660 research outputs found

    Evaluation of tractography-based myelin-weighted connectivity across the lifespan

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    IntroductionRecent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelin-weighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry.MethodsIn a group of 85 healthy controls aged between 18 and 68 years, we estimated myelin-weighted connectomes using Tractometry and MySD, and compared their modulation with age by means of three well-known global network metrics.ResultsFollowing the literature, our results show that myelin development continues until brain maturation (40 years old), after which degeneration begins. In particular, mean connectivity strength and efficiency show an increasing trend up to 40 years, after which the process reverses. Both Tractometry and MySD are sensitive to these changes, but MySD turned out to be more accurate.ConclusionAfter regressing the known predictors, MySD results in lower residual error, indicating that MySD provides more accurate estimates of myelin-weighted connectivity than Tractometry

    Comparison of aortic remodelling after conservative treatment or thoracic endovascular repair in type B dissections

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    The patients with diagnosed TBAD are initially treated with antihypertensive agents, reducing the heart rate and systolic blood pressure (Isselbacher, 2005). While the therapy of the non-complicated TBAD remains conservative to the chronic phase, the complicated TBADs are treated with TEVAR to prevent further extension and diameter progression, malperfusion, and aortic rupture in the acute phase (Onitsuka et al., 2004). The signs and symptoms which define complicated TBAD are aortic ruptures, rapid aortic expansion, malperfusion, shock, paraplegia, refractory pain, peri-aortic hematoma, and refractory hypertension (Riambau et al., 2017). The aim of the study was to compare the aortic remodeling in the patients with TBAD treated conservatively and those treated with TEVAR in the acute phase. All patients with TBAD admitted between 2011 and 2017 to our center with at least one CT follow-up (>6 months) were included in the current study. Group A included the conservative patients with uncomplicated TBAD, while Group B included the patients with complicated TBAD who were treated with TEVAR in the acute phase. Group A was divided into two subgroups consisting either of patients whose therapy remained conservative or those converted to TEVAR due to aortic growth in the chronic phase. The baseline CT scan and the CT of the last follow-up visit were used for three-dimensional centerline reconstruction of the aorta from the aortic valve to the 1 cm below the aortic bifurcation. Aortic diameters and aortic lengths were measured at the same anatomical landmarks in the 3D centerline reconstruction for all CT examinations (Mustafi et al., 2020). The study included 74 patients with TBAD: 50 patients in group A and 24 patients in group B. For group A the mean duration of follow-up was 1625 ± 209 days and for group B 554 ± 129 days. The prevalence of the male gender was higher compared to the female gender (A: 77%, B: 95%; P=0.17) and the mean age in both groups was 62 years (group A 62±2; group B 62±5; P=0.99) (Mustafi et al., 2020). In the mid-descending aorta, the aortic diameter growth rate was significantly higher in group A than in group B (A: +7 mm/year, B: -4 mm/year, P=0.003). The group B treated with TEVAR in the acute phase showed a significant increase in diameter at the celiac trunk landmark (+7±3 mm/year; P=0.023), while the diameter remained stable in the conservatively treated group A. At all other landmarks, there was no significant difference between the groups. During the follow-up period, 18 patients (36%) from conservatively treated Group A were converted to TEVAR due to aortic diameter progression. These patients showed a significant increase in the diameter of the descending aorta of 18 mm/year (P<0.001) before conversion. The proximal and mid-descending aorta showed a reduction in growth rate after conversion to TEVAR (preoperative +11 and +18 mm/year; postoperative -9 and -14 mm/year, P<0.001) (Mustafi et al., 2020). The study showed a significant diameter reduction after TEVAR in the acute phase in the descending aorta. However, an increase in diameter was spotted at the same landmark in the conservatively treated group. Despite the significant increase in diameter before conversion, TEVAR led to the most intensive remodeling after conversion in the chronic phase (Mustafi et al., 2020). This study indicated that TEVAR can prevent the development of thoracic aneurysms after type B dissections. Moreover, our findings underline the importance of regular follow-up examinations in all TBAD patients to prevent future complications. Patients with a prominent diameter increase in the conservative treatment arm can be early identified and subjected to TEVAR therapy, and those with TEVAR therapy in the acute phase need to be surveilled due to the risk of aortic growth in the distal (thoracoabdominal and abdominal) aortic segments

    Hydrocephalus: A neuropsychological and theoretical primer.

