Manganese Enhanced MRI for Use in Studying Neurodegenerative Diseases

MRI has been extensively used in neurodegenerative disorders, such as Alzheimer’s disease (AD), frontal-temporal dementia (FTD), mild cognitive impairment (MCI), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS). MRI is important for monitoring the neurodegenerative components in other diseases such as epilepsy, stroke and multiple sclerosis (MS). Manganese enhanced MRI (MEMRI) has been used in many preclinical studies to image anatomy and cytoarchitecture, to obtain functional information in areas of the brain and to study neuronal connections. This is due to Mn2+ ability to enter excitable cells through voltage gated calcium channels and be actively transported in an anterograde manner along axons and across synapses. The broad range of information obtained from MEMRI has led to the use of Mn2+ in many animal models of neurodegeneration which has supplied important insight into brain degeneration in preclinical studies. Here we provide a brief review of MEMRI use in neurodegenerative diseases and in diseases with neurodegenerative components in animal studies and discuss the potential translation of MEMRI to clinical use in the future

Thalamocortical Inputs Show Post-Critical-Period Plasticity

SummaryExperience-dependent plasticity in the adult brain has clinical potential for functional rehabilitation following central and peripheral nerve injuries. Here, plasticity induced by unilateral infraorbital (IO) nerve resection in 4-week-old rats was mapped using MRI and synaptic mechanisms were elucidated by slice electrophysiology. Functional MRI demonstrates a cortical potentiation compared to thalamus 2 weeks after IO nerve resection. Tracing thalamocortical (TC) projections with manganese-enhanced MRI revealed circuit changes in the spared layer 4 (L4) barrel cortex. Brain slice electrophysiology revealed TC input strengthening onto L4 stellate cells due to an increase in postsynaptic strength and the number of functional synapses. This work shows that the TC input is a site for robust plasticity after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity in contrast to the consensus that adult plasticity mainly occurs at cortico-cortical connections

Accounting for nonspecific enhancement in neuronal tract tracing using manganese enhanced magnetic resonance imaging

Manganese enhanced MRI (MEMRI) is an emerging technique for tracing neuronal pathways in vivo. However, manganese may leak into blood vessels or cerebrospinal fluid (CSF) after local injection and can be circulated to and taken up by brain regions that may not have connections to the targeted pathways. Comparing enhancement time courses after intranasal injection with intravenous infusion of MnCl in rats, the early enhancements in the pituitary gland (Pit) and hippocampus indicate the contrasts in those regions in the olfactory tract-tracing experiment were caused by such systemic effects. Since the Pit has easy access to manganese from the blood and its signal is proportional to other brain regions after intravenous infusion, it was used as an internal reference for the systemic effects. Applying intensity normalization by the Pit signal to tract-tracing data from the olfactory bulb led to reduced contrast in the hippocampus. These results demonstrate that nonspecific enhancements in MEMRI tract-tracing studies may have to be taken into account and that normalization by the Pit signal can compensate these effects

High calcium and dobutamine positive inotropy in the perfused mouse heart: myofilament calcium responsiveness, energetic economy, and effects of protein kinase C inhibition

<p>Abstract</p> <p>Background</p> <p>In perfused hearts, high calcium-induced inotropy results in less developed pressure relative to myocardial oxygen consumption compared to the β-adrenergic agonist dobutamine. Calcium handling is an important determinant of myocardial oxygen consumption. Therefore, we hypothesized that this phenomenon was due to reduced myofilament responsiveness to calcium, related to protein kinase C activation.</p> <p>Results</p> <p>Developed pressure was significantly higher with dobutamine compared to high perfusate calcium of 3.5 mM (73 ± 10 vs 63 ± 10 mmHg, p < 0.05), though peak systolic intracellular calcium was not significantly different, suggesting reduced myofilament responsiveness to intracellular calcium with high perfusate calcium. The ratio of developed pressure to myocardial oxygen consumption, an index of economy of contraction, was significantly increased with dobutamine compared to high perfusate calcium (1.35 ± 0.15 vs 1.15 ± 0.15 mmHg/μmoles/min/g dry wt, p < 0.05), suggesting energetic inefficiency with high perfusate calcium. The specific protein kinase C inhibitor, chelerythrine, significantly attenuated the expected increase in developed pressure when increasing perfusate calcium from 2.5 to 3.5 mM (3.5 mM: 64 ± 8 vs 3.5 mM + chelerythrine: 55 ± 5 mmHg, p < 0.05), though had no effects on dobutamine, or lower levels of perfusate calcium (1.5 to 2.5 mM).</p> <p>Conclusions</p> <p>By measuring intracellular calcium, developed pressures and myocardial oxygen consumption in perfused mouse hearts, these results demonstrate that high perfusate calcium positive inotropy compared to dobutamine results in reduced myofilament responsiveness to intracellular calcium, which is associated with energetic inefficiency and evidence of protein kinase C activation.</p