HD Lighthouse Contributing Editor's Comment: This was a small pilot study of humans that used the human equivalent of the creatine dose given to successfully treated HD mice. The dose for humans was 10g/day. For the one year of the study all patients remained stable with no significant measurable change in condition. These results illustrate the value of using HD mice models to determine dose.

Because creatine is generally safe some may not want to wait for larger more definitive creatine trials. The creatine used in the study was pure powder creatine monohydrate. This is creatine monohydrate with out additives of any kind.

From the study researchers: "The creatine was given as two large heaped teaspoons which measured 10g and then mixed in orange juice or water first thing in the morning. However it is important that people do this with their doctor's input as renal function can be affected in rare cases, one must not get dehydrated and one must reduce caffeine intake with this dose." --Jerry
Posted to the HDL: 12 Jul 2003

Creatine therapy for Huntington’s disease: Clinical and MRS findings in a 1-year pilot study

Human and transgenic animal studies have implicated defective energy metabolism and oxidative stress in Huntington’s disease (HD), with evidence for deficiencies of respiratory chain activity and defective adenosine triphosphate (ATP) synthesis in brain and skeletal muscle.(1,2) Correlation of the muscle bioenergetic defect and CAG repeat length provides a link between this biochemical abnormality and the HD molecular defect.(1) The role of calcium-mediated excitotoxicity and mitochondrial dysfunction is also supported by recent findings of a mitochondrial calcium handling defect.(3)

In the R6/2 HD transgenic mouse, 2% dietary creatine supplementation significantly improved survival, delayed motor progression, and slowed development of brain atrophy.(4) Creatine has several potential neuroprotective effects, including buffering intracellular mitochondrial energy reserves, stabilizing intracellular calcium, and inhibiting activation of the mitochondrial permeability transition pore, which have all been linked to apoptotic and oxidative cell death. Two trials have been reported where patients with HD were given 5 g for 12 months5 and 3g for 2 months followed by 5 g for 2 months.(6) Neither reported improvement in motor or cognitive function. These creatine doses are significantly lower than the equivalent dose given to the R6/2 HD mice.

We performed an open-label pilot study in gene positive preclinical and affected patients with HD to assess the tolerability, safety, and efficacy of high-dose creatine supplementation. Serial 31P MRS of muscle was used to assess defects and monitor changes in energy metabolism. 1H-MRS was used to assess brain creatine concentrations.

Patients and methods

Thirteen genetically confirmed patients with HD were recruited. Three were clinically unaffected and 10 were affected (clinical stages 1 to 3). Four age-matched normal spouse controls were recruited. Exclusion criteria were any intercurrent medical condition or drug or alcohol abuse. Patients took 10 g per day of creatine (SKB Pharmaceuticals, UK). They were advised to avoid caffeine and dehydration. Biochemical and hematologic tests were performed at baseline and 3 monthly intervals. Patients were assessed clinically (United Huntington’s Disease Rating Scale [UHDRS](7) and by MRS [Metabolite ratios omited] at baseline and 6 and 12 months. Adverse events were documented.

Results

All patients and controls tolerated creatine treatment, apart from mild nausea and diarrhea. In two patients the daily dose was reduced to 5 g after 6 months owing to diarrhea, which settled. Patient 13 discontinued treatment at 6 months owing to poor compliance. Patient 12 was removed from the study after 12 months because of a rise in serum creatinine (231 mmol/L; normal range 60 to 120), which corrected after creatine withdrawal.

Baseline and 12-month UHDRS scores are shown in the supplementary table. After 12 months there was no change in the mean total motor score (TMS), functional capacity scores, or neuropsychology testing. Statistical analysis did not reveal a difference in any scores between baseline and 12 months.

MRS studies demonstrated that creatine was significantly elevated in both brain and muscle (table), assessed by N-acetylaspartate/ creatine and phosphocreatine (PCr)/ATP ratios. However, the previously described defect in energy metabolism in HD muscle(1) was not corrected.

