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The British Journal of Radiology logoLink to The British Journal of Radiology
. 2019 Jun 3;92(1101):20180842. doi: 10.1259/bjr.20180842

Nigrosome 1 imaging: technical considerations and clinical applications

Eung Yeop Kim 1,✉, Young Hee Sung 2, Jongho Lee 3
PMCID: PMC6732928  PMID: 31067082

Abstract

A pathological study by Damier et al demonstrated that nigrosome 1, a dopaminergic neuron-rich region in the substantial nigra, is the most severely affected region in idiopathic Parkinson’s disease. Since then, researchers have identified the location of nigrosome 1 in the dorsal aspect of the substantia nigra using susceptibility-weighted imaging in MRI. Although this observation was reconfirmed by various imaging techniques and imaging planes, non-standardized imaging methods may rather limit the generalized use of this imaging finding. The aim of this review is to revisit the anatomical definition of the nigrosome 1 region using high-spatial-resolution susceptibility map-weighted MRI in order to help the readers to determine the presence or absence of an abnormality in the nigrosome 1 region. Thereafter, we discuss the current status of nigrosome 1 imaging at 3 T and show how to improve the imaging quality for better assessment of nigrosome 1. We also illustrate the imaging findings of various patients who presented with parkinsonism, which can help the readers to learn how to use these images in practice. Lastly, we discuss potential future works with nigrosome 1 susceptibility map-weighted MRI.

Introduction

In idiopathic Parkinson’s disease (IPD), it has been shown that loss of dopaminergic neurons occurs most severely in the lateral ventral tier, followed by the medial ventral tier of the substantia nigra pars compacta (SNpc).1 Based on calbindin D (28K) immunohistochemistry, another pathological study proposed a new concept of the subregions of the SNpc, nigrosome 1–5.2 They also suggested that nigrosome 1 is the most severely affected region in IPD.3 Despite these two successful works for demonstrating the most susceptible region of the SN in IPD, they may be limited because of incapability of in vivo application to subjects with parkinsonism.

From a pathological point of view, it was believed that imaging the area of the substantia nigra (SN) on MRI may help to differentiate IPD patients from healthy subjects. Using proton density-weighted images and fast short inversion time inversion-recovery (STIR) images, Oikawa et al demonstrated that the SN is mainly located below the red nucleus and cannot be localized by T 2 weighted imaging.4 They failed to identify a significant volume difference of the SN between IPD patients and healthy subjects. Since this study, more efforts were made to determine abnormality in the SN by using quantitative imaging techniques: diffusion tensor imaging and R2* mapping. Combining the results from these two imaging techniques, Du et al demonstrated that a higher discrimination performance than based on each imaging technique alone.5 Despite their promising results, the method may be limited for a generalized use because manual drawing of the SN is susceptible to inter rater discrepancy and is less practical for clinical practice than simple visual assessment.

After the pioneering work by Kwon et al in which the loss of hyperintensity in the dorsal region of the SN was shown in patients with IPD with susceptibility-weighted imaging (SWI) with ultra-high-field MRI,6 the hyperintense region in the dorsal SN on SWI was further assessed by a histology-MRI correlation which suggested it was the nigrosome 1.7 After these ultra-high-field MRI studies, the observations were reproduced by conventional 3 T scanners.8–19 All these studies focused on the subregion in the dorsal aspect of the SN. This specific region has been variously designated as the “swallow tail,”10,15,17,19 “dorsolateral nigral hyperintensity,”16 “hyperintensity between two hypointense regions in the dorsal SN,”9 “nigral hyperintensity,”8 and “nigrosome 1.”7,12–14,18,20 A recent meta-analysis of these imaging findings showed that the overall sensitivity and specificity of abnormality in this region for IPD v s healthy controls was 94.6 and 94.4%, respectively, at 3 T MRI.11 This study also showed that the absence of this hyperintense region may help to predict deficiency of the ipsilateral dopamine transporter (DAT) activity with a sensitivity of 87.5% and a specificity of 83.6%, which suggests this structure has potential as a biomarker for IPD. Compared to other imaging methods that have been suggested previously,4,5 the assessment of the nigrosome 1 region (hereafter, we use the designation, the nigrosome 1 region) on SWI has both strengths and weaknesses. As one of the strengths, it can be visually assessed, which is very practical and helpful for rapid interpretations. Additionally, the acquisition of SWI is also faster than other techniques such as neuromelanin-sensitive imaging.21 The downsides, however, are a lack of standardization of the imaging protocols including the spatial resolution and imaging planes, different anatomical definitions for the nigrosome 1 regions among the previous studies, and a lack of results from prospective studies. These may limit the generalized use of these promising imaging signs in daily practice.

