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Advanced neuroimaging in genetic neurodegenerative diseases
Full text linkQuesto lavoro di tesi è il risultato del percorso di tre anni di Dottorato in Genetica molecolare, Biotecnologie e Medicina Sperimentale (ciclo XXXVI), durante i quali ho avuto l’opportunità di occuparmi di studi di neuroimaging avanzato in forme genetiche di malattie neurodegenerative.
Le malattie neurodegenerative genetiche rivestono un particolare interesse nella ricerca in quanto permettono di studiare la fase preclinica, in cui iniziano a svilupparsi alterazioni cerebrali che possono essere rilevate con approcci di neuroimaging avanzato, con profonde implicazioni per lo sviluppo di possibili approcci terapeutici.
Il neuroimaging avanzato è costituito da diverse metodiche non invasive, che permettono di studiare la struttura e la funzione cerebrali (Capitolo 1); le principali sono rappresentate dalla risonanza magnetica (RM) strutturale, la RM di diffusione e la RM funzionale. Le differenti tecniche sono in grado di indagare aspetti diversi delle patologie neurodegenerative, come viene illustrato nella Review sulla Demenza frontotemporale (FTD) (Capitolo 2).
La sezione sperimentale della tesi è una raccolta di studi sviluppati nel corso del Dottorato, in cui sono state applicate diverse metodiche di neuroimaging avanzato nelle forme genetiche di FTD (Capitoli 3, 4 e 5) e nella malattia di Huntington (Capitolo 6). Come sarà illustrato, la ricerca di biomarcatori fluidi, come i neurofilamenti, risulta cruciale e complementare al neuroimaging, per una caratterizzazione approfondita di queste patologie.
Il primo studio (Capitolo 3) è stato condotto su una coorte di pazienti con FTD seguiti presso la Clinica Neurologica dell’Università di Brescia, allo scopo di confrontare le forme genetiche e quelle sporadiche della malattia. I risultati hanno evidenziato che le forme familiari e quelle sporadiche rappresentano entità cliniche simili, ma con differenti meccanismi biologici, diversa gravità di atrofia cerebrale al neuroimaging strutturale, e differenti velocità di progressione.
Il secondo ed il terzo studio (Capitoli 4 e 5, rispettivamente) sono stati condotti su una vasta coorte internazionale di soggetti con FTD genetica in fase presintomatica e sintomatica, inclusi nel GENFI (Genetic Frontotemporal Dementia Initiative). I due studi avevano lo scopo di indagare, rispettivamente, le alterazioni neurotrasmettitoriali e del sistema glinfatico, attraverso metodiche specifiche di neuroimaging avanzato. In particolare, nel primo studio è stato utilizzato JuSpace, un toolbox che permette di confrontare i pattern di alterazioni cerebrali con la distribuzione di specifici sistemi neurotrasmettoriali. È stato, quindi, possibile evidenziare, indirettamente ed in vivo, come le diverse mutazioni responsabili di FTD genetica siano associate a differenti deficit neurotrasmettoriali nella fase prodromica. Il secondo studio, invece, ha dimostrato che le alterazioni del sistema glinfatico risultano evidenti nelle fasi cliniche e costituiscono un possibile biomarcatore di progressione di malattia. In questo lavoro è stata applicata una particolare metodica denominata DTI-ALPS (Diffusion tensor image analysis along the perivascular space) per indagare l’attività del sistema glinfatico.
Infine, l’ultimo studio (Capitolo 6) si occupa di risonanza magnetica funzionale nella fase preclinica della malattia di Huntington, ed è stato realizzato in collaborazione con il Centro Huntington dell’University College London (Londra, UK). In questo lavoro, abbiamo dimostrato alterazioni precoci dei network visivi, che predicono la concentrazione dei neurofilamenti e l’esordio atteso della malattia.This thesis work is the result of a three-year PhD program in Molecular Genetics, Biotechnology, and Experimental Medicine (cycle XXXVI), during which I had the opportunity to focus on advanced neuroimaging studies in genetic forms of neurodegenerative diseases.
