Michelle C. Carlson

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.

A Social Model for Health Promotion for an Aging Population: Initial Evidence on the Experience Corps Model

This report evaluates whether a program for older volunteers, designed for both benerativity and health promotion, leads to short-term improvements inmultiple behavioral risk factors and positive effects on intermediary risk factors for disability and other morbidities. The Experience Corps® places older volunteers in public elementary schools in roles designed to meet schools’ needs and increase the social, physical, and cognitive activity of the volunteers. This article reports on a pilot randomized trial in Baltimore, Maryland. The 128 volunteers were 60–86 years old; 95% were African American. At follow-up of 4–8 months, physical activity, strength, people one could turn to for help, and cognitive activity increased significantly, and walking speed decreased significantly less, in participants compared to controls. In this pilot trial, physical, cognitive, and social activity increased, suggesting the potential for the Experience Corps to improve health for an aging population and simultaneously improve educational outcomes for children.

Benefits of fatty fish on dementia risk are stronger for those without APOE ε4

Objective: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE ε4 status in the Cardiovascular Health Cognition Study (CHCS). Methods: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physicians assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE ε4. Results: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 to 1.02), and AD by 41% (95% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE ε4 showed this effect to be selective to those without the ε4 allele. Adjustment by education and income attenuated the effect. Conclusion: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE ε4 allele.

Agreement Between Self-Report of Disease Diagnoses and Medical Record Validation in Disabled Older Women: Factors That Modify Agreement

Objectives: To determine the agreement between self‐report of chronic disease and validated evidence of disease using multiple ascertainment methods and to assess effects of cognition, education, age, and comorbidity.

Cognitive Impairment and Decline Are Associated with Carotid Artery Disease in Patients without Clinically Evident Cerebrovascular Disease

