Abstract
Purpose: Cell-based therapy offers new opportunities for the development of novel treatments to promote tissue repair, functional restoration, and cerebral metabolic balance. N-acetylasperate (NAA), Choline (Cho), and Creatine (Cr) are three major metabolites seen on proton magnetic resonance spectroscopy (MRS) that play a vital role in balancing the biochemical processes and are suggested as markers of recovery. In this preliminary study, we serially monitored changes in these metabolites in ischemic stroke patients who were treated with autologous bone marrow-derived mononuclear cells (MNCs) using non-invasive MRS.Materials and Methods: A sub-group of nine patients (3 male, 6 female) participated in a serial MRS study, as part of a clinical trial on autologous bone marrow cell therapy in acute ischemic stroke. Seven to ten million mononuclear cells were isolated from the patient's bone marrow and administered intravenously within 72 h of onset of injury. MRS data were obtained at 1, 3, and 6 months using a whole-body 3.0T MRI. Single voxel point-resolved spectroscopy (PRESS) was obtained within the lesion and contralesional gray matter. Spectral analysis was done using TARQUIN software and absolute concentration of NAA, Cho, and Cr was determined. National Institute of Health Stroke Scale (NIHSS) was serially recoreded. Two-way analysis of variance was performed and p < 0.05 considered statistically significant.Results: All metabolites showed statistically significant or clear trends toward lower ipsilesional concentrations compared to the contralesional side at all time points. Statistically significant reductions were found in ipsilesional NAA at 1M and 3M, Cho at 6M, and Cr at 1M and 6M (p < 0.03), compared to the contralesional side. Temporally, ipsilesional NAA increased between 3M and 6M (p < 0.01). On the other hand, ipsilesional Cho showed continued decline till 6M (p < 0.01). Ipsilesional Cr was stable over time. Contralesional metabolites were relatively stable over time, with only Cr showing a reduction 3M (p < 0.02). There was a significant (p < 0.03) correlation between ipsilesional NAA and NIHSS at 3M follow-up.Conclusion: Serial changes in metabolites suggest that MRS can be applied to monitor therapeutic changes. Post-treatment increasing trends of NAA concentration and significant correlation with NIHSS support a potential therapeutic effect.
Highlights
The only therapeutic options for patients with ischemic stroke are approaches that promote recanalization and reperfusion to restore blood flow to the brain
Patient P01 data were removed from spectroscopic measurement because of noisy spectra at two time points
Our finding is in-line with an animal study reporting a significant increase in NAA/Cr and NAA/Cho ratios within the lesion in treated animals with gadolinium labeled mesenchymal stem cells compared to the sham group [39]
Summary
The only therapeutic options for patients with ischemic stroke are approaches that promote recanalization and reperfusion to restore blood flow to the brain. There are no effective post stroke interventions that can promote repair of damaged tissues and restore brain function. Cell based therapies offer great potential to promote possible repair of damaged tissue, prevent atrophy, and help restore brain function. Extensive animal data have shown the safety and feasibility of the bone marrow-derived mononuclear cells (MNCs) as an attractive therapeutic option for stroke [1,2,3,4]. Clinical trials have shown the feasibility and safety of both autologous and allogenic cell administration in stroke patients [9,10,11,12,13]. An important advancement in this field would be to develop post-stroke therapeutic biomarkers
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