Atypical Parkinsonian Disorders

 

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It has been exactly 50 years since the publication of the seminal article by John Steele, J. Clifford Richardson, and Jerzy Olszewski describing the clinical and pathologic characteristics of a neurodegenerative disease they named “progressive supranuclear palsy” (but still known to many as the Steele–Richardson–Olszewski syndrome). Since that time, an enormous amount of progress has been made in our understanding of this and similar disorders, commonly referred to as atypical parkinsonian disorders. Because there has not been an issue of Seminars in Neurology dedicated to this topic, we felt that this year—2014—the 50^th anniversary of the original publication by Steele, Richardson, and Olszewski, was an appropriate time to provide a comprehensive update of these disorders. We are pleased to have the original paper reprinted in this issue in commemoration of their landmark article.

This issue appropriately begins with a historical perspective by John Steele himself. Next, we present authoritative clinical reviews on both tauopathy and synucleinopathy diseases within the atypical parkinsonian disorders (APDs), including monographs on progressive supranuclear palsy (PSP) by Larry Golbe, corticobasal syndrome (CBS) by Ana Grijalvo-Perez and Irene Litvan, multiple system atrophy (MSA) by Tasneem Peeraully, dementia with Lewy bodies (DLB) by Katie Mayo and Yvette Bordelon, and frontotemporal lobar degenerations (FTLD) by Elissaios Karageorgiou and Bruce Miller. These reviews include updated clinical diagnostic criteria, discussions of the presumed pathophysiological mechanisms of disease, and up-to-date summaries of current treatments. Next, we present a review on the role of brain imaging modalities in the diagnosis of APDs by Florian Holtbernd and David Eidelberg, and another on the neuropathology of the synucleinopathies by Jean-Paul Vonsattel and Etty Cortes Ramirez (the neuropathological features of PSP being already covered in the original Steele et al article). We then feature a review of the genetic contributions to these disorders by Dan Geschwind and colleagues, with insightful discussion of how rapidly expanding genomics approaches can aid not only in diagnosis and classification, but also in the treatment of these APDs. And finally we close the issue with an article that summarizes the latest data on clinical trials for these various disorders by Richard Tsai and Adam Boxer; they provide a window into the future of drug development and the rapid progress we will see in the next several years. We are delighted to have a complement of such distinguished leaders in the field contributing to this issue.

Although the occurrence of APDs is rare when compared with Alzheimer disease and Parkinson disease, the first and second most common neurodegenerative disorders, respectively, research in this area will provide critical information to guide therapeutic strategies for all related disorders. This is due to the significant overlap in pathophysiologic and genetic contributions to these diseases. The recognition that all of these disorders are characterized by protein misfolding, be it aggregated tau, α-synuclein, or other proteins, has unified research efforts further. These advances will continue to fuel discovery of treatments targeted at the genetic and pathologic levels, including mechanisms integral to tau and α-synuclein processing. In addition, clinical diagnosis of these rare disorders will continue to improve with greater awareness, refined criteria and improved diagnostic testing. This is extremely important, knowing that many patients spend several years with diagnostic uncertainty. The number of clinical trials focusing on APDs has increased over the past several years, perhaps because of the advantages that they represent more homogeneous populations, the clinical diagnostic criteria are better defined, and the underlying proteinopathy has been well characterized. Thus, tau-specific agents can be studied in the pure tauopathy syndromes (PSP and CBD), and when found to be effective could easily benefit other tau-associated disorders like Alzheimer disease or FTLD. As treatments emerge, early diagnosis will lead to earlier targeted therapies and significantly benefit patients and families dealing with these diseases.

We believe that we are at a turning point in the field of investigation in these atypical parkinsonian disorders. The growth in understanding of the overlapping pathologic and genetic contributions of these diseases coupled with improved diagnostic testing and clinical diagnostic criteria have set the stage for accelerated development of effective symptomatic as well as disease-modifying therapies. We anticipate that we will not have to wait another 50 years before we witness radical advances in the treatment of individuals and families dealing with these diseases, as therapeutic pipelines mature and produce meaningful treatments.

A special thanks goes to the Editor-in-Chief, David Greer, for allowing us to provide an update on the APDs and for obtaining permission to reprint Dr. Steele's original article. We thank all of our authors for their outstanding contributions and we hope that you enjoy this issue of Seminars in Neurology.