3,472 research outputs found

    When age-progressed images are unreliable: The roles of external features and age range

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    When children go missing for many years, investigators commission age-progressed images from forensic artists to depict an updated appearance. These images have anecdotal success, and systematic research has found they lead to accurate recognition rates comparable to outdated photos. The present study examines the reliability of age progressions of the same individuals created by different artists. Eight artists first generated age progressions of eight targets across three age ranges. Eighty-five participants then evaluated the similarity of these images against other images depicting the same targets progressed at the same age ranges, viewing either whole faces or faces with external features concealed. Similarities were highest over shorter age ranges and when external features were concealed. Implications drawn from theory and application are discussed

    Analyzing Heterogeneity In Neuroimaging With Probabilistic Multivariate Clustering Approaches

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    Automated quantitative neuroimaging analysis methods have been crucial in elucidating normal and pathological brain structure and function, and in building in vivo markers of disease and its progression. Commonly used methods can identify and precisely quantify subtle and spatially complex imaging patterns of brain change associated with brain diseases. However, the overarching premise of these methods is that the disease group is a homogeneous entity resulting from a single, unifying pathophysiological process that has a single imaging signature. This assumption ignores ample evidence for the heterogeneous nature of neurodegenerative diseases and neuropsychiatric disorders, resulting in incomplete or misleading descriptions. Accurate characterization of heterogeneity is important for deepening our understanding of neurobiological processes, thus leading to improved disease diagnosis and prognosis. In this thesis, we leveraged machine learning techniques to develop novel tools that can analyze the heterogeneity in both cross-sectional and longitudinal neuroimaging studies. Specifically, we developed a semi-supervised clustering method for characterizing heterogeneity in cross-sectional group comparison studies, where normal and patient populations are modeled as high-dimensional point distributions, and heterogeneous disease effects are captured by estimating multiple transformations that align the two distributions, while accounting for the effect of nuisance covariates. Moreover, toward dissecting the heterogeneity in longitudinal cohorts, we proposed a method which simultaneously fits multiple population longitudinal multivariate trajectories and clusters subjects into subgroups. Longitudinal trajectories are modeled using spatiotemporally regularized cubic splines, while clustering is performed by assigning subjects to the subgroup whose population trajectory best fits their data. The proposed tools were extensively validated using synthetic data. Importantly, they were applied to study the heterogeneity in large clinical neuroimaging cohorts. We identified four disease subtypes with distinct imaging signatures using data from Alzheimer’s Disease Neuroimaging Initiative, and revealed two subgroups with different longitudinal patterns using data from Baltimore Longitudinal Study on Aging. Critically, we were able to further characterize the subgroups in each of the studies by performing statistical analyses evaluating subgroup differences with additional information such as neurocognitive data. Our results demonstrate the strength of the developed methods, and may pave the road for a broader understanding of the complexity of brain aging and Alzheimer’s disease

    Development And Utilization Of Ultrasound Imaging Techniques To Evaluate The Role Of Vascularity In Adult And Aged Rat Achilles Tendon Healing

