Neuromelanin Magnetic Resonance Imaging Research Articles

Neuromelanin magnetic resonance imaging of substantia nigra and locus coeruleus in Parkinson's disease with freezing of gait.

The downregulation of monoamines, especially dopamine in substantia nigra (SN) and norepinephrine in locus coeruleus (LC), may be responsible for freezing of gait (FOG) pathological basis in Parkinson's disease (PD). Thirty-two Parkinson's disease patients with freezing of gait (PD-FOG), 32 Parkinson's disease patients without freezing of gait (PD-NFOG) and 32 healthy controls (HC) underwent neuromelanin magnetic resonance imaging (NM-MRI). The volume, surface area and contrast to noise ratio (CNR) of SN and LC were measured and compared. The correlation analyses were conducted between the measurements of SN and LC with clinical symptoms. We plotted the receiver operating characteristic (ROC) curve and determined the sensitivity and specificity of the CNR of SN and LC for discriminating the PD-FOG from the PD-NFOG. Both PD-FOG and PD-NFOG showed decreased volume, surface area and CNR of SN compared with HC. The PD-FOG exhibited decreased volume and surface area of LC compared with both PD-NFOG and HC groups, and decreased CNR of LC compared with HC group. The volume, surface area and CNR of SN were negatively correlated with the Unified Parkinson's Disease Rating Scale part III scores. The illness durations in PD patients were negatively correlated with the volume, surface area of SN, while not the CNR. And the volume and surface area of LC were negatively correlated with new freezing of gait questionnaire scores. ROC analyses indicated that the area under the curve (AUC) was 0.865 and 0.713 in the CNR of SN and LC, respectively, in PD versus HC, whereas it was 0.494 and 0.637 respectively, in PD-FOG versus PD-NFOG. Among these, for discriminating the PD from the HC, the sensitivity and specificity in the CNR of the SN was 90.6 and 71.9%, respectively, when the cut-off value was set at 2.101; the sensitivity and specificity in the CNR of the LC was 90.6 and 50.0%, respectively, when the cut-off value for CNR was set at 1.411. The dopaminergic changes in the SN were found across both PD-FOG and PD-NFOG, whilst LC noradrenergic neuron reduction was more evident in PD-FOG.

Application value of multiparametric MRI for evaluating iron deposition in the substantia nigra in Parkinson's disease.

This study aimed to investigate the application value of multi-parametric magnetic resonance imaging (MRI) in the diagnosis of iron deposition in the substantia nigra dense zone in Parkinson's disease (PD) and to evaluate the diagnostic value of the correlation among multi-parametric imaging indicators, clinical stage, and disease duration. Thirty-six patients with clinically confirmed PD and 36 healthy controls were enrolled. The disease course was recorded, and PD severity was graded using the Hoehn-Yahr (H-Y) scale. All subjects underwent magnetic sensitivity weighted imaging (SWI), neuromelanin magnetic resonance imaging (NM-MRI), and a T2*mapping sequence. Based on the fusion of the NM-MRI and SWI amplitude maps, phase maps, and T2*MAPPING value maps, NM-MRI was used to delineate the dense zone of the substantia nigra, which was divided into three sub-regions: upper, middle, and lower. In this way, the amplitude, phase, and R2* values of each sub-region and the average value of the sum of the three sub-regions were obtained simultaneously in the SWI amplitude, phase, and T2*MAPPING maps. The multi-parameter imaging indices were compared between the two groups, and the correlation between them and clinical indices was evaluated in the PD group. The upper (amplitude, phase value, R2* value), middle, and lower (amplitude) right substantia nigra compact zones were significantly different between the PD and control groups. The upper (phase value, R2* value) and middle (amplitude) areas of the left substantia nigra compact zone were also significantly different between the two groups (all P < 0.05). The mean values (amplitude, phase value, R2* value) of the right substantia nigra densification zone and the mean values (phase value) of the left substantia nigra densification zone were also significantly different (all P < 0.05). Amplitudes in the middle and lower parts of the right substantia nigra dense zone were negatively correlated with the H-Y grade (middle: r = -0.475, P = 0.003; lower: r = -0.331, P = 0.049). Amplitudes of the middle and lower parts of the dense zone of the left substantia nigra were negatively correlated with the H-Y grade (middle: r = -0.342, P = 0.041; lower: r = -0.399, P = 0.016). The average amplitude of the right substantia nigra compact zone was negatively correlated with the H-Y grade (r = -0.367, P = 0.027). The average R2* value of the compact zone of the left substantia nigra was positively correlated with the H-Y grade (r = 0.345, P = 0.040). Multiparametric MRI sequence examination has application value in the evaluation of iron deposition in the dense zone of the substantia nigra in PD. Combined with NM-MRI, fusion analysis is beneficial for accurately locating the substantia nigra compact zone and quantitatively analyzing the iron deposition in different sub-regions. Quantitative iron deposition in the middle and lower parts of the substantia nigra dense zone may become an imaging biological indicator for early diagnosis, severity evaluation, and follow-up evaluation of PD and is thus conducive for clinical diagnosis and treatment evaluation.

Neuromelanin-Sensitive Magnetic Resonance Imaging Changes in the Locus Coeruleus/Subcoeruleus Complex in Patients with Typical and Atypical Parkinsonism.

The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Locus coeruleus and substantia nigra neuromelanin magnetic resonance imaging differentiates Parkinson’s disease and essential tremor

BackgroundDifferential diagnosis of essential tremor (ET) and Parkinson’s disease (PD) can still be a challenge in clinical practice. These two tremor disorders may have different pathogenesis related to the substantia nigra (SN) and locus coeruleus (LC). Characterizing neuromelanin (NM) in these structures may help improve the differential diagnosis. MethodsForty-three subjects with tremor-dominant PD (PDTD), 31 subjects with ET, and 30 age- and sex-matched healthy controls were included. All subjects were scanned with NM magnetic resonance imaging (NM-MRI). NM volume and contrast measures for the SN and contrast for the LC were evaluated. Logistic regression was used to calculate predicted probabilities by using the combination of SN and LC NM measures. The discriminative power of the NM measures in detecting subjects with PDTD from ET was assessed with a receiver operative characteristic curve, and the area under the curve (AUC) was calculated. ResultsThe NM contrast-to-noise ratio (CNR) of the LC, the NM volume, and CNR of the SN on the right and left sides were significantly lower in PDTD subjects than in ET subjects or healthy controls (all P < 0.05). Furthermore, when combining the best model constructed from the NM measures, the AUC reached 0.92 in differentiating PDTD from ET. ConclusionThe NM volume and contrast measures of the SN and contrast for the LC provided a new perspective on the differential diagnosis of PDTD and ET, and the investigation of the underlying pathophysiology.

Magnetic resonance imaging of the dopamine system in schizophrenia - A scoping review.

For decades, aberrant dopamine transmission has been proposed to play a central role in schizophrenia pathophysiology. These theories are supported by human in vivo molecular imaging studies of dopamine transmission, particularly positron emission tomography. However, there are several downsides to such approaches, for example limited spatial resolution or restriction of the measurement to synaptic processes of dopaminergic neurons. To overcome these limitations and to measure complementary aspects of dopamine transmission, magnetic resonance imaging (MRI)-based approaches investigating the macrostructure, metabolism, and connectivity of dopaminergic nuclei, i.e., substantia nigra pars compacta and ventral tegmental area, can be employed. In this scoping review, we focus on four dopamine MRI methods that have been employed in patients with schizophrenia so far: neuromelanin MRI, which is thought to measure long-term dopamine function in dopaminergic nuclei; morphometric MRI, which is assumed to measure the volume of dopaminergic nuclei; diffusion MRI, which is assumed to measure fiber-based structural connectivity of dopaminergic nuclei; and resting-state blood-oxygenation-level-dependent functional MRI, which is thought to measure functional connectivity of dopaminergic nuclei based on correlated blood oxygenation fluctuations. For each method, we describe the underlying signal, outcome measures, and downsides. We present the current state of research in schizophrenia and compare it to other disorders with either similar (psychotic) symptoms, i.e., bipolar disorder and major depressive disorder, or dopaminergic abnormalities, i.e., substance use disorder and Parkinson’s disease. Finally, we discuss overarching issues and outline future research questions.

Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis.

BackgroundClinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin‐magnetic resonance imaging (NM‐MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings.ObjectivesThe aim was to investigate the diagnostic accuracy of NM‐MRI in early PD in a multiprotocol setting and to determine and compare serial NM‐MRI changes in PD and controls.MethodsIn this longitudinal case–control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template‐based analysis was applied for subregional substantia nigra NM‐MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed.ResultsAll NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity.ConclusionsWe demonstrate that NM‐MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker‐enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Midbrain atrophy related to parkinsonism in a non-coding repeat expansion disorder: five cases of spinocerebellar ataxia type 31 with nigrostriatal dopaminergic dysfunction

BackgroundSpinocerebellar ataxia type 31 (SCA31) is caused by non-coding pentanucleotide repeat expansions in the BEAN1 gene. Clinically, SCA31 is characterized by late adult-onset, pure cerebellar ataxia. To explore the association between parkinsonism and SCA31, five patients with SCA31 with concomitant nigrostriatal dopaminergic dysfunction (NSDD) development, including three cases of L-DOPA responsive parkinsonism, were analyzed.MethodsTo assess regional brain atrophy, cross-sectional and longitudinal imaging analyses were retrospectively performed using magnetic resonance imaging (MRI) planimetry. The midbrain-to-pons (M/P) area ratio and cerebellar area were measured on midsagittal T1-weighted MRI in five patients with SCA31 with concomitant NSDD (NSDD(+)), 14 patients with SCA31 without NSDD (NSDD(−)), 32 patients with Parkinson’s disease (PD), and 15 patients with progressive supranuclear palsy (PSP). Longitudinal changes in the M/P area ratio were assessed by serial MRI of NSDD(+) (n = 5) and NSDD(−) (n = 9).ResultsThe clinical characteristics assessed in the five patients with NSDD were as follows: the mean age at NSDD onset (72.0 ± 10.8 years), prominence of bradykinesia/akinesia (5/5), rigidity (4/5), tremor (2/5), dysautonomia (0/5), vertical gaze limitation (1/5), and abnormalities on 123I-ioflupane dopamine transporter scintigraphy (3/3) and 3-Tesla neuromelanin MRI (4/4). A clear reduction in the midbrain area and the M/P area ratio was observed in the NSDD(+) group (p < 0.05) while there was no significant difference in disease duration or in the pons area among the NSDD(+), NSDD(−), and PD groups. There was also a significant difference in the midbrain and pons area between NSDD(+) and PSP (p < 0.05). Thus, mild but significant midbrain atrophy was observed in NSDD(+). A faster rate of decline in the midbrain area and the M/P area ratio was evident in NSDD(+) (p < 0.05).ConclusionThe clinical characteristics of the five patients with SCA31 with concomitant NSDD, together with the topographical pattern of atrophy, were inconsistent with PD, PSP, and multiple system atrophy, suggesting that SCA31 may manifest NSDD in association with the pathomechanisms underlying SCA31.

Substantia nigra neuromelanin magnetic resonance imaging in patients with different subtypes of Parkinson disease

Neuromelanin (NM) is a dark pigment that mainly exists in neurons of the substantia nigra pars compacta (SNc). In Parkinson disease (PD) patients, NM concentration decreases gradually with degeneration and necrosis of dopamine neurons, suggesting potential use as a PD biomarker. We aimed to evaluate associations between NM concentration in in vivo SN and PD progression and different motor subtypes using NM magnetic resonance imaging (NM-MRI). Fifty-four patients with idiopathic PD were enrolled. Patients were divided into groups by subtypes with different clinical symptoms: tremor dominant (TD) group and postural instability and gait difficulty (PIGD) group. Fifteen healthy age-matched volunteers were enrolled as controls. All subjects underwent clinical assessment and NM-MRI examination. PD patients showed significantly decreased contrast-to-noise ratio (CNR) values in medial and lateral SN (P < 0.05) compared to controls. CNR values in lateral SN region decreased linearly with PD progression (P = 0.001). PIGD patients showed significant decreases in CNR mean values in lateral SN compared to TD patients (P = 0.004). Diagnostic accuracy of using lateral substantia nigra (SN) in TD and PIGD groups was 79% (sensitivity 76.5%, specificity 78.6%). NM concentration in PD patients decreases gradually during disease progression and differs significantly between PD subtypes. NM may be a reliable biomarker for PD severity and subtype identification.

