Well, the previous review had been some 10 years before, so it seemed like a good idea to sit back and get an appraisal of where we are in this field. The idea of the article was to say, "This is where we are, this is what the challenges are, this is what we know and what we don’t know, and this is what needs to be done."

They approached us, and they did so because we had written some papers for the journal the year before and we had also published a few papers in Nature Medicine on Parkinson’s. They wrote and said, "You seem to be doing some interesting work in Parkinson’s disease, would you like to give an appraisal of where we stand in the field?" We said, "Yes, but we can’t do it in the space of one article. We cannot handle the explosion of information that has occurred in such a small space—we need two." So they agreed with that and gave us two articles. This brings up the important point that I wrote this article with Dr. Anthony Lang and so he gets credit as well.

To answer that, let me tell you a little about the history of the field. The modern era of effective therapy for Parkinson’s disease began in the 1960s with the discovery of levodopa and the realization of its striking clinical potential. Prior to that there was no effective drug therapy and the main treatment was surgical. The operations were designed to try to help the tremor in Parkinson’s and involved cutting the neural pathways which were important in tremors. With the discovery of levodopa in 1960 and the realization that you didn’t have to cut into the brain to get a benefit, surgery disappeared almost entirely.

It was only in the late 1980s or early 1990s that more was known about the circuitry of Parkinson’s disease in the brain, that we had better neurosurgical techniques and patients treated with drugs who remained disabled; this led to a re-examination of the role of surgery in treating patients with Parkinson’s disease. This was when deep brain stimulation was introduced as an important, new technological advance. Rather than making lesions or cutting neurocircuitry, one could put electrodes in the brain and use a pacemaker to change the activity in specific brain areas. This led to a renaissance in interest and application of neurosurgeries to treat Parkinson’s disease and other disorders.

So when Andrew and I wrote that review in 1998, we were just beginning to evaluate the effectiveness and safety of deep brain stimulation. We had some indications that this would be useful, but we had limited experience and limited time of follow-up. We knew it was useful for a year or two, but after that we were still in the dark.

Well, the acronym for the major manifestations of Parkinson’s disease is TRAP. It stands for Tremor, Rigidity, Akinesia (which means lack of movement), and Postural and gait abnormalities. So deep brain stimulation can treat all four of these aspects of Parkinson’s disease to different extents. And the efficacy is roughly in the order of the sequence I just gave.

Correct.

This is what we do for controls: We put these pacemakers in the brain and we can either have them on or off. So the patients are their own controls, because we measure the patients when the thing is off, and then we measure them when it’s on, and the difference between those two is attributed to the effect of the stimulation. In other words, we can directly measure the impact of stimulation on the patient.

They don’t, but the blind is broken anyway, because if they’re shaking, for example, then I pass the wand to activate the pacemaker and they stop shaking. It happens all of a sudden—instantly. They know something has happened. So these devices are very effective. You don’t need any fancy measuring equipment. You have someone with a very severe tremor, you turn on the stimulator, and the tremor goes away. They don’t feel it, but they know the tremor is gone. So they know we’ve done something. The blind is broken by the effectiveness of the therapy.

The other thing we talked about was the genetic revolution in Parkinson’s disease and the realization of the very strong role played by genetic defects in the pathogenesis of the disease. Not just one but multiple genetic defects can contribute to Parkinson’s disease. So back at that point, the first gene or maybe even the first two had been discovered. Now we know of seven or eight genes that can cause Parkinson’s or a Parkinson’s-like syndrome.

Good question. The first one discovered was synuclein, and it is not entirely clear what it does. It is an extremely abundant protein in neurons. In Parkinson’s, these proteins accumulate in something called Lewy bodies, and we think this is the hallmark of the illness. The neurons develop these spherical deposits, Lewy bodies, within their cytoplasm, and these Lewy bodies are chock-full of synuclein. Healthy neurons do not do this kind of thing.

But we don’t know whether the abnormal accumulation of this protein is the cause of why neurons die, or whether these Lewy bodies represent a mechanism by which neurons corral or sequester or incarcerate these toxic proteins and so prevent them from doing more damage. We don’t know yet whether these bodies are good or bad.

You will find extensive discussions about this in the community. Maybe the synuclein itself is toxic, and so if it’s floating around it may cause trouble, but if it’s all glommed together into a body then it’s not creating havoc in the brain and in the cell. That’s one hypothesis. The other is the opposite: that having these clumps of protein deposits is not good for the cell and it’s these clumps that are killing the cell.

You make proteins and you break down proteins in the cell and there’s something called an ubiquitin proteosome complex that is the mechanism for breaking down proteins that are no longer useful into their individual amino acid blocks and recycling them. It’s the discovery of this proteosome mechanism that led to the Nobel Prize last year. It’s a rather important mechanism through which proteins disposed of. Proteins are run through this proteosome complex and degraded. One hypothesis is that this is the mechanism that is defective in Parkinson’s disease and it’s a breakdown in this protein recycling that leads to the accumulation of high levels of proteins. One manifestation of that is the appearance of these bodies, these protein aggregates, in the cell.

