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Background: SN hyperechogenicity (SN+), determined by transcranial sonography, has been proposed as a risk factor for Parkinson's disease (PD). Recently, we reported a 17.4-fold increased risk for PD in individuals with SN+ older than 50 years within 3 years., Methods: This is the second follow-up of a prospective, longitudinal, three-center observational study after 5 years. Of the initial 1,847 at baseline PD-free participants 50 years or older, 1,271 underwent the 5-year reassessment., Results: Within 5 years, 21 individuals developed incident PD. Participants with SN+ at baseline had a more than 20.6 times increased risk to develop PD in this time span than those without this echo feature., Conclusion: We thus confirm our finding of the 3-year follow-up examination in a longer observation time and higher number of individuals with incident PD and suggest SN+ as an important risk marker for PD., (Copyright © 2012 Movement Disorders Society.)

Objectives: To investigate the substantia nigra in patients with Parkinson's disease three-dimensional magnetic resonance spectroscopic imaging with high spatial resolution at 3 Tesla was performed. Regional variations of spectroscopic data between the rostral and caudal regions of the substantia nigra as well as the midbrain tegmentum areas were evaluated in healthy controls and patients with Parkinson's disease., Methods: Nine patients with Parkinson's disease and eight age- and gender-matched healthy controls were included in this study. Data were acquired by using three-dimensional magnetic resonance spectroscopic imaging measurements. The ratios between rostral and caudal voxels of the substantia nigra as well as the midbrain tegmentum areas were calculated for the main-metabolites N-acetyl aspartate, creatine, choline, and myo-inositol. Additionally, the metabolite/creatine ratios were calculated., Results: In all subjects spectra of acceptable quality could be obtained with a nominal voxel size of 0.252 ml. The calculated rostral-to-caudal ratios of the metabolites as well as of the metabolite/creatine ratios showed with exception of choline/creatine ratio significant differences between healthy controls and patients with Parkinson's disease., Conclusions: The findings from this study indicate that regional variations in N-acetyl aspartate/creatine ratios in the regions of the substantia nigra may differentiate patients with Parkinson's disease and healthy controls.

Much effort has been put in the identification of risk factors and pre-motor markers for Parkinson's disease (PD). In contrast to many of the pre-motor markers, SN hyperechogenicity (SN+) assessed by transcranial sonography (TCS) has been found to be conclusive for vulnerability for PD. In two centers in Germany 1204 individuals ≥50 years without the diagnosis of PD were recruited and the prevalence and relation of SN+ to a range of pre-motor markers was evaluated. SN+ was detected in 193 (16.0%) of 1204 subjects. Hyposmia (25.4%) was the most frequent sign in the cohort, followed by the occurrence of slight motor deficits. Male gender, positive family history of PD as possible risk factors and the pre-motor markers slight parkinsonian signs, one-sided reduced arm swing, and hyposmia were found to be significantly associated with SN+. The number of subjects who had more than one marker was significantly larger in the SN+ subgroup than in the non-hyperechogenic group (9.2% vs. 2.1%). Most of the discussed markers for PD seem to be unspecific with older age, but related to SN+. Co-occurrence of these markers is more probable in SN+ subjects. These findings may have implications for the design of high-risk cohorts for PD., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Objective: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population., Design: Longitudinal 3-center observational study with 37 months of prospective follow-up., Setting: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease., Participants: Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment., Main Outcome Measure: Incidence of new-onset PD in relation to baseline transcranial sonography status., Results: There were 11 cases of incident PD during the follow-up period. In participants with SN+ at baseline, the relative risk for incident PD was 17.37 (95% confidence interval, 3.71-81.34) times higher compared with normoechogenic participants., Conclusions: In this prospective study, we demonstrate for the first time a highly increased risk for PD in elderly individuals with SN+. Transcranial sonography of the midbrain may therefore be a promising primary screening procedure to define a risk population for imminent PD.

Friedreich's ataxia (FA) is a multisystemic degenerative disease, but the prevalence of restless legs syndrome (RLS) is unknown. FA patients might be particularly susceptible to develop RLS as FA presents with features commonly associated with RLS, e.g. multisystemic network dysfunction, peripheral neuropathy and disturbances in subcellular brain iron homeostasis. In this work, we assessed the following: (1) the prevalence of RLS; (2) the prevalence of sonographic hypoechogenicity of the substantia nigra (SN), which is known to be associated with idiopathic RLS; and (3) the relation between both in 28 FA patients. Thirty-two percent of the patients suffered from RLS, thus clearly exceeding the prevalence rate in the general population. SN hypoechogenicity was more frequent in FA patients (61%) compared to healthy controls (7%) and was significantly associated with RLS. However, as SN echogenicity also correlated inversely with disease severity, it seems to be related not only to RLS, but also to the neurodegenerative process in FA itself. The high prevalence of RLS in FA patients warrants specific assessment by neurologists involved in the care of FA patients as treatments are readily available. Similar to patients with idiopathic RLS, reduced SN echogenicity is a frequent finding in FA, possibly indicating regional changes in subcellular brain iron regulation in FA.

