Objective-Examine the correlation of cardiorespiratory fitness with brain atrophy and cognition in early-stage Alzheimer's disease (AD).Background-In normal aging physical fitness appears to mitigate functional and structural agerelated brain changes. Whether this is observed in AD is not known.

No abstract

Novobiocin is a C-terminal inhibitor of the Hsp90 protein folding machinery, which is responsible for the conformational maturation of numerous proteins involved in cancer growth and survival. Due to novobiocin's poor inhibitory activity ( approximately 700 muM), very little attention has been paid toward the development of novobiocin analogues for Hsp90 inhibition. In this study, a parallel library of 20 novobiocin derivatives was prepared and the biological activity of each evaluated by Western blot analysis of Hsp90 client proteins. A4 was found to be a potent inhibitor of Hsp90 as determined by its ability to cause the degradation of several Hsp90 client proteins in both breast and prostate cancer cell lines. In the presence of 1 muM A4, several Hsp90 client proteins were degraded, including AKT, Her2, Hif-1alpha, and the androgen receptor.

Objective-To examine the relationship between body mass index (BMI) and cognitive decline in subjects diagnosed with mild cognitive impairment (MCI).Methods-Neuropsychologic and clinical evaluations were conducted at baseline, 6-months, and 1-year on 286 MCI subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative. A global cognitive composite score was derived (mean Z-score) from performance on 9 neuropsychologic subtests. Height and weight were assessed at baseline and used to calculate BMI. Generalized estimating equations (linear and logistic) assessed the relationships of baseline BMI with cognitive outcomes, clinician judgment of "clinically significant decline" over 1-year, and diagnostic progression from MCI to Alzheimer disease.Results-Lower baseline BMI was associated with significant declines in cognitive performance in individuals with MCI over 1 year (Mini-Mental State Examination, Alzheimer Disease Assessment Scale-Cognitive subscale, and a global cognitive composite; all P<0.05). We observed a significant protective effect of baseline BMI in reducing the risk of a clinically significant decline in Alzheimer Disease Assessment Scale-Cognitive subscale and mini-mental state examination (P<0.05). No association was found between BMI and changes in the clinical dementia rating sum of boxes or conversion to Alzheimer disease.Conclusions-Lower baseline BMI is associated with more rapid cognitive decline in MCI. This relationship suggests either body composition may influence the rate of cognitive decline in MCI or factors related to MCI influence body composition. Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at www.loni.ucla.edu/ADNI/Collaboration/ADNI_Manuscript_Citations.pdf). outcomes is attenuated, and perhaps reversed, by age. 5 In longitudinal studies of older adult populations (generally aged 65 y and above), low BMI is associated with an increased risk of developing dementia, 6 whereas high BMI is associated with a lower risk of dementia. 5,7 In addition, weight loss is associated with an increased risk of dementia 5 suggesting it may be a risk factor or an early sign of AD. This is consistent with multiple studies demonstrating that weight loss is present several years before the onset of clinically recognizable AD symptoms. [8][9][10][11] Mild cognitive impairment (MCI) is characterized as a transition phase between normal aging and AD with 10% to 15% of MCI patients progressing to overt AD annually. There is little prospective data on body composition in MCI. Thus, we examined the relationship between BMI and cognitive decline in individuals with MCI enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). We hypothesized t...

Increased peripheral insulin is associated with reduced Alzheimer disease (AD)-related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.