Predictors and biomarkers of Alzheimer's Disease (AD) In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immune sorting using neuronal surface markers NCAM and L1 CAM. We conducted two case control studies measuring exosomal Ab, tau, and IRS-1 peptides and found highly significant differences between AD and control subjects that discriminate between the two groups with near 100% accuracy. In addition, exosomal differences are present at the preclinical stage and may predict AD by up to 10 years. I presented the findings at the 2014 Alzheimer's Association International Conference (AAIC), while one manuscript is in press in the journal Alzheimer's and Dementia, and a second one under review in the journal FASEB. One major goal is to validate exosomal markers as diagnostic and prognostic biomarkers of AD in large cohorts from the Baltimore Longitudinal Study of Aging (BLSA) and Alzheimer's Disease Neuroimaging Initiative (ADNI). The BLSA is ideal to assess longitudinal changes in these markers and their potential to predict AD at the preclinical stage, whereas ADNI is ideal for assessing changes with disease progression and conversion from MCI to AD. I implemented a data reduction technique called Independent Component Analysis to structural MRI images of subjects with AD and MCI from ADNI and studied how patterns of structural covariance predict clinical diagnosis and MCI conversion. This approach allowed us to classify subjects according to their future diagnosis with a high degree of accuracy (arguably, the highest ever achieved);the study is currently in press in the journal Psychiatry Research Neuroimaging. In a large cohort derived from the BLSA, I examined the performance of metabolic syndrome components (several measures of blood pressure, plasma lipids and glucose, and BMI) followed longitudinally as predictors for AD. I found that higher blood pressure, dyslipidemia and higher BMI increase possibility of AD diagnosis and their longitudinal trajectories may even be used to accurately predict future AD diagnosis with lead time of several years (the study is currently under review in the journal JAMA Neurology). In addition, I studied how peripheral insulin resistance is associated with regional brain glucose metabolism on FDG-PET in ADNI participants. We found that insulin resistance is associated with a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis;the study is currently under review in the journal Neurology. Together with Dr. Auriel Willette, a post-doctoral fellow whom I mentor, we conducted a systematic review of neuroimaging studies looking at associations of obesity and brain volume across the age-span. We found that increased obesity is associated with atrophy mainly in the frontal lobes. Our review was published by the journal Aging Research Reviews. In collaboration with the NIA 3T MRI Facility manager, Dr. David Reiter, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. First, I conducted a study of healthy volunteers combining MRS with resting fMRI, which provides measures of brain functional connectivity, and showed a link between neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In a case-control study of patients with MCI/AD and healthy volunteers, we showed higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. These findings were presented at the AAIC 2014 and the manuscript is under preparation. In addition, we are exploring associations of MRS measures with cognitive performance, functional connectivity within the default mode network;and CSF biomarkers. I also studied the association between cognitive performance and clinical status in AD and CSF inflammatory markers and found that higher levels of one particular pro-inflammatory cytokine, IL-12, predicts better cognition and clinical status;this study is currently under preparation. Finally, in collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted a study on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are impaired in AD. The study is under review in the journal Neuropsychology. Treatment studies in AD I conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exendin-4 (exenatide) treatment in participants with Mild Cognitive Impairment (MCI)/early AD. To this date, 38 participants have been enrolled, out of which 20 fulfilled inclusion criteria (clinical diagnosis of MCI/early AD, cerebrospinal fluid Ab(1-42) <192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). Participants receive study drug for 18 months and outcome measures are being collected every six months. Twelve participants completed the study, four participants withdrew from the study, and four continue participation. My goal for the new year is to reach the enrollment target of forty participants. I continue to conduct a Phase I, double-blind, placebo-controlled, ascending, single-dose, safety, tolerability and pharmacokinetic study of Bisnorcymserine, a selective butyrylcholinesterase inhibitor, in healthy volunteers. Inhibition of butyrylcholinesterase is a novel therapeutic approach for symptomatic treatment in moderate/advanced AD. Studies in Frontotemporal Dementia. As part of an ongoing collaboration with researchers at the National Institute of Neurological Disorders and Stroke and Texas Tech University, I contributed to a large GWAS study of Frontotemporal Dementia. We published our findings including identification Frontotemporal Dementia cohort in Neurobiology of Aging. In addition, I contributed to a GWAS study in FTD, which is currently under review in Nature Genetics.
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