Systemic Complement Activation in Age-Related Macular Degeneration

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes

Glutamine-to-glutamate ratio in the nucleus accumbens predicts effort-based motivated performance in humans

Substantial evidence implicates the nucleus accumbens in motivated performance, but very little is known about the neurochemical underpinnings of individual differences in motivation. Here, we applied 1H magnetic resonance spectroscopy (1H-MRS) at ultra-high-field in the nucleus accumbens and inquired whether levels of glutamate (Glu), glutamine (Gln), GABA or their ratios predict interindividual differences in effort-based motivated task performance. Given the incentive value of social competition, we also examined differences in performance under self-motivated or competition settings. Our results indicate that higher accumbal Gln-to-Glu ratio predicts better overall performance and reduced effort perception. As performance is the outcome of multiple cognitive, motor and physiological processes, we applied computational modeling to estimate best-fitting individual parameters related to specific processes modeled with utility, effort and performance functions. This model-based analysis revealed that accumbal Gln-to-Glu ratio specifically relates to stamina; i.e., the capacity to maintain performance over long periods. It also indicated that competition boosts performance from task onset, particularly for low Gln-to-Glu individuals. In conclusion, our findings provide novel insights implicating accumbal Gln and Glu balance on the prediction of specific computational components of motivated performance. This approach and findings can help developing therapeutic strategies based on targeting metabolism to ameliorate deficits in effort engagement