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    Tendons are hypovascular tissues, undergoing angiogenesis only during development, wound healing, and pathogenesis. Injured tendons exhibit a healing response with vascular ingrowth during the proliferative phase and vascular regression during remodeling. Despite this normal healing response, tendons never fully regain their original structure or composition. Additionally, aging further increases tendon risk of rupture and impairs healing response. Since the optimal vascularization level and timing during tendon healing is currently unknown, modulating the vascular response during healing could elucidate the role of angiogenesis in tendon injury and ultimately improve the tendon healing outcome. Furthermore, new ultrasound technologies allow for the evaluation of vascular response after injury, which could provide a measure for evaluating tendon healing in vivo. Therefore, the objective of this study is to develop methods for, and evaluate the effect of, vascular modulation in adult and aged rat Achilles tendons during healing using both in vivo ultrasound imaging measures of vascularity and structure and ex vivo measures of tendon compositional and mechanical properties. In Specific Aim 1, we will validate the use of in vivo high-frequency ultrasound technologies to measure vascular changes in rat Achilles tendons. In Specific Aim 2, we will develop methodologies for vascular modulation in an Achilles tendon injury model using the delivery of pro- and anti-angiogenic factors. Finally, in Specific Aim 3, we will apply methods of vascular modulation and ultrasound imaging to determine the role of angiogenesis in adult and aged Achilles tendon healing models. To achieve these goals, we will perform bilateral partial-rupture injuries in the Achilles tendons of adult and aged rats, followed by injections to modulate their vascular response after injury. The animals will receive vascular endothelial growth factor (VEGF), anti-VEGF antibody (B20.4-1-1, Genentech), or saline injections following injury. They will be evaluated using B-mode, color Doppler, photoacoustic, and contrast-enhanced ultrasound imaging weekly post-injury. Additionally, they will undergo in vivo functional assays to assess gait and passive ankle motion. Animals will be sacrificed for histological and mechanical analyses. This study will validate new in vivo methods for evaluating vascularity in tendon injury models, develop potential angiogenic therapies for improved healing outcome, and elucidate the differences in vascular response with age after tendon injury and vascular modulation

    Modeling Tuberculosis spreading for the evaluation of new vaccines

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    La Tuberculosis (TB) es una enfermedad infecciosa que causa más de 10 millones de nuevos casos y 1.5 millones de muertes al año. La actual vacuna, BCG, no es capaz de proporcionar una eficacia consistente, y por ello existe la imperiosa necesidad de desarrollar nuevas vacunas. En este contexto, la modelización matemática puede jugar un papel clave en la evaluación y comparación de estas nuevas vacunas con el propósito final de asistir en la elaboración de políticas y optimización de las estrategias de vacunación. El objetivo de esta tesis es la creación de un modelo apropiado para la evaluación del impacto de estas nuevas vacunas. Para ello centramos nuestros esfuerzos en dos vertientes distintas: la modelización de la propagación de la Tuberculosis per se, y la parametrización de estas nuevas vacunas para su evaluación con estos nuevos modelos. En lo que se refiere a la modelización de la propagación de la enfermedad, los principales avances propuestos en esta tesis están relacionados con la estructura de edad de las poblaciones. Específicamente implementaremos, por primera vez en un modelo de propagación de TB, contactos dependientes de la edad y la evolución temporal de las pirámides demográficas. Así, comenzamos la tesis estudiando el problema teórico de implementar patrones de contacto empíricos dependientes de la edad