High protein diet and cognitive function -
The third group was asked to take a composition that did not contain any amino acids placebo control group, PCG. The participants in the PCG ingested the placebo containing cornstarch and lactose twice a day. All participants were asked to record their daily intake.
The duration of the intervention period was set at 12 weeks. Cognitive assessments and questionnaires on psychosocial and daily function were administered before composition intake pre and 12 weeks after composition intake post. The primary outcomes included the assessments of cognitive function.
The secondary outcomes included the evaluation of psychological and social functions and safety evaluations. All participants were interviewed to obtain data on their baseline characteristics, including age, gender, years of education, mental health using a Japanese version of the WHO-Five Well-Being Index [WHOJ 18 ], and functional capacity using the Tokyo Metropolitan Institute of Gerontology Index of Competence TMIG-IC The WHOJ is an index of psychological health developed by the WHO.
This scale consists of five items on a six-point Likert scale, which ask about mental status in the last 2 weeks. The answers for each item are assigned 0—5 points, and the total value is used as the score range: 0—25 , with higher scores indicating better mental health.
The TMIG-IC consists of 13 multidimensional items classified under three subscales of instrumental self-maintenance, intellectual activity and social role. The following tests were conducted to evaluate each cognitive domain: The Logical Memory LM I and II tests, Digit Span Test DST and Visual Memory Span Test VMST , all of which are subscales from the Wechsler Memory Scale Revised [WMS-R 20 , 21 ]; the Rey Auditory-Verbal Learning Test [AVLT 22 ]; the Trail Making Test TMT Part A and Part B 23 ; verbal fluency tests 24 ; and Similarities, which is a subtest of Wechsler Adult Intelligence Scale-III [WAIS-III 25 ].
The LM I and II tests are story recall tests that assess immediate and delayed verbal memory. These tests directly reflect everyday memory. The LM I test is an assessment of immediate memory. In this test, the examiner told a story, and participants were asked to recall the contents of the story immediately.
Then, the examiner told a second story, and participants recalled the story. The LM II test is an assessment of delayed memory; the participants were asked to recall the two stories 30 min after the stories were read. Scores were calculated by adding the number of elements of the story that were recalled.
The maximum score for both immediate and delayed recall is 50 points. Higher scores indicate better memory function. The DST was used to evaluate verbal memory function. The DST is the sum of forward Digit Span Forward; DSF and backward Digit Span Backward; DSB task subscales.
In the DSF, the participant is required to memorize and repeat a sequence of numbers. In the DSB, the participants are required to memorize a sequence and repeat it in reverse. The score ranges of the DST, DSF, and DSB are from 0 to 24, 0 to 12, and 0 to 12, respectively.
The VMST was used to evaluate visual memory function. The VMST is the sum of forward Visual Memory Span Forward; VMSF and backward Visual Memory Span Backward; VMSB task subscales.
In the VMSF, the examiner touches random square sequences shown on a test paper, and the participants are required to repeat this sequence.
In the VMSB, the participants are required to memorize and repeat the sequence in reverse. The score ranges for the VMST, VMSF, and VMSB are from 0 to 26, 0 to 14, and 0 to 12, respectively.
The AVLT was used to evaluate memory and learning function. In this test, 15 nouns list A were read by the examiner, followed by free recall by the participants five times consecutively. After the fifth recall, the examiner read another list of 15 new words, followed by free recall by the participants.
Then, the participants were asked to carry out free recall of list A immediate recall. Twenty minutes later, the participants were asked to again carry out free recall of list A delayed recall. TMT Part A TMT-A and Part B TMT-B were conducted to evaluate attention and executive function.
TMT-A especially evaluates processing speed of the attention, and TMT-B especially evaluates working memory. Working memory involved in the performance of TMT-B includes cognitive flexibility in executive function and divided attention and alternating attention Both parts of the TMT consisted of 25 scattered circles drawn on the examination paper.
