Plasma antioxidants and risk of dementia in older adults.

INTRODUCTION: Plant-based diets rich in fruits and vegetables have been associated with lower risk of dementia, but the specific role of antioxidants, a key class of bioactive phytochemicals, has not been well ascertained. METHODS: We measured antioxidants in a case-cohort study nested within the Ginkgo Evaluation of Memory Study. We included 996 randomly selected participants and 521 participants who developed dementia, of which 351 were diagnosed with Alzheimer's disease (AD) during a median of 5.9 years of follow-up. We measured baseline plasma levels of retinol, α-, and γ-tocopherol; zeaxanthin and lutein (combined); beta-cryptoxanthin; cis-lycopene; trans-lycopene; α-carotene; and trans-ß-carotene by organic phase extraction followed by chromatographic analysis and related these to neurologist-adjudicated risks of all-cause dementia and AD. RESULTS: Plasma retinol, α-, and γ-tocopherol, and carotenoids were not significantly related to risk of dementia or AD. Associations were not significant upon Bonferroni correction for multiple testing and were consistent within strata of sex, age, apolipoprotein E ε4 genotype, mild cognitive impairment at baseline, and intake of multivitamin, vitamin A or ß-carotene, or vitamin E supplements. Higher trans-ß-carotene tended to be related to a higher risk of dementia (adjusted hazard ratio [HR] per 1 standard deviation [SD] higher trans-ß-carotene: 1.10; 95% confidence interval [CI]: 1.00, 1.20) and α-carotene tended to be associated with higher risk of AD only (adjusted HR per 1 SD higher α-carotene: 1.15; 95% CI: 1.02, 1.29). DISCUSSION: Plasma antioxidants were not significantly associated with risk of dementia or AD among older adults. Similar studies in younger populations are required to better understand the association between plasma antioxidants and dementia risk.

Blood amyloid levels and risk of dementia in the Ginkgo Evaluation of Memory Study (GEMS): A longitudinal analysis.

INTRODUCTION: Both high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects. METHODS: We examined baseline plasma ß-amyloid (Aß) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment. RESULTS: Increased plasma Aß1-40 and Aß1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aß1-42 and Aß1-42/Aß1-40 ratio compared with those who did not. Aß levels did not predict dementia in mild cognitive impairment participants. DISCUSSION: There was an inverse association between Aß1-42 and Aß1-42/Aß1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aß levels and must be considered in evaluations of relationship of plasma Aß and subsequent risk of dementia.

HIV infection and age effects on striatal structure are additive.

The age of the HIV-infected population is increasing. Although many studies document gray matter volume (GMV) changes following HIV infection, GMV also declines with age. Findings have been inconsistent concerning interactions between HIV infection and age on brain structure. Effects of age, substance use, and inadequate viral suppression may confound identification of GMV serostatus effects using quantitative structural measures. In a cross-sectional study of HIV infection, including 97 seropositive and 84 seronegative, demographically matched participants, ages 30-70, we examined serostatus and age effects on GMV and neuropsychological measures. Ninety-eight percent of seropositive participants were currently treated with anti-retroviral therapies and all were virally suppressed. Gray, white, and CSF volumes were estimated using high-resolution T1-weighted MRI. Linear regression modeled effects of serostatus, age, education, comorbidities, and magnetic field strength on brain structure, using both a priori regions and voxel-based morphometry. Although seropositive participants exhibited significant bilateral decreases in striatal GMV, no serostatus effects were detected in the thalamus, hippocampus, or cerebellum. Age was associated with cortical, striatal, thalamic, hippocampal, and cerebellar GMV reductions. Effects of age and serostatus on striatal GMV were additive. Although no main effects of serostatus on neuropsychological performance were observed, serostatus moderated the relationship between pegboard performance and striatal volume. Both HIV infection and age were associated with reduced striatal volume. The lack of interaction of these two predictors suggests that HIV infection is associated with premature, but not accelerated, brain age. In serostatus groups matched on demographic and clinical variables, there were no observed differences in neuropsychological performance. Striatal GMV measures may be promising biomarker for use in studies of treated HIV infection.

Inflammatory Biomarkers and Cognitive Decline: The Ginkgo Evaluation of Memory Study.

