Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.

OBJECTIVES: The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM. METHODS: Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes. RESULTS: Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity. CONCLUSIONS: Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.

In vivo assessment of amyloid-ß deposition in nondemented very elderly subjects.

OBJECTIVE: This study examined amyloid-ß (Aß) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aß-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment. METHODS: Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study. RESULTS: A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aß deposition as determined by PiB. INTERPRETATION: The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aß deposition.

Classification of amyloid-positivity in controls: comparison of visual read and quantitative approaches.

UNLABELLED: An important research application of amyloid imaging with positron emission tomography (PET) is detection of the earliest evidence of fibrillar amyloid-beta (Aß) deposition. Use of amyloid PET for this purpose, requires a reproducible method for defining a cutoff that separates individuals with no significant Aß deposition from those in which Aß deposition has begun. We previously reported the iterative outlier approach (IO) for the analysis of Pittsburgh Compound-B (PiB) PET data. Developments in amyloid imaging since the initial report of IO have led us to re-examine the generalizability of this method. IO was developed using full-dynamic atrophy-corrected PiB PET data obtained from a group of control subjects with a fairly distinct separation between PiB-positive [PiB(+)] and PiB-negative [PiB(-)] subjects. METHODS: We tested the performance of IO using late-summed tissue ratio data with atrophy correction or with an automated template method without atrophy correction and tested the robustness of the method when applied to a cohort of older subjects in which separation between PiB(+) and PiB(-) subjects was not so distinct. RESULTS: The IO method did not perform consistently across analyses and performed particularly poorly when separation was less clear. We found that a sparse k-means (SKM) cluster analysis approach performed significantly better; performing more consistently across methods and subject cohorts. We also compared SKM to a consensus visual read approach and found very good correspondence. CONCLUSION: The visual read and SKM methods, applied together, may optimize the identification of early Aß deposition. These methods have the potential to provide a standard approach to the detection of PiB-positivity that is generalizable across centers.

Cognitive slowing associated with elevated serum anticholinergic activity in older individuals is decreased by caffeine use.

OBJECTIVES: This study examined whether some of the age-associated decrements in basic cognitive resources (information-processing speed and working memory) result from anticholinergic medication use (as measured by serum anticholinergic activity [SAA]) and whether such decrements are lessened by caffeine. DESIGN: Cross-sectional observational study. SETTING: University medical center. PARTICIPANTS: One hundred fifty-two normal-elderly community volunteers. MEASUREMENTS: Two tests each of information-processing speed and of working memory were administered, and blood samples were drawn before and after cognitive testing to determine serum levels of anticholinergic activity and of paraxanthine-a caffeine metabolite. RESULTS: Elevated SAA was associated with a significant but modest slowing in information-processing time but only in those individuals who had low levels of serum paraxanthine. SAA did not correlate with performance on tests of working memory. CONCLUSIONS: These results suggest that anticholinergic medications are a relatively minor contributor to the decrements in basic processing resources commonly found in studies of normal aging.

Magnetic resonance imaging and neuropsychological results from a trial of memantine in Alzheimer's disease.

BACKGROUND: This study was designed to assess changes in brain volume and cognitive abilities in memantine-treated patients with Alzheimer's disease (AD) by using an exploratory, single-arm, delayed-start design. METHODS: Cholinesterase inhibitor-treated patients with AD (N = 47; Mini-Mental State Examination score range: 15-23) were enrolled in an observational lead-in period (weeks: 1-24), followed by an open-label period of add-on memantine treatment (weeks: 25-48). The patients underwent magnetic resonance imaging at weeks 0 (baseline), 24 (immediately before memantine initiation), and 48 (endpoint), and a battery of neuropsychological tests at weeks 0, 24, 28, 36, and 48. The primary outcome measure was the annualized rate of change (%) in total brain volume (TBV) between the two study periods. Data were analyzed using paired t-tests. RESULTS: There were no statistically significant differences in the rates of change in TBV, ventricular volume, or left hippocampal volume between the study periods; however, the memantine treatment period was associated with a significantly slower right hippocampal atrophy (-5.5% ± 12.0% vs -10.8% ± 7.2%; P = .038). Memantine treatment was also associated with superior performances on the Boston Naming Test (P = .034) and the Trail Making Test, Part B (P = .001), but also with a higher number of errors (i.e., repetitions and intrusions) on the California Verbal Learning Test. Memantine was found to be safe and well tolerated. CONCLUSIONS: In this study, no difference in the rates of TBV change between the two periods was observed; however, memantine treatment was found to be associated with slowing of right hippocampal atrophy, and with improvement on one test of executive functioning as well as a test of confrontation naming ability. Trials using structural magnetic resonance imaging and a delayed-start design may be a feasible option for the assessment of treatments for AD.

Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve.

Inverse correlations between amyloid-beta (Abeta) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [(18)F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local Abeta-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 Abeta 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 Abeta deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Abeta deposition or increasing the level of Abeta necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Abeta deposition has been present for longer periods of time does Abeta become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Prevalence of mild cognitive impairment by multiple classifications: The Monongahela-Youghiogheny Healthy Aging Team (MYHAT) project.

OBJECTIVES: To estimate and compare the frequency and prevalence of mild cognitive impairment (MCI) and related entities using different classification approaches at the population level. DESIGN: Cross-sectional epidemiologic study of population-based cohort recruited by age-stratified random sampling from electoral rolls. SETTING: Small-town communities in western Pennsylvania. PARTICIPANTS: Of 2,036 individuals aged 65 years and older, 1,982 participants with normal or mildly impaired cognition (age-education-corrected Mini-Mental State scores ≥ 21). MEASUREMENTS: Demographics, neuropsychological assessment expressed as cognitive domains, functional ability, and subjective reports of cognitive difficulties; based on these measurements, operational criteria for the Clinical Dementia Rating (CDR) scale, the 1999 criteria for amnestic MCI, the 2004 Expanded criteria for MCI, and new, purely cognitive criteria for MCI. RESULTS: A CDR rating of 0.5 (uncertain/very mild dementia) was obtained by 27.6% of participants, whereas 1.2% had CDR ≥ 1 (mild or moderate dementia). Among those with CDR <1, 2.27% had amnestic MCI and 17.66% had expanded MCI, whereas 35.17% had MCI by purely cognitive classification. Isolated executive function impairment was the least common, whereas impairment in multiple domains including executive function was the most common. Prevalence estimates weighted against the U.S. Census are also provided. CONCLUSIONS: The manner in which criteria for MCI are operationalized determines the proportion of individuals who are thus classified and the degree of overlap with other criteria. Prospective follow-up is needed to determine progression from MCI to dementia and thus empirically develop improved MCI criteria with good predictive value.

Cognitive test performance predicts change in functional status at the population level: the MYHAT Project.

In the community at large, many older adults with minimal cognitive and functional impairment remain stable or improve over time, unlike patients in clinical research settings, who typically progress to dementia. Within a prospective population-based study, we identified neuropsychological tests predicting improvement or worsening over 1 year in cognitively driven everyday functioning as measured by Clinical Dementia Rating (CDR). Participants were 1682 adults aged 65+ and dementia-free at baseline. CDR change was modeled as a function of baseline test scores, adjusting for demographics. Among those with baseline CDR = 0.5, 29.8% improved to CDR = 0; they had significantly better baseline scores on most tests. In a stepwise multiple logistic regression model, tests which remained independently associated with subsequent CDR improvement were Category Fluency, a modified Token Test, and the sum of learning trials on Object Memory Evaluation. In contrast, only 7.1% with baseline CDR = 0 worsened to CDR = 0.5. They had significantly lower baseline scores on most tests. In multiple regression analyses, only the Mini-Mental State Examination, delayed memory for visual reproduction, and recall susceptible to proactive interference, were independently associated with CDR worsening. At the population level, changes in both directions are observable in functional status, with different neuropsychological measures predicting the direction of change.

Temporal stability of receptiveness to clinical research on Alzheimer disease.

