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Steven E. Arnold, M.D.

Director, Geriatric Psychiatry Program
Director, Cellular and Molecular Neuropathology Program
Center for Neurobiology and Behavior
Translational Research Laboratory Building
125 South 31st Street
Philadelphia, PA 19104
(215) 573-2840 fax (215) 573-6382
email sarnold@med.upenn.edu

Click here for selected publications since Dr. Arnold's arrival at Penn

RESEARCH INTERESTS

RESEARCH TECHNIQUES

RESEARCH SUMMARY

Our research aims to discover the cellular and molecular bases of severe psychiatric illnesses, cognitive changes in aging, and neurodegenerative dementias. Given the uniquely human nature of these conditions, use of human postmortem tissues is our main approach while secondarily, we examine neuropathology in informative mouse and canine models of neurobehavioral dysfunction.

Schizophrenia and other severe mental illnesses
Schizophrenia is a common, severe mental illness characterized by auditory hallucinations, delusional beliefs, deficits in attention, memory and complex reasoning, a flattening of emotion, and apathy. These symptoms lead to a deterioration in personal, social, and occupational functioning. Schizophrenia typically occurs in late adolescence or early adulthood and causes lifelong suffering and disability. Many clinical, neuroimaging, and postmortem studies have identified a range of brain abnormalities in schizophrenia. And yet the signature genetic, molecular, and neuropathological lesions of the disease have remained elusive.

Together with Penn's Schizophrenia Research Center and Penn's Center for Neurodegenerative Disease Research, we have established a brain collection for cellular and molecular studies using brain tissue from very well-characterized persons with neuropsychiatric disorders and controls. To this end, we have a prospective clinicopathological correlation study of elderly individuals with refractory schizophrenia and other severe mental disorders in whom clinical evaluations are conducted followed by brain autopsy in the event of death. Brain tissues from other local and national sources are also used. In addition, we have developed a program for olfactory neuroepithelium biopsy to obtain tissues from living subjects that can be used in tissue culture and neurophysiological experiments as well as for molecular-histological studies.

Current projects include:
-- Molecular and Structural Plasticity in Stimulus Encoding Circuits in Schizophrenia
This project uses single cell gene expression profiling, in situ hybridization, immunohistochemistry, and quantitative microscopic analyses to identify differentially expressed gene products and subcellular structural abnormalities in axons, synapses, and dendrites in select brain regions that are important for attention, learning and memory.

-- Olfactory System Pathology and Physiology in Schizophrenia
This research investigates developmentally-relevant molecular neuropathology in biopsy and postmortem olfactory epithelium, and olfactory bulb and olfactory cortices from persons with schizophrenia and controls as well as odorant responsiveness in acutely dissociated and cultured olfactory epithelial biopsy cells.

-- Neurobiology of Dysbindin in Schizophrenia
Pursuing a genetic candidate in schizophrenia, we recently showed significant abnormalities in the expression of dysbindin, a novel protein whose putative function involves vesicle assembly and/or trafficking. Our research is characterizing the distribution, binding partners, molecular genetics and neurophysiology of dysbindin in schizophrenia and mutant mice.

Cognition in aging and neurodegenerative diseases
Impairments in memory, language, mental efficiency, and other aspects of cognition occur very frequently with advancing age. The neurobiological causes of such changes are many, including age-related changes in the structure and function of neurons, dendrites and synapses, common neurodegenerative diseases such as Alzheimer's disease, Lewy body diseases, and tauopathies, and large and small vessel ischemic disease. The specific ways in which each may affect the mental functioning of elders is not well understood.

Current projects include:
-- Risk Factors, Pathology, and the Clinical Expression of AD
This is a collaborative epidemiologic clinical-pathological study examining the mechanisms through which risk factors for Alzheimer's disease lead to clinical expression of the disease in the Religious Orders Study cohort. More than 800 subjects have annual neurological and neuropsychological assessments and all will have had autopsy at the time of death. We are performing high throughput quantitative neuropathological studies of neurons, synapses, neurofibrillary tangles and amyloid deposits.

-- Epidemiologic Study of Neural Reserve and Neurobiology of Aging
To expand the large scale, epidemiologic-neuropathological approach into more diverse populations, a second study has begun focused on a large ethnically, socially and economically diverse population. For this study, we are performing high throughput quantitative neuropathological studies of neurons, dendrites, and dendritic spines as indices of neural functional capacity in brain regions important for cognition.

-- Insulin Signaling pathways in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease
Increasing evidence points to abnormalities in brain insulin signaling in Alzheimer's disease. Using the Religious Orders Study cohort, we are examining insulin signaling molecules and their regulatory factors with a focus on the PI3K pathway and relating these data to cognition and other neuropathology.

KEY WORDS: