Special Article

Effects of glucose load on cognitive functions in elderly people Nikita L. van der Zwaluw, Ondine van de Rest, Roy P.C. Kessels, and Lisette C.P.G.M. de Groot Glucose is the main fuel for the brain, and manipulation of the glucose supply may consequently affect brain function. The present review was conducted to provide an overview of studies that investigated the acute effects of glucose load on memory and other cognitive functions in elderly people. The effects of sucrose on cognition and suggested mechanisms were also explored. A total of twenty studies met the inclusion criteria. In the majority of studies, episodic memory was investigated and a beneficial role for glucose in that specific cognitive domain was suggested. Other cognitive domains, i.e., working memory, semantic memory, visual memory, information-processing speed, attention, executive function, and visual/spatial function, have been studied less frequently and evidence for a beneficial effect of glucose was equivocal. Mechanisms are suggested to be mainly related to the human body’s need for glucose as a metabolic substrate for physiological mechanisms in both central and peripheral processes.

INTRODUCTION Glucose is the main fuel for metabolic processes in the brain. A constant supply of glucose is consequently important, and manipulation of the glucose supply may play a role in the modulation of cognitive processes. An increasing number of studies on the effects of glucose load on cognitive functions in different study populations such as young adults, patients with Alzheimer’s disease (AD), and healthy older adults (summarized by Smith et al.1) have been published. Aging is accompanied by cognitive decline, resulting in memory loss and a decline in attention, processing speed, and executive function2,3; this suggests that elderly people have more room for cognitive improvement compared with younger adults. Moreover, elderly people often have impaired glucose metabolism, which includes a reduced ability to normalize elevated blood glucose levels and decreased peripheral and central glucose utilization.4,5 Poor glucose regulation is associated

with memory impairment and age-related cognitive deficits.6 People with diabetes were shown to have more difficulties with attention, information-processing speed, and memory tasks and they performed worse on verbal fluency tasks than healthy elderly persons.6,7 Also, individuals without diabetes but with poor glucose regulation performed worse on cognitive performance tests compared with those who had better glucose regulation.8,9 Individual differences in glucose regulation as well as in baseline cognitive performance may influence the effects of glucose load on cognitive functions. These may, in part, explain differences between young, elderly, and cognitively impaired people.1 Also, mechanisms that underlie the effect of glucose may differ between young and older adults. Many studies have been conducted regarding the beneficial effect of glucose load on cognitive functions in the elderly. This review provides an overview of studies that investigated the effect of glucose on memory and other cognitive functions in healthy older adults

Affiliations: NL van der Zwaluw, O. van de Rest, and LCPGM de Groot are with the Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands. RPC Kessels is with the Department of Geriatrics, the Department of Medical Psychology, and Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. Correspondence: Nikita van der Zwaluw, Division of Human Nutrition, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, the Netherlands. E-mail: [email protected]. Phone: þ31-317-485548. Key words: aging, brain, cognition, cognitive decline, glucose, fructose, memory, sucrose, sugar. C The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For V

Permissions, please e-mail: [email protected]. 92

doi: 10.1093/nutrit/nuu002 Nutrition ReviewsV Vol. 73(2):92–105 R

and in elderly persons with mild cognitive impairment and AD. The effects of fructose and sucrose are also discussed, as are possible underlying mechanisms. LITERATURE SEARCH The MEDLINE database was searched for suitable articles through May 2013. Combinations of the following search terms were used: glucose, sugar, carbohydrates, sucrose, fructose, brain, memory, attention, cognition, cognitive, mental performance. Titles, abstracts, and key words were carefully examined when selecting articles. Reference lists of identified publications were also checked. Only articles that were written in English and covered original research that was placebo-controlled and performed in elderly people were included. The selected outcome measure was performance on cognitive function tasks after consumption of a glucose or sucrose drink compared with a placebo drink. In accordance with the inclusion criteria, 42 articles were excluded because they were not performed in elderly populations (34 studies in younger or middleaged adults, 8 studies in children or adolescents) and 4 studies were excluded because they focused on cognitive deficits other than age-related cognitive decline (e.g., patients with schizophrenia). In total, 20 studies were included, of which 19 investigated glucose and memory functions and 14 investigated glucose in relation to other nonmemory cognitive functions. GLUCOSE AND MEMORY IN ELDERLY PEOPLE A detailed overview of studies that addressed the effect of a glucose drink compared with a placebo drink on different aspects of memory in elderly people is provided in Table 1.9–27 More than one memory task was often administered in each study in order to capture different aspects of memory function. Although the effects varied among studies, the majority showed a positive effect of glucose on at least one memory task.10–12,14,16–19,21–24,26 In contrast, all studies that included more than one test also showed no effects of glucose on other memory tasks that were performed, and five studies showed no beneficial effects of glucose on any of the memory tasks performed.9,13,15,25,27 The domain of episodic memory, which governs memories of events and experiences with a specific temporal or spatial context, was studied most frequently. The majority of studies showed an improvement in one of the episodic memory tasks, most often tested with story recall, paired associate learning, or word-list learning tests. There were no clear differences in effects on performance when long-term episodic memory was tested, i.e., tasks with a delay between presentation and Nutrition ReviewsV Vol. 73(2):92–105 R

test or immediate recall (presentation directly followed by the test). Some studies showed a larger effect on long-term memory,10,14,23,24 while others showed a larger effect on immediate recall.11,18,22 Riby et al.11 showed that task difficulty played a role in glucose facilitation, with only the easier tasks resulting in improved performance after glucose consumption. In contrast to these free- or cued-recall tests, performance on recognition tests (yes–no decisions about previously presented stimuli) did not improve.10,12 This is probably because recognition tests are not very sensitive and ceiling performances were present. When tests are too difficult, a glucose load may be insufficient to improve performance.11 Two studies showed that only individuals with poor glucose regulation improved their episodic memory performance. Differences in memory function among people with poor versus better (relative to the median) glucose regulation became smaller after glucose ingestion13,15; this was primarily observed in the older participants and only in some of the tests.13 However, another study showed that glucose impaired the performance of episodic memory in individuals with better glucose regulation.17 Two studies showed that a smaller peak change in glucose levels was associated with larger memory improvement after glucose ingestion,23,24 while two other studies did not observe this association.19,22 Together with glucose regulation, baseline performance might also play a role in the effect glucose may have on cognitive performance. Healthy participants with poor baseline performance and with poor b-cell function were more sensitive to the memory-facilitating effects of glucose.15 Craft et al.20 observed similar beneficial effects in patients with mild AD who had poor glucose recovery; however, baseline performance did not always play a role.21 Another memory domain that was investigated was working memory, i.e., memory related to maintenance of information for a brief period of time, after which it is not stored into long-term memory. In the studies discussed here, working memory was primarily measured by digit-span forward and backward tests (brief maintenance of sequences of digits that increase in length). Overall, working memory performance was not affected after glucose intake. One study showed a beneficial effect on the digit-span forward test in women with poor glucose regulation, but women with better glucose regulation performed worse.17 In another study, a lower score on the digit-span backward test was observed after glucose intake.27 Visual memory was not extensively examined, and only one study showed a beneficial effect on the delayed Rey/Taylor complex figure test.26 The domain of semantic memory, i.e., memory for general knowledge in 93

94

Nutrition ReviewsV Vol. 73(2):92–105

R

N ¼ 13 elderly patients; 68 6 5.9 y;a 25 g glucose vs. placebo

N ¼ 20; 68.8 6 6 y (range 60–80 y); 25 g glucose vs. placebo

Riby et al. (2006)11

Riby et al. (2004)12

N ¼ 57; 71.9 6 7.2 y (range 55–84 y); 50 g glucose vs. placebo

N ¼ 24 patients with MCI, 73 6 5.4 y; N ¼ 24 healthy elderly patients, 71 6 5.6 y; 25 g glucose vs. placebo

Riby et al. (2009)10

Messier et al. (2003)13

N ¼ 93; 70.1 6 8.3 y (range 55–88 y); 50 g glucose vs. placebo

N ¼ 43; 78 6 8 y (range > 65 y); 50 g glucose, 100 g sucrose vs. placebo

Population description: N, age [mean 6 standard deviation (range)], and study design

Messier et al. (2010)9

Episodic memory Van der Zwaluw et al. (2014)27

Reference

PAL, easy and difficult, around 30-min delayed recall PAL recognition, easy and difficult, around 30min delayed recall PAL recognition, easy and difficult, 1-week delayed recall Story recall immediate (WMS-III) Story recall delayed (WMS-III) Verbal free recall Order reconstruction recall

PAL, easy and difficult, immediate recall

Word learning, easy and difficult, immediate recall Word learning, easy and difficult, delayed recall

PAL, easy and difficult, delayed recall

PAL, easy and difficult, direct recall

Picture recognition, delayed recognition

Story recall delayed (RBMT)

Word list recall immediate (RAVLT) Word list recall delayed (RAVLT) Story recall immediate (RBMT) Story recall delayed (RBMT) PAL easy (WMS-R) PAL difficult (WMS-R) Compound score Story recall immediate (WMS-III) Story recall delayed (WMS-III) Verbal free recall Order recall Story recall immediate (RBMT)

Cognitive test

Table 1 Summary of studies investigating the effect of glucose on memory function in elderly people.

