherapy. In regard to anxiety (35), aerobic exercises improved symptoms more than weight training or flexibility exercises. To significantly reduce trait anxiety,

exercise programmes need to exceed 21 minutes per session for a minimum of 10 weeks (36).
The mechanisms through which physical exercise could improve cognition in patients with MCI or dementia are: increasing in blood flow and oxygen supply to the brain, lowering blood pressure, reducing inflammatory markers, improving endothelial function (37). It may also increase the volume of the hippocampus (38). It has been shown in animal studies (39) that exercise stimulates neuron proliferation in hippocampal areas.
A controlled trial (40) of 33 patients with amnestic MCI aged 55 to 85 (with a mean age of 70 years) were randomized either to a high-intensity aerobic exercise or stretching control group. Six months of high- intensity aerobic exercise (4 days/week for 45 to 60 minutes per session using either treadmill, stationary bicycle or elliptical trainer) had sex-specific effects on cognition, glucose metabolism, and hypothalamic- pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. Their results suggest a sex bias in cognitive response may relate to sex-based differences in glucose metabolism and hypothalamic-pituitary-adrenal axis responses to aerobic exercise. The cognitive enhancement effect of aerobic exercises was better seen in executive control tasks in women together with increased insulin sensitivity and low levels of circulating cortisol and BDNF. For men, aerobic exercises increased the plasma level of insulin growth factor I and most improvements were also observed on the executive function.
A prospective study (41) of 9008 randomly selected men and women aged 65 or older explored the association between physical activity and the risk of cognitive impairment and dementia. Compared with no exercise, physical activity was associated with lower risks of cognitive impairment, Alzheimer disease and dementia of any type and high levels of physical activity were associated with increased protection of the above- mentioned diseases. However, given the study design (not randomized, placebo controlled), more evidence is needed to firmly draw a conclusion.
A control trial (42) of 100 older adults with mean age of 75 years and MCI were randomized to either a multicomponent exercise or an education group (ratio of
1:1). The exercise group worked out for 90 minutes/day, 2 days/week, 40 times for 6 months and it consisted in aerobic exercise (including stair stepping, endurance walking, and walking on balance boards), muscle strength training, postural balance retraining and dual-task training. The mean intensity of the aerobic exercise was approximately 60% of maximum heart rate. Compared with the control group, the physical exercise group showed a better MMSE and logical memories score. Patients with a low total cholesterol level before the intervention showed improvement of logical memory scores.
Another randomized control trial (43) showed modest improvement in cognition (ADAS-Cog scores) over an 18-month follow-up period (6 months of intervention with follow-up and then another follow-up 12 months after intervention ceased) in patients assigned to the physical activity group. The physical activity intervention consisted in 50 minutes sessions/day, 3 days/week for 6 months of individualized home-based program, with the most recommended activity being walking.
A RCT (44) concluded that a moderate to high intensity strength and aerobic programme did not slow the progression of dementia and may in fact worsen the cognitive decline. The exercise programme consisted of twice a week intervention for four months with each session lasting 60 to 90 minutes. In addition, the intervention arm was asked to do 150 minutes of physical activity per week at home. However, this study was done in people with dementia and the generalizability of the results are questionable.
A meta-analysis of 14 RCTs (45) revealed that 9 of the total RCTs reported improvements for at least one outcome. These were noticed in: verbal fluency, global cognition, fluid intelligence, executive function and memory. The intervention types of physical activity were mixt: moderate intensity aerobic, low intensity walking, resistance training, balance and coordination or combinations of the above. The same applied for the exercise dose and intensity: from 30-90 minutes/session, 2-4 sessions/week with durations of 6 to 52 weeks with intensities from high to low. Most interventions were provided in groups, few individual and the sites were mostly gymnasiums, home and care centres or homes. Overall results were inconsistent with benefits varying across exercise types and cognitive domains.
