Increasing attention is focused on developing mental and physical activity interventions for those with subjective memory complaints or mild cognitive impairment (MCI) to reduce the risk of dementia. Such interventions might also benefit other outcomes including sleep, depression, and quality of life. The MAX (Mental Activity and eXercise) Trial was a randomized, controlled trial in which 126 sedentary elders with cognitive complaints or MCI were randomized to 12-weeks of physical activity (aerobic exercise vs. stretching, 60 minutes, 3 days/week) and mental activity (computer training vs. educational DVDs, 60 minutes, 3 days/week) using a factorial design. Cognitive outcomes have previously been reported. Briefly, cognitive outcomes improved significantly in all groups, and improvements were greater with computer training than educational DVDs in subjects with MCI. Here, we examine the impact of the intervention on non-cognitive outcomes including sleep quality (Sleep Disorders Questionnaire), health-related quality of life (SF-12), and depressive symptoms (Geriatric Depression Scale). Participants had a mean age of 73 years; 63% were female and 35% were Hispanic or non-white. Among study participants with poor sleep at baseline, sleep quality improved significantly more (P = 0.02) in the stretching group (12.0 to 8.8 points, P <0.001) than the aerobic group (12.1 to 11.5 points, P = 0.13). Participants also experienced significant improvements in physical health-related quality of life (47.5 to 49.0 points, P = 0.05) and were more likely to report no depressive symptoms (24% to 38%, P = 0.008), but there were no differences in these outcomes between intervention groups. Results were similar in subjects with and without MCI. In sedentary older adults with cognitive complaints or MCI, 12 weeks of either aerobic or stretching exercises significantly improved quality of life and depressive symptoms; in addition, in those with poor sleep, stretching was more effective than aerobic exercise for improving sleep. Exercise, whether aerobic or stretching and toning, appears to have wide-ranging beneficial effects and should be encouraged in sedentary elders with cognitive complaints or MCI.
OBJECTIVES: Recent studies have suggested that estrogen may improve cognitive function or prevent cognitive decline in older women. Little research has been conducted on exogenous or endogenous sex hormones and cognition in older men, yet it has been hypothesized that testosterone, either directly or by conversion to estrogens, may improve cognitive function. We investigated whether serum level of testosterone and estradiol is associated with cognition in older community‐dwelling men. DESIGN: A cross‐sectional study. SETTING: Population‐based listings in the Monongahela Valley near Pittsburgh, Pennsylvania. PARTICIPANTS: Three hundred ten men (mean age ± standard deviation = 73.0 ± 7.1) who were part of a cohort study. MEASUREMENTS: We measured cognitive function using the Mini‐Mental State Examination (MMSE), Trails B, and Digit Symbol. Sex hormone levels were determined by radioimmunoassay from serum obtained at the time of cognitive testing and analyzed by tertile. RESULTS: No consistent association between total testosterone level and cognitive test scores was observed. However, men with high bioavailable (loosely protein‐bound) testosterone had better cognitive test scores on all three tests ( P ≤ .001). Total estradiol levels were associated with worse cognitive scores on Digit Symbol ( P < .001) and Trails B ( P = .002), but bioavailable estradiol levels were not associated with cognitive function. Level of sex hormone binding globulin (SHBG) was negatively associated with cognitive scores on all three tests ( P ≤ .001). After adjusting for age and education, the statistical significance lessened for bioavailable testosterone (MMSE, P = .086; Digit Symbol, P = .047; Trails B, P = .076) and became nonsignificant for SHBG (all cognitive tests P > .10). CONCLUSIONS: Our findings support the hypothesis that higher levels of bioavailable testosterone, but not of bioavailable estradiol, are associated with better cognitive function in older men. In addition, bioavailable measures of testosterone may better reflect hormone levels available to the brain and thus be more closely associated with central nervous system outcomes such as cognition. Future studies, especially randomized trials, should be undertaken to determine whether testosterone may protect against cognitive decline in older men.
Abstract Background Modifiable risk factors are hypothesized to account for 30‐40% of dementia; yet, few trials have demonstrated that risk reduction interventions, especially multi‐domain, improve risk factors or cognition. We conducted the Systematic Multi‐domain Alzheimer’s Risk Reduction Trial (SMARRT), a 2‐year personalized, pragmatic risk reduction intervention. Methods We recruited 172 adults at elevated risk for dementia (age 70‐89 and ≥ 2 targeted risk factors) from primary care clinics of Kaiser Permanente Washington. Participants were randomly assigned to the SMARRT intervention (personalized risk reduction goals with health/nurse coaching) or to Health Education (HE) control. The primary outcome was change in a composite modified Neuropsychological Test Battery (mNTB); pre‐planned secondary outcomes were change in risk factors and quality of life. Outcomes were assessed at baseline, 6, 12, 18, and 24 months (initially in person, then due to COVID‐19, by phone). We used linear mixed models to compare, by intention‐to‐treat, changes from baseline averaged over the four follow‐up assessments. Results Participants had a mean age of 75.7 years (sd 4.8), 63% were women and 81% non‐Hispanic White. After 2 years, compared to the 90 in the HE control, the 82 adults assigned to SMARRT demonstrated larger improvements in the composite cognitive score (average treatment effect 0.15 SD; 95% CI 0.04‐0.26, p = 0.008; an 80% improvement compared to HE change), better composite risk factor score (average treatment effect 0.11 SD; 95% CI 0.02‐0.21, p = 0.02) and improved quality of life (average treatment effect 1.11 points; 95% CI 0.08‐2.14, p = 0.03). There were no between‐group differences in serious adverse events or SAEs (HE = 23, SMARRT = 24, p = 0.59), but the intervention group had greater treatment related AEs such as musculoskeletal pain (14 vs. 0, p<0.001). Both groups expressed high level of satisfaction with the trial with greater satisfaction in intervention arm. Conclusion A 2‐year personalized, multidomain intervention led to modest improvements on cognition, most targeted risk factors, and quality of life. Modifiable risk reduction strategies should be considered for older adults at risk for dementia.
