Amyotropnic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects 30,000 Americans each year. Of these 3O,OO0 Americans, it has been suggested that up to 50o/o will experience cognitive and behavioral changes in the form of frontotemporal dysfunction and up to +OZo will meet criteria for frontotemporal dementia (FTD) (42, 43). Riluzole the only FDA approved agent for ALS extends a patient's lifespan by 2-3 months, and there are flo proven therapies tor tne cognitive changes associated with ALS. More effective therapy for this universally fatal disease is desperately needed' Results from an open label pitot trial of 20 patients treated with memantine at 10 mg BID suggested that treatment with the combination of memantine and riluzole slowed ALS disease pro{ression (1). This trial also showed that levels of specific protein biomarkers in the CSF at bs-etine correlated with the rate of disease progression. (1). A concurrent phase ll study performed by Dr Carvalho, found no effect with similar dosing(16); however, the study was iiriteO in terms of power. Comtnents on previous failed drug trials in ALS have raised the concern that many ALS trials study a potential therapeutic agent at only a single dose and thus may miss the potential efficacy of hon FDA approved d-oses; therefore, this proposed study will tesi a higher dose of memantine, 20 mg BlD, in a double blind, placebo controlled, randomized trial of g6 patients with ALS to determine if a combination therapy of memantine with riluzole can slow disease progression compared to treatment with riluzole alone. The primary outcome measure will be the rate of disease progression as measured by the ALS Functional Rating Scate- Revised (ALSFRS-R). ln addition we will examine the cognitive deficits seen in ALS patients measured by the ALS Cognitive Behavioral Screen (ALS-CBS) and the i.lrropsychiatric lnventory Questionnaire (NlP-Q). Finally we will examine specific validated protein blomarkers found in the cerebrospinal fluid to determine if there is a correlation between ihe levels of these biomarkers and the rate of disease progression. ln particular we will measure the ratio of phosphorylated heavy neurofilament to Complement 3 (31) to see if this ratio is predictive of disease progression and if the levels change during therapy with memantine' ' This project witl otfer unique insights into this untreatable disease. lf this study confirms earlier results and suggests that memantine, when used in conjunction with riluzole, significantly slows down the progression of the disease, as well as ameliorates cognitive deficits in patients with fronto-temporaidysfunction, it will set the groundwork for conducting a larger phase lll trial'
Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease which causes progressive muscle weakness resulting in death on average in 2-5 years. As many as 50% of patients with ALS also develop cognitive and behavioral problems consistent with frontotemporal dysfunction. This project will seek to validate preliminary open label data that suggested that memantine, a drug that is FDA approved for Alzheimer's Diseases, when used in conjunction with riluzole, may significantly slow down the course of ALS and also possibly im prove neu ropsychiatric deficits.
