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Microscopic diffusion anisotropy as a predictor of cognitive decline in asymptomatic adults
Hyeong-Geol Shin1,2, Sarvin Sasannia1,3, Sarara Mahmud3, Mykola Matsyuk3, Shimeng Wang4, Jinwei Zhang5, Filip Szczepankiewicz6, Xu Li1,2, Jerry Prince5, Linda Knutsson1,3,6, Peter van Zijl1,2,4, and Paul Nyquist3
1F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States, 2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 4Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 5Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, United States, 6Department of Medical Radiation Physics, Lund University, Lund, Sweden

Synopsis

Keywords: Dementia, Dementia

Motivation: Conventional diffusion MRI metrics like FA have limitations in assessing WMH lesions due to fiber orientation dispersion.

Goal(s): To improve MRI sensitivity to white matter integrity in WMH and assess its clinical relevance in predicting preclinical cognitive decline using advanced diffusion MRI.

Approach: FA and μFA maps were acquired in 54 adults using tensor-valued diffusion MRI and their quantitative correlation with cognitive decline were evaluated in WMH lesion and penumbra.

Results: While both μFA and FA differentiated WMH from other white matter regions, μFA demonstrated greater sensitivity to predict cognitive decline, suggesting its added specificity to probe white matter integrity in WMH.

Impact: Enhanced sensitivity of μFA to subtle white matter integrity and clinical aspect may offer better understanding of underlying histopathological alterations in white WMH, helping earlier detection of cerebrovascular pathology and aiding efforts to identify at-risk individuals and guide timely interventions.

Introduction

Cognitive decline can precede clinical detection of cognitive impairment, rendering early detection of disease symptoms essential for timely intervention to slow risk of progression1-3.Cerebrovascular small-vessel disease (cSVD), known to be associated with cognitive decline and dementia4,5, has emerged as an etiology of cognitive decline and is a target of disease modifying treatment6-8.

In neuroimaging studies, white matter hyperintensities (WMHs), typically visible in deep or periventricular white matter in T2-weighted FLAIR, are indicative of white matter pathologies related to cSVD, such as axonal loss and demyelination7,9,10, demonstrating its association with cognitive decline and cardiovascular risk factors11-13. However, WMH may represent the final visible stage of the continuous course of microstructural WM degeneration14. To understand the underlying WM alterations, conventional diffusion MRI parameters, such as fractional anisotropy (FA), have been studied to probe white matter integrity within WMH14. Despite its usefulness, the interpretation of FA is confounded by intra-voxel fiber orientation dispersion, which is prevalent across brain WM. Recent developments in diffusion MRI introduced the concept of microscopic FA (μFA), capable of capturing microscale-level diffusion anisotropy and offering a more specific characterization of white matter microstructure integrity15, independent of fiber orientation dispersion16,17.

In this study, we hypothesized that μFA will provide a stronger sensitivity to white matter degeneration compared to FA, given its superior specificity to subtle WM alterations, and compared the clinical relevance of μFA within WMH to that of FA for detecting preclinical cognitive decline. Our results demonstrated that μFA had superior sensitivity to clinical aspects over FA.

Methods

[Participants] Local IRB authorization was obtained, and all volunteers signed informed consent. This perspective study included 54 participants (age = 61.2 ± 9.8 y/o, 39 female) who are healthy family members or relatives with known early-onset coronary disease.

[Data acquisition] 54 participants underwent 3T brain MRI (Philips Ingenia-Elition-RX), including MPRAGE, T2-weighted FLAIR, and T2-weighted images for WMH lesion assessment and tensor-valued diffusion MRI (tdMRI) for μFA estimation. tdMRI was acquired using linear, planar, and spherical b-tensors generated by optimized gradient waveforms17,18, using the following scan parameters: resolution=1.8 mm-isotropic, max b-value = 2000 s/mm2.

[Clinical assessment] Neuropsychological tests to assess cognitive function and impairment included 14 assessments (MMSE/MoCA/CS21-immediate/CS21-delay/BCFT-immediate/ BCFT -delay/DS-F/DS-B/CFT/TMT-A/TMT-B/GPT/DSST/MINT; Fig.4). TMT and GPT are timed test, positively correlated with cognitive decline (others negative correlated).

[Postprocessing] Diffusion-weighted images from tdMRI were corrected for noise, signal drift, Gibbs-ringing, motion, and distortion19-23, before calculating FA and μFA maps using the open-source analysis framework (https://github.com/markus-nilsson/md-dmri).

