Parkinson’s disease does not exist.
There is nothing that we can point to and say, ‘that is Parkinson’s’. We have never found it in a brain, recreated it in a dish, nor given it to any animal.
What we have are people living with a diagnosis of Parkinson’s. There is currently nothing that allows us to separate the disease from the people that experience it.
We have assumed that there is an underlying biology that connects most, if not all, of those diagnosed, but we have no clear signs that what we are looking for exists.
And yet, we talk about it as if we know it does. Medical journals are filled with references to ‘Parkinson’s models’ and ‘Parkinson’s pathology’, without mention of the fact that we have no proof that there is anything there.
We even have two distinct categories of therapies: ‘symptom modifying’ and ‘disease modifying’, as if we know the difference. And how do we claim to modify what we cannot define? Through a series of motor tests that output a single number. Generally, the longer it has been since a person’s diagnosis, the higher that number is. Disease modifying trials aim to slow, stop or reverse that trend.
But that test is a test of patients’ motor symptoms. So, since we cannot uncouple the symptoms from the disease, why the distinction?
Levodopa, the gold standard therapy for Parkinson’s disease is not considered ‘disease modifying’, yet its introduction in the 1960’s doubled life expectancy for people diagnosed with Parkinson’s and has done more to help people live better lives than any other tool in the neurologist’s toolbox.
Again I ask, why do we try to separate the disease, which we have no way of measuring, from the symptoms we can measure?
The pathophysiology of Parkinson’s disease is murky at best. For decades experts have acknowledged that PD has a multi-causal heterogenous etiology that results in a wide spectrum of disorder. Yet, despite all that we have learned of its complexity, and the array of neurochemicals and brain regions and cell types involved, we continue to put forward therapies that target single pathways in groups of patients, acting as if all that heterogeneity converges on a unifying pathology.
Some might say that if we try and try and try again we might happen upon a solution that does hit the disease. We may, but what are the chances? What are the odds that if we use what knowledge we have and just try enough things, something is going to work? I don’t have the answer, (though it seems like one we might be able to compute?) but for now, we have no proof-of-concept, there is no chronic degenerative neurological condition that we have solved by trial and error.
So, how should we proceed? Perhaps until we know better (that is, have biomarkers that can tell us more about these diseases than symptoms can) we should dispense with the distinction between ‘disease modifying’ & ‘symptom modifying’ while being agnostic to any claims about what Parkinson’s is.
Such a shift would also give us clearer targets as outcome measures in trials. Measuring constipation, time spent On vs. Off, choking, or rate of falls, are much more tangible outcomes to measure in trials than the amorphous ‘disease-modification’. In fact, words like ‘disease-modifying’ and ‘neuroprotective’ are not even suitable goals for pharmacological intervention as they lack clear physiological definitions and thus are not something that can be put on a drug label.
Finally, when it comes to any attempt at a cure, we must remember that for patients, symptoms are the disease. People cannot feel genetic mutations, or mitochondrial dysfunction; we can only feel their macro effects. Since any functional cure would have to ameliorate symptoms to earn the name, perhaps, until we understand the biology well enough to purposefully intervene, the best way forward is not by trying to modify the amorphous blob that is disease, but instead focus on the only things we can empirically measure, the symptoms, and tackle each, one by one.
After all, if we get rid of the symptoms we will have no disease to speak of.
Advice to companies and research centers:
For short term gains (5-10 years): Hire a panel of knowledgeable patients who share a common symptom and work with them to find the best solution to that symptom.
For long-term gains (10-20 years): Invest in agnostic biomarker discovery programs. (More on this to come)
The Blind Leading the Blind is a painting by the Netherlandish Renaissance artist Pieter Bruegel the Elder, completed in 1568.