Title: Creatine Supplementation as a Therapeutic Approach in the Treatment of Neurodegenerative Disease Jac
1Creatine Supplementation as a Therapeutic
Approach in the Treatment of Neurodegenerative
DiseaseJacob Parks23 March
2009 HNFE 4004
2Introduction
- Why this particular topic
- Purpose of seminar
- Public health importance
3Seminar Overview
- Provide a brief overview on the pathogenesis of a
neurodegenerative disease - Provide some background on creatine (Cr) and its
proposed neuroprotective role - Integrate the proposed theoretical value Cr
supplementation would have on the effects of
disease - Review and evaluate three clinical trials in
which Cr supplementation was implemented - Provide some suggestions for future research
within the field
4Neurodegenerative Disease
- A condition in which the cells of the central
nervous system (CNS) are lost - These nerve cells, called neurons, process and
transmit information by electrochemical signaling - Neurons are not regenerated en masse therefore
excessive damage can be devastating - Lost of communication between your CNS and
muscles
5Neurons in comparison
- Image provided by http//www.unc.edu/courses/2004
spring/engl/012/009/bios/jlsink.html
6Axial FLAIRS in comparison
- Image provided by http//www.scielo.br/scielo.php
?scriptsci_arttextpidS0004-282X1999000600002
7Epidemiology
- Each neuromuscular disease exhibits its own
characteristics - Most affect middle aged to older individuals
- Conditions deteriorate over time
- Exception cerebral palsy which is non progressive
8Cause of Onset
- Dependent on location of neuronal loss, specific
pathogenesis and the course of progression - Substantial evidence suggests that impaired
energy metabolism, in concert with mitochondrial
dysfunction, plays a critical role in the
pathogenesis and progression of a neurological
disease as a primary or secondary mechanism in
the neuronal death cascade (Beal 2005
Tarnopolsky and Beal, 2001). - Not reserved for only neurodegenerative diseases
but also those that impact the PNS and CNS
9Mitochondria and Oxidative Stress in Cell Death
- Image provided by http//www.med.monash.edu.au/bi
ochem/research/projects/mitochondria.html
10On a Cellular Level
- Damage to mitochondria is caused by a toxic gain
of superoxide mutase 1 (SOD1), located in the
mitochondrial intermembrane space - SOD1 causes generation of free radicals which
causes oxidative damage - Oxidative phosphorylation is impaired and energy
production is therefore deficient - As cellular energy becomes depleted, postsynaptic
motoneuron death is inevitable
11Possible Therapeutic Intervention
- No curative treatment for the degeneration of
neurons - Improvement in mitochondrial function and
cellular bioenergetics represents a target for
possible intervention
12Animal Models
- In SOD1 mutant mice, Cr supplementation has been
observed to reduce mitochondrial loss and
increased survival rates in Cr versus control
treated animals - L-DOPA-induced dyskinesia, a major complication
that arise in Parkinson disease which is
characterized by abnormal voluntary movements has
been reduced in 6-hydrodopamine-lesioned rats
with Cr treatment
13The Neuroprotective Role of Creatine
- Cr may increase the energy available to injured
nerve cells or block the neuronal death cascade - Maintains cellular energy homeostasis by
providing a direct energy source in the form of
phosphocreatine - Provides an energy transfer mechanism (shuttle)
between mitochondria and sites of high energy
turnover - Cr suppresses the generation of reactive oxygen
species that lead to cell damage and inactivation
of Creatine Kinase - It is postulated that increased stores of
creatine in neuronal and muscle tissue may
provide a protective effect on cellular energy
dysfunction in neurodegenerative diseases
(Tarnopolsky and Beal, 2001).
14Beneficial Effects of Creatine Supplementation
in Dystrophic PatientsJournal Muscl
e Nerve 27 604-610Year 2003Authors Louis M,
Lebacq J, et. al.
15Objective, Test Subjects and Methods
- Objective Observe the effect of Cr
supplementation on muscle function and body
composition - Subjects 15 boys with muscular dystrophy, aged
between 6 and 16 years (10.8 /- 2.8 years) - Methods Double blind crossover study in which
subjects received either 3g of Cr or a placebo
(maltodextrin) daily for 3 months - Test Battery Tests of muscular function
including determination of maximum voluntary
contraction (MVC), fatigue resistance and
evaluation of total joint stiffness (TJS)
16Experimental Data
- Created by Jacob Parks
- 23 March 2009
- HNFE 4004
17Results
- In placebo group, no change was observed in MVC
or resistance to fatigue, whereas TJS increased
by 25 - In Cr group, no changes were reported in TJS,
improved MVC by 15 and almost doubled their
resistance to fatigue - In patients still independent of a wheelchair,
bone mineral density increased by 3 - Researchers concluded that Cr may provide some
symptomatic benefit in these patients
18Limitations and Critique
- Results of the study were specific to young boys
with muscular dystrophy therefore cant apply the
results to older populations - Dystrophic patients are known to accumulate less
Cr than healthy subjects due to a reduction in
their muscle Cr transporter - No evidence supports that other neurodegenerative
diseases has an effect on decreased Cr stores - Study concluded that bone mineral density
increased in the subjects however the influence
of Cr on this may have been masked by the normal
growth of young boys
19A Clinical Trial of Creatine in
ALSJournal Neurology
631656-1661Year 2004Authors Shefner J.M.,
Cudkowiez M.E., et. al.
