P1‐296: ALTERNATIVE CEREBRAL GLUCOSE UPTAKE METRICS DETECT EARLY METABOLIC CHANGES IN THE 5XFAD MOUSE MODEL OF ALZHEIMER'S DISEASE

this study, we shed a light on functional dipeptides from animal meat, imidazole dipeptide: carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-1-methyl-L-histidine). Since, recent animal studies have suggest the beneficial effects of these dipeptides on type 2 diabetes mellitus (T2DM), depression, and physical inactivity, risk factors on AD prevalence. In a previous study, we have also demonstrated that carnosine treatment ameliorated the cognitive decline occurring in a mouse model for T2DM/AD (Herculano et al., (2013) J. Alzheimer’s Disease). It might be more importantly, the daily consumption of animal meats in Japanese elderly people gradually decrease as age progresses. It is a hope that the encouragement of the consumption of low-fat animal meat, such as chicken breast, may lead to the reduction of AD prevalence in Japan. Methods: Healthy participants (40-84 ages) were recruited from June 2012 to September 2013 from Tokyo metropolitan area. Participants were required a willing to three visits during 3-month study period. Written informed consent was obtained from participants. Exclude criteria is following: 1) those who have a neuropsychiatric disorder or head injury. 2) having local lesions, such as a brain tumor or cerebral infarction, which affects a cognitive function by first-time MRI, are found. 3) having the metal or electrical conductivity is contained, or a problem arises at the time of an MRI image pick-up for claustrophobia. Participants were randomized to twice-daily doses of imidazole dipeptide formula (IDF, including 500 mg in total (carnosine:anserine1⁄41:3) from chicken, Nippon Meat Packers Inc., Japan), or an identical-appearing placebo (just including equivalent amount of essential amino acid in IDF, L-histidine (150 mg) and lysine (43 mg)), in a granular format for 3-months. Assignment to dipeptide or placebo was determined by age and gender. All clinical and coordinating personnel and participants were blinded to treatment assignment for the duration of study, with the exception of safety monitoring board. All MR experiments were performed in a 3 T scanner (Siemens, MAGNETOM Verio). rs-fMRI data from 120 EPI images was analyzed by SPM8 and its extension, REST. For the functional connectivity (FC) analysis, we put ROI at either the right or the left hippocampal formation (x,y,z 1⁄4 þ30, -12, -19 in MNI axis). We took structural MRI (3D T1-WI), for VBM analysis and spatial normalization. Neuropsychological and Behavioral test batteries (MMSE, ADAScog, computer-based memory assessment (CANTAB test), Beck Depression Inventory (BDI), and SF-36v2 Health Survey) was administered at the beginning, 1.5 month or 3 month visit. Participants were also corrected their blood sample for regular biochemical blood test, cytokine analysis, and DNA microarray analysis in each visit. Results: Participants randomized to either placebo (n1⁄413, 64.3+10.7, F/M1⁄48/5) or IDF (n1⁄415, 59.1+13.3, F/M1⁄410/5). In the FC analysis of the ROI with the whole right hippocampus, we detected the significant increase in the coupled activity at the anterior cingulated cortex (Brodmann Area 24) in IDFgroup, but not in placebo-group, when compared between the 3-month scan and the first scan before the intervention (P<0.003, voxel threshold>150). In the FC analysis with the left hippocampus ROI, we detected the significant increase in the coupled activity at the both side of temporal cortex and the right side of insular cortex in IDF-group, but not in placebo-group. In the VBM analysis, we detected the significant increase (P<0.005 uncorrected, voxel threshold 15) in the white matter (near posterior cingulated cortex x,y,z 1⁄4 -12, -54, 12, P<0.005 uncorrected, voxel threshold 15) as well as in thegray matter (at the left prefrontal cortex x,y,z 1⁄4 -48, 30, 6, and at the right temporal cortex x,y,z 1⁄4 60, -56, -10, P<0.001) in IDF-group, but no increase in placebo-group. In other test, we detected a trend of decrease in BDI score and blood glucose level in IDF-group, but not in placebo-group. We detected the decrease in inflammatory cytokines after the treatment of IDF, and the changes in the expression of many SLC family proteins. On ADAScog test, we detected a difference of participants with the improvement of score (>3) between IDF-group (5/15) and placebo-group (1/13) (Chi-square one-tailed P value 1⁄40.0496). Conclusions: For the future development of food-based preventive interventions for AD, in this study, we performed a small-scale pilot study to test the effect of functional dipeptide, imidazoledipeptide: carnosine and anserine, on the cognitive function as well as the functional connectivity of hippocampus-related circuit. We detected the clear significant increase in the hippocampal functional connectivity in the treatment group after resting-state fMRI analysis, as well as the particular increase in both the gray matter and the white matter volume. In addition, we observed a trend toward cognitive improvement in the treatment group by ADAScog test. Taken together data from animal model experiments into consideration, the part of this beneficial effect of imidazoledipeptide may stem from its direct effect on brain GABAergic system through hippocampal GABA transporters, which would affect on neuroinflammation as well as synaptic transmission.