Vulnerability of the nigrostriatal system as detected by transcranial ultrasound.

OBJECTIVE: To assess the incidence of a hyperechogenic substantia nigra (SN) by transcranial sonography (TCS) in healthy people and to evaluate whether an enlarged hyperechogenic SN area is associated with functional impairment of the nigrostriatal system. BACKGROUND AND METHODS: Until now, preclinical impairment of the nigrostriatal system could be identified only by functional neuroimaging techniques such as PET in selected groups of patients. TCS is a new, noninvasive ultrasound technique that has demonstrated an increased echogenicity of the SN in patients with PD, whereas in most healthy individuals, the SN is either barely detectable or undetectable by TCS. RESULTS: Of 330 healthy volunteers, 8.6% exhibited an increased echogenicity of the SN. From these, 10 clinically healthy individuals with distinct unilateral or bilateral hyperechogenic signals in the SN region (SN area above 0.25 cm2) underwent comprehensive motor testing, neuropsychological assessment, MRI, and [18F]-dopa PET examination. With regard to motor functions, these individuals did not differ from 10 age- and sex-matched controls with a low echogenic SN and an area of echogenic signals below 0.2 cm2. Enlargement of hyperechogenic areas in the 10 healthy individuals was associated with a marked decrease in the accumulation of [15F]-dopa in the caudate nucleus and putamen. CONCLUSIONS: Substantia nigra hyperechogenicity appears to indicate a functional impairment of the nigrostriatal system. Transcranial sonography may be a suitable method of identifying persons at risk of nigrostriatal alterations, making possible the introduction of early neuroprotective therapy.     

Relationship of substantia nigra echogenicity and motor function in elderly subjects

BACKGROUND: Patients with Parkinson's disease (PD) exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography. Some healthy adults with the same echo characteristics showed a reduced 18fluorodopa uptake on PET, indicating a subclinical alteration of the nigrostriatal system. OBJECTIVES: To determine whether the sonographic phenotype of hyperechogenic SN has any relevance for motor function in elderly subjects and whether an increased echogenicity of the SN is associated with an impaired motor function. METHOD: In a population-based, cross-sectional study, 93 subjects older then 60 years without history of extrapyramidal disorder underwent sonographic and neurologic examinations, with a quantitative motor assessment. RESULTS: Elderly healthy subjects without prediagnosed extrapyramidal disorder but with SN hyperechogenicity had more frequent and more severe parkinsonian symptoms and a slower finger tapping than those with a regular echogenicity of the SN (p < 0.05, U test). CONCLUSION: With increasing age, subjects with SN hyperechogenicity develop a more substantial slowing of movements than subjects without this echo pattern, stressing the functional relevance of this sonographic finding. The authors speculate that hyperechogenicity of the SN may be detected by transcranial sonography early in life and may serve as a risk marker for nigral injury, although only a minority of these subjects will develop the full clinical picture of PD.     

Echogenicity of substantia nigra determined by transcranial ultrasound correlates with severity of parkinsonian symptoms induced by neuroleptic therapy.

BACKGROUND: Increased echogenicity of the substantia nigra (SN) detected by transcranial sonography is a characteristic ultrasound feature of Parkinson's disease. This ultrasound feature can also be detected in a subgroup of healthy adults. In recent studies, healthy subjects with this ultrasound feature showed a reduced [(18)F]-Dopa uptake on positron emission tomography (PET), indicating a subclinical alteration of the nigrostriatal system. This study was designed to evaluate whether the severity of neuroleptic side effects is related to the echo-feature of the SN. METHODS: In the retrospective part of the study, 93 psychiatric patients with either definite and severe parkinsonism after neuroleptic treatment (n = 52) or with no or minimal parkinsonian symptoms (n = 41) were included and underwent transcranial sonography to measure the extension of hyperechogenic areas at the SN. In addition, in the prospective part 11 patients with an acute psychotic episode requiring first-ever neuroleptic treatment underwent ultrasound examination. Subsequently, neuroleptic-induced parkinsonian signs were assessed prospectively. RESULTS: In the retrospective part of the study, patients with severe neuroleptic-induced parkinsonism had more extended echogenic signals at the SN than those with low echogenic SN (U-test; p <.01). The prospective part of the study showed that the severity of parkinsonian symptoms correlated with the echogenicity of the substantia nigra (Spearman's rank: p <.01). CONCLUSIONS: Increased echogenicity of the substantia nigra is associated with impaired function of the nigrostriatal system that can be disclosed by neuroleptic drugs.     

