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AIAN REVIEW
Year : 2022 | Volume
: 25
| Issue : 6 | Page : 1029-1035
Nigrosome and neuromelanin imaging as tools to differentiate parkinson's disease and parkinsonism
Deblina Biswas1, Rebecca Banerjee1, Swagata Sarkar2, Supriyo Choudhury1, Pritimoy Sanyal3, Mona Tiwari4, Hrishikesh Kumar1
1 Department of Neurology, Institute of Neurosciences Kolkata, Kolkata, West Bengal, India
2 Department of Neurology, Institute of Neurosciences Kolkata; Department of Physiology, University of Calcutta, Kolkata, West Bengal, India
3 Department of Computer Science and Engineering, Maulana Abul Kalam Azad University of Technology, West Bengal, India
4 Department of Radiology, Institute of Neurosciences, Kolkata, West Bengal, India
Correspondence Address:
Hrishikesh Kumar
Institute of Neurosciences Kolkata, 185/1, A.J.C Bose Road, Kolkata - 700 017, West Bengal
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_285_22
Abstract
Parkinson's disease (PD) lacks a definitive diagnosis due to a lack of pathological validation of patients at antemortem. The risk of misdiagnosis is high in the early stages of PD, often eluded by atypical parkinsonian symptoms. Neuroimaging and laboratory biomarkers are being sought to aid in the clinical diagnosis of PD. Nigrosome imaging and neuromelanin (NM)-sensitive magnetic resonance imaging (MRI) are the new emerging tools, both technically simple plus cost-effective for studying nigral pathology, and have shown potential for authenticating the clinical diagnosis of PD. Visual assessment of the nigrosome-1 appearance, at 3 or 7 Tesla, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy controls. Moreover, midbrain atrophy and putaminal hypointensity in nigrosome-1 imaging are valid pointers in distinguishing PD from allied parkinsonian disorders. The majority of studies employed T2 and susceptibility-weighted imaging MRI sequences to visualize nigrosome abnormalities, whereas T1-weighted fast-spin echo sequences were used for NM imaging. The diagnostic performance of NM-sensitive MRI in discriminating PD from normal HC can be improved further. Longitudinal studies with adequate sampling of varied uncertain PD cases should be designed to accurately evaluate the sensitivity and diagnostic potential of nigrosome and NM imaging techniques. Equal weightage is to be given to uniformity and standardization of protocols, data analysis, and interpretation of results. There is tremendous scope for identifying disease-specific structural changes in varied forms of parkinsonism with these low-cost imaging tools. Nigrosome-1 and midbrain NM imaging may not only provide an accurate diagnosis of PD but could mature into tools for personally tailored treatment and prognosis.
Keywords: Diagnosis of Parkinson's disease, neuroimaging markers in Parkinson's disease, neuromelanin-sensitive MRI, nigrosome imaging
Introduction 
Parkinson's disease (PD), a clinical syndrome, is characterized by bradykinesia, rigidity, rest tremor, and postural instability. The clinical diagnostic criteria upon which the diagnosis of PD is primarily reliant[1] have been reviewed and improvised over the years, but still have shortcomings. One-fourth of patients diagnosed as PD at antemortem had an alternative diagnosis at postmortem.[2] Certain neurological disorders with extrapyramidal conditions mimic PD and are often difficult to diagnose. Moreover, early PD diagnosis is challenging as the clinical picture at presentation may differ. In PD, atypical motor and non-motor symptoms further leads to the dilemma. PD mimics (10–15% of parkinsonian syndromes) include essential tremor (ET), drug-induced parkinsonism, vascular parkinsonism (VaP) and Parkinson-plus conditions as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB).[3] Recognizing drug-induced parkinsonism is vital, as treatment is cessation of the offending agent. ET patients are often confused with early PD or PD tremor dominant (PDT), and the “Scan Without Evidence of Dopaminergic Deficit” (SWEDD) study revealed that patients (largely with dystonic tremor) were misdiagnosed as having PD.[4] Drug-induced parkinsonism, DLB, PD, PSP, and parkinsonian patients require differential diagnosis before initiating dopaminergic treatment.
