The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease

Dopamine transporter; Iron; NeuromelaninTransportador de dopamina; Hierro; NeuromelaninaTransportador de dopamina; Ferro; NeuromelaninaIn Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson’s disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson’s disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson’s disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.The ICEBERG study was funded by grants from the Investissements d'Avenir, IAIHU-06 (Paris Institute of Neurosciences – IHU), ANR-11-INBS-0006, Fondation d’Entreprise EDF, Biogen Inc., Fondation Thérèse and René Planiol, Fondation Saint Michel, Unrestricted support for Research on Parkinson’s disease from Energipole (M. Mallart), M.Villain and Société Française de Médecine Esthétique (M. Legrand)

Unifying turbulent dynamics framework distinguishes different brain states.

peer reviewedSignificant advances have been made by identifying the levels of synchrony of the underlying dynamics of a given brain state. This research has demonstrated that non-conscious dynamics tend to be more synchronous than in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that different brain states are underpinned by dissociable spatiotemporal dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep and disorders of consciousness after coma). The model-free approach was based on Kuramoto's turbulence framework using coupled oscillators. This was extended by a measure of the information cascade across spatial scales. Complementarily, the model-based approach used exhaustive in silico perturbations of whole-brain models fitted to these measures. This allowed studying of the information encoding capabilities in given brain states. Overall, this framework demonstrates that elements from turbulence theory provide excellent tools for describing and differentiating between brain states

Brain stem damage study in parkinsonian syndromes using magnetic resonance imaging

Ces dernières années de nombreux marqueurs de l’atteinte nigrostriatale ont été élaborés et testés dans la maladie de Parkinson (MP). Ces marqueurs peuvent détecter et quantifier la neurodégénérescence dans la substance noire (SN) des patients ainsi que dans les formes précoces prémotrices de la maladie. Leur performance diagnostique reste mal connue de même que l’atteinte extra-nigrale.Dans ce travail nous avons étudié l’atteinte de la SN dans les formes précliniques et prémotrices de la MP. La charge en fer était augmentée chez des porteurs des mutations symptomatiques mais également chez des porteurs sains. De plus, nous avons observé une atteinte pré-motrice de la SN chez des sujets touchés par les troubles des comportements en sommeil paradoxal (TCSP) qui n’ont pas encore développé un syndrome parkinsonien. Chez ces sujets, l’atteinte de la SN a été le mieux mise en évidence par l’imagerie sensible à la neuromélanine et le tenseur de diffusion avec la fraction d’anisotropie, suggérant un intérêt dans la caractérisation prodromale de la MP. Ces mêmes marqueurs présentaient également la meilleure performance diagnostique dans la MP. Finalement, nous avons trouvé des anomalies bulbaires en tenseur de diffusion dans la MP, qui étaient corrélées aux symptômes dysautonomiques cardiaques et respiratoires, suggérant l’intérêt de ce marqueur pour étude de l’atteinte bulbaire. Ceci ouvre une possibilité d’étude bulbaire chez des sujets présymptomatiques car une atteinte bulbaire devrait apparaître avant les symptômes moteurs selon le modèle de Braak. Ces marqueurs sont peut-être la première étape vers un diagnostic présymptomatique de la MP dans la pratique clinique.In recent years numerous biomarkers of nigro-striatal damage were proposed in Parkinson's disease (PD). These markers are able to detect and quantify neurodegenative changes in the substantia nigra (SN) of patients with PD as well as in subjects with premotor conditions. Their diagnostic performances to detect PD as well as the extent of extranigral pathology remain incompletely understood.In this work we observed the damage of the substantia nigra in preclinical and premotor forms of PD. Iron load was increased in both symptomatic and asymptomatic mutations carriers, suggesting the interest of the biomarker in PD related genetic mutations. In addition, we found a pre-clinical impairment of the SN in subjects affected by idiopathic sleep in REM behavioral disorders (iRBD) who have not yet converted to Parkinsonism. In these subjects, the SN damage was best demonstrated by neuromelanin-sensitive imaging and diffusion tensor imaging (DTI) with fractional anisotropy measure, suggesting an interest of these measures in the prodromal characterization of PD. These same markers had the best performance for PD diagnosis.Finally, we found medulla oblongata damage patients with PD using DTI. This damage was correlated with cardiac and respiratory autonomic symptoms, suggesting the importance of this biomarker in medulla oblongata damage exploration. It also opens a possibility of medulla oblongata study in presymptomatic subjects as medulla oblongata damage should appear before motor symptoms based on the Braak model.These biomarkers may be the first step towards a presymptomatic diagnosis of PD in clinical practice

Mesure de la charge en fer par IRM dans les formes génétiques de la maladie de Parkinson

Objectifs: Bien que la plupart des cas de maladie de Parkinson (MP) soient sporadiques, il existe des rares formes génétiques de MP. Dans la MP idiopathique (MPI), la charge en fer quantifiée par le taux de relaxation transversale R2* est augmentée dans la substance noire (SN). Notre objectif était d étudier la charge en fer des sujets porteurs de mutations génétiques associées à la MP en comparaison avec les sujets indemnes de mutations. Matériels et méthodes: Les données IRM (3D T1 et T2, mesure des taux de relaxation R2 et R2*) ont été acquises à 3T chez 20 patients avec MPI, 20 porteurs de mutations LRRK2 et Parkin (10 porteurs sains, 10 patients) et 20 sujets témoins. Les R2* et R2 moyens ont été calculés dans la SN et les noyaux gris centraux (NGC). Résultats: Les valeurs de R2* étaient augmentées dans la MPI et la MP génétique par rapport aux témoins (p<0,0001) et dans la MP génétique par rapport à la MPI (p=0,0023). Les porteurs sains présentaient des valeurs de R2* supérieures à celles des témoins (p=0,021) mais pas à celles des patients atteints de MP. Il n y avait pas de différence de R2 dans la SN ni de R2* et R2 dans les NGC. Conclusion: La charge en fer était élevée chez les malades atteints de MP génétique comme chez les porteurs sains. Chez les sujets atteints, elle était supérieure à celle des patients atteints de MPI. La charge en fer évaluée par le taux R2* peut être considérée comme un biomarqueur de l atteinte nigrostriatale associées à la neurodégénérescence chez les sujets porteurs de mutations. Le rôle causal de cette charge en fer reste à étudierPARIS12-CRETEIL BU Médecine (940282101) / SudocSudocFranceF

