The Neuromelanin-related T2* Contrast in Postmortem Human Substantia Nigra with 7T MRI

High field magnetic resonance imaging (MRI)-based delineation of the substantia nigra (SN) and visualization of its inner cellular organization are promising methods for the evaluation of morphological changes associated with neurodegenerative diseases; however, corresponding MR contrasts must be matched and validated with quantitative histological information. Slices from two postmortem SN samples were imaged with a 7 Tesla (7T) MRI with T1 and T2* imaging protocols and then stained with Perl???s Prussian blue, Kluver-Barrera, tyrosine hydroxylase, and calbindin immunohistochemistry in a serial manner. The association between T2* values and quantitative histology was investigated with a co-registration method that accounts for histology slice preparation. The ventral T2* hypointense layers between the SNr and the crus cerebri extended anteriorly to the posterior part of the crus cerebri, which demonstrates the difficulty with an MRI-based delineation of the SN. We found that the paramagnetic hypointense areas within the dorsolateral SN corresponded to clusters of neuromelanin (NM). These NM-rich zones were distinct from the hypointense ventromedial regions with high iron pigments. Nigral T2* imaging at 7T can reflect the density of NM-containing neurons as the metal-bound NM macromolecules may decrease T2* values and cause hypointense signalling in T2* imaging at 7T.ope

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases

Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases

Estudio clínico y de neuroimagen de la función noradrenérgica como indicador precoz de deterioro cognitivo

[spa] Los trastornos neurocognitivos (TNC) son un grupo heterogéneo de entidades clínicas cuya característica principal es el deterioro de todas o algunas de las capacidades funcionales y cognitivas previamente adquiridas por el individuo. Entre ellos encontramos el TNC mayor, tener múltiples etiologías, su causa más común es la enfermedad de Alzheimer (EA). Las marcas neuropatológicas distintivas de esta patología son la acumulación de placas de proteína β-amiloide y la de proteína tau hiperfosforilada que forma, entre otros, ovillos neurofibrilares. El primer lugar en el que se han detectado cambios en el proceso de formación de estas acumulaciones es el locus coeruleus (LC). Este es un núcleo situado en el tegmento pontino y es la mayor fuente de noradrenalina del sistema nervioso central. La integridad estructural del LC se ha investigado tanto en EA como en población en riesgo de desarrollar EA, sin embargo la preservación funcional de este núcleo a lo largo del continuum del TNC restaba sin estudiar. En esta tesis se presentan dos estudios centrados en la evaluación de la conectividad funcional entre el LC y diferentes regiones corticales y subcorticales, en grupos en riesgo de EA: hijos de pacientes con EA de inicio tardío (H-EAIT), individuos con deterioro cognitivo leve (DCL) y pacientes con trastorno depresivo mayor en edad avanzada (TDM); con el fin de comprobar si la medición de la funcionalidad del LC puede constituir un marcador precoz del comienzo del proceso neurodegenerativo en estas etapas tempranas del TNC. El primer estudio se centra en analizar la conectividad del LC en un grupo de H- EAIT, en comparación con sujetos sanos, durante una secuencia de resonancia magnética funcional en estado de reposo. En el segundo estudio se incluyó un grupo de DCL, de TDM y un grupo control; y se estudió la conectividad del LC durante la realización de una tarea oddball o de detección de estímulos, que permite estudiar la actividad neuronal del LC. En ambos casos correlacionamos los resultados de los análisis de neuroimagen con medidas clínicas, neuropsicológicas y conductuales, con el fin de caracterizar los patrones de alteración funcional y su asociación con posibles variables clínicas o cognitivas. Nuestros resultados apuntan a la disminución de la conectividad global del LC en el grupo de H-EAIT durante el estado de reposo y en TDM ante la detección de estímulos salientes (oddball). En ambos grupos observamos una disminución de la conectividad entre el LC y regiones del cerebelo posterior, implicadas en la modulación de la actividad de la red por defecto, de control ejecutivo y de saliencia. Igualmente, el grupo de TDM se caracteriza por presentar una disminución de la conectividad entre el LC y el giro fusiforme y la corteza cingulada anterior (CCA) ante los estímulos oddball. En los H-EAIT encontramos una correlación positiva entre la conectividad del LC-cerebelo posterior y medidas de recuerdo diferido que señala la implicación de este patrón en la función mnésica. Además, encontramos una asociación negativa entre la severidad de síntomas depresivos y la conectividad LC-cerebelo posterior. En los TDM, la conectividad LC-CCA se asocia negativamente con medidas de severidad y carga del trastorno depresivo, reflejo de la diferenciación entre dos subgrupos de pacientes depresivos: en episodio activo de depresión y en remisión. Los resultados de este estudio confirman que existen alteraciones en la conectividad del LC en estadios iniciales del TNC y en población con un riesgo incrementado de desarrollo de EA. Además, apoyan la modulación del LC de regiones corticales y subcorticales implicadas en función mnésica, atencional y regulación del arousal. Esta tesis supone un punto de base para la investigación más profunda del LC a lo largo del continuo del TNC, con el fin de poder desarrollar herramientas diagnósticas no invasivas que permitan detectar precozmente procesos neurodegenerativos y el desarrollo de tratamientos más personalizados.[eng] Neurocognitive disorders (NCD) are a heterogeneous group of clinical entities that share as a principal hallmark the impairment in all or some of the previously acquired cognitive and functional capacities. Among this group, Alzheimer’s disease (AD) is the most prevalent cause of NCD. The two biological hallmarks of AD are the β-amyloid plaques and hyperphosphorylated tau neurofibrillary tangles. The locus coeruleus (LC) nucleus, the major source of noradrenaline to the central nervous system, is the region where pathological changes start in the continuum of AD. Structural integrity of this nucleus has been investigated in AD and AD at-risk population, but its functional preservation remained unstudied. In this thesis, we present two studies focused in the LC functional connectivity. The first study included a group of offspring of late onset AD (O-LOAD) and we used a resting-state functional magnetic resonance (rs-fMRI). For the second study a group of mild cognitive impairment (MCI) and late-life major depressive disorder (MDD) were recruited and they performed an oddball task during the acquisition of functional magnetic resonance imaging (fMRI). In both works, neuroimaging results were correlated with clinical, neuropsychological and behavioral data. Firstly, we found that both O-LOAD and MDD groups showed a diminished LC global connectivity, and these groups also presented a lower connectivity between LC and posterior cerebellum regions, during rs-fMRI and the oddball task, respectively. Moreover, MDD showed a lower connectivity between LC and fusiform gyrus and anterior cingulate cortex (ACC) in front of oddball stimuli. In O-LOAD we observed a negative association between LC-posterior cerebellum and depression symptoms and memory measures; and MDD showed an inverse correlation between LC-CCA connectivity and depression severity and the number of episodes measures. Our results point to the presence of connectivity alterations of LC in early stages of NCD and in AD at- risk population. A deeper investigation of functional activity and connectivity of the LC through the NCD continuum would be useful for the development of non-invasive diagnostic tools and the development of personalized treatments