In TMT-A, the circles were numbered from 1 to 25, and the participant was asked to draw lines to connect the numbers in order as quickly as possible.
In TMT-B, the circles included either numbers from 1 to 13 or the first 12 letters of the Japanese Hiragana alphabet. Participants were required to connect the numbers and letters alternately. Faster performance in these examinations indicates higher attention and executive function.
Perceptual-motor function is also involved in the TMT, as participants need to coordinate the processing of visual information with the rapid movement of their fingers. Verbal fluency tests in which participants are asked to generate as many words as possible according to prescribed cues within a minute were used as verbal function measurements.
The Similarities subtest of WAIS-III was conducted to evaluate language comprehension and logical categorical thinking ability. In this task, the examiner verbally presents two words with a common concept, and participants are asked how these words are similar.
The score range for this task is from 0 to Psychological and social functions were evaluated with WHOJ, SF 26 — 28 , the Japan Science and Technology Agency Index of Competence to Assess Functional Capacity [JST-IC 29 ], and the abbreviated version of the Lubben social network scale [LSNS-6 30 ] and based on the anxiety of forgetfulness.
SF was used to measure health-related QOL. SF is composed of 36 questions and, when scored, yields 8 domains. Ten items assess limitations in physical activities Physical functioning , 4 items assess problems with work or other daily activities as a result of physical health problems Role physical , 2 items assess limitations due to pain Bodily pain , 5 items assess personal health and the expectation of changes in health General health , 4 items measure energy and tiredness Vitality , 2 items examine the effect of physical and emotional health on normal social activities Social functioning , 3 items measure problems with work or other daily activities as a result of emotional problems Role emotional , and 5 items assess happiness, nervousness and depression Mental health.
All domains were scored from 0 to based on the Japanese national standard score, and higher scores showed better QOL. JST-IC was used to measure higher vital function.
LSNS-6 was used to assess social interaction and to screen for social isolation. Three of the LSNS-6 items relate to kinship ties, and the remaining three relate to non-kin ties. The total scale score is the sum of all items range: 0— Clinical laboratory values were measured before and after the intervention period to assess the safety of Amino LP7.
The following blood parameters were measured: white blood cell WBC count, red blood cell RBC count, hemoglobin Hb , hematocrit Ht , platelet count, total protein, albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total bilirubin, alkaline phosphatase, γ-glutamyl transpeptidase, urea nitrogen, creatinine, uric acid, sodium, chlorine, potassium, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, fasting plasma glucose concentration FPG , and glycated hemoglobin HbA1c.
To determine if the baseline concentrations of blood amino acids and metabolites changed, these concentrations were measured under fasting after the intervention. The urine parameters urine protein, urine glucose, and urine occult blood were measured before and after the intervention.
Systolic and diastolic blood pressure, pulse rate, and body mass index BMI measurements were conducted before and after intervention. The full study population was analyzed based on the intention-to-treat concept.
The main analysis was the analysis of covariance ANCOVA to compare the 3gIG and 6gIG to the PCG. The covariates were age, gender, education level, BMI, and diastolic blood pressure, which are expected to affect cognitive function, and the pre-value of each dependent variable.
In the subanalysis, one-way analysis of variance 1-way ANOVA was used to compare the PCG, 3gIG, and 6gIG. Statistical tests for each endpoint were conducted at the two-sided significance level of 0.
Multiple comparisons between groups were conducted using Dunnett's method. In this exploratory analysis, the effects of Amino LP7 were judged by both the estimates of mean differences and the statistical results because of the issue of statistical multiplicity between outcomes.
These interpretations of the statistical results were consistent with the view of the American Statistical Association In addition, we examined the probability that the obtained statistical results would appear in the situation where Amino LP7 was not effective and have discussed the interpretation of the results.
All statistical analyses were performed using R ver. The mean intake rate of the compositions was Two participants in the 6gIG group dropped out for health reasons unrelated to this study.
