Is Parkinson's one disease or many?

Experts and patients tell me that Parkinson's is not a single disease, but rather a collection of many diseases with overlap between them. And that makes sense from several perspectives.

Certainly symptoms vary from one person to the next. Not all are equally affected by tremors or rigidity. Not all suffer from predominant motor symptoms; some are more impacted by autonomic nervous system function or cognitive abilities.

Variability extends to the disease course; some suffer from rapid progression of disability while others notice very little change over the first several years after diagnosis (though from talking to people, a very slow/barely noticeable rate of progression seems more rare than a noticeable rate of worsening).

Responses to therapy can be radically different. Those of us who watched the recent Michael J. Fox documentary "Still" may be impressed by how well he functioned with the help of levodopa/carbidopa. But even if we imagine an optimal response to dopaminergic therapy, it does not last. The disease progresses. Many people don't notice much of a response and many suffer side effects from the drugs. (I use the word "many" to emphasize that these are not uncommon rather than trying to give a sense of how frequently the drugs fail.)

These observations certainly support the point of view that PD is not one disease. But I have trouble agreeing with this way of interpreting such observations. The logic of this thinking does not appear to consider a few important perspectives.

First, the thinking is only valid in case where there are no potentially unifying pathologic causes. Today's knowledge-base does not include a unifying pathology, which is why there is no new approach to treatment since dopaminergic therapy was first tested in the 1960s. As you know, I've summarized how the published data show that excess cytosolic dopamine can serve as an explanation for each of the major pathologic mechanisms implicated as drivers of worsening PD. And RB-190 also appears capable of reversing the pathology - at least in experimental models.

Second, the thinking does not appear to consider that even with highly variable clinical presentations, a disease can be caused by unifying mechanisms that are treatable with a single medicine. I'll go back to my cardiology roots on this one. Clinical trials show that ACE inhibitors reverse disease progression, improve quality of life and reduce the risk of death irrespective of the presenting symptoms of people with chronic heart failure. Thus, a single pathophysiologic mechanism can cause different manifestations of disease and still be responsive to a therapy directed at this mechanism.

Third, why would we expect the effects of a disease to be the same for everyone, when there are so many examples of people responding differently to different stimuli. Do we all like lima beans and okra? I can tell you that I'm the only one in my family who does. Do we all feel the effects of hypoxia equally when we travel high in the mountains? Of course not. When we get heartburn, we don't all get complete resolution with a couple of Alka-Seltzers. We are different; we respond differently.

These perspectives undermine the voracity with which one can argue that PD is many diseases. And since I see a unifying cause of the disease - excess cytosolic dopamine - I expect that we will learn eventually with RB-190 that people with a wide range of disease symptoms/limitations will respond to the same therapy targeting this dopamine excess, showing it is a single disease (for the most part).