Major Depressive Disorder (MDD) is a common and important complication of Alzheimer's disease (AD) that increases the suffering of patients and their families, produces excess disability, promotes institutionalization, and hastens death. Emerging clinicopathological studies of MDD in AD suggest that the development of this behavioral complication of AD is associated with degeneration of the brainstem aminergic nuclei (SN, DR, LC) and the relative preservation of the cholinergic bnM. These neuropathologic and related neurochemical correlates of AD+MDD appear to be relatively specific for this behavioral complication of AD, and may explain aspects of the course and treatment responsiveness of MDD in this context. We propose to evaluate this primary etiologic hypothesis using 125 histopathologically-confirmed AID cases and controls who were prospectively characterized by a consortium of four NIA-funded ADRCs and the Geriatric Psychiatry Branch, DIRP, NIMI-t. All participating sites employ the Clinical Assessment of Depression in Dementia (CADD), a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize Major Depressive Episodes (MDEs) in this ongoing longitudinal study. Multidimensional assessments of neurodegeneration of the brainstem nuclei are performed using rigorous stereologic analyses of immunostained frozen serial sections, and determinatons of NTs/metabolites in defined cortical and subcortical projection areas are performed using flash-frozen tissue samples by established HPLC methods. Secondary. Hypotheses explore: a) the associations of clinical subtypes on these neuropathologic and neurochemical variables, b) the mechanism of cell death in these regions, and c) the influence of a family history of MDD and APOE genotype on the emergence of MDD in AD. The long-term goal of the proposed research plan is to better define the biological substrates MDD in AD, with the intention of augmenting the knowledge base that will facilitate the development of more effective treatments, and to provide additional insight into the clinical biology of Major Mood Disorders affecting the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH047346-12
Application #
7084619
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Evans, Jovier D
Project Start
1992-09-30
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
12
Fiscal Year
2006
Total Cost
$652,572
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zubenko, George S; Hughes 3rd, Hugh B; Jordan, Rick M et al. (2014) Differential hippocampal gene expression and pathway analysis in an etiology-based mouse model of major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 165B:457-66
Zubenko, George S; Hughes 3rd, Hugh B (2012) No evidence of non-homologous insertions in mouse model of MDD created by replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence. Am J Med Genet B Neuropsychiatr Genet 159B:1-4
Zubenko, George S; Hughes 3rd, Hugh B (2011) Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 156B:517-31
Zubenko, George S; Hughes 3rd, Hugh B (2010) Effects of the A(-115)G variant on CREB1 promoter activity in two brain cell lines: Interactions with gonadal steroids. Am J Med Genet B Neuropsychiatr Genet 153B:1365-72
Maher, Brion S; Hughes 3rd, Hugh B; Zubenko, Wendy N et al. (2010) Genetic linkage of region containing the CREB1 gene to depressive disorders in families with recurrent, early-onset, major depression: a re-analysis and confirmation of sex-specific effect. Am J Med Genet B Neuropsychiatr Genet 153B:10-6
Zubenko, George S; Jones, Michelle L; Estevez, Annette O et al. (2009) Identification of a CREB-dependent serotonergic pathway and neuronal circuit regulating foraging behavior in Caenorhabditis elegans: a useful model for mental disorders and their treatments? Am J Med Genet B Neuropsychiatr Genet 150B:12-23
Zubenko, G S; Hughes 3rd, H B (2009) Effects of the G(-656)A variant on CREB1 promoter activity in a neuronal cell line: interactions with gonadal steroids and stress. Mol Psychiatry 14:390-7
Zubenko, George S; Hughes 3rd, Hugh B (2008) Effects of the G(-656)A variant on CREB1 promoter activity in a glial cell line: interactions with gonadal steroids and stress. Am J Med Genet B Neuropsychiatr Genet 147B:579-85
Zubenko, G S; Stiffler, S; Stabler, S et al. (1994) Association of the apolipoprotein E epsilon 4 allele with clinical subtypes of autopsy-confirmed Alzheimer's disease. Am J Med Genet 54:199-205