Research advance directives are a proposed mechanism for ensuring that decisions with regard to research participation adhere to preferences voiced by persons with Alzheimer disease (AD) before losing decisional capacity. Although this approach rests on the assumption that preferences with regard to research participation are consistent over time, little is known about the stability of such preferences. The purpose of this study was to evaluate the temporal stability of older adults' receptiveness to participation in clinical trials, neuroimaging studies, and psychosocial investigations on AD. One hundred and four participants in the University of Pittsburgh Alzheimer Disease Research Center were annually surveyed with regard to their willingness to be contacted with regard to clinical drug trials, neuroimaging studies, and psychosocial research for which they might be eligible. Receptiveness to contact with regard to AD research was compared at 2 time points, 1 year apart. At baseline, most respondents were willing to be contacted with regard to their eligibility for drug trials, imaging studies, and psychosocial research. Thirty-seven percent of respondents voiced a different set of preferences at year 2 as compared with year 1. Differences included both increased and decreased willingness to be contacted. Neither stability of preferences nor direction of change (more vs. less willing) varied by diagnostic group. Bivariate analyses revealed that participation in at least 1 ancillary research study was associated with an overall increase in willingness to be contacted. We conclude that a significant proportion of research-friendly individuals voice different sets of preferences with regard to the possibility of research participation when queried at different points in time. Amenability to participating in clinical research on AD is a relatively dynamic personal attribute that may be influenced by personal experience with research participation. This finding has relevance for the policy debate around research advance directives, an approach which assumes that preferences with regard to research participation are consistent over time.

A novel approach to assessing memory at the population level: vulnerability to semantic interference.

BACKGROUND: There is increasing interest in identifying novel cognitive paradigms to help detect preclinical dementia. Promising results have been found in clinical settings using the Semantic Interference Test (SIT), a modification of an existing episodic memory test (Fuld Object Memory Evaluation) that exploits vulnerability to semantic interference in Alzheimer's disease. It is not yet known how broadly this work will generalize to the community at large. METHODS: Participants aged > or = 65 years from the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) were administered the SIT at study entry. Independent of neuropsychological assessment, participants were rated on the Clinical Dementia Rating (CDR) scale, based on reported loss of cognitively driven everyday functioning. In individuals free of dementia (CDR < 1), the concurrent validity of the SIT was assessed by determining its association with CDR using multiple logistic regression models, with CDR 0 (no dementia) vs. 0.5 (possible dementia) as the outcome and the SIT test variables as predictors. RESULTS: Poorer performance on all SIT variables but one was associated with higher CDR reflecting possible dementia (Odds Ratios 2.24-4.79). Younger age and female gender also conferred a performance advantage. Years of education and reading ability (a proxy for quality of education) evidenced a very weak association with SIT performance. CONCLUSIONS: The SIT shows promise as a valid, novel measure to identify early preclinical dementia in a community setting. It has potential utility for assessment of persons who may be illiterate or of low education. Finally, we provide normative SIT data stratified by age which may be utilized by clinicians or researchers in future investigations.

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 > or = 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.

Measurement and Structure of Cognition in the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia.

OBJECTIVES: To test whether a relatively complex model of human cognitive abilities based on Cattell-Horn-Carroll (CHC) theory, developed mainly in English-speaking samples, adequately describes correlations among tests in the Longitudinal Aging Study in India-Diagnostic Assessment of Dementia (LASI-DAD), and to develop accurate measures of cognition for older individuals in India. DESIGN: LASI-DAD participants were recruited from participants aged 60 years and older from 14 states in the core LASI survey, with a stratified sampling design. SETTING: Participants were interviewed at home or in a participating hospital, according to their preferences. PARTICIPANTS: Community-residing older adults aged 60 years and older (N = 3,224). MEASUREMENTS: A variety of cognitive tests were administered during two pretests and chosen for their appropriateness for measuring cognition in older adults in India and suitability for calibration with the core LASI survey and the Harmonized Cognitive Assessment Protocol. RESULTS: We evaluated the factor structure of the test battery and its conformity with a classical CHC factor model that incorporated measurement models for general cognition, five broad domains (orientation, executive functioning, language/fluency, memory, and visuospatial), and five narrow domains (reasoning, attention/speed, immediate memory, delayed memory, and recognition memory) of cognitive performance. Model fit was adequate (root mean square error of approximation = 0.051; comparative fit index = 0.916; standardized root mean squared residual = 0.060). CONCLUSION: We demonstrated configural factorial invariance of a cognitive battery in the Indian LASI-DAD using CHC theory. Broad domain factors may be used in future research to rank individuals with respect to cognitive performance and classify cognitive impairment. J Am Geriatr Soc 68:S11-S19, 2020.

