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By David Perlmutter, M.D. www.pcrm.org
Dr. David Perlmutter has accomplished a very courageous task in his monograph Functional Therapeutics in Neurodegenerative Diseases. He has crossed the disciplinary boundaries from the comfort of his profession as a board-certified Neurologist to put together a very compelling integrated model for the development of neurodegenerative diseases.
As he points out in the monograph, this model opens the door for a number of new therapies for these disorders which historically have had few therapeutic options.
Dr. Perlmutter couples the perspectives of both a clinical and experimental neurologist to help us understand the revolution that is occurring in the emerging treatment of neurological disease. This revolution is built upon the concepts of molecular medicine as first described by Linus Pauling in 1949.
Flint Beal, M.D., Ph.D., an experimental neurologist at Harvard University Medical School, has echoed Dr. Perlmutter’s vision of the future of neurology in his paper, Aging, Energy, and Oxidative Stress in Neurodegenerative Disease.1
The model that Dr. Perlmutter advances is an integrated model of neurodegeneration coupling genetics, environment, nutrition, lifestyle, and infection. The theme that Dr. Perlmutter develops is that many exposures can initiate an upregulation of the immune system, which in response releases the inflammatory cytokines. These in turn upregulate the expression of the immune inducible form of nitric oxide synthase. The increased production of nitric oxide in the microglia triggers the depletion of neuronal ATP which in turn increases the activity of xanthine oxidase. This enzyme converts purines to uric acid in the neuron with the production of the reactive oxygen species, superoxide. Superoxide then reacts with nitric oxide to yield peroxynitrite, which results in death of the cell.
Many agents can trigger this cascade in genetically susceptible individuals including bacterial lipopolysaccharides from enteric bacteria, toxic metals and pesticides, food and environmental antigens, stress responses mediated through the pituitary-thyroid-adrenal axis, and chronic infection.
Recently it has been shown that individuals who die of Alzheimer’s disease have a very high gene penetration of apo E4 and a chronic infection with herpes simplex Type 1 (cold sores). Only when both genetic factor apoE4, and the chronic infection are present simultaneously does Alzheimer’s disease result.2
Dr. Perlmutter points out that genetic impairment in detoxification ability may also render individuals more susceptible to neurotoxic effects of xenobiotics. The field of pharmacogenics has recently emerged as a discipline of science and medicine focused upon better understanding of how to assess individual detoxification ability.3 It has been recently reported that older-age individuals who have reduced detoxification ability may be at risk to Parkinsonism symptoms from the use of the drug metaclopramide (e.g., Reglanä ).4 Defects in sulfoxidation and Phase II glucuronidation and glutathione conjugation have all been identified as risks to neurodegenerative disease.
As Clough has pointed out there is generally a lapse of thirty years or more from the onset of accelerated neurodegeneration until the symptoms of diseases such as Alzheimer’s or Parkinson’s are diagnosed.5 As he points out, this is the period when “neuroprotective therapy” can be introduced, if the physician is aware of these functional neurological changes.
Dr. Perlmutter helps us to understand better how to ask the right questions concerning the early-stage development of neurodegeneration and provides clues as to its remediation from the answers to these questions.
As Cohen has observed, with many of the neurodegenerative diseases, “the brain is on fire” due to the uncoupling of neuronal mitochondrial function and the release of oxidants.6 Shifts to anaerobic metabolism often occur with accumulation of cis-aconitate, succinate, and lactate in biological fluids. It is interesting that this situation is observed not only in neurodegenerative diseases, but also with less severity in chronic fatigue syndrome, fibromyalgia, multichemical sensitivity, and individuals with Gulf War Syndrome.7 It is possible that the integrated mechanism for neurodegenerative disease described by Dr. Perlmutter in this monograph applies to these other conditions/syndromes as well.
Dr. Perlmutter’s contribution toward our understanding of the origin of neurodegenerative diseases converges with the model for the origin of chronic fatigue syndrome published by Martin Pall, Ph.D., from the Program in Basic Medical Sciences, Washington State University.8
Dr. Perlmutter offers us a most provocative model for many disorders of the central nervous system. More importantly, this model directs the clinician toward new therapies which hold the promise of improving therapeutic efficacy with a minimal risk to adverse drug reactions.
It is a great privilege to share the field of functional medicine with Dr. David Perlmutter as a colleague and fellow seeker for the understanding the origin of degenerative disease.
Jeffrey S. Bland, Ph.D.
Institute for Functional Medicine
1. Beal MF. Aging, energy and oxidative stress in neurodegenerative diseases. Ann Neurol 1995;38(3):357-366.
2. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus Type I in brain and risk of Alzheimer’s disease. Lancet 1997;349(9047):241-244.
3. Linder MW, Prough RA, Valdes R. Pharmacogenetics: a laboratory tool for optimizing therapeutic efficacy. Clin Chem 1997;43(2):254-266.
4. Drug induced Parkinsonism in the aged. Parkinson’s Disease Update 1995;50:285-286.
5. Clough CG. Parkinson’s disease management. Lancet 1991;337(8753):1324-1327.
6. Cohen G. The brain on fire? Ann Neurol 1994;36(3):333-334.
7. Rook GA, Zumla A. Gulf war syndrome: Is it due to a systemic shift in cytokine balance toward a Th2 profile? Lancet 1997;349(9068):1831-1833.
8. Pall ML. Elevated sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. In press 1998.
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