MEMRI and tumors: a method for the evaluation of the contribution of Mn(II) ions in the extracellular compartment

The purpose of the work was to set‐up a simple method to evaluate the contribution of Mn²⁺ ions in the intra‐ and extracellular tumor compartments in a MEMRI experiment. This task has been tackled by “silencing” the relaxation enhancement arising from Mn²⁺ ions in the extracellular space. In vitro relaxometric measurements allowed assessment of the sequestering activity of DO2A (1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid) towards Mn²⁺ ions, as the addition of Ca‐DO2A to a solution of MnCl₂ causes a drop of relaxivity upon the formation of the highly stable and low‐relaxivity Mn‐DO2A. It has been proved that the sequestering ability of DO2A towards Mn²⁺ ions is also fully effective in the presence of serum albumin. Moreover, it has been shown that Mn‐DO2A does not enter cell membranes, nor does the presence of Ca‐DO2A in the extracellular space prompt migration of Mn ions from the intracellular compartment. On this basis the in vivo, instantaneous, drop in SE% (percent signal enhancement) in T₁‐weighted images is taken as evidence of the sequestration of extracellular Mn²⁺ ions upon addition of Ca‐DO2A. By applying the method to B16F10 tumor bearing mice, T₁ decrease is readily detected in the tumor region, whereas a negligible change in SE% is observed in kidneys, liver and muscle. The relaxometric MRI results have been validated by ICP‐MS measurements. Copyright © 2015 John Wiley & Sons, Ltd.     

Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese‐enhanced MRI

Manganese‐enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional‐specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl₂, as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl₂. Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half‐life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T₁‐weighted signal intensities after manganese application, and manganese‐induced memory impairment has been suggested, we assessed hippocampus‐dependent learning as well as possible manganese‐induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn²⁺ application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for sufficient clearance of the paramagnetic ion from cerebral tissue. Copyright © 2012 John Wiley & Sons, Ltd.     

Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients

A non-invasive method to image the mass and/or function of human pancreatic islets is needed to monitor the progression of diabetes, and the effect of therapeutic interventions. As yet, no method is available for this purpose, which could be applied to in situ human islets. Animal and in vitro studies have documented that manganese infusion could improve the magnetic resonance imaging (MRI) of the endocrine pancreas. Here, we have tested whether a similar approach could discriminate diabetic and non-diabetic patients. In vitro, human isolated islets readily incorporated manganese. In vivo, 243 manganese-enhanced magnetic resonance imaging (MEMRI) examinations were reviewed, including 41 examinations which were run on 24 patients with type 2 diabetes and 202 examinations which were run on 119 normoglycemic patients. The results show that MEMRI discriminates type 2 diabetics from non-diabetic patients, based on the signal enhancement of pancreas.     

结合磁共振成像和脑机接口的新型在体生物电子鼻的研究

在体生物电子鼻利用了哺乳动物的嗅觉系统,因此具有很高的灵敏度和特异性,但在嗅球中植入电极的过程中其位置主要根据经验确定,因此成功率并不理想。利用锰离子的钙离子相似性和强顺磁性,在10只大鼠单侧鼻腔中滴入锰离子并给予气味刺激,进行磁共振扫描并标记出大鼠嗅球中的对特定气味的响应区域。在该区域中植入微丝阵列电极,记录电生理信号并就行神经信号解码,实验结果表明,受到该特异性气体刺激后,嗅球神经元的电生理信号中LFP信号β波能量增强,spike信号对该气体刺激也会有响应,并且有些通道的spike发放频率变化与刺激气体的浓度有较好的线性关系。此方法对乙酸异戊酯和正丁酸的检测下限分别为0.033和0.007 2 μM。第一次利用锰离子增强磁共振辅助定位的生物电子鼻,未来在爆炸物搜索、食品安全等方面都有广阔的前景。     

Microtubule-stabilizing peptides and small molecules protecting axonal transport and brain function: Focus on davunetide (NAP)

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.     

Manganese‐enhanced MRI visualizes V1 in the non‐human primate visual cortex

MRI at 7 Tesla has been used to investigate the accumulation of manganese in the occipital cortex of common marmoset monkeys (Callithrix jacchus) after administering four fractionated injections of 30 mg/kg MnCl₂ · 4H₂O in the tail vein. We found a statistically significant decrease in T₁ in the primary (V1) and secondary (V2) areas of the visual cortex caused by an accumulation of manganese. The larger T₁ shortening in V1 (ΔT₁ = 640 ms) relative to V2 (ΔT₁ = 490 ms) allowed us to robustly detect the V1/V2 border in vivo using heavily T₁‐weighted MRI. Furthermore, the dorso‐medial (DM) and middle‐temporal (MT) areas of the visual pathway could be identified by their T₁‐weighted enhancement. We showed by comparison to histological sections stained for cytochrome oxidase (CO) activity that the extent of V1 is accurately identified throughout the visual cortex by manganese‐enhanced MRI (MEMRI). This provides a means of visualizing functional cortical regions in vivo and could be used in longitudinal studies of phenomena such as cortical plasticity, and for non‐destructive localization of cortical regions to guide in the implementation of functional techniques. Published in 2009 by John Wiley & Sons, Ltd.     

