50 research outputs found

    Fully automated deep learning-based localization and segmentation of the locus coeruleus in aging and Parkinson's disease using neuromelanin-sensitive MRI

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    Purpose: Development and performance measurement of a fully automated pipeline that localizes and segments the locus coeruleus in so-called neuromelanin-sensitive magnetic resonance imaging data for the derivation of quantitative biomarkers of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Methods: We propose a pipeline composed of several 3D-Unet-based convolutional neural networks for iterative multi-scale localization and multi-rater segmentation and non-deep learning-based components for automated biomarker extraction. We trained on the healthy aging cohort and did not carry out any adaption or fine-tuning prior to the application to Parkinson’s disease subjects. Results: The localization and segmentation pipeline demonstrated sufficient performance as measured by Euclidean distance (on average around 1.3mm on healthy aging subjects and 2.2mm in Parkinson’s disease subjects) and Dice similarity coefficient (overall around 71% on healthy aging subjects and 60% for subjects with Parkinson’s disease) as well as promising agreement with respect to contrast ratios in terms of intraclass correlation coefficient of ≥0.80 for healthy aging subjects compared to a manual segmentation procedure. Lower values (≥0.48) for Parkinson’s disease subjects indicate the need for further investigation and tests before the application to clinical samples. Conclusion: These promising results suggest the usability of the proposed algorithm for data of healthy aging subjects and pave the way for further investigations using this approach on different clinical datasets to validate its practical usability more conclusively

    Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease

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    This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson’s disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson’s disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson’s disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson’s disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra’s morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson’s disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification

    Magnetic resonance imaging techniques for diagnostics in Parkinson’s disease and atypical parkinsonism

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    Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by rigidity, hypokinesia, tremor and postural instability. PD is a clinical diagnosis based on neurological examination, patient history and treatment response. Similar symptoms can be caused by other movement disorders such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), making it difficult to clinically separate them in early stages. However, these diseases differ in underlying pathology, treatment and prognosis. PSP and MSA have more rapid deterioration and develop additional symptoms such as impaired eye movements or autonomic dysfunction. Magnetic resonance imaging (MRI) is commonly performed as part of the clinical work-up in patients presenting with parkinsonism. There are no overt changes on structural MRI in PD. In atypical parkinsonian syndromes there are typically no visible changes until later disease stages. Purpose: The aim of this thesis is to evaluate novel MRI techniques for diagnostics and for investigation of disease processes in Parkinson’s disease, PSP and MSA. Paper I: A retrospective cohort from Karolinska University Hospital (102 participants; 62 PD, 15 PSP, 11 MSA, 14 controls) was assessed using susceptibility mapping processed from susceptibility weighted imaging. We show that there is elevated susceptibility in the red nucleus and the globus pallidus in PSP compared to PD, MSA and controls. Higher susceptibility levels were also seen in MSA compared to PD in the putamen, and in PD compared to controls in the substantia nigra. Using the red nucleus susceptibility as a diagnostic biomarker, PSP could be separated from PD with an accuracy of 97% (based on the area under the receiver operating characteristic curve, AUC), from MSA with AUC 75% and from controls with AUC 98%. We concluded that susceptibility changes, particularly in the red nucleus in PSP, could be potential biomarkers for differential diagnostics in parkinsonism. Paper II: A prospective cohort from Lund, the BioFINDER study (199 participants; 134 PD, 11 PSP, 10 MSA, 44 controls), was investigated using the susceptibility mapping pipeline developed for Paper I. The finding from Paper I with elevated susceptibility in the red nucleus was validated for PSP compared to PD, MSA and controls. The elevated putaminal susceptibility was also confirmed in MSA compared to PD. The potential role of red nucleus susceptibility as a biomarker for separating PSP from PD and MSA was also similar to the results in Paper I, with AUC 98% for separating PSP from PD and AUC 96% for separating PSP from MSA. We concluded that we could confirm our previous findings from Paper I, with the red nucleus susceptibility being a potential biomarker for separating PSP from PD and MSA. Paper III: A retrospective cohort from Karolinska University Hospital (196 participants; 140 PD, 29 PSP, 27 MSA) was evaluated to employ automated volumetric brainstem segmentation using FreeSurfer. The volumetric approach was compared to manual planimetric measurements: midbrain-pons ratio, magnetic resonance parkinsonism index 1.0 and 2.0. Intra- and inter-scanner as well as intra- and inter-rater reliability were calculated. We found good repeatability in both automated volumetric and manual planimetric measurements. Normalized midbrain volume performed better than the planimetric measurements for separating PSP from PD. We concluded that, if further developed and incorporated in a radiology workflow, automated brainstem volumetry could increase availability of brainstem metrics and possibly save time for radiologists conducting manual measurements. Paper IV: Two cohorts, a retrospective from Karolinska University Hospital (184 participants; 129 PD, 28 PSP, 27 MSA) and a prospective from Lund (185 participants; 125 PD, 11 PSP, 8 MSA, 41 controls), were studied to investigate a new method of creating T1-/T2-weighted ratio images and its diagnostic capabilities in differentiating parkinsonian disorders. In the explorative retrospective cohort, differences in white matter normalized T1-/T2- weighted ratios were seen in the caudate nucleus, putamen, thalamus, subthalamic nucleus and red nucleus in PSP compared to PD; in the caudate nucleus and putamen in MSA compared to PD and in the subthalamic nucleus and the red nucleus in PSP compared to MSA. These differences were validated externally in the prospective cohort, where the changes could be confirmed in the subthalamic nucleus and the red nucleus in PSP compared to PD and MSA. We concluded that there are different patterns of white matter normalized T1-/T2-weighted ratio between the disorders and that this reflects differences in underlying pathophysiology. The T1-/T2-weighted ratio should be further investigated for better understanding of pathological processes in parkinsonian disorders and could possibly be utilized for diagnostic purposes if further developed

