J. Eric Ahlskog, M.D., is a Professor of Neurology at the Mayo Medical School, and Chair of the Mayo Section of Movement Disorders, Mayo Clinic, Rochester, Minnesota. He has two OUP books on Parkinson’s Disease, The Parkinson’s Disease Treatment Book: Partnering With Your Doctor to Get the Most From Your Medications, which we have excerpted below and the new, Parkinson’s Disease Treatment Guide, For Physicians, which we will look at more closely next Monday. In the excerpt below, from Ahlskog’s patient orientated book, we learn about the obscure origins of Parkinson’s Disease.
…Parkinson’s disease (PD) is a neurodegenerative disorder, one of a variety of such conditions. To date, we have not identified the cause for any of them, despite major research efforts in laboratories and clinics around the world.
For decades, theories have been proposed for the cause of PD, but with little support from hard facts. Blame has been placed on everything from viruses and bacteria to the food we eat. Each hypothesis has had enough supporting evidence to stimulate research, mostly leading to dead ends. We need credible clues to point us in the right direction. Clues are slowly accumulating, although some may be red herrings. However, the answer is probably buried in what we already know. The trick is to figure out which of the many pieces of evidence will lead us to the cause of PD. Let’s first review two areas of investigation that have been a central focus in the past ten to twenty years-the MPTP story and the oxidative stress hypothesis.
The MPTP Story
About twenty years ago, a number of young illicit drug users in California were diagnosed with parkinsonism, which developed over a few days to weeks. The cause was found to be a street drug they injected for a high: a substance with chemical similarity to certain narcotics, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). We now know that this substance accumulates inside the sustantia nigra neurons in the brain and kills them. MPTP was subjected to intense study in hopes that this might provide clues to PD in the general population. Multiple investigators have looked for evidence that this or similar toxins might be present in either the environment or the body. Despite enormous research, toxins of this type have not surfaced as a cause of PD. At present, this appears to have been an isolated event. No similar epidemics of parkinsonism have occurred. This discovery, however, led to the development of animal models of PD. MPTP injected into mice or monkeys makes them parkinsonian, which allows drugs to be tested for treatment.
Oxidative Stress as the Cause of PD
The most popular theory for PD in the past decade has been the oxidative stress hypothesis. Oxidation is a natural chemical reaction that occurs in all of our cells. It is necessary for life. However, like too much of anything, too much oxidation is bad for cells. Why do the substantia nigra cells degenerate in PD? Perhaps it relates to the oxidation of dopamine inside those cells. Specifically investigators noted that dopamine is metabolized by way of oxidation reactions. This led to the proposal that excessive oxidation may damage substantia nigra neurons. Thus dopamine-generated oxidative stress was hypothesized to cause PD.
In fact, a myriad of oxidation reactions continuously occur in every cell of the body and are essential for life. There are many natural safeguards in all cells that control and counterbalance oxidation reactions. Although indirect evidence suggested dopamine oxidation reactions as a possible culprit, direct evidence has not surfaced, and enthusiasm for this hypothesis is waning. The most compelling argument against this theory relates to the fact that dopamine-containing cells are not the only neurons that degenerate in PD. They are the most visible, since their loss results in such prominent symptoms. However, the PD degenerative process similarly affects numerous other brain cells. In fact, recent pathologic studies suggest that nondopaminergic neurons in the lower brain stem may be the first affected in PD, rather than the dopaminergic substantia nigra cells. Thus scientists are looking in other directions.
PD researchers are like detectives trying to solve a crime. Further insight into the cause surfaces with each new clue…