Alzheimer's disease is a devastating eurodegenerative disorder affecting more than 5 million older people in the U.S.A. for which there is not treatment. It is imperative to define the earliest cellular, mechanisms that drive the earliest onset of dementia in order to develop novel disease modifying therapeutic approaches. The thrust of this PPG entitled """"""""Neurobiology of Mild Cognitive Impairment in the Elderly"""""""" continues to be to elucidate the cellular and molecular basis or chain of events leading from no cognitive impairment (NCI) to mild cognitive impairment (MCI), the time-point considered the most likely therapeutic window. Moreover, we will refocus our efforts to include NCI subjects with pathology suggestive of AD, in order to resolve the neuropathogenic sequela underlying preclinical AD. We will implement a series of interrelated circuit-based projects centered on the cholinergic basal forebrain cortical (CBF) projection system, which displays early cellular pathology prior to MCI (preclinical AD), plays a pivotal role in the onset of clinical dementia and is the basis for most of the current FDA approved drugs for AD. The investigations proposed for this competitive renewal application of the Program Project brings together a number of basic and clinician scientists from Chicago and outside universities to investigate circuit based neuronal system dysfunction at a very early stage in the disease progress termed preclinical AD compared to prodromal AD (mild cognitive impairment). The Program Project consists of an Administrative Core with a Clinical/Tissue Distribution component and a Statistics and Data Management Core. In addition the following four research projects complete the program: 1) Tau abnormalities and Mild Cognitive Impairment in the Elderly (Lester """"""""Skip"""""""" Binder, Northwestern University Medical School);2) Age-Related Neuropathology and Mild Cognitive Impairment in the Elderly (James Lah, Emory University School of Medicine);3) Cholinergic Basal Forebrain Neurotrophic Abnormalities and Mild Cognitive Impairment in the Elderly (Elliott Mufson, Rush Medical Center);and Synaptic Abnormalities and Mild Cognitive Impairment in the Elderly (Milos Ikonomovic, University of Pittsburgh). Each core supports all research projects and all projects interact.

Public Health Relevance

The proposed research program will allow the understanding of alterations in brain pathophysiology that can differentiate preclinical individuals from those with prodromal AD (MCI) so that treatment strategies can be targeted at the earliest phases of the disease. The proposed studies are relevant to the NIA mission to support research aimed at defining the cellular, proteomic and molecular processes of dementia at its earliest stage of onset

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Petanceska, Suzana
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Rush University Medical Center
Schools of Medicine
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Mahady, Laura; Nadeem, Muhammad; Malek-Ahmadi, Michael et al. (2018) Frontal Cortex Epigenetic Dysregulation During the Progression of Alzheimer's Disease. J Alzheimers Dis 62:115-131
Mufson, Elliott J; He, Bin; Ginsberg, Stephen D et al. (2018) Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study. J Neurotrauma 35:1260-1271
Alldred, Melissa J; Chao, Helen M; Lee, Sang Han et al. (2018) CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation. Hippocampus 28:251-268
Jeanneteau, Freddy; Barrère, Christian; Vos, Mariska et al. (2018) The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex. J Neurosci 38:1335-1350
Mahady, L; Nadeem, M; Malek-Ahmadi, M et al. (2018) HDAC2 dysregulation in the nucleus basalis of Meynert during the progression of Alzheimer's disease. Neuropathol Appl Neurobiol :
Peng, Katherine Y; Pérez-González, Rocío; Alldred, Melissa J et al. (2018) Apolipoprotein E4 genotype compromises brain exosome production. Brain :
Ginsberg, Stephen D; Alldred, Melissa J; Gunnam, Satya M et al. (2018) Expression profiling suggests microglial impairment in human immunodeficiency virus neuropathogenesis. Ann Neurol 83:406-417
Tiernan, Chelsea T; Ginsberg, Stephen D; He, Bin et al. (2018) Pretangle pathology within cholinergic nucleus basalis neurons coincides with neurotrophic and neurotransmitter receptor gene dysregulation during the progression of Alzheimer's disease. Neurobiol Dis 117:125-136
Kaur, Gurjinder; Gauthier, Sebastien A; Perez-Gonzalez, Rocio et al. (2018) Cystatin C prevents neuronal loss and behavioral deficits via the endosomal pathway in a mouse model of down syndrome. Neurobiol Dis 120:165-173
Jansen, Willemijn J; Wilson, Robert S; Visser, Pieter Jelle et al. (2018) Age and the association of dementia-related pathology with trajectories of cognitive decline. Neurobiol Aging 61:138-145

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