TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex.

BACKGROUND: Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. MATERIALS AND METHODS: To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF-/-) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF-/- mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. RESULTS: TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. CONCLUSION: TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.

Cognitive tests for the detection of mild cognitive impairment (MCI), the prodromal stage of dementia: Meta-analysis of diagnostic accuracy studies.

INTRODUCTION: Mild cognitive impairment (MCI) is regarded as a prodrome to dementia. Various cognitive tests can help with diagnosis; meta-analysis of diagnostic accuracy studies would assist clinicians in choosing optimal tests. METHODS: We searched online databases for "mild cognitive impairment" and "diagnosis" or "screening" from 01/01/1999 to 01/07/2017. Articles assessing the diagnostic accuracy of a cognitive test compared with standard diagnostic criteria were extracted. Risk of bias was assessed. Bivariate random-effects meta-analysis was used to evaluate sensitivity and specificity. RESULTS: Eight cognitive tests (ACE-R, CERAD, CDT-Sunderland, IQCODE, Memory Alteration Test, MMSE, MoCA, and Qmci) were considered for meta-analysis. ACE-R, CERAD, MoCA, and Qmci were found to have similar diagnostic accuracy, while the MMSE had lower sensitivity. Memory Alteration Test had the highest sensitivity and equivalent specificity to the other tests. DISCUSSION: Multiple cognitive tests have comparable diagnostic accuracy. The Memory Alteration Test is short and has the highest sensitivity. New cognitive tests for MCI diagnosis should not be compared with the MMSE.