Neuromelanin-sensitive Imaging Research Articles

Advanced Magnetic Resonance Imaging for Early Diagnosis and Monitoring of Movement Disorders.

Advanced magnetic resonance imaging (MRI) techniques are transforming the study of movement disorders by providing valuable insights into disease mechanisms. This narrative review presents a comprehensive overview of their applications in this field, offering an updated perspective on their potential for early diagnosis, disease monitoring, and therapeutic evaluation. Emerging MRI modalities such as neuromelanin-sensitive imaging, diffusion-weighted imaging, magnetization transfer imaging, and relaxometry provide sensitive biomarkers that can detect early microstructural degeneration, iron deposition, and connectivity disruptions in key regions like the substantia nigra. These techniques enable earlier and more accurate differentiation of movement disorders, including Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Lewy body and frontotemporal dementia, Huntington's disease, and dystonia. Furthermore, MRI provides objective metrics for tracking disease progression and assessing therapeutic efficacy, making it an indispensable tool in clinical trials. Despite these advances, the absence of standardized protocols limits their integration into routine clinical practice. Addressing this gap and incorporating these techniques more systematically could bring the field closer to leveraging advanced MRI for personalized treatment strategies, ultimately improving outcomes for individuals with movement disorders.

Diagnostic performance of a high-spatial-resolution voxelwise analysis of neuromelanin-sensitive imaging in early-stage idiopathic Parkinson’s disease

BackgroundQuantitative assessments of neuromelanin (NM) of the substantia nigra pars compacta (SNpc) in neuromelanin-sensitive MRI (NM-MRI) to determine its abnormality have been conducted by measuring either the volume or contrast ratio (CR) of the SNpc. A recent study determined the regions in the SNpc that are significantly different between early-stage idiopathic Parkinson’s disease (IPD) patients and healthy controls (HCs) using a high spatial-resolution NM-MRI template, which enables a template-based voxelwise analysis to overcome the susceptibility of CR measurement to inter-rater discrepancy. We aimed to assess the diagnostic performance, which has not been reported, of the CRs between early-stage IPD patients and HCs using a NM-MRI template.MethodsWe retrospectively enrolled early-stage IPD patients (n = 50) and HCs (n = 50) who underwent 0.8-mm isovoxel NM-MRI and dopamine-transporter PET as the standard of reference. A template-based voxelwise analysis revealed two regions in nigrosomes 1 and 2 (N1 and N2, respectively), with significant differences in each substantia nigra (SNpc) between IPD and HCs. The mean CR values of N1, N2, volume-weighted mean of N1 and N2 (N1 + N2), and whole SNpc on each side were compared between IPD and HC using the independent t-test or the Mann-Whitney U test. The diagnostic performance was compared in each region using receiver operating characteristic curves.ResultsThe mean CR values in the right N1 (0.149459 vs. 0.194505), left N1 (0.133328 vs. 0.169160), right N2 (0.230245 vs. 0.278181), left N2 (0.235784 vs. 0.314169), right N1 + N2 (0.155322 vs. 0.278143), left N1 + N2 (0.140991 vs. 0.276755), right whole SNpc (0.131397 vs. 0.141422), and left whole SNpc (0.127099 vs. 0.137873) significantly differed between IPD patients and HCs (all p < 0.001). The areas under the curve of the left N1 + N2, right N1 + N2, left N1, right N1, left N2, right N2, left whole SNpc, and right whole SNpc were 0.994 (sensitivity, 98.0%; specificity, 94.0%), 0.985, 0.804, 0.802, 0.777, 0.766, 0.632, and 0.606, respectively.ConclusionOur NM-MRI template-based CR measurements revealed significant differences between early-stage IPD patients and HCs. The CR values of the left N1 + N2 demonstrated the highest diagnostic performance.

Relationship between Substantia Nigra Neuromelanin Imaging and Dual Alpha-Synuclein Labeling of Labial Minor in Salivary Glands in Isolated Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease.