Discussion

This pilot study has shown that 10 g per day of creatine for 12 months is safe and well tolerated. The dose is comparable to that given to the R6/2 mice, and the highest dose given to humans over this time frame. As in the R6/2 mice, brain proton spectroscopy demonstrated that creatine crosses the blood– brain barrier and results in increased cerebral concentrations. Muscle MRS, however, demonstrated only a transient increase in PCr:ATP or PCr:inorganic phosphate ratios at 6 months, but no change at 12 months or improvement in maximum rate of mitochondrial ATP synthesis. These defects had previously been demonstrated in HD muscle.1 This suggests that long-term creatine supplementation does not directly affect muscle bioenergetics.

TMS, functional capacity, and neuropsychology testing showed no significant difference at 12 months. There was no deterioration, and these data may indicate possible stabilization of signs. We have extended the period of observation for a second year to look for evidence of a neuroprotective effect of creatine in HD.

From the Department of Neurodegenerative Disease (S.J. Tabrizi and Dr. Schapira), Institute of Neurology, Queen Square, London; MRC Magnetic Resonance Spectroscopy Unit (Drs. Blamire, Manners, Rajagopalan, and Styles), Department of Biochemistry, University of Oxford and John Radcliffe Hospital, Oxford; and University Department of Clinical Neurosciences (Drs. Schapira and Warner), Royal Free and University College Medical School, London, UK.

Supported by the UK Medical Research Council and the Peter Samuel Royal Free Fund. S.J.T. is a DoH National Clinician Scientist. Received November 15, 2002. Accepted in final form March 20, 2003. Address correspondence and reprint requests to Dr. T.T. Warner, University Department of Clinical Neurosciences, Royal Free & University College Medical School, Rowland Hill St, London NW3 2PF, UK; e-mail: twarner@rfc.ucl.ac.uk

Copyright © 2003 by AAN Enterprises, Inc.

References

1. Lodi R, Schapira AH, Manners D, et al. Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann Neurol 2000;48:72–76.
2. Tabrizi SJ, Cleeter MW, Xuereb J, et al. Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 1999;45:25–32.
3. Panov AV, Gutekunst C-A, Leavitt BR, et al. Early mitochondrial calcium defects in Huntington’s disease are the direct effect of polyglutamines. Nature Neurosci 2002;5:731–736.
4. Ferrante RJ, Andreassen OA, Jenkins BG, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 2000;20:4389–4397.
5. Verbessem P, Hespel P, Dom R. Oral creatine supplementation in patients with Huntington’s disease. Neurology 2002;58(suppl 7):A334.
6. Kieburtz K, Huntington Study Group. Placebo-controlled trial of creatine in HD. Neurology 2001;56(suppl 3):A386.
7. Huntington’s Disease Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord 1996;11:136–142.

Study Data(Word document)

# # #

---

From the HDL Forum
'Gayle -San Diego, CA', Creatine Capsules et al 18Jul03 16:18:02

Hi all,

My Phd husband, Steve, likes capsules so here's the best/cheapest I've found: http://www.affordablesupplements.com/creatine_caps_optimum.asp They have 1225 mg capsules of Creatine monohydrate -- so you would just have to take 8 to get 10 grams. Price there is $34.95 for 300 caps = 5 weeks supply.

Also, re: increasing to 10 grams creatine/day, our neuro, Dr. Susan Perlman at UCLA Medical Center said ok, but drink lots of water and do blood test for creatinine levels every 2 or 3 months. She also said something additionally hopeful: The study was relatively SHORT: 12 months. As they extend the study to 2 and 3 years, we may even see not only stabilization, but IMPROVEMENT...

This has been great and hopeful news for us!

Gayle

---

Tracked on the HDL: Creatine

Source: Neurology. 2003 Jul 8;61(1):141-2. Tabrizi SJ, et al.

printer friendly version

 

	Read the HDAC/HDLighthouse Forum. Post your comments