The African American Dementia and Aging Project (AADAPt): An Oregon-based Longitudinal Study.

Objectives: The vast majority of studies on aging, cognition, and dementia focus on non-Hispanic white subjects. This paper adds to the extant literature by providing insight into the African American aging experience. Here we describe the study design and baseline characteristics of the African American Dementia and Aging Project (AADAPt) study, which is exploring aging and cognition in African American older adults in Oregon. Methods: African American older adults (n=177) participated in AADAPt, a longitudinal study that collected data on cognitive, physical, and social functioning in annual visits since 2000. Results: AADAPt participants had risk factors for developing dementia in future, such as hypertension and hyperlipidemia, but also reported protective factors such as high social engagement. Conclusions: The AADAPt project offers new insights into aging in older African Americans that includes data on cognition, social engagement, and physical health, which are crucial for understanding the experience of under-represented groups and making future studies more inclusive. These findings reflect a window of time for a geographically-focused cohort, and the lessons learned from this study likely have broader implications for shaping the health of these older African American adults. Keywords: African American, Dementia, Observational Study.

Patient Portal Use Among Diabetic Patients With Different Races and Ethnicities.

Background: Patient portal (PP) use varies among different patient populations, specifically among those with diabetes mellitus (DM). In addition, it is still uncertain whether PP use could be linked to improved clinical outcomes. Therefore, the aim of this paper was to determine PP use status for patients, recognize factors promoting PP use, and further identify the association between PP use and clinical outcome among diabetic patients of different races and ethnicities. Methods: This was a single-center cross-section study. Patients were divided into non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic/Latino groups. PP use was compared among these three groups. Multivariate logistic regressions were used to determine factors associated with PP use, serum glycemic control, and emergency department (ED) hospitalizations. Results: A total of 77,977 patients were analyzed. The rate of PP use among patients of NHW (24%) was higher than those of NHB (19%) and Hispanic/Latinos (18%, P < 0.0001). The adjusted odds ratio (AOR) of insurance coverage associated with PP use was 2.12 (2.02 - 2.23, P < 0.0001), and having a primary care physician (PCP) associated with PP use was 3.89 (3.71 - 4.07, P < 0.0001). In terms of clinical outcomes, the AOR of PP use associated with serum glycemic control was 0.98 (0.90 - 1.05, P = 0.547) and ED hospitalization was 0.79 (0.73 - 0.86, P < 0.0001). Conclusion: PP use disparity occurred among NHB and Hispanic/Latino patients in the ED. Having insurance coverage and PCPs seem to correlate with PP use. PP use did not seem to associate with serum glycemic control among DM patients present in the ED but could possibly reduce patient hospitalizations.

Retention of Alzheimer Disease Research Participants.

INTRODUCTION: Participant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research. METHODS: We surveyed representative investigators from NIH-funded Alzheimer's Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer's Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics. RESULTS: Twenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P<0.001 for the middle compared with the lowest tertile survey scores; odds ratio=1.59, 95% confidence interval: 1.30, 1.94; P<0.001 for the highest compared with the lowest tertile survey scores) at the first follow-up visit. Participant characteristics such as normal cognition diagnosis, older age, higher education, and Caucasian race were also associated with higher retention. CONCLUSIONS: Retention in clinical research is more likely to be achieved by employing a variety of tactics.

Constructing a Local Potential Participant Registry to Improve Alzheimer's Disease Clinical Research Recruitment.

Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer's disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries.

Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia.

Purpose of review Alzheimer's disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance. Recent findings With the advent of 18F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be "imaging supported" based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology. Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.

Communicating mild cognitive impairment diagnoses with and without amyloid imaging.

BACKGROUND: Mild cognitive impairment (MCI) has an uncertain etiology and prognosis and may be challenging for clinicians to discuss with patients and families. Amyloid imaging may aid specialists in determining MCI etiology and prognosis, but creates novel challenges related to disease labeling. METHODS: We convened a workgroup to formulate recommendations for clinicians providing care to MCI patients. RESULTS: Clinicians should use the MCI diagnosis to validate patient and family concerns and educate them that the patient's cognitive impairment is not normal for his or her age and education level. The MCI diagnosis should not be used to avoid delivering a diagnosis of dementia. For patients who meet Appropriate Use Criteria after standard-of-care clinical workup, amyloid imaging may position specialists to offer more information about etiology and prognosis. Clinicians must set appropriate expectations, including ensuring that patients and families understand the limitations of amyloid imaging. Communication of negative results should include that patients remain at elevated risk for dementia and that negative scans do not indicate a specific diagnosis or signify brain health. Positive amyloid imaging results should elicit further monitoring and conversations about appropriate advance planning. Clinicians should offer written summaries, including referral to appropriate social services. CONCLUSIONS: In patients with MCI, there is a need to devote considerable time and attention to patient education and shared decision-making. Amyloid imaging may be a tool to aid clinicians. Careful management of patient expectations and communication of scan results will be critical to the appropriate use of amyloid imaging information.

