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  • Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins

    24 October 2018

    White matter ischemia is difficult to quantify histologically. Myelin-associated glycoprotein (MAG) is highly susceptible to ischemia, being expressed only adaxonally, far from the oligodendrocyte cell body. Myelin-basic protein (MBP) and proteolipid protein (PLP) are expressed throughout the myelin sheath. We compared MAG, MBP, and PLP levels in parietal white matter homogenates from 17 vascular dementia (VaD), 49 Alzheimer's disease (AD), and 33 control brains, after assessing the post-mortem stability of these proteins. Small vessel disease (SVD) and cerebral amyloid angiopathy (CAA) severity had been assessed in paraffin sections. The concentration of MAG remained stable post-mortem, declined with increasing SVD, and was significantly lower in VaD than controls. The concentration of MBP fell progressively post-mortem, limiting its diagnostic utility in this context. Proteolipid protein was stable post-mortem and increased significantly with SVD severity. The MAG/PLP ratio declined significantly with SVD and CAA severity. The MAG and PLP levels and MAG/PLP did not differ significantly between AD and control brains. We validated the utility of MAG and MAG/PLP measurements on analysis of 74 frontal white matter samples from an Oxford cohort in which SVD had previously been scored. MAG concentration and the MAG/PLP ratio are useful post-mortem measures of ante-mortem white matter ischemia. © 2013 ISCBFM.

  • Vulnerability to Alzheimer's pathology in neocortex: The roles of plasticity and columnar organization

    24 October 2018

    Two principal findings in the Pearson et al. paper [73] are commented on here. The first is the regional selectivity within the cerebrum of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) which targets association cortex and the primary olfactory cortex alone among regions of primary sensory cortex. The second finding is the clustering of NFT in columns of supra- and infra-granular layers of association cortex. We review recent evidence confirming these findings and comment on their possible significance. We consider that the most attractive hypothesis to explain the vulnerability of the olfactory system and association cortex is the persistent neural plasticity of these regions. On this basis there would be no need to postulate a progressive spreading process. The columnar distribution of clustered NFT can be well understood in the context of recent concepts of columnar organization of the cerebral cortex. The original interpretation that this distribution of NFT reflects pathology in neurons subserving cortico-cortical and cortico-subcortical connections seems to us to have stood the test of time. © 2006 - IOS Press and the authors. All rights reserved.

  • Genome-wide profiling of alternative splicing in Alzheimer's disease.

    24 October 2018

    Alternative splicing is a highly regulated process which generates transcriptome and proteome diversity through the skipping or inclusion of exons within gene loci. Identification of aberrant alternative splicing associated with human diseases has become feasible with the development of new genomic technologies and powerful bioinformatics. We have previously reported genome-wide gene alterations in the neocortex of a well-characterized cohort of Alzheimer's disease (AD) patients and matched elderly controls using a commercial exon microarray platform [1]. Here, we provide detailed description of analyses aimed at identifying differential alternative splicing events associated with AD.

  • Validation of NODDI estimation of dispersion anisotropy in V1 of the human neocortex

    24 October 2018

    Purpose: This work presents a validation of estimating dispersion anisotropy of neurites, using Bingham-NODDI [1]. Bingham-NODDI is a recent development of the diffusion MRI (d-MRI) technique called NODDI (neurite orientation dispersion and 3 density imaging) [2]. NODDI enables mapping of the morphology of neurites (axons and 0.7 dendrites) in the brain with indices that are sensitive and specific to the microstructural changes, resulting in a rapid uptake of NODDI in the field of neuroimaging [3,4]. But the β DAI original NODDI technique, Watson-NODDI, is limited, as it constrains the orientation 0 0 dispersion of neurites to be isotropic. Bingham-NODDI was developed to address this limitation and enables estimation of dispersion anisotropy and the primary dispersion (a) (b) orientation, along with the standard NODDI indices, without imposing any additional acquisition requirements compared to the Watson-NODDI. Dispersion anisotropy is widespread in the human brain [5]; its estimation is a potential biomarker [6] and can enhance the accuracy of tractography algorithms [7]. The in vivo feasibility of the Bingham-NODDI metrics has been evaluated in [1], but the estimates obtained need to be validated. Here we conduct such a validation study using high-resolution ex-vivo imaging data, acquired on post-mortem samples of the human primary visual cortex (V1). V1 is a very well characterised region of the neocortex, with a Watson-NODDI Bingham-NODDI diverse cytoarchitecture including fibres fanning/bending into the cortical layers, making it attractive for validating the measures from Bingham-NODDI. We hypothesise that using 4 Bingham-NODDI will enable a more detailed differentiation of these characteristics and explain the data better compared to Watson-NODDI.

  • Diffusion restriction along fibres: How coherent is the corpus callosum?

    24 October 2018

    PURPOSE. Diffusion weighted imaging aims to unravel the microstructural properties of white matter in the brain by detecting alterations to diffusive motion along different orientations. Increasingly sophisticated biophysical models are used to estimate properties like fibre orientation dispersion in addition to mean orientation. Most models assume an explicit or implicit assumption that water is able to diffuse freely along the primary fibre orientation. However, microstructural analysis with histology and electron microscopy in both rodent and human brains demonstrated a considerable amount of dispersion even in the corpus callosum [1,2,3], which is often used as a test-bed for diffusion models [4] based on its assumed extreme fibre coherence. The present study aims to investigate the coherence of fibre orientations at multiple scales in the human corpus callosum using two modalities: diffusion-time (∆) MRI measurements and direct estimation of fibre orientation from optical microscopy (polarized light imaging, PLI). A secondary aim of this work is to demonstrate the potential for using PLI-MRI comparisons in the same tissue sample to inform biophysical modeling aimed at in vivo diffusion MRI.

  • Longitudinally hindered diffusion of in vivo human white matter at long diffusion time

    24 October 2018

    Introduction Conventional diffusion MRI provides exquisite sensitivity to tissue microstructure through models of restricted and hindered diffusion within and around axons, respectively. These models often idealize axons as parallel, infinite and impermeable cylinders, where diffusion is often assumed to be free along the direction of axons. However, quantification of the degree of diffusion hindrance parallel to axon bundles, or the permeability of axon walls, may be possible with measurements at a range of diffusion times longer than those in typical experiments. At longer diffusion times, spins have an opportunity to probe longer length/time scales. Here, we present long diffusion time measurements of in vivo white matter using stimulated echoes and compare the fitting quality of successively simpler models of the diffusion attenuation accounting for overfitting.

  • Monte Carlo diffusion simulations disambiguate the biophysical mechanisms of diffusion hinderance along tracts

    24 October 2018

    PURPOSE – Diffusion imaging at long diffusion times can inform on microstructural features of tissue at scales spanning several hundreds of micrometers. At these scales the common approximation of axons as straight cylinders might not hold, even for tissues that are generally assumed to be coherently organized. The human corpus callosum is such a tract. It is often used as a reference structure for simple fibre configuration. Nevertheless, evidence from electron microscopy and histology suggests that corpus callosum fibres are far from coherent1,2. Fibres not only bend along the tract, but also twist and undulate, effects that could lead to specific signatures of hinderance “along” the tract. In this study, we investigated the diffusion time dependence of the apparent diffusion coefficient (ADC) along the direction of the fibres in the corpus callosum. Possible biophysical mechanisms of this dependence are explored by means of Monte Carlo simulations of various axon models.