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With the exception of ApoE4, genome-wide association studies have failed to identify strong genetic risk factors for late-onset Alzheimer's disease, despite strong evidence of heritability, suggesting that many low penetrance genes may be involved. Additionally, the nature of the identified genetic risk factors and their relation to disease pathology is also largely obscure. Previous studies have found that a cancer-associated variant of the cell cycle inhibitor gene p21cip1 is associated with increased risk of Alzheimer's disease. The aim of this study was to confirm this association and to elucidate the effects of the variant on protein function and Alzheimer-type pathology. We examined the association of the p21cip1 variant with Alzheimer's disease and Parkinson's disease with dementia. The genotyping studies were performed on 719 participants of the Oxford Project to Investigate Memory and Ageing, 225 participants of a Parkinson's disease DNA bank, and 477 participants of the Human Random Control collection available from the European Collection of Cell Cultures. The post mortem studies were carried out on 190 participants. In the in-vitro study, human embryonic kidney cells were transfected with either the common or rare p21cip1 variant; and cytometry was used to assess cell cycle kinetics, p21cip1 protein expression and sub-cellular localisation. The variant was associated with an increased risk of Alzheimer's disease, and Parkinson's disease with dementia, relative to age matched controls. Furthermore, the variant was associated with an earlier age of onset of Alzheimer's disease, and a more severe phenotype, with a primary influence on the accumulation of tangle pathology. In the in-vitro study, we found that the SNPs reduced the cell cycle inhibitory and anti-apoptotic activity of p21cip1. The results suggest that the cancer-associated variant of p21cip1 may contribute to the loss of cell cycle control in neurons that may lead to Alzheimer-type neurodegeneration

32. Incidence and predictors of progression of Coronary Artery Disease among high risk patients with recurrent symptoms

Background: Coronary Artery Disease (CAD) is the leading cause of mortality worldwide. In the current era with highly potent medical therapy, the rate of progression of angiographic CAD is not well described. Thus, the aim of this analysis is to describe the rate and predictors of progression of CAD among patients with recurrent symptoms. Methods: We reviewed 259 patients (Mean age 60;± 11 years, 71% males) who underwent two coronary angiograms between 2008 and 2013. Patients were excluded if they underwent bypass surgery between the two angiograms. Progressive CAD was defined as (A) obstructive CAD in a previously disease-free segment; or (B) new obstruction in a previously non-obstructive segment. Multivariate logistic regression was used to determine the independent predictors of progression of CAD. Results: The mean duration between the two angiograms was 29 ± 13 months. A total of 159 patients (61%) had progression of CAD. Included patients had high prevalence of coronary risk factors (Hypertension 71%, diabetes mellitus 69%, Dyslipidemia 75%). Most patients had controlled dyslipidemia (64% had LDL 5% was the only predictor of CAD progression (adjusted odds ratio 5.8, p = 0.042, 95% CI 1.1–31.2). Conclusions: Among high risk patients with recurrent symptoms, the short term rate of progression of CAD is high. A drop in LVEF >5% is the best predictor of progression of CAD. Further studies are needed to determine the prognostic value of CAD progression in the era of potent medical therapy