Why We Are Excited About MRI of Neuromelanin to Predict Parkinson's
Progress in treating PD may appear to be very slow – and it has been – but there are many potential new treatments at different stages of exploration. In contrast to the tried-and-true approaches, including L-DOPA, dopamine agonists, and deep brain stimulation, that treat symptoms of those who are already well into the disease, many of the new approaches are drug treatments that may halt PD progression. Indeed, one reason that treatments of advanced PD are so far ahead of treatments that prevent progression at early stages is because we can’t identify who is in early stages, and do not test them. So, we need a way to recognize PD before the disease brings someone into a neurologist’s office for diagnosis, since they have already experienced the first symptoms.
New work from our labs and others may finally have found a path. As most know, the motor symptoms of PD are due to the loss of the substantia nigra dopamine neurons, which are so-named due to the dark brown pigment found in these neurons, known as neuromelanin. In 2000, our labs found that this pigment was produced from oxidized dopamine accumulated into autophagsomes, structures related to the degradation pathways in cells. By examining post-mortem brains, Luigi’s lab found that these neuromelanin organelles are completely absent at birth, but increase linearly with age up to the age of about 100: unless someone has PD, in which case the dopamine neurons die and the neuromelanin is lost.
In 1993, Luigi’s group made another key observation, which is that neuromelanin is a “paramagnetic” substance. Technically this means that there are unpaired electrons in the chemical structure, but in practice it means that neuromelanin can be measured by “spin” techniques including electron spin resonance (ESR) and magnetic resonance imaging (MRI). ESR is not usable in people, but MRI uses a radio wave magnetic frequency, and at the time we recommended that it could be used to measure neuromelanin in living people.
There was however little interest, and not much more to report for years. We attempted to get imaging specialists interested, and they seemed to feel that it wasn’t doable or maybe that it wasn’t worth a try. Fortunately, Sasaki and colleagues in Japan in 2006 reported MRI readings of neuromelanin, using a 3 Tesla MRI machine that is widely used in medicine. This changed the perception of the imaging and neurology communities, and now several groups throughout the world are working on this topic.
This includes Guillermo Horga’s lab here at Columbia University, who with our labs have been developing improved measurement and analysis of brain images and postmortem tissues approaches in PD patients. These analysis methods are important, as people have different brain anatomies, and once the substantia nigra neurons containing neuromelanin die, they lose the neuromelanin and become invisible to the MRI. Therefore, our team is mapping everyone’s brain scans onto a standard, which requires some computational improvements.
At this point, the MRI measurements are sufficient to distinguish most people with PD vs. age-matched controls, but we think this is not the ultimate direction. Remember that neuromelanin increases in a predictable way with age, unless someone has PD. We think that, once more research is done, perhaps everyone over 50, and younger people who may have genetic or environmental risks for PD, could come in every few years for the MRI analysis of neuromelanin. If it increases linearly, this would reflect normal aging, and if there is a decrease, this would indicate early stage, pre-symptomatic PD. This clinical assessment would be analogous to the ten-year colonoscopies those of us over the age of 50 now receive.
Certainly at this time, it remains unclear exactly how early stage PD would be treated if it is identified, but this is part of the point. For example, there is currently a large Phase III trial on the use of dihydropyridines and monoamine oxidase inhibitors that is headed by Northwestern and NINDS that may block substantia nigra neuron death. To really confirm if these work, we would want to test people at early stages when most of the neurons are present. And if we can identify the early stage patient, we can also use the same approach to see if treatments are effectively halting the disease progression by determining the rate of loss of substantia nigra dopamine neurons, something that cannot be done well at this time.
We think that a way to detect early PD, record its progression, and its response to different clinical intervention is required to really move forward for better therapy. These MRI recordings can be conducted in a few minutes using machines that are common in hospitals and universities and could be very inexpensive once the techniques are solidly worked out, which may be soon: the new approach by Guillermo and our labs should be out this year, and we have a freely available detailed review that should be soon available to the general public. These methods do not require radioactive labels, as does PET, or require contrast agents. There are at least two obstacles to face, however. First, pharma is not interested in developing markers, as they do not make money from it: this research will likely need to be supported by private or government foundations. Second, before this approach could be widely used, we need studies that follow a large group of people and their MRIs over the course of several years, which obviously will require several years. But on the other hand, we have been advocating this for 15 years, are excited that it is finally taking flight, and so we don’t give up easily!
David Sulzer, PhD presented at the first World Parkinson Congress in Washington DC. He currently serves as a Professor at Columbia University Medical Center in the Departments of Psychiatry, Pharmacology, and Neurology. He is the founder of the Gordon Conference on Parkinson’s Disease, which is the first basic science conference devoted to PD, and the new journal Nature NPJ Parkinson’s Disease.
Luigi Zecca MD, PhD presented at the first World Parkinson Congress in Washington DC and presented several times in the last 9 years at the Annual Congress of Italian Association Parkinson's Patients (AIP). He currently serves as Associate Director of Research at the Institute of Biomedical Technologies-National Research Council of Italy in Milano.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®