Figure 1. (Click Image to Enlarge) Schematic showing patient tissue collection that is used in the search for novel biomarkers. | Biomarkers for Schizophrenia: Tissue Collection with Detailed Phenotypic Characterization In many diseases, such as liver and kidney diseases, use of biopsy from the patients facilitates accurate diagnosis and choice of best therapeutic strategies. In brain disorders, it is almost impossible to conduct a brain biopsy. To overcome this clinical limitation, we are exploring biopsy of olfactory epithelium (OE) because it contains neurons and their stem cells of central nervous system. Since 2005, we have conducted biopsies from more than 40 schizophrenic patients and normal controls with no complications. In parallel, we perform systematic clinical and neuropsychological assessment and establish lymphoblastoid cells from peripheral blood. These projects are ongoing, in part, with an affiliate laboratory in the Center of Excellence at the University of Tokyo and with support of Astellas Pharm. Co. Ltd. We plan to begin a new collection of OE sample in schizophrenic patients with a recent onset of the illness. This will eliminate the confounding effect of long-term exposure to the medications patients take for the treatment of their illness. During the new collection, we plan to obtain one OE biopsy per year for five years from the same patient so that we may follow the evolution of the illness from a molecular point of view and correlate gene expression with the time course of the illness, response to medication, cognitive performance, and possibly brain imaging variables. We are also trying to establish immortalized neurons from OE tissues of schizophrenics and control subjects. Such patient neurons will facilitate understanding of functional abnormalities underlying the disease process. This technique, once established, will have much broader application to other brain disorders, such as bipolar disorder, Alzheimer’s disease and Parkinson’s disease. | |
Figure 2. Each colored square in the matrix indicates the similarity (as measured by Pearsons’s correlation coefficient, r) of intensities from one microarray (or sample or gene expression profile) to another, from yellow (most similar) to red (least similar). | ||
| Translational Studies Between Human and Animal Models The unique strength of our program is in our expertise that spans from basic studies using animal models to clinical studies using patient subjects and tissues. To achieve scientific translations between humans and animal models, we are using biochemical markers and physiological markers. Biochemical markers: Through studies of gene expression profiling using collected tissues, we are getting novel biomarkers for schizophrenia. We are examining alternation of such markers in the animal models for the disease. To the contrary, via studies with genetically-engineered mice for the disease risk factors, we are obtaining key molecules that mediate the disease conditions. Such key factors originally identified in animal models are carefully examined in patient tissues, especially considering the correlation between molecular and phenotypic alterations. Physiological markers: We are also attempting to match findings obtained in patients with schizophrenia with those from animal models using MRI and PET. This study is being done in collaboration with faculty members from the Department of Radiology at Hopkins. We hope to identify useful physiological measures in patient brains that can be directly linked to the disease mechanisms manifested in model animals. Such physiological measures, in addition to biochemical markers being explored in our OE biopsy study, should be very useful in diagnosing and evaluating conditions in patients. Thus far, we have observed enlarged lateral ventricles and specific brain shrinkage that are shared both in brains from patients with schizophrenia and a type of model mice. | |
References N. Cascella, M. Takaki, S. Lin, A. Sawa Neurodevelopmental involvement in schizophrenia: The olfactory epithelium as an alternative model for research. J. Neurochem, In press (2007) N. Sawamura, T. Sawamura-Yamamoto, Y. Ozeki, C.A. Ross, A. Sawa A form of DISC1 enriched in nucleus: altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse. Proc. Natl. Acad. Sci. USA, 102(4); 1187-92 (2005) A. Sawa, S.H. Snyder Schizophrenia: diverse approaches to a complex disease. Science, 296; 692-695 (2002) A. Sawa, G.W. Wiegand, J.K. Cooper, R.L. Margolis, A.H. Sharp, J.E. Lawler, J.T. Greenamyre, S.H. Snyder, C.A. Ross Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nature Med., 5; 1194-1198 (1999) | ||
