Laura E. Middleton

Promising Strategies for the Prevention of Dementia

The incidence and prevalence of dementia are expected to increase several-fold in the coming decades. Given that the current pharmaceutical treatment of dementia can only modestly improve symptoms, risk factor modification remains the cornerstone for dementia prevention. Some of the most promising strategies for the prevention of dementia include vascular risk factor control, cognitive activity, physical activity, social engagement, diet, and recognition of depression. In observational studies, vascular risk factors-including diabetes, hypertension, dyslipidemia, and obesity-are fairly consistently associated with increased risk of dementia. In addition, people with depression are at high risk for cognitive impairment. Population studies have reported that intake of antioxidants or polyunsaturated fatty acids may be associated with a reduced incidence of dementia, and it has been reported that people who are cognitively, socially, and physically active have a reduced risk of cognitive impairment. However, results from randomized trials of risk factor modification have been mixed. Most promising, interventions of cognitive and physical activity improve cognitive performance and slow cognitive decline. Future studies should continue to examine the implication of risk factor modification in controlled trials, with particular focus on whether several simultaneous interventions may have additive or multiplicative effects.

The Mental Activity and eXercise (MAX) Trial A Randomized Controlled Trial to Enhance Cognitive Function in Older Adults

IMPORTANCEnThe prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed. Physical or mental activity alone result in relatively small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects.nnnOBJECTIVEnTo examine the combined effects of physical plus mental activity on cognitive function in older adults.nnnDESIGNnRandomized controlled trial with a factorial design.nnnSETTINGnSan Francisco, California.nnnPARTICIPANTSnA total of 126 inactive, community-residing older adults with cognitive complaints.nnnINTERVENTIONSnAll participants engaged in home-based mental activity (1 h/d, 3 d/wk) plus class-based physical activity (1 h/d, 3 d/wk) for 12 weeks and were randomized to either mental activity intervention (MA-I; intensive computer) or mental activity control (MA-C; educational DVDs) plus exercise intervention (EX-I; aerobic) or exercise control (EX-C; stretching and toning); a 2 × 2 factorial design was used so that there were 4 groups: MA-I/EX-I, MA-I/EX-C, MA-C/EX-1, and MA-C/EX-C.nnnMAIN OUTCOME MEASURESnGlobal cognitive change based on a comprehensive neuropsychological test battery.nnnRESULTSnParticipants had a mean age of 73.4 years; 62.7% were women, and 34.9% were Hispanic or nonwhite. There were no significant differences between the groups at baseline. Global cognitive scores improved significantly over time (mean, 0.16 SD; P < .001) but did not differ between groups in the comparison between MA-I and MA-C (ignoring exercise, P = .17), the comparison between EX-I and EX-C (ignoring mental activity, P = .74), or across all 4 randomization groups (P = .26).nnnCONCLUSIONS AND RELEVANCEnIn inactive older adults with cognitive complaints, 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function with no evidence of difference between intervention and active control groups. These findings may reflect practice effects or may suggest that the amount of activity is more important than the type in this subject population.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00522899.

Physical Activity Over the Life Course and Its Association with Cognitive Performance and Impairment in Old Age

OBJECTIVE: To determine how physical activity at various ages over the life course is associated with cognitive impairment in late life.

ACTIVITY ENERGY EXPENDITURE AND INCIDENT COGNITIVE IMPAIRMENT IN OLDER ADULTS

BACKGROUNDnStudies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on self-reports of physical activity, which only moderately correlate with objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.nnnMETHODSnWe calculated AEE as 90% of total energy expenditure (assessed during 2 weeks using doubly labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean age, 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998-1999). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination. Cognitive impairment was defined as a decline of at least 1.0 SD (9 points) between baseline and follow-up evaluations.nnnRESULTSnAfter adjustment for baseline Modified Mini-Mental State Examination scores, demographics, fat-free mass, sleep duration, self-reported health, and diabetes mellitus, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (odds ratio, 0.09; 95% confidence interval, 0.01-0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (Pxa0=xa0.05 for trend over tertiles).nnnCONCLUSIONSnThese findings indicate that greater AEE may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.