Another meta-analysis (46) of 30 trials reported an overall medium treatment effect for combined physical, cognitive, functional and behavioural outcomes. The mean duration of the exercise intervention was 23 weeks (with range from 2 to 112 weeks) with an average of 3.6 session/week (from 1 to 6 sessions) and each session lasting 45 minutes (ranging from 20 to 150 minutes). The main physical activity was walking combined with different isotonic exercises. This meta-analysis included patients with cognitive impairments nondemented and patients with dementia.
A meta-analysis of 15 prospective studies (47) which included non-demented patients showed that physical activity (both high level and low-to-moderate level) is a protective factor against cognitive decline. This meta-analysis lacks the specifics of the exercises used but shows no differences in results regarding intensity of physical activity.
A meta-analysis of 11 RCTs (48) concluded that aerobic exercises significantly improved global cognitive ability and weakly, but positively improved memory with no significant improvement in attention, verbal fluency or visuospatial domain. The exercises were: walking, handball training, Tai Chi, jogging, cycling, dance based aerobics and multicomponent aerobic. The sessions were 30-60 minutes/day, 2-5 days/week with a duration of 6 months to 1 year. The maximum heart rate was 60-80% (classified as moderate activity). The improvement in global cognitive function was defined as increases in scores of MMSE/MoCA/ADAS-Cog at follow-up.
One meta-analysis of 60 RCTs (49) showed that physical exercise had a small but positive effect on improving cognition in patients with MCI and that the effect was stronger when it came to patients with dementia. This study raised the concern of the high drop- out rate of patients in the active intervention group compared to control group. The duration of the intervention varied from 6 weeks to 1 year and it did not specify the type of exercises involved.
A meta-analysis of 12 prospective studies (50) concluded that a high level of physical activity can reduce the risk of cognitive decline and dementia. The assessment of physical activity was through questionnaires and exercise programmes where not described.
Physical activity could improve cognition in patients with MCI. The best results came from fitness programmes of moderate intensity (maximum heart rate between 60-80%) conducted by physiotherapists, that lasted around 45 minutes per session with 3 sessions per week for a total of about 6 months. Most improvements were found in global cognitive and executive function.
Another method of improving cognition is through cognitive training and cognitive rehabilitation programs. The concept of cognitive training and rehabilitation programs is based on enhancing neuronal plasticity, but probably different mechanisms are also in place (51). Today, cognitive programs are designed as computer softwares with an easy-to-use and accessible interface (Computerized cognitive training – CCT).
A meta-analysis of 31 RCTs (52) examined the effect of cognitive training and mental stimulation on healthy older (>50 years) adults. Compared to the control group, the cognitive intervention group showed significant improvements on the memory measures of face-name recall, immediate recall, and paired associates and on subjective measures of cognitive performance. Compared to active control group (who received educational DVDs, lectures, health-promoting training), cognitive intervention also showed significant improvements in memory measure of recognition, on the executive measures of working memory and processing speed and also on composite measures of cognitive function. Memory -based training was the most used in the cognitive intervention group. In the same meta analysis they compared the mental stimulation group (which included actions such as playing piano, acting, and helping children with reading difficulties) with control and active control groups. The mental stimulation group showed better results in fields of memory, executive function and on one measure of composite cognitive function compared to control group. Compared to the active control group there were no significant differences. It needs to be mentioned that results from the mental stimulation studies were not as strong as the ones from cognitive training due to lack of available data.
Participants with MCI showed improvements in free recall of lists of words and in memory for a persons’ name (2-month intervention with weekly 2 hour sessions) but not on text memory – in this specific study (53) it is mentioned that it might be a software bias by not designing the text memory task suitably.
In a study (54) of 127 patients whom during a 12 week period received Cognitive skills training (2 hours/week), Brain Coaching/Counselling (1hour/week) and neurofeedback therapy (2 hours/week) showed improved on average in 4,68 (an improvement of over 3 was labelled as “high impact” ) out of 10 cognitive domains. Most improvements belonged to patients who were below 60 years old and had a baseline MMSE score of minimum 28. All patients received an MRI at the beginning to exclude somatic causes and a random subset of 17 patients were also given an MRI after the completion of the trial. 9 out 17 patients shown a growth in their hippocampal volume, but it was not statistically correlated with the changes in cognitive functioning.