Background.Low literacy is common among the elderly and possibly more reflective of educational attainment than years of school completed. We examined the association between literacy and risk of likely dementia in older adults.
Alzheimer disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Nutritional compounds are postulated to play a role in the pathophysiological processes that are affected in AD. We here provide the first systematic review and meta-analysis that compares plasma levels of micronutrients and fatty acids in AD patients to those in cognitively intact elderly controls. A secondary objective was to explore the presence of different plasma nutrient levels between AD and control populations that did not differ in measures of protein/energy nourishment.We screened literature published after 1990 in the Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines for AD patients, controls, micronutrient, vitamins, and fatty acids, resulting in 3397 publications, of which 80 met all inclusion criteria. Status of protein/energy malnutrition was assessed by body mass index, mini nutritional assessment score, or plasma albumin. Meta-analysis, with correction for differences in mean age between AD patients and controls, was performed when more than five publications were retrieved for a specific nutrient.We identified five or more studies for folate, vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, copper, iron, and zinc but fewer than five studies for vitamins B1 and B6, long-chain omega-3 fatty acids, calcium, magnesium, manganese, and selenium (the results of the individual publications are discussed). Meta-analysis showed significantly lower plasma levels of folate and vitamin A, vitamin B12, vitamin C, and vitamin E (P < .001), whereas nonsignificantly lower levels of zinc (P = .050) and vitamin D (P = .075) were found in AD patients. No significant differences were observed for plasma levels of copper and iron. A meta-analysis that was limited to studies reporting no differences in protein/energy malnourishment between AD and control populations yielded similar significantly lower plasma levels of folate and vitamin B12, vitamin C, and vitamin E in AD.The lower plasma nutrient levels indicate that patients with AD have impaired systemic availability of several nutrients. This difference appears to be unrelated to the classic malnourishment that is well known to be common in AD, suggesting that compromised micronutrient status may precede protein and energy malnutrition. Contributing factors might be AD-related alterations in feeding behavior and intake, nutrient absorption, alterations in metabolism, and increased utilization of nutrients for AD pathology-related processes. Given the potential role of nutrients in the pathophysiological processes of AD, the utility of nutrition may currently be underappreciated and offer potential in AD management.
Prior studies indicate that olfactory function may be an early marker for cognitive impairment, but the body of evidence has been largely restricted to white populations.We studied 2,428 community-dwelling black and white older adults (baseline age 70-79 years) without dementia enrolled in the Health, Aging, and Body Composition (Health ABC) study. Olfaction was measured as odor identification (OI) with the 12-item Cross Cultural Smell Identification Test in year 3. We defined incident dementia over 12 years on the basis of hospitalization records, prescription for dementia medication, or 1.5-SD decline in race-stratified global cognition score. We assessed dementia risk associated with OI score (by tertile) using Cox proportional hazards models. All analyses were stratified by race.Poorer OI in older adults without dementia was associated with increased risk of dementia. After adjustment for demographics, medical comorbidities, and lifestyle characteristics, white participants in the poor or moderate OI tertile had greater risk of dementia (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 2.45-4.54; and HR 1.84, 95% CI 1.33-2.54, respectively) compared to those in the good tertile of function. Among blacks, worse OI was associated with an increased risk of dementia, but the magnitude of the effect was weaker (p for interaction = 0.04) for the poor OI tertile (adjusted HR 2.03, 95% CI 1.44-2.84) and for the moderate tertile (adjusted HR 1.42, 95% CI 0.97-2.10). There was no interaction between OI and APOE ε4 and risk of dementia.While the magnitude of the association was stronger in whites, we found that poor OI was associated with increased risk of dementia among both black and white older adults.
