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Beaumont Research Institute's Neurology Research Laboratory, directed by David Loeffler, D.V.M., Ph.D., moved to Beaumont Hospital, Royal Oak, MI in 2000 from Sinai Hospital of Metropolitan Detroit where it was started in 1990. The long-term goal of the laboratory's research is to improve the diagnosis and treatment of Alzheimer's and Parkinson's diseases. The laboratory's studies focus on the significance of brain immune and inflammatory processes in the development and progression of these disorders.
The laboratory's studies have been supported by the National Institutes of Health, the Michael J. Fox Foundation for Parkinson's Research, the Alzheimer's Association, and other private foundations. The laboratory recently received funding from Oakland University-Beaumont Multidisciplinary Research Grants and the Parkinson's and Movement Disorder Foundation, as well as generous donations from Mr. and Mrs. Frederick Erb and family, Mr. Norman Merollis, and Mrs. Martha Loeffler to support its research efforts. These funds have permitted the laboratory to pursue new directions.
Foremost in these studies is the investigation of Intravenous Immunoglobulin (IvIg), a commercial drug composed of pooled antibodies from thousands of healthy donors. IvIg treatment has resulted in improvement in cognitive scores in two clinical trials (performed elsewhere) with Alzheimer's patients; the laboratory's IvIg-related studies are focused on characterizing the antibodies in this drug which may be responsible for its benefits in Alzheimer's patients, as well as those which may be useful to treat individuals with Parkinson's disease and related disorders. The laboratory is collaborating in these studies with John Finke, Ph.D., and Xiangqun Zeng, Ph.D., from Oakland University's Department of Chemistry.
A key pathological finding in the Alzheimer's brain is senile plaques, whose major protein is amyloid-beta (Aβ). The laboratory recently published its findings (International Immunopharmacology 2010;10:115-119) in which antibodies to Aβ were compared between different IvIg preparations; antibodies to the most neurotoxic form of Aβ, termed Aβ soluble oligomers, were present in IvIg, and surprisingly, there were significant differences between different IvIg preparations in their levels of these antibodies. A related paper highlighted the difficulties posed by nonspecific antibody binding when these antibodies are measured by immunoassay (Journal of Neuroscience Methods 2010;187:263-9), and a recently accepted paper examined the specificity of the procedure most commonly used to measure Aβ soluble oligomers (Journal of Neuroscience Methods 2010, in press). A fourth manuscript investigated the effects of external beam radiation (radiation therapy) on Aβ fibrils, which is the conformation of Aβ present in senile plaques (Radiation Research 2011, in press). Studies are continuing to compare serum anti-Aβ antibodies from individuals with Alzheimer's disease, subjects with mild cognitive impairment, and aged normal individuals. Proteomics studies to look for combinations of plasma or urinary proteins which may serve as "biomarkers" for early detection of Alzheimer's are also planned for the coming year.
The main pathological finding in Parkinson's disease is extensive loss of dopaminergic neurons in an area of the brain called the substantia nigra. A protein called alpha-synuclein (α-synuclein) has been implicated in the loss of these neurons; it is found in a structure known as a Lewy body in some of the surviving Parkinson's dopamine neurons. Our laboratory recently published results showing that IvIg products contain specific antibodies to different conformations of α-synuclein (Clinical and Experimental Immunology 2010;161:527-35). Studies in the coming year will examine the protective ability of IvIg against the neurotoxic effects of α-synuclein on cultured dopamine neurons, as well as IvIg's effects on the development of different conformations of α-synuclein.
One of the laboratory's ongoing projects is to evaluate the development of Alzheimer's-type pathology in a mouse model of insulin resistance. The study is conducted in collaboration with investigators from the University of Toledo. Another long-term study is measuring pathological proteins and the antibodies to these proteins in serum samples from patients with Alzheimer's disease, mild cognitive impairment and aged normal controls. This work is in collaboration with investigators at the Rush University Medical Center in Chicago. A project that has recently begun compares two methodologies, enzyme-linked immunosorbent assay (ELISA) and piezoimmunosensor technology, for measurement of Alzheimer's-related serum antibodies. The Parkinson's disease-related studies are measuring the levels of antibodies to key Parkinson's pathological proteins in IvIg preparations.
Recent publications from the Neurology Research Laboratory include the following:
Research of Interest
David A. Loeffler, D.V.M., Ph.D.
Director, Neurology Research Laboratory
Inflammatory processes, complement activation, neuroimmunology/neuroinflammation