The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

AbstractBackgroundThe locus coeruleus (LC) is the brain’s main source of norepinephrine and plays a key role in modulating attention and memory processes. In Alzheimer’s disease (AD), the LC has been identified as an early site of tau accumulation and this tau pathology may spread via its connections to the transentorhinal cortex (TEC). Historically, this region has been nearly impossible to study in vivo. However, recent advances in structural magnetic resonance imaging (MRI) have provided opportunities to capture the integrity of LC neurons and their projections. We utilized a combination of neuromelanin‐sensitive and diffusion tensor MRI to examine LC integrity and its role in memory.Method31 older adults (26 cognitively normal; 5 MCI) underwent T1 fast spin echo and diffusion MRI scans as well as neuropsychological testing. Bilateral LC contrast ratios (CRs) were calculated as neuromelanin‐related signal intensities relative to a reference region. In a subset of participants (n=12; 10 cognitively normal, 2 MCI) LC‐TEC white matter pathways were reconstructed using probabilistic tractography in FSL and average fractional anisotropy (FA) was extracted. Logical Memory and CVLT‐2 were used to assess verbal learning and memory.ResultResults revealed lower bilateral LC‐CRs was associated with poorer performance on measures of story learning (LMI; r=0.425, p=.045) and word‐list recall (CVLT‐2 Short Delay Recall: r=.481, p=.006; CVLT‐2 Long Delay Recall: r=.375, p=.038). Tractography analyses indicated that higher FA of the left LC‐TEC tract was associated with poorer story learning (LM1: r=‐.651, p=.02), whereas higher FA of the right LC‐TEC tract was associated with poorer word‐list recall (CVLT‐2 Short Delay Recall: r=‐.599, p=.039; CVLT‐2 Short Delay Cued Recall, r=‐.705, p=.01).ConclusionPreliminary results indicate that neuromelanin and tractography MRI methods can be utilized for in vivo characterization of the human LC. Lower neuromelanin signal, but higher FA is associated with poorer memory performance in a sample of cognitively normal and MCI adults. Greater tau pathology may alter the LC signal and encroaching tau accumulation in the LC‐TEC pathway may initiate neuroinflammatory processes reflected by increased FA. Future work is needed to understand the temporal course and nature of LC changes across the aging‐MCI‐AD continuum.

A distinct neuromelanin magnetic resonance imaging pattern in parkinsonian multiple system atrophy

BackgroundParkinsonian variant of multiple system atrophy is a neurodegenerative disorder frequently misdiagnosed as Parkinson’s disease. No early imaging biomarkers currently differentiate these disorders.MethodsSimple visual imaging analysis of the substantia nigra and locus coeruleus in neuromelanin-sensitive magnetic resonance imaging and nigrosome 1 in susceptibility-weighted sequences was performed in thirty patients with parkinsonian variant of multiple system atrophy fulfilling possible/probable second consensus diagnostic criteria. The neuromelanin visual pattern was compared to patients with Parkinson’s disease with the same disease duration (n = 10) and healthy controls (n = 10). Substantia nigra semi-automated neuromelanin area/signal intensity was compared to the visual data.ResultsGroups were similar in age, sex, disease duration, and levodopa equivalent dose. Hoehn & Yahr stage was higher in parkinsonian multiple system atrophy patients, 69% of whom had normal neuromelanin size/signal, significantly different from Parkinson’s disease patients, and similar to controls. Nigrosome 1 signal was lost in 74% of parkinsonian multiple system atrophy patients. Semi-automated neuromelanin substantia nigra signal, but not area, measurements were able to differentiate groups.ConclusionsIn patients with parkinsonism, simple visual magnetic resonance imaging analysis showing normal neuromelanin substantia nigra and locus coeruleus, combined with nigrosome 1 loss, allowed the distinction of the parkinsonian variant of multiple system atrophy from Parkinson’s disease and healthy controls. This easy and widely available method was superior to semi-automated measurements in identifying specific imaging changes in substantia nigra and locus coeruleus.