Substantia nigra hyperechogenicity as a marker of predisposition and slower progression in Parkinson's disease.

Increased echogenic size (hyperechogenicity) of the substantia nigra (SN) is a characteristic transcranial sonography finding in patients with Parkinson's disease (PD). The SN echogenic size does not change in the course of the disease. In order to see whether this stable ultrasound marker may give any implications for the rate of PD progression, we sonographically investigated 16 PD patients in whom the rate of progression had been determined by serial 18-fluorodopa positron emission tomography over a follow-up period of 65.7+/-26.7 months. We found a significant negative correlation between the right-to-left averaged SN echogenic size and the rate of disease progression in the caudate nucleus and in the putamen. There was a tendency towards a younger age at symptom onset in patients with SN hyperechogenicity. It may therefore be hypothesized that a differing influence of factors determining SN echogenicity early in life and impairing forces occurring later in life may account for different pathogenetic subgroups of idiopathic PD.     

Transcranial midbrain sonography in narcoleptic subjects with and without concomitant REM sleep behaviour disorder

Substantia nigra (SN) hyperechogenicity—a sonographic vulnerability marker for Parkinson’s disease (PD)—has been recently described in patients with idiopathic REM sleep behaviour disorder (RBD). It is not known whether subjects with narcolepsy (who frequently have associated RBD) also show SN hyperechogenicity. The aim of this study was to (1) evaluate SN echogenicity in narcolepsy and (2) determine whether transcranial sonography (TCS) differs in narcoleptic subjects with and without RBD. A total of 16 patients with narcolepsy–cataplexy (7 had a concomitant, video-polysomnographically based diagnosis of RBD) were examined with TCS by two investigators blinded to the clinical data. The size of the SN echogenic area in both subgroups was within the range previously described for healthy subjects. The brainstem raphe, however, was reduced in five of seven narcoleptic subjects with RBD, whereas only two of nine narcoleptic subjects without RBD exhibited this TCS finding. We conclude that evaluation of SN echogenicity does not discriminate between both subgroups. The absence of SN hyperechogenicity in narcoleptic patients with RBD supports the hypothesis that SN hyperechogenicity in patients with presumed idiopathic RBD is an additional risk marker for subsequent evolvement of PD rather than an RBD-immanent finding. Reduced echogenicity of the brainstem raphe might indicate an involvement of the serotonergic system in narcoleptic subjects with RBD. W.H. Oertel and G. Mayer contributed equally to this work.     

Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder

Objectives

Transcranial sonography (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in people with Parkinson’s disease and in approximately 10% of healthy subjects. It is hypothesized that SN hyperechogenicity in healthy subjects and patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) patients is a marker of vulnerability for Parkinson’s disease.

Methods

TCS and positron emission tomography (PET) with 6-[¹⁸F] fluoro-meta-tyrosine (FMT), which can assess the level of the presynaptic dopaminergic nerve, were performed in 19 male patients with iRBD, mean age 66.4 (standard deviation [SD] 4.9) years, to assess nigrostriatal function.

Results

Nine patients had pathological SN hyperechogenicity (mean age 66.8 [SD 3.9] years; 0.31 [SD 0.12] cm²) and 10 patients did not have SN hyperechogenicity (mean age 66.0 [SD 5.8] years; 0.11 [SD 0.06] cm²). FMT uptake at the putamen and caudate was significantly lower in iRBD patients with pathological SN hyperechogenicity compared with those without SN hyperechogenicity. However, no correlation was found between SN echogenicity and FMT uptake. This is in conflict with previous findings which showed that subjects with hyperechogenicity had lower FMT uptake in the striatum.

Conclusion

Pathological hyperechogenic alterations in the SN in patients with iRBD may suggest the existence of preclinical SN dysfunction as determined by FMT-PET.     