[ROI analysis] For WMH lesion segmentation, MPRAGE, FLAIR, T2-weighted images were sequentially bias-corrected24, interpolated for 2D scans 25, co-registered to standard space, and then contrast-harmonized 26. The preprocessed contrast was segmented for WMH lesion using domain-adaptable segmentation model 27. Surrounding penumbra was defined as white matter tissue surrounding the lesions (2-voxel thickness). The remaining white matter, other than WMH and penumbra, was considered normal appearing white matter (NAWM). Pearson partial correlation with neuropsychological test outcomes were assessed for the averaged FA and μFA values in each ROI (WMH, penumbra, and NAWM), adjusting age and sex.

Results

Fig.1 shows the appearance of FA and μFA in WMH lesions. FA maps show the detrimental effects of intra-voxel orientation dispersion in crossing fiber areas (red arrows in Fig. 1), hampering the identification of changes in microstructure in WMH lesions. Conversely, μFA shows hypointensities localized in WMH lesion sites, regardless of crossing fiber. When combining all WMH lesions, FA and μFA show similar sensitivity to differentiate WMH with penumbra or NAWM, reporting significant (p<0.01) decrease of μFA and FA in WMH (Fig.2)

Both FA and μFA in WMH lesions show significant decrease with age (Fig.3), highlighting the potential of diffusion MRI metrics, particularly μFA, to serve as biomarkers of age-related WMH.

Despite the similar performance of both parameters (FA and μFA) in terms of quantitative differentiation of WMH from other WM, μFA in WMH demonstrated superior clinical sensitivity to detect cognitive decline over FA (Figs. 4,5). In WMH lesions and their penumbra, changes in μFA and FA were quantitatively associated with multiple cognitive impairment metrics (p<0.05), with higher sensitivity in μFA. This may indicate that the enhanced specificity of μFA to white matter integrity can provide better insight into understanding white matter alterations in cSVD. Fig.5 displays scatter plots for FA and μFA in WMH, with unique correlation for μFA across multiple domains.

Conclusion/discussion:

This study found a more sensitive characterization of clinical outcome with μFA compared to conventional FA measurement. These results suggest μFA may be a valuable predictor of future cognitive decline in adults even before symptoms appear, potentially enabling earlier interventions.

Acknowledgements

COI*

Peter van Zijl has research support from and technology licensed to Philips Healthcare and has also been a paid speaker. Linda Knutsson is conflicted by affiliation. Filip Szczepankiewicz is an inventor on patents related to the study, and he has financial interests in the company Random Walk Imaging AB

Funding:

National Institutes of Health grants: NINDS/NIA award RF1NS128135 and NIBIB award P41 EB031771.


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Figures

Fig. 1. Appearance of WMH in FA and μFA maps. In FA maps, hypointensities are detected not only in WMH lesions but also in crossing fiber areas, confounding identification of WMH lesions. For example, FA exhibits hypointensity in several non-WMH regions (e.g., red arrows), while μFA does not have hypointensities in these normal brain tissues. Overall, μFA map demonstrated hypointensity localized specifically to the lesion sites, independent of orientation dispersion (green and red arrows).

Fig. 2. ROI analysis quantitatively comparing FA and μFA values for distinguishing NAWM, WMH, and surrounding penumbral tissue. Both FA and μFA showed a significant decrease in WMH lesion compared to NAWM and penumbra (p<0.01).

Fig. 3. Pearson correlation of age with FA of μFA values in WMH lesion (r: correlation, p: p-value). Age showed a significant negative correlation with FA (r=-0.31, p=0.02) and μFA (r=-0.33, p=0.01) in WMH. This suggests that older individuals had lower white matter integrity in WMH, in line with previously demonstrated aging effects on WMH28,29.

Fig. 4. Pearson partial correlation between cognitive scores and MRI measures in penumbra (A) and WMH lesion (B), after adjustment of age and sex. Within both penumbra and WMH lesions, μFA generally showed stronger correlations with cognitive decline than FA. Compared to WMH lesion, interestingly, penumbra demonstrated added clinical sensitivity to MOCA, BCFT, CFT, and TMT-B, which may suggest that pathological processes are actively advancing in this surrounding region before they manifest as visible lesions30,31.

Fig. 5. Scatter plot comparing clinical correlations of FA and μFA in WMH. Only neuropsychological test outcomes having significant correlation with either FA or μFA are displayed (see Fig 4B). Each empty circle indicates a pair of neuropsychological test outcomes and white matter integrity measured by MRI (i.e., FA or μFA) for each participant. In WMH lesions, μFA significantly correlates with cognitive decline assessed by MMSE, TMT-B, and GPT, while FA is not (r: correlation, p: p-value).

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
4371
DOI: https://doi.org/10.58530/2024/4371