Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.

Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.

Obesity-induced changes in lipid mediators persist after weight loss.

BACKGROUND: Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated. SUBJECTS/METHODS: We fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma. RESULTS: We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD2, and downstream metabolites 15-deoxy PGJ2 and delta-12-PGJ2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss. CONCLUSIONS: These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight.