An Interview with Anthony E. Lang, M.D.
Jack Clark Chair in Parkinson’s Disease Research
University of Toronto
Director, Shulman Movement Disorders Clinic
Toronto Western Hospital
Q: You have proposed the concept of Parkinson’s diseases (plural). Why?
A: “Parkinson’s disease” is really a clinical syndrome characterized by the onset in adult life of a slowly progressive neurological disorder manifesting certain typical signs and symptoms. People with Parkinson’s disease almost always show an initial excellent response to treatment with levodopa, the dopamine precursor that has been the mainstay of therapy for 40 years, but this initial response is typically complicated by the eventual development of side effects such as “on-off” motor fluctuations and abnormal involuntary movements called dyskinesias.
Over the last few years we have come to recognize that this same clinical picture can be caused by a number of single gene mutations, or may be associated with certain genetic risk factors. While the most common neuropathological correlate of the syndrome is a degenerative process with alpha synuclein protein aggregates in Lewy body inclusions and Lewy neurites, certain genetic causes have been associated with other neuropathological changes, most notably the absence of Lewy bodies. In my view, as long as we are relegated to defining the disorder clinically, it is best to acknowledge that we are not dealing with a single nosological entity, but instead with several disorders with distinct etiologies, all capable of causing the same clinical picture.
Q: You have likened the “dopamaic view of Parkinson’s disease” to the Ptolemaic view of the universe. Why do you think it’s time to abandon this view?
A: The discovery of dopamine deficiency in Parkinson’s disease was a remarkable and critical milestone. The subsequent development of Levodopa replacement therapy was truly a modern miracle of neurotherapeutics and has had a tremendous impact on the quality of life of people suffering from Parkinson’s disease. The combination of these advances clearly warranted the Nobel Prize [Swedish scientist Arvid Carlsson received the Nobel in 2000 for this work].
Attempts to more effectively treat the dopamine deficiency or manage the long-term complications of Levodopa therapy have dominated efforts to further improve the treatment of Parkinson’s disease. Such efforts, however, fail to acknowledge the fact that Parkinson’s disease is far more than a degeneration of the nigrostriatal dopamine system. Instead, it is a widespread process involving multiple brain systems, including those involving noradrenaline, serotonin, acetylcholine, and other neurotransmitters.
Moreover, as the disease progresses, patients develop a number of symptoms that respond poorly if at all to dopamine replacement therapy. These symptoms—now commonly believed to occur due to involvement of non-dopaminergic brain regions—account for a very large proportion of the disability seen in the later stages of the disease.
Therefore, just as man needed to move beyond the Ptolemaic belief that the earth was the center of the universe around which the sun and planets revolved, I feel that we now need to go beyond the belief that dopamine is the center of the Parkinson universe.
This has important implications for clinical care and research. For example, I believe it is misguided and naïve to presume that creating an unlimited supply of dopaminergic neurons from embryonic stem cells for transplantation into the Parkinson striatum will have a major impact on the management of large numbers of patients. Even if completely successful, this approach to therapy would have little impact on some of the more disabling symptoms of later-stage Parkinson’s disease.
Q: In terms of patient care and quality of life, why is it important to distinguish between dopaminergic and non-dopaminergic symptoms?
A: Consistent with the idea that Parkinson’s disease is far more than a dopamine deficiency syndrome, recently it has been suggested that the disease begins in the lower brainstem and olfactory tract, and may only involve the dopaminergic substantia nigra of the midbrain after it is well established in other regions. This genesis could account for what have been termed the “pre-motor features” of Parkinson’s disease (i.e., symptoms that may be present long before the development of the classical motor syndrome), including loss of sense of smell, constipation, sleep disorders, and behavioral/personality changes.
As the disease progresses and regions other than the substantia nigra become affected, a number of symptoms that fail to respond to dopamine replacement therapy become apparent. These non-dopaminergic symptoms include “motor” symptoms (speech and swallowing dysfunction; certain abnormalities of gait; and postural instability that makes falls more common) and “non-motor” features (bowel, bladder, and blood pressure abnormalities; sensory complaints such as pain; and psychiatric problems including depression and, most notably, cognitive decline). “Parkinson’s disease dementia” (PDD) is a term recently introduced to acknowledge the very common eventual occurrence of dementia in patients with Parkinson’s disease.
Patients in the later stages of the disease may still have problems due to dopamine deficiency, and the majority experience Levodopa-related complications. But these problems often take a back seat to the non-dopaminergic features, which come to dominate the clinical picture and significantly impact patients’ quality of life.
Q: You have stated that we stand on the verge of a new era in Parkinson’s disease therapy and that we will see “a brand new face” of the disease. Please explain.
A: The expected “new face” of Parkinson’s disease relates to what could be considered eras in the management of the disease. In the Pre-Levodopa Era (up to 1970), dopaminergic motor features predominated, and because there was no effective control for these disabling motor symptoms, the non-dopaminergic features were overwhelmed by them. Patients typically died before many of the non-dopaminergic symptoms became very evident. In the Levodopa Era (1970 to the present), treated Parkinson’s disease became a new disorder, not only manifesting dopaminergic signs and symptoms, but also unexpected motor complications and other side effects (such as psychiatric side effects). With increasing longevity and better control of the dopaminergic features, the non-dopaminergic features have become much more evident and often predominate in the later stages of the disease.
For example, the kind of results that have been demonstrated recently with deep brain stimulation of the subthalamic nucleus (STN DBS) show us what I expect will be possible in the foreseeable future for the majority of patients with Parkinson’s disease, using a combination of new medical and surgical therapies. The best candidates for DBS are those who have an excellent response to Levodopa prior to surgery with little or no Levodopa-resistant (i.e. non-dopaminergic) manifestations, but who are experiencing disabling Levodopa-related motor fluctuations and dyskinesias. Patients with the best outcomes from this treatment have a resolution of the motor complications, show little in the way of the clinical manifestations of parkinsonism, and may be able to withdraw from dopamine replacement therapy altogether.
Unfortunately, the therapeutic benefit of DBS combined with any ongoing medication slowly declines over the course of five or more years of follow up. This decline is most notable in the same clinical features that become resistant to chronic Levodopa therapy in non-DBS patients (i.e., the non-dopaminergic motor features). In addition, patients begin to develop new symptoms that were not present at the time of surgery, including apathy and cognitive decline (i.e., non-dopaminergic non-motor features).
The responses seen in STN DBS suggest that we are now on the verge of a new stage in the treatment of Parkinson’s disease, which might be termed the Non-Dopaminergic Era. In this era, dopaminergic features will no longer be the major consideration in the disability; rather, non-dopaminergic features will dominate the clinical picture—a new clinical face for Parkinson’s disease. This expectation underscores the need to move away from the “dopamaic” thinking of the last three decades, move beyond concerns about nigrostriatal dopamine deficiency, and concentrate our efforts on the persisting unmet therapeutic needs. These include the treatment of the cognitive dysfunction and other non-dopaminergic, non-motor, and motor symptoms.
Most importantly, we require better understanding of the pathogenesis of the disease, which will hopefully lead to the development of effective neuroprotective therapies capable of slowing or even halting the progression of the disease and preventing its development in at-risk individuals.