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bioRxiv · 10.1101/2025.09.30.679612

Multimodal MR Imaging for quantification of brain lipid in mice at 9.4T

Khokhar, S. K.·Swain, A.·Soni, N. D.·Juul, H.·Mathur, A.·Roy, D.·Benyard, B.·Kumar, D.·Nanga, R. P. R.·Haris, M.·Reddy, R.
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Abstract

BackgroundAdvanced MR imaging techniques like steady state Nuclear Overhauser enhancement (ssNOE), transient NOE (tNOE), and myelin water fraction (MWF) provide a non-invasive way to assess the biochemical and structural integrity of brain tissue. Their sensitivity to endogenous lipids and macromolecules allows for the early detection of neuropathological changes, making them valuable tools in studying brain health and disease progression. In this study, we systematically evaluate the repeatability and sensitivity of NOEMTR, tNOE, and MWF for quantifying lipid and myelin content in the brains of wild-type (WT) mice, correlating the results with immunohistochemistry (IHC). MethodsFive 6-month-old C57BL6/J mice were imaged using 3D-NOE, and four mice underwent imaging with 2D tNOE and MWF across four repeated sessions using a 9.4T Scanner. For ssNOE imaging, CEST-weighted images at 56 frequency offsets were acquired using B1rms of 1.0 T and 3s saturation duration. For tNOE, 52 offsets were acquired with a hyperbolic secant inversion pulse (bandwidth = 400Hz, duration = 44ms) and a mixing time of 200ms. For MWF, a multi-echo spin-echo (MESE) sequence was acquired with 40 evenly spaced echoes from 5.5ms to 200ms. For both ssNOE and tNOE, B0 correction was performed using WASSR. Repeatability was quantified using intra- and inter-subject coefficients of variation (COV%). Pearson correlation was performed to see the association between imaging matrices and IHC measures, Luxol fast blue (LFB) stained sections, and myelin basic protein (MBP). ResultsAll techniques demonstrated high repeatability across the whole brain (WB) and selected regions of interest (ROIs). Whole-brain intra-subject COV% for NOEMTR ranged from 1.92% to 3.40%, with corresponding inter-subject COVs of 1.50%. tNOE exhibited improved intra-subject repeatability with COVs ranging from 0.75% to 5.57%, but a reduced inter-subject COV of 2.97%. MWF imaging showed the highest stability overall, with an intra-subject COV ranging from 0.47% to 2.03% and an inter-subject COV of 0.75%. Visually, tNOE offers superior contrast in myelin-rich areas compared to NOEMTR and MWF imaging, showing greater sensitivity to myelinated regions. tNOE strongly correlates with histological markers: r = 0.83 with MBP staining and r = 0.72 with LFB staining (both p < 0.001). MWF and NOEMTR showed correlations with MBP (r = 0.63 and r = 0.57, respectively). ConclusionNOEMTR, tNOE, and MWF imaging are reliable and repeatable methods for quantifying macromolecules in the brain. Among these, tNOE emerges as the most sensitive for detecting myelin lipids as confirmed by histological validation. These findings highlight the translational potential of tNOE for studying demyelinating disorders and neurodegenerative diseases.

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Khokhar, S. K., Swain, A., Soni, N. D., Juul, H., Mathur, A., Roy, D., Benyard, B., Kumar, D., Nanga, R. P. R., Haris, M., Reddy, R.. 2025-10-02. Multimodal MR Imaging for quantification of brain lipid in mice at 9.4T. https://doi.org/10.1101/2025.09.30.679612

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