OBJECTIVES: To examine the association between inflammatory biomarkers and global cognitive function. DESIGN: Case-cohort. SETTING: Ginkgo Evaluation of Memory Study. PARTICIPANTS: Individuals aged 75 and older free of neurological or neurodegenerative conditions recruited from 2000 to 2002 (N = 1,315). MEASUREMENTS: Outcome was cognitive function assessed using the modified Mini-Mental State Examination (3MSE) every 6 months for up to 7 years. Exposures were 10 biomarkers measured at baseline: interleukin-2, -6, and -10 (general systemic inflammation); pentraxin 3 (PTX3) and serum amyloid P (SAP) (vascular inflammation); plasminogen activator inhibitor-1, adiponectin, and resistin (metabolic function); receptor for advanced glycation endproduct (oxidative stress); and endothelin-1 (endothelial function). Associations between biomarkers and 3MSE scores (stratified according to mild cognitive impairment (MCI) at baseline) were analyzed using Cox regression (outcome: 3MSE decline of ≥5 points) and mixed-model regression. Bonferroni correction was used to determine significance threshold (P < .0025). RESULTS: In individuals with baseline MCI, PTX3 was associated with a 20% greater hazard of cognitive decline (95% confidence interval = 1.07-1.35), although this association was no longer statistically significant after adjustment for apolipoprotein (APO)E ε4 allele. Adiponectin was associated with faster rate of 3MSE decline in individuals without baseline MCI in mixed-model regression, but the association was similarly attenuated after adjustment for APOE-ε4. CONCLUSION: This study did not find strong evidence of the utility of the biomarkers evaluated for identifying individuals at risk of cognitive decline. Future studies investigating the association between PTX3, SAP, and adiponectin and 3MSE scores may be useful.

Amyloid, neurodegeneration, and small vessel disease as predictors of dementia in the oldest-old.

OBJECTIVE: To examine the association between brain structural changes and ß-amyloid deposition, and incident dementia in 183 elderly subjects without dementia (mean age 85.5 years) 2 years later. METHODS: Subjects had a brain structural MRI scan and a PET scan with (11)C-labeled Pittsburgh compound B (PiB) in 2009, and were evaluated clinically in 2011. RESULTS: At baseline evaluation, of the 183 participants (146 cognitively normal [CN]); 37 mild cognitive impairment [MCI]), 139 (76%) were PiB+, had small hippocampal volume (<25th percentile), or had high white matter lesion (WML) volume (>75th percentile). Two years later, 111 (61%) were classified as CN, 51 (28%) as MCI, and 21 (11%) as dementia. At baseline, 51% of the CN participants and 67.5% of the MCI cases were PiB+. Thirty percent of the CN and 51% of the MCI cases had small hippocampi, and 24% of the CN and 40.5% of the MCI cases had abnormal WMLs. Of the 21 participants who progressed to dementia, 20 (95%) had at least one imaging abnormality. Only 3 (14%) were only PiB+, 1 (5%) had only small hippocampi, 1 (5%) had only WMLs, 1 (5%) was biomarker negative, and the other 16 had various pairs of imaging abnormalities. Continuous variables of PiB retention, left and right hippocampal volume, and WML volume were independent predictors of dementia in a logistic regression analysis controlling for age, sex, education level, and Mini-Mental State Examination scores. CONCLUSIONS: The prevalence of ß-amyloid deposition, neurodegeneration (i.e., hippocampal atrophy), and small vessel disease (WMLs) is high in CN older individuals and in MCI. A combination of 2 or 3 of these factors is a powerful predictor of short-term incidence of dementia.

Pulse wave velocity is associated with ß-amyloid deposition in the brains of very elderly adults.

OBJECTIVE: To determine arterial stiffness and ß-amyloid (Aß) deposition in the brain of dementia-free older adults. METHODS: We studied a cohort of 91 dementia-free participants aged 83-96 years. In 2009, participants completed brain MRI and PET imaging using Pittsburgh compound B (PiB; a marker of amyloid plaques in human brain). In 2011, we measured resting blood pressure (BP), mean arterial pressure (MAP), and arterial stiffness by pulse wave velocity (PWV) in the central, peripheral, and mixed (e.g., brachial ankle PWV [baPWV]) vascular beds, using a noninvasive and automated waveform analyzer. RESULTS: A total of 44/91 subjects were Aß-positive on PET scan. Aß deposition was associated with mixed PWV, systolic BP, and MAP. One SD increase in baPWV resulted in a 2-fold increase in the odds of being Aß-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aß-negative individuals with low WMH burden, each SD increase in PWV was associated with a 2-fold to 4-fold increase in the odds of being Aß-positive and having high WMH. CONCLUSIONS: Arterial stiffness was associated with Aß plaque deposition in the brain, independent of BP and APOE ε4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Aß deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aß deposition and WMH, which has been suggested to be a "double hit" contributing to the development of symptomatic dementia.

