Beth E. Snitz

Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly

OBJECTIVE To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING University medical center. PARTICIPANTS From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES Regional PiB retention and cognitive test performance. RESULTS Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

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.

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimers disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Amyloid Imaging in Mild Cognitive Impairment Subtypes

We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimers disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome.

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.

Outcomes of mild cognitive impairment by definition: a population study.

BACKGROUND Mild cognitive impairment (MCI) has been defined in several ways. OBJECTIVE To determine the 1-year outcomes of MCI by different definitions at the population level. DESIGN Inception cohort with 1-year follow-up. Participants were classified as having MCI using the following definitions operationalized for this study: amnestic MCI by Mayo criteria, expanded MCI by International Working Group criteria, Clinical Dementia Rating (CDR) = 0.5, and a purely cognitive classification into amnestic and nonamnestic MCI. SETTING General community. PARTICIPANTS Stratified random population-based sample of 1982 individuals 65 years and older. MAIN OUTCOME MEASURES For each MCI definition, there were 3 possible outcomes: worsening (progression to dementia [CDR ≥ 1] or severe cognitive impairment), improvement (reversion to CDR = 0 or normal cognition), and stability (unchanged CDR or cognitive status). RESULTS Regardless of MCI definition, over 1 year, a small proportion of participants progressed to CDR > 1 (range, 0%-3%) or severe cognitive impairment (0%-20%) at rates higher than their cognitively normal peers. Somewhat larger proportions of participants improved or reverted to normal (6%-53%). Most participants remained stable (29%-92%). Where definitions focused on memory impairment and on multiple cognitive domains, higher proportions progressed and lower proportions reverted on the CDR. CONCLUSIONS As ascertained by several operational definitions, MCI is a heterogeneous entity at the population level but progresses to dementia at rates higher than in normal elderly individuals. Proportions of participants progressing to dementia are lower and proportions reverting to normal are higher than in clinical populations. Memory impairments and impairments in multiple domains lead to greater progression and lesser improvement. Research criteria may benefit from validation at the community level before incorporation into clinical practice.

Basal Cerebral Metabolism May Modulate the Cognitive Effects of Aβ in Mild Cognitive Impairment: An Example of Brain Reserve

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimers disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Age and education effects and norms on a cognitive test battery from a population-based cohort: The Monongahela–Youghiogheny Healthy Aging Team

Objectives: Performance on cognitive tests can be affected by age, education, and also selection bias. We examined the distribution of scores on several cognitive screening tests by age and educational levels in a population-based cohort. Method: An age-stratified random sample of individuals aged 65+ years was drawn from the electoral rolls of an urban US community. Those obtaining age and education-corrected scores ≥21/30 on the Mini-Mental State Examination (MMSE) were designated as cognitively normal or only mildly impaired, and underwent a full assessment including a battery of neuropsychological tests. Participants were also rated on the Clinical Dementia Rating (CDR) scale. The distribution of neuropsychological test scores within demographic strata, among those receiving a CDR of 0 (no dementia), are reported here as cognitive test norms. After combining individual test scores into cognitive domain composite scores, multiple linear regression models were used to examine associations of cognitive test performance with age and education. Results: In this cognitively normal sample of older adults, younger age and higher education were associated with better performance in all cognitive domains. Age and education together explained 22% of the variation of memory, and less of executive function, language, attention, and visuospatial function. Conclusion: Older age and lesser education are differentially associated with worse neuropsychological test performance in cognitively normal older adult representatives of the community at large. The distribution of scores in these participants can serve as population-based norms for these tests, and can be especially useful to clinicians and researchers assessing older adults outside specialty clinic settings.

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

Objective: To determine arterial stiffness and β-amyloid (Aβ) 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 Aβ-positive on PET scan. Aβ 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 Aβ-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aβ-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 Aβ-positive and having high WMH. Conclusions: Arterial stiffness was associated with Aβ 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 Aβ deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aβ deposition and WMH, which has been suggested to be a “double hit” contributing to the development of symptomatic dementia.

Functional and cognitive criteria produce different rates of mild cognitive impairment and conversion to dementia

Objective: To compare rates of mild cognitive impairment (MCI) and rates of progression to dementia using different MCI diagnostic systems. Methods: MCI was investigated at baseline in 3063 community dwelling non-demented elderly in the Ginkgo Evaluation of Memory (GEM) study who were evaluated every 6 months to identify the presence of dementia. Overall MCI frequency was determined using (1) a Clinical Dementia Rating (CDR) score of 0.5 and (2) neuropsychological (NP) criteria, defined by impairment on standard cognitive tests. Results: 40.2% of participants met CDR MCI criteria and 28.2% met NP MCI criteria (amnestic MCI = 16.6%). 15.7% were classified as MCI by both criteria and 47.4% as normal by both. Discordant diagnoses were observed in 24.5% who met NP normal/CDR MCI and in 12.4% who met NP MCI/CDR normal. Factors associated with CDR MCI among NP normal included lower education, lower NP scores, more instrumental activities of daily living impairment, greater symptoms of depression and subjective health problems. Individuals meeting NP MCI/CDR normal were significantly more likely to develop dementia over the median follow-up of 6.1 years than those meeting NP normal/CDR MCI. Conclusions: Different criteria produce different MCI rates and different conversion rates to dementia. Although a higher percentage of MCI was identified by CDR than NP, a higher percentage of NP MCI progressed to dementia. These findings suggest that the CDR is sensitive to subtle changes in cognition not identified by the NP algorithm but is also sensitive to demographic and clinical factors probably leading to a greater number of false positives. These results suggest that identifying all individuals with CDR scores of 0.5 as Alzheimer’s disease is not advisable.