Emerging neuroimaging techniques could improve our understanding of PD and parkinsonism. Identification of neuroimaging markers and refinement of techniques for enhanced resolution, sensitivity is instrumental for improving the diagnosis of PD and persons at risk. The dopamine transporter (DAT) scan, the current gold standard diagnostic tool for patients with suspected parkinsonism, has not proved infallible.[5] DAT images in pathologically proven atypical parkinsonism (AP) and PD revealed overlaps to an unacceptable level. Since structural changes through conventional magnetic resonance imaging (MRI) are less apparent, especially in the early phase of PD, newer MRI methods have been experimented further. Advanced MRI enabled us to visualize in vivo substantia nigra (SN) pathology in PD as changes within the SN may emerge as promising early diagnostic biomarkers of PD.
Nigrosome-1 has recently been proposed as a potential biomarker in PD.[6],[7],[8],[9],[10] The SN is functionally and structurally divided into substantia nigra pars compacta (SNpc) and pars reticulata (SNpr). Five calbindin-negative clusters or the nigrosomes have been identified in the selectively degenerating dopaminergic SNpc that projects toward the striatum. Nigrosomes have a low iron concentration and visualized as a T2* hypersignal, contrasting with the nigral matrix. The largest of the clusters is the nigrosome-1 that stands for the dorsolateral nigral hyperintensity. Normally, the nigrosome has a hypersignal in the axial section, in either linear or comma form. It is bordered anteriorly, laterally, and medially by a low-intensity signal, giving it a swallow-tailed appearance. Nigrosome-1 visualization at 7T MRI using high-resolution susceptibility-weighted imaging (SWI) has excellent diagnostic accuracy: sensitivity (100%), specificity (87–100%), positive predictive value (91–100%), and negative predictive value (100%). In PD, nigrosome-1 shows up as a hypointense region (or absence of the “swallow tail” sign) on MRI and is viewed as a reliable diagnostic criterion for PD [Figure 1].[11],[12],[13]
Figure 1: 3T Nigrosome-1 MR images of healthy control versus Parkinson's disease basal ganglia (a) clear swallow tail appearance in healthy controls, (b) Absence of swallow tail indicative of loss of nigrosomeOn the other hand, in PD, the percentage of neuromelanin (NM) pigmented neurons correlates directly with the loss of dopamine-producing cell groups and the density of DAT.[14],[15] The neurochemistry behind the disappearance of the swallow tail sign under MRI is an increase in free iron due to a decrease in NM pigment composed of melanin, proteins, lipids, and metal ions. NM-containing neurons concentrated in the SNpc (both nigral matrix and nigrosomes) and locus coeruleus (LC) have paramagnetic properties. An altered paramagnetic hyperintense signal can be easily detected by T1-weighted MRI.[16] In PD, NM signal is significantly decreased in the SN as well as LC. The T1 reduction is related to both melanin-iron complexes and the absorption values of the nigrostriatal DAT. Volumetric analysis of the NM-related signal also revealed a significant degree of atrophy. NM-sensitive images have a high diagnostic accuracy rate for PD.[17]
We have highlighted here the recent advancement in NM-sensitive MRI and nigrosome-1 imaging, both of which have shown incredible potential in assisting the differential diagnosis of PD from controls. To date, there are only a few studies that examined the MRI appearance of nigrosome-1 and NM in different cases of parkinsonism [see [Table 1]. Further validation of disease-specific structural changes would prove useful for correct diagnosis.
