Faculty Bibliography

RATIONALE AND OBJECTIVES/OBJECTIVE:To evaluate if incidental abdominopelvic calcified atherosclerosis (ACA) in patients under 50 years of age correlates with cardiovascular disease (CVD) risk factors. Most studies evaluating calcific atherosclerosis and associated increased risk of CVD have concentrated on middle age and older populations. MATERIALS AND METHODS/METHODS:A retrospective review of 519 emergency department patients, aged 25-50 years, receiving computed tomography (CT) was performed and ACA correlated with lipid panels obtained via chart review. Those with calcified atherosclerosis were subdivided by vessel location and calcification burden (mild, moderate, or severe). Patients were followed for six years. Normality, Wilcoxon-Mann-Whitney, Kruskal-Wallis, and chi-square tests were performed. RESULTS:Two hundred and sixty-nine patients with incidental ACA on CT and 250 without ACA were studied. Atherosclerotic calcifications had a statistically significant correlation with elevated triglyceride (128 mg/dL vs 105 mg/dL; p = 0.0003) and decreased high-density lipoprotein (38 mg/dL vs 41 mg/dL; p = 0.0032) as compared to the control. Patients with ACA were at higher risk of stroke, heart attack, and death (p < 0.0001) during a six-year follow-up period. CONCLUSION/CONCLUSIONS:Incidental atherosclerotic calcification on abdominopelvic CT in patients under 50 years of age correlated with elevated triglycerides and decreased high-density lipoprotein as well as higher risk of cardiovascular events. Since radiologists may be the first to identify this finding and CVD is the leading cause of US deaths, proper recognition and reporting of calcification is valuable.

Carotid artery dissection is a cause of stroke, especially in young and middle-aged patients. A dissection occurs when there is an intimal tear or rupture of the vasa vasorum, leading to an intramural hematoma, which is thought to result from trauma or can occur spontaneously, and is likely multifactorial, involving environmental and intrinsic factors. The clinical diagnosis of carotid artery dissection can be challenging, with common presentations including pain, partial Horner syndrome, cranial nerve palsies, or cerebral ischemia. With the use of noninvasive imaging, including magnetic resonance and computed tomography angiography, the diagnosis of carotid dissection has increased in frequency. Treatment options include thrombolysis, antiplatelet or anticoagulation therapy, endovascular or surgical interventions. The choice of appropriate therapy remains controversial as most carotid dissections heal on their own and there are no randomized trials to compare treatment options.

The death of motor neurons in amyotrophic lateral sclerosis (ALS) is thought to result from the interaction of a variety of factors including excitotoxicity, accumulation of toxic proteins, and abnormal axonal transport. Previously, we found that the susceptibility of motor neurons to excitotoxic insults can be limited by inhibiting signals evoked by brain-derived neurotrophic factor (BDNF) activation of the receptor tyrosine kinase B (TrkB). Here we show that this can be achieved by direct kinase inhibition or by blockade of a transactivation pathway that uses adenosine A2a receptors and src-family kinases (SFKs). Downstream signaling cascades (such as mitogen-activated protein kinase and phosphatidylinositol-3 kinase) are inhibited by these blockers. In addition to protecting motor neurons from excitotoxic insult, these agents also prevent toxicity that follows from the expression of mutant proteins (G85R superoxide dismutase 1; G59S p150(glued)) that cause familial motor neuron disease. TrkB, adenosine A2a receptors, and SFKs associate into complexes in lipid raft and nonlipid raft membranes and the signaling from lipids rafts may be particularly important because their disruption by cholesterol depletion blocks the ability of BDNF to render motor neurons vulnerable to insult. The neuroprotective versatility of Trk antagonism suggests that it may have broad utility in the treatment of ALS patients.

BACKGROUND:The death of motor neurons in amyotrophic lateral sclerosis (ALS) is believed to result, in part, from unrestrained activation of glutamate receptors (excitotoxicity). In some in vitro models, excitotoxic death only occurs if motor neurons develop in the presence of the growth factor, brain-derived neurotrophic factor (BDNF). OBJECTIVE:Since the increased vulnerability of motor neurons evoked by BDNF is mediated by activation of TrkB, we sought to identify pharmacological agents that can block this pathway. Adenosine receptors are known to transactivate Trk receptors, leading us to examine the effects of manipulating of adenosine receptor signaling on Trk signaling and excitotoxic sensitivity. METHODS:Spinal cord cultures were treated with adenosine receptor agonists and antagonists. The biochemical effects on Trk signaling and excitotoxic motor neuron death were examined. RESULTS:We show here that adenosine A(2a) antagonists can reduce activation of Trk receptors and are neuroprotective. Conversely, activating adenosine A(2a) receptors in the absence of BDNF signaling makes motor neurons vulnerable to excitotoxic challenge. CONCLUSION/CONCLUSIONS:Selective, high-affinity adenosine A(2a) antagonists merit consideration as therapeutic agents for the treatment of ALS.