Quantitative MRI of rostral spinal cord and brain regions is predictive of functional recovery in acute spinal cord injury.

Objective: To reveal the immediate extent of trauma-induced neurodegenerative changes rostral to the level of lesion and determine the predictive clinical value of quantitative MRI (qMRI) following acute spinal cord injury (SCI). Methods: Twenty-four acute SCI patients and 23 healthy controls underwent a high-resolution T1-weighted protocol. Eighteen of those patients and 20 of controls additionally underwent a multi-parameter mapping (MPM) MRI protocol sensitive to the content of tissue structure, including myelin and iron. Patients were examined clinically at baseline, 2, 6, 12, and 24 months post-SCI. We assessed volume and microstructural changes in the spinal cord and brain using T1-weighted MRI, magnetization transfer (MT), longitudinal relaxation rate (R1), and effective transverse relaxation rate (R2*) maps. Regression analysis determined associations between acute qMRI parameters and recovery. Results: At baseline, cord area and its anterior-posterior width were decreased in patients, whereas MT, R1, and R2* parameters remained unchanged in the cord. Within the cerebellum, volume decrease was paralleled by increases of MT and R2* parameters. Early grey matter changes were observed within the primary motor cortex and limbic system. Importantly, early volume and microstructural changes of the cord and cerebellum predicted functional recovery following injury. Conclusions: Neurodegenerative changes rostral to the level of lesion occur early in SCI, with varying temporal and spatial dynamics. Early qMRI markers of spinal cord and cerebellum are predictive of functional recovery. These neuroimaging biomarkers may supplement clinical assessments and provide insights into the potential of therapeutic interventions to enhance neural plasticity.

Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts.

The dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A possesses diverse roles in neuronal development and adult brain physiology, and increased activity has been linked to neurodegenerative diseases. Very few inhibitors of this kinase have been reported up to now. Screening of a library of > 900 plant and fungal extracts afforded 25 extracts with IC50s < 10 µg/mL against DYRK1A. To identify the active constituents, the extracts were submitted to a process integrating physicochemical data with biological information, referred to as HPLC-based activity profiling. Follow-up investigation of four extracts led to the targeted isolation of harmine (1, IC50 0.022 µM) from Peganum harmala, emodin (3, IC50 4.2 µM) from Cassia nigricans, kaempferol (4, IC50 0.91 µM) from Cuscuta chinensis, and 3,8-di-O-methylherbacetin (11, IC50 8.6 µM), 3,3',4'-tri-O-methylmyricetin (12, IC50 7.1 µM) and ombuin (15, IC50 1.7 µM) from Larrea tridentata as the active constituents. Active extracts and compounds were also tested on the closely related cdc2-like kinase CLK1. Finally, the selectivity profile of compounds was evaluated by including other members of the DYRKs and CLKs families. While the flavonoids and emodin did not show significant differences in the potency of their activities, harmine (1) was most active against DYRK1A, CLK1, and CLK4, and less potent against the other kinases, with selectivity ranging from 2- to 20-fold.