1Department of Integrated Biosciences, Graduate School of Frontier Sciences, and 2Department of Applied Biochemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan 3Graduate School of Systems Life Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan 4Integrative Brain Imaging Center (IBIC), National Center of Neurology and Psychiatry, Tokyo, Japan
In a previously reported double-blind, randomized controlled trial (RCT), we demonstrated that daily supplementation with anserine (750 mg) and carnosine (250 mg) improves brain blood flow and memory function in elderly people. Here, we conducted a sub-analysis of MRI data and test scores from the same RCT to determine whether anserine/carnosine supplementation specifically benefits elderly people carrying the APOE e4 allele, which is a risk gene for accelerated brain aging and for the onset of Alzheimer’s Disease. We collected data from 68 participants aged 65 years or older who received anserine/carnosine supplementation (ACS) or placebo for 12 months. Subjects were assessed at the start and end of the trial using several neuropsychological tests, including the Wechsler Memory Scale-Logical Memory (WMS-LM). We also collected two types of MRI data, arterial spin labeling (ASL) and diffusion tensor imaging (DTI) at the start and end of the trial. We found that ACS significantly preserved verbal memory (WMS-LM, F[1,65] = 4.2003, p = 0.0445) and blood flow at frontal areas of the brain (FWEcluster level, p < 0.001). Sub-analysis based on the APOE4 genotype showed a significant preservation of blood flow (p = 0.002, by ASL analysis) and white-matter microstructure (p = 0.003, by DTI analysis) at prefrontal areas in APOE4+ subjects in the active group, while there was no significant difference between APOE4- subjects in the active and placebo groups. The effect of ACS in preserving brain structure and function in elderly people carrying APOE4 should be verified by further studies.
Ding Qiong,Tanigawa Kitora,Kaneko Jun, et al. Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4[J]. Aging and disease,
2018, 9(3): 334-345.
Figure 1. Longitudinal changes in WMS-LM2 scores. A box plot of the WMS-LM2 data in Table 2 for subjects in the active (n = 30) and placebo (n = 37) groups. Each black dot indicates the difference between the first and final test scores for one volunteer. Box shows the 25-75 percentile, and solid bar shows the median. (One subject in the active group could not complete the final WMS-LM2 test.)
Active group
Placebo group
p value
Age
71.3 (4.8)
71.8 (4.8)
0.70
Gender (M/F)
14/17
15/22
0.61
BMI
22.1 (2.1)
21.9 (2.3)
0.67
Education, years
14.7 (2.0)
14.3 (3.1)
0.52
APOE4+ / APOE4-
8/23
4/33
0.09
Table 1 Characteristics of participants in a 12-month RCT of ACS.
Figure 2. Longitudinal changes in WMS-LM2 scores at the mid-term test. A box plot of the change of WMS-LM2 story A data (the score of 6-month test - the score of the initial test) in the active and placebo groups. Each black dot indicates the difference between the first and final test scores for one volunteer. Box shows the 25-75 percentile, and solid bar shows the median.
APOE4+ group
APOE4- group
E4/E4
E4/E3
E4/E2
E3/E3
E3/E2
E2/E2
Active
1
7
0
23
0
0
Placebo
2
2
0
33
0
0
Table 2 Subjects grouped by APOE genotype.
Figure 3. Longitudinal changes in brain perfusion. Brain blood flow was analyzed by ASL. Color indicates regions where changes in brain perfusion differed between the two groups (n = 31 active, 37 placebo). After repeated two-way ANOVA in SPM, the biggest difference was at (x, y, z) = (3, -1, -10) in Montreal Neurological Institute (MNI) coordinate, T=4.09; other two locations were (x, y, z) = (-30, 11, -37) and (24, 11, -43). SPM statistics showed significance between Active and Placebo (Active > Placebo). P(FWE-corr) < 0.001, KE=2857 voxels. Note that the brain locations of the preservation of blood flow by ACS included both sides of temporal lobes, orbitofrontal cortices, dorsolateral prefrontal cortices and anterior cingulate cortices.
Food
Active Group Ave.±SEM
Placebo Group Ave.±SEM
p value
Anserine
Poultry (656mg/80g)
120.9±17.6
132.6±17.2
0.37
(mg/day)
Pork (18.4mg/80g)
5.1±0.7
4.9±0.6
0.66
Beef (43mg/80g)
6.2±1.2
6.4±1.3
0.79
Red meat Fish (304mg/80g)
77.1±10.9
71.6±8.9
0.5
Blue back Fish (5.6mg/80g)
1.6±0.2
1.6±0.2
0.9
White Fish (2.3mg/80g)
130.0±23.4
145.1±25.2
0.39
Eel (0mg/80g)
0±0
0±0
N.D.