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    Hydrocephalus is a common neurological condition, the hallmark feature of which is an excess in production, or accumulation, of cerebrospinal fluid in the ventricles. Although it is associated with diffuse damage to paraventricular brain areas, patients are broadly typified by a particular pattern of cognitive impairments that include deficits in working memory, attention, and spatial abilities. There have, however, been relatively few neuropsychological accounts of the condition. Moreover, theories of the relationship between aetiology and impairment appear to have emerged in isolation of each other, and proffer fundamentally different accounts. In this primer, we aim to provide a comprehensive and contemporary overview of hydrocephalus for the neuropsychologist, covering cognitive sequelae and theoretical interpretations of their origins. We review clinical and neuropsychological assays of cognitive profiles, along with the few studies that have addressed more integrative behaviours. In particular, we explore the distinction between congenital or early-onset hydrocephalus with a normal-pressure variant that can be acquired later in life. The relationship between these two populations is a singularly interesting one in neuropsychology since it can allow for the examination of typical and atypical developmental trajectories, and their interaction with chronic and acute impairment, within the same broad neurological condition. We reflect on the ramifications of this for our subject and suggest avenues for future research. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

    Segment Anything Model for Medical Images?

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    The Segment Anything Model (SAM) is the first foundation model for general image segmentation. It designed a novel promotable segmentation task, ensuring zero-shot image segmentation using the pre-trained model via two main modes including automatic everything and manual prompt. SAM has achieved impressive results on various natural image segmentation tasks. However, medical image segmentation (MIS) is more challenging due to the complex modalities, fine anatomical structures, uncertain and complex object boundaries, and wide-range object scales. SAM has achieved impressive results on various natural image segmentation tasks. Meanwhile, zero-shot and efficient MIS can well reduce the annotation time and boost the development of medical image analysis. Hence, SAM seems to be a potential tool and its performance on large medical datasets should be further validated. We collected and sorted 52 open-source datasets, and build a large medical segmentation dataset with 16 modalities, 68 objects, and 553K slices. We conducted a comprehensive analysis of different SAM testing strategies on the so-called COSMOS 553K dataset. Extensive experiments validate that SAM performs better with manual hints like points and boxes for object perception in medical images, leading to better performance in prompt mode compared to everything mode. Additionally, SAM shows remarkable performance in some specific objects and modalities, but is imperfect or even totally fails in other situations. Finally, we analyze the influence of different factors (e.g., the Fourier-based boundary complexity and size of the segmented objects) on SAM's segmentation performance. Extensive experiments validate that SAM's zero-shot segmentation capability is not sufficient to ensure its direct application to the MIS.Comment: 23 pages, 14 figures, 12 table

    Neuroinflammatory and protein responses to TBI

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    Background: Traumatic brain injury (TBI) is a leading cause of death and disability world-wide, affecting approximately 69 million individuals each year. It is also recognised as one of the major, modifiable risk factors in the development of neurodegenerative disease in later life, with exposure to moderate to severe single TBI and repetitive, mild TBI both recognised as contributing factors in the development of dementia. However, the neuropathological mechanisms contributing to late neurodegeneration remain uncertain. The complex polypathology emerging from the initial biomechanical injury mirror other neurodegenerative disease and include abnormal aggregation of proteins such as tau and Aβ and neuroinflammation, which will be explored in this thesis. Methodology: Utilising material from the Glasgow TBI archive, in cohorts of patients aged ≤60 exposed to acute and long-term survival following moderate to severe, single TBI and appropriately age-matched controls, the role of the cellular adaptive immune response to injury was assessed through immunocytochemistry for T- and B-lymphocyte populations. These cohorts as well as tissue from patients exposed to repetitive mild TBI (rTBI) and appropriately matched controls were studied to characterise the differential astroglial response to injury across injury subgroups through measurement of GFAP, AQP4 and NQO1 immunoreactivity. A cohort of patients aged ≥60 years who survived acutely following moderate to severe, single TBI compared to age-matched, uninjured controls with no history of neurodegenerative disease, were examined to evaluate the effect of age and TBI using modifications of clinically recognised, standardised, semi-quantitative scoring systems of tau and Aβ immunoreactivity. Lastly, a protocol for the assessment of our archival, FFPE tissue was devised to allow comparison of proteomes of cohorts of patients exposed to mild rTBI, AD patients and appropriately matched controls, using liquid-chromatography mass-spectrometry. Results: There is no histological evidence of a significant cellular response from the adaptive immune system following exposure to moderate to severe, single TBI in patients surviving acutely or long-term after injury, with no increase in T- or B-lymphocytes. There was, unexpectedly, a decrease in T-lymphocytes in long-term survivors of TBI. Contrastingly, there was an increase in reactive astrogliosis following exposure to TBI; demonstrated by an increase in AQP4-immunoractive astrocytes in acutely surviving patients and increase in GFAP expression in long-term surviving patients and an increase in NQO1 expression in rTBI patients compared to age-matched uninjured controls. There was also an increase in both AQP4 and GFAP expression in elderly uninjured controls compared to younger uninjured controls. Examining the expression of Aβ and tau in elderly patients exposed to single, moderate to severe TBI showed an increase in neuritic Aβ plaque and in the regional distribution of all plaque compared to uninjured, elderly controls, but no increase in expression or distribution of NFTs. Finally, a protocol for processing archival FFPE resulted in identification of 267 proteins from across rTBI, AD and uninjured, non-NND controls with significantly differential expression in 84 of them. Conclusions: Together, these findings increase understanding of the neuropathological changes occurring following moderate to severe, single TBI and repetitive TBI. These data demonstrate that there is an astrogliotic but not adaptive cellular response after moderate to severe single TBI whilst also showing that age is correlated with an increase in reactive astrogliosis for several markers. Age was also examined in the examination of proteinopathic changes following acute survival after moderate to severe injury and changes suggest that TBI may occur as a result of increased amyloid pathology as neuritic plaque was observed > 2 weeks after injury. Lastly, that archival FFPE samples were successfully processed to allow identification of proteins from across a range of cohorts, revealing differences in protein expression that underpin the neuropathological changes which contribute to the long-term, post-TBI neurodegenerative process

    Analysis of the retina and visual pathway by OCT, OCTA and psychophysical tests in asymptomatic subjects at high genetic risk for the development of Alzheimer's disease

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    Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, leída el 15-07-2022La Enfermedad de Alzheimer (EA) es una enfermedad neurodegenerativa progresiva que se caracteriza: por una atrofia cortical difusa, declive de las funciones cognitivas, así como la agregación anormal de proteínas como la beta amiloide fibrilar (Aß) y tau hiperfosforilada (p-Tau).El factor de riesgo prevalente es la edad avanzada, tras el cual destaca la herencia genética. Elmayor factor de riesgo genético conocido es ser portador de al menos un alelo 4 del gen de la apoliproteina E (ApoE). Otro de los factores que incrementa el riesgo para desarrollar la EA, es la historia familiar de primer grado. Los signos cerebrales de la EA aparecen décadas antes del inicio clínico de la enfermedad. Dado que la relación entre cerebro y retina se establece ya desde la etapa embrionaria, los cambios retinianos detectados con técnicas de diagnóstico oftalmológico en sujetos con alto riesgo genético para el desarrollo de EA posibilitan la identificación de potenciales pacientes de EA en etapas muy tempranas...Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by: diffuse cortical atrophy, decline in cognitive functions, as well as abnormal aggregation of proteins such as fibrillar amyloid Beta (Aβ) and hyperphosphorylated tau(p-Tau).The prevalent risk factor is older age, after which genetic inheritance is the most important. The major known genetic risk factor is carrying at least one 4 allele of the apoliprotein E (ApoE 4)gene. Another factor that increases the risk of developing AD is a first-degree family history. Brain signs of AD appear decades before clinical onset of the disease. Since the relationship between brain and retina is established as early as the embryonic stage, retinal changes detected with ophthalmological diagnostic techniques in subjects at high genetic risk for developing AD make it possible to identify potential AD patients at very early stages..Fac. de MedicinaTRUEunpu

    Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles

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    The 3Rs principles—reduction, refinement, replacement—are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character in vivo imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments. The repetitive monitoring of pathology progression and the effects of therapy becomes feasible by assessment of quantitative biomarkers. Moreover, imaging has translational prospects by facilitating the comparison of studies performed in small rodents and humans. Also, learnings from the clinic may be potentially back-translated to preclinical settings and therefore contribute to refining animal investigations. By concentrating on activities around the application of magnetic resonance imaging (MRI) and ultrasound elastography to small rodent models of disease, we aim to illustrate how in vivo imaging contributes primarily to reduction and refinement in the context of pharmacological research

    Disease progression and genetic risk factors in the primary tauopathies

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    The primary tauopathies are a group of progressive neurodegenerative diseases within the frontotemporal lobar degeneration spectrum (FTLD) characterised by the accumulation of misfolded, hyperphosphorylated microtubule-associated tau protein (MAPT) within neurons and glial cells. They can be classified according to the underlying ratio of three-repeat (3R) to four-repeat (4R) tau and include Pick’s disease (PiD), which is the only 3R tauopathy, and the 4R tauopathies the most common of which are progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). There are no disease modifying therapies currently available, with research complicated by the wide variability in clinical presentations for each underlying pathology, with presentations often overlapping, as well as the frequent occurrence of atypical presentations that may mimic other non-FTLD pathologies. Although progress has been made in understanding the genetic contribution to disease risk in the more common 4R tauopathies (PSP and CBD), very little is known about the genetics of the 3R tauopathy PiD. There are two broad aims to this thesis; firstly, to use data-driven generative models of disease progression to try and more accurately stage and subtype patients presenting with PSP and corticobasal syndrome (CBS, the most common presentation of CBD), and secondly to identify genetic drivers of disease risk and progression in PiD. Given the rarity of these disorders, as part of this PhD I had to assemble two large cohorts through international collaboration, the 4R tau imaging cohort and the Pick’s disease International Consortium (PIC), to build large enough sample sizes to enable the required analyses. In Chapter 3 I use a probabilistic event-based modelling (EBM) approach applied to structural MRI data to determine the sequence of brain atrophy changes in clinically diagnosed PSP - Richardson syndrome (PSP-RS). The sequence of atrophy predicted by the model broadly mirrors the sequential spread of tau pathology in PSP post-mortem staging studies, and has potential utility to stratify PSP patients on entry into clinical trials based on disease stage, as well as track disease progression. To better characterise the spatiotemporal heterogeneity of the 4R tauopathies, I go on to use Subtype and Stage Inference (SuStaIn), an unsupervised machine algorithm, to identify population subgroups with distinct patterns of atrophy in PSP (Chapter 4) and CBS (Chapter 5). The SuStaIn model provides data-driven evidence for the existence of two spatiotemporal subtypes of atrophy in clinically diagnosed PSP, giving insights into the relationship between pathology and clinical syndrome. In CBS I identify two distinct imaging subtypes that are differentially associated with underlying pathology, and potentially a third subtype that if confirmed in a larger dataset may allow the differentiation of CBD from both PSP and AD pathology using a baseline MRI scan. In Chapter 6 I investigate the association between the MAPT H1/H2 haplotype and PiD, showing for the first time that the H2 haplotype, known to be strongly protective against developing PSP or CBD, is associated with an increased risk of PiD. This is an important finding and has implications for the future development of MAPT isoform-specific therapeutic strategies for the primary tauopathies. In Chapter 7 I perform the first genome wide association study (GWAS) in PiD, identifying five genomic loci that are nominally associated with risk of disease. The top two loci implicate perturbed GABAergic signalling (KCTD8) and dysregulation of the ubiquitin proteosome system (TRIM22) in the pathogenesis of PiD. In the final chapter (Chapter 8) I investigate the genetic determinants of survival in PiD, by carrying out a Cox proportional hazards genome wide survival study (GWSS). I identify a genome-wide significant association with survival on chromosome 3, within the NLGN1 gene. which encodes a synaptic scaffolding protein located at the neuronal pre-synaptic membrane. Loss of synaptic integrity with resulting dysregulation of synaptic transmission leading to increased pathological tau accumulation is a plausible mechanism though which NLGN1 dysfunction could impact on survival in PiD
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