Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury

BACKGROUND: Patients with Parkinson disease characteristically exhibit an increased echogenicity of the substantia nigra (SN) on transcranial sonography, a new neuroimaging technique. The same echo feature of the SN can be identified in 9% of healthy adults. OBJECTIVE: To evaluate the relevance of the echogenic SN in healthy adults. DESIGN: In the first part of the study, 10 healthy subjects younger than 40 years with a distinct SN hyperechogenicity underwent extensive neurological, motor, neuropsychological, and fluorine 18-dopa positron emission tomographic ([18F]-dopa PET) examinations. Results were compared with those of 10 subjects with a low echogenic SN. In the second part of the study, the postmortem brains of 20 patients without extrapyramidal disorders during their lifetime were sonographically examined with a particular focus on SN echogenicity. Subsequently, one half of the brain was prepared for heavy metal analysis, the other for a histological examination. RESULTS: Healthy subjects with SN hyperechogenicity exhibited a significant reduction of the [18F]-dopa uptake, especially in the putamen (Wilcoxon matched pair test: left side, P =.006; right side, P =.009), whereas their neuropsychological and motor performance were normal. Postmortem studies showed that the echogenicity of the SN correlated with its iron content. CONCLUSIONS: Increased echogenicity of the SN, characteristically seen in Parkinson disease, is related to a functional impairment of the nigrostriatal system (even in young healthy adults) that can be revealed by [18F]-dopa PET studies. Substantia nigra hyperechogenicity is related to a higher tissue iron level, which is known to enhance the cells' generation of reactive oxygen specimens. Therefore, we hypothesize that transcranial sonography may identify a susceptibility marker for the development of nigral injury that can be detected early in life, prior to the onset of Parkinson disease.     

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.     

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.     

Differences in substantia nigra echogenicity of nosological subtypes within the schizophrenic spectrum. A preliminary transcranial ultrasound study.

OBJECTIVE: Schizophrenic patients treated with neuroleptic drugs often develop neuroleptic-induced parkinsonism (NIP). Here, transcranial sonography (TCS) was used to test for differences in the susceptibility to NIP related to the echogenicity of the substantia nigra (SN) in different schizophrenic subforms. METHODS: 79 patients with schizophrenic spectrum psychoses treated by neuroleptic drugs and diagnosed according to ICD-10 and Leonhard's nosology were examined independently by TCS and, clinically, for NIP. RESULTS: Patients with larger echogenic SN had more severe NIP (p < 0.05). Diagnostic categories according to ICD-10 did not differ significantly in SN echogenicity (p > 0.2), whereas Leonhard's did (p < 0.05). CONCLUSIONS: These findings suggest altered SN echogenicity in subtypes of the schizophrenic spectrum. The putative role of the nigrostriatal system in the etiology of schizophrenic subtypes is discussed.     

Transcranial sonography in the early and differential diagnosis of Parkinson's disease

In recent years transcranial sonography (TCS) has become a widely used method for the visualization of the brain parenchyma through the intact scull. Using TCS, our group discovered changes of the echotexture--namely increased echogenicity--at the substantia nigra (SN) in about 90% of patients with Parkinson's disease (PD). These results assessed with an interrater reproducibility of r = 0.8 in several studies have been confirmed by several other groups. In contrast increased SN echogenicity is rarely found in patients with atypical or symptomatic Parkinsonian syndromes, providing a valuable tool for differential diagnosis. Interestingly, increased SN echogenicity can also be found in about 8 to 10% of healthy subjects. In PET analyses more than 60% of these clinically healthy individuals show a subclinical reduction of the striatal 18F-Dopa uptake indicating an alteration of the dopaminergic nigrostriatal system and nigral cell loss. Furthermore, it was possible to demonstrate that this ultrasound finding has a functional impact as subjects with an increased echogenicity of the SN (i) showed more frequently clinical symptoms of asymmetric hypokinesia with increasing age and (ii) developed more often and more severe Parkinsonian side effects when treated with neuroleptic therapy for neuropsychiatric disorders. Longitudinal studies indicate that the ultrasound signal does not change in the course of the disease. Moreover, presymptomatic carriers of mutations causative for monogenetic PD display the same echofeature as their relatives already affected by the disease. These findings indicate that increased SN echogenicity constitutes a biomarker for vulnerability of the nigrostriatal system in healthy subjects and eventually PD in a subgroup of persons with additional risk factors.     

Hyperechogenicity of the Substantia Nigra in Parkinson''s Disease

Substantia nigra (SN) was assessed by transcranial sonography (TCS) in 47 Parkinson's disease (PD) patients and in 39 healthy volunteers. A semiquantitative echogenicity scale was created with arbitrary values ranging from 1 to 5, zones with grade >or=3 and larger than 0.19 cm(2) were recorded as hyperechogenic SN. TCS examination of SN as a diagnostic test for PD in our study showed 87.2% sensitivity and 94.9% specificity.     

Susceptibility to neuroleptic-induced parkinsonism--age and increased substantia nigra echogenicity as putative risk factors.