    Theoretical and experimental considerations of selective vulnerability In Parkinson's disease

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    Les maladies neurodégénératives sont typiquement caractérisées en fonction de leurs symptômes et des observations pathologiques effectuées après le décès. Les symptômes spécifiques à la maladie sont également normalement associés aux dysfonctionnements et à la dégénérescence de certaines sous- populations spécifiques de neurones dans le système nerveux. La maladie de Parkinson (MP) est une maladie neurodégénérative principalement caractérisée par des symptômes moteurs dus à la dégénérescence spécifique des neurones dopaminergiques (DA) de la substantia nigra pars compacta (SNpc/SNc). Il semble cependant que les neurones DA de la SNc ne soient pas la seule population de neurones qui dégénère dans la MP. L'analyse post-mortem, l'imagerie in vivo et les symptômes cliniques démontrent que le dysfonctionnement et la dégénérescence se produisent dans plusieurs autres régions du système nerveux, incluant par exemple des neurones noradrénergiques (NA) du locus coeruleus (LC), des neurones sérotoninergiques des noyaux du raphé et des neurones cholinergiques du noyau moteur dorsal du nerf vague (DMV) et du noyau pédonculopontin. Comme d'autres maladies neurodégénératives, la MP est causée par plusieurs facteurs, tant génétiques qu'environnementaux. De nombreuses observations suggèrent que ces facteurs soient associés au dysfonctionnement de plusieurs systèmes ou fonctions cellulaires incluant la production d’énergie par la mitochondrie, l’élimination de protéines dysfonctionnelles par le protéasome et le lysosome, la régulation de l’équilibre entre la production d'espèces oxydatives réactives et les mécanismes antioxydants, la régulation des niveaux de calcium intracellulaire et l’inflammation. Il semble donc que le dysfonctionnement de ces facteurs converge pour provoquer la dégénérescence neuronale dans le contexte du vieillissement. Ce qui rend les neurones de certaines régions du système nerveux intrinsèquement plus vulnérables aux facteurs associés à la MP est une question fondamentale qui n’est pas résolue pour le moment. Les travaux de cette thèse sont basés sur l’hypothèse proposant que cette vulnérabilité sélective découle de propriétés communes retrouvées chez les neurones vulnérables. En particulier, les neurones vulnérables auraient en commun d’être des neurones de projections dotés d’un axone complexe qui projette sur de longues distances, formant un nombre très élevé de terminaisons axonales sur de vastes territoires du système nerveux. De plus, ces neurones présenteraient des propriétés physiologiques distinctives, incluant notamment une décharge autonome (pacemaker). Ensemble, ces caractéristiques pourraient contribuer à placer ces neurones dans des conditions de fonctionnement aux limites de leur capacités bioénergétiques et homéostatiques, rendant difficile toute adaptation aux dysfonctionnements cellulaires associés au vieillissement et causés par les facteurs de risques de la MP. Dans cette thèse, je présenterai une revue systématique de la littérature sur la perte de neurones dans le cerveau des personnes atteintes de la maladie de Parkinson, montrant que l'identité neurochimique précise des neurones qui dégénèrent dans la maladie de Parkinson, et l'ordre temporel dans lequel cela se produit, n’est pas clair. Cependant, en analysant les points de vue présentés dans les publications citant cette revue, nous avons remarqué que la majorité de ceux-ci ne reflètent pas le message central de notre publication. Puisque l’identification de l’identité des neurones vulnérables et non vulnérables à la MP est fondamentale pour le développement de théories et hypothèses sur les causes de la MP, nous suivons cette première publication avec une lettre réaffirmant l'importance de faire face aux problèmes identifiés dans notre revue. Nous présentons ensuite des données in vitro montrant que les neurones vulnérables à la MP, comparés à ceux qui sont moins vulnérables, ont une capacité intrinsèque à développer des champs axonaux plus importants et plus complexes, avec un nombre plus élevé de sites actifs de libération de neurotransmetteurs. De plus, nous constatons que ces observations sont corrélées à une vulnérabilité plus élevée face à un stress oxydatif pertinent pour la MP. Ces données sont en accord avec l'hypothèse selon laquelle le domaine axonal, et en particulier le nombre de sites de libération de neurotransmetteurs par neurone, est un facteur important qui contribue à rendre un neurone sélectivement vulnérable dans le contexte de la MP. Enfin, nous présentons une méthode d’analyse d’image open-source visant à aider les biologistes et les neuroscientifiques à automatiser la quantification du nombre de neurones dans des cultures primaires de neurones, telle qu’utilisée dans les travaux de cette thèse. Nous proposons que cet algorithme simple — mais