NODDI highlights recovery mechanisms in white and gray matter in ischemic stroke following human stem cell treatment

Abstract

Purpose Diffusion MRI offers insight into ischemic stroke progression in both human and rodent models. However, diffusion MRI to evaluate therapeutic application of mesenchymal stem cells is limited. Robust analytical techniques are required to identify potential physiological changes as a function of cell therapy in stroke. Here, we seek to establish Neurite Orientation Dispersion and Density Imaging (NODDI) as a feasible method in evaluating stroke evolution in response to cell‐based therapeutics. Methods Diffusion MRI data at 21.1T were acquired from 16 male rats. Rats were grouped randomly: naïve (baseline, N = 5), stroke with injections of phosphate buffered saline (N = 6), stroke with injection of 2D human mesenchymal stem cells (hMSC, N = 5). Data were acquired on days 1, 3, 7, and 21 post‐surgery. DTI and NODDI maps were generated, with regions of interest placed in the ischemic hemisphere external capsule and striatum. Diffusion parameters were compared between groups each day, and within groups across hemispheres and longitudinally. Behavioral characterizations were on days 0 (pre‐surgery), 3, 7, 14, and 21. Results The 2D hMSC preserved diffusional restriction in the external capsule compared to saline (day 1: MD, P = .4060; AD, P = .0220). NODDI indicates that hMSC may have preserved intracellular volume fractions (ICVF: day 1, P = .0086; day 3, P = .0021; day 21, P = .0383). Diffusion metrics of hMSC treated animals were comparable to naïve for the external capsule. Conclusions NODDI compliments DTI metrics, enhances interpretation of tissue outcome in ischemic stroke following hMSC application, and may be useful in evaluating or predicting therapeutic response.

Moving toward elucidating alternative motor pathway structures post-stroke: the value of spinal cord neuroimaging

“…Since DWI may be challenging in the spinal cord, additional imaging modalities have been identified to provide pathway-specific detail. Neurite Orientation Dispersion and Density Imaging (NODDI) is a multi-compartment diffusion model that is sensitive to white matter microstructure and neurite morphology ( 126 , 156 , 157 ). NODDI is similar to DWI, however it traditionally utilizes more HARDI shells (at least 2), with added multi-directional intermediate b-values ( 129 ).…”

“…The study observed a decrease in NODDI-derived intra-axonal volume fraction (v in ) in MS patients, signifying a decrease in dendrite and axon density at the site of the lesion ( 126 , 164 ). To date, however, very few studies have used NODDI in populations with stroke ( 156 , 165 – 167 ), and none have evaluated the spinal cord post-stroke; in fact there was a recent call for large rigorous studies to be completed in stroke to help further validate NODDI. We believe that NODDI may provide a method to improve knowledge around alternate motor pathway morphology post-stroke.…”

Mesenchymal stem cell therapy for ischemic stroke: Novel insight into the crosstalk with immune cells

“…Notably, white matter demyelination predates axonal injury in the early stage of ischemic stroke, indicating a time window for stroke intervention focusing on preventing or postponing axonal injury through myelin regeneration ( 36 ). Meanwhile, Bagdasarian et al ( 37 ) applied therapeutic MSC to a rodent stroke model and demonstrated their efficacy in white matter by comparison of Diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging metrics. MSCs exert many unique biological effects, including self-recovery via promoting post-stroke cell survival, providing a promising cellular therapeutic approach for treating white matter injury ( 38 ).…”

Neurofunctional and neuroimaging readouts for designing a preclinical stem-cell therapy trial in experimental stroke

“…There is a plethora of studies in the literature that evaluate stem cell therapy in rodent models of ischemic stroke using neurofunctional and imaging outcomes 5 . However, despite international recommendations 14 , 23 , most of them do not perform a priori sample size calculation and include a limited number of animals per group (sometimes down to 5–6 animals per group 24 , 25 ). Such studies are very likely to be underpowered 26 .…”