Prophylactic inhibition of soluble epoxide hydrolase delays onset of nephritis and ameliorates kidney damage in NZB/W F1 mice

Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease

Association between composite scores of domain-specific cognitive functions and regional patterns of atrophy and functional connectivity in the Alzheimer's disease spectrum

Background: Cognitive decline has been found to be associated with gray matter atrophy and disruption of functional neural networks in Alzheimer's disease (AD) in structural and functional imaging (fMRI) studies. Most previous studies have used single test scores of cognitive performance among monocentric cohorts. However, cognitive domain composite scores could be more reliable than single test scores due to the reduction of measurement error. Adopting a multicentric resting state fMRI (rs-fMRI) and cognitive domain approach, we provide a comprehensive description of the structural and functional correlates of the key cognitive domains of AD. Method: We analyzed MRI, rs-fMRI and cognitive domain score data of 490 participants from an interim baseline release of the multicenter DELCODE study cohort, including 54 people with AD, 86 with Mild Cognitive Impairment (MCI), 175 with Subjective Cognitive Decline (SCD), and 175 Healthy Controls (HC) in the AD-spectrum. Resulting cognitive domain composite scores (executive, visuo-spatial, memory, working memory and language) from the DELCODE neuropsychological battery (DELCODE-NP), were previously derived using confirmatory factor analysis. Statistical analyses examined the differences between diagnostic groups, and the association of composite scores with regional atrophy and network-specific functional connectivity among the patient subgroup of SCD, MCI and AD. Result: Cognitive performance, atrophy patterns and functional connectivity significantly differed between diagnostic groups in the AD-spectrum. Regional gray matter atrophy was positively associated with visuospatial and other cognitive impairments among the patient subgroup in the AD-spectrum. Except for the visual network, patterns of network-specific resting-state functional connectivity were positively associated with distinct cognitive impairments among the patient subgroup in the AD-spectrum. Conclusion: Consistent associations between cognitive domain scores and both regional atrophy and networkspecific functional connectivity (except for the visual network), support the utility of a multicentric and cognitive domain approach towards explicating the relationship between imaging markers and cognition in the AD-spectrum