robuste — permettra aux biologistes d'automatiser le comptage des neurones avec une grande précision, quelque chose de difficile à effectuer avec les autres approches open-source disponibles présentement. Nous espérons que les travaux présentés dans cette thèse permettront de contribuer à raffiner les théories visant à expliquer l’origine de la MP et à terme, de développer de nouvelles approches thérapeutiques.Neurodegenerative diseases are typically characterized based on their symptoms, and pathological factors identified after death. The disease-specific symptoms are due to the dysfunction and degeneration of specific subpopulations of neurons, which cause dysfunction in particular brain functions. Parkinson's disease (PD) is a neurodegenerative disease primarily characterized by motor symptoms due to the specific degeneration of dopamine (DA) neurons of the substantia nigra pars compacta (SNpc/SNc): a population of neurons essential for motor control. SNc DA neurons are, however, not the only population of neurons that degenerate in PD. Post-mortem analysis, in vivo imaging, and clinical symptoms demonstrate that dysfunction and degeneration occur in several other neuronal nuclei. These include, but are not limited to, noradrenergic (NA) locus coeruleus (LC) neurons, serotonin neurons of the raphe nuclei, and cholinergic neurons of the dorsal motor nucleus of the vagus (DMV) and pedunculopontine nucleus. Like other neurodegenerative diseases, PD is linked to several risk factors, both genetic and environmental. The evidence suggests that these risk factors are associated with the dysfunction in systems of cellular bioenergetics (including mitochondrial function); proteostatic homeostasis; endolysosomal function; an imbalance between the production of reactive oxidative species (ROS), and antioxidant mechanisms; calcium homeostasis; alpha-synuclein misfolding; and neuroinflammation. Consequently, together with aging, these risk factors converge on causing the selective degeneration of "PD-vulnerable" nuclei. What makes these neurons intrinsically vulnerable to PD-associated risk factors is a fundamental question — and understanding these neurons will reveal biological mechanisms that we can target to protect these cells from degeneration. Our best hypotheses to explain why these neurons are based on the observations that most PD- vulnerable neurons are long-range projection neuromodulatory neurons sharing common characteristics: projecting to voluminous territories, having very long and highly branched unmyelinated axonal domains with vast numbers of neurotransmitter release sites, and exhibiting a unique physiology such as pacemaker firing. Taken together, this suggests that these neurons function at the tail-end of their bioenergetic and homeostatic capacity, unable to tolerate any further demands, such as those incurred in the presence of risk factors associated with PD. In this thesis, I will present a systematic review on the literature on purported cell loss in PD brains, showing that — given the actual primary evidence — the precise neurochemical identity of neurons that degenerate in PD, and the temporal order of this degeneration, is far less clear than described by most publications. This review — at the time of writing — has gone on to be highly cited. However, analyzing the claims made in publications citing this review, we discover that the majority of claims do not reflect the core message of our publication. Since the identity of PD-vulnerable and non-PD-vulnerable neurons is fundamental to theory and hypotheses when trying to understand PD, we follow this first publication with a letter restating the importance to address our observations. We then present in vitro data showing that classically PD-vulnerable neurons, when compared to non-PD vulnerable neurons, have an intrinsic capacity to develop larger and more complex axonal domains, with higher numbers of active neurotransmitter release sites. Moreover, we find that these observations correlate to elevated vulnerability to PD-relevant stress assays. These data provide additional support for the hypothesis that the axonal domain — and in particular — the number of active neurotransmitter sites per neuron, is a cell-autonomous factor rendering a neuron selectively vulnerable in the context of PD. Finally, we present an open-source tool to support biologists and neuroscientists in automating the quantification of neuron numbers in medium-throughput primary cell cultures. Where the application of other open-source solutions is either too simplistic for the use-case or technically challenging to implement, this simple — yet robust algorithm — allows biologists with limited computational nous to automate neuron counting with high precision. We hope that the work presented in this thesis will contribute to the refinement of theories aimed at explaining the origin of PD and, ultimately, to the development of new therapeutic approaches

