Authors: Dr. Alberto Espay and Benjamin Stecher

Publisher: Cambridge University Press

ISBN: 978-1-108-74462-1

In Brain Fables: The Hidden History of Neurodegenerative Diseases and a Blueprint to Conquer Them, one of its co-authors, Dr. Alberto Espay, recounts how a patient of his living with Parkinson’s presented a curious question, “if he had unlimited funding, how would he transform the way we examine and treat Parkinson’s disease?” And thus introduces this admirable publication, which was co-authored with Benjamin Stecher.

Dr. Espay is a Professor of Neurology and Endowed Chair of the University of Cincinnati James J. and Jean a. Gardner Family Center for Parkinson’s Disease and Movement Disorders. Benjamin Stecher was diagnosed with Parkinson’s Disease at age 29 and has since become passionately engaged in PD research and advocacy. He is the founder of Tomorrow Edition, where he has interviewed close to 80 experts in PD.

Among the primary questions that the authors revisit throughout the work, are we focusing on the study of PD in the appropriate way? Are we asking the right questions? Their argument is that instead of treating PD as one disorder, we should recognize it as a collection of ailments. As explained: “despite all that we have learned of its complexity, and the array of neurochemicals and brain regions and cell types involved, we continue to put forward therapies that target single pathways in groups of patients, acting as if all that heterogeneity is applicable in one way or another to just about everyone.” Why are we not targeting defined subgroups of those diagnosed with PD?

As pointed out, “of the 72 therapies with presumed disease-modifying effects in clinical development, only 8 targets a defined subset.” The dilemma is that if there are dozens of biological subtypes of PD, how many medicines are we going to require to accurately care for them all? Will the pharmaceutical companies want to embark on this journey rather than continuing to identify a one shoe fits all scenario?

Another flaw of the present research is that the further we concentrate on the suspected proteins capable of PD, the more we may lose sight of the possibility that we may deal with the result of many biological diseases that produce PD. “The appeal of protein aggregation as explaining the heterogeneous universe of Parkinson’s, Alzheimer’s, and other brain aging diseases is it synthesizing power. It offers a universal explanation. If only we could understand everything about the proteins that aggregate, we could unlock the mystery of each of the diseases their aggregation defines-and lay the path for their cure (p.59). Is this the appropriate approach? Is it conceivable that the biological abnormalities that have been suspected of developing after the aggregation of proteins, may instead introduce the events?

What about the hypothesis that alpha-synuclein aggregation is the essential cause of PD disease? What do we know about alpha-synuclein? Do we know its role in the disease? What is its natural function? How does the misfolding occur? Is the clumping part of the cells’ defense mechanisms? How does it contribute to the manifestations we observe? Why has there not been any biomarkers developed and imaging agents to monitor the advancement of these clumps and disease progression? In other words, we know surprisingly little of alpha-synuclein. What is the best evidence we have that synuclein aggregates are an effect of having the disease rather than a cause?

The authors further raise the question of biomarkers, where dozens of review papers have been published. How accurate are the biomarkers in forecasting PD's progress if there are several sub-types of the disease? Are we to speculate that these biomarkers apply to all and that they all share the same slope of deterioration and advancement?

As the authors sum up, the critical issues concerning PD are that we don’t understand the biology driving it. We have been going after the wrong targets. PD represents a gamut of many biological disorders. There are noticeably few stimuli in place to promote the extensive collaborative efforts required to spur research forward. Science is primarily propelled by what publishers and grant reviewers want. This perpetuates a scientific culture that whirls around accepted concepts without prioritizing the needs of society. None of our animal models could come close to recapitulate a disease that shows up in many forms. Drug development is painstakingly slow. Even if a cure was discovered in the lab today, it would take 12 to 18 years to get the therapy to patients. Patients have inadequate access to the care they need.

Both the lay and specialist reader will be grateful for this illuminating book. Will the scientists heed the advice of Dr. Espay and Benjamin Stecher and embrace their suggestions is another matter?