Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer’s disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.
These studies were designed to determine whether genetically and experimentally induced hypertriglyceridemia were correlated with hyperlipogenesis, and whether inhibiting fatty acid synthesis would reduce serum triglyceride levels. Hypertrigylceridemia, resulting from genetic obesity in Zucker rats and fructose feeding or Triton administration to Charles River rats, was examined in relation to in vivo rates of heatic fatty acid synthesis, and the influence of (--)-hydroxycitrate (a potent competitive inhibitor of ATP citrate lyase) on serum triglyceride levels and lipogenesis was determined. Zucker obese rats demonstrated significantly increased rates of fatty acid synthesis and levels of serum triglycerides compared to their lean litter mates; lipogenic rates and circulating triglycerides were reduced markedly by the oral administration of (--)-hydroxycitrate. Fructose administered in the diet or drinking water induced a hypertriglyceridemia which was associated with a marked increase in hepatic lipogenesis, and (--)-hydroxycitrate reduced significantly both parameters. In contrast to the significant role that increased rates of lipogenesis apparently played in the development of hypertriglyceridemia in the Zucker rat and fructose-fed rat, Triton given intravenously produced a marked rise in serum triglycerides which could not be accounted for, to an appreciate extent, by increased rates of fatty acid synthesis. (--)-Hydroxycitrate reduced serum triglyceride levels and hepatic lipogenic rates equivalently in the Triton-treated and nontreated rats.
Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later.
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