Introduction: A critical and as-yet unmet need in Alzheimer’s disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. Methods: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. Results: Eight metabolites were associated with amyloid b and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. Discussion: PFAMs have been found increased and associated with amyloid b burden in CSF and clinical measures.
NFAT5 is induced and translocates to the nucleus in HLECs undergoing hyperosmolar stress through activation of p38. IL-1 beta and TNF-alpha are induced via NFAT5 activation. Our data collectively indicate that NFAT5 may be an important gene regulator and survival factor in hyperosmolar stressed HLECs.
We recently showed that Alzheimer's disease patients have lower plasma concentrations of the phosphatidylcholines (PC16:0/20:5; PC16:0/22:6; and PC18:0/22:6) relative to healthy controls. We now extend these findings by examining associations between plasma concentrations of these PCs with cognition and brain function (measured by regional resting state cerebral blood flow; rCBF) in non-demented older individuals. Within the Baltimore Longitudinal Study of Aging neuroimaging substudy, participants underwent cognitive assessments and brain (15)O-water positron emission tomography. Plasma phosphatidylcholines concentrations (PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6), cognition (California Verbal Learning Test (CVLT), Trail Making Test A&B, the Mini-Mental State Examination, Benton Visual Retention, Card Rotation, and Fluencies-Category and Letter), and rCBF were assessed. Lower plasma phosphatidylcholine concentrations were associated with lower baseline memory performance (CVLT long delay recall task-PC16:0/20:5: -2.17-1.39-0.60 p = 0.001 (β with 95% confidence interval subscripts)) and lower rCBF in several brain regions including those associated with memory performance and higher order cognitive processes. Our findings suggest that lower plasma concentrations of PC16:0/20:5, PC16:0/22:6, and PC18:0/22:6 are associated with poorer memory performance as well as widespread decreases in brain function during aging. Dysregulation of peripheral phosphatidylcholine metabolism may therefore be a common feature of both Alzheimer's disease and age-associated differences in cognition.
Type 2 diabetes is a multifactorial disease with multiple underlying aetiologies. To address this heterogeneity, investigators of a previous study clustered people with diabetes according to five diabetes subtypes. The aim of the current study is to investigate the etiology of these clusters by comparing their molecular signatures. In three independent cohorts, in total 15,940 individuals were clustered based on five clinical characteristics. In a subset, genetic (N = 12,828), metabolomic (N = 2,945), lipidomic (N = 2,593), and proteomic (N = 1,170) data were obtained in plasma. For each data type, each cluster was compared with the other four clusters as the reference. The insulin-resistant cluster showed the most distinct molecular signature, with higher branched-chain amino acid, diacylglycerol, and triacylglycerol levels and aberrant protein levels in plasma were enriched for proteins in the intracellular PI3K/Akt pathway. The obese cluster showed higher levels of cytokines. The mild diabetes cluster with high HDL showed the most beneficial molecular profile with effects opposite of those seen in the insulin-resistant cluster. This study shows that clustering people with type 2 diabetes can identify underlying molecular mechanisms related to pancreatic islets, liver, and adipose tissue metabolism. This provides novel biological insights into the diverse aetiological processes that would not be evident when type 2 diabetes is viewed as a homogeneous disease.
Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 21min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10−12) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.
In our study, not all patients required surgical removal of the implants. Repositioning the implant back into the vitreous cavity may be considered as an option in cases involving the first episode with no significant corneal endothelial decompensation. Considering potential anterior segment complications and the loss of drug effectiveness together, an individualized approach is recommended to obtain the best treatment outcomes and to minimize the risk of corneal complications.
Biomarker tests of Alzheimer’s disease (AD) are invasive and expensive. Recent developments in optical coherence tomography (OCT) and OCT angiography (OCTA) have enabled noninvasive, cost-effective characterization of retinal layer vasculature and thickness. Using OCTA and OCT, we characterized retinal microvascular changes in the mild cognitive impairment (MCI) stage of AD and assessed their correlation with structural changes in each retinal neuronal layer. We also evaluated the effect of the APOE-ε4 genotype on retinal microvasculature and layer thickness. Retinal layer thickness did not differ between MCI patients (40 eyes) and controls (37 eyes, all p > 0.05). MCI patients had lower vessel density (VD) (p = 0.003) of the superficial capillary plexus (SCP) and larger foveal avascular zone area (p = 0.01) of the deep capillary plexus (DCP) than those of controls. VD of the SCP correlated with the ganglion cell layer (r = 0.358, p = 0.03) and inner plexiform layer thickness (r = 0.437, p = 0.007) in MCI patients. APOE-ε4-carrying MCI patients had a lower VD of the DCP than non-carriers (p = 0.03). In conclusion, retinal microvasculature was reduced in patients with AD-associated MCI, but retinal thickness was not changed; these changes might be affected by the APOE genotype. OCTA of the retinal microvasculature may be useful to detect vascular changes in AD.
Aims To investigate the effect of intravitreal dexamethasone implant (IVD) on central foveal thickness (CFT), choroidal thickness (CT) and its correlation with visual acuity in eyes with refractory diabetic macular oedema (DMO). Methods This was a retrospective interventional case-series. Thirty-five eyes of 35 patients were treated with a single injection of IVD because of refractory DMO with CFT over 300 μm, and persistent intraretinal and subretinal fluid despite of multiple intravitreal bevacizumab injections. Patients were followed-up for 6 months for the evaluation of CFT and subfoveal CT by spectral-domain optical coherence tomography. Results All eyes (mean age: 59.4 ± 12.35 years; 18 males, 17 females) had been previously treated with multiple bevacizumab injections and showed persistent DMO (mean number of injections 4.08 ± 2.98) The preoperative logMAR BCVA was 0.49 ± 0.24, which gradually improved to 0.46 ± 0.32 at 6 months (P = 0.652) and 26% gained two or more lines of Snellen visual acuity. At baseline, the mean CFT was 526.29 ± 123.48 μm, which significantly improved to 316.15 ± 100.09 μm at 3 months (Po0.001). However, CFT deteriorated to 457.07 ± 136.53 μm at 6 months (P = 0.051). Similarly, the mean preoperative subfoveal CT was 288.91 ± 36.47 μm and it decreased to 266.85 ± 30.93 μm at 3 months (Po0.01), but increased to 278.63 ± 32.55 μm at 6 months (P = 0.137). The reduction of CFT from baseline showed significant correlation with that of subfoveal CT at 3 months (P = 0.041) and at 6 months (P = 0.008). Conclusions In DMO refractory to multiple bevacizumab injections, IVD significantly reduced CFT and subfoveal CT, with BCVA improvement in one-fourth of the patients. The reduction of CFT showed significant correlation with reduction of subfoveal CT.
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