Neuromelanin-sensitive magnetic resonance imaging: Possibilities and promises as an imaging biomarker for Parkinson's disease.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder characterized by both motor and non-motor symptoms resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus (LC). The current diagnosis of PD primarily relies on motor symptoms, often leading to diagnoses in advanced stages, where a significant portion of SNpc dopamine neurons has already succumbed. Therefore, the identification of imaging biomarkers for early-stage PD diagnosis and disease progression monitoring is imperative. Recent studies propose that neuromelanin-sensitive magnetic resonance imaging (NM-MRI) holds promise as an imaging biomarker. In this review, we summarize the latest findings concerning NM-MRI characteristics at various stages in patients with PD and those with atypical parkinsonism. In conclusion, alterations in neuromelanin within the LC are associated with non-motor symptoms and prove to be a reliable imaging biomarker in the prodromal phase of PD. Furthermore, NM-MRI demonstrates efficacy in differentiating progressive supranuclear palsy (PSP) from PD and multiple system atrophy with predominant parkinsonism. The spatial patterns of changes in the SNpc can be indicative of PD progression and aid in distinguishing between PSP and synucleinopathies. We recommend that patients with PD and individuals at risk for PD undergo regular NM-MRI examinations. This technology holds the potential for widespread use in PD diagnosis.

Increased iron in the substantia nigra pars compacta identifies patients with early Parkinson'sdisease: A 3T and 7T MRI study.

Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson's disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD. We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI). PD patients had higher QSM values in the SNc at both 3T (padj = 0.001) and 7T (padj = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (padj = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82-0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79-0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc. This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.

Imaging of the nigrostriatal system for evaluating the preclinical phase of Parkinson's disease development: the utility of neuromelanin, diffusion MRI, and DAT-SPECT.

OBJECTIVE: To assess the utility of examining the nigrostriatal system with MRI and dopamine transporter (DAT) imaging for evaluating the preclinical phase of Parkinson's disease (PD). METHODS: The subjects were 32 patients with early PD and a history of probable rapid eye movement sleep behavior disorder (RBD; PD group), 15 patients with idiopathic RBD (RBD group), and 24 age-matched healthy controls (HC group) who underwent neuromelanin and diffusion tensor MRI for analysis of the substantia nigra pars compacta (SNpc). The RBD and PD groups underwent DAT imaging. In the RBD group, totals of 39 MRI and 27 DAT imaging examinations were obtained longitudinally. For each value, intergroup differences and receiver operating characteristic analysis for diagnostic performance were examined statistically. RESULTS: The neuromelanin value was significantly lower and the diffusion tensor values except fractional anisotropy were significantly higher in the RBD and PD groups than in the HC group. The DAT specific binding ratio (SBR) was significantly lower in the PD group than in the RBD group. The areas under the receiver operating characteristic curves (AUCs) for neuromelanin/mean diffusivity value in the SNpc were 0.76/0.82 for diagnosing RBD and 0.83/0.80 for diagnosing PD. The area under the receiver operating characteristic curves for the SBR for discriminating PD from RBD was 0.87. CONCLUSION: MRI and DAT imaging may be useful for evaluating sequential nigrostriatal changes during the preclinical phase of PD. ADVANCES IN KNOWLEDGE: MRI detects nigrostriatal changes in both RBD and early PD, and DAT imaging detects nigrostriatal changes during the transition to PD in RBD.

Neuromelanin-sensitive magnetic resonance imaging in disease differentiation for parkinsonism or neurodegenerative disease affecting the basal ganglia.

