Neuromelanin-sensitive Magnetic Resonance Imaging Research Articles

A longitudinal study of neuromelanin-sensitive magnetic resonance imaging in Parkinson’s disease

PurposeNeuromelanin-sensitive MR imaging (NMI) is an increasingly powerful tool for the diagnosis of Parkinson’s disease (PD). This study was undertaken to evaluate longitudinal changes on NMI in PD patients. MethodsWe examined longitudinal changes on NMI in 14 PD patients. The area and contrast ratio (CR) of the substantia nigra pars compacta (SNc) were comparatively analyzed. ResultsThe total area and CR of the SNc upon follow-up NMI were significantly smaller than those on initial NMI (from 33.5±18.9 pixels and 6.35±2.86% to 21.5±16.7 pixels and 4.19±2.11%; Wilcoxon signed-rank test, p<0.001 and p=0.022, respectively). The area and CR of the dominant side SNc upon initial NMI were significantly greater than those on follow-up NMI (from 15.3±9.1 pixels and 6.5±2.7% to 7.9±8.5 pixels and 3.7±2.9%; Wilcoxon signed-rank test, p=0.002 and p=0.007, respectively). On a case-by-case basis, the area of the SNc invariably decreased upon follow-up NMI in all patients. We further demonstrated that the total area and CR of the SNc negatively correlated with disease duration (Pearson correlation coefficient, r=−0.63, p<0.001 and r=−0.41, p=0.031, respectively). In area analyses, our results demonstrated very high intraclass correlation coefficients for both intra- and inter-rater reliability. ConclusionNMI is a useful and reliable tool for detecting neuropathological changes over time in PD patients.

Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging

Leading a mentally stimulating life may build up a reserve of neural and mental resources that preserve cognitive abilities in late life. Recent autopsy evidence links neuronal density in the locus coeruleus (LC), the brain's main source of norepinephrine, to slower cognitive decline before death, inspiring the idea that the noradrenergic system is a key component of reserve (Robertson, I. H. 2013. A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease. Neurobiol. Aging. 34, 298–308). Here, we tested this hypothesis using neuromelanin-sensitive magnetic resonance imaging to visualize and measure LC signal intensity in healthy younger and older adults. Established proxies of reserve, including education, occupational attainment, and verbal intelligence, were linearly correlated with LC signal intensity in both age groups. Results indicated that LC signal intensity was significantly higher in older than younger adults and significantly lower in women than in men. Consistent with the LC-reserve hypothesis, both verbal intelligence and a composite reserve score were positively associated with LC signal intensity in older adults. LC signal intensity was also more strongly associated with attentional shifting ability in older adults with lower cognitive reserve. Together these findings link in vivo estimates of LC neuromelanin signal intensity to cognitive reserve in normal aging.

Substantia nigra neuromelanin-MR imaging differentiates essential tremor from Parkinson's disease.

Essential tremor (ET) is a very common movement disorder that has no diagnostic markers. Differentiation with Parkinson's disease (PD) can be clinically challenging in some cases, with a high rate of misdiagnosis. Magnetic resonance imaging (MRI) studies have been able to identify neuromelanin changes in the substantia nigra (SN) of PD patients, but they have thus far not been investigated in ET. In this study, we aimed to characterize neuromelanin-MR signal changes in ET and evaluate its diagnostic accuracy in the differential diagnosis with PD. The inclusion criteria were patients with ET and untreated "de novo" PD patients; in addition, age-matched controls were enrolled. These were studied with a high-resolution T1-weighted MRI sequence at 3.0 Tesla to visualize neuromelanin. The primary outcomes were the area and width of the SN region with high signal. A total of 15 ET patients and 12 "de novo" PD patients were evaluated. The area and width of the T1 high signal in the SN region were markedly decreased in the PD group compared with the ET and age-matched controls, and a greater decrease was seen in the ventrolateral segment. The neuromelanin measures in the ET group, although slightly lower, were not significantly different from the healthy control group. We obtained a sensitivity of 66.7% and a specificity of 93.3% in discriminating ET from early-stage PD. Neuromelanin-sensitive MRI techniques can discriminate ET from early-stage tremor-dominant PD and can be a useful clinical tool in the evaluation of tremor disorders. © 2015 International Parkinson and Movement Disorder Society.

