Biomarkers

Diffusion MRI is a promising approach to detecting brain microstructure changes associated with neurodegeneration. Unfortunately, diffusion tensor imaging (DTI) only provides limited specificity as it relies solely on single-dimensional diffusion encoding. Multi-dimensional diffusion encoding (MDE) is an emerging method for more specific brain microstructure mapping with advanced diffusion-encoding waveform design and modeling. However, MDE typically decreases the diffusion-encoding efficiency and SNR, resulting in relatively low voxel resolution (>2 mm isotropic). We aim to develop an MDE protocol of 1.8 mm isotropic with a clinically feasible scan time using an optimized MDE waveform design and an SNR-efficient readout, for studying brain microstructure changes in neurodegeneration. Moreover, we evaluate the scan-rescan reproducibility of the developed MDE protocol.

A customized MDE sequence was developed by jointly using two different diffusion-encoding waveforms: linear and spherical tensor-valued diffusion encoding (LTE and STE). An SNR-efficient multi-band multi-shot EPI sequence and reconstruction were used for data readout. Three cognitively normal elderly subjects (1F/2M, aged 62∼70 y/o) were scanned on a 3T GE scanner equipped with a UHP gradient coil. Detailed parameters are listed in Table 1. Quantitative diffusion metrics were calculated, including mean diffusivity (MD), microscopic fractional anisotropy (μFA), anisotropic and isotropic mean kurtosis (MK_a and MK_i). Each subject was scanned twice to assess reproducibility, in the left and right hippocampal cingulum bundle and fornix (using FSL XTRACT) and global white matter/gray matter (using FSL FAST).

High-quality quantitative diffusion metric maps are achieved with the developed MDE protocol (Figure 1). Pearson correlation coefficients (marked in Figure 2) range from r=0.951-0.995 for MD, μFA, MK_a, and MK_i in the global GM and WM, left and right hippocampal cingulum and fornix (Figure 2).

We have developed a MDE protocol of 1.8 mm isotropic and demonstrated its high scan-rescan reproducibility, globally and in four critical WM regions for cognitive function. The achieved 1.8 mm isotropic resolution, together with a large slice coverage (∼70 mm) within a clinically feasible scan time (∼13 min), sets the foundation for more specifically mapping brain microstructure changes in critical brain regions (e.g., the medial temporal lobe) to capture neurodegeneration.