Pilot Projects

Project Title: Oxidative Stress and ALS

Principal Investigator: Hiroshi Mitsumoto, M.D. (Dept. of Neurology)

Collaborators: Pam Factor Litvak, Ph.D. (CEHNM), Xinhua Liu, Ph.D. (CEHNM), Regina Santella, Ph.D. (CEHNM), Leslie Andrews Dr.P.H. (Dept. of Environmental Health Sciences)

Year: 2006
Award Amount: $25,000

Summary. Amyotrophic lateral sclerosis (ALS) is a devastating and uniformly lethal neurodegenerative disease marked by progressive muscle paralysis and eventual respiratory failure. Although little is known regarding the etiology of ALS, recent evidence suggests a common pathway, that is, oxidative injury, for factors associated with the disorder. Such data is evident from animal models, patients with sporadic ALS, and human epidemiologic studies. Our long term aim is to examine markers of oxidative stress, both those measured in blood and/or urine, and those measured by structured questionnaires and the occurrence and progression of ALS. We propose to examine whether the timing of exposure to factors associated with oxidative stress is associated with the occurrence of ALS. This Pilot Project will recruit 50 ALS cases, 50 controls and generate pilot data on oxidative stress markers. We will examine markers of oxidative stress in blood and urine including urinary isoprostanes and 8-oxodeoxyguanosine and oxidized plasma proteins.

Results. One hundred study subjects were rapidly recruited and their biospecimens collected. The IHS Facility Core analyzed urine for isoprostanes, 8-oxodeoxyguanosine and creatinine and plasma samples for oxidized plasma proteins. The mean age of cases was 61, compared to 55 in controls (p=0.04). 61% of cases were male compared to 33% of controls (p=.009). Plasma protein carbonyl did not differ between cases and controls. Mean (+ standard deviation) urinary isoprostanes/creatinine was 0.81+0.81 in ALS and 0.47+0.20 nmol/mmol (p=0.0023) in controls, respectively. Mean (+ s.d.) urinary 8-oxodG was 60.4+44.2 in and 41.2+20.6 nmol/mol (p=0.018) in cases and controls, respectively. 8-oxodG/creatinine increased with age (r=0.30, p=0.06 in controls and r=0.25, p=0.08 in cases). No relationship was found between isoprostanes and age. Logistic regression analysis, controlling for gender and age, found statistically significant and independent associations between urinary isoprostanes and urinary 8-oxodG (both adjusted for creatinine) and ALS. No association was found between plasma protein carbonyl and ALS. These results support the need for a larger study to explore markers of non-neural oxidative stress

Outcomes/Publications. One grant proposal was submitted to the Muscular Dystrophy Association in June of 2006 (under revision for resubmission), and a second proposal will be submitted to the NIH on February 5, 2007.