Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective:To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods:A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results:Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion:Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD

Assessment of female-specific SPECT parameters for prediction of cardiac outcomes in women with suspected Ischemia

Thesis (Ph. D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Community and Preventive Medicine, 2009.Purpose. Evidence suggests that the value of scintigraphic variables best used to diagnose, treat, or predict cardiac events may differ according to gender. The purpose of this study was to develop female-specific diagnostic values for function and perfusion variables generated from Single Photon Emission Computed Tomography (SPECT) using logistic regression models, and to compare the diagnostic accuracy of these values for predicting cardiac death (CD) to literature-based mixed-gender and female-specific diagnostic values. Other goals of this study were to: (1) determine the association between SPECT parameters and CD and acute non-fatal myocardial infarction (ANFMI) after adjusting for clinical covariates over a five year follow-up period; and (2) construct a statistical model to simplify risk prediction in female populations evaluated for suspected ischemia. Methods. This retrospective cohort study included 1,811 women with suspected ischemia who had an initial SPECT scan between June 2000 – December 2005 at Strong Memorial Hospital (SMH). Women were excluded if they had a history of heart disease, were <18 years old, or did not consent to the study. Clinical, demographic, and scintigraphic information was obtained from the Nuclear Cardiology Database System (NCDS), medical records, SMH billing data, and the Clinical Information System (CIS) database. Cardiac death was defined as ICD-9 code: 410-411; 414-417; 425; 427-428; 430-438; 440-448, and was obtained from the National Center for Health Statistics (NCHS), National Death Index (NDI). ANFMI outcomes were identified from Strong Memorial, Rochester General, and Park Ridge hospital billing data and included ICD-9 codes: 410, 429.7. Receiver Operating Characteristic (ROC) curves were developed to determine female-specific diagnostic cut-points for function and perfusion variables, left ventricular ejection fraction (LVEF) and summed stress score (SSS), which were the scintigraphic variables most predictive of the primary outcome, cardiac death. A Cox Proportional Hazards model was derived using the most sensitive values of LVEF and SSS to assess their association with cardiac outcomes after adjusting for clinical covariates. Results. The incidence (95% CI) of CD over the course of follow-up was 13.9% (10.5-17.3); the incidence of ANFMI was 3.9% (2.1-5.7). Maximizing the combination of sensitivity and specificity to predict cardiac death resulted in a LVEF cut-off of 2. Comparisons of sensitivity among 1,731 women with complete information on independent and dependent variables of interest showed that we were able to increase the sensitivity of predicting cardiac death from 26% in the mixed-gender model, and 38% in the literature-based female-specific model, to 59% using the new cut-off value for LVEF. The new cut-off value for SSS provided negligible improvements in sensitivity of predicting cardiac death. We created a modified Framingham Risk Score (mFRS) that was included as a baseline covariate to illustrate that scintigraphic variables provided incremental predictive information beyond clinical variables. After controlling for confounders mFRS and stress type, risk of cardiac death was 2.3 times greater among women with an LVEF 58% (p = 0.003) during the 5 year follow-up period. SSS was no longer significant after controlling for LVEF and clinical covariates for prediction of CD. A small number of events limited our ability to accurately predict ANFMI. The prognostic model, limited to age and LVEF, accurately predicted the observed risk of cardiac death. Conclusions. Our new diagnostic cut-off value for LVEF substantially increased the sensitivity of cardiac death prediction among our population of women with suspected ischemia compared with traditionally used mixed-gender cut-off values and literature based-female specific values. While our prognostic model accurately predicted the risk of cardiac death, it may be too simplistic for clinical use. Results from this study suggest that a female-specific, SPECT-derived, LVEF value of <58% provides incremental value beyond routinely collected clinical variables for the prediction of cardiac death. Use of this cut-off value for cardiac event prediction should be externally validated in a new population of women with suspected ischemia referred to SPECT imaging