As far as I can tell there have been two major advances. One is that we now have discovered a number of genes that can cause Parkinson’s disease, and many of these genes encode proteins that are involved in the processing of proteins in the cell. So even in the so-called sporadic cases of Parkinson’s disease, the same pathways are implicated as in the genetic forms of Parkinson’s. So I think just identifying the genes and deciphering what they do has been a major advance in the last 10 years. The other major advance has been the establishment of deep brain stimulation surgery as really a mainstay of treatment in patients with advanced Parkinson’s.

The drugs have been mostly add-ons—variations on drugs we already have. There has been no new classes of drug, no significant novel developments in the drugs. In other words, there have been no home runs—maybe a couple of singles.

First of all, about 35,000 patients with Parkinson’s have received deep brain stimulation so far. We know that for the tremors, rigidity, and akinesia, the effects last for at least five years. We have five years of data and we do not see the effect wearing off. But not all is well, because for the walking and gait and posture abnormalities, those results are not holding up. We are seeing that patients are getting one or two years of benefits when it comes to posture and gait.

We’re also seeing other aspects of disease progressing in an unimpeded way, at their own pace. And particularly, we’re recognizing there are cognitive deficits in Parkinson’s disease that are not addressed by surgery. There are deficits in psychiatric aspects like hallucinations, sleep disorders, speech disorders, balance, and sexual function. These aspects of Parkinson’s disease usually do not respond to medicines, and they tend not to respond to surgery.

Yes, as the disease progresses, degeneration of the brain becomes more widespread. Initially, the first signs of the disease may be the tremor, but as time goes on and as we get better and better at treating motor problems of Parkinson’s disease, patients are living longer and now they’re manifesting other problems. These were always there, but we tended to never be as aware of them as we are now.

So, now, getting back to the question of efficacy: If you have Parkinson’s disease and if the electrodes are placed in the correct position, it works. We have data on several thousand patients now treated, and we know that the tremor improves usually by about 80 percent, and akinesia by about 60 percent. Depending on the symptoms, I can tell you what the expected response is. We have scales to measure each one of these things. So we can tell you that if you have these symptoms, then this is the expectation of what will happen should you have the operation.

There are some things, however, for which surgery is not an effective treatment. If you have a speech problem or a balance problem, then we will say that you may not be a good candidate because we cannot help this aspect of your illness. On the other hand, one thing that deep brain stimulation is very good at treating is motor fluctuations.

Patients with Parkinson’s disease often spend part of the time frozen and stiff. They can’t move. It’s called being "off." Then part of the time they’re "on" and they can move around. And they can go on and off, unpredictably, many times during the day. This is called motor fluctuation, and the surgery is very good at dealing with that. So if your problem is mostly tremor or rigidity or the fact that you are on and off in an unpredictable fashion, then we can tell you that you are a very good candidate for this treatment.

It’s very important, because it means the patient can function through the day and doesn’t have to worry about going out and getting stuck in off. They don’t have to call an ambulance. It can smooth this roller coaster ride patients can go through.

No, no, there are many more to be identified.

There are many families where there is a clear-cut inheritance and we still don’t know what the gene is.

We will have identified more genes, for one. And the thing that is coming down the line now that’s very exciting from surgical standpoint is that we are now having trials of gene therapy for Parkinson’s disease. This involves putting gene products into the brains of patients. Some of these trials are directed at making more dopamine in the brain; some are putting in neurotrophic factors. These are factors that enhance the survival of neurons that may be affected in Parkinson’s disease.

A third gene therapy trial currently underway involves neutralizing abnormal activity in Parkinson’s. It turns out that when you’re missing dopamine in the brain, the neurons that normally depend on it start to act in an abnormal way. They start to misfire and cause other abnormalities. These neurons can be targeted with gene therapy and can be told to stop firing in this abnormal way. In fact, that’s what we do with deep brain stimulation: we tell neurons to stop misbehaving.

These trials have progressed from animals to now, as we speak, in humans. We should have results in the next few years as these trials become completed.

Given that we now know some of the genes that are causing Parkinson’s disease. I would learn how to go into the brain and replace the defective genes. Or, in the case, where some genes are causing toxicity in the brain, I would learn how to remove that pathological function. I am interested in getting to the root cause of the illness and directly attacking the disease by fixing the molecular defects responsible for producing it.

There are currently 4.5 million men and women in the world with Parkinson’s disease. The main risk factor is advanced age. It is one of a group of disorders which are called neurodegenerative disorders, and these are disorders caused by the death of neurons. They include Alzheimer’s, Parkinson’s and ALS or Lou Gehrig’s disease. It is estimated that by the year 2030, deaths secondary to neurodegenerative diseases will overcome deaths caused by cancer. This is related to the fact that we have an aging population, and as we are getting more successful at treating certain cancers and preventing them, the rate of increase in neurodegenerative diseases will continue to rise, unless we come up with something to stop them.

So it is tremendously important to identify the causes of these disorders—why neurons are dying in the brain, why abnormal proteins are deposited in the brain. It is also tremendously important to develop novel therapies to treat these disorders. That’s what we’re dedicated to doing and, with hard work and maybe some luck as well, we will succeed.

Andres M. Lozano, BSc, MD, PhD, FRCSC, BmedSci
Toronto Western Research Institute
University Health Network
University of Toronto
Toronto, Ontario, Canada