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

BACKGROUND: Clinical 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. OBJECTIVES: The 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. METHODS: In 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. RESULTS: All 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. CONCLUSIONS: We 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.

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

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

Limbic grey matter changes in early Parkinson's disease.

The purpose of this study was to investigate local and network-related changes of limbic grey matter in early Parkinson's disease (PD) and their inter-relation with non-motor symptom severity. We applied voxel-based morphometric methods in 538 T1 MRI images retrieved from the Parkinson's Progression Markers Initiative website. Grey matter densities and cross-sectional estimates of age-related grey matter change were compared between subjects with early PD (n = 366) and age-matched healthy controls (n = 172) within a regression model, and associations of grey matter density with symptoms were investigated. Structural brain networks were obtained using covariance analysis seeded in regions showing grey matter abnormalities in PD subject group. Patients displayed focally reduced grey matter density in the right amygdala, which was present from the earliest stages of the disease without further advance in mild-moderate disease stages. Right amygdala grey matter density showed negative correlation with autonomic dysfunction and positive with cognitive performance in patients, but no significant interrelations were found with anxiety scores. Patients with PD also demonstrated right amygdala structural disconnection with less structural connectivity of the right amygdala with the cerebellum and thalamus but increased covariance with bilateral temporal cortices compared with controls. Age-related grey matter change was also increased in PD preferentially in the limbic system. In conclusion, detailed brain morphometry in a large group of early PD highlights predominant limbic grey matter deficits with stronger age associations compared with controls and associated altered structural connectivity pattern. This provides in vivo evidence for early limbic grey matter pathology and structural network changes that may reflect extranigral disease spread in PD. Hum Brain Mapp 38:3566-3578, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

In Vivo Assessment of Brainstem Depigmentation in Parkinson Disease: Potential as a Severity Marker for Multicenter Studies.

Purpose To investigate the pattern of neuromelanin signal intensity loss within the substantia nigra pars compacta (SNpc), locus coeruleus, and ventral tegmental area in Parkinson disease (PD); the specific aims were (a) to study regional magnetic resonance (MR) quantifiable depigmentation in association with PD severity and (b) to investigate whether imaging- and platform-dependent signal intensity variations can be normalized. Materials and Methods This prospective case-control study was approved by the local ethics committee and the research department of Nottingham University Hospitals. Written informed consent was obtained from all participants before enrollment in the study. Sixty-nine participants (39 patients with PD and 30 control subjects) were investigated with neuromelanin-sensitive MR imaging by using two different 3-T platforms and three differing protocols. Neuromelanin-related volumes of the anterior and posterior SNpc, locus coeruleus, and ventral tegmental area were determined, and normalized neuromelanin volumes were assessed for protocol-dependent effects. Diagnostic test performance of normalized neuromelanin volume was investigated by using receiver operating characteristic analyses, and correlations with the Unified Parkinson's Disease Rating Scale scores were tested. Results Reduction of normalized neuromelanin volume in PD was most pronounced in the posterior SNpc (median, -83%; P < .001), followed by the anterior SNpc (-49%; P < .001) and the locus coeruleus (-37%; P < .05). Normalized neuromelanin volume loss of the posterior and whole SNpc allowed the best differentiation of patients with PD and control subjects (area under the receiver operating characteristic curve, 0.92 and 0.88, respectively). Normalized neuromelanin volume of the anterior, posterior, and whole SNpc correlated with Unified Parkinson's Disease Rating Scale scores (r2 = 0.25, 0.22, and 0.28, respectively; all P < .05). Conclusion PD-induced neuromelanin loss can be quantified across imaging protocols and platforms by using appropriate adjustment. Depigmentation in PD follows a distinct spatial pattern, affords high diagnostic accuracy, and is associated with disease severity. ©RSNA, 2016 Online supplemental material is available for this article.

Ultra-high-field 7T MRI in Parkinson's disease: ready for clinical use?-a narrative review.

