Substantia Nigra Hyperechogenicity Research Articles

Assessment of Substantia Nigra Echogenicity in German and Filipino Populations Using a Portable Ultrasound System

Transcranial sonography of the substantia nigra for diagnosing premotor stages of Parkinson disease has been attracting increasing interest. Standard reference values defining an abnormal increased echogenic size (hyperechogenicity) of the substantia nigra have been established in several populations using high-end stationary ultrasound systems. It is unknown whether a portable ultrasound system can be appropriately used and how the Filipino population would compare with the well-studied white population. We prospectively studied substantia nigra echogenic sizes and third ventricle widths in 71 healthy adult German participants and 30 age- and sex-matched Filipino participants using both a well-established stationary ultrasound system (in the German cohort) and a recently distributed portable ultrasound system (in both ethnic cohorts). Mean substantia nigra echogenic sizes, cutoff values defining abnormal hyperechogenicity, and intra-rater reliability were similar with both systems and in both ethnic cohorts studied. The Filipino and German participants did not differ with respect to the frequency of insufficient insonation conditions (each 3%) and substantia nigra hyperechogenicity (10% versus 9%; P = .80). However, third ventricle widths were smaller in the Filipino than the German participants (mean ± SD, 1.6 ± 1.1 versus 2.4 ± 1.0 mm; P = .004). The frequency of substantia nigra hyperechogenicity appears to be homogeneous in white and Asian populations. Screening for this feature may well be performed with a present-day portable ultrasound system.

Transcranial sonography (TCS) in Parkinson's disease (PD) and essential tremor (ET) in relation with putative premotor symptoms of PD

Background: Hyperechogenicity of substantia nigra (SN+) is a common finding in transcranial ultrasound studies of parkinsonian patients. However, this feature is also found in 13–16% of ET patients. The possible links between ET and PD are of special interest, particularly with the familial aggregated data supporting this association. However, few studies have been conducted regarding the factors associated with the emergence of PD in the ET population. In this study, we investigated the possible association between SN+ and putative premotor symptoms of PD in patients with ET. Methods: A total of 47 patients with PD and 64 patients with ET were enrolled in the study. All patients underwent TCS and completed a structured interview for putative premotor symptoms of PD. Results: As expected, there were significant differences observed in the frequency and size of SN+, and the prevalence of the putative premotor symptoms of PD. More interestingly, in the ET group a significant association between SN+ and each premotor symptom was observed and a trend was also found that ET cases with more putative premotor symptoms of PD had a greater size of SN+. In contrast, in the PD group, SN+ was not influenced by the cumulative effect of premotor symptoms. Conclusion: The results of this study suggest that SN+ in patients with ET is influenced by the putative premotor symptoms of PD.

No correlation of substantia nigra echogenicity and nigrostriatal degradation in Parkinson's disease

Substantia nigra hyperechogenicity assessed by transcranial sonography is a typical finding in up to 90% of patients with idiopathic Parkinson's disease, although its value as a surrogate marker for disease progression in Parkinson's disease is controversial. (123) I-FP-CIT-single photon emission computed tomography (SPECT) represents an established paraclinical surrogate marker to quantify the nigrostriatal dopaminergic deficit in Parkinson's disease. Whereas most studies found no correlation between extent of substantia nigra echogenicity and the putaminal FP-CIT binding ratio, a more recent analysis reported opposite results. In 92 patients with Parkinson's disease the substantia nigra echogenicity was compared with the putaminal FP-CIT binding ratio using an investigator-independent SPECT analysis protocol and with several clinical parameters. No correlation was found between the substantia nigra hyperechogenicity and the FP-CIT binding ratio or the disease severity. Substantia nigra hyperechogenicity does not reflect the degree of the nigrostriatal degeneration or the clinical state of the disease progression.