A RCT of 47 patients with MCI (55) found that the intervention group had a tendency to improve the effect sizes for measures of verbal learning and memory compared to control. On the other hand, the effect sizes for learning and visuospatial function tended to favour the control group (whose activities were listening to books, reading and playing the visuospatial-oriented computer game Myst). Although the results were not statistically significant it is still enough to warrant further investigation. The active intervention group did the training for 100 minutes/day, 5 days/week for 6 weeks and it consisted of exercises specifically designed to improve auditory processing speed and accuracy.
Another RCT of 27 patients (56) found an improvement on a measure of visual sustained attention in the intervention group compared to control. The active intervention group completed 30 sessions of a computerised cognitive training program. The exercises targeted the following cognitive functions: attention, processing speed, visual memory and executive functions.
A meta analysis (57) of 17 RCTs found moderate and statistically significant improvements in the active group compared to control. The improvements were seen in: global cognition, verbal learning, verbal memory, nonverbal learning, working memory (largest effect size of all cognitive domains), attention and psychosocial functioning. There were a few individual studies that reported improvements at further follow-ups after the cognitive training had ceased. The majority of studies (meaning 15 out of 17) administered supervised training. The number sessions varied from 6 to 72 with a session length between 20 and 100 minutes and a 1 to 5 sessions per week. The meta analysis mentions that the lowest risk of bias was in the studies that used the COGPACK software (which contains exercises for verbal memory, nonverbal memory, executive functions, attention and speed). There were no mentions of the effect of cognitive training on the progression of MCI to dementia.
Another meta analysis (58) of 17 RCTs concluded that cognitive intervention improves overall cognition and has small benefits on episodic memory, semantic memory, executive functioning, visuospatial ability, attention and MMSE in patients with MCI. The interventions varied a lot from 4 weeks to 6 months of total intervention time, with 1 to 5 sessions per week, each lasting between 30 minutes and 2 hours.
Cognitive training is linked to moderate improvements in cognition in patients with MCI, best results seen in: global cognition, executive function and memory. The domains of improvement depend on the software used, with COGPAK having the lowest risk of bias. The mean session time was between 60-75 minutes, 1 to 5 sessions per week, for about 14 weeks.
In order to obtain benefits from both techniques, the researchers combine physical activity with group based cognitive stimulation training and individual cognitive stimulation training.
One study of this type (59) had 67 participants and its design consisted of 24 weeks divided into 2 phases. First phase consisted in a control period where patients did not receive any treatment, it lasted for 12 weeks and at the end of these weeks they were re-evaluated. The second phase consisted in the active intervention for 12 weeks. At the end of these weeks patients were re-evaluated. They found out that participants showed improvements in physical fitness whilst cognitive outcome measures revealed either stable performance during the control period with improvement following the intervention period (backward- digit span, letter fluency), or deterioration during the control period with stability or improvement following the intervention.
A meta analysis of 46 (21 only with cognitive training, 23 only with physical activity and 2 with both intervention) studies (60) concluded that both cognitive training and physical exercises improve executive functions with cognitive training showing a potential advantage, whereas physical exercise interventions were more consistent in results. It appears that group interventions for physical exercises produced a greater effect than individual intervention and this difference was not notable with cognitive training. This underlines the importance of social engagement as part of the programmes. Studies with the largest effect sizes from the physical exercise intervention used either fitness, strength or a combination of the two. The largest effect size for the cognitive intervention was obtained from studies with programmes containing verbal working memory exercises.

CONCLUSION
There is little evidence that physical activity and cognitive training improve cognitive function in patients with MCI but more studies with clearer methodology are needed because the current literature is of moderate quality which makes it difficult to draw a firm conclusion. It is believed that physical activity improves cognition in patients with MCI because it lowers the cardiovascular and metabolic risk factors, improves tissue oxygenation and endothelial function.
Results are mixed when it comes to slowing progression to dementia, hence more studies with longer follow-up periods are needed. To accurately measure the impact of physical exercise and cognitive training in slowing progression to dementia the follow-up must be long enough so that the control group shows clear signs of deterioration of cognitive functioning.