We investigated the presence of misfolded alpha-Synuclein (α-Syn) in minor salivary gland biopsies in relation to substantia nigra pars compacta (SNc) damage measured using magnetic resonance imaging in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and Parkinson’s disease (PD) as compared to healthy controls. Sixty-one participants (27 PD, 16 iRBD, and 18 controls) underwent a minor salivary gland biopsy and were scanned using a 3 Tesla MRI. Deposits of α-Syn were found in 15 (55.6%) PD, 7 (43.8%) iRBD, and 7 (38.9%) controls using the anti-aggregated α-Syn clone 5G4 antibody and in 4 (14.8%) PD, 3 (18.8%) iRBD and no control using the purified mouse anti-α-Syn clone 42 antibody. The SNc damages obtained using neuromelanin-sensitive imaging did not differ between the participants with versus without α-Syn deposits (irrespective of the antibodies and the disease group). Our study indicated that the α-Syn detection in minor salivary gland biopsies lacks sensitivity and specificity and does not correlate with the SNc damage, suggesting that it cannot be used as a predictive or effective biomarker for PD.

Evaluation of the Swallow-Tail Sign and Correlations of Neuromelanin Signal with Susceptibility and Relaxations.

The presence of a swallow-tail sign in the nigrosome-1 with hyperintense signal shown on the susceptibility-weighted imaging (SWI) has been shown to be sensitive in detecting the abnormal iron deposits in this area. A systematic evaluation in healthy subjects is required before this tool can be recommended in a widespread application. We evaluated a simple and practical SWI approach using a multiecho gradient-echo sequence with an improved contrast-to-noise ratio (CNR). We also evaluated the association of the neuromelanin imaging contrast behavior with the susceptibility and relaxation measurements. Twenty-five older and 23 young healthy adults were evaluated. The CNRs of the nigrosome-1 were compared along with method and group. Correlations of the nigrosome-1 neuromelanin signal in the neuromelanin-sensitive imaging with CNRs in the susceptibility, T1 and T2 mappings were examined. Two different coils were used to confirm the reproducibility. Compared with the single-echo, multiecho SWI can improve the CNR of the swallow-tail sign. We found significant correlations between neuromelanin signal and CNRs in the susceptibility and T2 mappings, and T1 value. The older subjects exhibited increased CNRs compared with the young adults. No significant difference was observed in the measurements between 20 and 64 channels. The multiecho technique allows the high-quality nigrosome-1 images in SWI and allows for a joint analysis of T2* and quantitative-susceptibility mapping at high spatial resolution. The correlations of neuromelanin-sensitive imaging with susceptibility and T2 imply that the iron content in the nigrosome-1 may have significant influences on the hyperintensity of neuromelanin in the magnetization transfer-related contrast.

Parkinson Disease Propagation Using MRI Biomarkers and Partial Least Squares Path Modeling.

The classic Braak neuropathologic staging model in Parkinson disease (PD) suggests that brain lesions progress from the medulla oblongata to the cortex. An alternative model in which neurodegeneration first occurs in the cortex has also been proposed. These 2 models may correspond to different patient phenotypes. To test these 2 models and to investigate whether they were influenced by the presence of REM sleep behavior disorder (RBD), we used multimodal MRI and partial least squares path modeling (PLS-PM) assuming that patients with RBD followed distinct neurodegeneration pattern. Fifty-four patients with PD (34 with RBD) and 25 healthy volunteers were scanned with T1-weighted, diffusion tensor, and neuromelanin-sensitive imaging. Volume, signal, and mean, axial, and radial diffusivities were calculated in brainstem, basal forebrain, and cortical regions. PLS-PM, estimating a network of causal relationships between blocks of variables, was used to build and test an analytical model based on Braak staging. The overall quality of the model was assessed with goodness of fit coefficient (Gof). PLS-PM was run on patients with PD with RBD and without RBD separately. In PD with RBD, a brainstem-to-cortex model had significant Gof (0.71, p = 0.01), whereas a cortex-to-brainstem model did not. In contrast, in patients with PD without RBD, the brainstem-to-cortex model was not significant (Gof = 0.64, p = 0.27), and the cortex-to-brainstem model was highly significant (Gof = 0.72, p = 0.008). With the PLS-PM imaging-based model, the neurodegeneration pattern of patients with PD with RBD was consistent with the Braak brainstem-to-cortex model, whereas that of patients without RBD followed the cortex-to-brainstem model.

