Neurodegenerative Disease Parkinson's Disease
Approaches to the Diagnosis of Parkinson’s Disease during the Pre-motor Phase
Nuri Jacoby, MD,1 Jacqueline B Stone, MD1 and Claire Henchcliffe, MD, DPhil2 1. Resident in Neurology; 2. Associate Professor in Neurology and Neuroscience, Weill Medical College of Cornell University
Abstract
Parkinson’s disease (PD) remains a clinical diagnosis based primarily upon motor features of tremor, rigidity, and bradykinesia. However, by the time motor symptoms occur, the underlying pathology may be widespread. Approaches using a combination of clinical batteries and sophisticated biomarker technology now hold promise for identifying individuals earlier in the course of the disease, including those at risk of PD who may not yet have manifested any motor symptoms. Non-motor symptoms, such as specific sleep disorders, olfactory dysfunction, and autonomic changes, occur during a pre-motor phase, and their use in PD risk stratification is being actively evaluated. Neuroimaging techniques, in particular those focused upon measuring dopamine transporter density, are now in use in many specialist centers, molecular markers are in development and validation phases, and the use of genomic analyses has expanded the number of loci identified as contributing to PD risk. Identifying those at risk of developing PD will aid in the clinical management of the disease, and perhaps enable the use of disease-modifying drugs at as early a stage as possible.
Keywords
Parkinson’s disease, rapid eye movement (REM) sleep behavior disorder, neurodegeneration, Parkinsonism, biomarkers, autonomic dysfunction, olfactory dysfunction
Disclosure: Nuri Jacoby, MD, and Jacqueline B Stone, MD, have no conflicts of interest to declare. Claire Henchcliffe, MD, DPhil, has served on advisory boards for GE, Teva Pharmaceuticals, and UCB, and serves on the speakers’ bureaus of Novartis and Teva Pharmaceuticals. Acknowledgments: The authors thank Penelope Swope, PhD, for critical reading of the manuscript. Editorial support was provided by Touch Briefings. Received: May 31, 2011 Accepted: June 17, 2011 Citation: US Neurology, 2011;7(1):15–20 Correspondence: Claire Henchcliffe, MD, DPhil, Weill Medical College of Cornell University, 428 East 72nd Street, Suite 400, New York, NY 10021. E:
clh2007@med.cornell.edu
Support: The publication of this article was funded by Teva Neuroscience. The views and opinions expressed are those of the authors and not necessarily those of Teva Neuroscience.
The prevalence of Parkinson’s disease (PD) is now estimated to be approximately 1 % in individuals over 60 years of age, with 4.1–4.6 million people affected worldwide,1 by 2030.2
a number predicted to more than double Clinical diagnosis is based upon the recognition of the motor
features of tremor, rigidity, and bradykinesia, with other supporting features including asymmetric symptoms and signs, and the absence of signs of other etiologies of Parkinsonism. However, improved diagnostic tools are desirable for several reasons. By the time that motor symptoms are recognized, the PD pathologic process may already be advanced in the central and peripheral nervous systems. In addition, symptoms and signs may overlap with other neurodegenerative disorders, leading to the risk for misdiagnosis. This is particularly true in early PD, when only subtle motor signs are present, leading also to delayed diagnosis. Therefore, in order to identify PD earlier and more accurately, a number of approaches are being tested. One focus is the well-described non-motor symptoms of PD, as it is now clear that they may occur prior to motor symptoms in some cases, and might therefore define a ‘pre-motor’ phase of PD. Biomarker development is also being intensively pursued as an aid to diagnosis,
© TOUCH BRIEFINGS 2011
with potential markers including neuroimaging as well as sophisticated biochemical and molecular techniques. Advances in understanding the genetic contribution to PD are expanding the number of gene loci that are not only causes of heritable PD but are also identified in genome-wide association studies (GWAS) as PD risk loci. Improved diagnosis would not only impact upon clinical management, but such approaches are also desirable in order to identify disease-modifying treatments.
Where Does Parkinson’s Disease Pathology Begin?
PD has long been attributed to pathology in the substantia nigra (SN), with loss of pigmented dopaminergic neurons observed at autopsy. Surviving SN neurons often have intracytoplasmic proteinaceous inclusions, termed Lewy bodies, containing aggregates of a misfolded pre-synaptic protein, α-synuclein.3
The α-synuclein protein is well recognized as key to PD pathogenesis, with Lewy bodies, as well as dystrophic Lewy neurites containing concentrations of α-synuclein, having been widely described in other tissues. PD pathology is therefore detected in, and may in some
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