Η εφαρμογή της οπτογενετικής στην έρευνα των αγχωδών διαταραχών

Διπλωματική εργασία--Πανεπιστήμιο Μακεδονίας, Θεσσαλονίκη, 2018.Η οπτογενετική είναι μια τεχνική, που χρησιμοποιεί γενετικές και οπτικές μεθόδους. Τα τελευταία χρόνια υπάρχει ένα διαρκώς αυξανόμενο ενδιαφέρον για τη χρήση της οπτογενετικής, στην έρευνα των ψυχικών διαταραχών. Αυτή η εργασία αποτελεί μια βιβλιογραφική ανασκόπηση της χρήσης της οπτογενετικής, στην έρευνα των αγχωδών διαταραχών. Αρχικά, θα αναφερθούν οι μέθοδοι της οπτογενετικής, τα εργαλεία, που χρησιμοποιούνται, και οι διαδικασίες που τη συνοδεύουν. Στο δεύτερο μέρος, η εργασία θα εστιάσει στις αγχώδεις διαταραχές και -κυρίως- στην κατηγοριοποίησή τους, στη συμπτωματολογία και στα αίτια εμφάνισής τους. Στο τρίτο μέρος, θα παρουσιαστούν μελέτες και ευρήματα από έρευνες, όπου μέθοδοι της οπτογενετικής εφαρμόζονται σε νευρωνικά κυκλώματα, που συνδέονται με το άγχος και το φόβο. Τέλος, στον επίλογο, θα αναφερθούν περιορισμοί και σκέψεις για τη μελλοντική χρήση της οπτογενετικής. Η εργασία αναμένεται να αναδείξει τη χρήση της οπτογενετικής στην έρευνα των αγχωδών διαταραχών, κυρίως, μέσω της παρουσίασης του τρόπου, με τον οποίο η οπτογενετική χρησιμοποιείται στο εν λόγω πεδίο αλλά και μέσω της παρουσίασης ευρημάτων, που έχουν ήδη φανερώσει κρυφές πτυχές για τη νευροβιολογική βάση της λειτουργίας του φόβου και του άγχους. Επίσης, αποσκοπεί στη σύνδεση των πεδίων της οπτογενετικής και της ψυχοπαθολογίας, υπό το πρίσμα της διεπιστημονικότητας στις νευροεπιστήμες.Optogenetics is a technique that uses genetic and optical methods. Over the last few years, there has been an increasing interest in the use of optogenetics in the research of mental disorders. This paper constitutes a bibliographic examination of the use of optogenetics in the research of anxiety disorders. Initially, this essay will report the methods of optogenetics, the tools used, and the procedures that accompany it. In the second part, the thesis will focus on anxiety disorders and, especially, on their categorization, their symptomatology and the causes of their occurrence. In the third chapter, studies and research findings will be presented, where methods of optogenetics are applied to neuronal circuits associated with anxiety and fear. Finally, in the concluding chapter of the paper, restrictions and thoughts on the future use of optogenetics will be addressed. This work is expected to highlight the use of optogenetics in the research of anxiety disorders, primarily, through the presentation of the way, in which optogenetics is used in this field, and, also, through the exposition of findings, that have, already, revealed hidden aspects of the neurobiological basis of fear and anxiety. Additionally, it aims to link the fields of optogenetics and psychopathology, in the light of the interdisciplinarity, which characterizes neuroscience