Neuromelanin Magnetic Resonance Imaging of the Substantia Nigra in Huntington's Disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder inducing motor, psychiatric changes and cognitive decline, characterized pathologically by striatal atrophy. Pathological changes in the extra-striatal structures, such as the substantia nigra (SN), and abnormalities in pre-synaptic striatal dopamine neurotransmission are also known to occur. Neuromelanin (NM)-sensitive magnetic resonance imaging (NM-MRI) is an innovative technique that was recently developed allowing the in vivo study of pathological changes in the dopaminergic neurons of the SN. To investigate the SN MR signal in HD patients. We performed a cross-sectional study using a specific T1-weighted MR sequence to visualize NM. The areas and signal intensity contrast ratios of the T1 hyperintense SN regions were obtained using a semi-automatic segmentation method. A total of 8 HD patients and 12 healthy subjects were evaluated. The SN area was markedly reduced in the HD group compared with the control group (p = 0.02), even after normalization of the SN area with the midbrain area and age correction (p = 0.01). There was a significant reduction in the intensity contrast ratio of the hyperintense SN areas to crus cerebri in HD patients comparing with controls (p = 0.04) after correction for age. NM-sensitive MR techniques were used for the first time to study the SN in HD patients, showing loss of NM in this region, supporting the implication of dopaminergic neuronal changes in disease pathology. Future research needs to be conducted to evaluate the potential of SN area and intensity contrast as biomarkers for HD.

Convolutional neural network-based segmentation can help in assessing the substantia nigra in neuromelanin MRI

PurposeThis study aimed to evaluate the accuracy and diagnostic test performance of the U-net-based segmentation method in neuromelanin magnetic resonance imaging (NM-MRI) compared to the established manual segmentation method for Parkinson’s disease (PD) diagnosis.MethodsNM-MRI datasets from two different 3T-scanners were used: a “principal dataset” with 122 participants and an “external validation dataset” with 24 participants, including 62 and 12 PD patients, respectively. Two radiologists performed SNpc manual segmentation. Inter-reader precision was determined using Dice coefficients. The U-net was trained with manual segmentation as ground truth and Dice coefficients used to measure accuracy. Training and validation steps were performed on the principal dataset using a 4-fold cross-validation method. We tested the U-net on the external validation dataset. SNpc hyperintense areas were estimated from U-net and manual segmentation masks, replicating a previously validated thresholding method, and their diagnostic test performances for PD determined.ResultsFor SNpc segmentation, U-net accuracy was comparable to inter-reader precision in the principal dataset (Dice coefficient: U-net, 0.83 ± 0.04; inter-reader, 0.83 ± 0.04), but lower in external validation dataset (Dice coefficient: U-net, 079 ± 0.04; inter-reader, 0.85 ± 0.03). Diagnostic test performances for PD were comparable between U-net and manual segmentation methods in both principal (area under the receiver operating characteristic curve: U-net, 0.950; manual, 0.948) and external (U-net, 0.944; manual, 0.931) datasets.ConclusionU-net segmentation provided relatively high accuracy in the evaluation of the SNpc in NM-MRI and yielded diagnostic performance comparable to that of the established manual method.

The utility of the combined use of 123I-FP-CIT SPECT and neuromelanin MRI in differentiating Parkinson's disease from other parkinsonian syndromes.