OBJECTIVE: Patients treated by neuroleptics often develop neuroleptic-induced parkinsonism (NIP) to a varying extent. The reasons for this are discussed controversially in the literature. Previous transcranial sonography (TCS) findings of the substantia nigra (SN) in patients with idiopathic Parkinson's disease suggest a correlation of echogenicity with nigrostriatal dysfunction. METHOD: One hundred psychiatric patients receiving neuroleptics were included. They underwent clinical examination for NIP (Simpson and Angus-scale) and, independently, TCS of the SN. History of smoking habits and medication were taken from the patient's chart. RESULTS: We found a significant positive association of the prevalence of NIP with age (P < 0.01) and the echogenic area of the SN (P < 0.05). Neither type nor dosage of the neuroleptics was found to have any significant impact on the occurrence of NIP. Smokers displayed lower prevalence of NIP (P < 0.05) and lower EPS scores (P < 0.01). CONCLUSIONS: These findings suggest that age and increased size of SN echogenicity are possible risk factors for NIP. In contrast, smoking seems to have a certain protecting effect.     

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.     

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.     

Substantia nigra hyperechogenicity assessed by transcranial sonography is related to neuropsychological impairment in the elderly population

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+.     

Substantia nigra echogenicity: A structural correlate of functional impairment of the dopaminergic striatal projection in Parkinson's disease

Transcranial sonography (TCS) reveals abnormal spatial extension of substantia nigra (SN) echogenicity in a high proportion of patients with Parkinson's disease (PD). It has been proposed that this abnormality represents a structural trait that is mechanistically distinct from degeneration of dopaminergic nigrostriatal projection neurons. We sought to clarify the relationship between sonographic abnormalities of SN and dysfunction of striatal dopaminergic neurotransmission. We studied 50 patients with PD. The spatial extension of the echogenic SN area was compared with the activity of presynaptic striatal dopamine reuptake transporters, assessed in the same patients by I‐123‐2‐beta‐carbomethoxy‐3‐beta‐(4‐iodophenyl)‐tropane (β‐CIT) single‐photon emission computed tomography (SPECT). Extension of echogenic SN area correlated (inversely) with striatal activity of presynaptic dopamine reuptake transporter in PD patients (R = ?0.417; P = 0.003) and with the equivalent levodopa dose (R = 0.380; P = 0.006; linear regression analysis). Findings support the hypothesis that in PD abnormal extension of echogenic SN area provides a direct structural marker of degeneration of SN neurons. Therefore, in PD, TCS and β‐CIT assess pathophysiologically related phenomena. © 2009 Movement Disorder Society     

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.     

Echogenic substantia nigra in patients with orthostatic tremor

Summary. Objectives: Previous studies suggest that the nigrostriatal dopaminergic transmission is impaired in patients with primary orthostatic tremor. Methods: We used transcranial sonography (TCS) to examine the morphology of the substantia nigra (SN) in four patients with primary orthostatic tremor (OT). Results: TCS revealed an SN echogenicity in all patients, in three patients unilaterally, in one patient bilaterally. Conclusions: Our data suggest nigrostriatal dopaminergic deficits in OT patients. The exact impact of these dopaminergic deficits on OT generation is unclear.     

Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome.

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.     

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.     

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.     

Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings

Recently an increased echogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD) was demonstrated by transcranial ultrasound (TCS). In this study we set out to compare SN echogenicitiy with disease characteristics (time of onset, duration, toxin exposure) in a large patients sample. Patients' history and exposure to toxins were recorded from 112 PD patients who underwent a thorough neurological examination including assessment of disease stage according to Hoehn and Yahr and CURS (Columbia University Rating Scale). Personality was assessed according to the Freiburg Personality Inventory. In all patients the area of SN echogenicity was encircled and measured by TCS. All except 9 patients had hyperechogenic SN areas exceeding the mean plus standard deviation values of an age matched control group (0.19cm²). The age of disease onset was lower in patients who displayed an area of SN echogenicity above this value. The area of SN echogenicity was larger contralateral to the side with more severe symptoms. None of the other characteristics correlated with ultrasound findings. We conclude that SN hyperechogenicity is a typical finding in PD. The cause of hyperechogenicity is so far unknown. Investigation of the underlying reason might disclose a pathogenic factor in PD. Received: 13 November 2000 / Received in revised form: 24 January 2001 / Accepted: 19 February 2001     

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

Early diagnosis of Parkinson's disease (PD) in nonsymptomatic patients is a key issue. An increased echogenicity of the substantia nigra (SN) was found previously in Parkinsonian patients and in a low percentage of healthy adults. These nonsymptomatic subjects also showed a reduced 18F-dopa uptake in striatum, suggesting a preclinical injury of the nigrostriatal system that could later proceed into PD. To investigate the ability of ultrasonography to detect markers of SN degeneration, such as iron deposition and neuromelanin depletion, we scanned postmortem brains from normal subjects at different ages by ultrasound and measured the echogenic area of the SN. The SN was then dissected and used for histological examinations and determination of iron, ferritin, and neuromelanin content. A significant positive correlation was found between the echogenic area of the SN and the concentration of iron, H- and L-ferritins. Multivariate analysis carried out considering the iron content showed a significant negative correlation between echogenicity and neuromelanin content of the SN. In PD, a typical loss of neuromelanin and increase of iron is observed in this brain area. The finding of a positive correlation between iron and ferritin levels and a negative correlation of neuromelanin content with the area of echogenicity at the SN could therefore provide an interesting basis for diagnosis and therapeutic follow-up studies in PD.     

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.