Multimodal assessment of nigrosomal degeneration in Parkinson's disease

BackgroundApproximately forty percent of all dopaminergic neurons in SNpc are located in five dense neuronal clusters, named nigrosomes. T2- or T2*-weighted images are used to delineate the largest nigrosome, named nigrosome-1. In these images, nigrosome-1 is a hyperintense region in the caudal and dorsal portion of the T2- or T2*-weighted substantia nigra. In PD, nigrosome-1 experiences iron accumulation, which leads to a reduction in T2-weighted hyperintensity. Here, we examine neuromelanin-depletion and iron deposition in regions of interest (ROIs) derived from quantitative-voxel based morphometry (qVBM) on neuromelanin-sensitive images and compare the ROIs with nigrosome-1 identified in T2*-weighted images. MethodsNeuromelanin-sensitive and multi-echo gradient echo imaging data were obtained. R2* was calculated from multi-echo gradient echo imaging data. qVBM analysis was performed on neuromelanin-sensitive images and restricted to SNpc. Mean neuromelanin-sensitive contrast and R2* was measured from the resulting qVBM clusters. Nigrosome-1 was segmented in T2*-weighted images of control subjects and its location was compared to the spatial location of the qVBM clusters. ResultsTwo bilateral clusters emerged from the qVBM analysis. These clusters showed reduced neuromelanin-sensitive contrast and increased mean R2* in PD as compared to controls. Cluster-1 from the qVBM analysis was in a similar spatial location as nigrosome-1, as seen in T2*-weighted images. ConclusionqVBM cluster-1 shows reduced neuromelanin-sensitive contrast and is in a similar spatial position as nigrosome-1. This region likely corresponds to nigrosome-1 while the second cluster may correspond to nigrosome-2.

Multimodal Magnetic Resonance Imaging Quantification of Brain Changes in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative clinically heterogeneous disorder, formal diagnosis being based on postmortem histological brain examination. We aimed to perform a precise in vivo staging of neurodegeneration in PSP using quantitative multimodal MRI. The ability of MRI biomarkers to differentiate PSP from PD was also evaluated. Eleven PSP patients were compared to 26 age-matched healthy controls and 51 PD patients. Images were acquired at 3 Tesla (three-dimensional T1 -weighted, diffusion tensor, and neuromelanin-sensitive images) and 7 Tesla (three-dimensional-T2 * images). Regions of interest included the cortical areas, hippocampus, amygdala, basal ganglia, basal forebrain, brainstem nuclei, dentate nucleus, and cerebellum. Volumes, mean diffusivity, and fractional anisotropy were measured. In each region, a threshold value for group categorization was calculated, and four grades of change (0-3) were determined. PSP patients showed extensive volume decreases and diffusion changes in the midbrain, SN, STN, globus pallidus, basal forebrain, locus coeruleus, pedunculopontine nucleus, and dentate nucleus, in close agreement with the degrees of impairment in histological analyses. The predictive factors for the separation of PSP and healthy controls were, in descending order, the neuromelanin-based SN volume; midbrain fractional anisotropy; volumes of the midbrain, globus pallidus, and putamen; and fractional anisotropy in the locus coeruleus. The best predictors for separating PSP from PD were the neuromelanin-based volume in the SN, fractional anisotropy in the pons, volumes of the midbrain and globus pallidus, and fractional anisotropy in the basal forebrain. These results suggest that it is possible to evaluate brain neurodegeneration in PSP noninvasively, even in small brainstem nuclei, in close agreement with previously published histological data. © 2019 International Parkinson and Movement Disorder Society.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Locus Coeruleus atrophy doesn\u2019t relate to fatigue in Parkinson\u2019s disease

