This is a request for continuing support to study the density of gamma-aminobutyric acid (GABA)-A/benzodiazepine neurotransmitter receptors in the central nervous system in the neurodegenerative disease, progressive supranuclear palsy (PSP), and relate the findings to the cognitive and motor disturbances in this disease. Evidence suggests that changes in these receptors may be important in the pathophysiology of this disorder. In PSP the cognitive and movement disorders are thought to result from neuropathological changes in subcortical structures, but positron emission tomography (PET) studies with [18F]fluorodeoxyglucose (FDG) demonstrate widespread hypometabolism in the central nervous system (CNS), including the cerebral cortex. This raises the possibility that the cognitive disorders result from cerebral cortical and not subcortical pathology. The development of a ligand, [11C]flumazenil (FMZ), to study gamma-aminobutyric acid (GABA)-A/benzodiazepine (BDZ) neurotransmitter receptors with PET makes it possible to examine functional alterations localized to cortical and subcortical structures. In the studies proposed, PET scans with FMZ will be used to examine the density of BDZ neurotransmitter receptors in the cerebral cortex and subcortical structures in patients with PSP as compared with normal control subjects. The findings will be correlated with studies of local cerebral metabolic rates for glucose (LCMRG) measured with FDG and PET and with quantitative tests of cognitive, motor and speech function. Preliminary studies suggest that in PSP, FMZ binding will be decreased in the frontal regions of the cerebral cortex but normal in the parietal and occipital regions. These studies also suggest that the decrease in binding will correspond to performance on neuropsychological tasks mediated by this region of the brain.

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Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Michaud, Tzeyu L; High, Robin; Charlton, Mary E et al. (2017) Dependence Stage and Pharmacoeconomic Outcomes in Patients With Alzheimer Disease. Alzheimer Dis Assoc Disord 31:209-217
Monin, Joan K; Poulin, Michael J; Brown, Stephanie L et al. (2017) Spouses' daily feelings of appreciation and self-reported well-being. Health Psychol 36:1135-1139
Jun, Gyungah R; Chung, Jaeyoon; Mez, Jesse et al. (2017) Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement 13:727-738
Cary, Brian P; Brooks, Allen F; Fawaz, Maria V et al. (2016) Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts. ACS Chem Neurosci 7:391-8
Karch, Celeste M; Ezerskiy, Lubov A; Bertelsen, Sarah et al. (2016) Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci. PLoS One 11:e0148717
Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-121
Ridge, Perry G; Hoyt, Kaitlyn B; Boehme, Kevin et al. (2016) Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging 41:200.e13-200.e20
Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-150
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17

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