Genetic neurodegenerative diseases are of particular interest in research as they allow for the study of the preclinical phase, where early brain alterations begin to develop and can be detected through advanced neuroimaging approaches, with profound implications for the development of potential therapeutic approaches.
Advanced neuroimaging encompasses various non-invasive techniques, that enable the study of brain structure and function (Chapter 1). They include structural magnetic resonance imaging (MRI), diffusion-weighted imaging and functional MRI. These different techniques can investigate various aspects of neurodegenerative pathologies, as illustrated in the Review on Frontotemporal Dementia (FTD) (Chapter 2).
The experimental section of the thesis is a collection of studies conducted during the PhD, where various advanced neuroimaging techniques were applied in genetic forms of FTD (Chapters 3, 4, and 5) and in Huntington's disease (HD) (Chapter 6). As will be explained, the search for fluid biomarkers, such as neurofilaments, is crucial and complementary to neuroimaging for a comprehensive characterization of these pathologies.
The first study (Chapter 3) was conducted on a cohort of FTD patients followed at the Neurological Clinic of the University of Brescia, with the aim of comparing genetic and sporadic forms of the disease. We found that familial and sporadic FTD are very similar clinical entities, but with different biological mechanisms, diverse atrophy severity at structural MRI, and different rates of progression.
The second and third studies (Chapters 4 and 5) were conducted on a large international cohort of subjects with genetic FTD from GENFI (Genetic Frontotemporal Dementia Initiative). The two studies aimed to investigate, respectively, neurotransmitter alterations and changes of the glymphatic system, through specific advanced neuroimaging techniques. In particular, in the first study, we applied JuSpace, a toolbox able to explore if the spatial patterns of observed brain changes in the disease of interest are related to the distribution of specific neurotrasmitters pathways. Therefore, it allows to investigate, indirectly and in vivo, neurotransmitter deficits. We highlighted that different mutations responsible for genetic FTD are associated with diverse neurochemical deficits in the prodromal phase. In the second study, on the other hand, we found that glymphatic system alterations are evident in the clinical phase and constitute a possible disease progression biomarker. We applied a technique called DTI-ALPS (Diffusion tensor image analysis along the perivascular space) to investigate in vivo the glymphatic system.
Finally, the last study (Chapter 6) focused on functional MRI in the preclinical phase of HD. It is the result of the collaboration with the HD Centre at University College London (London, UK). In this work, we demonstrated early alterations in visual networks, which predicted neurofilament concentration and the expected disease onset
Retinal inner nuclear layer thinning is decreased and associates with the clinical outcome in ocrelizumab-treated primary progressive multiple sclerosis
Full text linkBACKGROUND: Ocrelizumab was found to decrease brain atrophy rate in primary progressive multiple sclerosis (PPMS), but no data are currently available on the effect of ocrelizumab on retinal layer thicknesses in the PPMS population. OBJECTIVE: To assess retinal layer changes in ocrelizumab-treated PPMS and test their possible application as biomarkers of therapy response. METHODS: 36 PPMS patients, treated with ocrelizumab for at least 6 months, and 39 sex- and age-matched healthy controls (HC) were included in a blind, longitudinal study. Spectrum-domain optical coherence tomography (SD-OCT) was performed at study entry (T0) and after 6 (T6) and 12 months (T12). At month 24 (T24), patients were divided into responders (no evidence of 1-year confirmed disability progression, 1y-CDP) and non-responders (evidence of 1y-CDP). RESULTS: At T24, 23/36 (64%) patients were considered responders and 13/36 (36%) non-responders. At T0, peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell–inner plexiform layer (GCIPL) and inner retinal layer (IRL) volume were significantly lower in PPMS compared to HC (p = 0.001 for all comparisons). At T6 and T12, non-responders significantly differed in the inner nuclear layer (INL) thinning rate compared to responders (p = 0.005 at both time-points). CONCLUSIONS: Ocrelizumab significantly slows down INL thinning rate in PPMS responders. The longitudinal analysis of retina layer changes by means of OCT may be a promising prognostic test, and merits further investigations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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