Fatigue is a frequent complaint among healthy population and one of the earliest and most debilitating symptoms in Parkinson’s disease (PD). Earlier studies have examined the role of dopamine and serotonin in pathogenesis of fatigue, but the plausible role of noradrenalin (NA) remains underexplored. We investigated the relationship between fatigue in Parkinsonian patients and the extent of degeneration of Locus Coeruleus (LC), the main source of NA in the brain. We quantified LC and Substantia Nigra (SN) atrophy using neuromelanin-sensitive imaging, analyzed with a novel, fully automated algorithm. We also assessed patients’ fatigue, depression, sleep disturbance and vigilance. We found that LC degeneration correlated with the levels of depression and vigilance but not with fatigue, while fatigue correlated weakly with atrophy of SN. These results indicate that LC degeneration in Parkinson’s disease is unlikely to cause fatigue, but may be involved in mood and vigilance alterations.

Motor asymmetry and neuromelanin imaging: Concordance in Parkinson's disease

BackgroundThe onset of motor symptoms in Parkinson's disease (PD) is characteristically asymmetric and correlates with dopaminergic deficit of contralateral basal ganglia. This study explored the concordance between motor asymmetry and changes of substantia nigra pars compacta (SNc) using neuromelanin-sensitive imaging. MethodsForty-four subjects with PD and fifteen healthy controls were included in this study. Clinical laterality (CL) was based on the motor sub scores of the Unified Parkinson's Disease Rating Scale-Part III. All subjects underwent neuromelanin-sensitive imaging and imaging laterality (IL) was based on the differences between contrast ratios of the right and left lateral SNc. Concordance was evaluated by correlating CL and IL. ResultsMotor asymmetry at disease onset was reported in 97.72% of subjects with PD, of which 65.90% reported right-sided onset. Forty-three subjects were right-handed and 68.18% reported onset of symptoms on dominant side. Right CL was observed in 59.09%, left CL in 40.90%, right IL in 11.36% and left IL in 88.63%. Concordance was established in 61.36%, majority of whom had a combination of right CL and left IL. In healthy controls, a significantly lower contrast ratio of the left lateral SNc was also noted. ConclusionsHandedness may correlate with motor asymmetry and left hemisphere may have a predilection for neurodegeneration. The finding of significant neuronal loss of left SNc in controls warrants further evaluation for better understanding of motor asymmetry in PD. Neuromelanin sensitive imaging can be a useful tool to study the relationship between motor asymmetry and nigrostriatal dysfunction.

Imaging Parkinsonian Pathology in Substantia Nigra with MRI

The substantia nigra pars compacta (SNc) and its projection to the striatum undergo profound degeneration in Parkinson’s disease (PD). Literature on imaging PD-related changes in the nigrostriatal system using iron-sensitive and diffusion-sensitive MRI contrasts has been contentious, with both negative and positive results reported in each contrast. These incompatible findings may be due to the inaccurate placement of regions of interest for the SNc. Histologically, SNc is characterized by the presence of melanized dopamine neurons, whereas the substantia nigra pars reticulata is characterized by high iron content. Despite this histology, previous studies have frequently relied upon iron-sensitive MRI contrast when segmenting the SNc. This is also problematic since recent work found iron-sensitive and neuromelanin-sensitive contrasts are largely non-overlapping in substantia nigra. Since neuromelanin-sensitive MRI contrast colocalizes with the melanized dopamine neurons of the SNc upon radiologic–histologic correlation, the use of neuromelanin-sensitive MRI will allow for accurate localization of SNc and better capture parkinsonian pathobiology than iron-sensitive MRI. This article outlines iron-sensitive and diffusion-sensitive MRI contrasts, and provides an overview of neuromelanin-sensitive MRI techniques. The application of these techniques to image parkinsonian pathobiology in substantia nigra is then reviewed, with a focus on neuromelanin-sensitive imaging methods for the accurate and reproducible study of PD-related changes in SNc. These advances may help resolve current controversies surrounding MRI investigations of substantia nigra in PD and related disorders.

Nigrosome Imaging and Neuromelanin Sensitive MRI in Diagnostic Evaluation of Parkinsonism.