Neuromelanin magnetic resonance imaging (NmMRI) and 123I-FP-CIT dopamine transporter single photon emission computed tomography (DAT-SPECT) provide specific information that distinguishes Parkinson's disease (PD) from non-degenerative parkinsonian syndrome (NDPS). To determine whether a multiparametric scoring system (MSS) could improve accuracy compared to each parameter of DAT-SPECT and NmMRI in differentiating PD from NDPS. A total of 49 patients, including 14 with NDPS, 30 with PD, and five with atypical parkinsonian disorder (APD) underwent both NmMRI and DAT-SPECT and were evaluated. The average (Ave) and the asymmetry index (AI) were calculated in the substantia nigra compacta area (SNc-area), SNc midbrain-tegmentum contrast ratio (SNc-CR), and specific binding ratio (SBR). Cut-off values were determined, using receiver operating characteristic (ROC) analysis, for the differentiation of PD from NDPS on the statistically significant parameters. All cases were scored as either 1 (PD) or 0 (NDPS) for each parameter according to its threshold. These individual scores were totaled for each case, yielding a combined score for each case to obtain a cut-off value for the MSS. The Ave-SNc-area, Ave-SNc-CR, and Ave-SBR in PD were significantly lower than those in NDPS. The AI-SNc-area and AI-SBR in PD were significantly higher than those in NDPS. Of the five parameters, the highest accuracy was 93% for the Ave-SNc-area. For the MSS, a cut-off value of 3 was the accuracy of 96%. Besides, no significant difference was observed between PD and APD on all parameters. An MSS has comparable or better accuracy compared to each parameter of DAT-SPECT and NmMRI in distinguishing PD from NDPS.

Neuromelanin MRI is useful for monitoring motor complications in Parkinson's and PARK2 disease.

Parkinson's disease (PD) is caused by the loss of dopaminergic neurons. Recently, specific T1-weighted magnetic resonance imaging (MRI) at 3 Tesla was reported to visualize neuromelanin (NM)-related contrast of dopaminergic neurons. Using NM-MRI, we analyzed whether disease severity and motor complications (MC) are associated with the degree of dopaminergic neuronal degeneration in the substantia nigra pars compacta (SNc) in patients with idiopathic PD (PD) and PARK2. We examined 27 individuals with PD, 11 with PARK2, and a control group of 18. A 3T MRI was used to obtain a modified NM-sensitive T1-weighted fast-spin echo sequence. The size of the SNc was determined as the number of pixels with signal intensity higher than background signal intensity +2 standard deviations. NM-MRI indicated that the T1 hyperintense area in the SNc in patients with PD and PARK2 was significantly smaller than that in control subjects. When compared with the PD group without MC, both PD with MC and PARK2 showed a markedly smaller size of NM-rich SNc area. Receiver operating characteristic curve analysis revealed a sensitivity of 86.96% and a specificity of 100% in discriminating between patients with and without MC (area under the curve=0.98). Correlation analysis between the T1 hyperintense SNc area and L-dopa and L-dopa equivalent dose demonstrated a significant negative correlation. The association between a reducing SNc NM-rich area and MC with increasing dopaminergic medication dose suggests that NM-MRI findings might be a useful tool for monitoring the development of MC in PD and PARK2.

Neuromelanin magnetic resonance imaging reveals increased dopaminergic neuron activity in the substantia nigra of patients with schizophrenia.

PurposeThe dopamine hypothesis suggests that excessive dopamine release results in the symptoms of schizophrenia. The purpose of this study was to elucidate the dopaminergic and noradrenergic neurons using 3-T neuromelanin magnetic resonance imaging (MRI) in patients with schizophrenia and healthy control subjects.MethodsWe prospectively examined 52 patients with schizophrenia (M: F = 27∶25, mean age, 35 years) and age- and sex-matched healthy controls. Using a 3T MRI unit, we obtained oblique T1-weighted axial images perpendicular to the brainstem. We measured the signal intensity and area for the substantia nigra (SNc), midbrain tegmentum, locus ceruleus (LC), and pons. We then calculated the contrast ratios (CR) for the SNc (CRSN) and LC (CRLC), which were compared between patients and healthy controls using unpaired t-tests.ResultsThe SNc and LC were readily identified in both patients and healthy controls as areas with high signal intensities in the posterior part of the cerebral peduncle and in the upper pontine tegmentum. The CRSN values in patients were significantly higher than those in healthy controls (10.89±2.37 vs. 9.6±2.36, p<0.01). We observed no difference in the CRLC values between the patients and healthy controls (14.21±3.5 vs. 13.44±3.37, p = 0.25). Furthermore, there was no difference in area of the SNc and LC between schizophrenia patients and controls.ConclusionsNeuromelanin MRI might reveal increased signal intensity in the SNc of patients with schizophrenia. Our results indicate the presence of excessive dopamine products in the SNc of these patients.

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.

