Prevention of psychiatric illness in the elderly, I: Path to prevention of dementia
Associate Professor Toshihisa Tanaka, D3, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. Email: email@example.com
The 14th Congress of the International Psychogeriatric Association was held in Montreal, Canada, on 1–5 September 2009 (IPA 2009 Montreal). The main theme of the congress was ‘Path to Prevention’ and several interventional studies of dementia, depression, anxiety, and psychosis in the elderly were presented and discussed at the Congress. Pharmaceutical treatment of psychiatric illnesses and patient care are important, but we are now almost at the stage of the prevention of psychiatric illnesses in the elderly. Recent progress in prevention strategies is reviewed in this editorial.
The number of demented elderly has been increasing worldwide and considerable effort has gone into elucidating the pathologenesis of Alzheimer's disease (AD) and related disorders, as well as into the development of diagnostic methods and therapeutics. The prevention, if possible, is more important than therapeutics since no one will have pain or distress and no cost will be required for therapeutics. Primary prevention of dementia is decreasing the risk of dementia in the elderly and is based on lifestyle modification. For example, exercise, leisure, and diet are important factors in the primary prevention of dementia.
EXERCISE FOR THE PREVENTION OF DEMENTIA
Laurin et al. reported a Canadian cohort study of health and aging, in which 4615 normal subjects aged 65 years or older were followed for 5 years.1 Among this group, 436 were diagnosed as having mild cognitive impairment and 285 were diagnosed as having dementia. Compared with no exercise, physical activity was associated with lower risks of cognitive impairment, AD, and dementia of any type. Laurin et al. reported that increased exercise lowered the risk of dementia.1
Lytle et al. conducted a prospective study of a representative rural community containing 1146 people aged 65 years or older, in which self-reported exercise habits and global cognitive function using the Mini-Mental State Examination (MMSE) were examined.2 In a multiple regression model, high exercise level at baseline assessment was negatively associated with cognitive decline and exercise may have implications for the prevention of cognitive decline.
Larson et al. also conducted a prospective cohort study in Seattle of 1740 healthy subjects aged 65 years or older.3 Over a mean follow-up of 6.2 years, 158 participants developed dementia, with an incidence of dementia of 13.0 per 1000 person-years for participants who exercised three or more times per week compared with 19.7 per 1000 person-years for those who exercised less than three times per week. The age- and sex-adjusted hazard ratio for dementia was 0.62 (95% confidence interval (CI), 0.44–0.86; P = 0.004). The interaction between exercise and performance-based physical function was significant (P = 0.013).3
Lautenschlager et al. reported a randomized controlled trial of a 24-week physical activity intervention conducted between 2004 and 2007 in Western Australia.4 One hundred and seventy individuals aged 50 years or older who had memory problems without dementia were randomized and 138 participants completed the 18-month assessment. Participants were randomly allocated to an education and usual care group or to a 24-week home-based program of physical activity. Participants in the intervention group improved 0.26 points, whereas those inthe usual care group deteriorated 1.04 points, on the Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) at the end of the intervention period.4 The significant difference of the outcome measure between the intervention and control groups was observed at the end of the intervention. At 18 months, participants in the intervention group improved 0.73 points on the ADAS-Cog, whereas those in the usual care group improved 0.04 points. Word list delayed recall and Clinical Dementia Rating sum of boxes improved modestly as well. Completion of randomized controlled studies is difficult and the study of Lautenschlager et al. showed strong evidence of a protective effect of exercise against dementia.4
Although exercise may have protective effects against dementia, the underlying mechanism remains unclear. However, exercise may improve cerebral blood flow, maintaining appropriate blood pressure and appropriate serum lipids level, and suppressing platelet agglutination, and these effects may contribute to the lowered risk of dementia.
LEISURE ACTIVITIES FOR THE PREVENTION OF DEMENTIA
An interesting study was reported regarding the relationship between an everyday leisure activities and the risk of dementia. Verghese et al. conducted a prospective cohort study of 469 subjects aged 75 years or older who resided in the community and did not have dementia at baseline.5 They measured the frequency of participation in leisure activities at enrollment and derived cognitive–activity and physical–activity scales. Over a median follow-up period of 5.1 years, dementia developed in 124 subjects (AD in 61 subjects, vascular dementia in 30) and, among the leisure activities, reading, playing board games, playing musical instruments, and dancing were associated with a reduced risk of dementia. Results were similar for AD and vascular dementia. Participation in leisure activities is associated with a reduced risk of dementia, even after adjustment for baseline cognitive status and after the exclusion of subjects with possible preclinical dementia.