Recent developments in magnetic resonance imaging (MRI) techniques have offered new research opportunities to visualize in vivo substantia nigra pathology in Parkinson's disease (PD). This paper summarizes the main findings of nigrosome imaging and neuromelanin sensitive MRI studies in patients with PD and other parkinsonisms. The PubMed database was searched from 2005 to 2017 using the following keywords: Parkinson's disease and parkinsonism, in combination with MRI, nigrosome, neuromelanin, and iron. Only publications in English were included. Nigrosome or dorsal nigral hyperintensity abnormalities are studied using T2* and susceptibility weighted imaging MRI sequences in most studies, whereas Neuromelanin imaging is usually performed using T1-weighted fast spin echo sequence. Nigrosome abnormalities have been consistently demonstrated in PD patients, and nigrosome imaging has high sensitivity and specificity in distinguishing PD from healthy controls, though it is unable to reliably separate PD from atypical parkinsonisms. Reduced neuromelanin-related signals and/or volume loss in neuromelanin containing structures have been found in PD patients, and neuromelanin sensitive MRI imaging can also discriminate PD patients from healthy controls with high accuracy, though there is a degree of heterogeneity in the imaging findings. Preliminary findings suggested that longitudinal change of neuromelanin signal could be detected in PD, raising the possibility of using it as a marker of disease progression. Nigrosome imaging and neuromelanin sensitive MRI are promising tools to study nigral pathology and to improve the diagnosis of PD. However, further studies are required to standardize analysis approaches, confirm longitudinal changes, and assess their generalizability.

Three‐dimensional neuromelanin‐sensitive magnetic resonance imaging of the substantia nigra in Parkinson's disease

The aim was to investigate the diagnostic utility of signal intensity measurement of the substantia nigra pars compacta (SNc) using three-dimensional (3D) neuromelanin-sensitive magnetic resonance imaging (MRI), for discrimination of patients with Parkinson's disease (PD) from healthy controls. T1-weighted neuromelanin-sensitive images of 16 patients with PD and 15 controls were quantitatively analyzed by placing circular 10 mm2 regions of interest over the central and lateral parts of the bilateral SNc and anterior to the cerebral aqueduct at three levels of the midbrain. Signal intensities and contrast ratios (CRs) were calculated, after which significant differences, correlations, sensitivity and specificity were calculated. The CRs of the central and lateral SNc were significantly lower in patients with PD. Lateral CRs were lower than the central CRs in both groups and significantly correlated with duration of illness. CRs of central and lateral parts of the SNc also correlated with the Unified Parkinson's Disease Rating Scale III OFF state scores. Receiver operating characteristic analysis revealed lateral CRs to be more sensitive and central CRs to be more specific for the discrimination of patients with PD from controls. Contrast ratio analysis of the SNc using 3D neuromelanin-sensitive MRI may serve as a quick and accurate tool to discern between patients with PD and healthy controls.

Advances in MRI Methodology.

Magnetic resonance imaging (MRI) is a non-invasive technique which can provide comprehensive, multi-parametric information on brain anatomy, function and metabolism. This chapter will give a brief introduction to the basic principles of MR and cover the evolution of image acquisition. Given the versatility of MR, a vast range of MR applications will be discussed, including structural, diffusion tensor, functional, perfusion and neuromelanin-sensitive imaging, as well as quantitative susceptibility mapping. This chapter will also cover methodological developments in MRI, including image analysis approaches that can be tailored according to experimental design or aims. The ultimate goal of this chapter is to equip readers with a fundamental understanding of the proficiencies and limitations of MR techniques and their corresponding analysis approaches.

Neuromelanin-sensitive imaging in patients with idiopathic rapid eye movement sleep behaviour disorder.

This scientific commentary refers to ‘The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder’, by Ehrminger et al. (doi: 10.1093/brain/aww006 )

The coeruleus/subcoeruleus complex in idiopathic rapid eye movement sleep behaviour disorder.