The aim of this review is to revisit the anatomical definition of the nigrosome 1 region using high-spatial-resolution susceptibility map-weighted MRI (SMWI)12 in order to help readers determine the presence or absence of an abnormality in the nigrosome 1 region. Thereafter, we discuss the current status of nigrosome 1 imaging at 3 T and show how to improve imaging quality for a better assessment of nigrosome 1. We also provide imaging findings of various patients who presented with parkinsonism, which can help the readers to learn how to use this imaging method in practice. Lastly, we discuss potential future works with nigrosome 1 SMWI.

Anatomy of nigrosome 1 revisited by using high-spatial resolution SMWI at 3t

In previous studies regarding the nigrosome 1 region in the SN, some researchers assessed this region at either the level of the lower aspect of the red nucleus or the level below the red nucleus, while others assessed it exclusively below the red nucleus. Although Damier et al suggested that the nigrosome 1 is observed both above and below the level of the lower border of the red nucleus and its upper portion is larger at the level of the lower portion of the red nucleus than its lower part,2 it may be incorrect given the images seen in Figures 1 and 2 of their report (the images are in the horizontal plane in the figure legends, but they are probably in the coronal plane when considering the designations of the direction in the figures). If these figures are not in the horizontal, but in the coronal plane, the main portion of nigrosome 1 would be located below the red nucleus in contrast to the original definition in which the larger part of nigrosome 1 is located above the red nucleus. The description of the location of the nigrosome 1 region by Damier et al is not furthermore in agreement with that by Oikawa et al which states that the main portion of the SN is located below the red nucleus.4 It is therefore reasonable to surmise that the main portion of nigrosome 1 is located below the red nucleus. This suggestion is supported by a recent study using SWI at 9.4 T MRI which defined the major part of the hyperintense, presumed nigrosome 1 region below the red nucleus.22 We also recently evaluated the location of nigrosome 1 and found that its main portion is present below the red nucleus irrespective of the imaging planes (Figure 3).23 The main portion of the hyperintense areas in the SN is consistently observed immediately below the red nucleus irrespective of the imaging planes (Figure 4). It is therefore most appropriate to assess the nigrosome 1 region on SWI below the level of the red nucleus.

Figure 1. .

Figure 1. 

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Identification of nigrosome 1 and nigrosome 4 on SMWI in a 79-year-old female with drug-induced parkinsonism, the bilateral nigrosome 1 and nigrosome 4 regions are all intact. We evaluate the nigrosome 1 region below the red nucleus (yellow dotted lines) on oblique axial SMWI, and the nigrosome 4 region in the medial aspect of the substantia nigra at the lower part of the red nucleus on coronal-reformatted SMWI (orange dotted line). SMWI, susceptibility map-weighted MRI.

Figure 2. .

Figure 2. 

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SMWI and dopamine transporter imaging in vascular parkinsonism. An 80-year-old female presented with asymmetric parkinsonism and visual hallucination. The first impression was dementia with Lewy body disease when considering the Mini-Mental State Examination score of 9. As there is an abnormality in the right globus pallidus on SWI, the abnormality in the right basal ganglia on dopamine transporter imaging may be caused by this structural lesion or may reflect presynaptic dopaminergic dysfunction. Because the bilateral nigrosome 1 regions are intact on SMWI, the abnormality on dopamine transporter imaging may be associated with the structural lesion of the right globus pallidus, which is responsible for the patient’s parkinsonism (i.e. vascular parkinsonism). Memory impairment is an incidental pathology. SMWI, susceptibility map-weighted MRI; SWI, susceptibility-weighted imaging.