Background: Friedreich's ataxia (FA) is essentially characterized by degeneration of the dorsal root ganglia, the dorsal nuclei of Clarke, and the long spinal fiber tracts, yet there is accumulating evidence that neurodegeneration extends beyond these predilection sites. Transcranial sonography (TCS) has evolved as a valuable complementary neuroimaging tool in the assessment of neurodegenerative diseases due to its capacity to well depict structural changes and the accumulation of heavy metals. Its use for assessing cerebellar neurodegeneration, however, has not yet been investigated.Here we investigated whether TCS allows to assess particular features of cerebellar as well as midbrain and forebrain abnormalities in FA., Methods: Comprehensive TCS imaging of 34 FA patients and 34 age-matched healthy controls., Results: Hyperechogenicity of the dentate nucleus was very frequent in FA patients (85%) and could even be observed in patients with short disease duration, suggesting that dentate alterations are a common and probably early feature of FA. Substantia nigra was significantly hypoechogenic, possibly indicating regional changes in subcellular brain iron regulation. FA patients showed significantly enlarged 4th, 3rd, and lateral ventricles, thus corroborating earlier MRI and postmortem findings of substantial cerebellar and forebrain atrophy in FA., Conclusions: TCS provides a quick-to-apply and inexpensive in vivo assessment of both cerebellar and noncerebellar abnormalities in FA, in particular highlighting dentate hyperechogenicity as a core feature. It might serve as a promising tool for imaging aspects of cerebellar neurodegeneration also in other neurodegenerative disorders., (Copyright © 2011 S. Karger AG, Basel.)

Introduction: When scanning the size of the substantia nigra (SN), for example in Parkinson's disease, it is important to precisely locate its true anatomic location. The hypointense areas on T2-weighted magnetic resonance images (T2w) at the level of the upper midbrain are usually labeled as the SN. Recent studies showed that the line of demarcation between the SN and the crus cerebri (CC) in T2w images seems not to be clear. The purpose of our study was to evaluate the depiction of the SN and the CC on calculated R2 maps by analyzing the regional distribution of T2 values in both regions., Methods: In 36 healthy subjects, triple echo turbo spin echo were obtained at 1.5 T and R2 maps calculated. Proton density-weighted turbo spin echo images (PDw) were used as reference. The CC and SN were manually traced on PDw sections (CCP and SNP) and also the hyperintense areas on the R2 maps, suggestive of the SN (DT2). The obtained volumes were evaluated in terms of total size, intersections size, and residual areas, as well as the corresponding T2 values., Results: DT2 corresponded to anterolateral parts of the SNP and showed an extension to anteromedial part of the CC. The intersections between DT2 and CCP and DT2 and SNP presented both decreased but different T2 values (102 +/- 5 and 95 +/- 4 ms)., Conclusion: An exact differentiation of the SN from the CC is not possible on the basis of T2w images but rather on the basis of the underlying calculated T2 values from the triple echo sequence.

Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinson's disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross-sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined. The echostatus of the SN was assessed by TCS, motor performance by the Unified Parkinson's Disease Rating Scale (UPDRS) motor score, and olfactory function with Sniffin' Sticks. From the 1,603 subjects included in the analysis, 16.2% were SN+, 23.0% scored above zero in the UPDRS motor section, and 28.0% were hyposmic as defined by less than 75% correctly classified Sniffin' Sticks. SN+ was associated with a UPDRS motor score above zero (OR 1.45, 95% CI 1.08-1.96) and with a lower odor identification capability (OR 1.48, 95% CI 1.12-1.96). The combination of these two features (OR 1.98, 95% CI 1.25-3.15) and UPDRS motor scores >or=3 lead to higher OR. It is concluded that SN+, impaired motor performance, and hyposmia are frequently observed in the elderly and in isolation are unspecific and of limited use to predict a subject's risk for PD. Whether the association of SN+ with both impaired motor performance and hyposmia as seen in this study predicts an increased risk for the development of PD needs to be evaluated in the follow-up investigations., ((c) 2010 Movement Disorder Society.)

Substantia nigra (SN) hypoechogenicity assessed by transcranial B-mode sonography (TCS) is typical for idiopathic restless legs syndrome (RLS). Here, we investigated whether SN hypoechogenicity may differentiate between polyneuropathy (PNP) patients with and without RLS. Seventy-five patients with PNP, 65 healthy controls, and 75 patients with idiopathic RLS were investigated. A total of 41.2% patients with PNP additionally suffered from RLS. A total of 44.1% patients with PNP, 10.2% of healthy controls, and 91.2% of patients with idiopathic RLS exhibited SN hypoechogenicity. SN echogenicity did not differ significantly between PNP patients with and without RLS. Thus, TCS seems not suitable for the diagnosis of RLS in patients with PNP.

