Grants and Contracts Details
Description
Arnyotrophic lateral sclerosis (ALS) is a devastating, rapidly fatal neurodegenerative disease of largely
unknown cause. It is clinically characterized by progressive skeletal muscle paralysis and eventual
respiratory failure. Although the mean survival is about 40 months after symptom onset, it varies widely,
ranging from several months to more than 10 years. No prospective studies have attempted to determine
what factor(s) accelerate or slow disease progression. Recent clinical and epidemiological studies based
largely on historical recall suggest that diverse extrinsic factors such as environmental and lifestyle factors
are associated with ALS and that oxidative stress (OS) is a final common pathway in potential pathologic
mechanisms of those extrinsic factors. We hypothesize that these extrinsic factors continue to act throughout
the disease course, generating increased OS and thus influencing disease progression in ALS. We propose
to test this hypothesis in 420 newly diagnosed ALS patients from 11 ALS centers. We specifically aim: 1) To
determine whether continued exposure to oxidative stress, measured via structured interview or
biomarkers, is associated with the disease progression of ALS, ALS progression will be determined with
a widely used and well-validated ALS functional scale (the ALSFRS-R) every 3 to 6 months for 24 months.
At baseline and follow-up, we will obtain OS markers (urinary 15-F2risoprostane and 8-oxodeoxyguanosine,
plasma paraoxonase I (PON1) levels, and PON1 functional status) and lipid profile and current environmental,
psychological, dietary, and lifestyle factors by structured interviews. We will determine whether ongoing OS
is associated with rapid disease progression; 2) To examine the associations between OS biomarkers,
the OS index, lipid profile and patient survival, An OS index will be developed based on a sum of the
external factors (Goodman et al. 2007). Survival will be followed during the grant period and thereafter by
using National Death Index data. We will test whether increased and continuing OS and abnormal lipid
profile affect survival; 3) To determine whether environmental, lifestyle, dietary, and psychological
factors are associated with abnormal biomarkers of OS. We will determine whether a number of extrinsic
(environmental, psychological, dietary, and lifestyle) factors are linked to increases in OS biomarkers in
patients with ALS; and 4) To examine, in exploratory analyses, associations between markers of OS
and ALS subtypes, Including fronto-temporal dementia. To our knowledge, this is the first prospective,
in-depth multicenter molecular epidemiological investigation of OS in ALS; moreover, it is interdisciplinary.
Our project will increase the understanding of the disease mechanisms involved not only in disease
prognosis but also in potential causes, and may be the first step toward new treatment and prevention
approaches, such as multiple anti-oxidant therapy, to target oxidative stress sites in ALS.
Status | Finished |
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Effective start/end date | 7/22/09 → 4/30/15 |
Funding
- Columbia University: $15,071.00
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