Figure 3. .

Figure 3. 

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The location of nigrosome 1. In a 68-year-old male with drug-induced parkinsonism, the red nucleus and substantia nigra are superimposed on three-dimensional T 1 weighted images. The volume-rendered images in the bottom row show the spatial relationship of the right red nucleus (the red sphere) and the ipsilateral substantia nigra (the green structure). Note the nigrosome 1 region (arrowhead) is located below the red nucleus. Figure reproduced from Kim EY, Sung YH, Lee J. Interlinking brain mapping and Parkinson's disease: MRI analysis, nigrosome 1 and nigrosome 4. In: Martin & Preedy ed. The Neuroscience of Parkinson's Disease: Genetics, Neurology, Behavior, and Diet. in press by permission of Elsevier.

Figure 4. .

Figure 4. 

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The location of nigrosome 1 according to the imaging planes. (a) On the reformatted images perpendicular to the midbrain in a 64-year-old healthy female subject, the main portion of the hyperintense areas in the substantia nigra (arrowheads) is located immediately below the RN. On the images immediately above the lower portion of the red nucleus, however, the hyperintense areas are smaller (bottom row), which is inconsistent with the results by Damier et al. (b) On the reformatted images parallel to the anterior commissure–posterior commissure line in the same subject, the main portion of the hyperintense areas in the substantia nigra (arrowheads) is observed immediately below the RN, which mimics the “Swallow tail” sign. On the images immediately above the lower portion of the red nucleus, however, the hyperintense areas are smaller (bottom row). RN, red nucleus.

Given that the nigrosome 1 region is curvilinear in direction, it is not easy to set up an optimal imaging protocol. Moreover, obtaining high-spatial resolution isovoxel imaging to visualize this small region is challenging due to the signal-to-noise ratio and scan time. Instead of obtaining isovoxel imaging, we propose 0.5 × 0.5 × 1.0 mm3 SWI at an imaging plane perpendicular to the long axis of the dorsal SN, which is approximately parallel to the imaging plane from the posterior commissure to the anterosuperior border of the pons (Figure 5). The last approach to improve the visualization of nigrosome 1 is to increase the contrast-to-noise ratio (CNR) by taking advantage of SMWI.24 This approach combines susceptibility contrasts from multiecho magnitude images (TE = 14.38, 26.71 and 39.0 ms) and quantitative susceptibility mapping mask and has been shown to improve the visualization of nigrosome 1.12 With this optimized imaging protocol, we can identify both the hyperintense presumed nigrosome 1 region below the red nucleus and the presumed nigrosome 4 at the level of the lower part of the red nucleus (Figure 1).23

Figure 5. .

Figure 5. 

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Imaging plane for nigrosome 1 susceptibility map-weighted imaging in a 68-year-old male with drug-induced parkinsonism, the red nucleus (red) and the substantia nigra (green) are superimposed on a three-dimensional T 1 weighted sagittal image (left column). The blue dotted line from the posterior commissure and the anterosuperior border of the pons serves as an imaging plane for visualization of nigrosome 1 (left column). This imaging plane is approximately perpendicular to the longitudinal axis of the substantia nigra (left column). At this imaging plane, SMWI demonstrates the hyperintense regions below the red nucleus (arrowheads), which are located within the hyperintense neuromelanin-containing areas. The bottom-row images show normal dopamine transporter activity on both sides. Figure reproduced from Kim EY, Sung YH, Lee J. Interlinking brain mapping and Parkinson's disease: MRI analysis, nigrosome 1 and nigrosome 4. In: Martin & Preedy ed. The Neuroscience of Parkinson's Disease: Genetics, Neurology, Behavior, and Diet. in press by permission of Elsevier. SMWI, susceptibility map-weighted MRI.