INTRODUCTION: Several reports have shown that neuromelanin-sensitive magnetic resonance imaging (NMI) using 3T magnetic resonance imaging is useful for the differential diagnosis of Parkinson's disease (PD), progressive supranuclear palsy (PSP), and other neurological diseases. However, the number of cases in previous studies has been insufficient. We aimed to determine the relationship between NMI and severity of PD and related disorders, and thereby establish the diagnostic utility of NMI for diagnosing neurological diseases. METHODS: We enrolled 591 patients (531 subjects after removal of duplicates) with parkinsonism who underwent NMI. The contrast ratio of the locus coeruleus (LC-CR) and the area of the substantia nigra pars compacta (SNc) were analyzed in each patient. RESULTS: The patients' clinical diagnoses were as follows: 11 patients in the disease control group (DCG), 244 patients with PD, 49 patients with PSP, and 19 patients with multiple system atrophy with predominant parkinsonism. Additionally, some patients were diagnosed with dementia with Lewy bodies, vascular parkinsonism, and drug-induced parkinsonism. SNc in the patients with PD and PSP was significantly smaller than that in DCG. LC-CR in the patients with PD was lower than that in DCG; furthermore, LC-CR in the patients with PD was significantly lower than that in the patients with PSP. We found that an area under the receiver-operating characteristic curve, indicating diagnostic efficacy, of 0.85 for LC-CR is a promising biomarker for differentiating PD from PSP. CONCLUSION: NMI effectively contributes to differentiating neurodegenerative diseases, such as PD and PSP.

Early-stage Parkinson's disease: Abnormal nigrosome 1 and 2 revealed by a voxelwise analysis of neuromelanin-sensitive MRI.

Previous pathologic studies evaluated the substantia nigra pars compacta (SNpc) of a limited number of idiopathic Parkinson's disease (IPD) patients with relatively longer disease durations. Therefore, it remains unknown which region of the SNpc is most significantly affected in early-stage IPD. We hypothesized that a voxelwise analysis of thin-section neuromelanin-sensitive MRI (NM-MRI) may help determine the significantly affected regions of the SNpc in early-stage IPD and localize these areas in each nigrosome on high-spatial-resolution susceptibility map-weighted imaging (SMwI). Ninety-six healthy subjects and 50 early-stage IPD patients underwent both a 0.8 × 0.8 × 0.8 mm3 NM-MRI and a 0.5 × 0.5 × 1.0 mm3 multi-echo gradient-recalled echo imaging for SMwI. Both NM-MRI and SMwI templates were created by using image data from the 96 healthy subjects. Permutation-based nonparametric tests were conducted to investigate spatial differences between the two groups in NM-MRI, and the results were displayed on both NM-MRI and SMwI templates. The posterolateral and anteromedial regions of the SNpc in NM-MRI were significantly different between the two groups, corresponding to the nigrosome 1 and nigrosome 2 regions, respectively, on the SMwI template. There were the areas of significant spatial difference in the hypointense SN on SMwI between early-stage IPD patients and healthy subjects. These areas on SMwI were slightly greater than those on NM-MRI, including the areas showing group difference on NM-MRI. Our voxelwise analysis of NM-MRI suggests that two regions (nigrosome 1 and nigrosome 2) of the SNpc are separately affected in early-stage IPD.

Diagnostic accuracy of the appearance of Nigrosome-1 on magnetic resonance imaging in Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: There is currently no definitive diagnostic test for Parkinson's disease (PD) and the current diagnostic procedure primarily relies on clinical manifestations. A hypointense appearance of nigrosome-1 (or absence of the "swallow tail" sign) on magnetic resonance imaging (MRI) has been proposed as a biomarker for PD. This meta-analysis examined the diagnostic accuracy of the appearance of nigrosome-1 on Magnetic Resonance Imaging (MRI) in differentiating idiopathic PD patients from healthy adults. METHODS: Databases (MEDLINE, Embase, Scopus) were searched from 2012 (first publication of nigrosome-1 MRI scans) up until September 2019. Two researchers independently screened all titles and abstracts to identify studies that met the inclusion criteria and extracted relevant articles in a uniform manner. Two authors independently extracted data and assessed the risk of bias using a customized QUADAS-2 tool. Pooled sensitivity and specificity were calculated using a hierarchical summary receiver operating characteristic approach, as were positive and negative likelihood ratios. RESULTS: Nineteen studies containing a total of 1508 participants (903 idiopathic PD patients and 605 healthy controls) were included. The overall sensitivity and specificity were 0.94 (95%CI, 0.93-0.96) and 0.90 (95%CI, 0.88-0.92), respectively. The likelihood ratios for positive and negative test results were 9.72 (95%CI, 5.58-16.04) and 0.08 (95%CI, 0.05-0.12). The pooled area under the receiver operating characteristics curve (AUC) in the diagnosis of idiopathic PD was 0.98. CONCLUSIONS: Visual assessment of the nigrosome-1 appearance, at 3 or 7T, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy adults.