Unlike physical exercise programmes, cognitive training programmes are better defined, thus the more solid evidence seen in studies using the latter. There are still uncertainties regarding the effect of the two active interventions on the progression to dementia and the method through which these produce any change on cognitive functions. Also we need to better understand the subgroups which are to benefit most of each intervention.
Given the fact that this kind of interventions are virtually without side effects, are rather easy to implement and the benefits may be thorough (both mental and physical) it is to expected that this kind of treatments will largely expand in the future.

REFERENCES
1.Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.
Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2011; 7(3):270 279.
2.https://www.alz.org/professionals_and_researchers_13518.asp
3.American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: Author; 605-610
4.Petersen RC. Clinical practice. Mild cognitive impairment. The New England journal of medicine. 2011; 364(23):2227–2234.
5.Petersen RC, Roberts RO, Knopman DS, et al. Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging.
Neurology. 2010; 75(10):889–897
6.Oscar L. Lopez, MD; William J. Jagust; Corinne Dulberg, PhD; et al. Risk Factors for Mild Cognitive Impairment in the Cardiovascular Health Study Cognition StudyPart 2 Arch Neurol. 2003;60(10):1394- 1399.
7.Lin, JS.; O’Connor, E.; Rossom, R. Et al. Screening for Cognitive
Impairment in Older Adults: An Evidence Update for the US Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2013. Evidence Report No. 107. AHRQ Publication No. 14- 05198-EF-1.
8.Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study.
Neurology 2001; 56: 37–42.
9.Palmer K, Wang HX, Bäckman L, Winblad B, Fratiglioni L.
Differential evolution of cognitive impairment in nondemented older persons: results from the Kungsholmen Project. Am J Psychiatry 2002; 159: 436–42.
10.Yaffe K1, Petersen RC, Lindquist K, Kramer J, Miller B. Subtype of mild cognitive impairment and progression to dementia and death.Dement Geriatr Cogn Disord. 2006;22(4):312-9.
11.Rockwood K, Howard K, MacKnight C, Darvesh S.. Spectrum of disease in vascular cognitive impairment. Neuroepidemiology 1999; 18: 248–54
12.Herve´ Allain , Danie`le Bentue´-Ferrerand Yvette Akwa. Treatment
of the mild cognitive impairment (MCI). Hum. Psychopharmacol Clin Exp 2007; 22: 189–197.
13.Watson GS, Cholerton BA, Reger MA, Baker LD et al. Preserved
cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry. 2005 Nov;13(11):950-8.
14.de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2012 Jun;27(6):592-600.
15.Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer’s disease. Int Clin Psychopharmacol. 2003 Mar;18(2):61-71.
16.Craft S, Baker LD, Montine TJ et al. Intranasal insulin therapy for
Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38.
17.P. Newhouse, MD,corresponding author K. Kellar, PhD, P. Aisen,
MD et al. Nicotine treatment of mild cognitive impairment. A 6-month double-blind pilot clinical trial. Neurology. 2012 Jan 10; 78(2): 91–101.
18.Furio AM, Brusco LI, Cardinali DP. Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study.
J Pineal Res. 2007 Nov;43(4):404-9.
19.Mowla A, Mosavinasab M, Pani A. Does fluoxetine have any effect on the cognition of patients with mild cognitive impairment? A double- blind, placebo-controlled, clinical trial. J Clin Psychopharmacol. 2007 Feb;27(1):67-70.
20.Park SK, Jung IC, Lee WK. A combination of green tea extract and l- theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011 Apr;14(4):334-43.
21.Mori K, Inatomi S, Ouchi K, Azumi Y, Tuchida T. Improving effects of the mushroom Yamabushitake (Hericium erinaceus) on mild cognitive impairment: a double-blind placebo-controlled clinical trial. Phytother Res. 2009 Mar;23(3):367-72.
22.Wang Z, Nie B, Li D. Effect of acupuncture in mild cognitive impairment and Alzheimer disease: a functional MRI study. PLoS One. 2012;7(8):e42730.