Table 1: Case studies of nigrosome and NM sensitive MRI differentiating PD from parkinsonism Case Studies Evolution of NM-sensitive MRI-aided detection of neuropathology in PD patients
Zecca, Sulzer, and colleagues (2002) pioneered the idea of empowering the NM in vivo imaging technique to measure the NM concentration as a potential marker to quantify the damage in SNpc in PD subjects.[17] Using the new NM-sensitive 3T MRI tool, a significant reduction of signal intensity in both LC and SNpc was shown by Sasaki et al., 2006.[16] The study, consisting of 17 PD patients and 22 healthy controls (HCs), paved the way for further refinement of the technique in order to directly visualize the LC and SNpc. The key to the best visualization of NM imaging lies in the contrast-to-noise ratio (CNR) and the optimization of imaging parameters. The contrast ratio (CR) of LC in PD significantly and gradually decreased (p = 0.01) from the age groups of 40s and 50s to 70s compared to HC. This suggested that NM-imaging could positively assess functional changes in LC with increasing age.[16]
Later, a novel NM-sensitive MRI approach employing a 3D turbo field echo sequence and a semi-automated method for measuring SNpc volume has been claimed to offer a better demarcation of 18 PD patients from 27 HC in terms of higher sensitivity and specificity, especially for early PD. The difference in average SNpc volume between the PD and control groups was statistically significant (p < 0.01).[33]
In another study, a simultaneous NM-sensitive imaging procedure of LC and SN was adopted for quantification of early changes in PD.[34] Instead of a T1-weighted turbo spin echo sequence, a two-gradient recalled echo (GRE) with magnetization transfer contrast (MTC) preparation pulses were developed. Several other groups have used GRE MTC approaches, either 2D[34],[35] or 3D[36] but with limited coverage, single echo, and single flip angle acquisitions.
According to a more recent study, the loss of NM signal in the whole SN from posterior to anterior bore a significant correlation with PD severity.[37] Furthermore, a recent NM-sensitive imaging-based investigation on 16 PD subjects and 15 HC showed concordance between motor asymmetry and changes in SNpc.[38]
There have been a growing number of NM-MRI-based studies dealing with standardization of the method, varying in terms of acquisition and analysis protocols. The reproducibility and consistency of NM-imaging of SNpc and LC delineation was confirmed by comparing two separate MRI scans of each healthy individual (10 males and 1 female).[35] Here, volume measurements showed excellent reproducibility with a high intraclass correlation coefficient (SNpc: 0.94, P < 0.001; LC: 0.96, P < 0.001).
The diagnostic utility of signal intensity measurement of the SNpc, 3T NM imaging technique was highlighted in the works of Prasad et al.,[38] which successfully discriminated 16 PD from 15 HC. Significantly lower CRs were observed in the central SNpc of PD patients (p = 0.01). Furthermore, the relationship between motor symptom asymmetry and changes in the SNpc among 45 PD and 15 HC was explored using 3T NM-MRI. Subjects with PD had significantly lower CRs of both right lateral CR (RLCR) and left lateral CR (LLCR) compared to controls, and the LLCR was even lower than the RLCR (p = 0.0015).
A NM-sensitive 3T MRI sequence was combined with T2* relaxometry iron quantification analysis to study the SN of early-stage PD patients.[39] The study recruited 32 PD, 10 early PD, and 10 de novo PD. No statistically significant difference in T2* values was found. They concluded that iron content in the SN of early-stage PD patients does not have a significant correlation with NM MRI signal changes.
Nigral changes were quantified with a focus on their spatial variation within the SNpc for diagnosing the early phase of PD.[40] A total of 18 patients with early-stage PD and 18 HC underwent quantitative susceptibility mapping (QSM) and 7T NM imaging. In both SNpc, QSM values were significantly higher and NM areas were significantly lower in the PD group compared to HC (p<0.05)
The CNR of the SNpc and the CNR of the LC were measured on NM-MRI among 54 PD and 28 HC.[19] CNRs of the left LC in PD patients were significantly reduced as compared to control subjects (p = 0.011). The width and the CNR values of all SNpc parts in the PD group were significantly decreased in comparison to the control group (p < 0.001).