    Multiparametric MRI for Characterization of the Basal Ganglia and the Midbrain

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    Objectives To characterize subcortical nuclei by multi-parametric quantitative magnetic resonance imaging.Materials and Methods: The following quantitative multiparametric MR data of five healthy volunteers were acquired on a 7T MRI system: 3D gradient echo (GRE) data for the calculation of quantitative susceptibility maps (QSM), GRE sequences with and without off-resonant magnetic transfer pulse for magnetization transfer ratio (MTR) calculation, a magnetization−prepared 2 rapid acquisition gradient echo sequence for T1 mapping, and (after a coil change) a density-adapted 3D radial pulse sequence for 23Na imaging. First, all data were co-registered to the GRE data, volumes of interest (VOIs) for 21 subcortical structures were drawn manually for each volunteer, and a combined voxel-wise analysis of the four MR contrasts (QSM, MTR, T1, 23Na) in each structure was conducted to assess the quantitative, MR value-based differentiability of structures. Second, a machine learning algorithm based on random forests was trained to automatically classify the groups of multi-parametric voxel values from each VOI according to their association to one of the 21 subcortical structures.Results The analysis of the integrated multimodal visualization of quantitative MR values in each structure yielded a successful classification among nuclei of the ascending reticular activation system (ARAS), the limbic system and the extrapyramidal system, while classification among (epi-)thalamic nuclei was less successful. The machine learning-based approach facilitated quantitative MR value-based structure classification especially in the group of extrapyramidal nuclei and reached an overall accuracy of 85% regarding all selected nuclei.Conclusion Multimodal quantitative MR enabled excellent differentiation of a wide spectrum of subcortical nuclei with reasonable accuracy and may thus enable sensitive detection of disease and nucleus-specific MR-based contrast alterations in the future

    Development of functional MRI protocols in the study of neurodegenerative diseases: MRI study in patients with REM sleep behavior disorder, idiopathic Parkinson's disease and multisystem atrophy

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    In the central nervous system, iron in several proteins is involved in many important processes: oxygen transportation, oxidative phosphorylation, mitochondrial respiration, myelin production, the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation, modification of lipids, proteins, carbohydrates, and DNA, lead to neurotoxicity. Moreover increased levels of iron are harmful and iron accumulations are typical hallmarks of brain ageing and several neurodegenerative disorders particularly PD. Numerous studies on post mortem tissue report on an increased amount of total iron in the substantia nigra in patients with PD also supported by large body of in vivo findings from Magnetic Resonance Imaging (MRI) studies. The importance and approaches for in vivo brain iron assessment using multiparametric MRI is increased over last years. Quantitative MRI may provide useful biomarkers for brain integrity assessment in iron-related neurodegeneration. Particularly, a prominent change in iron- sensitive T2* MRI contrast within the sub areas of the SN overlapping with nigrosome 1 were shown to be a hallmark of Parkinson's Disease with high diagnostic accuracy. Moreover, differential diagnosis between Parkinson's Disease (PD) and atypical parkinsonian syndromes (APS) remains challenging, mainly in the early phases of the disease. Advanced brain MR imaging enables to detect the pathological changes of nigral and extranigral structures at the onset of clinical manifestations and during the course of the disease. The Nigrosome-1 (N1) is a substructure of the healthy Substantia Nigra pars compacta enriched by dopaminergic neurons; their loss in Parkinson’s disease and atypical parkinsonian syndromes is related to the iron accumulation. N1 changes are supportive MR biomarkers for diagnosis of these neurodegenerative disorders, but its detection is hard with conventional sequences, also using high field (3T) scanner. Quantitative susceptibility mapping (QSM), an iron-sensitive technique, enables the direct detection of Neurodegeneratio

    Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo

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    BACKGROUND Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo . METHODS Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent in vivo concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging. The in vivo results were verified against structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 Tesla and scanning transmission X-ray microscopy (STXM) of perfused brains. Brain slice immunofluorescence and Prussian blue staining were further performed to validate the detection of alpha-synuclein inclusions and iron deposition in the brain, respectively. RESULTS THK-565 showed increased fluorescence upon binding to recombinant alpha-synuclein fibrils and alpha-synuclein inclusions in post-mortem brain slices from patients with Parkinson's disease and M83 mice. i.v. administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 minutes post-injection by wide-field fluorescence compared to non-transgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe 3+^{3+} form, as evinced by the STXM results. CONCLUSION We demonstrated in vivo mapping of alpha-synuclein by means of non-invasive epifluorescence and vMSOT imaging assisted with a targeted THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo
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