Calcium-mediated excitotoxicity and defective energy metabolism have been implicated in the pathogenesis of Huntington disease (HD). 1 In R6/2 HD transgenic mice, administration of 2% dietary creatine presymptomatically at 6 and 8 weeks improved survival, delayed motor progression, and reduced weight loss and brain atrophy. 2,3 Creatine buffers intracellular energy reserves and has several neuroprotective effects demonstrated both in vivo and in vitro. 4 A placebo-controlled pilot trial of 5 g/day of creatine for 1 year appeared ineffective in 26 patients with HD, 5 although this dose was lower than the equivalent dose given to R6/2 HD mice. We previously reported clinical and MR spectroscopy (MRS) findings in a 1-year open-label pilot study of high-dose creatine (10 g/day) supplementation in 13 patients with HD. 6 Serial 31 P-MRS of muscle monitored changes in energy metabolism in vivo, and 1 H-MRS was used to determine creatine levels in brain tissue. High-dose creatine was well tolerated, and total motor score (TMS), functional capacity, and neuropsychology testing remained stable at 12 months. We now report 2-year data in the same cohort.Methods. Thirteen patients with genetically confirmed HD (including three unaffected) and four age-matched normal spouse control subjects were recruited to the trial at baseline as previously described. 6 Patients took 10 g/day of creatine powder (SKB Pharmaceuticals, UK) dissolved in orange juice. Biochemical and hematology screening was performed every 3 months.Patients were assessed at baseline and at 6-,12-, and 24-month time-points using the Unified Huntington's Disease Rating Scale (UHDRS) by the same neurologist. MR spectra were collected using a 2 T Bruker spectrometer. 31 P-MRS on the right calf and 1 H-MRS were performed as previously described. 6 The study had local hospital ethics committee approval.Results. Patient details and UHDRS scores are documented in table E-1 on the Neurology Web site (at www.neurology.org). An abnormal rise in serum creatinine for Patient 12 at 1 year (70 to 231 mol/L) led to his removal from the study, after which the creatinine level normalized. Patients 1, 3, and 13 were excluded from the 24-month assessment data owing to noncompliance (two of these cited the recommendation to avoid caffeine-containing drinks while taking creatine as the reason), and control subjects also ceased creatine at 12 months. Eight affected patients and one unaffected patient completed the assessment. High-dose creatine was generally well tolerated at 24 months. Creatinine levels rose in these patients, indicating compliance (baseline creatinine 81.7 Ϯ 11.2 mol/L; 1 year 87.0 Ϯ 10.8; 2 year 91.1 Ϯ 9.0; p Ͻ 0.02 for 1-and 2-year levels). There were no other significant changes in blood variables measured.After 24 months of creatine treatment, there was no significant change in the mean TMS, functional capacity scores (figure), or neuropsychological testing (see table E-1). MRS studies demonstrated that creatine was still elevated in vivo in both brain and i...

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