Changes in Cognition and Mortality in Relation to Exercise in Late Life: A Population Based Study

Background On average, cognition declines with age but this average hides considerable variability, including the chance of improvement. Here, we investigate how exercise is associated with cognitive change and mortality in older people and, particularly, whether exercise might paradoxically increase the risk of dementia by allowing people to live longer. Methods and Principal Findings In the Canadian Study of Health and Aging (CSHA), of 8403 people who had baseline cognition measured and exercise reported at CSHA-1, 2219 had died and 5376 were re-examined at CSHA-2. We used a parametric Markov chain model to estimate the probabilities of cognitive improvement, decline, and death, adjusted for age and education, from any cognitive state as measured by the Modified Mini-Mental State Examination. High exercisers (at least three times per week, at least as intense as walking, nu200a=u200a3264) had more frequent stable or improved cognition (42.3%, 95% confidence interval: 40.6–44.0) over 5 years than did low/no exercisers (all other exercisers and non exercisers, nu200a=u200a4331) (27.8% (95% CI 26.4–29.2)). The difference widened as baseline cognition worsened. The proportion whose cognition declined was higher amongst the high exercisers but was more similar between exercise groups (39.4% (95% CI 37.7–41.1) for high exercisers versus 34.8% (95% CI 33.4–36.2) otherwise). People who did not exercise were also more likely to die (37.5% (95% CI 36.0–39.0) versus 18.3% (95% CI 16.9–19.7)). Even so, exercise conferred its greatest mortality benefit to people with the highest baseline cognition. Conclusions Exercise is strongly associated with improving cognition. As the majority of mortality benefit of exercise is at the highest level of cognition, and declines as cognition declines, the net effect of exercise should be to improve cognition at the population level, even with more people living longer.

Targets for the Prevention of Dementia

The prevalence of dementia is expected to increase dramatically over the upcoming decades due to the aging population. Since treatment is still short of a cure, preventative strategies are of the utmost importance. Stimulating activity (cognitive, physical, and social), vascular risk factors, and diet may be important in preventative strategies. Dementia risk may be modified by participation in stimulating activities. One study suggested that the cognitive, physical, and social components of activity were of equal importance to cognitive outcomes. However, while exercise interventions appear to benefit global cognition, the benefits from cognitive training appear to be domain specific. People with vascular risk factors (hypertension, diabetes, dyslipidemia, and obesity) appear to be at higher risk for dementia than those without in observational and clinical trials. Controlled trials suggest that vascular risk management via some pharmaceutical interventions may benefit cognition, though results are inconsistent. Finally, people who adhere to a Mediterranean diet or who have high intake of antioxidants and omega-3 fatty acids have reduced likelihood of dementia in observational studies. However, supplementation in controlled trials has not generally proved successful at improving cognitive outcomes. A single supplement may be insufficient to prevent dementia; it may be that the overall diet is more important. Future large randomized controlled studies should examine whether interventions can reduce the risk of dementia and whether combining cognitive, physical, and social activity, vascular risk reduction, and dietary interventions might have additive or multiplicative effects.

Neuropathologic features associated with Alzheimer disease diagnosis Age matters

Objective: To examine whether the association between clinical Alzheimer disease (AD) diagnosis and neuropathology and the precision by which neuropathology differentiates people with clinical AD from those with normal cognition varies by age. Methods: We conducted a cross-sectional analysis of 2,014 older adults (≥70 years at death) from the National Alzheimers Coordinating Center database with clinical diagnosis of normal cognition (made ≤1 year before death, n = 419) or AD (at ≥65 years, n = 1,595) and a postmortem neuropathologic examination evaluating AD pathology (neurofibrillary tangles, neuritic plaques) and non-AD pathology (diffuse plaques, amyloid angiopathy, Lewy bodies, macrovascular disease, microvascular disease). We used adjusted logistic regression to analyze the relationship between clinical AD diagnosis and neuropathologic features, area under the receiver operating characteristic curve (c statistic) to evaluate how precisely neuropathology differentiates between cognitive diagnoses, and an interaction to identify effect modification by age group. Results: In a model controlling for coexisting neuropathologic features, the relationship between clinical AD diagnosis and neurofibrillary tangles was significantly weaker with increasing age (p < 0.001 for interaction). The aggregate of all neuropathologic features more strongly differentiated people with clinical AD from those without in younger age groups (70–74 years: c statistic, 95% confidence interval: 0.93, 0.89–0.96; 75–84 years: 0.95, 0.87–0.95; ≥85 years: 0.83, 0.80–0.87). Non-AD pathology significantly improved precision of differentiation across all age groups (p < 0.004). Conclusion: Clinical AD diagnosis was more weakly associated with neurofibrillary tangles among the oldest old compared to younger age groups, possibly due to less accurate clinical diagnosis, better neurocompensation, or unaccounted pathology among the oldest old.