A previous study suggested that SWI and neuromelanin-sensitive imaging can visualize the SN, but the areas of the SN on both imaging techniques are not perfectly matched, and the SNpc is better visualized by neuromelanin-sensitive imaging.25 It could therefore be suggested that neuromelanin-sensitive imaging is better than SWI for assessment of the SN. In that previous report, however, the nigrosome 1 region was not conspicuously delineated on SWI. In contrast to their results, we have recently observed that the SN areas on SMWI and our optimized high-spatial-resolution neuromelanin sensitive imaging are overlapping in more areas than the results by Langley et al. (Figure 5). The discrepancy between the previous study by Langley et al and our observation is probably due to the difference in the echo times used for SWI. Langley et al obtained SWI with an echo time of 20 ms alone,25 whereas we acquired images with multiple echo times (14.38, 26.71 and 39.0 ms). Additionally, the spatial resolution of our SMWI is higher than that of Langley et al. We were also able to show that the nigrosome 1 region is located within the hyperintense SNpc on neuromelanin sensitive imaging (Figure 5). Taken together, we can better visualize smaller hypointense SN areas below the red nucleus, which is imperative for assessing the small hyperintense nigrosome 1 regions on SWI.

Our suggested protocol for obtaining SMWI is as follows: repetition time, 48 ms; three echo times (14.38, 26.71 and 39 ms); field of view, 192 mm; matrix, 384 × 384; slice thickness, 1 mm; slices per slab, 32; flip angle, 20; acceleration factor of 2; three-dimensional elliptical sampling, and total scan time, 5 min 3 s. After reconstructing both the magnitude and phase images, these DICOM images are used to reconstruct both the quantitative susceptibility mapping and SMWI with a MATLAB-based tool (v. 0.91; it can be requested via snu.list.application@gmail.com).

Acquisition and assessment of nigrosome 1 imaging: Further considerations

Previous studies obtained SWI for nigrosome 1 imaging with various spatial resolutions that ranged from 0.4 to 0.69 × 0.4–0.92 × 0.7–2.4 mm3. Our suggested protocol with a spatial resolution of 0.5 × 0.5 × 1.0 mm3 is not the highest resolution but is a good compromise between the resolution and the CNR. When the CNR of nigrosome 1 imaging was compared among five different susceptibility weighted contrasts (i.e. magnitude, phase, QSM, SWI, and SMWI), SMWI was shown to provide the highest CNR.12 After comparing SMWI (0.5 × 0.5 × 1.0 mm3) at an imaging plane perpendicular to the longitudinal axis of the SN with SWI (0.8 × 0.8 × 2.0 mm3) parallel to the anterior commissure–posterior commissure line in a limited number of subjects, we found that a 2 mm thick SWI may be suboptimal due to a partial volume effect when compared to SMWI (Figure 6). Nonetheless, there is no formal comparison study between SMWI and a higher-spatial-resolution SWI (e.g. 0.4 × 0.4 × 0.7 mm3) that can be obtained currently with the available 3 T scanner. Thus, it may be necessary to conduct a study that tests various imaging protocols to determine the best one for nigrosome 1 imaging in terms of the imaging quality and acquisition time.

Figure 6. .

Figure 6. 

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2-mm SWI vs SMWI. A 77-year-old male presents with right hand tremor. SMWI shows an abnormality in the nigrosome 1 regions with the left more affected than right, which is similarly identified on dopamine transporter imaging. On SWI that was obtained in parallel to the anterior commissure–posterior commissure line in 2 mm thickness, however, the dorsal hyperintensity in the substantia nigra is relatively preserved on both sides (arrowheads). SMWI, susceptibility map-weighted MRI; SWI, susceptibility-weighted imaging.

Qualitative, not quantitative, analysis is another important concern about the results from previous studies using SWI or SMWI. Most previous studies claimed that they achieved a high interobserver reliability by a simple and quick visual assessment. From our experience, however, a training period is necessary for the reviewers to get used to interpreting nigrosome 1 images. Thanks to the improved imaging quality of SMWI, interpretation of the nigrosome 1 region has become an easier task compared to SWI, but a training period is still necessary. Although quantitative imaging techniques such as DTI, QSM, and R2* mapping may provide more objective and less rater-dependent results, they also have limitations for nigrosome 1 SMWI. As for DTI, it is very challenging to obtain high-spatial-resolution imaging at 3 T MRI, which is required for the proper assessment of the nigrosome 1 region or the SN as a whole. Drawing a region of interest (ROI) is also needed when assessing DTI. We can obtain both QSM and R2* values from our imaging protocol for SMWI, but we need to define the nigrosome 1 region manually, which may be another source of inter rater discrepancy.

