Creatine Supplementation as a Therapeutic Approach in the Treatment of Neurodegenerative Disease Jac

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Creatine Supplementation as a Therapeutic
Approach in the Treatment of Neurodegenerative
DiseaseJacob Parks23 March
2009 HNFE 4004
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Introduction

• Why this particular topic
• Purpose of seminar
• Public health importance

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Seminar 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

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Neurodegenerative 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

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Neurons in comparison

• Image provided by http//www.unc.edu/courses/2004
  spring/engl/012/009/bios/jlsink.html

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Axial FLAIRS in comparison

• Image provided by http//www.scielo.br/scielo.php
  ?scriptsci_arttextpidS0004-282X1999000600002

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Epidemiology

• 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

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Cause 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

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Mitochondria and Oxidative Stress in Cell Death

• Image provided by http//www.med.monash.edu.au/bi
  ochem/research/projects/mitochondria.html

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On 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

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Possible Therapeutic Intervention

• No curative treatment for the degeneration of
  neurons
• Improvement in mitochondrial function and
  cellular bioenergetics represents a target for
  possible intervention

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Animal 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

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The 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).

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Beneficial Effects of Creatine Supplementation
in Dystrophic PatientsJournal Muscl
e Nerve 27 604-610Year 2003Authors Louis M,
Lebacq J, et. al.
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Objective, 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)

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Experimental Data

• Created by Jacob Parks
• 23 March 2009
• HNFE 4004

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Results

• 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

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Limitations 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

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A Clinical Trial of Creatine in
ALSJournal Neurology
631656-1661Year 2004Authors Shefner J.M.,
Cudkowiez M.E., et. al.
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Objective, 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

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Change in Maximum Voluntary Isometric Contraction
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Change in ALS Functional Rating Scale
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Change in Motor Unit Estimation
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Conclusions

• 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

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Limitations 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

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Creatine Supplementation in Huntingtons Disease
A placebo-controlled pilot
trialJournal Neurology 61
925-930Year 2003Authors Verbessem P, Lemiere
J, et. al.
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Objective and Test Subjects

• Objective To evaluate the effect of Cr
  supplementation in Huntingtons disease
• Subjects 41 patients within stages 1-3 of
  Huntingtons disease

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Methods

• 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

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UHDRS scores
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Isokinetic Dynamometer scores
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Conclusions

• 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

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Limitations 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

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Future Research
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Future 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

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Other Potential Applications

• Not just for athletes!
• Immobilized states i.e. disuse atrophy
• Aging
• Fatigue

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References

• 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.

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References

• 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.