Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages.

OBJECTIVE: Describe magnetic resonance imaging (MRI) susceptibility changes in progressive multifocal leukoencephalopathy (PML) and identify neuropathological correlates. METHODS: PML cases and matched controls with primary central nervous system lymphoma (PCNSL) were retrospectively identified. MRI brain at 3 T and 7 T were reviewed. MRI-pathology correlations in fixed brain autopsy tissue were conducted in three subjects with confirmed PML. RESULTS: With PML (n = 26 total, n = 5 multiple sclerosis natalizumab-associated), juxtacortical changes on susceptibility-weighted imaging (SWI) or gradient echo (GRE) sequences were noted in 3/3 cases on 7 T MRI and 14/22 cases (63.6%) on 1.5 T or 8/22 (36.4%) 3 T MRI. Similar findings were only noted in 3/25 (12.0%) of PCNSL patients (odds ratio (OR) 12.83, 95% confidence interval (CI), 2.9-56.7, p < 0.001) on 1.5 or 3 T MRI. On susceptibility sequences available prior to diagnosis of PML, 7 (87.5%) had changes present on average 2.7 ± 1.8 months (mean ± SD) prior to diagnosis. Postmortem 7 T MRI showed SWI changes corresponded to areas of increased iron density along the gray-white matter (GM-WM) junction predominantly in macrophages. CONCLUSION: Susceptibility changes in PML along the GM-WM junction can precede noticeable fluid-attenuated inversion recovery (FLAIR) changes and correlates with iron accumulation in macrophages.

Distinct subdivisions of subcortical U-fiber regions in the gyrencephalic ferret brain.

The human cerebrum contains a large amount of cortico-cortical association fibers. Among them, U-fibers are short-range association fibers located in white matter immediately deep to gray matter. Although U-fibers are thought to be crucial for higher cognitive functions, the organization within U-fiber regions are still unclear. Here we investigated the properties of U-fiber regions in the ferret cerebrum using neurochemical, neuronal tracing, immunohistochemical and electron microscopic techniques. We found that U-fiber regions can be subdivided into two regions, which we named outer and inner U-fiber regions. We further uncovered that outer U-fiber regions have smaller-diameter axons with thinner myelin compared with inner U-fiber regions. These findings may indicate functional complexity within U-fiber regions in the cerebrum.

U-fiber analysis: a toolbox for automated quantification of U-fibers and white matter hyperintensities.

Background: Whether white matter hyperintensities (WMHs) involve U-fibers is of great value in understanding the different etiologies of cerebral white matter (WM) lesions. However, clinical practice currently relies only on the naked eye to determine whether WMHs are in the vicinity of U-fibers, and there is a lack of good neuroimaging tools to quantify WMHs and U-fibers. Methods: Here, we developed a multimodal neuroimaging toolbox named U-fiber analysis (UFA) that can automatically extract WMHs and quantitatively characterize the volume and number of WMHs in different brain regions. In addition, we proposed an anatomically constrained U-fiber tracking scheme and quantitatively characterized the microstructure diffusion properties, fiber length, and number of U-fibers in different brain regions to help clinicians to quantitatively determine whether WMHs in the proximal cortex disrupt the microstructure of U-fibers. To validate the utility of the UFA toolbox, we analyzed the neuroimaging data from 246 patients with cerebral small vessel disease (cSVD) enrolled at Zhongshan Hospital between March 2018 and November 2019 in a cross-sectional study. Results: According to the manual judgment of the clinician, the patients with cSVD were divided into a WMHs involved U-fiber group (U-fiber-involved group, 51 cases) and WMHs not involved U-fiber group (U-fiber-spared group, 163 cases). There were no significant differences between the U-fiber-spared group and the U-fiber-involved group in terms of age (P=0.143), gender (P=0.462), education (P=0.151), Mini-Mental State Examination (MMSE) scores (P=0.151), and Montreal Cognitive Assessment (MoCA) scores (P=0.411). However, patients in the U-fiber-involved group had higher Fazekas scores (P<0.001) and significantly higher whole brain WMHs (P=0.046) and deep WMH volumes (P<0.001) compared to patients in the U-fiber-spared group. Moreover, the U-fiber-involved group had higher WMH volumes in the bilateral frontal [P(left) <0.001, P(right) <0.001] and parietal lobes [P(left) <0.001, P(right) <0.001]. On the other hand, patients in the U-fiber-involved group had higher mean diffusivity (MD) and axial diffusivity (AD) in the bilateral parietal [P(left, MD) =0.048, P(right, MD) =0.045, P(left, AD) =0.015, P(right, AD) =0.015] and right frontal-parietal regions [P(MD) =0.048, P(AD) =0.027], and had significantly reduced mean fiber length and number in the right parietal [P(length) =0.013, P(number) =0.028] and right frontal-parietal regions [P(length) =0.048] compared to patients in the U-fiber-spared group. Conclusions: Our results suggest that WMHs in the proximal cortex may disrupt the microstructure of U-fibers. Our tool may provide new insights into the understanding of WM lesions of different etiologies in the brain.

Low signal intensity in U-fiber identified by susceptibility-weighted imaging in two cases of progressive multifocal leukoencephalopathy.

Magnetic resonance imaging (MRI) is a useful tool for diagnosing and monitoring progressive multifocal leukoencephalopathy (PML). Although characteristic MRI findings of PML are well known, we noted a potential new finding for this disease on susceptibility-weighted imaging (SWI). Two patients with PML were studied and followed using MRI. SWI revealed low signal intensities in U-fibers adjacent to the white matter lesions of PML. These findings progressed along with the disease progression. The cause underlying these findings remains unclear. This new finding suggests that SWI is useful for the diagnosis of PML. It can provide a helpful clue in a clinical setting.

High-resolution fiber tract reconstruction in the human brain by means of three-dimensional polarized light imaging.

Functional interactions between different brain regions require connecting fiber tracts, the structural basis of the human connectome. To assemble a comprehensive structural understanding of neural network elements from the microscopic to the macroscopic dimensions, a multimodal and multiscale approach has to be envisaged. However, the integration of results from complementary neuroimaging techniques poses a particular challenge. In this paper, we describe a steadily evolving neuroimaging technique referred to as three-dimensional polarized light imaging (3D-PLI). It is based on the birefringence of the myelin sheaths surrounding axons, and enables the high-resolution analysis of myelinated axons constituting the fiber tracts. 3D-PLI provides the mapping of spatial fiber architecture in the postmortem human brain at a sub-millimeter resolution, i.e., at the mesoscale. The fundamental data structure gained by 3D-PLI is a comprehensive 3D vector field description of fibers and fiber tract orientations - the basis for subsequent tractography. To demonstrate how 3D-PLI can contribute to unravel and assemble the human connectome, a multiscale approach with the same technology was pursued. Two complementary state-of-the-art polarimeters providing different sampling grids (pixel sizes of 100 and 1.6 µm) were used. To exemplarily highlight the potential of this approach, fiber orientation maps and 3D fiber models were reconstructed in selected regions of the brain (e.g., Corpus callosum, Internal capsule, Pons). The results demonstrate that 3D-PLI is an ideal tool to serve as an interface between the microscopic and macroscopic levels of organization of the human connectome.