パーキンソン病とその関連疾患における経頭蓋超音波検査を用いた黒質高輝度変化のGray Scale Medianを応用した半定量的評価の検討

パーキンソン病とその関連疾患における経頭蓋超音波検査を用いた黒質高輝度変化のGray Scale Medianを応用した半定量的評価の検討

Transcranial sonography on Parkinson’s disease and essential tremor in a Chinese population

We analyzed the results of transcranial sonography (TCS) on 110 Parkinson's disease (PD) patients, 30 essential tremor (ET) patients and 110 controls in a Chinese population and compared our findings to the previous literatures. The echo signal intensity of midbrain substantia nigra (SN) was measured and divided into grade I-V. If the high echo signal intensity (grade III, IV or V) was detected in either side of SN, it was measured as well as the whole area of midbrain and the ratio of both sides of SN hyperechogenicity to the whole area of midbrain (S/M) were calculated. In addition, the width of the third ventricle in the level of thalamus was also determined. There were more individuals with the grade of SN ≥ III in PD group (100/110, 85.45%) than these in ET group (4/30, 13.33%, x ( 2 ) = 58.38, P < 0.001) and control group (11/110, 10%, x ( 2 ) = 125.51, P < 0.001). The median and quartile range of SN hyperechogenicity area and S/M in PD patients were greater than those in ET patients and controls. Both the area of SN hyperechogenicity ≥0.2 cm(2) and the S/M ≥ 0.07 were useful indexes to distinguish PD and ET in Chinese population. In conclusion, TCS is an effective and useful tool to detect PD and to distinguish PD from ET in Chinese patients.

Does idiopathic REM sleep behavior disorder (iRBD) really exist? What are the potential markers of neurodegeneration in iRBD?

REM sleep behavior disorder (RBD) may be idiopathic or associated with other neurologic disorders. A strong association between RBD and α-synucleinopathies has recently been observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of patients with RBD. Some clinical follow-up studies revealed that a large proportion of these patients will eventually develop a parkinsonian syndrome or a dementia of the Lewy bodies type in the years following the RBD diagnosis. The estimated 10-year risk of neurodegenerative disease for idiopathic RBD is about 40%. Moreover, it has been reported that the median interval between RBD and subsequent neurologic syndrome is 25years. Several studies have looked at neurophysiologic and neuropsychological functions in idiopathic RBD and have found evidence of CNS dysfunction during both wakefulness and sleep in a variable proportion of these patients, challenging the concept of idiopathic RBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial to develop early intervention strategies. Prospective studies in idiopathic RBD showed that potential markers of neurodegeneration include: (1) marked EEG slowing on spectral analysis; (2) decreased striatal 123I-FP-CIT binding and substantia nigra hyperechogenicity; (3) impaired olfactory function; (4) impaired color vision.

Autosomal dominant Parkinson’s disease in a large German pedigree

While several genes have been identified to cause Parkinson's disease (PD), monogenic forms explain only a small proportion of cases. We report clinical and genetic results in a large family with late-onset autosomal dominant PD. Thirty-eight family members of a five-generation Northern German PD family underwent a detailed neurologic examination, and transcranial sonography was performed in fifteen of them. Comprehensive mutation analysis of known PD-causing genes and a genome-wide linkage analysis were performed. Late-onset definite PD was found in five subjects with a mean age at onset of 63 years. Another six individuals presented either with probable/possible PD or with subtle parkinsonian signs. Six members with a mean age of 79 years had an essential tremor phenotype. Mode of PD inheritance was compatible with autosomal dominant transmission. One of three examined patients with definite PD demonstrated an increased area of substantia nigra hyperechogenicity upon transcranial sonography. Comprehensive linkage and mutational analysis excluded mutations in known PD-causing genes. Genome-wide linkage analysis suggested a putative disease gene in an 11.3-Mb region on chromosome 7p15-21.1 with a multipoint LOD score of 2.0. The findings in this family further demonstrate genetic heterogeneity in familial autosomal dominant late-onset PD.

Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder

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. TCS and positron emission tomography (PET) with 6-[(18)F] 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. Nine patients had pathological SN hyperechogenicity (mean age 66.8 [SD 3.9] years; 0.31 [SD 0.12] cm(2)) and 10 patients did not have SN hyperechogenicity (mean age 66.0 [SD 5.8] years; 0.11 [SD 0.06] cm(2)). 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. Pathological hyperechogenic alterations in the SN in patients with iRBD may suggest the existence of preclinical SN dysfunction as determined by FMT-PET.