Five‐year follow‐up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder

Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson's disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow‐up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty‐one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 ± 0.09 cm² vs. 0.19 ± 0.07 cm²; P = 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P = 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow‐up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains stable over time. © 2014 International Parkinson and Movement Disorder Society     

Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease

BackgroundSeveral studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients.MethodsWe performed TCS in 30 subjects and SPECT with [^99mTc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [^99mTc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared.ResultsThere were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere.ConclusionIncrease in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism.     

Brain parenchyma sonography detects preclinical parkinsonism.

Substantia nigra (SN) hyperechogenicity on brain parenchyma sonography (BPS) is highly characteristic for idiopathic PD. We studied 7 symptomatic and 7 asymptomatic parkin mutation carriers (PMC) from a large kindred with adult-onset parkinsonism. BPS revealed larger SN echogenic sizes in PMC with parkin mutations on both alleles (homozygous, compound-heterozygous), compared to PMC with only one mutated allele (Mann-Whitney U test, P = 0.007). In symptomatic PMC, larger SN echogenic size was correlated with younger age at onset of the disease (Spearman rank correlation, Rho = -0.937, P = 0.002) but not with age, disease duration, or disease severity. BPS demonstrated SN hyperechogenicity, in concordance with abnormal nigrostriatal (18)F-dopa positron emission tomography (PET), in all symptomatic and 3 asymptomatic PMC. In 2 asymptomatic PMC, PET and BPS were normal. However, in another 2 asymptomatic PET-normal PMC, SN hyperechogenicity could be detected. Data suggest SN hyperechogenicity as an early marker to detect preclinical parkinsonism.     

Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease

Summary. Transcranial sonography (TCS) revealed substantia nigra (SN) hyperechogenicity in idiopathic Parkinson's disease (IPD). To further evaluate specificity of this finding, we examined 30 IPD patients and 30 age-matched subjects with non-extrapyramidal cerebral disorders (NED). All IPD patients showed a SN hyperechogenicity, in 17 it was bilateral and in 13 unilateral. 7 NED patients had a SN hyperechogenicity, in all it was unilateral, confirming previous results in healthy subjects. Bilateral SN hyperechogenicity indicates IPD and normal SN echogenicity indicates NED. In 30% of patients TCS does not distinguish between IPD and NED. Data further support the assumption that bilateral SN hyperechogenicity is specific for IPD. Received April 30, 2001; accepted October 17, 2001     

Substantia nigra hyperechogenicity correlates with subtle motor dysfunction in tap dancers

Hyperechogenicity of the substantia nigra (SN) detected by transcranial sonography is a typical finding in more than 90% of patients with Parkinson's disease (PD) but may also be visible in about 9% of healthy adults. In this study, we found a correlation between SN hyperechogenicity and subtle motor dysfunction in otherwise healthy young tap dancers. In accordance with former findings, results of the present study confirm the hypothesis that SN hyperechogenicity is a marker for a possible functional impairment of the nigrostriatal system, that may become evident under challenging conditions.     

In vivo detection of iron and neuromelanin by transcranial sonography – a new approach for early detection of substantia nigra damage

Summary. In more than 90% of patients with idiopathic Parkinson’s disease (PD) hyperechogenicity of the substantia nigra (SN) can be found by transcranial sonography (TCS) as a typical, stable sign. Animal experiments provided first evidence that SN hyperechogenicity may be associated with increased tissue iron levels. Two consecutive studies revealed the same association in human brain. Postmortem brains of 60 subjects without clinical signs for Parkinson’s disease during life time at different ages were scanned by ultrasound with planimetric measurement of the echogenic area of the SN. Afterwards the SN was dissected and used for histological examination and determination of iron content in all brains as well as ferritin and neuromelanin content in 40 brains. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. A multivariate analysis performed considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. Iron staining confirmed the biochemical findings. In PD a typical loss of neuromelanin and increase of iron is observed in this brain area. However, it is not clear yet, whether iron accumulation is a primary cause or a secondary phenomenon in the disease process. Screening of genes involved in brain iron metabolism showed a significant association of some sequence variations of the ceruloplasmin gene with PD. Others were associated with the ultrasound marker for increased iron levels in both PD patients and control subjects. As SN hyperechogenicity is typical for PD or subjects with a preclinical impairment of the nigrostriatal system, these findings indicate that TCS enables the detection of increased iron and decreased neuromelanin levels at the SN, even before the clinical manifestation of PD.     