Cue-Evoked Dopamine Promotes Conditioned Responding during Learning.

Dopamine neurons mediate the association of conditioned stimuli (CS) with reward (unconditioned stimuli, US) by signaling the discrepancy between predicted and actual reward during the US. Some theoretical models suggest that learning is also influenced by the salience or associability of the CS. A hallmark of CS associability models is that they can explain latent inhibition, i.e., the observation that novel CS are more effectively learned than familiar CS. Novel CS are known to activate dopamine neurons, but whether those responses affect associative learning has not been investigated. Here, we used fiber photometry to characterize dopamine responses to inconsequential familiar and novel stimuli. Using bidirectional optogenetic modulation during conditioning, we then show that CS-evoked dopamine promotes conditioned responses. This suggests that Pavlovian conditioning is influenced by CS dopamine, in addition to US reward prediction errors. Accordingly, the absence of dopamine responses to familiar CS might explain their slower learning in latent inhibition.

MRI T2 and T2* relaxometry to visualize neuromelanin in the dorsal substantia nigra pars compacta.

Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study aimed to identify the origin of the mismatch region between magnetic resonance transverse relaxation times (T2 and T2*) in the substantia nigra and investigate its feasibility and implications for in vivo detection of neuromelanin as a clinical biomarker. The relationships between neuromelanin distribution assessed by histological staining and the area of T2 and T2* mismatch determined by high- and low-resolution magnetic resonance relaxometry at 7T were directly compared in two normal and one depigmented substantia nigra collected at postmortem. In vivo feasibility of assessing T2 and T2* mismatch, clinically, was investigated using 3T magnetic resonance imaging. In the normal postmortem substantia nigra tissue, the T2 and T2* mismatch region exhibiting a linear pattern was strongly colocalized with neuromelanin distribution along the dorsal substantia nigra pars compacta, but a negligible amount of dorsal mismatch was observed in the depigmented brain. The regions of T2 and T2* mismatch from MRI, neuromelanin pigments from histology, and elevated iron signals from mass spectrometry were spatially overlapped for a normal postmortem brain. In preliminary in vivo studies, a similar, linear T2 and T2* mismatch region was observed in the dorsal area of the substantia nigra in eight normal subjects; this mismatch was significantly obscured in eight Parkinson's disease patients. The length of the dorsal linear mismatch line based on the T2*-T2 mask was significantly shorter in the Parkinson's disease patients compared to normal controls; this result was corroborated by reduced striatal uptake of [18F] FP-CIT dopamine transporters assessed by positron emission tomography scans. In conclusion, the measurement of T2 and T2* mismatch could serve as a complementary imaging biomarker to visualize the dorsal region of the substantia nigra pars compacta, which contains large amounts of neuromelanin.

Nigrosome 1 imaging in REM sleep behavior disorder and its association with dopaminergic decline.

OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) patients have a high risk of developing a Parkinsonian disorder, offering an opportunity for neuroprotective intervention. Predicting near-term conversion, however, remains a challenge. Dopamine transporter imaging, while informative, is expensive and not widely available. Here, we investigate the utility of susceptibility-weighted MRI (SWI) to detect abnormalities of the substantia nigra in RBD, and explore their association with striatal dopaminergic deficits. METHODS: SWI of the substantia nigra was performed in 46 RBD patients, 27 Parkinson's patients, and 32 control subjects. Dorsal nigral hyperintensity (DNH) was scored by two blinded raters, and separately quantified using a semiautomated process. Forty-two RBD patients were also imaged with 123 I-ioflupane single-photon emission computed tomography (DaT SPECT/CT). RESULTS: Consensus visual DNH classification was possible in 87% of participants. 27.5% of RBD patients had lost DNH, compared with 7.7% of control subjects and 96% of Parkinson's patients. RBD patients lacking DNH had significantly lower putamen dopaminergic SPECT/CT activity compared to RBD patients with DNH present (specific uptake ratios 1.89 vs. 2.33, P = 0.002). The mean quantified DNH signal intensity declined in a stepwise pattern, with RBD patients having lower intensity than controls (0.837 vs. 0.877, P = 0.01) but higher than PD patients (0.837 vs. 0.765, P < 0.001). INTERPRETATION: Over one quarter of RBD patients have abnormal substantia nigra SWI reminiscent of Parkinson's, which is associated with a greater dopaminergic deficit. This modality may help enrich neuroprotective trials with early converters.