23.Russ TC, Morling JR. Cholinesterase inhibitors for mild cognitive impairment. Cochrane Database Syst Rev. 2012(9):CD009132.
24.Serge Gauthier, Barry Reisberg, Michael Zaudig et al. Mild cognitive impairment; Lancet 2006; 367: 1262–70.
25.Bartels C, Wagner M, Wolfsgruber S, Ehrenreich H, Schneider A;
Alzheimer’s Disease Neuroimaging Initiative. Impact of SSRI mpact of SSRI Therapy on Risk of Conversion From Mild Cognitive Impairment to Alzheimer’s Dementia in Individuals With Previous Depression. Am J Psychiatry. 2018 Mar 1;175(3):232-241.
26.Orestes V. Forlenza, Breno S. Diniz, Ma´rcia Radanovic, Franklin S.
Santos, Leda L. Talib and Wagner F. Gattaz. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. The British Journal of Psychiatry (2011) 198, 351–356.
27.Forlenza OV1, de Paula VJ, Machado-Vieira R, Diniz BS, Gattaz WF. Does lithium prevent Alzheimer’s disease? Drugs Aging. 2012 May 1;29(5):335-42
28.Snitz BE, O’Meara ES, Carlson MC, et al. Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA.
2009; 302(24):2663–2670.
29.Bosch J, Yusuf S, Pogue J, et al. Use of ramipril in preventing stroke: double blind randomised trial. Bmj. 2002; 324(7339):699–702
30.Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the
primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation. 2011; 42(2):517–584.
31.Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention
of stroke in patients with stroke or transient ischemic attack: a guideline f o r h e a l t h c a r e p r o f e s s i o n a l s f r o m t h e a m e r i c a n h e a r t association/american stroke association. Stroke; a journal of cerebral circulation. 2011; 42(1):227–276.
32.Darren E.R. Warburton, Crystal Whitney Nicol, Shannon S.D. Bredin. Health benefits of physical activity: the evidence; CMAJ
2006;174(6):801-9.
33.Stephens T. Physical activity and mental health in the United States and Canada: evidence from four population surveys. Prev Med. 1988 Jan;17(1):35-47.
34.Griest JH, Klein MH, Eischens RR, et al. Running as treatment for depression. Comp Psych 1979; 20 (1): 41-54
35.Scott A. Paluska and Thomas L. Schwenk. Physical Activity and Mental Health Current Concepts. Sports Med 2000 Mar; 29 (3): 167-180.
36.Petruzzello SJ, Landers DM, Hatfield BD, et al. Ameta-analysis of the anxiety-reducing effects of acute and chronic exercise.
Sports Med 1991; 11 (3): 143-82.
37.Kivipelto M, Ngandu T, Fratiglioni L et al. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol 2005;62:1556–1560.
38.Erickson KI, Voss MW, Prakash RS et al. Exercise training increases size of hippocampus and improves memory. Proc Nat Acad Sci USA 2011; 108:3017–3022.
39.Hillman CH, Erickson KI, Kramer AF: Be smart, exercise your heart: exercise effects on brain and cognition. Nature 2008;9:58–65.
40.Laura D. Baker, PhD; Laura L. Frank, PhD, MPH; Karen Foster- Schubert, MD; et al. Effects of Aerobic Exercise on Mild Cognitive Impairment A Controlled Trial. Neurol. 2010;67(1):71-79.
41.Danielle Laurin, MSc; René Verreault, MD, PhD; Joan Lindsay, PhD;
et al. Physical Activity and Risk of Cognitive Impairment and Dementia in Elderly Persons. Arch Neurol. 2001;58(3):498-504.
42.Suzuki T, Shimada H, Makizako H. A randomized controlled trial of
multicomponent exercise in older adults with mild cognitive impairment. PLoS One. 2013 Apr 9;8(4):e61483.
43.Lautenschlager NT, Cox KL, Flicker L. Effect of physical activity on
cognitive function in older adults at risk for Alzheimer disease: a randomized trial. JAMA. 2008 Sep 3;300(9):1027-37.