There were no significant differences observed in age, gender, education, MMSE-J, MoCA-J, WHOJ, and TMIG-IC among the three groups. As primary outcomes, scores of the dependent variables for cognitive function in each group are shown in Table 2.
The time of TMT-B in the 6gIG group improved by The results of other measurements of the cognitive function battery WMS-R, AVLT, verbal fluency, and WAIS-III were not significant between groups LM I, LM II, DSF, DSB, DST, VMSF, VMSB, VMST, AVLT immediate recall, AVLT delayed recall, TMT-A, verbal fluency tasks, Similarities.
Table 2. The mean scores and ANCOVA results of cognitive tests before and after intervention. Figure 2. TMT-B before and after intervention for each group. The mean values were plotted and the standard deviations were displayed as error bars.
As secondary outcomes, scores of the psychosocial function in each group are shown in Table 3. We conducted ANCOVA between groups for these dependent variables as well as the dependent variables for cognitive function.
The ANCOVA adjusted for multiplicity by Dunnett's method in the main analysis showed that the differences between the PCG and the 3gIG were not significant for any of the above variables.
For other measured variables, the effects of the group were not significant by ANCOVA SF Physical functioning, SF Role physical, SF Bodily pain, SF General health, SF Vitality, SF Social functioning, SF Role emotional, SF Mental health, JST-IC Technology usage, JST-IC Information Practice, JST-IC Life management, anxiety of forgetfulness.
Table 3. The mean scores and ANCOVA results of psychosocial functions before and after intervention. By comparing the 6gIG and PCG, 4 out of 32 outcomes, including primary and secondary outcomes, showed significant results.
In addition, these 4 outcomes showed consistently that the 6gIG showed a stronger effect than the PCG. There were no abnormalities or fluctuations in clinical laboratory values, urine laboratory test results, vital data or BMI that could lead to safety concerns.
The baseline concentrations of the seven essential amino acids included in this study did not increase under fasting. The assessment of safety was made through medical interviews with each subject, and no issues related to these interventions were reported.
The participants who dropped out from the 6gIG did not do so because of side effects of the intervention. The purpose of the present study was to examine the effect of intake of Amino LP7 on cognitive function as the primary outcome and psychosocial function as the secondary outcome in middle-aged and older adults.
The results demonstrated that attention and cognitive flexibility assessed by TMT-B was improved in the 6gIG, whereas no significant changes were observed in either the 3gIG or PCG.
An effect of intervention on TMT-B was observed, and the s improvement of 6gIG was similar to the intervention effects reported by previous intervention studies 32 , The faster performance of the TMT-B suggests the improvement of the ability to concentrate on the task, pay attention to multiple tasks and memorize information needed for doing tasks, which is related with working memory.
These results indicate that daily intake of 6 g of amino LP7 contributes to improved attention and executive function. In addition, psychological health and social interaction were also improved in the 6gIG group. A good WHOJ score indicates positive emotion cheerful, active, fresh, interesting and vigorous emotion , and expanding social networks indicate improved social interaction.
Although there was a potential limitation in the interpretation of the results because of multiple testing due to the study design, all 4 statistically significant results showed that Amino LP7 had positive effects only in the 6gIG.
These results suggested that 6gIG may have an effect on cognitive function. Two models can be considered for understanding why 6gIG was effective in improving attention and executive function and psychosocial function. The first model is that the intake of essential amino acids directly affects brain function through the transfer of amino acids to the brain.
The effect of the intervention on attention and executive function in the 6gIG suggests that the intake of Amino LP7 affected frontal lobe function. If the intake of Amino LP7 had an effect on improving general health, there should have been an improvement in processing speed, as seen in an exercise-based intervention Given that there was no change in processing speed and that the intervention had an effect on only working memory, intake of Amino LP7 perhaps had a specific positive effect on frontal lobe function.
