Background Behind The LDN-193189 Successes

Discussion In older adults with MCI and IR, 6 months of PIO had no apparent effect on cognitive performance relative to CON. Six months of EET also had no apparent effect on cognitive performance relative to CON, although the high attrition and lack of training effect in the EET group limits the interpretation of these results. To our knowledge, this pilot study is the first to examine both of these interventions in a rigorous randomized controlled trial in a population at high risk for cognitive decline by virtue of having both diglyceride MCI and IR. TZDs are agonists of the peroxisome proliferator-activated receptor-�� (PPAR-��) that decrease plasma insulin and glucose, and improve insulin sensitivity [21]. TZDs also have ancillary properties that make them an attractive potential therapy for the prevention or delay of cognitive decline and AD. Specifically, TZDs have been shown to decrease markers of inflammation and promote vasodilation in humans [21]. Recent evidence suggests that PPAR-�� agonists may also reduce accumulation and increase clearance of this website ��-amyloid [54]. Two studies of rosiglitazone have found improvements in some areas of cognitive function in participants with aMCI and mild to moderate AD [23,24]. However, more recent studies failed to find any effect of rosiglitazone on cognition in participants with mild to moderate AD either as monotherapy [55] or as an adjunct to treatment with cholinesterase inhibitors [56]. To our knowledge, only 2 other groups have studied the effects of PIO on cognition in participants with MCI or AD. One group reported improvements in the ADAS-Cog and WMS-R logical memory in participants with mild to moderate AD or aMCI and noninsulin-dependent type 2 diabetes who received PIO for 6 months (15-30 mg daily) compared find more with placebo in a randomized open controlled study [25,26]. A second double-blind randomized controlled trial of the safety of PIO (up to 45 mg daily) in nondiabetic participants with probable AD found that PIO was well tolerated over an 18-month period, but had no effect on the secondary cognitive outcomes [57]. To our knowledge, ours is the first study to rigorously investigate the mechanistic role of IR in cognitive decline. We found that PIO significantly improved IR but not cognitive function. Although GDR determined by hyperinsulinemic-euglycemic clamp is the gold standard for assessing insulin sensitivity, there is no accepted cutoff value for determining IR; rather, GDR exists on a spectrum from extremely sensitive to extremely resistant. A GDR of