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Article

Clinical and Genetic Characteristics of Parkinson’s Disease Patients with Substantia Nigra Hyperechogenicity

by
Łukasz Milanowski
1,*,
Piotr Szukało
2,
Małgorzata Kowalska
1,
Alicja Sikorska
2,
Dorota Hoffman-Zacharska
3 and
Dariusz Koziorowski
1
1
Department of Neurology, Faculty of Health Science, Medical University of Warsaw, 02-091 Warsaw, Poland
2
Student Scientific Group, Department of Neurology, Faculty of Health Science, Medical University of Warsaw, 02-091 Warsaw, Poland
3
Department of Medical Genetics, Institute of Mother and Child, 01-211 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(12), 5492; https://doi.org/10.3390/ijms26125492
Submission received: 3 April 2025 / Revised: 30 May 2025 / Accepted: 5 June 2025 / Published: 8 June 2025
(This article belongs to the Special Issue Parkinson’s Disease and Related Diseases: Mechanisms, Genetic Factors and Treatments)
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Abstract

:
Hyperechogenicity of the substantia nigra (SN) is observed using transcranial ultrasonography in patients with Parkinson’s Disease. In this study, we investigated whether monogenic forms of PD are more prevalent in these patients and clinically defined their characteristics. Eighty-eight PD patients were part of the analysis. All patients received clinical diagnoses from experienced movement disorder specialists. Each patient underwent transcranial ultrasonography and genetic testing for mutations in the SNCA, PRKN, LRRK2, DJ1, and PINK1 genes. SN hyperechogenicity was identified in 48 patients. Compared to the non-hyperechogenicity group, these patients did not have monogenic forms of PD more frequently, but they did have REM sleep behavior disorder significantly more often, lived in rural areas, and experienced a later age of disease onset. Our study indicated no association between substantia nigra echogenicity and the presence of mutations in the SNCA, LRRK2, DJ1, PRKN, and PINK1 genes. Hyperechogenicity of the substantia nigra, however, remains a common finding in patients with Parkinson’s Disease, correlating with certain features of the disease.

1. Introduction

Parkinson’s Disease (PD) is a progressive neurodegenerative movement disorder characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta and the accumulation of aggregated alpha-synuclein protein in Lewy bodies identified within the surviving neurons. The loss of dopamine signaling in the striatum presents as parkinsonism—a clinical syndrome that includes movement disorders such as tremor, rigidity, bradykinesia, hypokinesia, and akinesia [1]. The diagnosis of the disease is based on clinical symptoms, as no specific test for PD has been developed yet.
The pathogenesis of the most common idiopathic form of PD is the result of the interaction of environmental factors and genetic susceptibility. Most patients develop PD due to the combined effects of several common variants with smaller impacts (detectable via genome-wide association study (GWAS) panels) and environmental influences [2,3]. Among the environmental factors linked to PD occurrence are age [4] and exposure to pesticides and heavy metals [5]. Other factors, such as tobacco and caffeine intake, may provide a protective effect [6]. Approximately 5–10% of patients, however, develop a “monogenic form of Parkinson’s Disease”, which is caused by pathogenic variants in SNCA, LRRK2, and VPS35, genes exhibiting autosomal dominant inheritance, along with PRKN, PINK1, and DJ-1, genes which follow autosomal recessive inheritance [7]. These rare variants show high penetrance, and nearly all carriers develop the disease [2].
Transcranial ultrasonography (TCS) has been utilized to measure the substantia nigra, a crucial brain region impacted in Parkinson’s Disease (Figure 1). Increased echogenicity in the substantia nigra has been linked to the presence of parkinsonian symptoms, indicating dopaminergic neuron loss. During TCS, the probe is placed at temporal bone windows. In about 10% of patients, the bone window is not accessible, preventing the assessment of the SN using ultrasound machines [8]. In an axial section through the midbrain, the butterfly-shaped hypoechogenic midbrain is easily distinguishable from the highly echogenic basal cisterns. According to published studies, SN hyperechogenicity appears to be a valuable marker for diagnosing PD, regardless of the disease stage and severity. However, it seems unsuitable for monitoring disease progression. SN hyperechogenicity has also been identified in individuals carrying mutations of PD genes (SNCA, PRKN, PINK1, DJ-1, LRRK2), both in PD patients exhibiting clinical symptoms and in asymptomatic individuals [9,10,11]. Moreover, asymptomatic LRRK2 Gly2019Ser mutation carriers with SN hyperechogenicity are more prone to developing PD in the future [12]. The hyperechogenicity of the substantia nigra was also present more frequently in dopa-responsive dystonia patients, despite its different pathophysiology than PD [13].
Recent reports emphasize the value of TCS as a diagnostic and prognostic tool in the case of PD patients [14]. However, the identification of factors leading to the development of PD in presymptomatic carriers remains an unresolved problem. The purpose of this study was to perform an assessment of whether monogenic forms of Parkinson’s Disease occur more frequently among patients with hyperechogenicity of the substantia nigra. Additionally, we analyzed the clinical factors associated with SN hyperechogenicity in PD patients.