(Continued)

Dgl-plac ¼ 0.1, n.s. Dgl-plac ¼ 0.4, n.s. Dgl-plac ¼ 0.5, n.s. Dgl-plac ¼ 0.6, n.s. Dgl-plac ¼ 0, n.s. Dgl-plac ¼ 0.2, n.s. Dgl-plac ¼ 0.12, n.s. n.s. n.s. n.s. n.s. MCI: Dgl-plac ¼ 0.0; healthy: Dgl-plac ¼ 0.9, n.s. MCI: Dgl-plac ¼ 0.8; healthy: Dgl-plac ¼ 1.5, P < 0.05 MCI: Dgl-plac ¼ 0.1; healthy: Dgl-plac ¼ 0.6, n.s. Easy: Dgl-plac ¼ 0.8, P < 0.05; difficult: Dgl-plac ¼ 0.1, n.s. Easy: Dgl-plac ¼ 0.3, n.s.; difficult: Dgl-plac ¼ 0.4, n.s. Easy: Dgl-plac ¼ 1.6, P < 0.05; difficult: Dgl-plac ¼ 0.4, n.s. Easy: Dgl-plac ¼ 1.7, P < 0.05; difficult: Dgl-plac ¼ 0.0, n.s. Easy: Dgl-plac ¼ 1.3; difficult: Dgl-plac ¼ 1.3, n.s. overall, but 2 (drink)  2 (delay)  2 (difficulty) analysis of variance showed greater recall after glucose (P < 0.05) Easy: Dgl-plac ¼ 0.4; difficult: Dgl-plac ¼ 0.3, n.s. Easy: Dgl-plac ¼ 0.2; difficult: Dgl-plac ¼ 0.2, n.s. Easy: Dgl-plac ¼ 1.7; difficult: Dgl-plac ¼ 0.9, n.s. n.s. n.s. n.s. n.s.

Results

Nutrition ReviewsV Vol. 73(2):92–105

R

95

N ¼ 20; 67 y (range 60–83 y); 50 g glucose vs. placebo. Pretraining, glucose on day 1; pretesting, glucose on day 2 N ¼ 15; 62.3 6 6.5 y (range  55 y); 50 g glucose vs. placebo

N ¼ 20 patients with very mild to mild AD, 69.1 6 6.5 y; N ¼ 12 age- and sex-matched healthy controls, 65.3 6 10.5 y; intravenous raise in glucose levels to 9.7 mmol/L or 12.5 mmol/L

N ¼ 23 patients with AD; 82 y (range 68–94 y); 75 g glucose vs. placebo N ¼ 21 mild and very mild patients with AD, 71.5 6 8.5 y; N ¼ 14 age- and sex-matched controls, 73.5 6 4.7 y; 50 g glucose vs. placebo

N ¼ 22; 67 y (range 60–81 y); 50 g glucose vs. placebo ingested before or after cognitive test

Manning et al. (1998)16

Messier et al. (1997)17

Craft et al. (1993)18

Manning et al. (1993)19

Manning et al. (1992)21

Craft et al. (1992)20

N ¼ 20; 72.3 6 1.4 y (range 60–82 y); 50 g glucose vs. mashed potatoes, barley, and placebo

Population description: N, age [mean 6 standard deviation (range)], and study design N ¼ 22; 71.2 6 1.3 y (range 61–79 y); 50 g glucose vs. fat, protein, and placebo

Kaplan et al. (2000)15

Kaplan et al. (2001)14

Reference

Table 1. Continued

Story recall delayed, 24-h delay (WMS-R)

PAL delayed (WMS-R)

Story recall delayed (WMS-R) PAL immediate (WMS-R) PAL delayed (WMS-R) Story recall (WMS-R) Word list learning (modified RAVLT) Story recall immediate (WMS-R) Story recall delayed (WMS-R) PAL immediate (WMS-R)

Word recognition (ADAS) Story recall immediate (WMS-R)

Story recall delayed (WMS-R) PAL (WMS-R) Word recall (ADAS)

Story recall immediate (WMS-R)

Story recall, 24-h delay (WMS-R)

Story recall immediate (WMS-R) Story recall delayed (WMS-R) Word list recall (RAVLT) Story recall immediate (WMS-R) Story recall delayed (WMS-R)