Context While stroke is a known cause of cognitive impairment, the relationship between carotid artery stenosis and cognitive function in people without a history of stroke is unclear. Contribution In this study of 4006 right-handed individuals 65 years of age and older, left-sided carotid artery stenosis of at least 75% was associated with cognitive impairment at baseline and cognitive decline over 5 years. This association persisted after right-sided carotid stenosis and cardiovascular risk factors were taken into account, which means that left-sided stenosis is more than simply an indicator of cardiovascular disease. Cautions This observational study does not constitute evidence that treatment of left-sided stenosis would benefit cognition. The Editors Cognitive impairment is common in elderly persons, with a prevalence of 25% in those 65 years of age or older and 65% in those 85 years of age or older (1). It is associated with disability, institutionalization, and early death (2, 3). Cerebral infarction contributes to cognitive impairment in approximately 50% of cases (3), sometimes in conjunction with Alzheimer disease (4). Imaging studies of the brain may reveal infarction in patients without history of stroke or transient ischemic attack (5), and these silent infarctions have been associated with cognitive impairment (5, 6). Furthermore, brain hypoperfusion may result in ischemic injury without evidence of infarction (7). Thus, silent cerebral infarction and brain hypoperfusion may be important causes of cognitive impairment. Markers of atherosclerotic disease of the internal carotid artery and common carotid artery have been associated with brain injury. High-grade stenosis of the internal carotid artery accounts for 20% to 30% of ischemic strokes (8). Stenosis of the internal carotid artery and intimamedia thickness of the internal and common carotid arteries are associated with silent cerebral infarction and symptomatic infarctions that are ipsilateral or contralateral to the side of maximal disease (9-11). Some studies have suggested that stenosis of the internal carotid artery may be a risk factor for cognitive impairment even in persons without a history of stroke, but other studies have not demonstrated such an association (12). Small samples, variable definitions of internal carotid artery stenosis, and case selection may have contributed to these inconsistent results. Carotid artery disease is also associated with underlying vascular disease and its risk factors. Hypertension, diabetes mellitus, cigarette smoking, and dyslipidemia are associated with an increased risk for carotid artery disease (13, 14), but these same risk factors may also cause ischemic injury to the brain independent of carotid disease (15). Furthermore, several risk factors for vascular disease are associated with cognitive impairment (16-25). This may be because carotid artery disease causes cognitive impairment, or because it is a marker for underlying risk factors and vascular disease that are themselves the cause. Epidemiologic studies have not distinguished between these possibilities (12). The distinction is important because a direct intervention, such as endarterectomy, may prevent cognitive decline if a measure of carotid artery disease is associated with a cause of decline, whereas if the disease measure is a marker for underlying risk factors, treatment of the risk factors might be more appropriate. The effect of medical or surgical management of left carotid artery disease on cognitive function has not been specifically evaluated. The Modified Mini-Mental State Examination (26, 27) primarily measures cognitive function in the dominant cerebral hemisphere (28), which is the left hemisphere in more than 98% of right-handed persons (29). Results of the Modified Mini-Mental State Examination and the similar, more familiar Mini-Mental State Examination are often normal in right-handed patients with right hemispheric strokes or mass lesions (28, 30, 31). If carotid artery disease is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination, impairment should be associated with left-sided disease but not right-sided disease. Because both arteries should be affected equally by systemic vascular risk factors, a causal association should persist after adjustment for right-sided disease and for vascular risk factors. Alternatively, if measures of carotid artery disease are markers for underlying risk factors for vascular disease, measures of both left and right carotid disease should be similarly associated with cognitive impairment. We hypothesized that high-grade stenosis of the left, but not the right, internal carotid artery is a cause of cognitive impairment as measured by the Modified Mini-Mental State Examination in right-handed persons and that an association would persist after adjustment for contralateral stenosis and risk factors for vascular disease. We also hypothesized that intimamedia thickness of both the left and right common carotid artery would be associated with cognitive impairment because we assumed that intimamedia thickness was a marker for underlying vascular disease and its risk factors rather than a direct cause of cerebral ischemia and cognitive impairment. Methods Sample The Cardiovascular Health Study is an observational, prospective study of men and women 65 years of age or older drawn from 4 U.S. communities: Sacramento County, California; Allegheny County, Pennsylvania; Washington County, Maryland; and Forsyth County, North Carolina. Participants were enrolled by random sampling of Medicare eligibility lists. The Cardiovascular Health Study enrolled 5201 participants in 1989 to 1990 and an additional 687 African-American participants in 1992 to 1993. Annual clinic examinations were conducted during follow-up. Details of recruitment into (32) and design of (33) the Cardiovascular Health Study are reported elsewhere. The study was approved by the institutional review board at each site, and all participants gave informed consent. We restricted our analysis to right-handed participants. Participants were classified as right-handed if they reported using their right hand to brush their teeth and throw a ball and were observed to write with their right hand. We excluded participants with a history of stroke, transient ischemic attack, or carotid endarterectomy as of the 19921993 examination, on the basis of self-report at study entry and surveillance during follow-up (34, 35). Data Collection The baseline examination included standard questionnaires about medical and personal history and an array of physical and laboratory evaluations (33). Testing for the apolipoprotein E 4 (ApoE 4) genotype was done in participants who consented to genetic research. Ultrasonography of the carotid arteries was performed at the 19921993 examination. Measurements were standardized among field centers and were interpreted centrally by readers who were blinded to clinical information (13, 36). The left and right common and internal carotid arteries were imaged longitudinally by using high-resolution B-mode ultrasonography. The intimamedia thickness of the common carotid artery was defined as the mean of the maximum intimamedia thicknesses of the near and far walls. Pulsed-wave Doppler frequency spectra were used to measure the peak systolic flow velocity in each internal carotid artery. Stenosis of the internal carotid artery lumen of 50% to 74% was defined as peak flow velocity of 1.5 to 2.5 m/s, and stenosis of 75% to 99% as peak velocity of 2.5 m/s or greater. No flow indicated 100% stenosis. Stenosis of 0%, 1% to 24%, or 25% to 49% was estimated visually from imaging data. Inter-reader agreement in measures of carotid disease was assessed by comparing ratings from different reviewers for more than 4800 ultrasonograms. Agreement in measurement of internal carotid artery stenosis was high ( = 0.68 for a cut-point of 75% stenosis), as was measurement of common carotid artery intimamedia thickness (Spearman rank correlation coefficient = 0.72). Cognitive function was measured annually by using the Modified Mini-Mental State Examination. Higher scores indicate greater cognitive function. Cognitive impairment was defined as a score of less than 80 of 100 points (37). The Digit Symbol Substitution Test (number of correct answers in 90 seconds) was used as a secondary measure of cognitive function (38). This test measures function in both cerebral hemispheres but is thought to be more dramatically affected by left-sided injuries. Impairment was defined as a score of less than 19; this cut-point was chosen at 1.5 SDs below the mean score. Cranial magnetic resonance imaging was performed at the 19921994 examinations. Infarct on magnetic resonance imaging was defined as an area with abnormal signal intensity in a vascular distribution, without mass effect (39). Outcome Measures We examined the association between asymptomatic carotid artery disease and cognitive impairment in a cross-sectional analysis based on data from the 19921993 examination and in a longitudinal analysis of cognitive decline during 5 years of follow-up. Carotid artery measures of primary interest were the degree of internal carotid artery stenosis and quartiles of intimamedia thickness of the common carotid artery. Results are shown for participants with 75% or greater (high-grade) stenosis compared with those with no stenosis and participants in the fourth compared with the first quartile of intimamedia thickness. Statistical Analysis Characteristics were compared between carotid artery groups by using the chi-square test or the t-test. Cognitive scores were compared between carotid groups using the Wilcoxon rank-sum test. The average rate of cognitive decline was calculated for each participant by using linear regression, based on the slope of the line fitting all cognitive measures from baseline and follow-up. Thus