Clinical applications of Nigrosome 1 SMWI

When patients present with parkinsonism, clinicians generally request a structural head MRI to rule out conditions that can cause parkinsonism without neurodegenerative changes, such as normal pressure hydrocephalus (NPH) and subdural hematoma (SDH). After ruling out these conditions and cerebrovascular lesions, they also assess MRI to determine the structural changes in the putamen, pons-brachium pontis-cerebellum, and midbrain for multisystem atrophy with predominant parkinsonism (MSA-P), multisystem atrophy with cerebellar features (MSA-C), and progressive supranuclear palsy (PSP), respectively. The problem, however, is that these diseases are frequently difficult to differentiate from IPD in their early stage because there are minimal or insignificant structural changes in the specific regions for each disease on conventional MRI. Moreover, approximately 20% of patients with IPD are not clinically diagnosed.26 DAT imaging is particularly useful in this regard because it can reflect neurodegenerative changes in the SN. Although the presence of an abnormality on DAT imaging is not essential for diagnosis of IPD, normal DAT imaging can help to rule out the diagnosis of IPD.27 Despite its utility, DAT imaging may be limited due to its cost and accessibility. It also imposes a high dose of radiation on patients. Thus, it would be desirable to predict DAT activity by using MRI. We propose a diagnostic algorithm for patients with parkinsonism, which is based on SMWI (Figure 7).

Figure 7. .

Figure 7. 

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Suggested diagnostic algorithm by using MRI for subjects with parkinsonism Note. DAT, dopamine transporter imaging; IPD, idiopathic Parkinson’s disease; MCP, middle cerebellar peduncle; MIBG, metaiodobenzylguanidine; MRPI, magnetic resonance parkinsonism index; MSA, multiple system atrophy; NPH, normal pressure hydrocephalus; PSP, progressive supranuclear palsy; SDH, subdural haemorrhage; SWI, susceptibility-weighted imaging; QSM, quantitative susceptibility mapping; VP, vascular parkinsonism.

Subjects with a normal nigrosome 1 region on SMWI

For those who have normal nigrosome 1 regions on both sides of the SN (Figure 1), we may consider the following conditions: essential tremor, drug-induced parkinsonism, vascular parkinsonism, or rarely false negative interpretations.

Essential tremor or drug-induced parkinsonism may show asymmetric symptoms and signs, which make it difficult for clinicians to differentiate these two conditions from IPD. From our experience with 238 subjects who underwent both SMWI and DAT imaging, we had no false-negative interpretations per patient (the diagnosis of neurodegenerative diseases on SMWI was made when either side of the nigrosome 1 region showed an abnormality).28 Thus, for subjects without an abnormality in the nigrosome 1 regions on SMWI, we may consider drug-induced parkinsonism if they are taking any medications that can cause this condition. If not, we may deem that they have essential tremor. In subjects with extensive white matter lesions or structural lesion(s) in their basal ganglia, however, we may also consider vascular parkinsonism. DAT imaging may then be considered for those who have equivocal findings on MRI.

Clinicians with expertise in movement disorders often have difficulty differentiating vascular parkinsonism (VP) from IPD. Some may use DAT imaging to determine a normal presynaptic dopaminergic function. However, this strategy is only effective in a small portion of patients with VP (32.5%)29 because many of them have a diffuse reduction of DAT with a pattern similar to that described in IPD.29,30 From our series of 16 patients with VP,28 we found that these patients showed no abnormalities in the nigrosome 1 regions on SMWI whereas DAT imaging showed unilateral or bilateral abnormalities in the basal ganglia due to the presence of structural lesions (Figure 2) (for more details, see ref. ). Such abnormalities in the basal ganglia on DAT imaging may make it difficult to determine normal presynaptic dopaminergic function in VP. In this case, nigrosome 1 imaging by SMWI may provide valuable diagnostic information.

