Primary motor cortex long‐term plasticity in multiple system atrophy

In humans, intermittent and continuous theta‐burst stimulation (iTBS and cTBS) elicit long‐term changes in motor‐evoked potentials (MEPs) reflecting long‐term potentiation (LTP)‐ and depression (LTD)‐like plasticity in the primary motor cortex (M1). In this study, we used TBS to investigate M1 plasticity in patients with MSA. We also assessed whether responses to TBS reflect M1 excitability as tested by short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), short‐interval intracortical facilitation (SICF), and the input/output curves. We studied 20 patients with MSA and 20 healthy subjects (HS). Patients were clinically evaluated with the Unified Multiple System Atrophy Rating Scale. The left M1 was conditioned with TBS. Twenty MEPs were recorded from the right first dorsal interosseous muscle before TBS and 5, 15, and 30 minutes thereafter. In a subgroup of 10 patients, we also tested MEPs elicited by SICI, ICF, SICF, and input/output curves, before TBS. Between‐group analysis of variance showed that at all time points after iTBS MEPs increased, whereas after cTBS they decreased only in HS. In both subgroups tested, patients with predominant parkinsonian and cerebellar features, iTBS and cTBS left MEPs unchanged. MSA patients had reduced SICI, but normal ICF, SICF, and input/output curves. No correlation was found between patients' clinical features and responses to TBS and M1 excitability variables. These findings suggest impaired M1 plasticity in MSA. © 2013 International Parkinson and Movement Disorder Society     

Synergistic Inhibition on Acetylcholinesterase by the Combination of Berberine and Palmatine Originally Isolated from Chinese Medicinal Herbs

Alzheimer’s disease is a multi-factorial neurodegenerative disorder devastatingly affecting the aged population worldwide. Previous studies have shown that medicinal herbs used in traditional Chinese medicine might be benefit to Alzheimer’s disease patients. Berberine and palmatine, two isoquinoline alkaloids found in several medicinal herbs, were used for memory enhancement in China. In this study, the inhibitory effects of combined berberine and palmatine on acetylcholinesteras were evaluated using recombinant human acetylcholinesterase. Our results showed that the combination of berberine and palmatine inhibited acetylcholinesterase in a mixed competitive pattern. By the median-effect principle, the calculated combination index of the combination was less than 1, suggesting that berberine and plamatine inhibited acetylcholinesterase synergistically. Furthermore, the drug-reducing index of berberine and palmatine were 2.98 and 2.66, respectively. Taken together, the results showed that the combination of the two alkaloids might potentially be developed as a more effective therapeutic strategy for Alzheimer’s disease patients.     

Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases

Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2‐generated superoxide has become an effective strategy for developing disease‐modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long‐acting NOX2 inhibitor. However, due to its non‐specificity for NOX2 and high cytotoxicity at standard doses (µM), DPI has been precluded from human studies. In this study, using ultra‐low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra‐low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10^?14 and 10^?13 M) displays no toxicity in primary midbrain neuron‐glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)‐induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein‐containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post‐treatment study. When subpicomolar DPI was added to neuron‐glia cultures pretreated with lipopolysaccharide, 1‐methyl‐4‐phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPI's unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post‐treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. GLIA 2014;62:2034–2043     

Pressure-dependent attenuation in ultrasound contrast agents

Although microbubble contrast agents are believed to respond differently under different driving-pressure amplitudes, few studies have been performed to extensively study the pressure-dependence of their properties. In this paper, attenuation coefficients of two contrast agents (Optison and Definity) were measured under different driving-pressure amplitudes using a narrowband incident pulse. The attenuation of both contrast agents was found to increase with increasing driving pressure. Simulations using the Rayleigh, Plesset, Noltingk, Neppiras, Poritsky (RPNNP) equation were performed to study this behavior. Simulation results show that significant harmonic generation at high driving-pressure amplitudes contributes to the higher attenuation. Other possible explanations for this behavior were also examined. Attenuation coefficients of two contrast agents were also measured using a broadband method. The results showed great inconsistency when the center frequency of the incident broadband pulse was changed, indicating that broadband techniques may not be suitable for contrast-agent attenuation measurements.     

Dual antiplatelet therapy plus postoperative heparin and dextran is safe and effective for reducing risk of embolic stroke during aneurysm coiling

Background

Thromboembolic events represent a clinically significant cause of neurological morbidity during the endovascular management of cerebral aneurysms. We have implemented an anti-thromboembolic regimen consisting of pre- and postoperative dual antiplatelet therapy, as well as postoperative anticoagulation using heparin and dextran. The aims of our study were to examine the effect of this regimen on thromboembolic rates during elective aneurysm coiling, and to elucidate risk factors associated with the development of thromboembolic events in this setting.

Methods

We conducted a retrospective review of patients who underwent elective intracranial aneurysm coiling between January 2005 and February 2012. The primary outcome of interest was the occurrence of a clinically significant peri-procedural thromboembolic event. Secondary outcomes included the occurrence of a central nervous system (CNS) or systemic hemorrhage.

Results

During the study period, 312 patients underwent elective aneurysm coiling and six (2 %) thromboembolic events occurred; three (1 %) occurred in the group that received the anti-thromboembolic regimen (261 patients) and three (6 %) occurred in the group that did not receive the regimen (51 patients), resulting in a statistically significant difference (P?=?0.024). Both the presence of a hypercoagulable state (P?=?0.014) and the lack of the anti-thromboembolic regimen (P?=?0.043) were significantly associated with the occurrence of a thromboembolic event.

Conclusions

This study provides evidence that the regimen described here is safe and reduces thromboembolic complications during elective aneurysm coiling. Ours is likely the most aggressive regimen in the published literature and significantly reduced the rate of thromboembolism without any significant increase hemorrhagic complications.