2. Results

A total of 88 participants were included in the analysis. The transtemporal bone window was available in 79 patients (88.8%). The hyperechogenicity of the substantia nigra was confirmed in 48 patients (60.8%)—23 on the left side, 15 on the right side, and 10 on both sides. The mean age of the patients with hyperechogenicity was 58.2 ± 13.4 vs. 48.3 ± 11.4 without (p = 0.04). The mean age of disease onset with hyperechogenicity was 51.5 ± 13.7 vs. 40.9 ± 13.1 without (p = 0.04). One compound heterozygote of PRKN was revealed in each group: in one patient with hyperechogenicity, PRKN biallelic heterozygous mutations—Exon 4 deletion and a nonsense p.Glu79Ter variant—and in one patient without hyperechogenicity, heterozygous biallelic Exon 2 and Exon 4 deletions. The LRRK2 heterozygous missense variant p.Asn1437His was identified in one patient without hyperechogenicity (genotypes according to HGVS recommendation are described in the Section 4).
The presence of pathogenic mutations was 2.1% vs. 6.5% in the hyperechogenicity and non-hyperechogenicity groups, respectively (p = 0.55781). Detailed clinical data were available for 29 patients. REM sleep behavior disorder (RBD) was observed more frequently in patients with hyperechogenicity: 60% (N = 9) vs. 7.1% (N = 1), (p = 0.00442) (Figure 2).
Patients living in cities were more common in the non-hyperechogenicity group, 85.7% (N = 12), than in the hyperechogenicity group, 42.9% (N = 6), (p = 0.04607) (Figure 2) (Table 1). The calculated power of the statistically significant analysis via the chi-square test was at least 99%.