Cognitive trajectories associated with ß-amyloid deposition in the oldest-old without dementia.

OBJECTIVE: To determine whether a high prevalence (55%) of Aß deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging. METHODS: A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aß status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models. RESULTS: At GEMS screening (2000-2002), participants who were Aß-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aß-positive relative to Aß-negative participants (ps < 0.05). CONCLUSIONS: Highly prevalent Aß deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aß-status groups may be detectable 7-9 years before neuroimaging.

Effect of Ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women.

BACKGROUND: Accumulating evidence suggests that Ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure (BP)-lowering effects in humans is lacking. METHODS: We determined the effects of G. biloba extract (240 mg/day) on BP and incident hypertension in 3,069 participants (mean age, 79 years; 46% female; 96% white) from the Ginkgo Evaluation of Memory (GEM) study. We also examined whether the treatment effects are modified by baseline hypertension status. RESULTS: At baseline, 54% of the study participants were hypertensive, 28% were prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in BP and pulse pressure (PP) in the G. biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of G. biloba, it did influence the changes in BP variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in prehypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the odds ratio (95% confidence interval (CI)) for being a never-user in the G. biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ between participants assigned to G. biloba vs. placebo (hazard ratio (HR), 0.99, 95% CI, 0.84-1.15). CONCLUSIONS: Our data indicate that G. biloba does not reduce BP or the incidence of hypertension in elderly men and women.

Does Ginkgo biloba reduce the risk of cardiovascular events?

BACKGROUND: Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory Study. The trial previously reported that Ginkgo biloba had no effect on the primary outcome, incident dementia. METHODS AND RESULTS: The double-blind trial randomly assigned 3069 participants over 75 years of age to 120 mg of G biloba EGb 761 twice daily or placebo. Mean follow-up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and sex. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151) between G biloba and placebo. There were 24 hemorrhagic strokes, 16 on G biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease events, 12 (0.8%) on G biloba and 23 (1.5%) on placebo (P=0.04, exact test). Most of the peripheral vascular disease cases had either vascular surgery or amputation. CONCLUSIONS: There was no evidence that G biloba reduced total or CVD mortality or CVD events. There were more peripheral vascular disease events in the placebo arm. G biloba cannot be recommended for preventing CVD. Further clinical trials of peripheral vascular disease outcomes might be indicated. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00010803.

Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial.

CONTEXT: The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning. OBJECTIVE: To determine whether G. biloba slows the rates of global or domain-specific cognitive decline in older adults. DESIGN, SETTING, AND PARTICIPANTS: The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years. INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or identical-appearing placebo (n = 1524). MAIN OUTCOME MEASURES: Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests. RESULTS: Annual rates of decline in z scores did not differ between G. biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05). CONCLUSION: Compared with placebo, the use of G. biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00010803.

Ginkgo biloba for prevention of dementia: a randomized controlled trial.

CONTEXT: Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G. biloba on dementia incidence are lacking. OBJECTIVE: To determine effectiveness of G. biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI). DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia. INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or placebo (n = 1524). MAIN OUTCOME MEASURES: Incident dementia and AD determined by expert panel consensus. RESULTS: Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G. biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G. biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G. biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39). CONCLUSIONS: In this study, G. biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. Trial Registration clinicaltrials.gov Identifier: NCT00010803.

The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.

The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) study was initially designed as a 5-year, randomized double-blind, placebo-controlled trial of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow-up. Initial power calculations based on estimates of incidence rates of dementia in the target population (age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. Primary outcome is incidence of all-cause dementia; secondary outcomes include rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants are required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6 months. Significant decline at any visit, defined by specific changes in cognitive screening scores, leads to a repeat detailed neuropsychological battery, neurological and medical evaluation and MRI scan of the brain. The final diagnosis of dementia is achieved by a consensus panel of experts. Side effects and adverse events are tracked by computer at the central data coordinating center and unblinded data are reviewed by an independent safety monitoring board. Studies such as these are necessary for this and a variety of other potential protective agents to evaluate their effectiveness in preventing or slowing the emergence of dementia in the elderly population.