Amyotrophic Lateral Sclerosis (ALS) is a rapidly fatal neurological disease characterized by the degeneration of motor neurons involved in voluntary muscle control. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective long-term treatments. The identification and characterization of novel protein biomarkers could improve the speed and accuracy of disease diagnosis, and assist in predicting and tracking disease progression. Additionally, the utilization of such biomarkers could also expedite the development of effective treatments by both providing insight into disease pathogenesis, and improving the efficacy of clinical trials. In this work, I examined two cerebrospinal fluid (CSF) proteins, cystatin C and free hemoglobin, for biomarker utility and functional relationships with disease pathogenesis. Cystatin C is a constitutively expressed cysteine protease inhibitor that appears to be reduced in the CSF of ALS patients. I evaluated cystatin C concentration by ELISA in CSF and plasma samples from ALS patients, normal controls, and neurological disease controls. These data were used to evaluate cystatin C as a diagnostic, surrogate, and prognostic biomarker in ALS. Plasma cystatin C was equally elevated in ALS patients and disease controls, demonstrating no biomarker utility. However, CSF levels were confirmed to be lower in ALS patients than in healthy controls, and may possess diagnostic utility when used in conjunction with other biomarkers. CSF cystatin C also exhibited potential for one surrogate biomarker application, and for prognostic biomarker utility. The trends in CSF cystatin C abundance suggest a neuroprotective role for cystatin C in ALS. Accordingly, reductions in CSF cystatin C may contribute to disease development through the loss of a protective function mediated by cysteine protease inhibition. CSF free hemoglobin levels were also measured by ELISA, and were evaluated for utility as a biomarker of blood-CNS barrier damage in ALS. The proportion of ALS patients exhibiting elevated CSF free hemoglobin was higher than in either control group, suggesting that blood-CNS barrier damage may occur in this disease. Overall, the results of this work identify and clarify potential biomarker applications of two CSF proteins, and also provide new insight into potential pathogenic mechanisms of ALS.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04282011-192616 |
| Date | 29 April 2011 |
| Creators | Wilson, Meghan Elise |
| Contributors | Robert Bowser, Ph.D., Michael J. Zigmond, Ph.D., Clayton A. Wiley, M.D., Ph.D., Teresa G. Hastings, Ph.D., Brian M. Davis, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04282011-192616/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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