Substantia nigra neuromelanin magnetic resonance imaging in de novo Parkinson's disease patients

Depigmentation of the substantia nigra (SN) and locus coeruleus (LC) is a conspicuous pathological feature of Parkinson's disease (PD) and is related to the loss of neuromelanin, whose paramagnetic properties result in high signal on specific T1-weighted magnetic resonance imaging (MRI). Recent studies have suggested that neuromelanin decrease in the SN and LC of PD patients may emerge as a possible diagnostic biomarker. The SN neuromelanin signal in de novo and early stage PD patients was studied to assess its diagnostic accuracy. This is the first study based on a semi-automated MRI analysis of the neuromelanin signal in de novo PD patients. The inclusion criteria were untreated de novo PD and a 2-5year disease duration; in addition, age matched healthy controls were enrolled. These were studied with a high-resolution T1-weighted MRI sequence at 3T to visualize neuromelanin. The primary outcome was SN high signal area, length and neuromelanin/midbrain ratio obtained with semi-automated methods. A total of 12 de novo PD patients and 10 PD patients with a 2-5year disease duration were evaluated. The area, length of the SN T1 high signal and the SN neuromelanin/midbrain ratio were markedly decreased in the PD groups compared with age-matched controls, with a substantial overlap between the two PD groups. Neuromelanin-sensitive MRI techniques can discriminate PD patients from healthy individuals with high sensitivity and specificity. Our findings are consistent with recent findings showing that PD neuromelanin changes remain stable during the course of the disease.

Differentiation of early-stage parkinsonisms using neuromelanin-sensitive magnetic resonance imaging.

The purpose of this study was to investigate whether the signal intensity of the substantia nigra pars compacta (SNc) and locus coeruleus (LC) on neuromelanin-sensitive magnetic resonance imaging (MRI) can discriminate early-stage parkinsonism disorders, for which differential diagnosis is generally difficult. Neuromelanin-sensitive MRI at 3 T was performed in 53 patients with early parkinsonism and 22 healthy controls. After an observation period of >1.5 year, the patients were clinically diagnosed with Parkinson's disease (PD; n = 30), multiple system atrophy with predominant parkinsonism (MSA-P; n = 10), or progressive supranuclear palsy syndrome (PSPS; n = 13). The signal intensity of the lateral, central, and medial parts of the SNc and the LC were measured and the contrast ratios (CR) against adjacent white-matter structures was calculated. The CR of the lateral SNc was lower in the PD and MSA-P groups than in the PSPS and control groups (p = 0.0001-0.05). The CR of the LC was lower in the PD group than in the other groups (p = 0.0001-0.05). Sensitivity and specificity of the CRs for discriminating PD from MSA-P was 60% and 90%, respectively, those for PD/PSPS were 63-88% and 77-92%, respectively, and those for MSA-P/PSPS were 80% and 85%, respectively. These properties were comparable or better to MIBG scintigraphy. Neuromelanin-sensitive MRI can depict differences in signal intensity of the lateral SNc and the LC among the parkinsonism disorders at their early stages.

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.

3D neuromelanin-sensitive magnetic resonance imaging with semi-automated volume measurement of the substantia nigra pars compacta for diagnosis of Parkinson’s disease

Neuromelanin-sensitive MRI has been reported to be used in the diagnosis of Parkinson's disease (PD), which results from loss of dopamine-producing cells in the substantia nigra pars compacta (SNc). In this study, we aimed to apply a 3D turbo field echo (TFE) sequence for neuromelanin-sensitive MRI and to evaluate the diagnostic performance of semi-automated method for measurement of SNc volume in patients with PD. We examined 18 PD patients and 27 healthy volunteers (control subjects). A 3D TFE technique with off-resonance magnetization transfer pulse was used for neuromelanin-sensitive MRI on a 3T scanner. The SNc volume was semi-automatically measured using a region-growing technique at various thresholds (ranging from 1.66 to 2.48), with the signals measured relative to that for the superior cerebellar peduncle. Receiver operating characteristic (ROC) analysis was performed at all thresholds. Intra-rater reproducibility was evaluated by intraclass correlation coefficient (ICC). The average SNc volume in the PD group was significantly smaller than that in the control group at all the thresholds (P < 0.01, student t test). At higher thresholds (>2.0), the area under the curve of ROC (Az) increased (0.88). In addition, we observed balanced sensitivity and specificity (0.83 and 0.85, respectively). At lower thresholds, sensitivity tended to increase but specificity reduced in comparison with that at higher thresholds. ICC was larger than 0.9 when the threshold was over 1.86. Our method can distinguish the PD group from the control group with high sensitivity and specificity, especially for early stage of PD.

Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging

Neuromelanin-sensitive magnetic resonance imaging is able to visualize changes associated with neuronal loss in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) in patients with Parkinson's disease (PD). However, the diagnostic accuracy of this technique in the early stages of PD remains unknown. Therefore, changes in the SNc and LC observed using neuromelanin imaging were evaluated in patients with early PD. The signal intensities of the lateral, central, and medial parts of the SNc and that of the LC were measured, and the contrast ratios (CRs) were calculated against the adjacent white matter structures. CRs in the lateral part of the SNc and in the LC were significantly reduced in the early PD group when compared with the controls. Sensitivities and specificities in discriminating early PD patients from healthy controls were 73% and 87% in lateral SNc and 82% and 90% in LC, respectively. Neuromelanin imaging can depict signal alterations in the lateral part of the SNc and in the LC in patients with PD, even in its early stage, and can discriminate between these patients and healthy individuals with high sensitivities and specificities.

Monoamine neurons in the human brain stem: anatomy, magnetic resonance imaging findings, and clinical implications

By using high-resolution, conventional, and neuromelanin-sensitive magnetic resonance imaging techniques, we reviewed the normal anatomy of the nuclei consisting of monoamine neurons such as dopaminergic, noradrenergic, and serotoninergic neurons and noted the changes in these nuclei that occur in some degenerative and psychiatric disorders. Multimodal MR images can directly or indirectly help in identifying the substantia nigra, locus ceruleus, and raphe nuclei that contain monoamine neurons. Neuromelanin-sensitive magnetic resonance imaging can detect signal alterations in the substantia nigra pars compacta and/or locus ceruleus that occur in Parkinson's disease and psychiatric disorders such as depression and schizophrenia. This technique seems to be promising for the noninvasive evaluation of the pathological or functional changes in the monoamine system that occur in degenerative and psychiatric disorders.

Neuromelanin-Sensitive MRI

The basics and the technique of magnetic resonance imaging (MRI) for visualizing the neuromelanin present in dopaminergic and noradrenergic nuclei in the substantia nigra pars compacta (SNc) and locus caeruleus (LC) are introduced. Neuromelanin, a black pigment produced during catecholamine synthesis, has paramagnetic T1-shortening effects. Conventional MRI techniques fail to depict the contrast generated by neuromelanin, but neuromelanin-sensitive T1-weighted fast spin echo technique at 3 T allows the direct visualization of the SNc and LC as hyperintense areas. In Parkinson's disease, neuromelanin-related signals from the SNc and LC are diminished, suggesting neuronal degeneration in both the nuclei. In depression and schizophrenia, signals from the LC are reduced while those from the SNc are augmented, suggesting monoamine and dopamine hypotheses, respectively. Neuromelanin-sensitive MRI is a promising technique to elucidate the pathologic or functional changes in the catecholamine neurons of the brain stem that occur in degenerative and psychiatric diseases.

Use of Neuromelanin-Sensitive MRI to Distinguish Schizophrenic and Depressive Patients and Healthy Individuals Based on Signal Alterations in the Substantia Nigra and Locus Ceruleus

We investigated alterations in the substantia nigra pars compacta (SNc) and locus ceruleus (LC) in schizophrenic and depressive patients by using a neuromelanin-sensitive magnetic resonance imaging (MRI) technique that enables direct visualization of these nuclei and examined whether this technique could distinguish between these disorders and healthy subjects. Using a neuromelanin-sensitive T1-weighted MRI technique, we examined 20 schizophrenia patients, 18 depressive patients, and 34 healthy control subjects. The signal intensities of the areas corresponding to the SNc and LC were measured, and the contrast ratios (CR) to the adjacent white matter were calculated. The CR of the SNc was significantly higher in schizophrenic patients (22.6 +/- 5.6) than in depressive patients (19.2 +/- 4.7) and healthy control subjects (19.6 +/- 3.8), whereas the CR of the LC in depressive patients (7.7 +/- 2.4) was significantly lower than that in healthy control subjects (11.0 +/- 3.9) and schizophrenic patients (10.0 +/- 3.1). Further, the difference in the CR between the SNc and LC was significantly greater in schizophrenic patients (12.6 +/- 6.7) than in control subjects (8.6 +/- 4.1). Neuromelanin-sensitive MRI enables visualization of alterations in the SNc and LC that are observed in schizophrenia and depression.