Word list recall (RAVLT)

Cognitive test

(Continued)

Dgl-plac ¼ 1.18, P ¼ 0.001 Dgl-plac ¼ 2.53, P ¼ 0.003 Treatment, n.s. Treatment, n.s. Healthy: Dgl-plac ¼ 2.4, AD: Dglplac ¼ 1.6. treatment, n.s. Healthy: Dgl-plac ¼ 0.4; AD: Dglplac ¼ 0.7 Treatment, n.s. F (2.42) ¼ 6.7, P < 0.01

P ¼ 0.03, impaired performance after glucose in men (n.s. with Bonferroni correction), P ¼ 0.02 P ¼ 0.001 n.s. n.s. overall, but people with poor GR performed better after glucose intake, while people with good GR performed worse F (1.19) ¼ 11.60, P < 0.01 overall; pretraining glucose gave better recall than pretesting glucose n.s.; tendency for better recall after glucose, but worse in men with poor GR n.s. n.s. Glucose improved performance in better-recovery males n.s. Significant effect in the 12.5mmol/L condition, especially seen in patients with very mild AD n.s. n.s.

Results

96

Nutrition ReviewsV Vol. 73(2):92–105

R

N ¼ 15; 62.3 6 6.5 y (range 55 y); 50 g glucose vs. placebo

N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo N ¼ 11 elderly patients; 67.4 y (range 58–77 y); 50 g glucose vs. placebo

Manning et al. (1990)23

Hall et al. (1989)24

N ¼ 10; 63 6 5 y; 50 g glucose vs. placebo

N ¼ 20; 68.8 6 6 y (range 60–80 y); 25 g glucose vs. placebo N ¼ 57; 71.9 6 7.2 y (range 55–84 y); 50 g glucose vs. placebo

Messier et al. (1997)17

Knott et al. (2001)25

Messier et al. (2003)13

Riby et al. (2004)12

Messier et al. (2010)9

N ¼ 43; 78 6 8 y (range >65 y); 50 g glucose, 100 g sucrose vs. placebo N ¼ 93; 70.1 6 8.3 y (range 55–88 y); 50 g glucose vs. placebo

N ¼ 11 elderly patients; 67.4 y (range 58–77 y)b; 50 g glucose vs. placebo

Hall et al. (1989)24

Working memory Van der Zwaluw et al. (2014)27

N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo

Population description: N, age [mean 6 standard deviation (range)], and study design N ¼ 10; 67.6 y (range 60–82 y); 10, 25, and 50 g glucose vs. placebo

Manning et al. (1990)23

Parsons and Gold (1992)22

Reference

Table 1. Continued

Digit span backward (WMS-R) Digit span forward (WAIS-R) Digit span backward (WAIS-R) Digit span forward (WMS-R) Digit span backward (WMS-R)

Digit span forward (WAIS-III) Digit span backward (WAIS-III) Digit span forward (WMS-R) Digit span backward (WMS-R) Arithmetic (WAIS-III) Letter–number sequencing (WAIS-III) Modified Brown–Peterson Digit span forward (WMS-III) Digit span backward (WMS-III) Digit span forward (WAIS-III) Digit span backward (WAIS-III) Arithmetic (WAIS-III) Letter–number sequencing (WAIS-III) Modified Brown–Peterson Sternberg memory scanning–accuracy Memory scanning–reaction time Digit span forward (WMS-R)

Word list learning immediate (selective reminding test) World list learning delayed (selective reminding test) Story recall immediate (WMS-R) Story recall delayed (WMS-R) PAL easy and difficult, immediate (WMS-R) PAL 24-h delayed (WMS-R) Story recall delayed (WMS-R)

Story recall 40-min delay (WMS-R)

Story recall 5-min delay (WMS-R)

Cognitive test

(Continued)

Dgl-plac ¼ 0.1, n.s. Dgl-plac ¼ 0.6, P < 0.05 n.s. n.s. n.s. n.s. n.s. Dgl-plac ¼ 0.0, n.s. Dgl-plac ¼ 0.0, n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. Women with poor GR improved performance after glucose, while performance in women with good GR was impaired n.s. Dgl-plac ¼ 0.33, n.s. Dgl-plac ¼ 0.14, n.s. n.s. n.s.

Dgl-plac ¼ 2.12, P ¼ 0.004 Dgl-plac ¼ 2.75, P ¼ 0.002 n.s. n.s. Dgl-plac ¼ 2.0, P ¼ 0.024

Dgl-plac ¼ 8.63, P ