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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000975-03
Application #
8336004
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$487,612
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Goetzl, Edward J; Nogueras-Ortiz, Carlos; Mustapic, Maja et al. (2018) Deficient neurotrophic factors of CSPG4-type neural cell exosomes in Alzheimer disease. FASEB J :fj201801001
El Haj, Mohamad; Coello, Yann; Kapogiannis, Dimitrios et al. (2018) Negative Prospective Memory in Alzheimer's Disease: ""Do Not Perform That Action"". J Alzheimers Dis 61:663-672
Becker, Robert E; Greig, Nigel H; Lahiri, Debomoy K et al. (2018) (-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer's Disease. Curr Alzheimer Res 15:883-891
Mullins, Roger; Reiter, David; Kapogiannis, Dimitrios (2018) Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer's brain. Ann Clin Transl Neurol 5:262-272
Guix, Francesc X; Corbett, Grant T; Cha, Diana J et al. (2018) Detection of Aggregation-Competent Tau in Neuron-Derived Extracellular Vesicles. Int J Mol Sci 19:
Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E et al. (2018) Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry. World J Biol Psychiatry 19:244-328
Gill, Jessica; Mustapic, Maja; Diaz-Arrastia, Ramon et al. (2018) Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel. Brain Inj 32:1277-1284
Fitzgerald, Kathryn C; Vizthum, Diane; Henry-Barron, Bobbie et al. (2018) Effect of intermittent vs. daily calorie restriction on changes in weight and patient-reported outcomes in people with multiple sclerosis. Mult Scler Relat Disord 23:33-39
Becker, Robert E; Kapogiannis, Dimitrios; Greig, Nigel H (2018) Does traumatic brain injury hold the key to the Alzheimer's disease puzzle? Alzheimers Dement 14:431-443
Goetzl, Edward J; Abner, Erin L; Jicha, Gregory A et al. (2018) Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer's disease. FASEB J 32:888-893

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