Anserine(Total)
340.9±38.7
362.2±342.1
0.46
Carnosine
Poultry (184mg/80g)
33.9±4.9
37.2±4.8
0.37
(mg/day)
Pork (246mg/80g)
68.8±9.5
65.7±7.9
0.66
Beef (209mg/80g)
30.0±6.0
31.1±6.1
0.79
Red meat Fish (24mg/80g)
6.1±0.9
5.6±0.7
0.5
Blue back Fish (152mg/80g)
43.5±5.9
44.0±5.2
0.9
White Fish (0mg/80g)
0±0
0±0
N.D.
Eel (336mg/80g)
7.3±0.8
7.6±0.7
0.65
Carnosine(Total)
189.6±17.3
191.3±17.3
0.89
Table 3 Anserine/carnosine intake from the dieta
Figure 4. ACS preserves blood flow in the prefrontal brain of elderly people. Location of differential longitudinal changes in brain perfusion (red) in the active and placebo groups, on a brain montage from the SPM platform based on equivalent calculations to those in Fig. 3. In the active group, blood flow in these areas was elevated in the follow-up MRI scan.
Figure 5. Longitudinal changes in brain perfusion in APOE4+ subjects, assessed by ASL. Color indicates brain regions with differences in longitudinal changes in brain perfusion between the active (n = 8) and placebo (n = 4) groups. After repeated two-way ANOVA in SPM, the biggest difference was at (x, y, z) = (-3, 44, -16), T=9.03. SPM statistics showed significance between Active and Placebo (Active > Placebo). P(FWE-corr) = 0.002, KE=378 voxels.
Figure 6. Longitudinal changes in FA (fraction anisotropy) values in APOE4+ subjects, assessed by DTI. Color indicates areas of the brain where FA values differed between the active (n = 8) and placebo (n = 4) groups. After repeated two-way ANOVA in SPM, the biggest difference was at (x, y, z) = (-32, 32, -4), T=5.75; other two locations were (x, y, z) = (-38, 44, 8) and (-50, 36, 18). SPM statistics showed significance between Active and Placebo (Active > Placebo). P(FWE-corr) = 0.003, KE=754 voxels.
1st test
Follow-up
Change
Active
Placebo
Active
Placebo
Active
Placebo
p value
WMS-LM-1a
13.3 (3.9)
15.0 (3.7)
14.3 (3.9)
14.3 (4.4)
0.93 (2.8)
-0.65 (3.6)
0.054
WMS-LM-2a
12.6 (4.0)
14.3 (3.9)
13.3 (3.9)
13.5 (4.4)
0.73 (2.9)
-0.84 (3.3)
0.044*
MMSEb
27.5 (1.7)
27.6 (1.9)
28.2 (2.4)
28.5 (1.7)
0.74 (2.0)
0.92 (1.9)
0.53
ADASb
9.3 (5.5)
8.2 (4.2)
7.9 (4.6)
6.8 (4.4)
-1.4 (3.5)
-1.4 (3.3)
0.92
SF-36 PCSb
48.0 (7.7)
49.1 (6.6)
45.8 (10.2)
48.1 (5.8)
-2.2 (7.5)
-1.0 (6.1)
0.45
SF-36 MCSb
54.3 (4.7)
52.8 (5.8)
56.8 (6.9)a
52.4 (7.0)
2.3 (7.0)
-0.4 (7.4)
0.13
BDIb
8.2 (6.7)
6.8 (4.3)
8.0 (6.2)
7.2 (5.8)
-0.1 (3.7)
0.4 (4.5)
0.60
Table 4 Changes in psychological test scores in the active and placebo groups.
Figure 7. Tract-graph analysis of APOE4/E4 subject (#75) in the active group. Top panel shows a seed ROI (x, y, z) = (-30, 30, -4), Sphere Radius = 3.00 mm. Middle panel: a tract-graph using this spherical seed ROI at the start-up scan (Pre). Bottom panel: a tract-graph using this spherical seed ROI at the follow-up scan (Post). Note the longer tract (green) toward the frontal pole seemed to be stronger at the follow-up scan.
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2018,
Vol. 9
