Mechanisms of psychosis in Alzheimer's disease and schizophrenia.
My research program is focused on understanding the mechanisms which lead to the generation of psychotic symptoms (delusions and hallucinations) which may occur in multiple disorders. These symptoms are core features of the most common psychotic disorder, schizophrenia, but also occur in about 50% of individuals with Alzheimer Disease. We have proposed that there are common genetic risk factors and vulnerable brain circuits that act together to cause positive symptoms across these disorders. My research program has both clinical and laboratory components.
In my lab, we conduct studies of post-mortem brain tissue from subjects with schizophrenia and with psychosis in Alzheimer Disease. Structural imaging studies in subjects with schizophrenia have identified gray matter volume reductions in the auditory cortex that are present prior to treatment and are correlated with impaired auditory sensory processing. Our findings to date have demonstrated reductions of excitatory synaptic structures in the auditory cortex. We are currently testing the hypothesis that schizophrenia is associated with alterations in mediators of structural synaptic plasticity, creating a vulnerability to loss of excitatory synapses in auditory cortex. Our approach uses novel quantitative anatomic techniques, including multiple label confocal imaging in combination with the rigorous application of unbiased stereologic methods in immunohistochemical preparations. Complementary protein chemistry studies are conducted. Control studies are conducted in brain tissue from neuroleptic-treated non-human primates and mechanisms tested in mouse models.
My clinical research program conducts studies to refine the definition of psychotic phenotypes and outcomes in Alzheimer Disease, and relate these to underlying genetic variation. We have demonstrated that the presence of psychotic symptoms in Alzheimer Disease subjects is familial, identifies a subgroup with greater cognitive deficits, and may be associated with greater synapse loss than in Alzheimer Disease subjects without psychosis. We have hypothesized that psychosis in Alzheimer Disease identifies one or more genetically homogenous subgroups, and that some of the genetic liability to psychosis in Alzheimer Disease is shared with schizophrenia. We are currently testing this hypothesis in both case-control and family-based study designs. To date, we have identified novel associations of psychosis in Alzheimer Disease with two putative genes for schizophrenic psychosis: neuregulin-1 and catechol-O-methyltransferase. Our laboratory research program is further addressing the mechanisms of the underlying excess synapse loss using postmortem brain tissue from subjects with psychotic symptoms during the course of their Alzheimer Disease.
Sweet, R.A., Henteleff, R.A., Zhang, W., Sampson, A.R. and Lewis, D.A. Reduced Dendritic Spine Density in Auditory Cortex of Subjects with Schizophrenia. Neuropsychopharmacology. May 7, 2008. [Epub ahead of print] PMID: 18463626
Fish, K.N., Sweet, R.A., Deo, A.J. and Lewis, D.A. An automated segmentation methodology for quantifying immunoreactive puncta number and fluorescence intensity in tissue sections. Brain Res. Sep 3, 2008. [Epub ahead of print] PMID: 18793619 [PubMed - as supplied by publisher]
Konopaske, G.T., Dorph-Petersen, K.A., Sweet, R.A., Pierri, J.N., Zhang, W., Sampson, A.R. and Lewis, D.A. Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys. Biol Psychiatry. 2008 Apr 15;63(8):759-65. Epub Oct 22, 2007. PMID: 17945195 [PubMed - indexed for MEDLINE]
Sweet, R.A., Bergen, S.E., Sun, Z., Marcsisin, M.J., Sampson, A.R. and Lewis, D.A. Anatomical evidence of impaired feedforward auditory processing in schizophrenia. Biol Psychiatry. Apr 1;61(7):854-64, 2007. Epub 2006 Nov 21. PMID: 17123477 [PubMed - indexed for MEDLINE]
Sweet, R.A., Devlin, B., Pollock, B.G., Sukonick, D.L., Kastango, K.B., Bacanu, S.A., Chowdari, K.V., DeKosky, S.T. and Ferrell, R.E. Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. Mol Psychiatry. Nov; 10(11):1026-36, 2005. PMID: 16027741 [PubMed - indexed for MEDLINE]
Sweet, R.A., Nimgaonkar, V.L., Devlin, B. and Jeste, D.V. Psychotic symptoms in Alzheimer disease: evidence for a distinct phenotype. Mol Psychiatry. Apr;8(4): 383-92, 2003. Review. PMID: 12740595 [PubMed - indexed for MEDLINE]