Deep learning-based segmentation in MRI-(immuno)histological examination of myelin and axonal damage in
Gemma Solé-Guardia1, Matthijs Luijten1, Esther Janssen1
1Department of Medical Imaging, Anatomy, Research Institute for Medical Innovation, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands.
Abstract:
The major vascular cause of dementia is cerebral small vessel disease (SVD). Its diagnosis relies on imaging hallmarks, such as white matter hyperintensities (WMH). WMH present a heterogenous pathology, including myelin and axonal loss. Yet, these might be only the "tip of the iceberg." Imaging modalities imply that microstructural alterations underlie still normal-appearing white matter (NAWM), preceding the conversion to WMH. Unfortunately, direct pathological characterization of these microstructural alterations affecting myelinated axonal fibers in WMH, and especially NAWM, is still missing. Given that there are no treatments to significantly reduce WMH progression, it is important to extend our knowledge on pathological processes that might already be occurring within NAWM. Staining of myelin with Luxol Fast Blue, while valuable, fails to assess subtle alterations in white matter microstructure. Therefore, we aimed to quantify myelin surrounding axonal fibers and axonal- and microstructural damage in detail by combining (immuno)histochemistry with polarized light imaging (PLI). To study the extent (of early) microstructural damage from periventricular NAWM to the center of WMH, we refined current analysis techniques by using deep learning to define smaller segments of white matter, capturing increasing fluid-attenuated inversion recovery signal. Integration of (immuno)histochemistry and PLI with post-mortem imaging of the brains of individuals with hypertension and normotensive controls enables voxel-wise assessment of the pathology throughout periventricular WMH and NAWM. Myelin loss, axonal integrity, and white matter microstructural damage are not limited to WMH but already occur within NAWM. Notably, we found that axonal damage is higher in individuals with hypertension, particularly in NAWM. These findings highlight the added value of advanced segmentation techniques to visualize subtle changes occurring already in NAWM preceding WMH. By using quantitative MRI and advanced diffusion MRI, future studies may elucidate these very early mechanisms leading to neurodegeneration, which ultimately contribute to the conversion of NAWM to WMH.
Insights
Cerebral small vessel disease (SVD) causes dementia. Microstructural damage, including myelin and axonal loss, occurs in normal-appearing white matter (NAWM) before white matter hyperintensities (WMH) develop, especially in hypertension.
Area of Science:
- Neurology
- Neuroscience
- Pathology
Background:
- Cerebral small vessel disease (SVD) is a major cause of vascular dementia.
- Diagnosis of SVD relies on imaging hallmarks like white matter hyperintensities (WMH), but these may only represent advanced pathology.
- Early microstructural alterations in normal-appearing white matter (NAWM) preceding WMH are not well understood pathologically.
Purpose of the Study:
- To investigate and quantify early microstructural damage, including myelin and axonal integrity, in both NAWM and WMH.
- To compare pathological changes in individuals with hypertension versus normotensive controls.
- To explore the utility of advanced imaging and histological techniques for detecting subtle white matter changes.
Main Methods:
- Combined (immuno)histochemistry with polarized light imaging (PLI) for detailed microstructural analysis.
- Utilized deep learning for advanced segmentation of white matter, correlating with fluid-attenuated inversion recovery (FLAIR) signals.
- Performed voxel-wise pathological assessment on post-mortem brain tissue from hypertensive and normotensive individuals.
Main Results:
- Myelin loss, axonal damage, and microstructural alterations are present not only in WMH but also significantly within NAWM.
- Axonal damage was notably higher in individuals with hypertension, particularly in NAWM.
- Advanced segmentation techniques effectively visualized subtle changes in NAWM preceding WMH.
Conclusions:
- Microstructural white matter damage in SVD begins in NAWM, prior to the formation of WMH.
- Hypertension exacerbates axonal damage within NAWM, highlighting its role in early SVD progression.
- These findings underscore the importance of studying NAWM to understand SVD pathogenesis and neurodegeneration.
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