20Objective, Test Subjects and Methods
- Objective To evaluate the efficacy of Cr
supplementation in patients with ALS treated over
6 months and evaluated monthly - Subjects 104 patients from 14 sites with a
disease duration of no more than five years - Methods Randomized double blind placebo
controlled, subjects received either 5g Cr or 5g
placebo per day - Test Battery Maximum voluntary isometric
contraction, grip strength, ALS Functional Rating
Scale and motor unit number estimates
21Change in Maximum Voluntary Isometric Contraction
22Change in ALS Functional Rating Scale
23Change in Motor Unit Estimation
24Conclusions
- Cr at a dose of 5g daily was found to provide no
benefit over a 6-month period - Results were consistent with earlier study in
which Cr at 10g daily provided no benefit
25Limitations and Critique
- Some patients in the placebo group were taking Cr
and not reporting it, determined through urinary
Cr - Researchers did not evaluate other medications
taken by the test subjects (Celebrex, minocycline
and coenzyme Q) - High patient dropout 12 in Cr group and 24 in
placebo group, primary reasons were patient death
and disease progression - Variance in dosage and timing in mice vs. human
trials
26Creatine Supplementation in Huntingtons Disease
A placebo-controlled pilot
trialJournal Neurology 61
925-930Year 2003Authors Verbessem P, Lemiere
J, et. al.
27Objective and Test Subjects
- Objective To evaluate the effect of Cr
supplementation in Huntingtons disease - Subjects 41 patients within stages 1-3 of
Huntingtons disease
28Methods
- Methods A 1-year double-blind placebo-controlled
study. At baseline and after 6 and 12 months,
functional, cognitive and neuromuscular status
was assessed - Test battery included
- The Unified Huntingtons Disease Rating Scale
(UHDRS) - An isokinetic dynamometer to assess the strength
of the elbow flexor muscles - A maximal exercise test on a cycle ergometer to
assess cardiorespiratory fitness - A test to assess bilateral coordination ability
29UHDRS scores
30Isokinetic Dynamometer scores
31Conclusions
- Cr supplementation had no impact on the
functional or neuromuscular status of the test
subjects - The test battery demonstrated the anticipated
deterioration of the functional status of the
patients within the 1 year follow up period
32Limitations and Critique
- The trials results contrasted with findings in
animal models with HD - Dosage could be a issue (1.5g /kg of body weight
in animal models vs. 0.3 g/kg of body weight in
humans) - Timing of supplementation could also present an
issue, onset vs. symptomatic - Researchers failed to measure initial Cr content
in the muscle or brain therefore could not
indicate whether a subject was deficient
33Future Research
34Future Research
- Evaluate effect of Cr administration regimen
duration on results - Examine effect of higher dosages on results in
human trials - Study the safety and effects of long-term use of
Cr - Establish causation of the neuronal death cascade
as well as the effects it has on the generation
of energy - Determine which diseases could be altered with Cr
treatment as one pathogenesis does not apply to
all diseases
35Other Potential Applications
- Not just for athletes!
- Immobilized states i.e. disuse atrophy
- Aging
- Fatigue
36References
- Adhihetty P, Beal M. Creatine and Its Potential
Therapeutic Value for Targeting Cellular Energy
Impairment in Neurodegerative Diseases. Neuromol
Med 200810275-290. - Andres R, Ducray A, Schlattner U, Wallimann T,
Widmer H. Functions and effects of creatine in
the central nervous system. Brain Research
Bulletin 200876329-343. - Bender A, Koch W, et al. Creative
Supplementation in Parkinson disease A
placebo-controlled randomized pilot trial.
Neurology 2006671262-1264. - Bender A, Samteben W, et al. Long-term
supplementation is safe in aged patients with
Parkinson disease. Nutritional Research
200828172-178. - Derave W, Bosch L, et al. Skeletal muscle
properties in a transgenic mouse model for ALS
effects of creatine treatment. Neurobiology of
Disease 200313264-272. - Gropper S, Smith J, Groff J. Advanced Nutrition
and Human Metabolism 5th edition. Wadsworth,
Cengage Learning 2009 201.
37References
- Houston M. Biochemistry Primer for Exercise
Science 3rd edition. Human Kinetics 200648-51. - Louis M, Lebacq J, et al. Beneficial Effects of
Creatine Supplementation in Dystrophic Patients.
Muscle Nerve 200327604-610. - Salomons G, Wyss M. Creatine and Creatine Kinase
in Health and Disease. Subcellular Biochemistry
200746 205-243. - Shefner J.M., Cudkowicz M.E., et al. A clinical
trial of creatine in ALS. Neurology
2004631656-1661. - Valastro B, Dekundy A, Danysz W, Quack G. Oral
creatine supplementation attenuates
L-DOPA-induced dyskinesia in 6-hydroxydopamine-les
ioned rats. Behavioral Brain Research
200919790-96. - Verbessem P, Lemiere J, et al. Creatine
supplementation in Huntingtons disease A
placebo-controlled pilot trial. Neurology
200361925-930.