The following first appeared on the blog parkinsonsecrets.com on September 21, 2020. It was written with Prof. Alberto Espay.
Myth #1: We think we know the truth.
When people first go to see a neurologist, it is often at the end of a long and frustrating process of being referred from one doctor to another until they finally land in the clinic of the right specialist. They then go through a battery of movement and cognitive tests used to narrow down which disease label the doctor can pin on the individual in front of them.
That label, whether it be Alzheimer’s, Parkinson’s, Multiple Sclerosis or any one of the other names we have given to degenerative brain diseases, will then be attached to that individual for the rest of their lives. It will eventually be told to that person’s friends and family, changing not only how they are viewed by others, but often how they view themselves.
There is comfort that comes with finally getting diagnosed. For one it gives community and lets patients know that they are not the only ones going through this. The label also comes with the assurance that scientists and doctors know what is wrong and that they are working on ways to do something about it.
In truth, these labels have been created arbitrarily by doctors to bring a sense of order to the many ways in which people can age abnormally. There is nothing in biology confined to what is called Parkinson’s or Alzheimer’s. Each were labels created by astute observers based on a clinical spectrum of symptoms long before there were tools to evaluate them. The labels became so entrenched as to be accepted as the truth from which any new observations are to be compared. As a result, we have accrued enormous knowledge about Parkinson’s –the disease, and about Alzheimer’s –the disease, but we have come to know precious little about each individual’s form of Parkinson’s or Alzheimer’s. We have lost sight of the individuality of the trees from the proverbial forest.
Myth #2: One therapy will eventually modify progression in everyone diagnosed with one of these diseases.
Walk into any room of people with one of these conditions and you will see a wide spectrum of different symptoms and disorders. Yet, when it comes to our trials, we still tend to lump all of those different people into the same bucket and give them the same drug, believing that it might be able to modify what is going wrong in all those individuals.
It is time we embrace what patients have long known, that these diseases are a spectrum of biologically unique disorders and that to move forward we need to start learning how to properly divide these groups of people into the discreet biological categories into which they belong in order to match them to therapies most likely to alter the biology driving their form of disease.
That is the central message of the book we wrote, Brain Fables, it also happens to be the guiding principle behind a program called the Cincinnati Cohort Biomarker Program, which is studying populations of individuals that have been diagnosed with Parkinson’s or Alzheimer’s looking for biomarkers that we can match to therapies.
Go to ccbpstudy.com to learn about the CCBP.
Myth #3: Toxic protein aggregates are the main driver of neurodegenerative diseases.
The gold standard by which we confirm the diagnoses of most neurodegenerative diseases is post-mortem analysis. We wait until patients pass way, by which time they have usually spent years, if not decades living with these diseases, and then we look inside their brains to see what might have gone wrong. The diagnosis is confirmed if a pathologist can document the presence of protein aggregates that tend to build up in the brains of patients with these diseases. These aggregates are thought to be toxic and are believed to be the cause of these diseases.
This is akin to coming to the site of a fire after it has burned out and concluding that what is left in the ashes must have set off the blaze. Or coming to the site of a landscape ravaged by a storm to see fallen, uprooted trees and claiming that those trees must have caused the damage. The reality is that we still know very little about what causes each of these diseases in the individuals affected. Our current reductionist understanding is that the protein aggregates that accumulate in the brain are so pervasive that they must bear some responsibility for the disease in everyone and if we have a therapy that can clean these proteins from the brain, then we will slow down the progression of these diseases in all of those affected.
These aggregates are not the cause of the problem –but a sign that the brain is fighting against some form of biological injury. Nevertheless, the aggregation is a problem because normal proteins are lost in the process of becoming aggregated. As these normal proteins change into so-called amyloid plaques (Alzheimer’s) or Lewy bodies (Parkinson’s), they lose the role they played in the healthy functioning of our cells. We don’t know exactly the full extent of their roles, but it is clear that when proteins transform into shapes called ‘fibrils’ and ‘amyloids’, their new stiff conformation prevents them from carrying out their normal function and the cells around them suffer.
This is leading some investigators from Karolinska Institute and the University of Cincinnati to a startling conclusion – the right strategy might be exactly the opposite of everything we have tried so far. Instead of removing the protein aggregates or stopping the proteins from clumping together, what we might need to do is inject more of the proteins in their normal state –not aggregated and with a mechanism to prevent their transformation into aggregated proteins. Once in our systems, these proteins can carry on doing what they used to do.
While this approach is not meant to be true precision medicine, it can be a sort of “rescue” medicine meant to replenish the forest with its nutrients while we find what source has caused the “fire” or “pest” in the individual trees.