The mechanism underlying the protective effects of leisure activity against dementia has not been elucidated. However, in an interesting experimental study, Lazarov et al. reported that exposure of transgenic mice with overexpression of AD-linked amyloid precursor protein (APP) and presenilin (PS)-1 variants to an ‘enriched environment’ resulted in pronounced reductions in cerebral amyloid β levels and amyloid deposits compared with animals raised under ‘standard housing’ conditions.6 The enzymatic activity of the amyloid β-degrading endopeptidase neprilysin was elevated in the brains of ‘enriched’ mice and inversely correlated with amyloid burden.6 Moreover, DNA microarray analysis revealed selective upregulation of transcripts encoded by genes associated with learning and memory, vasculogenesis, neurogenesis, cell survival pathways, amyloid β sequestration, and prostaglandin synthesis. Thus, environmental enrichment may lead to reductions in steady state levels of cerebral amyloid β peptides and amyloid deposition and selective upregulation of specific transcripts in the brains of transgenic mice.
Even though the data described above support the notion, we cannot conclude that leisure activities reduce amyloid β in the human brain by direct interpolation. However, this may be an important hypothesis to explain the protective effect of leisure activities against dementia and should be tested in the future.
DIETS FOR THE PREVENTION OF DEMENTIA
Epidemiologic studies of dietary factors can be traced back to the Rotterdam study. Kalmijn et al. conducted the population-based prospective Rotterdam study in which the association between fat intake and incident dementia among participants aged 55 years or older was investigated.7 Food intake of 5386 non-demented participants was assessed at baseline with a semiquantitative food-frequency questionnaire. At baseline and after an average of 2.1 years follow-up, high intake of total fat, saturated fat, and cholesterol was associated with an increased risk of dementia. Fish consumption, an important source of omega-3 polyunsaturated fatty acids, was inversely related to incident dementia and, in particular, to AD. This study suggested that a high intake of saturated fats and cholesterol increases the risk of dementia, whereas fish consumption may decrease this risk.7
As reviewed by Asada, mechanisms underlying the effects of dietary factors on the prevention of dementia and be classified as follows: (i) caloric restriction; (ii) components of dietary fat; (iii) regulation of glucose and insulin; and (iv) anti-oxidants.8 All these factors have been shown to be related to each other, as well as to the production of amyloid β or inflammatory processes in brain.
Caloric restriction has been reported to decrease glucose and to attenuate free radical generation.9,10 In addition, caloric restriction may be related to the production of amyloid β. Mattson et al. reported that 3xTgAD mice, a tripe transgenic mouse model overexpressing PS1(M146V), APP(Swe), and tau(P301L), treated with caloric restriction (40%) exhibited higher levels of exploratory behavior and performed better in both the goal latency and probe trials of the swim task compared with 3xTgAD mice on a control diet.11 The 3xTgAD mice in the caloric restriction group had lower levels of amyloid β40, amyloid β42, and phosphorylated tau in the hippocampus compared with the control diet group. However, epidemiologic studies are very limited in terms of the effects of caloric restriction on the development of dementia; thus, the protective effects of caloric restriction against dementia remain contentious.
Of the components of dietary fat, dietary omega-3 polyunsaturated fatty acids have been shown to improve brain functioning in animal studies. Cole et al. reported that 3xTgAD mice fed with fish oil and curcumin for 1 month had significant improvement memory on the Y-maze, and that the combination showed more significant inhibition of c-Jun N-terminal kinase and tau phosphorylation in brain.12 Morris et al.13 conducted a prospective study from 1993 through to 2000 in which a total of 815 residents aged 65–94 years who were initially unaffected by AD were followed for an average of 2.3 years before clinical evaluation of incident disease. In that study, 131 participants developed AD. Participants who consumed fish once a week or more had 60% less risk of AD than those who rarely or never ate fish in a model adjusted for age and other risk factors. Total intake of omega-3 polyunsaturated fatty acids was associated with reduced risk of AD, as was intake of docosahexaenoic acid. However, no association or very limited association has been found in other recent studies,14,15,16 and the existing data may favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). Therefore, large clinical trials of extended duration are required to provide definitive answers.