en distintas esructuras demográficas. Es una tendencia actual en epidemiología utilizar estos patrones de contacto por edades heterogéneos, superando así la asunción clásica de mezcla homogénea. Sin embargo, estos patrones de contacto han sido medidos en poco más de una decena de localizaciones diferentes, y queda pendiente la cuestión de hasta que punto unos patrones de contacto que corresponden a una población específica son transferibles a otra localización diferente. En esta tesis estudiamos distintos métodos para proyectar matrices de contacto de una población a otra con distinta estructura demográfica, y analizaremos las difierencias que existen en los patrones de contacto de distintos países. Este estudio es fundamental para la construcción de nuestro modelo en el que pretendemos acoplar patrones de contacto por edades con una evolución temporal de la estructura por edades de la población, de forma que deberemos adaptar esas matrices de contacto por edades en cada paso temporal. En el siguiente capítulo desarrollamos un modelo de propagación de la Tuberculosis en el que integramos una gran cantidad de datos sobre una Historia Natural para la enfermedad con 19 estados diferentes (incluyendo dos estados de latencia, tres tipos distintos de enfermedad con distinta infecciosidad, y distintos resultados del tratamiento). Así, nuestro modelo utilizará como input, datos de incidencia y mortalidad específicos de cada país, parámetros epidemiológicos con dependencia de la edad obtenidos de diferentes estudios, y, como ya hemos avanzado, incorporamos por primera vez en el campo proyecciones demográficas y matrices de contacto por edades. En este trabajo, identificamos sesgos substanciales arraigados en una descripción inadequada de estos aspectos, a nivel tanto de incidencia y mortalidad agregadas como en su distribución por edades. Una vez que la base del modelo de propagación de Tuberculosis está establecida, el siguiente paso es el estudio de la parametrización de los efectos de la vacuna en el contexto del modelo introducido. Aunque nuestro objetivo último es estudiar el impacto final que tendrán hipotéticas nuevas vacunas, es fundamental obtener toda la información posible de la actual vacuna BCG, ya que muchos de los efectos y problemas que tiene esta vacuna podrían darse también de forma inevitable en las nuevas vacunas. En concreto, sobre BCG estudiaremos la serie de ensayos clínicos BCG-REVAC, diseñados para intentar discernir qué mecanismo, producido por exposición previa a micobacterias (enmascaramiento y/o bloqueo), está detrás de la variabilidad en la eficacia de BCG medida en distintos lugares. Aunque esta discusión ya había sido realizada cualitativamente, en esta tesis proponemos varios modelos matemáticos (con bloqueo, con enmascaramiento y con los dos efectos), comprobamos cúal de ellos ajusta mejor a los datos obtenidos por esta serie de ensayos clínicos y cuantificamos estos efectos. A continuación, estudiamos el diseño de ensayos clínicos que se implementarán sobre las nuevas vacunas y que nos proveerán de toda la información posible para su evaluación con un modelo de propagación, ya que debido a la falta de correlaciones de protección de Tuberculosis, los ensayos clínicos son la única forma de determinar la eficacia de una vacuna. La formulación clásica de estos ensayos clínicos ofrece una parametrización muy limitada de la vacuna. En concreto, ofrece un único dato de eficacia contra enfermedad, cuando en realidad existen múltiples mecanismos con los que una vacuna puede interrumpir el ciclo del patógeno, y que permanecen indistinguibles en un ensayo clínico lo que provoca grandes incertidumbre en la posterior evaluación de impacto. Estudiaremos un nuevo diseño para estos ensayos clínicos, capaz de ofrecer una parametrización más completa de la vacuna. Finalmente, una vez que ya hemos desarrollado un nuevo modelo de propagación de Tuberculosis y hemos estudiado en detalle la descripción de las vacunas en este contexto, evaluamos diferentes vacunas hipotéticas. Nos centraremos en el debate actual sobre la edad óptima de vacunación.<br /