Transcranial ultrasound in different monogenetic subtypes of Parkinson's disease

Abstract Hyperechogenicity of the substantia nigra (SN) has been found to be a typical sign in idiopathic Parkinson's disease (PD), prevalent in more than 90% of affected individuals. To see whether SN hyperechogenicity is also characteristic for monogenetically caused PD, we investigated PD patients with alpha-synuclein, LRRK2, parkin, PINK1 and DJ-1 mutations by transcranial sonography (TCS). In all these patients the area of SN echogenicity was significantly larger than in healthy controls, but smaller, than in idiopathic PD. As SN hyperechogenicity could be related to an increased iron content of the SN, these findings suggest that iron may play a less significant role in the pathogenesis of monogenetically caused compared to idiopathic PD.     

Ultrasound in the (premotor) diagnosis of Parkinson's disease

A number of independent studies provide evidence that transcranial sonography (TCS) is helpful in the diagnosis of idiopathic and monogenetic Parkinson's disease (PD). In the clinical setting, it may exclude a number of secondary or atypical parkinsonian syndromes at very early stages. TCS may additionally depict morphological alterations of symptoms associated with PD motor features like midline alterations in PD-associated depression. Importantly, substantia nigra (SN) hyperechogenicity, the typical ultrasound marker of PD, can also be found in approximately 9% of healthy subjects. PET studies and conditions challenging the dopaminergic system indicate that this stable ultrasound feature has a functional relevance. Ongoing longitudinal studies test the hypothesis that SN hyperechogenicity is a risk marker for nigrostriatal vulnerability.     

Transcranial brain sonography in Parkinson's disease with restless legs syndrome

Substantia nigra (SN) hyperechogenicity assessed by transcranial brain sonography (TCS) is a characteristic finding in idiopathic Parkinson's disease (PD). In contrast, SN hypoechogenicity on TCS has been recently demonstrated in restless legs syndrome (RLS). RLS is one of the most common sleep problems in PD, but the pathophysiologic relationship between these two disorders has not been thoroughly elucidated. We compared the SN echogenicities of PD patients with and without RLS to investigate whether comorbid RLS in PD affects SN echogenicity and to explain the echogenic differences between idiopathic RLS (iRLS) and secondary PD–related RLS (pRLS). Sixty‐three PD patients (median age 64.6 ± 10.6 years), 40 iRLS patients (53.1 ± 11.7 years), and 40 healthy controls (69.1 ± 2.3 years) were enrolled in our study. All subjects answered a sleep questionnaire and underwent TCS. PD patients were subdivided into two groups, PD with RLS (PD+RLS, n = 26) and PD without RLS (PD‐RLS, n = 37), and the sonographic findings of each group were compared. Although significant hyperechogenicity was detected in both the SN and SN/midbrain ratios in both PD subgroups compared with the controls and the iRLS group (P < 0.001), there were no significant differences in SN echogenicity between the PD+RLS and PD‐RLS groups. Meanwhile, iRLS patients showed significant SN hypoechogenicity. In conclusion, comorbid RLS in PD did not have an impact on the sonographic SN findings. These results suggest that the pathogenesis of pRLS and iRLS involve different mechanisms. Further study will be required to clarify the association between RLS and PD. © 2010 Movement Disorder Society     

