Exendin-4 for the treatment of Alzheimer's Disease. In collaboration with researchers in the NIA Laboratory of Neurosciences we produced and published additional preclinical evidence for beneficial effects of exendin-4 in cellular and animal models of Alzheimer's disease, specifically, decreased concentrations of APP, Ab, tau and decreased number of plaques (Li et al, 2010, Journal of Alzheimer's disease). Based on these and similar previously published findings, we designed a double blind randomized placebo-controlled clinical trial to assess the safety and efficacy (phase II/III) of exendin-4 treatment in participants with early Alzheimer's disease. This study acquired Institutional Review Board approval in January 2010. The Data Safety Monitoring Board convened in June 2010 and approved the initiation of the trial. A contract was concluded with Dr. Leslie Shaw from the University of Pennsylvania in July 2010 to provide laboratory support for the study. Enrollment of participants is currently under way. 16 participants were screened, out of which 8 fulfilled all inclusion criteria (including symptoms and signs characteristic of early AD, objective impairment in cognitive performance and cerebrospinal fluid Ab <192 pg/dl) and were started on treatment with the study drug (exendin-4 or placebo). Alzheimer's disease pathogenesis. I collaborated with Dr. Mark Mattson to outline our views on AD pathogenesis in an extensive review article published in Lancet Neurology. In particular, we reviewed evidence that alterations in brain energetics, neurotransmitter levels and synaptic re-organisation, and functional connectivity within brain networks, are early events in the AD cascade and determine its regional spread. In our view, the microscopic synaptic level drives connectivity changes;in pursuit of this hypothesis, I am conducting a combined fMRI/MRS study to link changes in glutamate and GABA in the precuneus and functional connectivity within the default mode network. Reward processing in Parkinson's disease (PD). It is increasingly recognized that a significant portion of morbidity in PD is associated with non-motor, behavioral and cognitive, manifestations, such as impairments in the cognitive processing of rewards. Moreover, dopamine agonists may cause additional impairment in reward processing, culminating in impulse control disorders, such as pathological gambling. I contributed to the field with a combined TMS/behavioral study that showed: patients with PD do not have a physiologic cortical signal associated with reward expectation and measured with TMS;restoration of this signal with pramipexole;an increase in risk taking with both levodopa and pramipexole;a correlation between increased risk taking and the reward TMS signal when patients took pramipexole. The study was published at the journal """"""""Movement Disorders"""""""". Genetic and phenotypic characterization studies in Frontotemporal Lobar Degeneration. I collaborated with researchers at the Cognitive Neuroscience Section of the National Institute of Neurological Disorders and Stroke to perform natural history studies in individuals with Frontotemporal Dementia, Corticobasal Syndrome and related disorders. As part of these studies, we published the finding of a novel mis-sense mutation in charged multivesicular body protein 2B in a patient with Frontotemporal Dementia. In addition, I collaborated with geneticists at the Texas Tech University to write a review article on the clinical, pathological and genetic links between Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
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