3. Discussion

We comprehensively characterized Parkinson’s Disease patients with and without hyperechogenicity in the substantia nigra. Our study did not reveal any associations of the genetic variants with the ultrasonographic findings. The variants were chosen based on previously well-established monogenic inheritance and previous associations with SN hyperechogenicity [15].
Similar negative findings were observed in Gly2019Ser patients. Brügemann et al. compared 34 LRRK2 Gly2019Ser mutation carriers manifesting PD and 24 non-manifesting mutation carriers and did not find statistically significant differences (p = 0.439) [16]. A study performed in patients with ATP13A2-associated PD did not reveal any hyperechogenicity in these patients [17].
The increased availability of high-throughput testing will allow for the identification of more monogenic forms and cases of PD. The pathophysiology of the different genetic forms of PD may also differ [18]. It was revealed that the typical alpha-synuclein pathology is rare in LRRK2, PINK1, and PRKN patients, which shows that the biological definition of PD has started to become more important [19]. Therefore, the clinical and radiological characterization of genetically defined PD subtypes may vary, and this needs to be recognized.
The hyperechogenicity of the substantia nigra is a well-established auxiliary test in diagnosing Parkinson’s Disease (PD). In our population, hyperechogenicity was observed in 60.8% of patients, which is lower than in previous studies [20,21]. The prevalence of substantia nigra hyperechogenicity among PD patients is notably high, ranging from 68% to 99%, although small spots or lines of hyperechogenicity can also be observed in healthy individuals [8]. SN hyperechogenicity in PD may be detectable in the very early stages of the disease when clinical symptoms are insufficient for a definitive diagnosis. However, the extent of the echo signal is not correlated with disease severity and remains unchanged throughout the disease’s progression. SN hyperechogenicity was noted in patients with a later onset of the disease. Additionally, it was observed more frequently in patients with RBD and those living in rural areas.
Microglia activation and gliosis formation appear to be the primary mechanisms contributing to substantia nigra hyperechogenicity [22], which remains stable throughout PD [23]. Several earlier studies emphasized the significance of iron accumulation [22], though this hypothesis is considered less critical [24]. It may also correlate with disease duration in certain subgroups of PD patients, such as middle-aged males with non-tremor-dominant subtypes [25]. In our patient cohort, we did not find a correlation between echogenicity and prolonged disease duration. These findings align with the results presented in a previous study [26]. However, the onset of the disease occurred later in PD patients exhibiting SN hyperechogenicity.
The prevalence of RBD in PD patients ranges from 14.6% [27] to 77% [28] in general PD populations. In our work, we show that PD patients with SN hyperechogenicity (SN+) have RBD significantly more frequently than PD patients without hyperechogenicity (SN−). In contrast to our results, we have found only one article that shows SN echogenicity in PD patients with RBD not to be significantly different from its presence in PD patients without RBD [29]. However, there are several papers highlighting the value of SN echogenicity as a biomarker. In idiopathic REM sleep behavior disorder patients, SN hyperechogenicity is correlated with an increased risk of developing neurodegenerative conditions such as PD [30], and when combined with 123I-FP-CIT SPECT it may be a useful marker in identifying individuals at a higher risk of developing synucleinopathies [31].
According to published studies, the comparison of patients from rural areas and cities has not identified any differences regarding the extent of SN echogenicity. However, a larger proportion of patients with SN hyperechogenicity live in rural areas [32]. The authors, however, did not assess the statistical power of this finding. In our research, we discovered that patients living in rural areas were more prevalent in the hyperechogenicity group (57.1%) than in the non-hyperechogenicity group (14.3%). This may be explained by the presence of pesticides and toxins used in agriculture in the country, as they may facilitate the occurrence of SN hyperechogenicity
Studies indicate that in patients with monogenic forms of PD, the area of SN echogenicity was significantly larger than that of healthy controls, yet smaller than in idiopathic PD [33,34,35]. This may suggest distinct pathomechanisms within these disease entities. In our study, the presence of pathogenic mutations was 2.1% in the hyperechogenicity group compared to 6.5% in the non-hyperechogenicity group. The frequency of mutations was statistically insignificant between the groups. The genetic variants analyzed did not appear to be specific to substantia nigra hyperechogenicity. One interpretation of the incidence of SN hyperechogenicity is that it may be associated with increased iron deposition, meaning that it reflects ultrasound waves more than the surrounding tissues. This could be independent of genetic variants [36,37]. Other studies do not confirm this first interpretation and instead suggest microglia proliferation [8]. Model studies confirm that the hyperechogenicity of substantia nigra is caused by structural changes within the brain tissue rather than by increased iron concentration [24]. It may also be caused by long-lasting dopamine deficiency [13].
There are several limitations to this study. Firstly, due to the retrospective nature of the study, some patients’ clinical data are missing. Secondly, the strength of the group we included is limited regarding the analysis of clinical data, although it is satisfactory considering the number of patients who underwent genetic testing. However, we conducted a power analysis, which was sufficient for the statistically significant values observed in the clinical data. Moreover, we examined patients for only a limited number of genes, which may have resulted in us missing certain mutations in different regions. The genetic testing, which only included Sanger sequencing and MLPA, may have led to the omission of some variants such as intronic or copy number variants (CNVs) in the analyzed genes. Further investigation is needed to draw more precise conclusions.