Characterization of age-related microstructural changes in locus coeruleus and substantia nigra pars compacta.

Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or whether these markers predict aspects of cognition. Here, we use high-resolution diffusion-weighted MRI to investigate microstructural and compositional changes in LC and SNpc in young and older adult cohorts, as well as their relationship with cognition. In LC, the older cohort exhibited a significant reduction in mean and radial diffusivity, but a significant increase in fractional anisotropy compared with the young cohort. We observed a significant correlation between the decrease in LC mean, axial, and radial diffusivities and measures examining cognition (Rey Auditory Verbal Learning Test delayed recall) in the older adult cohort. This observation suggests that LC is involved in retaining cognitive abilities. In addition, we observed that iron deposition in SNpc occurs early in life and continues during normal aging.

Accuracy of nigrosome-1 detection to discriminate patients with Parkinson's disease and essential tremor.

PURPOSE: The use of susceptibility weighted imaging in high field magnetic resonance imaging scanners can detect the nigrosome-1 area located in the caudo-lateral region of the pars compacta in the substantia nigra. This structure comprises a significant amount of dopaminergic neurons and degenerates in the early stages of Parkinson's disease. Essential tremor is a neurological condition that in some cases could be confused with the early stages of Parkinson's disease with a possible error in clinical diagnosis. Our purpose is to evaluate the accuracy of nigrosome-1 detection by high resolution magnetic resonance imaging to discriminate Parkinson's disease from essential tremor. METHODS: A case-control study compared patients with a clinical diagnosis of Parkinson's disease and essential tremor. Magnetic resonance imaging studies were performed using a 3T magnetic resonance imaging scanner. The susceptibility weighted imaging sequence was obtained in the axial plane with an isotropic voxel of 0.75 mm. Two independent neuroradiologists evaluated the images without access to clinical patient data. RESULTS: Sixteen patients were included in each group (Parkinson's disease and essential tremor). Average age: Parkinson's disease group: 71.3 (SD 6.3) and essential tremor group: 68.3 (SD 12.3). For the first evaluator, the nigrosome-1 area was absent in 15 patients with Parkinson's disease and in two with essential tremor and for the second evaluator was absent in 15 patients with Parkinson's disease and four with essential tremor. The sensitivity/specificity for the diagnosis of Parkinson's disease was 93.75%/87.5% for the first evaluator and 93.75%/75% for the second evaluator. CONCLUSION: The detection of the nigrosome-1 area is a useful tool in the differential diagnosis between Parkinson's disease and essential tremor, with high sensitivity and specificity.

The early diagnosis of Parkinson's disease through combined biomarkers.

OBJECTIVE: This study primarily aims to explore the value of combining the measurement of plasma α-synuclein oligomer levels with enhanced T2 star-weighted angiography (ESWAN) in the early diagnosis of Parkinson's disease. METHODS: Sixty patients with early Parkinson's disease and 30 normal adults, with similar ages and genders, were enrolled in the study. Their levels of plasma α-synuclein oligomers were measured, and ESWAN was performed. The amplitudes, phases and R2* values of the head, body and tail of the ipsilateral and contralateral substantia nigra pars compacta (SNc) were measured, at the side of the limb with severe symptoms or early symptoms. The receiver operating characteristic (ROC) curve was used to explore the value of these indexes in the early diagnosis of Parkinson's disease. RESULTS: The plasma level of α-synuclein oligomer was significantly higher in the experimental group than in the control group (P < 0.05). The amplitude values of the head and tail of contralateral SNcs were significantly lower in the experimental group than in the control group (P < 0.05). In the single-index assessment, the serum α-synuclein oligomer had the highest specificity (70%), while the sensitivity of the amplitude of the head and tail of the contralateral SNc was 75% and 80%, respectively. The area under the curve, for the combination of these three indicators, was 0.827, diagnostic efficiency was particularly high, and sensitivity and specificity both reached 80%. CONCLUSION: The combined detection of plasma α-synuclein oligomer and amplitude of the head and tail of the SNc has high diagnostic specificity and sensitivity.