Clinical and brain imaging characteristics in leucine‐rich repeat kinase 2–associated PD and asymptomatic mutation carriers

The objective of this research was to evaluate a possible endophenotype in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Ten symptomatic LRRK2 patients, 24 sporadic Parkinson's disease patients as well as 10 asymptomatic LRRK2 mutation carriers and 29 matched healthy controls underwent comprehensive clinical assessments with respect to motor and non-motor symptoms. Transcranial sonography and magnetic resonance imaging (voxel-based morphometry [VBM]) were assessed to evaluate morphological imaging characteristics. LRRK2 patients had an earlier onset of motor symptoms and a more benign phenotype of motor and non-motor characteristics compared to sporadic Parkinson's disease patients. However, depression scores were higher in LRRK2 patients. No clinical differences were found regarding motor and non-motor symptoms in asymptomatic LRRK2 mutation carriers in comparison to controls. Transcranial sonography showed hyperechogenicity of the substantia nigra in both patients' cohorts as well as in asymptomatic LRRK2 mutation carriers. Voxel-based morphometry revealed increased gray matter volume of the cerebellum and precentral gyrus in LRRK2 patients and of the cuneus in asymptomatic LRRK2 mutation carriers. In contrast, we found decreased basal ganglia gray matter volume in LRRK2 patients compared to controls. Increased gray matter volume of different anatomical structures associated with motor loops in LRRK2 patients and asymptomatic LRRK2 mutation carriers compared to age-matched sporadic Parkinson's disease patients and controls might indicate compensatory mechanism in LRRK2 mutation carriers due to motor network plasticity not only in the symptomatic stage of the disease but even in the premotor phase. Substantia nigra hyperechogenicity in yet unaffected LRRK2 mutation carriers indicates morphologic alterations in an asymptomatic stage of disease.

Combination of transcranial sonography, olfactory testing, and MIBG myocardial scintigraphy as a diagnostic indicator for Parkinson’s disease

Appropriate diagnostic biomarkers are useful for improving speed and accuracy of a diagnosis. Substantia nigra (SN) hyperechogenicity visualized by transcranial sonography (TCS), olfactory dysfunction, and the reduced uptake of (123) I-metaiodobenzylguanidine (MIBG) in myocardial scintigraphy have been suggested as potential biomarkers for the identification of Parkinson's disease (PD). To evaluate the diagnostic potential of these tests and to determine whether combining them increases their diagnostic power. Subjects were 44 patients with clinically diagnosed PD and 36 healthy controls. TCS of the SN, the odor stick identification test for Japanese (OSIT-J), and MIBG myocardial scintigraphy were conducted. Eleven patients with PD (25%) and four controls (11%) were excluded because of an insufficient acoustic temporal bone window in the TCS. Thus, 33 patients with PD and 32 healthy controls were finally included. The diagnostic sensitivity of TCS, OSIT-J, and MIBG myocardial scintigraphy was 78.8%, 84.8%, and 60.6%, respectively. The specificity of TCS and OSIT-J was 93.8% and 78.1%, respectively. The combination of TCS of the SN and OSIT-J substantially increased the sensitivity to a sufficient level for discriminating patients with PD from controls. TCS of the SN and olfactory testing play complementary roles in increasing diagnostic power in PD. As both tests are easy to perform, noninvasive, and inexpensive, the combination of TCS of the SN and olfactory testing may contribute to early and accurate diagnosis of PD.

Transcranial sonography findings in spinocerebellar ataxia type 3 (Machado–Joseph disease): A cross-sectional study