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.

Evidence for Neurocognitive Plasticity in At-Risk Older Adults: The Experience Corps Program

OBJECTIVE To determine whether Experience Corps (EC), a social service program, would improve age-vulnerable executive functions and increase activity in brain regions in a high-risk group through increased cognitive and physical activity. METHODS Eight community-dwelling, older female volunteers and nine matched wait-list controls were recruited to serve in the ongoing EC: Baltimore program in three elementary schools. We employed functional magnetic resonance imaging (fMRI) preintervention and postintervention to examine whether EC volunteers improved executive function and showed increased activity in the prefrontal cortex relative to controls. fMRI volunteers were trained and placed with other volunteers 15 h/wk for 6 months during the academic year to assist teachers in kindergarten through third grade to promote childrens literacy and academic achievement. RESULTS Participants were African American and had low education, low income, and low Mini-Mental State Examination scores (M = 24), indicative of elevated risk for cognitive impairment. Volunteers exhibited intervention-specific increases in brain activity in the left prefrontal cortex and anterior cingulate cortex over the 6-month interval relative to matched controls. Neural gains were matched by behavioral improvements in executive inhibitory ability. CONCLUSIONS Using fMRI, we demonstrated intervention-specific short-term gains in executive function and in the activity of prefrontal cortical regions in older adults at elevated risk for cognitive impairment. These pilot results provide proof of concept for use-dependent brain plasticity in later life, and, that interventions designed to promote health and function through everyday activity may enhance plasticity in key regions that support executive function.

Training and Maintaining Memory Abilities in Healthy Older Adults: Traditional and Novel Approaches

This article reviews both traditional and novel approaches for training and maintaining memory abilities in older adults. Despite variations in training methods and participant samples, growing evidence suggests that healthy, nondemented elders can improve and maintain their memory skills. However, traditional approaches have not been as successful in demonstrating transfer of training, and there are constraints on widescale dissemination of trainer-led, group-based formats. We discuss novel platforms, including collaborative training, videotapes and audiotapes, and online and CD-ROM-based training. We also consider approaches that combine multiple training modalities and that embed memory enhancement within cognitively stimulating activities of everyday life, such as Experience Corps. These newer approaches may enhance the accessibility, affordability, and applicability of memory training and cognitive stimulation programs.

Neuropsychological characteristics of mild cognitive impairment subgroups

Objective: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study. Methods: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition. Results: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits. Conclusions: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.

Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8 years prior to onset.

Objective: To determine if individuals ultimately diagnosed with Alzheimer disease (AD) exhibited evidence of cognitive impairment on neuropsychological tests administered between 1.5 years and 8.1 years before dementia onset. Methods: A total of 693 community-dwelling individuals, part of the Cardiovascular Health Study, completed a neuropsychological test battery in 1991/92. Subjects were followed annually over the next 8 years (median follow-up = 7.4 years). Seventy-two individuals were ultimately diagnosed with AD (median follow-up = 4.5 years): 24 with AD onset 1.5 to 3.4 years after baseline neuropsychological testing, 20 with AD onset 3.5 to 5.0 years after testing, and 28 with onset 5.1 to 8.1 years after testing. A total of 621 individuals remained nondemented throughout the 8 years of follow-up (median follow-up = 7.5 years). Results: Subjects ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained nondemented. Although individuals closest to AD onset (i.e., 1.5 to 3.4 years) performed the most poorly, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later. Conclusions: Cognitive changes can be detected well before onset of Alzheimer disease.