Use of Ketogenic Compounds for Treatment of Age-Associated Memory Impairment

Abstract

This invention relates to the field of therapeutic agents for the treatment of Age-Associated Memory Impairment (AAMI). In particular, the present invention utilizes compositions comprising at least one compound capable of elevating ketone body concentrations in a mammal (e.g., ketogenic compounds), administered in an amount effective for treatment or prevention of loss of cognitive function caused by reduced neuronal metabolism in AAMI. In one embodiment, the composition includes medium chain triglycerides (MCT). In another embodiment, the compositions are administered in the presence of carbohydrate. The present invention also relates to oral dosage forms, in particular, a nutritional drink comprising at least one compound capable of elevating ketone body concentrations in a mammal.

What is claimed is: 
     
         1 . A method of treatment for Age-Associated Memory Impairment (AAMI), comprising administration comprising the steps of:
 identifying a mammal having AAMI; and   administering to the mammal a composition comprising a compound selected from the group consisting of acetoacetate, D-β-hydroxybutyrate, an ester of acetoacetate, and an ester of D-β-hydroxybutyrate, wherein the compound is effective to induce hyperketonemia, in an amount effective for the treatment of AAMI.   
     
     
         2 . The method of  claim 1 , wherein the compound is an ester of a compound selected from the group consisting of D-β-hydroxybutyrate and acetoacetate and a compound selected from the group consisting of a monohydric, dihydric, or trihydric alcohol. 
     
     
         3 . The method of  claim 2 , wherein the compound is a trihydric alcohol ester of D-β-hydroxybutyrate or a trihydric alcohol ester of acetoacetate. 
     
     
         4 . The method of  claim 3 , wherein the compound comprises a glycerol ester of acetoacetate or a glycerol ester of D-β-hydroxybutyrate. 
     
     
         5 . The method of  claim 4 , wherein the compound is acetoacetylglycerol. 
     
     
         6 . The method of  claim 2 , wherein the compound is a dihydric alcohol ester of D-β-hydroxybutyrate or a dihydric alcohol ester of acetoacetate. 
     
     
         7 . The method of  claim 6 , wherein the compound comprises R-1-3-butanediol ester of acetoacetate or R-1,3-butanediol ester of D-β-hydroxybutyrate. 
     
     
         8 . The method of  claim 1 , wherein the composition further comprises glucose. 
     
     
         9 . The method of  claim 1  wherein the composition increases the circulating concentration of at least one type of ketone body in the mammal. 
     
     
         10 . The method of  claim 9 , wherein the amount of D-β-hydroxybutyrate is raised in the blood of the mammal. 
     
     
         11 . The method of  claim 10 , wherein the amount of D-β-hydroxybutyrate is raised to between about 0.1 millimolar to about 10 millimolar at about two hours post administration. 
     
     
         12 . The method of  claim 10 , wherein the amount of D-β-hydroxybutyrate is raised to between about 0.15 millimolar to 0.3 millimolar at about two hours post administration. 
     
     
         13 . The method of  claim 10  wherein urinary excretion level of D-β-hydroxybutyrate is from about 5 to about 160 mg/dL. 
     
     
         14 . The method of  claim 1  wherein the composition is administered at a dose of about 0.05 g/kg/day to about 10 g/kg/day. 
     
     
         15 . The method of  claim 1  wherein the composition is administered at a dose of about 0.1 g/kg/day to about 2 g/kg/day. 
     
     
         16 . The method of  claim 1 , wherein the composition is a ready-to-drink beverage, powdered beverage formulation, nutritional or dietary supplement selected from the group consisting of gelatin capsule or tablet, suspension, parenteral solution, or a food product formulated for human consumption. 
     
     
         17 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         18 . The method of  claim 1 , wherein the administering step is on a regular basis comprising at least once daily. 
     
     
         19 . The method of  claim 1 , comprising the further step of determining the ApoE status of the mammal and selecting the mammal for treatment if the mammal is ApoE4(−). 
     
     
         20 . The method of  claim 7 , wherein efficacy for treatment of AAMI is determined by results from at least one neuropsychological test. 
     
     
         21 . The method of  claim 20 , wherein the neuropsychological test is selected from the group consisting of Clinical Global Impression of Change (CGIC), Rey Auditory Verbal Learning Test (RAVLT), First-Last Names Association Test (FLN), Telephone Dialing Test (TDT), Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol Digit Coding (SDC), SDC Delayed Recall Task (DRT), Divided Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), and Geriatric Depression Scale (GDS).