Image courtesy of Marina Noordegraaf @sparkspd. Click here for the full poster.
Myth #4: If we had recruited patients at an earlier point in their disease our previous clinical trials would have worked.
Unfortunately, as we discuss in Brain Fables, many of our previous trials not only failed to meet their desired end points, but a substantial proportion of patients in those trials actually got worse as a result of the treatment that was being tested. This was particularly true for immunotherapy trials targeting protein aggregates believed to be the cause of Alzheimer’s disease. In nearly 40% of the trials, individuals in the treatment arm experienced faster disease progression than those in the placebo arm.
The idea that the treatments would have worked if we had just gotten to those patients sooner contradicts the available human data. In fact, 7 of the 35 published trials of anti-amyloid therapies selected people with so-called prodromal Alzheimer’s disease (some cognitive impairment but no dementia) and in 3 of these trials, the individuals who were in the treatment arm progressed toward dementia faster than those in the placebo arm. That we continue to insist with this same approach is a clear indication that we protect the hypothesis driving the trials despite the data those trials have generated. We defend the ideas behind the trials, arguing that the problem is in the imperfections of the trials in which our ideas were tested.
Myth #5: If one therapy can effectively alleviate symptoms in everyone, one therapy can effectively target the actual disease and not just the symptoms.
We do in fact have several therapies that help many patients have a much better quality of life. The most pronounced is levodopa, which allows the majority of patients with Parkinson’s disease to replace some of the dopamine that they have lost and thus regain some lost function.
All available therapies available are “symptomatic”, that is, they help mitigate the deficiency of certain neurotransmitters, most notably by increasing the concentration in the brain of dopamine in patients with Parkinson’s and acetylcholine in patients with Alzheimer’s. However, we still do not have any therapies proven to slow the pace, let alone stop, these diseases in anyone. Ironically, in the case of Parkinson’s, this might in part be due to the “eloquence” of dopamine deficiency (slowness, stiffness, tremor) and the success in eliminating, at least transiently, these symptoms with levodopa. This medication was considered a cure when it was discovered given the substantial improvement people felt when exposed to it.
If almost all patients with one of these disease labels benefits from this kind of therapy, does that not open the door to the possibility that other therapies will be discovered to slow disease progression in almost all patients with a certain neurodegenerative disease?
Unfortunately, it is not that simple. Just because individuals with a particular diagnosis share similar symptoms, it does not mean that the cause of those deficits is similar in them. The reason is pretty simple: there are possibly hundreds of ways a specific group of cells may be killed, and each of these ways is unique to individuals. What is common in everyone with “the same disease” is the symptoms that emerge from the loss of those groups of cells. Once gone, the function lost is about the same in everyone, even though the expression remains quite variable. But the only way to treat the disease in an individual is to target the unique biology which lead to that disease in that individual. While one therapy can treat the symptoms of most individuals with Parkinson’s, no single therapy can treat the underlying disease of most individuals. A treatment for someone’s actual disease may not work, or be harmful, for most others, despite sharing the same label (e.g., “Parkinson’s”).
Myth #6: Patients must continue participating in clinical trials to accelerate research.
Nearly every disease foundation or patient organization promotes and encourages participation in clinical trials. For good reason, clinical research cannot be done without the willing participation of human subjects. If we want to test therapies and develop better treatments, we are going to need patients to participate in those trials.
Enrolling in trials can also be fulfilling for patients, giving them a sense of being invested into something for the benefit of the wider community of people with their disease.
However, patients need to be a little more critical when deciding in which trials to participate. Despite all that we have learned about degenerative brain diseases, the clinical trials testing drugs for “disease modification,” (to slow progression) continue to be built on two of the myths highlighted above, namely that (1) we know what disease each patient has and (2) there will one day be a drug that cures everyone with that disease. Those are myths based on hope but not on evidence, nor on the experience of other fields of medicine beyond neurology and psychiatry. It is time that patients start asking their doctors this important question: “what might the therapy under evaluation in the trial I am being asked to participate do to the specific disease I have.” The answer, “You have Parkinson’s disease and this therapy has been shown to work well in a model of Parkinson’s” should not suffice. The one-size-fits-all approach has never been a path to precision medicine in oncology or other fields of medicine. Success in disease modification for Parkinson’s, Alzheimer’s, and other neurodegenerative disorders will require matching each patient to the right intervention, in the right trial. Cures will only come by targeting biological subtypes of disease, clustered in small subgroups, one at a time.
Order Brain Fables to learn more about how these and other myths got created –and ways to make them part of the past.