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ISSN: 2155-9562
Journal of Neurology & Neurophysiology
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Substantia Nigra Hyperechogenicity for the Early Detection of Parkinson’s Disease

Rezzak Yilmaz* and Daniela Berg

 

Department of Neurology, Christian-Albrechts-University of Kiel, Germany

*Corresponding Author:
Rezzak Yilmaz
Department of Neurology
Christian-Albrechts-University of Kiel
Arnold-Heller-Str. 3, 24105, Kiel, Germany
Tel: +4943150023849
Fax: +4943150023804
E-mail: [email protected]

Received date: March 28, 2017; Accepted date: April 26, 2017; Published date: April 29, 2017

Citation: Yilmaz R, Berg D (2017) Substantia Nigra Hyperechogenicity for the Early Detection of Parkinson’s Disease. J Neurol Neurophysiol S13:002. doi:10.4172/2155-9562.1000S13-002

Copyright: © 2017 Yilmaz R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

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Abstract

Hyperechogenicity of the substantia nigra (SN+) is an imaging marker which may be detected in individuals at risk for Parkinson’s disease (PD). In this short commentary, the evidence of SN+ as a risk marker for PD including its predictive value, stability and the limitations in assessment are discussed based on the current literature.

Keywords

Transcranial sonography; Substantia nigra hyperechogenicity; Parkinson’s disease

Introduction

Since the first publication by Becker and colleagues in 1995 [1], substantia nigra hyperechogenicity (SN+) detected by the transcranial B-mode sonography (TCS) has gained increasing popularity for clinical application and as a topic of research. Supported by numerous studies of different groups, SN+ has meanwhile been established as a reliable marker for PD diagnosis with a sensitivity of 85-90% and a specificity of 77-86% [24]. Besides the interest in SN+ as diagnostic marker, it has attracted considerable attention in the discussion of markers that may predict the risk of individuals for developing clinical PD [5]. In this short communication, we discuss the role of SN+ as a risk marker for PD.

Discussion

Early detection of Parkinson’s disease

Unfortunately, PD can only be diagnosed after at least half of the dopaminergic neurons of the substantia nigra has degenerated, which indicates that neurodegeneration precedes the clinical diagnosis by many years [6]. Therefore, much effort has been put into the detection of markers that indicate individuals at risk (risk markers) or indicate the neurodegenerative phase before motor symptoms allow the clinical diagnosis (prodromal markers) [5]. Risk markers such as sex, age, positive family history, genetic variances and prodromal markers like REM sleep behavior disorder, constipation, olfactory impairment or abnormal functional imaging of the dopaminergic systems have been followed in longitudinal cohort studies to determine the predictive value of single markers or marker combinations for the development of PD [7].

SN hyperechogenicity as a potential premotor marker

SN+ has also been considered as a predictive marker, since it can be detected in about 90% of PD patients, even in the very early stages [2]. Importantly, about 10% of healthy individuals older than 50 years of age also display SN+ [8]. Considering the possibility of on-going neurodegeneration, these healthy individuals without a sign of parkinsonism but with SN+ were further investigated in several studies, which revealed that, (i) healthy individuals with SN+ may have nigrostriatal impairment detected by reduced presynaptic dopaminergic tracer uptake [9,10], (ii) show sub-clinical motor slowing [11,12], (iii) perform slightly worse in cognitive or olfaction tests [13,14] compared to individuals with normal SN echogenicity and (iv) are more prone to develop severe extrapyramidal symptoms after disposure to neuroleptic drugs [15]. Furthermore, healthy individuals with increased risk for PD, such as positive family history, asymptomatic carriers of mutations associated with PD [16,17] or REM sleep behavior disorder [18,19] also exhibited a higher rate of SN + compared to the ones without these risk and prodromal markers. All these findings in non-PD individuals support the hypothesis that SN+ may be present before clinical diagnosis. Results of the histological analyses in postmortem brains of healthy individuals with SN+ demonstrated an association between the size of the area of increased echogenicity and the amount of iron and microglia activity in the substantia nigra [9,20,21], histological features known to be present in PD, which gave further indication that SN+ may reflect, or at least be related to an on-going neurodegenerative process.

To define the possible role and the strength of SN+ in the prediagnostic stage of neurodegeneration, longitudinal studies were initiated. In the “Prospective validation of risk markers for the development of idiopathic Parkinson’s disease” (PRIPS) study, 1847 healthy individuals older than 50 years were assessed biennially for the presence of SN+ and other markers known to constitute a risk for future PD [14]. After three years of follow up, it was found that 8 out of 10 individuals with incident PD, had SN+ at baseline assessment, indicating a 17-fold increased risk for PD for the participants in this range with SN+ after three years [22]. Extension of the follow-up period to five years increased the relative risk to 20 [23]. This longitudinal study proved that SN+ is indeed a premotor marker for PD.

Stability of SN hyperechogenicity as risk marker for prodromal PD

So far, most studies indicate that the size of the increased echogenicity does not change over the course of the disease [24], is not related to disease severity [25], disease progression or dopamine transporter uptake [26]. Therefore, it has been categorized as a risk marker. This classification is further supported by the fact that SN+ can also be found in very young ages unlikely to have neurodegeneration [27]. However, although the majority of the published data describe SN+ as a stable marker, some more recent studies report correlation with disease severity or transporter uptake [28,29]. This may be due to a better resolution of modern ultrasound devices and thus more accurate measurements. For this reason, it is not entirely clear, whether SN+ will be classified as risk or prodromal marker in the future.

The role of SN hyperechogenicity in the diagnosis of prodromal PD

In 2013, recommendations for the diagnosis of PD were published by the European Federation of Neurological Societies (EFNS) and Movement Disorders Society (MDS). In this EFNS/MDS guideline, TCS was recommended as an effective tool for the detection of individuals at risk for PD as well as early and differential diagnosis of PD with a high recommendation level (Level A) [30]. Further in 2015, the MDS Task Force on the definition of PD, published research criteria for the detection of prodromal PD [7]. The Task Force defined a likelihood ratio (LR) for each risk and prodromal marker according to their predictive value derived from prospective studies, and described a method based on Bayesian statistics to calculate the future probability for PD using these LRs. Among the risk and prodromal markers, presence of SN+ is described as a strong risk marker with a positive likelihood ratio of 4.7, which affects the calculation of the probability score more than many of the other markers [7].

Limitations of SN hyperechogenicity for PD diagnosis

Although considered as a strong risk marker, SN+ should always be evaluated together with other markers as recommended in the MDS criteria. As already mentioned, about 10% of healthy individuals display SN+, but the prevalence of PD is 1-2% in the elderly population, which indicates that about 80% of the healthy individuals with SN+ will never be diagnosed with PD in their lifetime. Moreover, presence of SN+ can also be found in other types of parkinsonism such as corticobasal degeneration or Wilson’s disease [8], suggesting that additional TCS markers such as basal ganglia hyperechogenicity and size of the ventricular system are also required for the differential diagnosis. Furthermore, skill and experience are necessary to perform the assessment adequately. And finally, in around 10-15% of the population the echogenicity of the SN cannot be assessed due to the lack of bone window which prevents passing of the ultrasound waves through the skull, and limits the usage of TCS [8].

Conclusion

Today, SN+ is recognized as a risk marker for future PD. However, the presence of SN+ should only be taken into account in combination with other risk and prodromal markers, as indicated by the MDS research criteria for prodromal PD.

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