    Biometrics

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    Biometrics-Unique and Diverse Applications in Nature, Science, and Technology provides a unique sampling of the diverse ways in which biometrics is integrated into our lives and our technology. From time immemorial, we as humans have been intrigued by, perplexed by, and entertained by observing and analyzing ourselves and the natural world around us. Science and technology have evolved to a point where we can empirically record a measure of a biological or behavioral feature and use it for recognizing patterns, trends, and or discrete phenomena, such as individuals' and this is what biometrics is all about. Understanding some of the ways in which we use biometrics and for what specific purposes is what this book is all about

    Statistical/Geometric Techniques for Object Representation and Recognition

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    Object modeling and recognition are key areas of research in computer vision and graphics with wide range of applications. Though research in these areas is not new, traditionally most of it has focused on analyzing problems under controlled environments. The challenges posed by real life applications demand for more general and robust solutions. The wide variety of objects with large intra-class variability makes the task very challenging. The difficulty in modeling and matching objects also vary depending on the input modality. In addition, the easy availability of sensors and storage have resulted in tremendous increase in the amount of data that needs to be processed which requires efficient algorithms suitable for large-size databases. In this dissertation, we address some of the challenges involved in modeling and matching of objects in realistic scenarios. Object matching in images require accounting for large variability in the appearance due to changes in illumination and view point. Any real world object is characterized by its underlying shape and albedo, which unlike the image intensity are insensitive to changes in illumination conditions. We propose a stochastic filtering framework for estimating object albedo from a single intensity image by formulating the albedo estimation as an image estimation problem. We also show how this albedo estimate can be used for illumination insensitive object matching and for more accurate shape recovery from a single image using standard shape from shading formulation. We start with the simpler problem where the pose of the object is known and only the illumination varies. We then extend the proposed approach to handle unknown pose in addition to illumination variations. We also use the estimated albedo maps for another important application, which is recognizing faces across age progression. Many approaches which address the problem of modeling and recognizing objects from images assume that the underlying objects are of diffused texture. But most real world objects exhibit a combination of diffused and specular properties. We propose an approach for separating the diffused and specular reflectance from a given color image so that the algorithms proposed for objects of diffused texture become applicable to a much wider range of real world objects. Representing and matching the 2D and 3D geometry of objects is also an integral part of object matching with applications in gesture recognition, activity classification, trademark and logo recognition, etc. The challenge in matching 2D/3D shapes lies in accounting for the different rigid and non-rigid deformations, large intra-class variability, noise and outliers. In addition, since shapes are usually represented as a collection of landmark points, the shape matching algorithm also has to deal with the challenges of missing or unknown correspondence across these data points. We propose an efficient shape indexing approach where the different feature vectors representing the shape are mapped to a hash table. For a query shape, we show how the similar shapes in the database can be efficiently retrieved without the need for establishing correspondence making the algorithm extremely fast and scalable. We also propose an approach for matching and registration of 3D point cloud data across unknown or missing correspondence using an implicit surface representation. Finally, we discuss possible future directions of this research

    Protein synthesis in slowed aging: insights into shared characteristics of long-lived mouse models

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    2014 Spring.The following dissertation describes a series of experiments with the overall aim to understand the role that changes in protein synthesis have in slowed aging. The specific aims of the three sets of experiments were 1) to determine if chronic administration of the mTORC1 inhibitor rapamycin to mice increases proteostatic mechanisms in skeletal muscle, heart, and liver; 2) to determine if an underdeveloped anterior pituitary, caused by deletion of the Pit-1 gene in mice, increases proteostatic mechanisms in skeletal muscle, heart, and liver of long-lived Snell dwarf mice; 3) and to determine if transient nutrient restriction during the suckling period in mice (i.e. crowded litter), increases proteostatic mechanisms in skeletal muscle, heart, and liver later in life. In Experiment #1 we found that mitochondrial proteins were preferentially synthesized in skeletal muscle and that global protein synthesis in the heart was maintained despite reduced cellular proliferation and mTORC1 activity in mice fed rapamycin compared to normal diet controls. Originally we determined that these data were indicative of an improved somatic maintenance of skeletal muscle mitochondria and the heart proteome. Since we could not account for changes to other energetic processes (e.g. metabolism), we reasoned that our data was more consistent with proteostasis, a component of somatic maintenance. In Experiment #2 we developed a novel method for assessing proteostasis and determined that Snell dwarf mice had an increase in proteostatic mechanisms across sub-cellular fractions within skeletal muscle and heart compared control mice, despite differential rates of protein synthesis in the face of decreased mTORC1. Together with our previous investigations into rapamycin fed and caloric restriction models of long-life we concluded that increased proteostatic mechanisms may be a shared characteristic of models of slowed aging. In Experiment #3 we demonstrate that the crowded litter mouse transitions from growth to maintenance as it ages. Furthermore, in the crowded litter mouse, we demonstrate that proteostasis is not dependent upon decreased mTORC1. Our results indicate that decreased mTORC1 does not necessarily correlate to decreases in protein synthesis across all sub-cellular fractions. Discerning which proteins and the mechanism(s) of how specific proteins can be preferentially synthesized despite decreases in protein synthesis in other fractions and decreased mTORC1, may give further insight into characteristics of slowed aging. Further, we demonstrate that increases in proteostasic mechanisms are a shared characteristic of multiple unique models of slowed aging and therefore, provides a basis for future work aimed at slowing the aging process

    Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

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    Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (11C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of 11C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified 11C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain 11C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with 11C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified 11C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). 11C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical 11C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased 11C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p11C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with 11C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.Alzheimerin taudin beta-amyloidipatologian varhainen toteaminen. 11C-PIB-amyloidimerkkiaineella tehtävän positroniemissiotomografian soveltuvuus Beeta-amyloidin (Abeta) kertyminen aivoihin on tyypillistä Alzheimerin taudille (AT). Hiili-11-isotoopilla leimattu 2-(4’-metyyliaminofenyyli)-6-hydroksibentsotiatsoli (11C-PIB) on uusi positroniemissiotomografiassa (PET) käytettävä merkkiaine, joka vaikuttaa soveltuvan amyloidiplakkien toteamiseen ja niiden määrän arvioimiseen. 11C-PIB:n jakautumista kehossa ja sen aiheuttamaa säderasitusta tutkittiin 16 terveellä henkilöllä. Yksinkertaistettujen 11C-PIB-analyysimenetelmien toistettavuutta selvitettiin toistomittausasetelmalla 6 AT-potilaalla ja 4 terveellä verrokilla. 11C-PIB-kertymän muutosta sekä 11C-PIB-kertymän ja aivojen kutistumisnopeuden välistä suhdetta mitattiin kahden vuoden seurantatutkimuksella, jossa oli 14 AT-potilasta ja 13 tervettä verrokkia. Tutkimalla 9 samanmunaista ja 8 erimunaista muistihäiriön suhteen toisistaan poikkeavaa kaksosparia sekä 9 iäkästä verrokkihenkilöä 11C-PIB PET:lla selvitettiin, voisiko aivoamyloidia olla havaittavissa sellaisilla kognitiivisesti terveillä henkilöillä, joilla on suurentunut riski sairastua AT:iin. Sappirakon seinämä sai elimistä suurimman määrän säteilyä, 41.5 mjuGy/MBq. Noin 20 % annetusta radioaktiivisuusannoksesta erittyi virtsaan. Efektiivinen sädeannos oli 4.7 mjuSv/MBq. Tämä annos mahdollistaa toistetut tutkimukset samoilla henkilöillä. Yksinkertaistettujen 11C-PIB PET –analyysimenetelmien toistettavuus oli hyvää tai erinomaista sekä alueittain (VAR 0.9-5.5%) että kuva-alkioittain (VAR 4.2-6.4%) tarkasteltuna. 11C-PIB-kertymä ei lisääntynyt AT-potilailla seuranta-ajan kuluessa, vaikka aivojen kutistuminen ja kognitiivinen heikentyminen etenivät. Alkutilanteen 11C-PIB-kertymä vaikutti ennustavan terveiden verrokkien aivojen tilavuusmuutoksia seuranta-aikana (r = 0.725, p = 0.005). Kognitiivisesti terveillä muistihäiriöisten samanmunaisilla kaksosilla – mutta ei erimunaisilla kaksosilla - oli suurentuneita 11C-PIB-kertymiä (117-121% verrokkien keskiarvosta) ohimo- ja päälakialueen aivokuorella sekä posteriorisessa cingulumissa (p11C-PIB PET voi olla käypä menetelmä tutkittavien valinnassa ja seurannassa, kun tehdään varhaisen sairausvaiheen tutkimuksia uusilla lääkkeillä. AT saatetaan voida todeta 11C-PIB PET:n avulla täysin oireettomassa vaiheessa sellaisilla henkilöillä, joilla on suurentunut riski sairastua. Tällä voisi olla merkittäviä vaikutuksia taudinmääritykselle ja sellaisten hoitojen tutkimiselle, jotka tähtäävät taudin kulun muuttamiseen.Siirretty Doriast

