Materials and Methods
Study Design and Participants
Patients with a clinical diagnosis of probable Alzheimer's disease based on neurological and neuropsychological evaluation (National Institute on Ageing-Alzheimer's Disease Association, NINCDS-ADRDA criteria),[45,46]Mini-Mental State Examination (MMSE) score of 19 to 27, and 50 to 95 years were enrolled in this pilot phase 2 double-blind, randomized, placebo-controlled study. For inclusion, FDG-PET baseline scans were also evaluated to confirm a lack of a frontotemporal dementia or Lewy body disease pattern of hypometabolism. All participants were stable on acetylcholinesterase (AChE) inhibitors for at least 2 months before starting the trial and continued to take AChE throughout the study with the exception of one participant who had never been on AChE therapy. The study was conducted at two sites (Rockefeller University Hospital and Icahn School of Medicine at Mount Sinai, both in New York City), with the approval of the Institutional Review Boards (IRB) of both Institutions. All neuroimaging was performed at Citigroup Biomedical Imaging at Weill Cornell Medicine under an IRB protocol separately approved by that Institution. Memantine, which acts on the glutamatergic system through a different mechanism than riluzole, was not allowed for 6 weeks before study entrance nor over the study duration. Other exclusion criteria were: abnormal liver function [>2 times the upper limit of normal for alanine aminotransferase (ALT) or aspartate aminotransferase (AST); or bilirubin >1.5 times the upper limit of normal, positive hepatitis serology (Hep. B antigen+ or Hep. C antibody+)], uncontrolled diabetes mellitus (Hba1c > 7), chronically uncontrolled hypertension, MRI contraindication, history of brain disease, current smoker or user of nicotine-containing products, currently taking medications with evidence of glutamatergic activity or effects on brain glutamate levels such as lamotrigine, lithium, opiates, psychostimulants such as amphetamines and methylphenidate, tricyclic antidepressants, benzodiazepines and any other drug that the investigators judged might interfere with the study (participants on those medications could be included in the study but without MRS measurements) and others (full criteria at clinicaltrial.gov NCT01703117).
