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Pallebage-Gamarallage, M.

Publications and source records attributed to Pallebage-Gamarallage, M..

2 recordsLinked to original sources

Joint modelling of diffusion MRI and microscopy

The combination of diffusion MRI with microscopy provides unique opportunities to study microstructural features of tissue, particularly when acquired in the same sample. Microscopy is frequently used to validate diffusion MRI microstructure models, addressing the indirect nature of dMRI signals. Typically, these modalities are analysed separately, and microscopy is taken as a gold standard against which dMRI-derived parameters are validated. Here we propose an alternative approach in which we combine diffusion MRI and microscopy data obtained from the same tissue sample to drive a single, joint model. This simultaneous analysis allows us to take advantage of the breadth of information provided by complementary data acquired from different modalities. By applying this framework to a spherical-deconvolution analysis, we are able to overcome a known degeneracy between fibre dispersion and radial diffusion. Spherical-deconvolution based approaches typically estimate a global fibre response function to determine the fibre orientation distribution in each voxel. However, the assumption of a brain-wide fibre response function may be challenged if the diffusion characteristics of white matter vary across the brain. Using a generative joint dMRI-histology model, we demonstrate that the fibre response function is dependent on local anatomy, and that current spherical-deconvolution based models may be overestimating dispersion and underestimating the number of distinct fibre populations per voxel.

neuroscience

White matter changes in the perforant path in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and incurable motor neuron disease. Some ALS patients are affected by a level of cognitive or behavioural decline that meets the criteria for frontotemporal dementia (FTD). ALS and FTD share genetic and pathological features; for example, the deposition of phosphorylated 43 kDa TAR DNA-binding protein (pTDP-43) in the brain. Spreading of pTDP-43 pathology in ALS towards brain areas that connect via the Papez circuit is a possible indicator of progression towards FTD. For example, pTDP-43 aggregates in the granule cells of the hippocampus correlate well with clinically manifest FTD. Here, we test the hypothesis that white matter degeneration of the perforant path - as part of the Papez circuit - in the hippocampus is a feature of ALS, even in the absence of fully developed FTD or deposition of pTDP-43 inclusions in hippocampal granule cells. We used diffusion MRI (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of hippocampus sections from controls (n=5) and ALS patients (n=14) to perform an in-depth study of white matter in the perforant path. The dMRI results show a significant decrease in fractional anisotropy (p=0.01) and an increase in mean diffusivity (p=0.01), axial diffusivity (p=0.03) and radial diffusivity (p=0.03) in the perforant path in ALS patients compared to controls, possibly indicating a loss of white matter fibres. Myelin density (measured with PLI retardance) was lower in ALS patients compared to controls (p=0.05) and correlated with dMRI fractional anisotropy (r=0.52, p=0.03). The dMRI and PLI results were confirmed by the immunohistochemistry; both myelin (proteolipid protein, p=0.03) and neurofilaments (SMI-312, p=0.02) were lower in ALS patients. The activated microglial (CD68) density was similar in ALS and controls. Only two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus; however, while these two ALS-FTD cases showed reduced myelination in the perforant path, the values were comparable to other ALS cases. We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of clinically observed cognitive decline to the amount of white matter atrophy in the perforant path.

neuroscience