It should be noted that a higher sensitivity may come with a lower specificity. In our results, eight subjects were on SMWI categorized as false-positive interpretations (specificity of 94.4%), which were confirmed by DAT imaging. This level of false positivity is not negligible, but the method showed a higher sensitivity and comparable specificity when compared to recent meta-analysis results (sensitivity of 94.6% and specificity of 94.4%) from 307 patients with IPD [diagnosis based on DAT imaging (n = 198) or clinical findings (n = 107)] and 184 healthy subjects who underwent T 2* weighted imaging, SWI, or three-dimensional FLAIR imaging at 3 T.11 In terms of predicting pre-synaptic dopaminergic function per the SN-striatum, we showed for SMWI a sensitivity of 94.5% and a specificity of 95.3%,28 which were higher than the recent meta-analysis results (sensitivity of 87.5% and specificity of 83.6%).11

Subjects with an abnormal nigrosome 1 region on SMWI

In the current diagnostic criteria for IPD, DAT imaging is not mandatory to make a diagnosis of IPD.27 The criteria rather describe that normal DAT activity is one of the exclusion criteria. IPD can thus be diagnosed in the absence of any exclusion criteria. Thus, clinical findings and the results after a drug trial are enough to make a diagnosis of IPD. In many patients, however, clinicians may want to asses if there are any abnormalities in their nigrostriatal dopaminergic projections to rule out other mimickers such as essential tremor or drug-induced parkinsonism in the first place. DAT imaging has been considered a diagnostic test of choice for this purpose.31,32 As outlined in the previous paragraph, we can utilize SMWI in this regard because it may help to predict presynaptic dopaminergic function.

When an abnormality is observed in either side of the nigrosome 1 regions (Figure 8), we may consider several diseases including IPD, MSA (MSA-P in particular), PSP, and dementia with Lewy body disease as a potential origin of the abnormality. In its early stage, patients with IPD typically present with asymmetric motor symptoms and signs.33 Thus, we usually check if the patient has asymmetric motor symptoms and then see if the more affected side-of the nigrosome 1 region corresponds to more severe contralateral motor symptoms. We previously reported this congruency in 19 out of 24 patients with IPD.13 This congruency may also help to improve the diagnostic confidence of the nigrosome 1 imaging by SMWI, especially when the abnormality in the nigrosome 1 region is equivocal.

Figure 8.

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Typical findings of the nigrosome 1 regions on SMWI in idiopathic Parkinson’s disease. A 67-year-old male presents with asymmetric parkinsonism with the left more affected than the right. SMWI demonstrates an abnormality in the bilateral nigrosome 1 regions with the right more affected than the left. When considering the normal features of the nigrosome 1 region in Figure 5, hypointensity is observed in greater than 50% of the right nigrosome 1 region (arrowheads), whereas it is observed in less than 50% of the left nigrosome 1 region below the red nucleus (arrows). Dopamine transporter imaging shows bilateral abnormalities with the right more affected than the left, which are well correlated with the findings on the SMWI. SMWI, susceptibility map-weighted MRI

It has been reported that atrophy of the putamen, cerebellum, middle cerebellar peduncle, and pons on MRI is one of the additional features for possible MSA.34 It has also been shown that putaminal hypointensity is specific for MSA-P.35 The drawback of these imaging features for the diagnosis of MSA-P is their lower sensitivity. This is particularly true in the early stage of MSA-P. The qualitative, not quantitative, method for assessing these features in previous studies would be another limitation. Once we see both putaminal hypointensity on either side and a more severe abnormality in the ipsilateral nigrosome 1 region, we can suggest a diagnosis of MSA-P (Figure 9). If we see an abnormality in the nigrosome 1 region on SMWI, but fail to identify the above imaging features, we may be unable to differentiate IPD from MSA-P on MRI.

Figure 9.

Figure 9.

