Biology subjects

Casella, C.

Publications and source records attributed to Casella, C..

6 recordsLinked to original sources

bioRxiv2024

Verifying the concordance between motion corrected and conventional MPRAGE for pediatric morphometric analysis

PurposeTo validate a retrospective motion correction technique, Distributed and Incoherent Sample Orders for Reconstruction Deblurring using Encoding Redundancy (DISORDER), for pediatric brain morphometry. MethodsTwo T1-weighted MPRAGE 3D datasets were acquired at 3T in thirty-seven children, median age 7.75 years; one with conventional linear phase encoding and one using DISORDER. MPRAGE images were scored as motion-free or motion-corrupt. Cortical morphometry and regional brain volumes were measured with FreeSurfer, subcortical grey matter (GM) with FSL-FIRST, and hippocampal volumes with HippUnfold. Intraclass correlation coefficient (ICC) was used to determine agreement between the 2 MPRAGE acquisitions. Mann-Whitney U was used to test the difference between measures obtained using DISORDER and (i) motion-free and (ii) motion-corrupt conventional MPRAGE data. ResultsICC measures were good/excellent for most subcortical GM (motion-free, 0.75-0.96; motion-corrupt, 0.62-0.98) and regional brain volumes (motion-free 0.47-0.99; motion-corrupt, 0.54-0.99) between conventional MPRAGE and DISORDER data, except for the amygdala and nucleus accumbens (motion-free, 0.38-0.65; motion- corrupt, 0.1-0.42). However, these values were less consistent for motion-corrupt conventional MPRAGE data for hippocampal volumes (motion-free 0.65-0.99; motion-corrupt, 0.11-0.91) and cortical measures (motion-free 0.76-0.98; motion- corrupt, 0.09-0.74). Mann-Whitney U showed percentage differences in measures obtained with motion-corrupt conventional MPRAGE compared to DISORDER data were significantly greater than in those obtained using motion-free conventional MPRAGE data in 22/58 structures. ConclusionIn the absence of motion, morphometric measures obtained using DISORDER are largely consistent with those from conventional MPRAGE data, whereas improved reliability is obtained by DISORDER for motion-degraded scans. This study validates DISORDER for brain morphometric studies in children.

neuroscience↗

bioRxiv2023

Differences in white matter detected by ex vivo 9.4T MRI are associated with axonal changes in the R6/1 model of Huntington's Disease

White matter (WM) volume loss has been reported in people with Huntingtons disease (HD), but the cellular basis of this deficit remains to be elucidated. To address this, we assessed ex vivo WM microstructure in the transgenic R6/1 mouse model of HD with magnetic resonance imaging (MRI) and studied the neurobiological basis of the MRI brain signals with histological and electron microscopy analyses in a separate cohort of age- and sex-matched mice. Differences in the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) as a proxy myelin measure, and the intra-axonal signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) as a proxy marker of axon density, were assessed alongside diffusion tensor imaging (DTI) parameters. A tractometry approach was employed to inspect region-specific differences across the corpus callosum (CC). Furthermore, voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) were used to explore brain-wise WM macro- and microstructure abnormalities. To gain insight into disease-associated impairments in attentional and visuospatial processing, a third cohort of age-matched mice was assessed with the 5-choice serial reaction time task (5-CSRTT). We report cognitive impairments in R6/1 mice and, by evaluating MRI and light and electron microscopy results, we show that this HD mouse model presents disruptions in axonal morphology (i.e. less complex, thinner axons) and organization (i.e. more densely packed axons). Furthermore, we show that, at least early in disease progression, R6/1 mice present a reduction in the expression or content of myelin-associated proteins without significant alterations in the structure of myelin sheaths. Finally, our findings indicate that neuroinflammation-driven glial and axonal swelling might also affect this mouse model early in disease progression. Crucially, we demonstrate the potential of FR, an in vivo estimate of axon density, as a novel MRI biomarker of HD-associated changes in WM microstructure.

neuroscience↗

bioRxiv2022

Widespread, depth-dependent microstructural damage in the cortex of children with drug resistant focal epilepsy: A quantitative T1 and T2 mapping study

ObjectiveTissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes, treatment-related side-effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilised quantitative MRI, which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. MethodsTo assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy [age-range=4-18 years] and 46 typically-developing children [age-range=2-18 years]. We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically-defined abnormalities (MRI-positive) and healthy controls, and tested if this could classify patients without reported radiological abnormalities (MRI-negative). ResultsWe uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 62% at 100% specificity on held-out MRI-negative patients. SignificanceThese findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically-identified abnormalities, and potentially evident pre-symptomatically. Key PointsO_LIWe assessed cortical microstructure in children with focal epilepsy C_LIO_LIQuantitative T1 and T2 relaxometry (qT1 and qT2) was measured in the neocortex C_LIO_LIPatients showed extensive qT1/qT2 increases and intracortical organization changes C_LIO_LIAlterations may appear during cerebral development, prior to disease onset C_LI

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bioRxiv2021

Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

White matter (WM) alterations have been observed early in Huntingtons disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.

neuroscience↗

bioRxiv2021

Multi-compartment analysis of the complex gradient-echo signal quantifies myelin breakdown in premanifest Huntington's disease

White matter (WM) alterations have been identified as a relevant pathological feature of Huntingtons disease (HD). Increasing evidence suggests that WM changes in this disorder are due to alterations in myelin-associated biological processes. Multi-compartmental analysis of the complex gradient-echo MRI signal evolution in WM has been shown to quantify myelin in vivo, therefore pointing to the potential of this technique for the study of WM myelin changes in health and disease. This study first characterized the reproducibility of metrics derived from the complex multi-echo gradient-recalled echo (mGRE) signal across the corpus callosum in healthy participants, finding highest reproducibility in the posterior callosal segment. Subsequently, the same analysis pipeline was applied in this callosal region in a sample of premanifest HD patients (n = 19) and age, sex and education matched healthy controls (n = 21). In particular, we focused on two myelin-associated derivatives: i. the myelin water signal fraction (fm), a parameter dependent on myelin content; and ii. the difference in frequency between myelin and intra-axonal water pools ({Delta}{omega}), a parameter dependent on the ratio between the inner and the outer axonal radii. fm was found to be lower in HD patients ({beta} = -0.13, p = 0.03), while {Delta}{omega} did not show a group effect. Performance in tests of working memory, executive function, social cognition and movement was also assessed, and a greater age-related decline in executive function was detected in HD patients ({beta} = -0.06, p = 0.006), replicating previous evidence of executive dysfunction in HD. Finally, the correlation between fm, executive function, and proximity to disease onset was explored in patients, and a positive correlation between executive function and fm was detected (r = 0.542; p = 0.02). This study emphasises the potential of complex mGRE signal analysis for aiding understanding of HD pathogenesis and progression. Moreover, expanding on evidence from pathology and animal studies, it provides novel in vivo evidence supporting myelin breakdown as an early feature of HD.

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bioRxiv2019

Drumming motor sequence training induces myelin remodelling in Huntington's disease: a longitudinal diffusion MRI and quantitative magnetization transfer study

1.BackgroundImpaired myelination may contribute to Huntingtons disease (HD) pathogenesis. This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. MethodsParticipants undertook two months of drumming exercises. Working memory and executive function were assessed before and after training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking the putamen and the supplementary motor area (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics (TBSS). ResultsMPF was reduced in HD patients compared to controls in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. ConclusionsIncreased MPF suggests training-induced myelin changes in HD. Tailored behavioural stimulation may lead to neural benefits in early HD that could be exploited for delaying disease progression.

neuroscience↗