Background and Objective: The maturation of ultra-high-field magnetic resonance imaging (MRI) [≥7 Tesla (7T)] has improved our capability to depict and characterise brain structures efficiently, with better signal-to-noise ratio (SNR) and spatial resolution. We evaluated whether these improvements benefit the clinical detection and management of Parkinson's disease (PD). Methods: We performed a literature search in March 2023 in PubMed (MEDLINE), EMBASE and Google Scholar for articles on "7T MRI" AND "Parkinson*", written in English, published between inception and 1st March, 2023, which we synthesised in narrative form. Key Content and Findings: In deep-brain stimulation (DBS) surgical planning, early studies show that 7T MRI can distinguish anatomical substructures, and that this results in reduced adverse effects. In other areas, while there is strong evidence for improved accuracy and precision of 7T MRI-based measurements for PD, there is limited evidence for meaningful clinical translation. In particular, neuromelanin-iron complex quantification and visualisation in midbrain nuclei is enhanced, enabling depiction of nigrosomes 1-5, improved morphometry and vastly improved radiological assessments; however, studies on the related clinical outcomes, diagnosis, subtyping, differentiation of atypical parkinsonisms, and monitoring of treatment response using 7T MRI are lacking. Moreover, improvements in clinical utility must be great enough to justify the additional costs. Conclusions: Together, current evidence supports feasible future clinical implementation of 7T MRI for PD. Future impacts to clinical decision making for diagnosis, differentiation, and monitoring of progression or treatment response are likely; however, to achieve this, further longitudinal studies using 7T MRI are needed in prodromal, early-stage PD and parkinsonism cohorts focusing on clinical translational potential.

High resolution magnetic susceptibility mapping of the substantia nigra in Parkinson's disease.

PURPOSE: To determine if tissue magnetic susceptibility is a more direct marker of tissue iron content than other MR markers of iron. This study presents the first quantitative, in vivo measurements of the susceptibility of the substantia nigra in patients with Parkinson's disease. MATERIALS AND METHODS: Nine patients and 11 controls were studied at 7 Tesla. Susceptibility maps were created by inverting the filtered phase maps associated with T2* weighted images. RESULTS: On average, patients showed an increase in susceptibility of the pars compacta compared with controls, which correlates with the predicted increase in brain iron in Parkinson's disease. A rostral-caudal gradient in susceptibility was also observed in controls and patients. CONCLUSION: Susceptibility mapping may provide a new tool for studying the development of Parkinson's disease.

T1-weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson's disease.

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1-weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin-sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high-resolution T1-weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity+3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n=6) and late stage (n=4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (-60%, P<.01), and contrast was reduced (-3%, P<.05). Size reduction was even more pronounced in more advanced disease (-78%) than in early-stage disease (-47%). We present preliminary findings using a modified T1-weighted magnetic resonance imaging technique showing stage-dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin-rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease.

Coordinate based meta-analysis of motor functional imaging in Parkinson's: disease-specific patterns and modulation by dopamine replacement and deep brain stimulation.

OBJECTIVE: To investigate factors affecting the pattern of motor brain activation reported in people with Parkinson's (PwP), aiming to differentiate disease-specific features from treatment effects. METHODS: A co-ordinate-based-meta-analysis (CBMA) of functional motor neuroimaging studies involving patients with Parkinson's (PwP), and healthy controls (HC) identified 126 suitable articles. The experiments were grouped based on subject feature, medication status (onMed/offMed), deep brain stimulation (DBS) status (DBSon/DBSoff) and type of motor initiation. RESULTS: HC and PwP shared similar neural networks during upper extremity motor tasks but with differences of reported frequency in mainly bilateral putamen, insula and ipsilateral inferior parietal and precentral gyri. The activation height was significantly reduced in the bilateral putamen, left SMA, left subthalamus nucleus, right thalamus and right midial global pallidum in PwPoffMed (vs. HC), and pre-SMA hypoactivation correlated with disease severity. These changes were not found in patients on dopamine replacement therapy (PwPonMed vs. HC) in line with a restorative function. By contrast, left SMA and primary motor cortex showed hyperactivation in the medicated state (vs. HC) suggesting dopaminergic overcompensation. Deep-brain stimulation (PwP during the high frequency subthalamus nucleus (STN) DBS vs. no stimulation) induced a decrease in left SMA activity and the expected increase in the left subthalamic/thalamic region regardless of hand movement. We further demonstrated a disease related effect of motor intention with only PwPoffMed showing increased activation in the medial frontal lobe in self-initiated studies. CONCLUSION: We describe a consistent disease-specific pattern of putaminal hypoactivation during motor tasks that appears reversed by dopamine replacement. Inconsistent reports of altered SMA/pre-SMA activation can be explained by task- and medication-specific variation in intention. Moreover, SMA activity was reduced during STN-DBS, while dopamine-induced hyperactivation of SMA which might underpin hyperdynamic L-dopa related overcompensation.

Protocol of a single group prospective observational study on the diagnostic value of 3T susceptibility weighted MRI of nigrosome-1 in patients with parkinsonian symptoms: the N3iPD study (nigrosomal iron imaging in Parkinson's disease).