Frequency of domain-specific cognitive impairment in sub-acute and chronic stroke.

BACKGROUNDnFunctional contributions of cognitive impairment may vary by domain and severity.nnnOBJECTIVEn(1) To characterize frequency of cognitive impairment by domain after stroke by severity (mild: -1.5 ≤ z-score < -2; severe: Z ≤ -2) and time (sub-acute: < 90d; chronic: 90d-2yrs); and (2) To assess the association of cognitive impairment with function in chronic stroke.nnnMETHODSnCognitive function was characterized among 215 people with sub-acute or chronic stroke (66.8 years, 43.3% female). Z-scores by cognitive domain were determined from normative data. Function was defined as the number of IADLs minimally independent.nnnRESULTSn76.3% of sub-acute and 67.3% of chronic stroke participants had cognitive impairment in ≥ 1 domain (p-for-difference = 0.09). Severe impairment was most common in psychomotor speed (sub-acute: 53.5%; chronic: 33.7%). Impairment in executive function was common (sub-acute: 39.5%; chronic: 30.7%) but was usually mild. Severe impairment in psychomotor speed, visuospatial function, and language and any impairment in executive function and memory was associated with IADL impairment (p < 0.03).nnnCONCLUSIONSnMild cognitive impairment is common after stroke but is not associated with functional disability. Impairment in psychomotor speed, executive function, and visuospatial function is common and associated with functional impairment so should be a focus of screening and rehabilitation post-stroke.

Modeling the Impact of Sex on How Exercise Is Associated with Cognitive Changes and Death in Older Canadians

Background: Exercise improves cognition and lessens the risk of death in older adults. Cognition and mortality are each also affected by biological sex, which might modify the effect of exercise. We investigated how sex mediates the impact of exercise on mortality and 5-year changes in cognition. Methods: In the Canadian Study of Health and Aging (n = 8,403, 60.7% women), cognitive states were defined as errors in the Modified Mini-Mental State Examination. Improvement and declines were modeled using a 4-parameter truncated Poisson distribution. Results: Men and women showed similar levels of improvement or stabilization (34.1%, 95% CI = 32.1–35.9 in women and 30.2%, 95% CI = 28.2–32.4 in men). In unadjusted analysis, more men died (34%, 95% CI = 32.3–36.3) than did women (30.3%, 95% CI = 28.4–32.2). Higher education was beneficial for cognitive function in both sexes, but did not impact survival when other factors were considered. The effect of exercise differed by sex: women had a survival advantage compared with men, but men most benefited in cognitive functioning. Conclusions: Exercise is strongly associated with cognitive improvement and stabilization in men, and with better survival in women. In contrast to conventional approaches, our model allows us to analyze how different risk factors affect cognition to any degree, and simultaneously to assess their impact on survival.

The inclusion of cognition in vascular risk factor clinical practice guidelines.

Background: People with vascular risk factors are at increased risk for cognitive impairment as well as vascular disease. The objective of this study was to evaluate whether vascular risk factor clinical practice guidelines consider cognition as an outcome or in connection with treatment compliance. Methods: Articles from PubMed, EMBASE, and the Cochrane Library were assessed by at least two reviewers and were included if: (1) Either hypertension, high cholesterol, diabetes, or atrial fibrillation was targeted; (2) The guideline was directed at physicians; (3) Adult patients (aged 19 years or older) were targeted; and (4) The guideline was published in English. Of 91 guidelines, most were excluded because they were duplicates, older versions, or focused on single outcomes. Results: Of the 20 clinical practice guidelines that met inclusion criteria, five mentioned cognition. Of these five, four described potential treatment benefits but only two mentioned that cognition may affect compliance. No guidelines adequately described how to screen for cognitive impairment. Conclusion: Despite evidence that links cognitive impairment to vascular risk factors, only a minority of clinical practice guidelines for the treatment of vascular risk factors consider cognition as either an adverse outcome or as a factor to consider in treatment.