4. Materials and Methods

4.1. Clinical and Ultrasonography Analysis

Diagnosis of PD was made based on the UK Brain Bank diagnostic criteria [38] by experienced movement disorder specialists (D.K. and L.M.). Clinical and demographic data were collected through neurological, neuropsychological, speech therapy, and radiological examinations during hospitalization in the Department of Neurology, Faculty of Health Science, Medical University of Warsaw. The study received approval from the Bioethics Committee of the Medical University of Warsaw and was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Transcranial ultrasonography was performed using a Philips device with a 1–5 MHz probe by skilled ultrasonographers (D.K. and M.K.). The probe was positioned next to the transtemporal bone window and focused at a depth of 6–8 cm to image the brainstem. The anatomical region of the SN normally appears hypoechogenic. If a hyperechogenic area was detected, it was manually outlined and assessed planimetrically (significant surface area > 0.2 cm2).

4.2. Genetic Analysis

For all the patients included in the study, full-length coding sequences of the genes PRKN (Exons 1–12), PINK1 (Exons 1–8), DJ-1 (Exons 1–6), SNCA (Exons 1–6), and the diagnostically recommended exons of the LRRK2 gene (Exons 30, 31, 34, 35, 41, 48) were analyzed through direct sequencing using the Sanger method or as part of whole-exome sequencing (WES) performed in the Deptartment of Medical Genetics Of Institute of Mother and Child. Additionally, exon-level copy number variation (deletion/duplication) analysis was conducted for all patients using the multiplex ligation-dependent probe amplification method (MLPA) (MRC Holland Salsa P051, P052, Amsterdam, the Netherlands). The analyzed genes and identified variants were those most frequently observed in the European PD patients, especially in the Polish population [39].
The variants identified in the PRKN and LRRK2 genes and patients’ genotypes were described according to HGVS v.21.0.4 recommendations (https://hgvs-nomenclature.org/stable/ accessed on 30 April 2025) and the canonical reference sequences GRCh38 NM_004562.3 MANE Select and NM_198578.4 MANE Select, respectively (https://www.ncbi.nlm.nih.gov/genbank/ accessed on 30 April 2025).
The identified variants in PRKN and LRRK2 have been previously documented in the Human Gene Mutation Database Professional (HGMD Professional 2024.2, https://my.qiagendigitalinsights.com/bbp/view/hgmd/pro accessed on 30 April 2025) and/or ClinVar database (www.ncbi.nlm.nih.gov/clinvar accessed on 30 April 2025).
Variants and patient genotypes according to the HGVS recommendations [https://hgvs-nomenclature.org/stable/ accessed on 30 April 2025] are characterized in Table 2.

4.3. Statistical Analysis and Data Visualization

The statistical analyses were conducted using STATISTICA v.13.5 software, TIBCO, Palo Alto, CA, USA. The normality of distribution was evaluated with the Shapiro–Wilk test. Continuous variables were presented as means and standard deviations. Categorical variables were presented as frequencies (percentages). Parametric data were compared using the independent t-test, and the categorical data were compared with Fisher’s exact test (two-sided). Statistical power analysis was performed for the statistically significant chi-square values. GraphPad Prism 10 software was used to create the graphs.

5. Conclusions

In conclusion, we found no association between substantia nigra echogenicity and mutations in the DJ-1, SCNA, LRRK2, PRKN, and PINK1 genes that cause Parkinson’s Disease. In our cohort, PD patients with SN hyperechogenicity may exhibit RBD more frequently compared to those without SN hyperechogenicity, have a later onset of the disease, and are more often from rural areas. While transcranial ultrasonography is a valuable diagnostic tool for Parkinson’s Disease, it may not effectively identify patients at a higher risk of monogenic forms of the disease. However, these conclusions should be interpreted very cautiously. As we have stated above, the study has several limitations, and further analysis with more genetic variants should be conducted.