Idiopathic rapid eye movement sleep behaviour disorder is characterized by nocturnal violence, increased muscle tone during rapid eye movement sleep and the lack of any other neurological disease. However, idiopathic rapid eye movement sleep behaviour disorder can precede parkinsonism and dementia by several years. Using 3 T magnetic resonance imaging and neuromelanin-sensitive sequences, we previously found that the signal intensity was reduced in the locus coeruleus/subcoeruleus area of patients with Parkinson's disease and rapid eye movement sleep behaviour disorder. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex with neuromelanin-sensitive imaging in 21 patients with idiopathic rapid eye movement sleep behaviour disorder and compared the results with those from 21 age- and gender-matched healthy volunteers. All subjects underwent a clinical examination, motor, cognitive, autonomous, psychological, olfactory and colour vision tests, and rapid eye movement sleep characterization using video-polysomnography and 3 T magnetic resonance imaging. The patients more frequently had preclinical markers of alpha-synucleinopathies, including constipation, olfactory deficits, orthostatic hypotension, and subtle motor impairment. Using neuromelanin-sensitive imaging, reduced signal intensity was identified in the locus coeruleus/subcoeruleus complex of the patients with idiopathic rapid eye movement sleep behaviour. The mean sensitivity of the visual analyses of the signal performed by neuroradiologists who were blind to the clinical diagnoses was 82.5%, and the specificity was 81% for the identification of idiopathic rapid eye movement sleep behaviour. The results confirm that this complex is affected in idiopathic rapid eye movement sleep behaviour (to the same degree as it is affected in Parkinson's disease). Neuromelanin-sensitive imaging provides an early marker of non-dopaminergic alpha-synucleinopathy that can be detected on an individual basis.

Quantitative Analysis Versus Visual Assessment of Neuromelanin MR Imaging for the Diagnosis of Parkinson's disease.

Specific MR sequences have been able to identify the loss of neuromelanin in the substantia nigra (SN) of early stage Parkinson's disease (PD) patients. Since this technique may have a significant impact in clinical patient management, easy and widely available imaging analysis is needed for routine use. In this study we compared a quantitative analysis with a visual assessment of SN neuromelanin-sensitive MR images in early stage PD patients, in terms of pattern changes recognition and diagnostic accuracy. The inclusion criteria were untreated "de novo" PD patients or a 2-5 year PD duration; in addition, age matched controls were enrolled. These were studied with a high-resolution T1-weighted MR imaging sequence at 3.0 Tesla to visualize neuromelanin. The primary outcome was the comparison of quantitative width measurement with visual assessment by experienced neuroradiologists of SN neuromelanin sensitive MR images for PD diagnosis. A total of 12 "de novo" PD patients, 10 PD patients with 2-5 year disease duration and 10 healthy controls were evaluated. We obtained a good accuracy in discriminating early-stage PD patients from controls using either a quantitative width measurement of the T1 high signal or a simple visual image inspection of the SN region. Visual inspection of neuromelanin-sensitive MR images by experienced neuroradiologists provides comparable results to quantitative width measurement in the detection of early stage PD SN changes and may become a useful tool in clinical practice.

Neuromelanin-sensitive magnetic resonance imaging: a promising technique for depicting tissue characteristics containing neuromelanin.