Late-Onset Alzheimer Disease.

The oldest-old represent the fastest growing segment of society, and the risk of developing dementia continues to increase with advancing age into the 9th and 10th decades of life. The most common form of dementia in the oldest-old is Alzheimer disease (AD), although there are often mixed pathologies contributing to dementia in addition to amyloid plaques and neurofibrillary tangles. Diagnosing AD in the oldest-old is challenging due to cognitive and physical changes associated with aging. Treatment remains supportive, with current approved medications able to provide modest symptomatic benefit but unable to slow the progression of disease.

Dementia in the oldest old: Beyond Alzheimer disease.

In a Perspective, Aimee Pierce and Claudia Kawas discuss risk factors and pathologies of dementia in the oldest-old.

Attitudes toward Potential Participant Registries.

Difficult participant recruitment is a consistent barrier to successful medical research. Potential participant registries represent an increasingly common intervention to overcome this barrier. A variety of models for registries exist, but few data are available to instruct their design and implementation. To provide such data, we surveyed 110 cognitively normal research participants enrolled in a longitudinal study of aging and dementia. Seventy-four (67%) individuals participated in the study. Most (78%, CI: 0.67, 0.87) participants were likely to enroll in a registry. Willingness to participate was reduced for registries that required enrollment through the Internet using a password (26%, CI: 0.16, 0.36) or through email (38%, CI: 0.27, 0.49). Respondents acknowledged their expectations that researchers share information about their health and risk for disease and their concerns that their data could be shared with for-profit companies. We found no difference in respondent preferences for registries that shared contact information with researchers, compared to honest broker models that take extra precautions to protect registrant confidentiality (28% versus 30%; p = 0.46). Compared to those preferring a shared information model, respondents who preferred the honest broker model or who lacked model preference voiced increased concerns about sharing registrant data, especially with for-profit organizations. These results suggest that the design of potential participant registries may impact the population enrolled, and hence the population that will eventually be enrolled in clinical studies. Investigators operating registries may need to offer particular assurances about data security to maximize registry enrollment but also must carefully manage participant expectations.

Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function.

Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.

Model-guided microarray implicates the retromer complex in Alzheimer's disease.

Although, in principle, gene expression profiling is well suited to isolate pathogenic molecules associated with Alzheimer's disease (AD), techniques such as microarray present unique analytic challenges when applied to disorders of the brain. Here, we addressed these challenges by first constructing a spatiotemporal model, predicting a priori how a molecule underlying AD should behave anatomically and over time. Then, guided by the model, we generated gene expression profiles of the entorhinal cortex and the dentate gyrus, harvested from the brains of AD cases and controls covering a broad age span. Among many expression differences, the retromer trafficking molecule VPS35 best conformed to the spatiotemporal model of AD. Western blotting confirmed the abnormality, establishing that VPS35 levels are reduced in brain regions selectively vulnerable to AD. VPS35 is the core molecule of the retromer trafficking complex and further analysis revealed that VPS26, another member of the complex, is also downregulated in AD. Cell culture studies, using small interfering RNAs or expression vectors, showed that VPS35 regulates Abeta peptide levels, establishing the relevance of the retromer complex to AD. Reviewing our findings in the context of recent studies suggests how downregulation of the retromer complex in AD can regulate local levels of Abeta peptide.

Combining brain imaging with microarray: isolating molecules underlying the physiologic disorders of the brain.

Many diseases of the nervous system cause dysfunction by impairing neuronal physiology more than by altering brain anatomy--including age-related cognitive decline, most psychiatric disorders, and even the earliest stages of Alzheimer's disease. The absence of clear anatomical markers makes it difficult to identify targeted cells, which in turn impedes attempts to isolate the pathogenic molecules that cause physiologic disruption. Here we show how brain imaging and microarray can be used as complimentary techniques that together can characterize the cellular and molecular aspects of this class of diseases.