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• W2895879937 abstract "Dysfunctional glucose and lipid metabolism may be key drivers underlying pathological pathways ultimately resulting in Alzheimer's disease (AD). The family of peroxisome proliferator activated receptors (PPARs), consisting of alpha, delta, and gamma are each distinct nuclear receptors that transcriptionally activate metabolic pathways critical to insulin signaling, fatty acid, cholesterol and protein metabolism. Recent clinical trials with PPAR-gamma agonists (rosiglitazone and pioglitazone) to effect cognitive improvement have not succeeded. Limited brain expression of PPAR-gamma, poor blood brain barrier penetration, and pharmacokinetic properties, may underlie their lack of clinical effect. T3D-959 is novel, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta potency. Ubiquitous brain expression of PPAR-delta, its critical role in regulating glucose and lipid metabolism and phenotype of PPAR-delta null mice motivated an exploratory Phase 2a clinical trial (NCT02560753) examining the effects of T3D-959 in patients with mild-to-moderate AD. Thirty-six patients with mild-to-moderate AD were orally administered 3, 10, 30, or 90mg of T3D-959 daily for 14 days. The relative CMRgl in AD-effected regions and brain reference regions was measured by FDG-PET at the beginning and end of treatment and analysis of plasma metabolome. Cognitive function was assessed by ADAS-Cog11 and DSST. ApoE genotype was obtained on all subjects. FDG-PET demonstrated that T3D-959 effected changes in brain glucose uptake in a dose-dependent fashion, and may increase relative glucose uptake in AD-vulnerable regions. Cognitive evaluation by ADAScog11 demonstrated that all ApoE4-negative patients improved (4.8-6.1 points) at low-to-mid (3-30mg) doses, ApoE4-positive patients improved (1-3.5 points) at mid-to-high 30-90mg doses. DSST results showed average improvement of 2.4 points in moderate AD subjects, and 7.0 points in mild subjects, irrespective of genotype or dose. Results suggest that agonist stimulation of PPAR delta may be an effective therapeutic strategy addressing dysfunctional metabolism underlying Alzheimer's disease. While efficacy observations are limited by the short duration of drug exposure, small numbers of patients and open-label design, the combined pharmacological changes observed in the brain (FDG-PET) and periphery (metabolome) combined with apparent neuropsychological improvements (ADAS-cog11 and DSST), justify further clinical testing in a larger and longer randomized placebo-controlled trial." @default.
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• W2895879937 date "2018-07-01" @default.
• W2895879937 modified "2023-10-16" @default.
• W2895879937 title "O1‐12‐04: EFFECTS OF A PPAR DELTA/GAMMA AGONIST, T3D‐959, ON METABOLIC AND COGNITIVE FUNCTIONS IN MILD TO MODERATE ALZHEIMER'S DISEASE SUBJECTS" @default.
• W2895879937 doi "https://doi.org/10.1016/j.jalz.2018.06.2399" @default.
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