Funded Programs Prevention

Neural basis for the combined effects of cognitive stimulation and aeric exercise on cognition in aging

Summary:
Dr. Yaakov Stern has been funded by the National Institute on Aging (NIA) to investigate the separate and combined effects of two interventions for cognition and day- to-day function in healthy older adults: aerobic exercise and computer brain training. The purpose of this proposal to the ADDF is to enhance this clinical trial by adding a combination of structural, metabolic, and cognitive activation fMRI studies to evaluate the neural substrates of the effect of these interventions on cognition.

Effects of a Social Health Promotion Program on Neurocognitive

Summary:
With the proportion of people aged 65 and older expected to rise dramatically by 2020, it is critical to develop and test large-scale cognitive interventions for their effectiveness in promoting cognitive and functional health. This Brain Health Study proposal within the ongoing Baltimore Experience Corps Trial seeks to assess whether a \'real-world\', multi- modal activity intervention will directly result in neurocognitive gains and a maintenance of cognitive and IADL functions among 120 older adults randomized to participate in the Experience Corps (EC) program or a low-activity, volunteer control condition. Functional magnetic resonance imaging (fMRI) data have been collected at baseline to assess brain health and risk for executive dysfunction. FMRI measures will be readministered one year later to assess executive, memory, and functional gains in EC participants relative to controls, and whether those at elevated risk for cognitive impairment and dementia benefited. The marriage of this novel methodology and intervention will allow us to sensitively measure the direct effects of exposure on neurocognitive plasticity and on rates of cognitive and functional aging.

Effects of Brain Beta-Amyloid on Postoperative Cognition

Summary:
The overall goal of this proposal is to test the hypothesis that preoperative presence of brain beta-amyloid plaques in non-demented subjects increases postoperative cognitive decline in elderly subjects scheduled for hip or knee replacement. Postoperative Cognitive Decline affects up to 50% of non-cardiac surgical patients >65 years of age, and adversely affects other patient outcomes including mortality rates. Our hypothesis is that preoperative beta-amyloid plaques predict postoperative cognitive decline. The beta-amyloid complexes can now be detected with PET scans of the brain using the amyloid specific tracer AV-45. We propose to examine whether the presence and severity of preoperative beta-amyloid brain load (as measured with AV-45 PET scanning) predicts incidence of postoperative cognitive decline. Methods: Preoperatively, 44 patients aged >65 years scheduled for knee or hip replacement, will undergo PET imaging with an amyloid specific ligand AV-45, and detailed neuropsychological assessment. During the postoperative in-hospital stay, subjects will undergo daily assessments for delirium. The follow-up neuropsychological assessment will be undertaken one week and 3 months after surgery for diagnosis of postoperative cognitive dysfunction. Analysis: The primary analysis for this pilot study will evaluate the association of preoperative beta-amyloid deposition with postoperative cognitive decline, while controlling for potential confounders including age, gender, and co-morbidities. Significance: Sensitive and specific methods to preoperatively detect patients with Alzheimer’s Disease neuropathology may identify patients at risk for postoperative cognitive decline, and will represent the enriched patient population in whom preventative and treatment interventions will be trialed. A successful therapeutic pre-emptive treatment to prevent surgery-induced cognitive decline has been recently reported by members of our group in the murine model.

Effect of Memantine on Alzheimer\'s Disease pathogenesis induced by anesthesia in vivo Investigator(s): Emmanuel Planel, PhD Institution(s): Columbia University Medical Center/Research Foundation for Mental Hygiene

Summary:
Alzheimer\'s disease is the most common form of senile dementia. The cause of sporadic AD is likely to be multifactorial, and it is therefore a worthwhile endeavor to identify environmental factors that modulate the onset or progression of the disease. Among these factors, anesthesia appears to negatively impact brain function in the elderly, and exposure to anesthesia has been associated with enhanced AD-like pathology in vivo and in vitro. About 40 million people receive general anesthesia per year in the USA, and perioperative administration of therapeutic compounds able to prevent or reduce the deleterious effects of anesthetics on the brain would likely be of great benefit. One possible compound is memantine. Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that has been shown to reduce clinical deterioration in moderate to severe AD. Memantine has also been shown to improve spatial learning in mice expressing mutant Amyloid Precursor Protein (APP) and Presenilin 1 (PS) genes (PS/APP). In addition, memantine can prevent abnormal tau hyperphosphorylation induced by inhibition of ser/thr protein phosphatase 2A (PP2A) in rat brain slices. The mechanism by which PP2A inhibition is countered by memantine is not yet clear, but it seems to involve a complex formed by NMDA receptors, PP2A, and I2PP2A - an endogenous inhibitor of PP2A. The ability of memantine to modulate PP2A activity is important, as PP2A activity and expression level are decreased in AD, and because PP2A inhibition can lead to increased tau phosphorylation and β-amyloid (Aβ) production both in vitro and in vivo. In addition, we have reported that PP2A is inhibited by hypothermia during anesthesia, and have suggested that it could accelerate both plaque and tangle pathologies under these conditions. Thus, any counteracting effect of a PP2A enhancer such as memantine could potentially impact both tau and Aβ pathogenesis, and perioperative administration of a PP2A enhancer is likely to be beneficial.

The use of high-dose intravenous erythropoietin to prevent cognitive dysfunction following cardiopulmonary bypass Investigator(s): Edward Nemergut, MD Institution(s): University of Virginia

Summary:
Cognitive dysfunction is frequently observed after cardiac surgery and presents a major problem for physicians, patients, and their families. Up to this point, no therapy has yet been shown to successfully treat this dangerous complication which can ultimately result in permanent brain injury. Recombinant human erythropoietin (rhEPO) is a drug that is routinely used to treat the anemia associated with kidney failure or cancer and has tremendous potential to protect the injured brain during vulnerable periods. Previously, the applicant conducted a small study which demonstrated that rhEPO was able to improve outcome after stroke. The PI now proposes a short proof of concept clinical pilot study in which patients undergoing cardiac surgery will be randomly assigned to receive either rhEPO or routine perioperative care (without erythropoietin).