Aumento de los depósitos cerebrales de hierro en una familia de donantes de sangre con síndrome de piernas inquietas / Brain iron accumulation in a blood donor family with restless legs síndrome

Introducción. La fisiopatología del síndrome de piernas inquietas (SPI) es compleja. El mecanismo a través del cual la ferropenia favorece el desarrollo del SPI no está esclarecido, aunque se sugiere la presencia de una alteración en la homeostasis cerebral del hierro. Casos clínicos. Se presentan los hallazgos inusuales en una familia de donantes de sangre con SPI. Tres miembros de la misma familia fueron diagnosticados de SPI, cumpliendo los criterios definidos por el grupo internacional para el estudio del SPI (International Restless Legs Syndrome Study Group). Todos eran donantes de sangre habituales (rango de donación: 10-40 años) y los síntomas de SPI tenían un curso de 3-5 años. La exploración general y neurológica fue normal en todos los casos, así como los electromiogramas. El estudio fenotípico y genotípico descartó la presencia de hemocromatosis y otras causas genéticas de sobrecarga cerebral de hierro. Los estudios polisomnográficos mostraron sueño nocturno perturbado, con reducción de su eficiencia, y un aumento del índice de movimientos periódicos de las piernas. La resonancia magnética craneal evidenció un aumento de los depósitos cerebrales de hierro en los ganglios basales, la sustancia negra, el núcleo rojo y los dentados. Conclusión. Este aumento patológico de los depósitos cerebrales de hierro sugiere la presencia de un complejo trastorno del metabolismo cerebral del hierro en nuestros pacientes. Futuros estudios deben confirmar estos hallazgos y profundizar en el estudio de su relación con la fisiopatología del SPI

Introduction. The pathophysiology of restless legs syndrome (RLS) is complex. Secondary RLS with iron deficiency - which suggests disturbed iron homeostasis - remains to be elucidated. Case reports. We report the findings from a unique blood donor family with RLS. Three blood donors family members were diagnosed with RLS defined by the International RLS Study Group and without history of neurologic diseases and RLS symptoms in the last 3-5 years (range of blood donation: 10-40 years). The neurological examination and electromyographies were normal. A polisomnography showed disturbed nocturnal sleep with a reduction in sleep efficiency and an increased periodic limbs movement index. The cranial MRI showed brain iron deposits in basal ganglia, substantia nigra, red nuclei and dentate nuclei. Phenotypic and genotypic studies rule out genetic haemochromatosis or iron overload. Conclusion. The abnormal iron accumulation in the basal ganglia indicated a complex iron metabolism disorder of the central nervous system. Further studies are warranted to confirm our findings and its role in the pathophysiology of RLS

Comprehensive MRI quantification of the substantia nigra pars compacta in Parkinson's disease.

PURPOSE: To quantify dopaminergic neurodegeneration and iron overload in the substantia nigra pars compacta (SNpc) to evaluate Parkinson's disease (PD) using both quantitative susceptibility mapping (QSM) and neuromelanin imaging. MATERIALS AND METHODS: We studied 39 PD patients (PD group) and 25 healthy controls (HC group) who underwent brain MRI with QSM and neuromelanin imaging. QSM and neuromelanin values of the SNpc were obtained using a voxel-based automated region segmentation system. The signal-to-noise ratio (SNR) of the SNpc in the neuromelanin images was calculated based on the mean value for the background region. The neuromelanin value was defined as the neuromelanin volume with an SNR higher than that of the background. The significance of the intergroup differences, and according to the severity stages in the PD group was tested for each QSM and neuromelanin value. Receiver-operating characteristic (ROC) analysis for diagnosing PD was performed for QSM and neuromelanin values. RESULTS: The QSM value was significantly higher in the PD group than in the HC group (P < 0.05). The neuromelanin value was significantly smaller in the PD group than in the HC group (P < 0.05). The areas under the ROC curve were 0.68 and 0.86 for QSM and neuromelanin values, respectively. Using QSM and neuromelanin imaging to classify the PD stage was difficult. CONCLUSIONS: Quantifying the SNpc alterations with our region-based approach is useful for the diagnosis of PD.

Quantifying changes in nigrosomes using quantitative susceptibility mapping and neuromelanin imaging for the diagnosis of early-stage Parkinson's disease.