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Department of Biomedical EngineeringIn the brain, iron is an essential element in oxygen supply through blood vessels, energy metabolism, myelin formation, and neurotransmitter synthesis for brain development with maintaining homeostasis. However, even in healthy people, as they grow older, iron levels increase steadily in some regions of the brain. Among the inevitable iron deposits with aging, the unbound labile iron generates reactive oxygen and free radicals, which produce stress on the brain tissue and necrosis of cells, which are closely associated with neurodegenerative diseases. These finally promote neurodegenerative diseases, including Parkinson???s disease and Alzheimer???s disease, which accompany the damage in behavior and cognitive function. Therefore, developing magnetic resonance imaging-based biomarkers to detect various iron clusters deposited in the brain is crucial work for diagnosing and monitoring related diseases. However, it???s still impossible to classify the states of iron and separate the various forms of iron deposited in the brain. The aim of this study was to develop multi-color iron magnetic resonance imaging and the investigation of its in vivo feasibility through translation research from the preclinical trials including postmortem magnetic resonance imaging with histopathological validation to clinical application. In the first section, it was discovered that the neuromelanin pigment within the human substantia nigra is only sensitive to T2* than other magnetic resonance contrast due to its paramagnetic property. Subsequently, the technique for specific visualization of neuromelanin-iron clusters in postmortem substantia nigra tissue was developed using combined T2 and T2* (T2*/T2 or T2*/T22) with histopathological validation supported by the Monte Carlo simulation. Separate segmentations of the areas of iron detected in the T2 map and neuromelanin observed in the T2*/T2 map (or T2*/T22 map) were available within the substantia nigra. The dorsal linear mismatch of T2 and T2* was consistently detected in the brains of healthy controls. However, it was shortened in the diseased brains. In vivo feasibility and implication of developed technique as a clinical biomarker were quantitatively demonstrated in the patients of Parkinson???s disease compared to healthy subjects. In the second section, the iron deposition along the myelinated fiber of white matter was identified in the diseased brains. The iron-rich white matter at the frontal subcortical area contributes to the positive susceptibility in the patients of Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Susceptibility-weighted imaging presented the noticeable phase signal showing the tree-like structure in the white matter of the frontal brain, with striking atrophy. This kind of rare tissue contrast in susceptibility-weighted imaging can aid to define Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Besides, the deposited iron was verified on the myelinated fibers of the 3rd cranial nerve, which is the oculomotor nerve within the brain of progressive supranuclear palsy. Our results demonstrated the enhanced magnetic resonance susceptibility value between the area of substantia nigra and red nucleus shown in the brain of progressive supranuclear palsy derives from exaggerated iron concentration on the myelinated fibers of the nerves between two structures. In conclusion, the developed techniques of multi-color iron magnetic resonance imaging in this thesis can be useful imaging biomarkers to evaluate the progressive change of several iron-related neurodegenerative diseases, such as Perry syndrome, progressive supranuclear palsy, Parkinson???s disease, and Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. The advanced research will be implemented to validate the alteration of magnetic resonance signal with the presence of iron molecules chelated to beta-amyloid or tau with Alzheimer???s disease progression.ope