Few studies on transcranial brain sonography have been performed in hereditary and non-hereditary ataxias. The objective of the present study was to report transcranial brain sonography findings in a sample of clinically and molecularly proven Machado–Joseph disease patients and to compare these data against those of an age- and gender-matched control group. A cross-sectional study on transcranial brain sonography was conducted in 30 Machado–Joseph disease patients. Transcranial brain sonography was performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The results were compared with those of a control group of 44 healthy subjects matched for age and gender. The sonographic findings were also correlated with clinical features and genetic data in Machado–Joseph disease group. A significantly higher frequency of substantia nigra and lenticular nucleus hyperechogenicity was found in the Machado–Joseph disease group compared to an age- and gender-matched healthy control group (p<0.001). The substantia nigra echogenic area proved to be the best predictor for differentiating cases from controls. Third and lateral ventricles were significantly larger in the Machado–Joseph disease patients than in the control subjects. No significant correlations were found between transcranial brain sonography findings and Machado–Joseph disease demographic/clinical data. Transcranial brain sonography findings in Machado–Joseph disease patients differed significantly to those in age- and gender-matched controls. Substantia nigra hyperechogenicity occurred frequently in Machado–Joseph disease patients and was found to be the best predictor for differentiating cases from controls. Additionally, this data describes the occurrence of brain atrophy in Machado–Joseph disease group.

Sonographic Alteration of Lenticular Nucleus in Focal Task-Specific Dystonia of Musicians

Background/Aims: In distinct movement disorders, transcranial sonography detects alterations of deep brain structures with higher sensitivity than other neuroimaging methods. Lenticular nucleus hyperechogenicity on transcranial sonography, thought to be caused by increased local copper content, has been reported as a characteristic finding in primary spontaneous dystonia. Here, we wanted to find out whether deep brain structures are altered in task-specific dystonia. Methods: The frequency of sonographic brainstem and basal ganglia changes was studied in an investigator-blinded setting in 15 musicians with focal task-specific hand dystonia, 15 musicians without dystonia, and 15 age- and sex-matched nonmusicians without dystonia. Results: Lenticular nucleus hyperechogenicity was found in 12 musicians with task-specific dystonia, but only in 3 nondystonic musicians (Fisher’s exact test, p = 0.001) and 2 nonmusicians (p < 0.001). The degree of lenticular nucleus hyperechogenicity in affected musicians correlated with age, but not with duration of music practice or duration of dystonia. In 2 of 3 affected musicians with normal echogenic lenticular nucleus, substantia nigra hyperechogenicity was found. Conclusions: Our findings support the idea of a pathogenetic link between primary spontaneous and task-specific dystonia. Sonographic basal ganglia alteration might indicate a risk factor that in combination with extensive fine motor training promotes the manifestation of task-specific dystonia.

Brain tissue echogenicity—implications for substantia nigra studies in parkinsonian patients

The aim of the present study was to assess the origin of the substantia nigra hyperechogenicity in Parkinson disease patients. The cause of hyperechogenicity was tested on an animal model. Fresh porcine brains were injected consecutively with ferritin, apoferritin and water. Then, glioma samples were inserted into animal model. The echogenicity of the region of interest was assessed before and after experimental procedures. We observed the same echogenicity of porcine brain before and after injections of iron-loaded ferritin, apoferritin and water. Increased echogenicity of glioma samples compared to surrounding porcine brain tissue could be clearly seen. We postulate that the relative gliosis might be, at least partially, responsible for the increased echogenicity of the substantia nigra in Parkinson disease patients. Keeping in mind all limitations and inaccuracies of animal model used, it seems that hyperechogenicity of substantia nigra is caused rather by structural changes within the brain tissue than by increased iron concentration.

Sleep–wake changes in the premotor stage of Parkinson disease

Longitudinal studies in Parkinson disease (PD) have shown that the prevalence of sleep disorders increases with advanced disease. However, two sleep disorders, namely excessive daytime sleepiness (EDS) and REM sleep behavior disorder (RBD) have been described to antedate the development of the classical motor signs and symptoms of PD. One epidemiological study from the Honolulu-Asia Aging Study showed that aging men who reported “being sleepy most of the daily” had a threefold excess risk for developing PD after a seven-year follow-up. The origin and nature of EDS were not investigated. This study needs to be replicated. More robust data exist regarding RBD as the first manifestation of PD. RBD subjects commonly develop parkinsonism and cognitive impairment with time. Patients with the idiopathic form of RBD with decreased striatal dopamine transporters imaging, substantia nigra hyperechogenicity and hyposmia have an increased short-term risk for developing the classical motor, dysautonomic and cognitive symptoms of a synucleinopathy. Patients with idiopathic RBD, particularly those with abnormal subclinical features seen in the synucleinopathies such as decreased striatal dopamine transporters uptake, are the ideal population to be tested with disease-modifying agents in order to stop or slow down neurodegeneration in the brain.