INTRODUCTION: Parkinson's disease (PD) is the most common movement disorder in the elderly and is characterised clinically by bradykinesia, tremor and rigidity. Diagnosing Parkinson's can be difficult especially in the early stages. High-resolution nigrosome MRI offers promising diagnostic accuracy of patients with established clinical symptoms; however, it is unclear whether this may help to establish the diagnosis in the early stages of PD, when there is diagnostic uncertainty. In this scenario, a single photon emission CT scan using a radioactive dopamine transporter ligand can help to establish the diagnosis, or clinical follow-up may eventually clarify the diagnosis. A non-invasive, cost-effective diagnostic test that could replace this would be desirable. We therefore aim to prospectively test whether nigrosome MRI is as useful as DaTSCAN to establish the correct diagnosis in people with minor or unclear symptoms suspicious for PD. METHODS AND ANALYSIS: In a prospective study we will recruit 145 patients with unclear symptoms possibly caused by Parkinson's from three movement disorder centres in the UK to take part in the study. We will record the Movement Disorder Society - Unified Parkinson's Disease Rating Scale, and participants will undergo DaTSCAN and high-resolution susceptibility weighted MRI at a field strength of 3T. DaTSCANs will be assessed visually and semiquantitatively; MRI scans will be visually assessed for signal loss in nigrosome-1 by blinded investigators. We will compare how the diagnosis suggested by MRI compares with the diagnosis based on DaTSCAN and will also validate the diagnosis based on the two tests with a clinical examination performed at least 1 year after the initial presentation as a surrogate gold standard diagnostic test. ETHICS AND DISSEMINATION: The local ethics commission (Health Research Authority East Midlands - Derby Research Ethics Committee) has approved this study (REC ref.: 16/EM/0229). The study is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. We have included a number of 15 research-funded DaTSCAN in the research protocol. This is to compensate for study site-specific National Health Service funding for this investigation in affected patients. We therefore have also obtained approval from the Administration of Radioactive Substances Administration Committee (ARSAC Ref 253/3629/35864). All findings will be presented at relevant scientific meetings and published in peer-reviewed journals, on the study website, and disseminated in lay and social media where appropriate. TRIAL REGISTRATION NUMBER: NCT03022357; Pre-results.

Co-expression of heat sensitive vanilloid receptor subtypes in rat dorsal root ganglion neurons.

Expression of the heat sensitive cation channels TRPV1 and TRPV2 was investigated by immunofluorescence in rat dorsal root ganglion (DRG) neurons. TRPV1-positive neurons were more frequent and had smaller diameters than TRPV2-positive neurons (35.7% vs 7.3%; 22.3 microm vs 27.6 microm), but size distributions overlapped and significant co-expression was seen in 20.7% of TRPV2-positive neurons (1.7% of all). Expression patterns did not differ between tissue sections typically used in immunocytochemistry and dissociated DRG neurons typically used in electrophysiology. Rectangular temperature pulses revealed two patterns of heat-evoked inward currents in small DRG neurons: low-threshold rapidly activating and high-threshold slowly activating. Slowly activating heat-evoked currents have not been described previously, but correspond to the type I heat responses of primary nociceptive afferents, which have been suggested to be mediated by TRPV2.

The 'swallow tail' appearance of the healthy nigrosome - a new accurate test of Parkinson's disease: a case-control and retrospective cross-sectional MRI study at 3T.

There is no well-established in vivo marker of nigral degeneration in Parkinson's disease (PD). An ideal imaging marker would directly mirror the loss of substantia nigra dopaminergic neurones, which is most prominent in sub-regions called nigrosomes. High-resolution, iron-sensitive, magnetic resonance imaging (MRI) at 7T allows direct nigrosome-1 visualisation in healthy people but not in PD. Here, we investigated the feasibility of nigrosome-1 detection using 3T - susceptibility-weighted (SWI) MRI and the diagnostic accuracy that can be achieved for diagnosing PD in a clinical population. 114 high-resolution 3T - SWI-scans were reviewed consisting of a prospective case-control study in 19 subjects (10 PD, 9 controls) and a retrospective cross-sectional study in 95 consecutive patients undergoing routine clinical SWI-scans (>50 years, 9 PD, 81 non-PD, 5 non-diagnostic studies excluded). Two raters independently classified subjects into PD and non-PD according to absence or presence of nigrosome-1, followed by consensus reading. Diagnostic accuracy was assessed against clinical diagnosis as gold standard. Absolute inter- and intra-rater agreement was ≥94% (kappa≥0.82, p<0.001). In the prospective study 8/9 control and 8/10 PD; and in the retrospective study 77/81 non-PD and all 9 PD subjects were correctly classified. Diagnostic accuracy of the retrospective cohort was: sensitivity 100%, specificity 95%, NPV 1, PPV 0.69 and accuracy 96% which dropped to 91% when including non-diagnostic scans ('intent to diagnose'). The healthy nigrosome-1 can be readily depicted on high-resolution 3T - SWI giving rise to a 'swallow tail' appearance of the dorsolateral substantia nigra, and this feature is lost in PD. Visual radiological assessment yielded a high diagnostic accuracy for PD vs. an unselected clinical control population. Assessing the substantia nigra on SWI for the typical 'swallow tail' appearance has potential to become a new and easy applicable 3T MRI diagnostic tool for nigral degeneration in PD.