Detection of necrotic neural response in super‐acute cerebral ischemia using activity‐induced manganese‐enhanced (AIM) MRI

Immediate and certain determination of the treatable area is important for choosing risky treatments such as thrombolysis for brain ischemia, especially in the super‐acute phase. Although it has been suggested that the mismatch between regions displaying ‘large abnormal perfusion’ and ‘small abnormal diffusion’ indicates a treatable area on an MRI, it has also been reported that the mismatch region is an imperfect approximation of the treatable region named the ‘penumbra’. Manganese accumulation reflecting calcium influx into cells was reported previously in a middle cerebral artery occlusion (MCAO) model using activity‐induced manganese‐enhanced (AIM) MRI. However, in the super‐acute phase, there have been no reports about mismatches between areas showing changes to the apparent diffusion coefficient (ADC) and regions that are enhanced in AIM MRI. It is expected that the AIM signal can be enhanced immediately after cerebral ischemia in the necrotic core region due to calcium influx. In this study, a remote embolic rat model, created using titanium‐oxide macrospheres, was used to observe necrotic neural responses in the super‐acute phase after ischemia. In addition, images were evaluated by comparison between ADC, AIM MRI, and histology. The signal enhancement in AIM MRI was detected at 2 min after the cerebral infarction using a remote embolic method. The enhanced area on the AIM MRI was significantly smaller than that on the ADC map. The tissue degeneration highlighted by histological analysis corresponded more closely to the enhanced area on the AIM MRI than that on the ADC map. Thus, the manganese‐enhanced region in brain ischemia might indicate ‘necrotic’ irreversible tissue that underwent calcium influx. Copyright © 2009 John Wiley & Sons, Ltd.     

Pancreatic magnetic resonance imaging after manganese injection distinguishes type 2 diabetic and normoglycemic patients

A non-invasive method to image the mass and/or function of human pancreatic islets is needed to monitor the progression of diabetes, and the effect of therapeutic interventions. As yet, no method is available for this purpose, which could be applied to in situ human islets. Animal and in vitro studies have documented that manganese infusion could improve the magnetic resonance imaging (MRI) of the endocrine pancreas. Here, we have tested whether a similar approach could discriminate diabetic and non-diabetic patients. In vitro, human isolated islets readily incorporated manganese. In vivo, 243 manganese-enhanced magnetic resonance imaging (MEMRI) examinations were reviewed, including 41 examinations which were run on 24 patients with type 2 diabetes and 202 examinations which were run on 119 normoglycemic patients. The results show that MEMRI discriminates type 2 diabetics from non-diabetic patients, based on the signal enhancement of pancreas.     

Mn‐citrate and Mn‐HIDA: intermediate‐affinity chelates for manganese‐enhanced MRI

In this study we investigated two manganese chelates in order to improve the image enhancement of manganese‐enhanced MRI and decrease the toxicity of free manganese ions. Since both MnCl₂ and a low‐affinity chelate were associated with a slow continuous decrease of cardiac functions, we investigated intermediate‐affinity chelates: manganese N‐(2‐hydroxyethyl)iminodiacetic acid (Mn‐HIDA) and Mn‐citrate. The T₁ relaxivity values for Mn‐citrate (4.4 m m ^?1 s^?1) and Mn‐HIDA (3.3 m m ^?1 s^?1) in artificial cerebrospinal fluid (CSF) were almost constant in a concentration range from 0.5 to 5 m m at 37 °C and 4.7 T. In human plasma, the relaxivity values increased when the concentrations of these Mn chelates were decreased, suggesting the presence of free Mn²⁺ bound with serum albumin. Mn‐HIDA and Mn‐citrate demonstrated a tendency for better contractility when employed with an isolated perfused frog heart, compared with MnCl₂. Only minimal changes were demonstrated after a venous infusion of 100 m m Mn‐citrate or Mn‐HIDA (8.3 µmol kg^?1 min^?1) in rats and a constant heart rate, arterial pressure and sympathetic nerve activity were maintained, even after breaking the blood–brain barrier (BBB). Mn‐citrate and Mn‐HIDA could not cross the intact BBB and appeared in the CSF, and then diffused into the brain parenchyma through the ependymal layer. The responses in the supraoptic nucleus induced by the hypertonic stimulation were detectable. Therefore, Mn‐citrate and Mn‐HIDA appear to be better choices for maintaining the vital conditions of experimental animals, and they may improve the reproducibility of manganese‐enhanced MRI of the small nuclei in the hypothalamus and thalamus. Copyright © 2012 John Wiley & Sons, Ltd.