To determine the relationship between NM and dopamine terminals within the striatum of the PD brain, 30 non-demented mild-to-moderate stage PD and 15 HC were recruited in another study.[41] A 3T MRI was used for acquiring the images. Significantly lower NM CRs were observed in ventral SNpc than in dorsal SNpc (p < 0.001)
Available literature shows that NM loss in PD in the SNpc is well documented. Despite having several advantages and potential as a biomarker in parkinsonian syndrome, this method has limitations. When CR was considered, 2D NM-MRI could not accurately evaluate the area or volume of SNpc due to inappropriate slice thickness and slice gap. Additionally, it does not provide the exact boundaries of the SNpc. Longitudinal multi-imaging studies with a higher sample size are needed to establish NM-MRI as a useful diagnostic tool as well as a biomarker. A handful of studies are available that were conducted to determine if NM-imaging could discriminate pathological phenotypes of parkinsonism[17],[18],[33],[34],[35],[36] [see [Table 1]].
Abbreviations
IPD-Idiopathic Parkinson's disease
AP-Atypical parkinsonism
APP- Atypical progressive parkinsonism
tSWI-True susceptibility weighted imaging
CNR-contrast-to-noise ratio
CR-contrast ratio
RLCR-right lateral CR
PD-Parkinson's disease
ET-Essential tremor
MSA-Multiple system atrophy
PSP-Progressive supranuclear palsy
DIP-Drug-induced parkinsonism
AUC-Area under the curve
DAT- Dopamine transporter
FLAIR- Fluid-attenuated inversion recovery
MRI-Magnetic resonance imaging
SN-Substantia nigra
SNpc-Substantia nigra pars compacta
PDT-Parkinson's disease tremor dominant
SNpr-Substantia nigra pars reticulata
MSA-P Multiple system atrophy parkinsonian type
MSA-C Multiple system atrophy cerebellar type
QSWM -Quantitative susceptibility-weighted mapping
PIGD-postural instability and gait difficulty
T-Tesla
NM-Neuromelanin
QSM-Quantitative susceptibility mapping
MRI-Magnetic resonance imaging
HC-Healthy control
PSP-Progressive supranuclear palsy
GRE-gradient recalled echo
MTC-magnetization transfer contrast
LC-Locus coeruleus.
Nigrosome-1 imaging
Several studies evaluated the diagnostic accuracy of nigrosome-1 by 3T/7T MRI and SWI. Blazejewska et al., 2013 studied nigrosome visualization in vivo (10 PD vs 9 HC) and 2 postmortem brains with high field MRI. Along with the MRI data, the histochemical data also showed that regions with high dopaminergic cell content do not overlap with the iron-positive region or the hypointense region on the T2*w images. PD detection sensitivity = 100%, specificity = 88%.[6]
Further, a comparative study to evaluate 3T MRI and 7T susceptibility weighted angiography of SN for the diagnosis of PD was conducted in 14 PD patients and 13 healthy subjects.[7] The study revealed that susceptibility-weighted angiography at 7T MRI could diagnose PD with a mean sensitivity of 93%, specificity of 100%, and diagnostic accuracy of 96%, whereas 3T MRI diagnosed PD with a mean sensitivity of 79%, specificity of 94%, and diagnostic accuracy of 86%, respectively.
The diagnostic sensitivity, specificity, and accuracy of loss of nigrosome-1 in PD were also reported to be decent in many studies.[8],[10],[20],[42]
Whether changes in the nigrosome-1 correlate to clinical measures of PD was investigated among 30 PD patients.[43] Linear regression tests consistently identified the voxel intensity ratio derived from the dorsolateral SN and nigrosome-1 as predictive of MDS-UPDRS Part I Sub score 1A (complex behavior) (p = 0.0377) and MDS-UPDRS Part I Sub score 1B (daily living) (p = 0.03856) for manual segmentation.[43]
Poor visualization of nigrosome-1 in PD with high sensitivity (98.5%) and specificity (93.6%) was confirmed from the study of archived neuroimaging data and medical records of 90 PD and 68 healthy subjects.[44] In addition, this study showed that the poor visualization of SN was significantly associated with higher motor asymmetry in the contralateral side in 64.8% of subjects (p = 0.004).