Diffusion tensor imaging of nigral degeneration in Parkinson's disease: A region-of-interest and voxel-based study at 3 T and systematic review with meta-analysis.

There is increasing interest in developing a reliable, affordable and accessible disease biomarker of Parkinson's disease (PD) to facilitate disease modifying PD-trials. Imaging biomarkers using magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) can describe parameters such as fractional anisotropy (FA), mean diffusivity (MD) or apparent diffusion coefficient (ADC). These parameters, when measured in the substantia nigra (SN), have not only shown promising but also varying and controversial results. To clarify the potential diagnostic value of nigral DTI in PD and its dependency on selection of region-of-interest, we undertook a high resolution DTI study at 3 T. 59 subjects (32 PD patients, 27 age and sex matched healthy controls) were analysed using manual outlining of SN and substructures, and voxel-based analysis (VBA). We also performed a systematic literature review and meta-analysis to estimate the effect size (DES) of disease related nigral DTI changes. We found a regional increase in nigral mean diffusivity in PD (mean ± SD, PD 0.80 ± 0.10 vs. controls 0.73 ± 0.06 · 10(- 3) mm(2)/s, p = 0.002), but no difference using a voxel based approach. No significant disease effect was seen using meta-analysis of nigral MD changes (10 studies, DES = + 0.26, p = 0.17, I(2) = 30%). None of the nigral regional or voxel based analyses of this study showed altered fractional anisotropy. Meta-analysis of 11 studies on nigral FA changes revealed a significant PD induced FA decrease. There was, however, a very large variation in results (I(2) = 86%) comparing all studies. After exclusion of five studies with unusual high values of nigral FA in the control group, an acceptable heterogeneity was reached, but there was non-significant disease effect (DES = - 0.5, p = 0.22, I(2) = 28%). The small PD related nigral MD changes in conjunction with the negative findings on VBA and meta-analysis limit the usefulness of nigral MD measures as biomarker of Parkinson's disease. The negative results of nigral FA measurements at regional, sub-regional and voxel level in conjunction with the results of the meta-analysis of nigral FA changes question the stability and validity of this measure as a PD biomarker.

Visualization of nigrosome 1 and its loss in PD: pathoanatomical correlation and in vivo 7 T MRI.

OBJECTIVE: This study assessed whether high-resolution 7 T MRI allowed direct in vivo visualization of nigrosomes, substructures of the substantia nigra pars compacta (SNpc) undergoing the greatest and earliest dopaminergic cell loss in Parkinson disease (PD), and whether any disease-specific changes could be detected in patients with PD. METHODS: Postmortem (PM) midbrains, 2 from healthy controls (HCs) and 1 from a patient with PD, were scanned with high-resolution T2*-weighted MRI scans, sectioned, and stained for iron and neuromelanin (Perl), TH, and calbindin. To confirm the identification of nigrosomes in vivo on 7 T T2*-weighted scans, we assessed colocalization with neuromelanin-sensitive T1-weighted scans. We then assessed the ability to depict PD pathology on in vivo T2*-weighted scans by comparing data from 10 patients with PD and 8 age- and sex-matched HCs. RESULTS: A hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense SNpc was identified in the HC brains on in vivo and PM T2*-weighted MRI. Location, size, shape, and staining characteristics conform to nigrosome 1. Blinded assessment by 2 neuroradiologists showed consistent bilateral absence of this nigrosome feature in all 10 patients with PD, and bilateral presence in 7/8 HC. CONCLUSIONS: In vivo and PM MRI with histologic correlation demonstrates that high-resolution 7 T MRI can directly visualize nigrosome 1. The absence of nigrosome 1 in the SNpc on MRI scans might prove useful in developing a neuroimaging diagnostic test for PD.

Heat-induced action potential discharges in nociceptive primary sensory neurons of rats.

Although several transducer molecules for noxious stimuli have been identified, little is known about the transformation of the resulting generator currents into action potentials (APs). Therefore we investigated the transformation process for stepped noxious heat stimuli (42-47 degrees C, 3-s duration) into membrane potential changes and subsequent AP discharges using the somata of acutely dissociated small dorsal root ganglion (DRG) neurons (diameter