OBJECTIVES: To investigate the association between objectively measured sleep‐disordered breathing (SDB) and cognitive impairment in community‐dwelling older women and to determine whether the apolipoprotein E (APOE) ɛ4 allele modifies this association. DESIGN: Cross‐sectional. SETTING: Participants' homes and two sites of the Study of Osteoporotic Fractures (SOF). PARTICIPANTS: Four hundred forty‐eight women with a mean age±standard deviation (SD) of 82.8±3.4. MEASUREMENTS: Participants completed the Mini‐Mental State Examination (MMSE), Trail Making Test Part B (Trails B), and polysomnography (PSG). SDB indices were the apnea–hypopnea index (AHI), the central apnea index (CAI), and oxygen saturation (SaO 2 ) nadir less than 80%. APOE ɛ4 was determined for a subset of 242 women. Cognitive impairment was defined as 1.5 SDs or more from the sample mean on either cognitive test (MMSE or Trails B). RESULTS: All SDB indices were associated with cognitive impairment according to the MMSE (AHI (per SD, odds ratio (OR)=1.4, 95% confidence interval (CI)=1.03–1.9), AHI of ≥30 (OR=3.4, 95% CI=1.4–8.1), SaO 2 nadir <80% (OR=2.7, 95% CI=1.1–6.6), and CAI (per SD, OR=1.4, 95% CI=1.1–1.7)). Weaker, nonsignificant associations emerged between SDB and Trails B. In women who completed genotyping, each SD increase in AHI was associated with 70% greater odds of cognitive impairment according to the MMSE (OR=1.7, 95% CI=1.2–2.6). Women with the ɛ4 allele had a nearly five times greater odds of impairment (per SD, OR=4.6, 95% CI‐1.0–20.7); the association was smaller and nonsignificant in women without the ɛ4 allele (per SD, OR=1.5, 95% CI‐0.9–2.4; P for interaction=.08). CONCLUSION: SDB is an important risk factor for cognitive impairment in older women, especially those with the APOE ɛ4 allele. Mechanisms linking these disorders need to be identified.
Possible involvement of complement (C) systems in the pathogenesis of traumatic brain injury (TBI) was investigated by quantifying Cproteins in plasma astrocyte-derived exosomes (ADEs) of subjects with sports-related TBI (sTBI) and TBI in military veterans (mtTBI) without cognitive impairment. All sTBI subjects (n = 24) had mild injuries, whereas eight of the mtTBI subjects had moderate, and 17 had mild injuries. Plasma levels of ADEs were decreased after acute sTBI and returned to normal within months. Cprotein levels in ADEs were from 12- to 35-fold higher than the corresponding levels in neuron-derived exosomes. CD81 exosome marker-normalized ADE levels of classical pathway C4b, alternative pathway factor D and Bb, lectin pathway mannose-binding lectin (MBL), and shared neurotoxic effectors C3b and C5b-9 terminal C complex were significantly higher and those of C regulatory proteins CR1 and CD59 were lower in the first week of acute sTBI (n = 12) than in controls (n = 12). Most C abnormalities were no longer detected in chronic sTBI at 3-12 months after acute sTBI, except for elevated levels of factor D, Bb, and MBL. In contrast, significant elevations of ADE levels of C4b, factor D, Bb, MBL, C3b and C5b-9 terminal C complex, and depressions of CR1 and CD59 relative to those of controls were observed after 1-4 years in early chronic mtTBI (n = 10) and persisted for decades except for normalization of Bb, MBL, and CD59 in late chronic mtTBI (n = 15). Complement inhibitors may be useful therapeutically in acute TBI and post-concussion syndrome.
greater neuropathology in aging.Indeed, there is strong evidence that diabetes mellitus is a risk factor for cognitive decline and dementia. 2As Dr Kawada mentioned, some studies examining both diabetes mellitus and APOE ε4 status have found interactive effects (eg, Bangen et al 3 ).In referring to our findings, Dr Kawada stated, "Regarding diabetes mellitus, the authors could not elucidate it as a significant predictor of cognitive resilience."In fact, we did find associations between diabetes mellitus and cognitive resilience, especially among black APOE ε4 carriers.Our random forest results suggested that being free of diabetes mellitus is one of the most important predictors of cognitive resilience among black APOE ε4 carriers.A follow-up analysis (which estimated the independent effects of each of the variables identified as important predictors in the random forest analyses) showed that, among black APOE ε4 carriers, being free of diabetes mellitus was associated with 1.45 times increased odds of cognitive resilience.Although this did not reach statistical significance (perhaps owing to sample size/power limitations), we think the substantial effect size is suggestive of an important effect.For white APOE ε4 carriers, although we found a statistically significant bivariate association between diabetes mellitus and cognitive resilience, our random forest analysis did not identify diabetes mellitus as one of the strongest predictors of cognitive resilience.We were surprised by this, and the reason for the apparent discrepancy between this and results of prior related studies is unclear.It is possible that our study's focus on a relatively unique outcome measure (cognitive resilienceie, optimal cognitive trajectory) and application of a novel multivariable analysis (ie, random forest analysis) may have contributed to differing results from previous studies.Additionally, Dr Kawada suggested we "consider including baseline psychological factors as predictors of cognitive resilience."We agree that psychological factors are important to examine in this context.We were able to investigate depression, self-reported sleep, and recent experience of negative life events in our study; future studies may benefit from a more comprehensive assessment of psychological functioning or objective sleep measures.
