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Background: MR imaging of the spinal cord (SC) gray matter (GM) at the cervical and lumbar enlargements' level may be particularly informative in lower motor neuron disorders, e. g., spinal muscular atrophy, but also in other neurodegenerative or autoimmune diseases affecting the SC. Radially sampled averaged magnetization inversion recovery acquisition (rAMIRA) is a novel approach to perform SC imaging in clinical settings with favorable contrast and is well-suited for SC GM quantitation. However, before applying rAMIRA in clinical studies, it is important to understand (i) the sources of inter-subject variability of total SC cross-sectional areas (TCA) and GM area (GMA) measurements in healthy subjects and (ii) their relation to age and sex to facilitate the detection of pathology-associated changes. In this study, we aimed to develop normalization strategies for rAMIRA-derived SC metrics using skull and spine-based metrics to reduce anatomical variability. Methods: Sixty-one healthy subjects (age range 11-93 years, 37.7% women) were investigated with axial two-dimensional rAMIRA imaging at 3T MRI. Cervical and thoracic levels including the level of the cervical (C4/C5) and lumbar enlargements (Tmax) were examined. SC T2-weighted sagittal images and high-resolution 3D whole-brain T1-weighted images were acquired. TCA and GMAs were quantified. Anatomical variables with associations of |r| > 0.30 in univariate association with SC areas, and age and sex were used to construct normalization models using backward selection with TCAC4/C5 as outcome. The effect of the normalization was assessed by % relative standard deviation (RSD) reductions. Results: Mean inter-individual variability and the SD of the SC area metrics were considerable: TCAC4/5: 8.1%/9.0; TCATmax: 8.9%/6.5; GMAC4/C5: 8.6%/2.2; GMATmax: 12.2%/3.8. Normalization based on sex, brain WM volume, and spinal canal area resulted in RSD reductions of 23.7% for TCAs and 12.0% for GM areas at C4/C5. Normalizations based on the area of spinal canal alone resulted in RSD reductions of 10.2% for TCAs and 9.6% for GM areas at C4/C5, respectively. Discussion: Anatomic inter-individual variability of SC areas is substantial. This study identified effective normalization models for inter-subject variability reduction in TCA and SC GMA in healthy subjects based on rAMIRA imaging.
The potential for directed differentiation of human-induced pluripotent stem (iPS) cells to functional postmitotic neuronal phenotypes is unknown. Following methods shown to be effective at generating motor neurons from human embryonic stem cells (hESCs), we found that once specified to a neural lineage, human iPS cells could be differentiated to form motor neurons with a similar efficiency as hESCs. Human iPS-derived cells appeared to follow a normal developmental progression associated with motor neuron formation and possessed prototypical electrophysiological properties. This is the first demonstration that human iPS-derived cells are able to generate electrically active motor neurons. These findings demonstrate the feasibility of using iPS-derived motor neuron progenitors and motor neurons in regenerative medicine applications and in vitro modeling of motor neuron diseases.
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