Author Contributions

Ł.M.: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing—Review and Editing; P.S.: Formal Analysis, Investigation, Software, Validation, Writing—Original Draft, Writing—Review and Editing; A.S.: Formal Analysis, Investigation, Software, Validation, Writing—Original Draft, Writing—Review and Editing; M.K.: Investigation, Validation, Writing—Review and Editing; D.H.-Z.: Data Curation, Formal Analysis, Investigation, Methodology, Writing—Review and Editing; D.K.: Conceptualization, Data Curation, Funding Acquisition, Investigation, Project Administration, Resources, Supervision, Validation, Writing—Review and Editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee) of the Medical University of Warsaw (KB/230/2017 approval date 23 December 2017).

Informed Consent Statement

Written informed consent has been obtained from the patient(s) to publish this paper.

Data Availability Statement

Data are available on request due to restrictions, e.g., privacy or ethical concerns. The data presented in this study are available on request from the corresponding author. The data are not publicly available due to patient’s privacy.

Acknowledgments

We thank all patients and family members.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
PDParkinson’s Disease
SNCAα-synuclein
LRRK2Leucine-rich repeat kinase family 2
VPS35Vacuolar protein sorting ortholog 35
PRKNParkin
PINK1PTEN-induced kinase 1
RBDREM sleep behavior disorder
HGMDHuman Gene Mutation Database
HGVSHuman Genome Variation Society
ATP13A2ATPase cation transporting 13A2
SNSubstantia nigra
TCSTranscranial ultrasonography