The Role of Magnetic Resonance Imaging for the Diagnosis of Atypical Parkinsonism

International audienceThe diagnosis of Parkinson's disease and atypical Parkinsonism remains clinically difficult, especially at the early stage of the disease, since there is a significant overlap of symptoms. Multimodal MRI has significantly improved diagnostic accuracy and understanding of the pathophysiology of Parkinsonian disorders. Structural and quantitative MRI sequences provide biomarkers sensitive to different tissue properties that detect abnormalities specific to each disease and contribute to the diagnosis. Machine learning techniques using these MRI biomarkers can effectively differentiate atypical Parkinsonian syndromes. Such approaches could be implemented in a clinical environment and improve the management of Parkinsonian patients. This review presents different structural and quantitative MRI techniques, their contribution to the differential diagnosis of atypical Parkinsonian disorders and their interest for individual-level diagnosis

Increased 18F-FDG Uptake in Lhermitte-Duclos Disease With Cowden Syndrome Revealed by PET-MRI

International audienceA 62-year-old woman, with the history of breast and colorectal cancer, presented intermittent diplopia. A cerebellar lesion was revealed by F-FDG PET-MRI without post-gadolinium enhancement, but with increased perfusion and strong F-FDG uptake. The diagnosis of Cowden syndrome with PTEN gene mutation, linked to higher risk of neoplasia and occurrence of hamartomatous lesions characteristic of the Lhermitte-Duclos disease (LDD), was confirmed by genetic investigation

Low ADC in CNS Lymphoma

International audiencePatients with primary central nervous system lymphomas (PCNSLs) present with nonspecific clinical symptoms, which makes correct imaging evaluation essential for diagnostic and therapeutic management. In this work, we examined an 81-year-old man with recently discovered PCNSL using F-FDG PET/MRI, and we were able to differentiate between 2 lesions-PCNSL lymphoma extension and a recent ischemia. Our work shows that ischemia should be considered as a differential diagnosis for lymphoma progression. Although F-FDG PET or MRI alone cannot always give unambiguous solution, PET/MRI can greatly improve the diagnosis accuracy and help decide on the appropriate patient management

A review of the use of magnetic resonance imaging in Parkinson’s disease

To date, the most frequently used Parkinson’s disease (PD) biomarkers are the brain imaging measures of dopaminergic dysfunction using positron emission tomography and single photon emission computed tomography. However, major advances have occurred in the development of magnetic resonance imaging (MRI) biomarkers for PD in the past decade. Although conventional structural imaging remains normal in PD, advanced techniques have shown changes in the substantia nigra and the cortex. The most well-developed MRI markers in PD include diffusion imaging and iron load using T2/T2* relaxometry techniques. Other quantitative biomarkers such as susceptibility-weighted imaging for iron load, magnetization transfer and ultra-high-field MRI have shown great potential. More sophisticated techniques such as tractography and resting state functional connectivity give access to anatomical and functional connectivity changes in the brain, respectively. Brain perfusion can be assessed using non-contrast-agent techniques such as arterial spin labelling and spectroscopy gives access to metabolites concentrations. However, to date these techniques are not yet fully validated and standardized quantitative metrics for PD are still lacking. This review presents an overview of new structural, perfusion, metabolic and anatomo-functional connectivity biomarkers, their use in PD and their potential applications to improve the clinical diagnosis of Parkinsonian syndromes and the quality of clinical trials

Pseudo-asymmetry of cerebral blood flow in arterial spin labeling caused by unilateral fetal-type circle of Willis: Technical limitation or a way to better understanding physiological variations of cerebral perfusion and improving arterial spin labeling acquisition?

International audienceIn the recently published article, "Unilateral fetal-type circle of Willis anatomy causes right-left asymmetry in cerebral blood flow with pseudo-continuous arterial spin labeling: A limitation of arterial spin labeling-based cerebral blood flow measurements?", it was shown by the method of arterial spin labeling (ASL) that unilateral fetal-type circle of Willis could induce variation of blood flow in cerebellar and posterior cerebral artery territory. We believe that the reported observation, rather than being a limitation, gives several interesting cues for understanding the ASL sequence. In this commentary, we formulate some suggestions regarding the use of ASL in clinical practice, discuss the potential causes of the above-mentioned pseudo-asymmetry and consider future improvements of the ASL technique

Potential Effect of Fetal Origin of Posterior Cerebral Artery on the Arterial Spin Labeling Sequence

International audienceArterial Spin Labeling (ASL) is prone to a number of artifacts, which may affect its diagnostic accuracy. To avoid these pitfalls, possible effects on the ASL measurements should be identified. Perfusion asymmetry in the posterior cerebral artery (PCA) territory may be induced by the fetal-type PCA. Whenever a posterior left-right asymmetry is observed on the ASL, structural MR images should be taken into account to rule out cerebrovascular pathology mimickers such as unilateral fetal-type PCA