👤 Heather Volk

Prior studies have demonstrated the existence of cognitively-defined subgroups among dementia free older adults, however, it is unclear whether such subgroups are characterized by distinct neuroimaging measures of brain function and structure. To address this gap, the current study used latent profile analysis (LPA) to identify cognitively-defined subgroups in a sample of 167 (mean age = 69 years) dementia-free older adults with cognitive testing, amyloid PET, and multimodal brain MRI scans. The cognitive test scores covered the domains of episodic memory, executive function, language, and visuospatial processing. Linear regression models tested the associations between subgroup membership and neuroimaging measures, adjusting for age, sex, and years of education. Based on the LPA, three cognitive subgroups were identified: (1) high-average cognition (n = 61, 36%), (2) average cognition (n = 88, 53%), and low-average cognition (n = 18, 11%). Compared to the high-average group, the low-average group had lower volumes in cortical regions sensitive to Alzheimer's disease, lower global white matter microstructural integrity measured by diffusion tensor imaging, and higher global white matter hyperintensity burden. There were no group differences in global PET amyloid burden. Additionally, the high-average group tended to have higher resting-state functional connectivity within large-scale cognitive networks than the other two groups. These results suggest that cognitively-defined subgroups among older adults without dementia are associated with several measures of brain structure and function. Evaluating brain structure/function differences among dementia-free older adults may help identify individuals at greatest risk for future cognitive decline. Show less

In the March issue of the Journal in 2012, we reported on a girl with Langer-Giedion syndrome (LGS) phenotype and a 7.5 Mb interstitial deletion at 8q23.3q24.13, encompassing the EXT1, but not the TRPS1 gene. Recent discoveries have shown that heterozygous intragenic mutations or contiguous gene deletions including the RAD21 gene, which is located downstream of the TRPS1 gene, are the cause of Cornelia de Lange syndrome-4. Considering that the interstitial deletion in our patient included the RAD21 and 30 other RefSeq genes, we would like to suggest a revision of the diagnosis reported in our previous paper and compare our patient to other reported patients with Cornelia de Lange syndrome-4 caused by heterozygous deletions of chromosome 8q24. © 2015 Wiley Periodicals, Inc. Show less

Langer-Giedion syndrome (LGS) is a contiguous gene syndrome caused by a hemizygous deletion on chromosome 8q23.3-q24.11 involving TRPS1 and EXT1 genes. We report on a girl with LGS phenotype and a 7.5 Mb interstitial deletion at chromosome 8q23.3-q24.13. Array-comparative genomic hybridization (a-CGH) revealed a deletion encompassing only the EXT1 and not the TRPS1 gene. Even though the deletion of TRPS1 and EXT1 genes is responsible for craniofacial and skeletal features of LGS, there have been previous reports of patients with LGS phenotype and 8q24 deletions leaving the TRPS1 gene intact. To our knowledge, this is the third such case. Our patient differs from previously reported LGS patients without TRPS1 gene deletion in that she has the typical LGS facial dysmorphism and skeletal abnormalities. However, the girl is of normal height and has only a mild developmental delay. Additionally, she has dyslalia and premature adrenarche classified as Tanner stage 3 premature pubarche which have not yet been described as features of LGS. We examine the molecular breakpoints and phenotypes of our patient and previously reported cases. Show less

To identify sepsis-related dysregulations of protein expression in the liver, we used a baboon model of acute endotoxemia and performed comparative proteome analysis. Treatment with lipopolysaccharide (LPS) was followed by an early but long-lasting (5-48 h) generation of N-terminal fragments of carbamoyl phosphate synthase-1 (CPS-1), an abundant enzyme of the hepatic urea cycle, which is normally located in the mitochondrial matrix. In addition, we developed a new sandwich immunoassay to determine circulating CPS-1 in human and baboons. We found CPS-1 to be induced by LPS and to be released into the circulation of healthy humans and baboons as early as 4 to 5 h after stimulation. Similarly, CPS-1 levels increased after injection of gram-positive bacteria in another baboon model. Enhanced CPS-1 levels were also detected in serum of patients with sepsis. Our data demonstrate fragmentation of CPS-1 in the liver and early increase in circulating CPS-1 levels under septic conditions. We suggest that circulating CPS-1 might serve as a novel serum marker indicating mitochondrial impairment of the liver and/or the small intestine in critically ill patients. Show less