Progress and Parkinson’s disease
Peter A. LeWItt, M.D., Parkinson’s Disease and Movement Disorders Program, Henry Ford Hospital – West Bloomfield
The question comes up so often - when will there be some meaningful progress against Parkinson disease (PD)? I hear it from patients and from fellow physicians frustrated by the slow advance of improvements and breakthroughs in treatment options, and I hear it from my own inner voice, asking when the many strands of knowledge and insights about PD will come together. It seems that the know-how for turning out the secrets of this malady should arise from the thousands of laboratories and clinics around the world, but it hasn’t happened yet. Next year will be two centuries since Dr. James Parkinson first described the “shaking palsy” (that is, PD). He did so in a manner that is clearly recognizable to all of us today (negating any concerns that PD originates from our modern diet or contemporary chemicals). Next year will signify one-half century for availability of levodopa (the active ingredient of Sinemet) to treat PD, a drug that is still the most robust means for reversing most of the signs and disabilities of Parkinsonism – but in great need of improvement in its mode of delivery. These not-so-recent milestones of PD represent the start of a trajectory of progress, and there have been many more gains, some less widely recognized by the patient community. Now would be an excellent opportunity to highlight some of the most important advances against PD, especially since we have a milestone to celebrate in the form of our own Michigan Parkinson Foundation’s (MPF’s) 33 years of existence. This anniversary coincides with Debby Orloff’s career of dedicated service to this organization. She has been one of its founders, a volunteer in its early activities, a Board of Directors member for many years, and in another leadership role as CEO. She has been integral to the growth and productivity of MPF and we wish her well in her retirement from this organization.
In the 33-year span of the MPF, PD itself has been greatly transformed in how scientists and physicians view it. The very identity of the disorder has changed with the genetics revolution and study of PD families around the world. More than 20 gene variants associated with enhanced risk for Parkinsonism have been recognized, even though the majority of PD cases are not hereditary. Nonetheless, the rare familial forms have provided important mechanistic insights into how even the much more common sporadic version of PD arises. The mutation of the gene directing formation of a protein named alpha-synuclein is an important example. Discovered in the mid-1990s, this extremely uncommon gene mutation (arising exclusively in the Mediterranean region) has focused attention on this naturallyoccurring protein. Aggregation of alpha-synuclein is one of the final steps in the development of PD. Furthermore, there is evidence that this damaged form of the protein can spread from nerve cell to nerve cell. How this protein’s aggregation occurs has spawned a massive international effort to unravel this neurodegenerative change and how the associated biochemical processes might be reversed. One of the most exciting experimental therapeutic approaches arising from these insights is the use of immunological mechanisms – administration of antibodies directed against alpha-synuclein – in experimental efforts to slow disease progression. Many other ideas are arising from laboratories dedicated to learning how alpha-synuclein toxicity might be avoided. Some of these therapeutic options are undergoing translation from laboratories to treatment options. Important tools for this research are experiments in mice for which these human genetic forms of Parkinsonism can be induced. Early recognition of alpha-synuclein changes in the brain has the potential for detection by other means, since researchers have found deposits of abnormal alpha-synuclein aggregates elsewhere in the body (in biopsies of colon and even skin). Various research groups, including my own program, have found other ways to discover biomarkers of PD that could provide early diagnosis for determining who might need to start neuroprotective treatments of the future. Progress in the diagnostic realm also includes a specific type of brain scan (dopamine transporter imaging) that is available to look inside the living brain for establishing the diagnosis of Parkinsonism.
What about progress in treatment? In 33 years, a great deal has happened. Only a limited group of medications were available in 1983: anticholinergics (developed in the 1950s), levodopa (developed in 1969), amantadine (also from 1969), and bromocriptine (from 1974). Since then, more than 3 dozen therapies, including several new classes of medications, have become available or have entered into human testing. Progress in therapeutics includes a continuing search for new options - today, my clinic at Henry Ford Hospital is engaged in testing 7 of them and several new treatments for both the motor and non-motor features of PD are planned for upcoming clinical trials. The range of treatments tested in the past 3 decades includes cellular transplants (including fetal tissue and porcine cells) and laboratory-engineered gene therapies in attempts to reverse the brain changes of PD. Another widely-used development in the past 3 decades has been the advent of localized electrical stimulation into regions of the brain for suppressing medication-unresponsive problems of PD including tremor, involuntary movements, and gait disorders.
There are some less dramatic developments arising during the span of MPF’s existence that also have had an impact on improving quality of life with PD. Examples including botulinum toxin injections to control drooling or painful foot muscle spasms, medications useful at controlling symptoms of low blood pressure, and rapid rescue therapy for relief of “off” states. Efficient rolling walking frames like the U-Step have made it possible for imbalanced patients to walk safely in and out of their homes with diminished risk for falls. Specialized forms of physical and speech therapies (such as Lee Silverman Voice Training, or LSVT) have arisen for efficient targeting of impaired mobility and communication. Increasing attention to the value of exercise in enhancing health and functionality has had several important developments, including programs available in our community that use dance and boxing as ways for bringing PD patients to improved levels of motor capabilities.
Progress against PD can also be measured by the growth of information and awareness in the PD community. Within the era of Internet, a wide range of information sources (perhaps too much for some of us!) provide access to the worldwide sources of what’s available or new in PD care. Of course, this option hasn’t made personal connections obsolete. Here in Michigan over the past 33 years, we have the continuing growth of support groups and other regional meetings to enhance the learning and sharing of information and experience. At the heart of many of these services, of course, are volunteers, for whom the dedicated MPF office staff has provided guidance and resources. It is a source of pride for all of us linked to the MPF than persons new to PD, merely by finding our website or phone number, can efficiently receive vital guidance, reassurance, and practical ways to cope with this disorder.
A long list of accomplishments doesn’t disguise the current and future challenges for progress against PD. For some patients, the disorder is progressively disabling and without continuing treatment options. Though more than 2 dozen clinical trials for neuroprotection have been carried out in the past 3 decades, none of them have been successful - however, several promising trials are about to start. PD is still poorly understood by large segments of society; as a result, discrimination in the workplace or elsewhere still exists, in part by misperceptions of what it is (and isn’t). Many physicians haven’t learned enough about PD to properly offer the full range of what modern medicine can offer for its management. Government support of PD medical research is a fraction of what it could be, and many promising projects go unfunded. The increasing price of medications (even generic drugs) threatens access of effective therapy for some persons living on limited incomes. The care of persons with PD in hospitals or nursing care facilities is sometimes problematic because staff are often uninformed regarding the importance of timely medications. In many ways, progress for matters big and small with regard to PD is in need of better communication, better allocation of resources, and better public policy decisions.
Contrast what has been accomplished for PD with progress for so many other neurological disorders over the timespan of our MPF’s existence and you will see a marked difference – we have been fortunate for many accomplishments and the promise for new advances ahead.