Transcranial sonography (TCS) is a valuable tool in the diagnosis of Parkinson's disease (PD). However, substantia nigra hyperechogenicity (SN+) in TCS has been shown to be also evident in about 8-10% of healthy persons. Neuroimaging studies and slight motor deficits in subjects with SN+ indicate functional impairment of the nigrostriatal system associated with the ultrasound sign. We questioned, whether SN+ may also be associated with neuropsychological deficits and whether there is a relation to other PD premotor markers. Thirty-six subjects with SN+ and 34 control persons (SN-) older than 50 years were investigated. The delayed verbal memory recall (LogII) of subjects with SN+ was significantly reduced compared to the performance of the control group (P=0.02). Binary logistic regression analysis revealed that, besides UPDRS-III (P<0.001) and positive family history for PD (P<0.01), LogII (P<0.05) seems to be independently associated with SN+.

Pathological studies demonstrate a decreased iron content in the substantia nigra (SN) contributing to the pathophysiology of restless legs syndrome (RLS). SN echogenicity as measured by transcranial sonography (TCS) correlates with the SN iron content. The objective of this study was to determine a critical value to define SN hypoechogenicity as a potential marker for RLS. There were 49 RLS patients (39 idiopathic, 10 secondary) and 49 age- and sex-matched controls who underwent TCS by 2 independent and blinded examiners to determine the area of SN echogenicity. We found that SN echogenicity is significantly decreased in RLS patients compared to healthy controls (P < 0.001). SN hypoechogenicity (sum area of SN echogenicity of both sides < 0.2 cm(2)) is more common in idiopathic than in secondary RLS patients. The area under curve for idiopathic RLS versus controls (receiver operating characteristics) is 0.91, specificity is 0.90, and sensitivity is 0.82. TCS provides an interesting additional instrument in the diagnosis of RLS. Therefore, SN hypoechogenicity (SN sum area < 0.2 cm(2)), which is supposed to indicate a decreased SN iron content, is a marker for RLS. Further studies are needed to investigate its significance for the pathophysiology of this frequent movement disorder and possible clinical applications., ((c) 2006 Movement Disorder Society.)

Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Using transcranial B-mode sonography (TCS), the first morphological marker for restless legs syndrome (RLS), hypoechogenicity of the substantia nigra (SN) has been found. The aim of this study was to validate SN hypoechogenicity as a morphological marker for RLS in a large patient cohort and to investigate further RLS-associated brain abnormalities using TCS. Methods: One hundred forty-three RLS patients (37 with symptomatic RLS) and 45 controls, matched for age and gender, underwent TCS by an experienced and independent rater who was blinded to clinical data. Results: The basal ganglia, ventricular system and cerebral lobes showed no RLS-specific abnormalities. SN hypoechogenicity correlated with a family history of RLS (p <0.001) and showed good sensitivity (82%), specificity (83%) and positive predictive value (94%). Red nucleus hyperechogenicity and brainstem raphe (BR) hypoechogenicity were more prevalent in RLS than in controls (both p <0.001) and correlated with reported periodic limb movements and depression, respectively (both p <0.001). Seventy-six percent of the patients (7% of controls) showed a co-occurrence of two or more sonographical abnormalities; 60% of symptomatic RLS patients showed the same sonographic features as the majority of RLS patients. Conclusions: TCS is a useful additional tool for diagnosing RLS and RLS-related disorders that demonstrate various brainstem abnormalities. [Copyright &y& Elsevier]

Summary: Background: Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinson''s disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made. Methods: 60 patients who presented with the first, but still unclear, clinical symptoms of parkinsonism had TCS in this prospective blinded study. Investigators were blinded to the results of the clinical investigations, the ultrasound findings, and the diagnosis at time of investigation. The patients were followed-up every 3 months for 1 year to assess and re-evaluate the clinical symptoms. The patients in whom a clinical diagnosis could not be made with certainty were investigated with raclopride PET or dopamine transporter single-photon emission computed tomography (SPECT), or both. Findings: A clinical diagnosis of parkinsonism could not be established at baseline in 38 patients. At 12 months, 39 patients were clinically categorised as having iPD. Compared with endpoint diagnosis, the sensitivity of TCS at baseline was 90%7% and the specificity was 82·4%; the positive predictive value of TCS for iPD was 92·9% and the classification accuracy was 88·3%. Interpretation: TCS is an easy to implement, non-invasive, and inexpensive technique that could help in the early differential diagnosis of parkinsonian syndromes. The routine use of TCS in the clinic could enable disease-specific therapy to be started earlier. Funding: Michael J Fox Foundation for Parkinson''s Research. [Copyright &y& Elsevier]