Aimee Pierce

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.

Communicating mild cognitive impairment diagnoses with and without amyloid imaging

BackgroundMild 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.MethodsWe convened a workgroup to formulate recommendations for clinicians providing care to MCI patients.ResultsClinicians 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.ConclusionsIn 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.

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.

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

AbstractPurpose 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.

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.

COMMUNICATING MILD COGNITIVE IMPAIRMENT DIAGNOSIS WITH AND WITHOUT AMYLOID IMAGING: RECOMMENDATIONS FROM AN EXPERT WORKGROUP

IMPAIRMENT DIAGNOSIS WITH ANDWITHOUT AMYLOID IMAGING: RECOMMENDATIONS FROM AN EXPERT WORKGROUP Joshua D. Grill, Liana G. Apostolova, Szofia S. Bullain, Jeffrey M. Burns, Chelsea Cox, Malcolm Dick, Dean Hartley, Claudia H. Kawas, Sarah Kremen, Jennifer Lingler, Oscar L. Lopez, Nancy Lundebjerg, Mark Mapstone, Aimee Pierce, Gil D. Rabinovici, J Scott Roberts, Seyed Ahmad Sajjadi, Edmond Teng, Jason Karlawish, University of California, Irvine, Irvine, CA, USA; 2 Indiana University School of Medicine, Indianapolis, IN, USA; 3 University of Kansas Alzheimer’s Disease Center, Fairway, KS, USA; Alzheimer’s Association, Chicago, IL, USA; University of California Los Angeles, Los Angeles, CA, USA; 6 University of Pittsburgh, Pittsburgh, PA, USA; 7 American Geriatrics Society, New York, NY, USA; 8 University of Rochester, Rochester, NY, USA; University of California San Francisco, San Francisco, CA, USA; University of Michigan, Ann Arbor, MI, USA; 11 Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, Los Angeles, CA, USA; 12 University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: jgrill@uci.edu