OBJECTIVE: To quantify nigral changes with a focus on their spatial variation within the substantia nigra pars compacta (SNpc) for diagnosing early-stage Parkinson's disease (PD). METHODS: The study participants were 18 patients with early-stage PD (PD group) and 18 healthy controls (HC group) who underwent quantitative susceptibility mapping (QSM) and neuromelanin imaging. The QSM and neuromelanin values in each whole SNpc containing the entire nigrosome and dorsolateral SNpc containing nigrosome 1 were calculated. The neuromelanin area was defined as the volume with a signal-to-noise ratio higher than that of the background region. The significance of intergroup differences in the QSM value and neuromelanin area in each SNpc region was tested. Logit (p) was used to estimate the probability of PD in relation to the QSM value and the neuromelanin area, and receiver operating characteristic analyses were performed for each value. RESULTS: In both SNpc, QSM values were significantly higher and neuromelanin areas were significantly lower in the PD group compared with the HC group (p < 0.05). The respective areas under the receiver operating characteristic curve for the two groups were 0.70/0.73 for the QSM value, 0.81/0.78 for the neuromelanin area in the whole/dorsolateral SNpc, and 0.86 for logit (p) in relation to the QSM value of the dorsolateral SNpc and the neuromelanin area of the whole SNpc. CONCLUSION: Comprehensive MRI assessment of the abnormality involving the nigrosomes can yield a high diagnostic performance for early-stage PD. Advances in knowledge: Focusing on spatial differences in nigral changes within the SNpc can increase the sensitivity of the detection of PD-related neurodegenerative changes.

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.

Subtypes evaluation of motor dysfunction in Parkinson's disease using neuromelanin-sensitive magnetic resonance imaging.

Parkinson's disease (PD) is characterized by the loss of neuromelanin (NM)-containing neurons in the substantia nigra pars compacta (SNc), and it is divided into two motor subtypes: the postural instability gait difficulty (PIGD) and the tremor dominant (TD) subtypes. With NM-sensitive Magnetic Resonance Imaging (NM-MRI), investigators have been able to accurately detect signal attenuation in SNc of PD; however, the difference of NM loss between PIGD and TD subtypes is still unclear. Thus, the aim of this study was to evaluate the differences in NM-MRI between PD motor subtypes. PD patients were classified into PIGD (n=14) and TD groups (n=9); 20 age and sex matched controls were recruited. We compared the signal intensity contrast ratios in medial and lateral regions of the SNc using NM-MRI in PIGD, TD, and controls, respectively. Remarkable signal attenuation was observed in the lateral part of SNc in PD when compared with the controls, and we were able to detect more severe signal attenuation in the medial part of SNc in PIGD patients in comparison with that in the TD group. Also, the medial part of SNc, ipsilateral to the most clinically affected side, showed the highest power to discriminate the PD motor subtypes (AUC, 81%; sensitivity, 71.4%; specificity, 77.8%). Our results indicated a potential diagnostic value of NM-MRI to discriminate the PD motor subtypes, providing new evidence for the neuropathology-based differences between the two subtypes.

Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta.

BACKGROUND: In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T2 / T2*-weighted contrasts to define the regions of interest in the SN. Given that T2 / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately. OBJECTIVES: To examine regions of the SNpc, defined by neuromelanin-sensitive MRI, exhibiting iron deposition in PD. METHODS: T1 -weighted and susceptibility weighted imaging data were obtained in a cohort of 82 subjects (54 controls and 28 PD patients). The PD patients were clinically diagnosed with an average UPDRS-III score of 37.9 ± 12.5 in the off medication state. Susceptibility weighted imaging data were analyzed using SNpc regions of interest defined by neuromelanin-sensitive MRI. RESULTS: Compared to control subjects, significantly more hypointense signal was observed in the SNpc defined by neuromelanin-sensitive MRI in the PD patients. In the PD group, the lateral ventral region of SNpc exhibited the greatest increase of hypointensity. This increase in the lateral ventral region of SNpc robustly differentiated PD patients from controls. CONCLUSION: T2*-weighted hypointense signal in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. It is most likely a measure sensitive to PD-related iron deposition and may serve as a robust biomarker of PD. © 2016 International Parkinson and Movement Disorder Society.