Methodological considerations in designing and implementing the harmonized diagnostic assessment of dementia for longitudinal aging study in India (LASI-DAD).

The Harmonized Diagnostic Assessment of Dementia for Longitudinal Aging Study in India (LASI-DAD) is a population-representative, prospective cohort study of late-life cognition and dementia. It is part of an ongoing international research collaboration that aims to measure and understand cognitive impairment and dementia risk by collecting a set of cognitive and neuropsychological assessments and informant reports, referred to as the Harmonized Cognitive Assessment Protocol (HCAP). LASI-DAD provides nationally representative data drawn from a subsample of the ongoing Longitudinal Aging Study in India (LASI). One of LASI-DAD's distinctive features is its rich geriatric assessment, including the collection of venous blood samples and brain imaging data for a subsample of respondents. In this paper, we discuss the methodological considerations of developing and implementing the HCAP protocol in India. The lessons we learned from translating and applying the HCAP protocol in an environment where illiteracy and innumeracy are high will provide important insights to researchers interested in measuring and collecting data on late-life cognition and dementia in developing countries. We further developed an innovative blood management system that enables us to follow the collection, transportation, assay, and storage of samples. Such innovation can benefit other population surveys collecting biomarker data.

A brief instrument to assess treatment response in the patient with advanced Alzheimer disease.

The availability of effective treatments for severe Alzheimer disease (AD) has accentuated the need for brief, simple tools to evaluate treatment response in busy clinical settings for patients with advanced dementia. To develop such a tool, data on 875 patients from 4 double-blind-randomized studies of donepezil in severe AD [Mini-Mental State Examination (MMSE) 0 to 12 inclusive] were pooled and analyzed to identify Severe Impairment Battery (SIB) items, which are sensitive to change over time. Eight of the 51 SIB items were chosen based on effect sizes and relative ease of administration. The resulting SIB-8 was then applied to a validation data set (not used to generate the short form) to characterize its usefulness. The items, Month, Months of Year, Write Name, Sentence, Fluency, Confrontational Naming-Spoon, Using Spoon-Photograph, and Digit Span, were sensitive to change with treatment (P<0.0001) and easy to administer. Baseline SIB-8 scores were correlated with baseline MMSE and full-scale SIB scores, and provided a good distribution of scores in patients at the lower end of the MMSE. The SIB-8 is a brief (< or =3 min) assessment for patients with severe AD that is sensitive to change and able to detect treatment response.

High medical co-morbidity and family history of dementia is associated with lower cognitive function in older patients.

BACKGROUND: Risk factors for cognitive decline in ageing are multifactorial, including medical co-morbidities and familial genetic risk. OBJECTIVES: To assess the effect of medical co-morbidity and family history of dementia on cognitive performance in older outpatients of family practitioners. METHODS: Analysis of 535 outpatients from 11 practices aged 65 and older, without a diagnosis of dementia. Information on medical co-morbidities, family history of dementia and cognitive test data were obtained. RESULTS: Patients were classified into high or low medical co-morbidities (<7 versus >8) and positive or negative family history of dementia. After controlling for age, education, gender and depression, global cognitive test scores, as well as memory, executive function, spatial ability and attention were significantly lower for persons having a high number of medical co-morbidities. Cognitive test scores were not significantly different for persons with or without a family history of dementia. A significant interaction between medical co-morbidities and family history of dementia was observed for the global cognitive score, executive function and spatial ability. Those persons with a high number of medical co-morbidities and positive family history of dementia had the lowest performance. Separate regression analysis assessing individual disease risk factors (e.g. hypertension and diabetes) did not find any relationship between specific medical variables and cognitive test scores for any of the subgroups. CONCLUSIONS: A high number of medical co-morbidities in addition to a reported family history of dementia are particularly detrimental to cognitive performance in elderly non-demented family practice patients.

