Diffuse Lewy body disease is a distinct neuropathological entity that occurs in a pure form, pDLBD, or in association with other dementing and neurodegenerative disorders like Alzheimer disease and progressive supranuclear palsy, aDLBD. Clinically this disorder is associated with progressive dementia, extrapyramidal signs and not uncommonly with psychiatric symptoms. The disorder is being increasingly recognized in neuropathologic practice and is by some authorities believed to be the second most common dementing disorder. The underlying disease mechanism is unknown, although the characteristic hallmark of the disease, the presence of cortical Lewy Bodies, appears to be preferentially localized to neocortical, limbic, and subcortical projection areas of the ventral tegmental dopamine system. These changes are accompanied by dystrophic neuritic change in the same areas. As previously demonstrated by this laboratory, these abnormalities are associated with profound neuronal loss of the ventro-medial pigmented nuclei of the substantia nigra complex, as well as a moderate loss of cholinergic neurons of the nucleus basalis of Meynert (nbM). In this proposal we wish to test the hypothesis that DLBD is a dying back phenomenon of the ventral tegmental dopamine system, which projects to the cerebral cortex and limbic areas with rostral to caudal anatomic gradient of decreasing density. To test this hypothesis we propose to examine the temporal and spatial occurrence of histopathological abnormalities using quantitative morphometric techniques combined with extensive light microscopic and ultrastructural immunocytochemical methodologies. The temporal occurrence of dystrophic changes in terminal dopaminergic axons and cell somata, deafferentiation of the target neurons in the projection ares, the presence of subsequent transsynaptic occurrence of Lewy bodies, and cell death in the nuclei of origin in the ventral tegmental nuclei will be reconstructed by comparing the quantity of the various structural abnormalities in a number of locations along the spatial gradient. The sequence of postsynaptic events will be approached by comparing the extent of postsynaptic receptor loss, assessed by autoradiographic binding assays, with immunocytochemical abnormalities and the occurrence and composition of lewry bodies in the targeted neurons. The significance of the abnormalities affecting the cholinergic basal forebrain system in pDLBD and DLBD associated with AD will be examined by correlating the quantitative pathology with quantitative psychological and cognitive tests performed by the Clinical Core of the MADRC ante-mortem. We anticipate examine 15 cases each of pDLBD, DLBD/AD, and normal age-matched controls.
| 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 |
| 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 |
| Hohman, Timothy J; Cooke-Bailey, Jessica N; Reitz, Christiane et al. (2016) Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement 12:233-43 |
| Mossine, Andrew V; Brooks, Allen F; Jackson, Isaac M et al. (2016) Synthesis of Diverse (11)C-Labeled PET Radiotracers via Direct Incorporation of [(11)C]CO2. Bioconjug Chem 27:1382-9 |
Showing the most recent 10 out of 274 publications
