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A Clinical Trials Expert Asks: Is Neuroprotection Our Only Goal in the Fight Against Parkinsonís Disease?

By Karl Kieburtz, M.D., M.P.H.

Uncertainty about the future is one of the most troublesome and difficult aspects of Parkinson’s disease (PD) for people living with PD, their families and loved ones.  The progressive nature of PD has been well recognized since its original description in 1817.  The initial problems individuals with PD encounter may be mild and largely surmountable, but in time, virtually everyone with PD experiences more disabling aspects of the disease.  Despite the development of therapies, such as levodopa, that improve many of the symptoms of PD, there are no treatments that effectively slow the course of the disease.  Finding such treatments is a major goal of PD research. 

The History of Neuroprotection

After the initial clinical description of PD in the early 19th century, little was understood about its cause for the next 100 years.  During the 20th century, clinicians and researchers came to understand that one of the major problems in PD is the early death of nerve cells in the brain.  These nerve cells were found in very specific parts of the brain and the changes in these small areas seemed to explain many of the problems that people with PD experience.  The concept that this underlying “neurodegeneration,” or dying of nerve cells, was the cause of the onset and perhaps the progression of PD, led to a search for therapies which may stop that neurodegeneration.  In fact, there is even hope for therapies that may actually be restorative, that is, they may replace some of the brain cells that have been lost in PD. 

Current Research

Researchers have done experiments in test tubes and in laboratory animals to try to find treatments that may improve the course of PD by stopping or slowing this neurodegeneration.  While this work is very helpful, PD only really exists in humans and cannot be found in animals or in test tubes.  Still, lessons learned from such laboratory experiments have led scientists to study potential new treatments for PD.  For instance, there are clinical trials of compounds, such as Coenzyme Q10, inosine and isradipine, that were inspired by these findings.  These potential treatments are often referred to as “neuroprotective.”  This comes from the idea that if a treatment could help limit the loss of cells (as seen in laboratory experiments), then perhaps it would also slow the progression of a person’s Parkinson’s.

Challenges to Neuroprotection

The idea of finding “neuroprotective” treatments for PD might be an excessively difficult goal.  This is because, while in laboratory experiments, researchers can actually count the number of brain cells and determine if a potential therapy has preserved or protected those cells, in clinical trials studying new drugs in PD, we cannot count cells or determine the extent of “neurodegeneration.”  We can only measure the symptoms of PD and the extent of disability.  While these clinical measures may reflect the extent of nerve cell loss, they could be reflecting other things, such as the effects of PD medications. 

Is Neuroprotection The Only Thing We Want?

A realistic goal for Parkinson’s therapies is to prevent disability and to minimize symptoms, rather than to see if we can extend the life of brain cells.  Plus, it may be possible to limit the amount of disability without changing the underlying number of brain cells. 

For this reason, many clinical trials focus on trying to modify the clinical course of disease or to reduce the amount of disability that accumulates over time.  Various terms have been used for these kinds of treatments such as “disease modifying,” “changing the clinical progression,” or “reducing accumulated disability.” These different terms can be confusing and suggest that the treatments are trying to do different things.  In fact, the terms are just emphasizing that clinical trials largely measure the observable, clinical aspects of PD (like tremor or slowness), not brain cells.   

Some individuals with PD and researchers may think it is necessary to show that such treatments actually preserve nerve cells.  Others, myself included, take a more practical approach.  That is, we are trying to find therapies which reduce the amount of disability individuals experience with PD.  In time, we may be able to measure the extent of brain cell loss, but this should not delay attempts to develop new treatments that favorably influence the overall course of PD.

Future Clinical Trials

Clinical researchers, regulators and sponsors of research are all seeking efficient clinical trial methods to identify these important new therapies to slow PD disability.  In addition, these individuals are working to develop treatments that immediately improve the symptoms of PD, although they may not change the overall course of disease.  Especially important are those symptoms that aren’t effectively dealt with by our current drugs such as tremor, fatigue, pain and gastrointestinal or bladder symptoms.  My feeling is that the best current clinical research approach is to try to find new treatments that address PD symptoms that are not currently well managed, and to simultaneously seek treatments that will, in the long run, reduce the disability that individuals with PD experience.

Dr. Kieburtz is the Director of the Center for Human Experimental Therapeutics and Professor of Neurology, Environmental Medicine, and Community & Preventive Medicine at the University of Rochester Medical Center.  He is also Chair of the Parkinson Study Group (PSG).


The opinions expressed in this article are not necessarily those of the scientific advisory committees of the Parkinson’s Disease Foundation.