The second model is that Amino LP7 brings about improvement in psychosocial function, and changes in behavior in daily life led to improvement in attention and executive function.
A study on social interactions showed that older people with more satisfactory interactions are at lower risk of developing dementia An intervention study focusing on social interactions showed improvements in verbal memory and working memory due to the acquisition of new intellectual skills that accompany social interaction In a study that examined the effects of social interaction among cognitive interventions, intervention via acquisition of new intellectual skills through analog games was found to affect visual working memory, and the effect increased with social interaction It is also possible that intake of Amino LP7 first improved psychological health, which in turn led to improved social interaction and attention and executive function.
Furthermore, it is possible that the two models mentioned above had a synergistic effect. No intervention effect was observed with 3gIG in either model, suggesting that additional doses of Amino LP7 were ineffective at low doses and that a dose of 6 g or more was required per day.
It is not possible to elucidate the mechanism based solely on the results of this study, which aimed to investigate the intervention effect of essential amino acid intake.
Our initial hypothesis regarding this composition, Amino LP7 8 , was based on the amino acid influx rate to the brain, which would reflect the requirement for each amino acid to maintain brain homeostasis against neurodegenerative processes; we composed a mixture of seven essential amino acids rich in leucine, phenylalanine, and lysine to directly match the ratios associated with the brain influx rate.
It is possible that Amino LP7 acts via multiple mechanisms, including neurotransmitter compensation 8 and competitive inhibition of neurotoxic substance influx into the brain. As the constituents of Amino LP7 have high rates of influx into the brain via specific transporters e. These metabolites are known to exert proinflammatory effects that induce neuroinflammation 40 , 41 , and thus, competitive inhibition of these neurotoxic metabolites may be involved in the efficacy observed herein.
To clarify the mechanism underlying the improvement in attention and executive function via ingestion of Amino LP7, it is necessary to measure neurotransmitters and brain inflammation in human studies.
As mentioned in the previous paragraph, the improvement of attention and executive function may be preceded by the improvement of psychosocial function. Of the seven amino acids used in this study, some amino acids such as tryptophan and phenylalanine may have antidepressant-like effects associated with mental health 42 , A study of community dwelling older adults in Japan found an association between frequency of going out and depression 44 , and it is possible that prevention of depressive mood caused by tryptophan intake activated daily activities.
In our study, the blood sample was collected under fasting condition to evaluate the safety of the intervention. Evaluating the dynamics of amino acid concentrations immediately after ingestion will help elucidate the mechanism in the future.
Based on the cognitive reserve hypothesis, it is possible to delay the onset of dementia by improving cognitive function in normal conditions 1 , Improvement of attention and executive function associated with frontal lobe function by ingestion of Amino LP7 may counteract not only the development of dementia due to Alzheimer's disease but also cognitive decline associated with aging.
It would be of great significance if actual behaviors could be transformed to positive ones for health via easily accessible interventions such as supplements. In the present study, it was possible to confirm the effect of intervention on attention and executive function, but there was no effect on learning function, which was observed in a previous study conducted in mice.
The reason for this lack of effect was that the participants in this study were healthy adults with no impairment in learning function. To examine the effect of essential amino acid intake on learning function, it may be necessary to perform the experiment in terms of recovery of cognitive decline, not prevention of cognitive disorder.
This finding may also be related to the lack of a deliberately created low-protein state. No improvement in QOL or elimination of forgetfulness was observed in any of the intervention groups.
It is suggested that short-term intervention with Amino LP7 for 3 months does not affect general subjective health in daily life. In the 6gIG, which showed an intervention effect on mental function and social interaction, subjective QOL may be improved by continuing the intervention.
This study has a few limitations. The first is that the improvement of social interaction was indicated by a questionnaire, and it was not possible to evaluate what kind of interaction was specifically affected.
Although it is difficult to objectively evaluate social interaction, it is important to evaluate whether the effects of essential amino acid intake also affect the total amount of communication and daily enjoyment in order to enhance the significance of the intervention.