Subregional Pattern of Striatal Dopamine Transporter Loss on 18F FP-CIT Positron Emission Tomography in Patients With Pure Akinesia With Gait Freezing.

IMPORTANCE: Pure akinesia with gait freezing (PAGF) is a clinical syndrome characterized by freezing of gait, handwriting, and speech without abnormal eye movement or cognitive impairment. Several studies have suggested that PAGF may be a variant of progressive supranuclear palsy (PSP). However, the characteristics of striatal dopamine transporter loss in PAGF are unknown. OBJECTIVE: To investigate the subregional pattern of striatal dopamine transporter loss in patients with PAGF in comparison with patients with PSP and those with Parkinson disease (PD). DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-control study included 15 patients with PAGF, 27 with PD, 20 with PSP, and 11 healthy controls who underwent F-18-fluorinated-N-3-fluoropropyl-2ß-carboxymethoxy-3ß-(4-iodophenyl)-nortropane (18F FP-CIT) positron emission tomography between September 1, 2008, and July 31, 2014. The positron emission tomographic images were analyzed with 12 striatal subregional and 1 occipital volume-of-interest templates. The specific to nonspecific binding ratio (SNBR) and intersubregional ratio (ISR) in patients with PAGF were compared with those in patients with PD and those with PSP. MAIN OUTCOMES AND MEASURES: Comparisons of SNBRs of striatal subregions and ISR among patients with PAGF, PD, and PSP and healthy controls. RESULTS: The mean (SD) SNBRs (1.4 [0.7]) of the whole striatum in the 15 patients with PAGF (mean [SD] age, 71.4 [6.6] years; 7 men and 8 women) were similar to those in the 20 patients (mean [SD] age, 70.6 [4.5] years; 11 men and 9 women) with PSP (1.5 [0.5]) but significantly lower than those in the 27 patients (mean [SD] age, 67.7 [5.3] years; 10 men and 17 women) with PD (3.0 [1.3]). The mean (SD) SNBRs of the caudate nuclei in patients with PAGF (1.3 [0.9]) were significantly lower than those in patients with PD (3.5 [1.5]; P < .001) but slightly higher than those in patients with PSP (1.2 [0.5]). The mean [SD] anterior caudate to ventral striatum ISRs in patients with PAGF (0.5 [0.3]) were similar to those in patients with PSP (0.4 [0.2]) but not in patients with PD (1.0 [0.2]). The mean (SD) posterior to anterior putamen ISRs in patients with PAGF (0.4 [0.2]) were similar to those in patients with PD (0.5 [0.2]) and those with PSP (0.4 [0.2]). CONCLUSIONS AND RELEVANCE: On 18F FP-CIT positron emission tomography, patients with PAGF show a pattern of preferential dopaminergic loss similar to that seen in patients with PSP. These results suggest a similar distribution of regional neuronal loss in the substantia nigra pars compacta between PAGF and PSP. This finding may be one of the pathophysiological results suggesting that PAGF is a phenotypic variant of PSP.

Resting-State Functional Connectivity of the Locus Coeruleus in Humans: In Comparison with the Ventral Tegmental Area/Substantia Nigra Pars Compacta and the Effects of Age.

The locus coeruleus (LC) provides the primary noradrenergic inputs to the cerebral cortex. Despite numerous animal studies documenting the functions of the LC, research in humans is hampered by the small volume of this midbrain nucleus. Here, we took advantage of a probabilistic template, explored the cerebral functional connectivity of the LC with resting-state fMRI data of 250 healthy adults, and verified the findings by accounting for physiological noise in another data set. In addition, we contrasted connectivities of the LC and the ventral tegmental area/substantia nigra pars compacta. The results highlighted both shared and distinct connectivity of these 2 midbrain structures, as well as an opposite pattern of connectivity to bilateral amygdala, pulvinar, and right anterior insula. Additionally, LC connectivity to the fronto-parietal cortex and the cerebellum increases with age and connectivity to the visual cortex decreases with age. These findings may facilitate studies of the role of the LC in arousal, saliency responses and cognitive motor control and in the behavioral and cognitive manifestations during healthy and disordered aging. Although the first to demonstrate whole-brain LC connectivity, these findings need to be confirmed with high-resolution imaging.