Wilson, Meghan Elise
(2011)
PROTEIN BIOMARKERS FOR AMYOTROPHIC LATERAL SCLEROSIS: CHARATERIZATION AND IMPLICATIONS FOR DISEASE PATHOGENESIS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Wilson, Meghan Elise | mew36@pitt.edu | MEW36 | |
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| ETD Committee: |
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| Date: |
29 April 2011 |
| Date Type: |
Completion |
| Defense Date: |
28 March 2011 |
| Approval Date: |
29 April 2011 |
| Submission Date: |
28 April 2011 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Amyotrophic lateral sclerosis; biomarkers; blood plasma; cerebrospinal fluid; cystatin C; free hemoglobin |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04282011-192616/, etd-04282011-192616 |
| Date Deposited: |
10 Nov 2011 19:43 |
| Last Modified: |
19 Dec 2016 14:35 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/7722 |
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