Transcranial sonography in spinocerebellar ataxia type 2

Objective   To study the use of transcranial brain parenchyma sonography (TCS), in particular the echogenic signal in the substantia nigra (SN), in patients with spinocerebellar ataxia type 2 (SCA2), recently recognized as an uncommon cause of parkinsonism. Methods   Six consecutive and unrelated SCA2 patients without parkinsonian signs, 30 consecutive patients with Parkinson’s disease (PD), and 30 healthy, age- and sexmatched controls were prospectively studied with TCS according to a standardized protocol. Results   Four (67 %) of the six SCA2 patients exhibited SN hyperechogenicity. In two patients, the hyperechogenicity was classified as moderate (unilateral in both) and in two as marked. Differences between the SN echogenicity of the SCA2 group or the PD group and controls were statistically significant (p < 0.001), while there was no difference between the two groups of patients. Conclusions   Transcranial brain parenchyma sonography detects SN hyperechogenicity in the majority of patients with SCA2 without parkinsonian signs. It would be important to reproduce our TCS findings in a larger number of SCA2 patients, as well as to test their possible significance in differentiating SCA2 from other types of SCA.     

Substantia nigra echogenicity and imaging of striatal dopamine transporters in Parkinson's disease: A cross-sectional study

Approximately 10% of patients with a presumed diagnosis of Parkinson's disease (PD) remain misdiagnosed despite recent advances in neuroimaging. The current study addresses the use of transcranial sonography and single-photon emission computed tomography (SPECT) using ^99mTc-TRODAT-1 to evaluate the echogenicity of the substantia nigra (SN) and the density of striatal presynaptic dopamine transporters, respectively, in a sample of 20 PD patients (13 males and 7 females) and 9 healthy subjects. The median age of the PD patients was 62 years. The median age at disease onset was 56 years, and the median disease duration was 5 years. The SN echogenic area was larger in PD patients than healthy subjects. The cut-off value of 0.22 cm² for the SN echogenic area was associated with 100% sensitivity and 78% specificity for the diagnosis of PD. Striatal and putaminal ^99mTc-TRODAT-1 binding was lower in PD patients than healthy subjects. The cut-off value of 0.90 for the striatal ^99mTc-TRODAT-1 binding was associated with 100% sensitivity and an 89% specificity for the diagnosis of PD, and the cut-off value of 0.76 for putaminal ^99mTc-TRODAT-1 binding was associated with an 85% sensitivity and an 89% specificity. The size of the SN echogenic area did not correlate with the degree of striatal ^99mTc-TRODAT-1 binding in PD patients. In conclusion, both SN hyperechogenicity and decreased striatal or putaminal ^99mTc-TRODAT-1 binding constitute surrogate markers for differentiating PD patients from healthy individuals with a slightly higher diagnostic specificity of ^99mTc-TRODAT-1 SPECT.     

Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson's disease.

Using transcranial sonography, an area of hyperechogenicity at the substantia nigra (SN) may be detected as a typical marker in patients with Parkinson's disease (PD) as well as in approximately 9% of healthy subjects vulnerable to nigrostriatal impairment. In this longitudinal study, we provide evidence that the area of SN hyperechogenicity does not change in the course of PD. In conjunction with earlier findings in children and adolescents, this evidence indicates that, from late adolescence onward, this ultrasound finding is a trait marker for nigrostriatal vulnerability.     

Substantia nigra hyperechogenicity in healthy controls: a [18Fluoro] Dopa-PET follow-up study

In order to assess nigrostriatal function over time in healthy subjects with substantia nigra hyperechogenicity (SN+) believed to be at higher risk for Parkinson’s disease (PD), ten healthy SN+ subjects underwent [¹⁸Fluoro] Dopa positron emission tomography (PET) twice—at baseline and after a mean of 7.3 years. Neurological examination took place at study inclusion followed by a structured telephone interview focusing on early Parkinsonian symptoms at the time point of second PET study and 3.5 years later. The [¹⁸Fluoro] Dopa uptake remained unchanged in eight of ten participants. In the other two subjects marked unilateral reduction of putaminal [¹⁸Fluoro] Dopa uptake ratios appeared over the time, followed by complaints of a clinically manifest PD in one. We suggest that the progressive pathological PET findings in 20 % and PD conversion in 10 % of our cohort may be in accordance with the presumed proportion of SN+ individuals eventually developing PD based on SN+ prevalence of 10 % within the healthy population, being ten times higher than PD prevalence in the age of over 60 years. Our findings hint towards a significance of SN+ indicating a high risk for PD in some extrapyramidally healthy SN+ individuals.     

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.