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Figure 1. The figure presents a schematic representation of the transcranial sonography (TCS) of the substantia nigra. The ultrasound probe is positioned to visualize a transverse section of the brainstem, highlighting the anatomical location of the substantia nigra, where a region of increased echogenicity is commonly observed in patients with Parkinson’s Disease. Imaging artifacts, which may mimic the hyperechogenicity of the substantia nigra, should be considered during TCS image interpretation.
Figure 1. The figure presents a schematic representation of the transcranial sonography (TCS) of the substantia nigra. The ultrasound probe is positioned to visualize a transverse section of the brainstem, highlighting the anatomical location of the substantia nigra, where a region of increased echogenicity is commonly observed in patients with Parkinson’s Disease. Imaging artifacts, which may mimic the hyperechogenicity of the substantia nigra, should be considered during TCS image interpretation.
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Figure 2. The association of substantia nigra hyperechogenicity with rural living and REM sleep behavior disorder (A): there was a significant difference in the number of patients living in rural areas with or without substantia nigra hyperechogenicity (** p < 0.05, Fisher’s exact test). (B): A significant difference was found in the number of patients with REM sleep behavior disorder with or without substantia nigra hyperechogenicity (** p < 0.05, Fisher’s exact test).
Figure 2. The association of substantia nigra hyperechogenicity with rural living and REM sleep behavior disorder (A): there was a significant difference in the number of patients living in rural areas with or without substantia nigra hyperechogenicity (** p < 0.05, Fisher’s exact test). (B): A significant difference was found in the number of patients with REM sleep behavior disorder with or without substantia nigra hyperechogenicity (** p < 0.05, Fisher’s exact test).
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Table 1. Genetic, gender (total number of patients, N = 79), and other clinical data (total number, N = 29) in patients with and without hyperechogenic substantia nigra.
Table 1. Genetic, gender (total number of patients, N = 79), and other clinical data (total number, N = 29) in patients with and without hyperechogenic substantia nigra.
Variable Hyperechogenicity (N = 48)No Hyperechogenicity (N = 31)p Value
Pathogenic mutations (LRRK2, DJ1, PRKN, PINK1, SNCA)1 (2.1%)2 (6.5%)0.558
Gender (males)33 (67.4%)15 (50%)0.157
Family history11 (73.3%)8 (57.1%)0.450
Dyskinesia5 (33.3%)4 (28.6%)1.000
Fluctuations6 (40%)4 (28.6%)1.000
Tobacco smoking6 (40%)7 (50%)0.819
Alcohol3 (20%)2 (14.3%)1.000
Place of residence (city)6 (42.9%)12 (85.7%)0.020
RLS5 (33.3%)4 (28.6%)1.000
Depression3 (20%)5 (35.7%)0.678
Dementia1 (6.7%)2 (14.3%)1.000
Dysarthria5 (33.3%)7 (50%)0.704
Dysphagia4 (26.7%)2 (14.3%)0.420
RBD9 (60%)1 (7.1%)0.004
First symptom:
-Bradykinesia8 (53.3%)3 (21.4%)0.677
-Rigidity11 (73.3%)4 (28.6%)0.656
-Rest tremor9 (60%)6 (42.9%)0.435
First treatment:
-Levodopa13 (86.7%)11 (78.6%)0.480
-Other12 (80%)12 (85.7%)1.000
Agonist usage (now)1 (6.7%)4 (28.6%)0.327
Age of onset (years)51.5 ± 13.740.9 ± 13.10.040
Age at study (years)58.2 ± 13.448.3 ± 11.40.040
Disease duration (years)6.8 ± 3.87.5 ± 7.70.730
RBD—REM sleep behavior disorder; RLS—restless leg syndrome.
Table 2. Pathogenic variants in PD genes identified in patients’ cohort, and genotypes of patients.
Table 2. Pathogenic variants in PD genes identified in patients’ cohort, and genotypes of patients.
GeneVariantcDNA HGVS #HGVS ProteinHGMD
Path. Class.		ClinVar *
Path. Class.		ACMG Class.
PRKNEx2 delc.(?_40)_(109_?)delp.?DMpathogenic-
Ex4 delc.(?_440)_(534_?)delp.?DMpathogenic-
p.Glu79Terc.235G>Tp.Glu79TerDM-LPath
LRRK2p.Asn1437Hisc.4309A>Cp.Asn1437HisDMnot providedVUS/LPath
Patients’ genotypes
PRKNc.[(?-40)_(109_?)del];[(?-440_534_?)del]; p.[?];[?]
PRKNc.[(?-40)_(109_?)del];[235G>T]; p.[?];[(Glu79Ter)]
LRRK2c.[4309A>C];[=]; p.[(Asn1437His)];[=]
# description based on MLPA analysis; * in case of deletion compared to structural variant (≥50 bps).
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Milanowski, Ł.; Szukało, P.; Kowalska, M.; Sikorska, A.; Hoffman-Zacharska, D.; Koziorowski, D. Clinical and Genetic Characteristics of Parkinson’s Disease Patients with Substantia Nigra Hyperechogenicity. Int. J. Mol. Sci. 2025, 26, 5492. https://doi.org/10.3390/ijms26125492

AMA Style

Milanowski Ł, Szukało P, Kowalska M, Sikorska A, Hoffman-Zacharska D, Koziorowski D. Clinical and Genetic Characteristics of Parkinson’s Disease Patients with Substantia Nigra Hyperechogenicity. International Journal of Molecular Sciences. 2025; 26(12):5492. https://doi.org/10.3390/ijms26125492

Chicago/Turabian Style

Milanowski, Łukasz, Piotr Szukało, Małgorzata Kowalska, Alicja Sikorska, Dorota Hoffman-Zacharska, and Dariusz Koziorowski. 2025. "Clinical and Genetic Characteristics of Parkinson’s Disease Patients with Substantia Nigra Hyperechogenicity" International Journal of Molecular Sciences 26, no. 12: 5492. https://doi.org/10.3390/ijms26125492

APA Style

Milanowski, Ł., Szukało, P., Kowalska, M., Sikorska, A., Hoffman-Zacharska, D., & Koziorowski, D. (2025). Clinical and Genetic Characteristics of Parkinson’s Disease Patients with Substantia Nigra Hyperechogenicity. International Journal of Molecular Sciences, 26(12), 5492. https://doi.org/10.3390/ijms26125492

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