Transcranial ultrasound in neurodegeneration with brain iron accumulation (NBIA)

NBIA/HSS is a neurodegenerative disorder associated with iron accumulation in specific brain regions. To date, the diagnosis is obtained by typical MRI changes followed by genetic mutation analysis. This procedure is laborious and limited to a few specially equipped medical centres. Since transcranial sonography (TCS) is widely used for the early diagnosis of PD in adults displaying parenchymal metal deposits, it is likely to be a reliable diagnostic tool for the early diagnosis of NBIA.In 7 patients with proven NBIA and 13 age-matched controls without record of neurological disease TCS was performed by an experienced ultrasound examiner. Data were analysed by two blinded investigators regarding hyperechogenicity and size of the substantia nigra (SN). SN size and hyperechogenicity was significantly increased in patients with NBIA compared to controls (students t-test: p < 0.001).TCS appears to be a non-invasive and inexpensive screening technique in patients with suspected NBIA. Performed by an experienced physician, it could enable an earlier diagnosis and pre-selection of patients for the MRI scan and genetic testing, which are still the diagnostic gold standard.

Enlarged Substantia Nigra Hyperechogenicity and Risk for Parkinson Disease

To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population. Longitudinal 3-center observational study with 37 months of prospective follow-up. Individuals 50 years or older without evidence of PD or any other neurodegenerative disease. Of 1847 participants who underwent a full medical history, neurological assessment, and transcranial sonography at baseline, 1535 could undergo reassessment. Incidence of new-onset PD in relation to baseline transcranial sonography status. 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. 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.

Substantia nigra echogenicity in Parkinson’s disease: relation to serum iron and C-reactive protein

In Parkinson's disease (PD), substantia nigra hyperechogenicity (SN-h) has been related to both, local iron accumulation and microglia activation. We analysed its relationship in PD patients with serum iron (n=31) and C-reactive protein (CRP; n=193). SN-h correlated with lower CRP and iron levels. Also, patients with a first-degree relative with PD had lower iron levels. Microglia activation, if reflected by SN-h, may be therefore unrelated to serum CRP. Findings support the idea that SN-h indicates inherited alteration of iron metabolism.

P148 No correlation between substantia nigra (SN) hyperechogenicity and dopaminergic degeneration measured by FP-CIT-SPECT in idiopathic parkinson’s disease (IPS)

P148 No correlation between substantia nigra (SN) hyperechogenicity and dopaminergic degeneration measured by FP-CIT-SPECT in idiopathic parkinson’s disease (IPS)

P144 Substantia nigra hyperechogenicity and MIBG scintigraphy findings are of different value in the diagnostic of Parkinson’s disease

P144 Substantia nigra hyperechogenicity and MIBG scintigraphy findings are of different value in the diagnostic of Parkinson’s disease

Substantia nigra hyperechogenicity with LRRK2 G2019S mutations.

Transcranial sonography (TCS) area of hyperechogenicity in the substantia nigra (aSN) is increased in idiopathic and genetic Parkinson's disease (PD). We performed TCS in 34 LRRK2 G2019S mutation carriers manifesting PD, 24 non-manifesting mutation carriers, and 28 idiopathic PD patients and compared them with 40 healthy controls (total, n = 126). Compared with the controls (mean 0.15 cm(2) ), the aSN values in all other groups were increased. The mean aSN was 0.23 cm(2) in nonmanifesting mutation carriers (P = .015), 0.34 cm(2) in idiopathic PD patients (P < .0001), 0.32 cm(2) in LRRK2-associated PD patients (P < .0001), and 0.33 cm(2) in the overall PD group (P < .0001). LRRK2-associated PD patients had a higher aSN than did nonmanifesting carriers (P = .011), but there was no significant difference in aSN between patients with idiopathic and LRRK2-associated PD (P = .439). Our results suggest that SN pathoanatomical alterations may not be substantially different between idiopathic and LRRK2-associated PD. The findings in the nonmanifesting mutation carriers suggest the presence of intermediate nigrostriatal pathology consistent with the age-dependent reduced penetrance of this mutation.