Alzheimer's & Dementia: The Journal of the Alzheimer's Association - Articles in Press

Deliberative assessment of surrogate consent in dementia research - Corrected Proof

2010-03-02

Abstract: Background: Research involving incapacitated persons with dementia entails complex scientific, legal, and ethical issues, making traditional surveys of layperson views on the ethics of such research challenging. We therefore assessed the impact of democratic deliberation (DD), involving balanced, detailed education and peer deliberation, on the views of those responsible for persons with dementia.Methods: One hundred and seventy-eight community-recruited caregivers or primary decision-makers for persons with dementia were randomly assigned to either an all-day DD session group or a control group. Educational materials used for the DD session were vetted for balance and accuracy by an interdisciplinary advisory panel. We assessed the acceptability of family-surrogate consent for dementia research (“surrogate-based research”) from a societal policy perspective as well as from the more personal perspectives of deciding for a loved one or for oneself (surrogate and self-perspectives), assessed at baseline, immediately post-DD session, and 1 month after DD date, for four research scenarios of varying risk-benefit profiles.Results: At baseline, a majority in both the DD and control groups supported a policy of family consent for dementia research in all research scenarios. The support for a policy of family consent for surrogate-based research increased in the DD group, but not in the control group. The change in the DD group was maintained 1 month later. In the DD group, there were transient changes in attitudes from surrogate or self-perspectives. In the control group, there were no changes from baseline in attitude toward surrogate consent from any perspective.Conclusions: Intensive, balanced, and accurate education, along with peer deliberation provided by democratic deliberation, led to a sustained increase in support for a societal policy of family consent in dementia research among those responsible for dementia patients.

Drug treatment of Alzheimer's patients leads to expression changes in peripheral blood cells - Corrected Proof

Margaret A. Calciano, Weiyin Zhou, Peter J. Snyder, Richard Einstein — 2010-02-26

Abstract: Background: Increasing cholinergic activity has been the primary mechanism for treating dementia due to Alzheimer's disease. However, the effectiveness of cholinesterase inhibitors (ChEIs) is still widely debated. The identification of specific biomarkers capable of identifying patients more likely to respond to these treatments could potentially provide specific evidence to clearly address this controversy through patient stratification. The goal of this study was to determine the feasibility of discovering biomarkers specific for the treatment of Alzheimer's disease.Methods: Peripheral blood was collected from a cohort of patients treated with different ChEIs. Total RNA was isolated and profiled on the human Genome-Wide SpliceArray (GWSA) to test the feasibility of discriminating the different treatment subgroups of subjects based on the expression patterns generated from the Genome-Wide SpliceArray.Results: Specific expression differences were identified for the various treatment groups that lead to a clear separation between patients treated with ChEIs versus naïve patients when Principal Component Analysis was performed on probe sets selected for differential expression. In addition, specific probe sets were identified to be dependent on the inhibitor used among the treated patients.Conclusions: Distinct separation between non-treated, galantamine, donepezil, and rivastigmine-treated patients was clearly identified based on small sets of expression probes. The ability to identify drug-specific treatment expression differences strengthens the potential for using peripheral gene signatures for the identification of individuals responding to drug treatment.

The FAS gene, brain volume, and disease progression in Alzheimer's disease - Corrected Proof

Deniz Erten-Lyons, Anne Jacobson, Patricia Kramer, Andrew Grupe, Jeffrey Kaye — 2009-09-22

Abstract: Objective: We sought to identify single-nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) progression and brain volume.Methods: Ninety-seven SNPs were genotyped in 243 subjects from a longitudinal study of healthy aging. Subjects who received a diagnosis of cognitive impairment (CI) at any study visit (before their most recent visit) and had DNA in the study's DNA bank were included. Progression of AD was defined as the duration from onset of CI to diagnosis of AD. Association of each of the 97 SNPs with AD progression was tested via Cox model. Those SNPs meeting a criterion of nominal significance (P < 0.05) for association with AD progression were reassessed to account for multiple testing by repeating the marker selection process in 10,000 random permutations. Next, the association between the one SNP that survived the multiple-testing adjustment and brain volume was determined by multiple regression analysis in a subgroup of subjects for whom magnetic-resonance imaging (MRI)-derived brain-volume data were available. Brain volumes were adjusted for age at MRI, gender, and time from MRI to onset of CI.Results: The minor allele of rs1468063 in the FAS gene, which is member 6 of the tumor necrosis factor receptor superfamily, was significantly associated with faster AD progression after adjustment for multiple testing (Ppermutation = 0.049). The same allele in rs1468063 was associated with smaller brain volumes and larger ventricular volumes (P = 0.02 and 0.04, respectively).Conclusions: The FAS gene, which plays a role in apoptosis, may be associated with AD by modulating the apoptosis and neuronal loss secondary to AD neuropathology.

Temporal lobe functional activity and connectivity in young adult APOE ε4 carriers - Corrected Proof

2009-09-10

Abstract: Background: We sought to determine if the APOE ε4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTLs) during successful memory encoding in young adults.Methods: Twenty-four healthy young adults, i.e., 12 carriers and 12 noncarriers of the APOE ε4 allele, were scanned in a subsequent-memory paradigm, using event-related functional magnetic resonance imaging. The neuroanatomic correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTLs, as well as whole-brain functional connectivity with the MTLs, were assessed.Results: In the absence of demographic or performance differences, APOE ε4 allele carriers exhibited greater bilateral MTL activity relative to noncarriers while accomplishing the same encoding task. Moreover, whereas ε4 carriers demonstrated a greater functional connectivity of ESA-related MTL activity with the posterior cingulate and other peri-limbic regions, reductions in overall connectivity were found across the anterior and posterior cortices.Conclusions: These results suggest that the APOE ɛ4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTLs to other regions implicated in memory encoding. Enhanced functional connectivity of the MTLs with the posterior cingulate in young adult ε4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease, long before late-onset dementia is a practical risk or consideration. These functional connectivity differences may also reflect pleiotropic effects of APOE during early development.