Predicting Parkinson's disease – why, when, and how?

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Summary

Parkinson's disease (PD) is a progressive disorder with a presymptomatic interval; that is, there is a period during which the pathologic process has begun, but motor signs required for the clinical diagnosis are absent. There is considerable interest in discovering markers to diagnose this preclinical stage. Current predictive marker development stems mainly from two principles; first, that pathologic processes occur in lower brainstem regions before substantia nigra involvement and second, that redundancy and compensatory responses cause symptoms to emerge only after advanced degeneration.

Decreased olfaction has recently been demonstrated to predict PD in prospective pathologic studies, although the lead time may be relatively short and the positive predictive value and specificity are low. Screening patients for depression and personality changes, autonomic symptoms, subtle motor dysfunction on quantitative testing, sleepiness and insomnia are other potential simple markers. More invasive measures such as detailed autonomic testing, cardiac MIBG-scintigraphy, transcranial ultrasound, and dopaminergic functional imaging may be especially useful in those at high risk or for further defining risk in those identified through primary screening. Despite intriguing leads, direct testing of preclinical markers has been limited, mainly because there is no reliable way to identify preclinical disease.

Idiopathic RBD is characterized by loss of normal atonia with REM sleep. Approximately 50% of affected individuals will develop PD or dementia within 10 years. This provides an unprecedented opportunity to test potential predictive markers before clinical disease onset. The results of marker testing in idiopathic RBD with its implications for disease prediction will be detailed.

Introduction

As a progressive neurodegenerative disorder, Parkinson's disease (PD) starts with a presymptomatic period during which degeneration is present, but disease is not clinically evident. This suggests that it should be possible to predict PD using clinical examination, symptom screens, and other markers. This review summarizes the pathophysiologic basis for disease prediction and what is currently known about predictive markers of PD, and discusses how studying patients with idiopathic RBD can help understand preclinical PD.

Section snippets

Defining the goal – why predict PD?

Before beginning to study disease prediction, it is first essential to why it is important to do so. The first question is whether foreknowledge of PD is, in itself, a sufficient motivation for using predictive measures. Theoretically, knowledge of an impending neurodegenerative condition could help in family planning, deciding on retirement, etc., but such knowledge could also lead to inadvertent effects such as psychological distress, discrimination at work, or inability to obtain health

Who could be tested?

PD is relatively uncommon, with a population prevalence of approximately 1.5% at age 65 [2]. There are currently no methods to reliably identify persons at high risk of disease – risk factors such as family history and environmental exposures increase relative risk of PD usually by a factor of 2–3, implying a risk increase from 1.5% to only 4% [2, 3]. If there are no methods to reliably identify persons at substantial risk of disease, screening in an age of effective neuroprotection may need to

Non-motor manifestations – the key to predicting PD?

In addition to the motor manifestations that define PD, patients have numerous abnormalities of other systems, which may occur before motor signs. A staging study proposed by Braak et al, examining deposition patterns of α-synuclein in a large brain bank, suggested that the initial stage of PD involves deposition in anterior olfactory nucleus and dorsal motor nucleus of the vagus [4]. Peripheral autonomic ganglia and unmyelinated lamina-1 spinal cord neurons are also involved in stage 1 [5]. In

The potential markers

There are a considerable number of potential clinical markers for prediction of PD. In general, their potential usefulness as predictors is suggested by involvement in early PD – direct evidence for predictive value is often limited.

Using RBD to test predictors of disease

With the exception of olfaction, all of the above markers have not been proven as predictive markers of PD – that is, they have not been assessed before development of PD. A major barrier to testing potential predictive markers is the inability to identify patients at high risk of disease. To illustrate, PD incidence estimates [49], suggest it would require over 10,000 patients followed for 5 years to detect 15 patients with new-onset PD. However, by following patients with RBD, one can detect

Conclusion

Although there is considerable promise for clinical predictors of PD, no single marker is presently able to predict PD with good reliability and sensitivity. Therefore multiple lines of investigation should be encouraged. So far, direct testing of predictive markers has been limited, but ongoing studies, including those in patients with idiopathic RBD, will soon be able to identify markers that can predict PD. The ability to predict neurodegeneration will be critical to development of

Conflict of interests

We have no competing interests to declare in relation to this paper. JY Montplaisir received personal compensation as consultant (Boehringer Ingelheim, Servier, Shire Biochem), speaker (Boehringer, Shire), and received financial support for research activities from Sanofi Synthelabo, GlaxoSmithKline. RB Postuma received personal compensation as a consultant and speaker for Teva Neuroscience.

Acknowledgements

This study was supported by a grant from the Fonds de la recherche en santé du Québec to RP and by grants from the Canadian Health Research Institute to JM.

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