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Findings of SMWI and SWI in MSA-P. A 58-year-old male presents with asymmetric parkinsonism, which began 6 months ago. The SMWI shows an abnormality in the bilateral nigrosome 1 regions. The left putamen is decreased in volume, showing hypointensity in the posterolateral aspect on SWI. Dopamine transporter imaging shows decreased activity in the bilateral basal ganglia with the left more affected than right. The findings on the SMWI are not specific for IPD, MSA-P, or PSP. When considering the findings of the SMWI, SWI, and dopamine transporter imaging, however, MSA-P is the most likely diagnosis in this particular patient. IPD, idiopathic Parkinson’s disease; MSA-P, multisystem atrophy with predominant parkinsonism; PSP, progressive supranuclear palsy; SMWI, susceptibility map-weighted MRI; SWI, susceptibility-weighted imaging.

Another important mimicking disease that can show abnormalities in the nigrosome 1 region is PSP. As in patients with MSA-P, it is very difficult to make an early diagnosis of PSP in patients with parkinsonism. Although volume loss in the midbrain and superior cerebellar peduncle is a salient feature and specific for PSP, it has recently been reported that the diagnostic value of hummingbird and morning glory sign is limited due to low sensitivity.36 The magnetic resonance-Parkinson index (MRPI) was proposed to improve the diagnostic accuracy between PSP and IPD.37 A recent study, however, suggested that measuring the mid-sagittal midbrain area and the mid-sagittal pons area is the most reliable biomarker for PSP and MSA-C, respectively.38 They also suggested that the midbrain/pons ratio is better than the MRPI for differentiating PSP from MSA-C. A recent review describes that these imaging signs are supportive of early clinical diagnosis, but they have a lower level of reliability.39 DAT imaging is very sensitive for determining abnormal presynaptic dopaminergic function in PSP. However, it is not specific because other diseases such as IPD and MSA-P show a similar abnormality. Combining measurements of the areas of the midbrain and pons on mid-sagittal imaging and visual assessment of the nigrosome 1 region on SMWI and the shape of the midbrain (the hummingbird and morning glory sign) may be an easy alternative approach to patients who are suspected to have PSP (Figure 10). As in MSA-P, however, the sole abnormality in the nigrosome 1 region on SMWI without atrophy of the midbrain may not help to differentiate PSP from other neurodegenerative diseases such as IPD and MSA-P.

Figure 10.

Figure 10.

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Findings of SMWI and conventional MRI in PSP. A 73-year-old male presents with bradykinesia and rigidity with the right greater than the left. SMWI shows an abnormality in the bilateral nigrosome 1 regions, which is similarly observed on dopamine transporter imaging. 3D MPRAGE imaging indicates small volumes of the midbrain and bilateral superior cerebellar peduncles, which raises the possibility of PSP. PSP, progressive supranuclear palsy; SMWI, susceptibility map-weighted MRI.

Potential future works

Although the aforementioned studies showed promising results, they need to be further validated. Their downsides are as follows: first, there has been no prospective study using SWI or SMWI for nigrosome 1 assessment. The aim of the current ongoing study40 is to evaluate the following issues: (A) does the absence of the “swallow tail” sign at 3 T correlate with a final diagnosis of IPD 12 months after initial presentation? (B) Is this correlation as accurate as that of DAT imaging? (C) Is nigrosome MRI at 3 T at least 80% sensitive and 80% specific to predict a final diagnosis of IPD v s other movement disorders in patients with indeterminate or atypical parkinsonian features? (D) Is the “swallow tail” an accurate marker of early IPD? We anticipate that this study can help to justify the application of nigrosome 1 imaging in patients who present with parkinsonism, if it has positive results.

Second, the previous studies with regard to nigrosome 1 have not conducted a longitudinal analysis (i.e. assessment of both initial and follow-up imaging), which is necessary to determine disease progression or even reversal if disease-modifying therapies are available. The study by Du et al suggested that R2* of the SN, particularly in its caudal region, is strongly associated with the progression of IPD.41 The same group recently reported a longitudinal increase of R2* values in the SNpc in patients with IPD.42 We also recently demonstrated that the putative nigrosome 4 region is more frequently affected along with the involvement of the ipsilateral nigrosome 1 in advanced-stage IPD (Figure 11),23 which partly explains the increase of R2* values in the SNpc. Although our study assessed the subregions in the SN by taking advantage of higher spatial-resolution imaging, it is not based on a longitudinal analysis. It is therefore necessary to confirm the results in a prospective longitudinal study. Our high spatial-resolution SMWI may be appropriate because it provides both R2* mapping and QSM.