Another method like SWI, the susceptibility map-weighted imaging (SMWI) has been attempted to refine the nigrosome imaging technique. The SMWI method significantly improved the CNR of nigrosome-1 (P = 0.014 for magnitude, P = 0.030 for QSM and P < 0.001for frequency and SWI, respectively) as compared to conventional susceptibility contrast images.[45]
To better visualize, the nigrosome-1 at 3T and to see its susceptibility effect, 3T MRI was followed by quantitative susceptibility-weighted mapping (QSWM) in 15 HC.[45] The visualization was improved when the head was tilted to the right and left in the B0 direction. No significant difference was observed between the right nigrosome-1 and left nigrosome-1 for each head tilt for both visualization and susceptibility.[46] The effect of the magic angle was remarkable in the non-tilted heads, and it was supported by QSM.
Recently, 3T MRI was performed with 15 head coils to find the presence or absence of the nigrosome-1 sign for a differential diagnosis of PD, including ET patients who showed the nigrosome-1 sign bilaterally.[21] Since the unilateral or bilateral absence of nigrosome-1 signal is indicative of degenerative PD, nigrosome-1 imaging may prove as a useful tool for distinguishing PD from parkinsonian conditions.
Histopathological evidence suggests a differential disarrangement of SN in the pathophysiology of PD when compared to MSA and PSP.[47] In PSP, the medial part of SNpc is involved, whereas in PD and MSA, the ventrolateral part of SNpc is mostly affected. Despite the existing pathological nigral heterogeneity, by SW1 on 3T scanner, SN aspects varying from PD could not be demonstrated among MSA or PSP patients.[48] With 7T MRI, the swallow tail nigral presentation unlike in PD was shown to be relatively preserved in CBS patients.[49] In contrast, the abnormal swallow tail sign in the Parkinson's plus syndrome LBD, closely resembled PD and this finding was significantly more common than any other dementia.[50] In the same study, the authors doubt the solidarity of the swallow tail sign as a sole diagnostic marker in LBD due to its lower predictive value and specificity. We have enlisted a few studies from PubMed that compared the visualization of nigrosome-1 among PD, ET, and other forms of parkinsonism [see [Table 1]]. The studies mostly suffer from reliability due to the absence of a confirmatory DAT scan and a small sample size. Some studies have even produced contradictory results on the differentiating power of nigrosome-1 imaging between idiopathic PD and atypical parkinsonian syndromes.[51] Even in cases, where nigrosome-1 could delineate PD from HC with high specificity and accuracy, histological validation of the defined nigrosome-1 region and the effect of aging on nigrosome is lacking. The other aspects of PD poorly understood are the differentiation of neuroanatomical substrates across motor phenotypes in PD: mainly the postural instability and gait difficulty (PIGD) and tremor-dominant (TD) subtypes. Distinct regional patterns of nigral neurodegeneration observed in PIGD and TD patients coincide with deficits in striato-thalamo-cortical and cerebello-cortical circuitries, respectively.[52],[53],[54] Quantitative analysis of whole nigrosome imaging with a larger sample size is warranted in order to discriminate motor-subtypes of PD and monitor PD progression.
Conclusion Nigrosome and NM neuroimaging offer excellent opportunities to precisely visualize nigral pathology in PD. Nigrosome abnormalities and reduced NM paramagnetic signals with or without volumetric changes are consistently demonstrated in PD. Empowered with high sensitivity and specificity, both these techniques undoubtedly demarcate PD from HC and may aid in precision diagnosis of PD. The advantage of the NM imaging method is that it is quantitative and could be a promising longitudinal tracker. The issue at hand is the possibility that nigrosomal imaging could be helpful for either discriminating progression in PD (lending itself to disease modifying trials as a biomarker) or for confident differential diagnosis, which will require further clinicopathological correlation studies. The imaging tools also hold potential, for distinguishing PD from atypical forms and for discriminating various motor subtypes. Heterogeneity of findings appears to undermine the strength of these methods since reliability and sensitivity are the main pillars for data interpretation. The consistency issue can be resolved with well-designed prospective and large multicentric studies aiming to differentially diagnose PD and parkinsonian syndromes. The potency of nigrosome and NM neuroimaging for predicting neuropathological changes in prodromal PD is another arena to be pursued for investigation.
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