Diabetes has attracted considerable attention as a risk factor for AD because glucose regulatory mechanisms can also affect APP and insulin and can reduce intracellular accumulation of amyloid β by accelerating APP trafficking.17,18 The incidence of other dementia was higher in individuals with diabetes than in those without diabetes. Kimura reported that among 221 Japanese diabetic subjects aged 65 years or older, 39 patients (17.6%) were diagnosed with dementia, including 13 patients with AD (5.9%) and 8 patients with vascular dementia (VaD) (3.6%), and that the prevalence of AD and VaD in these subjects was more frequent than in the general population.19 It has been also reported that individuals with Type 2 diabetes who have the ApoE ε4 allele have twice the risk of developing AD compared with non-diabetic individuals with ApoE ε4.20 Together, these findings indicate that abnormalities in glucose metabolism may have considerable effects on cognitive performance.
As anti-oxidants, vitamins are important to protect proteins, lipids, and nucleic acids from oxidative stress. Vitamin E, namely α-tocopherol, has an anti-oxidant action to erase produced free radicals and is protective especially for lipids. Sano et al. conducted a double-blind placebo-controlled randomized multicenter trial in patients with AD.21 A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), vitamin E (2000 IU a day), both selegiline and vitamin E, or placebo for 2 years. In analyses that included the baseline score on the MMSE as a covariate, there were significant delays in the time to death, institutionalization, or loss of activities of daily living (ADL) for the patients treated with selegiline (median time 655 days; P = 0.012), vitamin E (670 days; P = 0.001) or combination therapy (585 days; P = 0.049) compared with the placebo group (440 days). However Petersen et al. reported a randomized double-blind study in which subjects with the amnestic subtype of mild cognitive impairment (MCI) were treated with 2000 IU vitamin E daily, 10 mg donepezil daily, or placebo for 3 years.22 A total of 769 subjects were enrolled in that study, and possible or probable AD developed in 212. Compared with the placebo group, there were no significant differences in the probability of progression to AD in the vitamin E- or donepezil-treated groups during the 3 years of treatment. Only the treatment effects at 6-month intervals showed that the donepezil-treated group had a reduced likelihood of progression to AD during the first 12 months of the study (P = 0.04) compared with the placebo group.22 There were no significant differences in the rate of progression to AD between the vitamin E-treated and placebo groups at any point, either among all patients or among ApoE ε4 carriers. Therefore, vitamin E may have delay the development of AD, but it may not have protective effects against the conversion of MCI to AD and more clinical studies are needed to prove its protective actions. Other vitamins, including B6, B12, and folate, are related to homocycsteine metabolism, which is related to the production of amyloid β and is a risk factor for AD.23–25 McMahon et al. conducted 2 year, double-blind, placebo-controlled, randomized clinical trial involving 276 healthy participants aged 65 years or older.26 The participants were treated with homocysteine-lowering treatment, which consisted of a daily supplement containing folate (1000 µg) and vitamins B12 (500 µg) and B6 (10 mg). However, there were no significant differences between the vitamin-treated and placebo groups in terms of scores on tests of cognition. Further studies are required to test the importance of homocysteine-lowering vitamins in the prevention of AD.
Progress in the prevention of dementia has been reviewed and exercise, leisure activities, and nutrition appear to be very important. However, the precise mechanisms underlying the protective effects of these three factors are uncertain, and the best way which in which to prevent dementia has yet to be determined scientifically. At IPA 2009 Montreal, there was a plenary symposium on the prevention of dementia, where many trials were reviewed and discussed. The symposium concluded that at this moment a healthy, active, socially integrated lifestyle with balanced nutrition, in combination with monitoring of metabolic and cardiovascular risk factors, is recommended to reduce the risk of dementia. Further investigations are required to elucidate the best lifestyle for the prevention of dementia.