Identifying mild cognitive impairment at baseline in the Ginkgo Evaluation of Memory (GEM) study.

OBJECTIVES: To identify, characterize and compare the frequency of mild cognitive impairment (MCI) subtypes at baseline in a large, late-life cohort (n = 3063) recruited into a dementia prevention trial. METHOD: A retrospective, data-algorithmic approach was used to classify participants as cognitively normal or MCI with corresponding subtype (e.g. amnestic vs. non-amnestic, single domain vs. multiple domain) based on a comprehensive battery of neuropsychological test scores, with and without Clinical Dementia Rating (CDR) global score included in the algorithm. RESULTS: Overall, 15.7% of cases (n = 480) were classified as MCI. Amnestic MCI was characterized as unilateral memory impairment (i.e. only verbal or only visual memory impaired) or bilateral memory impairment (i.e. both verbal and visual memory impaired). All forms of amnestic MCI were almost twice as frequent as non-amnestic MCI (10.0% vs. 5.7%). Removing the CDR = 0.5 ('questionable dementia') criterion resulted in a near doubling of the overall MCI frequency to 28.1%. CONCLUSION: Combining CDR and cognitive test data to classify participants as MCI resulted in overall MCI and amnestic MCI frequencies consistent with other large community-based studies, most of which relied on the 'gold standard' of individual case review and diagnostic consensus. The present data-driven approach may prove to be an effective alternative for use in future large-scale dementia prevention trials.

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.

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-beta protein is an initiating event in Alzheimer's 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.

Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B.

We evaluated the region-to-region correlation, laterality and asymmetry of amyloid deposition in subjects with mild cognitive impairment (MCI) or Alzheimer's disease (AD) using the amyloid tracer, Pittsburgh Compound B (PiB). Seventeen subjects, including 7 with MCI (MMSE 26.7+/-2.4) and 10 with AD (MMSE of 24.8+/-2.7) underwent PiB imaging. Measures of laterality (i.e., group-wise predilection for right or left) and asymmetry (i.e., group-wise predilection for unequal PiB retention between the two hemispheres) were calculated for 17 Regions of Interest (ROIs). Regional correlations were calculated along with within-group and between-groups statistical analyses of laterality and asymmetry metrics. The median correlation between PiB retention across all pairs of ROIs was 0.65, with highest correlations found in areas of highest PiB retention (r=0.74). Overall, PiB retention was symmetric bilaterally, but there was PiB laterality in MCI in dorsal frontal cortex [(t(6)=3.05, p=0.02, L>R] and sensory-motor area [t(6)=3.10, p=0.02, L>R] and in AD in the occipital pole (t(9)=-2.63, p=0.03, R>L). The most significant asymmetries in PiB retention were found in sub-cortical white matter (t(6)=3.99, p=0.01) and middle precuneus [(t(6)=3.57, p=0.01] in MCI, and in lateral temporal cortex (t(9)=3.02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42].

Subjective memory complaints and concurrent memory performance in older patients of primary care providers.

Subjective memory complaints (SMCs) are known to be inconsistently related to current memory impairment in older adults but this association has not been well investigated in primary care provider (PCP) settings. To characterize the complexity of the relationship between SMCs and objective memory in older outpatients of PCPs, we collected neuropsychological, subjective memory, depression and medical chart data from outpatients aged 65 and older, without documented dementia diagnoses, in eleven PCP offices in and around the Pittsburgh metropolitan area. Results indicated that self-estimates of current memory ability were most strongly associated with objective memory performance; in contrast, perception of worsening memory over the past year showed no association; and specific memory-related activities were only weakly associated. Women were more likely than men to show inconsistency between SMCs and objective memory performance. Only two of the 11 most significantly memory-impaired participants endorsed SMCs and only four had PCP chart documentation of memory problems. Eliciting SMCs in non-demented older adults can be of clinical value in a PCP setting, but significant limitations of patient self-report in more memory-impaired patients underscore the need to develop brief, objective indicators of memory impairment for PCP office use when there is suspicion of decline.