Neuromelanin Magnetic Resonance Imaging in Parkinson's Disease and Multiple System Atrophy

Pigmented neurons in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) show decreased numbers differentially in Parkinson's disease (PD) and multiple system atrophy (MSA). Recent reports have described that fast spin-echo T1-weighted magnetic resonance imaging (MRI) by a 3-tesla machine can visualize neuromelanin-related contrast of the noradrenergic and dopaminergic neurons respectively in the LC and the SNc. Using neuromelanin MRI at 3 T, we investigated possible alterations of these catecholaminergic neurons in 32 PD and 9 MSA patients, and compared the results with those of 23 normal volunteers. The contrast ratio of the LC and SNc was decreased in MSA and PD patients, most prominently in the LC in MSA patients. The contrast ratio of the SNc was correlated with the Hoehn-Yahr stage of PD and the severity of neuroradiological abnormalities in MSA. These results indicate a potential diagnostic value of neuromelanin MRI to distinguish MSA patients from normal and PD patients.

Neuromelanin MRI in a family with mitochondrial parkinsonism harboring a Y955C mutation in POLG1

BackgroundProgressive external ophthalmoplegia (PEO) and parkinsonism can be caused by genetic mutations that affect mitochondrial DNA (mtDNA) maintenance. We characterized parkinsonism in a family with dominantly inherited PEO. MethodsWe conducted clinical, histological and genetic analyses on two affected members suffering from PEO and parkinsonism, and reviewed the cases in the literature. To clarify parkinsonism related to multiple mtDNA deletions, we used 3-T neuromelanin magnetic resonance imaging (MRI) to assess signal changes in the substantia nigra (SN) and locus ceruleus (LC) in our patients, and compared the results to those observed in idiopathic Parkinson's disease (iPD) (n = 35). ResultsWe report the first case of a Japanese family harboring a heterozygous p.Y955C mutation in POLG1. The clinical features of parkinsonism related to the Y955C mutation in a total of 16 patients, including our two cases, are indistinguishable from iPD. However, neuromelanin MRI showed a distinct pattern in our cases compared to iPD. The neuromelanin imaging results were consistent with the neuropathological findings reported in cases of POLG1 mutations, in which neurons of the SN were profoundly affected while those in the LC were preserved. ConclusionsOur results suggest that 3-T neuromelanin MRI may be useful for differentiating POLG1 mutation-associated parkinsonism from iPD, and that POLG1 mutations may cause selective neuronal loss in the SN via a mechanism different from that of iPD.

Neuromelanin magnetic resonance imaging of nigral volume loss in patients with Parkinson’s disease

Parkinson’s disease (PD) is characterized by progressive degeneration of melanin-containing neurons in the substantia nigra pars compacta (SNc). Pathological change has not been detected by neuroimaging techniques in patients with PD in vivo. We examined 80 patients with PD to determine whether degeneration of the SNc is detectable in vivo by MRI. The age-matched controls consisted of 54 patients who had suffered mild acute ischemic stroke. Axial T1-weighted MRI were obtained with a 3-Tesla MRI scanner. The border of the neuromelanin-sensitive region in the SNc was traced manually on these images, and the volume of this area was calculated. The mean volumes for the left and right SNc were significantly reduced in patients with PD compared to the controls. Volume loss became marked in parallel with disease severity and duration. Neuromelanin MRI may be considered as a biomarker of nigral degeneration in patients with PD.

Reduced signal of locus ceruleus in depression in quantitative neuromelanin magnetic resonance imaging

We used a neuromelanin-magnetic resonance imaging technique to investigate abnormalities in the locus ceruleus in depression. We examined 20 patients with major depression and 43 age-matched controls using a 3 T scanner with a neuromelanin-sensitive sequence. The signal intensities of the areas corresponding to the rostral, middle, and caudal portions of the locus ceruleus were measured, and the contrast ratio relative to the adjacent pontine tegmentum was calculated. In controls, the contrast ratio in the middle portion was higher than in the rostral and caudal areas. In patients, contrast ratios in the rostral and middle portions were significantly decreased in comparison with controls, suggesting dysfunction of the ascending noradrenergic system. Neuromelanin-magnetic resonance imaging can be used to visualize abnormalities in the locus ceruleus of depressive patients.