Idiopathic Parkinson's disease (IPD) is a progressive, neurodegenerative movement disorder characterized by bradykinesia, muscular rigidity, postural instability and tremor. IPD is usually diagnosed based on clinical findings, but diagnoses are only 75–90% accurate when compared with autopsy results. Improving diagnostic accuracy is critical for the early differentiation of IPD from other Parkinsonism-related disorders because of differences in their prognoses and treatment. Furthermore, IPD is clinically heterogeneous, with variable prognosis. Although the biological function of neuromelanin has not yet been determined, the selective vulnerability of neuromelanin-containing neurons in patients with IPD suggests a role for this pigment in neurodegeneration. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images with very high spatial resolution, enabling the depiction of tissue containing neuromelanin. Here we review recent advances in neuromelanin-sensitive MRI in IPD and related conditions suggesting that neuromelanin may be a potential diagnostic biomarker for IPD. Neuromelanin is a dark polymer produced in specific populations of catecholaminergic neurons in the brain. Three main regions of the brain contain neuromelanin-producing cells: the substantia nigra (SN) of the midbrain, the locus coeruleus (LC) within the pons and the ventrolateral reticular formation and nucleus of the solitary tract in the medulla oblongata. Moreover, two of these regions, the SN and the LC, contain large clusters of pigmented neurons that appear macroscopically as darkened areas (Fedorow et al., 2005). Parkinsonian syndrome is a heterogeneous group of movement disorders, which can be subdivided into IPD, genetic forms of Parkinson's disease (PD) and atypical parkinsonian syndrome. In addition, several other neurodegenerative disorders may show clinical signs of parkinsonism. The etiology, histopathology, clinical manifestation and disease course of these disorders vary significantly. The loss of neuromelanin-containing cells within the SN and LC is a primary pathological diagnostic criterion for IPD. The presence of neuromelanin in these vulnerable cells suggests a role for this pigment in the neurodegenerative process of IPD. The amount of neuromelanin contained within the dopaminergic neurons of the midbrain has been reported to be inversely related to the relative vulnerability of these cells to IPD (Hirsch et al., 1988). In addition to the degree of neuromelanin pigmentation, the position of neuromelanin-containing cells within the nigral complex was also found to be a key factor for neuronal survival in IPD (Damier et al., 1999). Neuromelanin has a high chelating ability for iron, and has been shown to bind neurotoxic and toxic metals that could promote neurodegeneration, such as pesticides and MPP +, suggesting a neuroprotective role of neuromelanin (Zecca et al., 2001). Cell death observed in IPD may be partly due to oxidative stress. This oxidation may also be relieved by neuromelanin. Following its binding of iron, neuromelanin acts as a paramagnetic agent. Recently developed ultra-high-field magnetic resonance imaging (MRI) systems produce T1-weighted neuromelanin-sensitive images of very high spatial resolution (Enochs et al., 1997; Sasaki et al., 2006; Bolding et al., 2013). On these images, neuromelanin-containing tissues appear as foci of high signal intensity, with the intensity proportional to the neuromelanin concentration. Neuromelanin-sensitive MRI can be used to directly measure the volume or concentration of neuromelanin in the SN and LC, suggesting that this modality may be able to distinguish IPD from other related conditions. We review here the usefulness of neuromelanin MRI for the diagnosis of parkinsonian syndrome, with special reference to neuropathological findings.

The coeruleus/subcoeruleus complex in rapid eye movement sleep behaviour disorders in Parkinson’s disease

In Parkinson’s disease, rapid eye movement sleep behaviour disorder is an early non-dopaminergic syndrome with nocturnal violence and increased muscle tone during rapid eye movement sleep that can precede Parkinsonism by several years. The neuronal origin of rapid eye movement sleep behaviour disorder in Parkinson’s disease is not precisely known; however, the locus subcoeruleus in the brainstem has been implicated as this structure blocks muscle tone during normal rapid eye movement sleep in animal models and can be damaged in Parkinson’s disease. Here, we studied the integrity of the locus coeruleus/subcoeruleus complex in patients with Parkinson’s disease using combined neuromelanin-sensitive, structural and diffusion magnetic resonance imaging approaches. We compared 24 patients with Parkinson’s disease and rapid eye movement sleep behaviour disorder, 12 patients without rapid eye movement sleep behaviour disorder and 19 age- and gender-matched healthy volunteers. All subjects underwent clinical examination and characterization of rapid eye movement sleep using video-polysomnography and multimodal imaging at 3 T. Using neuromelanin-sensitive imaging, reduced signal intensity was evident in the locus coeruleus/subcoeruleus area in patients with Parkinson’s disease that was more marked in patients with than those without rapid eye movement sleep behaviour disorder. Reduced signal intensity correlated with the percentage of abnormally increased muscle tone during rapid eye movement sleep. The results confirmed that this complex is affected in Parkinson’s disease and showed a gradual relationship between damage to this structure, presumably the locus subcoeruleus, and abnormal muscle tone during rapid eye movement sleep, which is the cardinal marker of rapid eye movement sleep behaviour disorder. In longitudinal studies, the technique may also provide early markers of non-dopaminergic Parkinson’s disease pathology to predict the occurrence of Parkinson’s disease.