The second point is that the intervention period was only 3 months long, and the long-term effects were not considered. From the perspective of dementia prevention, it is necessary to examine whether the effect of an intervention on attention and cognitive flexibility continues for a long duration.
Moreover, it is not clear whether the intervention effect remains after intake is stopped. Long-term observational studies are also valuable in examining whether the efficacy of amino acids impacts the prevention of future cognitive decline.
Third, due to the exploratory nature of this study, there should be a potential limitation in the interpretation of the results because of multiple testing due to the study design. However, if Amino LP7 was not effective, it is believed that both 6gIG and PCG would have shown effectiveness randomly.
In the case where Amino LP7 was not effective, the probability that 4 out of 32 outcomes would show significant differences and that all 4 outcomes would be effective in only the 6gIG was only 0.
Our research results demonstrated that all 4 statistically significant results showed that Amino LP7 had positive effects in only the 6gIG group, suggesting the effectiveness of Amino LP7 on cognitive function.
Further research with narrowed evaluation outcomes or larger clinical trials to adjust for the multiplicity of the outcomes is needed in the future. In conclusion, daily intake of seven essential amino acids resulted in improved attention and cognitive flexibility and psychosocial functioning, but the effect required 6 g of daily intake.
Intake of essential amino acids is associated with prevention of low protein status, although the mechanism underlying the intervention effect and the long-term effect are unclear.
For older adults who need to work on not only cognitive decline but also frailty, health promotion through easily accessible methods such as supplements may be useful as an adjunct approach. The datasets presented in this article are not readily available due to ethical and commercial restrictions but are available from the corresponding author on reasonable request.
The studies involving human participants were reviewed and approved by the Institutional Review Board and Ethics Committee of the Tokyo Metropolitan Institute of Gerontology H and Ajinomoto Co. The safety assessment for the test food MT-Y, MT, and HS: conceptualization, methodology, project administration, and writing—review and editing.
KN: writing—review and editing. SO, DY, DC, and HS: data curation. SO, MI, MT-Y, and DY: formal analysis. SO, MK, DC, AI, MI, and HS: investigation. MT-Y and MT: resources. DY and MT: software. YF: supervision.
SO, DY, and HS: visualization. MK, DY, and HS: writing—original draft. All authors have read and approved the published version of the manuscript. This study was supported by grants from Ajinomoto Co. The funder was involved in the study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication.
MT-Y, MT, MI, and KN are employees of Ajinomoto Co. The Amino LP7 and placebo were provided by Ajinomoto Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to acknowledge Makoto Ishi for helping with the design of this study and Yumiko Kato for measuring the amino acid levels in blood.
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One of the many reasons to pick a low-calorie, low-fat diet rich in vegetables, fruits, and cognitivw is that funcction host of epidemiological studies have suggested that proteun a ufnction may delay the onset Body composition and weight management slow the progression Metabolism-boosting supplements from nature Alzheimer's disease AD. Now Metabolism-boosting foods study published qnd BioMed Central's open High protein diet and cognitive function journal Molecular Neurodegeneration tests fnuction Metabolism-boosting foods of proyein diets, head-to-head, for High protein diet and cognitive function effects on Cognitiive pathology in a mouse model of the disease. Although the researchers were focused on triggers for brain plaque formation, they also found that, unexpectedly, a high protein diet apparently led to a smaller brain. A research team from the US, Canada, and the UK tested four differing menus on transgenic mouse model of AD, which express a mutant form of the human amyloid precursor protein APP. APP's role in the brain is not fully understood; however it is of great interest to AD researchers because the body uses it to generate the amyloid plaques typical of Alzheimer's. These mice were fed either. The researchers then looked at the brain and body weight of the mice, as well as plaque build up and differences in the structure of several brain regions that are involved in the memory defect underlying AD.
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