Exenatide for the treatment of Alzheimer's Disease (AD). In collaboration with researchers from the NIA Laboratories of Neurosciences, Clinical Investigations and Behavioral Neurosciences, I designed and continue to conduct a pilot Phase II (N = 40), double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exenatide treatment in participants with early AD. To this date, 24 participants have been enrolled, out of which 13 fulfilled all inclusion criteria (including receiving clinical diagnosis of MCI/early AD, showing appropriate impairment in cognitive performance and having cerebrospinal fluid Ab(1-42) <192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). One participant reached the 18-month end-point, 2 were withdrawn due to protocol-specified criteria, and 10 continue treatment. Developing novel AD biomarkers. Together with Dr. Mark Mattson from LNS, we advocate the view that abnormalities in neocortical energy metabolism, imbalances in excitatory and inhibitory neurotransmission, and consequent changes in functional connectivity play important roles in AD pathogenesis and determine its regional spread (this view was presented in an extensive review article in Lancet Neurology). Consequently, I have been using: Magnetic Resonance Spectroscopy (MRS) to obtain in vivo measures on brain energetics (concentration of glucose), neurotransmitter levels (glutamate and GABA);resting fMRI to obtain measures of intrinsic functional connectivity within brain networks;and CSF sampling to obtain Abeta and tau measures of brain amyloidosis and neurodegeneration. Preliminary (unpublished) results from these combined cross-sectional fMRI/MRS/CSF studies suggest the presence of associations between: glucose, glutamate and GABA in the precuneus;functional connectivity within the default mode network;and CSF Abeta(1-42). 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 from the National Institute of Neurological Disorders and Stroke and Texas Tech University to perform genetic studies in a closed Frontotemporal Dementia cohort. This last year, we published our findings of C9ORF72 expansions in our Frontotemporal Dementia cohort. In addition, we collaborated in writing a review article on the clinical, pathological and genetic links between Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Institute on Aging
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Mustapic, Maja; Eitan, Erez; Werner Jr, John K et al. (2017) Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. Front Neurosci 11:278
Bassil, Fares; Canron, Marie-Hélène; Vital, Anne et al. (2017) Insulin resistance and exendin-4 treatment for multiple system atrophy. Brain :
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Mullins, Roger J; Diehl, Thomas C; Chia, Chee W et al. (2017) Insulin Resistance as a Link between Amyloid-Beta and Tau Pathologies in Alzheimer's Disease. Front Aging Neurosci 9:118
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Goetzl, Edward J; Mustapic, Maja; Kapogiannis, Dimitrios et al. (2016) Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. FASEB J 30:3853-3859
El Haj, Mohamad; Kapogiannis, Dimitrios (2016) Time distortions in Alzheimer's disease: a systematic review and theoretical integration. NPJ Aging Mech Dis 2:16016

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