44.Sarah E Lamb, Bart Sheehan, Nicky Atherton et al. Dementia And
Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ
2018;361:k1675.
45.Gates N, Fiatarone Singh MA, Sachdev PS, Valenzuela M. The effect
of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry. 2013 Nov;21(11):1086-97.
46.Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training
on elderly persons with cognitive impairment and dementia: a meta- analysis. Arch Phys Med Rehabil. 2004 Oct;85(10):1694-704.
47.Sofi F, Valecchi D, Bacci D. Physical activity and risk of cognitive
decline: a meta-analysis of prospective studies. J Intern Med. 2011 Jan;269(1):107-17.
48.Zheng G, Xia R, Zhou W, Tao J, Chen L. Aerobic exercise ameliorates
cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials. Br J Sports Med. 2016 Apr 19. pii: bjsports-2015-095699.
49.Ströhle A, Schmidt DK, Schultz F. Drug and Exercise Treatment of
Alzheimer Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of Effects on Cognition in Randomized Controlled Trials. Am J Geriatr Psychiatry. 2015 Dec;23(12):1234- 1249.
50.Blondell SJ, Hammersley-Mather R, Veerman JL. Does physical
activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies. BMC Public Health. 2014 May 27;14:510.
51.Sherry L. Willis and K. Warner Schaie. Cognitive training and
plasticity: Theoretical perspective and methodological consequences. Restor Neurol Neurosci. 2009; 27(5): 375–389.
52.Kelly ME, Loughrey D, Lawlor BA, Robertson IH, Walsh C, Brennan
S. The impact of cognitive training and mental stimulation on cognitive and everyday functioning of healthy older adults: a systematic review and meta-analysis. Ageing Res Rev. 2014 May;15:28-43.
53.Belleville S, Gilbert B, Fontaine F, Gagnon L, Ménard E, Gauthier S.
Improvement of Episodic Memory in Persons with Mild Cognitive Impairment and Healthy Older Adults: Evidence from a Cognitive Intervention Program. Dement Geriatr Cogn Disord. 2006;22(5-6):486- 99.
54.M. Fotuhi, B. Lubinski, M. Trullinger et al. A Personalized 12-week
“Brain Fitness Program” for Improving Cognitive Function and Increasing the Volume of Hippocampus in Elderly with Mild Cognitive Impairment; J Prev Alzheimers Dis. 2016;3(3):133-137.
55.Deborah E. Barnes, PhD, Kristine Yaffe, MD, Nataliya Belfor, PhD. Computer-Based Cognitive Training for Mild Cognitive Impairment: Results from a Pilot Randomized, Controlled Trial. Alzheimer Dis Assoc Disord. 2009 Jul–Sep; 23(3): 205–210.
56.Finn, M., & McDonald, S. (2011). Computerised Cognitive Training for Older Persons With Mild Cognitive Impairment: A Pilot Study Using a Randomised Controlled Trial Design. Brain Impairment, 12(3), 187- 199.
57.Hill NT, Mowszowski L, Naismith SL, Chadwick VL, Valenzuela M,
Lampit A. Computerized Cognitive Training in Older Adults With Mild Cognitive Impairment or Dementia: A Systematic Review and Meta- Analysis. Am J Psychiatry. 2017 Apr 1;174(4):329-340.
58.Li H, Li J, Li N, Li B, Wang P, Zhou T. Cognitive intervention for persons with mild cognitive impairment: A meta-analysis. Ageing Res Rev. 2011 Apr;10(2):285-96.
59.Dannhauser TM, Cleverley M, Whitfield TJ, Fletcher BC, Stevens T,
Walker Z. A complex multimodal activity intervention to reduce the risk of dementia in mild cognitive impairment–ThinkingFit: pilot and feasibility study for a randomized controlled trial. BMC Psychiatry. 2014 May 5;14:129.
60.Karr JE, Areshenkoff CN, Rast P, Garcia-Barrera MA. An empirical
comparison of the therapeutic benefits of physical exercise and cognitive training on the executive functions of older adults: a meta-analysis of controlled trials. Neuropsychology. 2014 Nov;28(6):829-45.

***