    Developing a cationic contrast agent for computed tomographic imaging of articular cartilage and synthetic biolubricants for early diagnosis and treatment of osteoarthritis

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    Osteoarthritis (OA) causes debilitating pain for millions of people, yet OA is typically diagnosed late in the disease process after severe damage to the articular cartilage has occurred and few treatment options exist. Furthermore, destructive techniques are required to measure cartilage biochemical and mechanical properties for studying cartilage function and changes during OA. Hence, research and clinical needs exist for non-destructive measures of cartilage properties. Various arthroscopic (e.g., ultrasound probes) and imaging (e.g., MRI or CT) techniques are available for assessing cartilage less destructively. However, arthroscopic methods are limited by patient anesthesia/infection risks and cost, and MRI is hindered by high cost, long image acquisition times and low resolution. Contrast-enhanced CT (CECT) is a promising diagnostic tool for early-stage OA, yet most of its development work utilizes simplified and ideal cartilage models, and rarely intact, pre-clinical animal or human models. To advance CECT imaging for articular cartilage, this dissertation describes further development of a new cationic contrast agent (CA4+) for minimally-invasive assessment of cartilage biochemical and mechanical properties, including glycosaminoglycan content, compressive modulus, and coefficient of friction. Specifically, CA4+ enhanced CT is compared to these three cartilage properties initially using an ideal bovine osteochondral plug model, then the technique is expanded to examine human finger joints and both euthanized and live mouse knees. Furthermore, CECT attenuations with CA4+ map bovine meniscal GAG content and distribution, signifying CECT can evaluate multiple tissues involved in OA. CECT's sensitivity to critical cartilage and meniscal properties demonstrates its applicability as both a non-destructive research tool as well as a method for diagnosing and monitoring early-stage OA. Additionally, CECT enables evaluation of efficacy for a new biolubricant (2M TEG) for early-stage OA treatment. In particular, CECT can detect the reduced wear on cartilage surfaces for samples tested in 2M TEG compared to samples tested in saline (negative control). With its sensitivity to cartilage GAG content, surface roughness, and mechanical properties, CA4+ enhanced CT will serve as a valuable tool for subsequent in vivo animal and clinical use

    Assessing Midbrain Abnormalities In Parkinson’s Disease Using Magnetic Resonance Imaging

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    Diagnosing early-stage Parkinson’s disease (PD) and its manifestations is still a clinical challenge. Previous imaging studies using iron, neuromelanin (NM) and the Nigrosome-1 (N1) measures in the substantia nigra (SN) by themselves have been unable to provide sufficiently high diagnostic performance for these methods to be adopted clinically. In this dissertation, we start by studying idiopathic PD patients at their intermediate stages of the disease to evaluate the role of global and regional iron in the major deep gray matter nuclei. Then, we only focus on the NM complex in the midbrain and how neuronal loss interact with iron overload as well as their relationship with clinical scores strictly on early PD patients. Finally, by taking one more step back in the disease progression process, we investigate the impact of iron deposition and N1 appearance in idiopathic rapid eye movement sleep behavior disorder (RBD) as the prodromal stage of PD. The results of this work are summarized as the following: 1) the increase in iron in the SN in some PD patients is higher than the normal range in healthy controls (HC) as found in both regional and global analyses and that regional high iron content may provide a means to separate two populations of PD patients; one with and one without iron increases in the SN; 2) we have introduced a rapid five-minute 3D approach to depict NM degeneration and iron deposition simultaneously which provides a practical MR imaging method to differentiate early stage subjects with PD from HCs with an approximately 98% accuracy; and finally 3) iRBD patients were found to have a higher incidence of N1 loss, reduced volume and elevated iron levels in a few brain structures as well as cognitive and motor impairment scores being correlated with iron deposition of several cerebral nuclei. All these in vivo biomarkers put together can significantly contribute to a better understanding of the underlying pathophysiology in PD onset and progression with the ultimate goal being a more confident clinical diagnosis prior to symptomatic dysfunction
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