Figure 11.

Figure 11.

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Differential involvement of nigrosome 1 and nigrosome 4 in IPD In the early stage of IPD (Hoehn & Yahr 1), the nigrosome 1 regions are affected while the nigrosome 4 regions (arrowheads) are relatively preserved. In the advanced stage of IPD (Hoehn & Yahr 4), the nigrosome 4 regions (arrows) are more frequently affected in addition to the involvement of the bilateral nigrosome 1 regions. IPD, idiopathic Parkinson’s disease.

Third, the imaging techniques or parameters for nigrosome 1 have not been standardized. It may be necessary to provide the minimum requirements for proper nigrosome 1 imaging, which include the magnet strength (1.5 vs 3 T), spatial resolution, single-echo or multiecho time imaging for SMWI, and the imaging plane. Our high spatial-resolution SMWI may be a good choice because it provides both R2* mapping and QSM in addition to offering images for quick visual assessment. It is not until we determine the best technique for nigrosome 1 imaging that we may be able to conduct a multicenter, prospective study to confirm the utility of nigrosome 1 imaging.

Fourth, it has been shown that subjects with rapid eye movement sleep behaviour disorder may progress to overt neurodegenerative diseases such as IPD when they have abnormality in the nigrosome 1 region (Figure 12).43 Similar results were found in a study on hyposmic patients, where they only assessed DAT imaging.44 DAT imaging, however, is more expensive and less accessible than MRI. SMWI may be able to replace DAT imaging because it showed 100% sensitivity in our recent study.28 Thus, it would be interesting to conduct a similar study using SMWI in hyposmic subjects.

Figure 12.

Figure 12.

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SMWI in idiopathic REM sleep behaviour disorder. In a 63-year-old female with idiopathic REM sleep behaviour disorder, which was confirmed by polysomnography, SMWI shows a subtle abnormality in the left nigrosome 1 region. Although she did not have parkinsonian features, she willingly underwent dopamine transporter imaging because of the abnormality on the SMWI. Dopamine transporter imaging shows a mild abnormality in the left putamen, which is concordant with the findings on the SMWI. According to the previous study results, she has a higher chance of proceeding to a neurodegenerative disease in a couple of years. Thus, this particular patient may be a good candidate for protective therapies that are currently in development. In this regard, SMWI can be applied to screening such candidates. REM, rapid eye movement; SMWI, susceptibility map-weighted MRI.

Last, it may be necessary to compare nigrosome 1 imaging with neuromelanin-sensitive imaging. The latter has also been a hot topic among researchers who seek a new imaging biomarker for neurodegenerative diseases and has shown promising results.45–47 In fact, it has yet to be determined which technique is better for assessing patients with parkinsonism.

Conclusion

It is important to know the precise location of the nigrosome 1 region on SWI or SMWI for proper assessment. The main portion of the nigrosome 1 region is located below the lower border of the red nucleus. Because nigrosome 1 SMWI is very sensitive for determining SN pathology, the presence of normal nigrosome 1 regions on both sides can confidently exclude neurodegenerative diseases such as IPD, MSA-P, and PSP. An abnormality in either side-of the nigrosome 1 regions, however, is not specific for a particular disease unless it is associated with other imaging features such as atrophy of the midbrain, cerebellum, pons, putamen, or middle cerebellar peduncle and putaminal hypointensity. Despite the limitation in specificity, nigrosome 1 imaging still has diagnostic utility because it may negate the need for DAT imaging when it shows no abnormality on both sides of the SN. Further multicenter longitudinal studies with a standardized protocol and objective assessment may improve its utility in daily clinical practice.

Footnotes

Acknowledgment: This research was supported by the grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1135), and by the National Research Foundation of Korea (NRF-2018R1A2B3008445).

Contributor Information

Eung Yeop Kim, Email: neuroradkim@gmail.com.

Young Hee Sung, Email: atmann02@gilhospital.com.

Jongho Lee, Email: jonghoyi@snu.ac.kr.

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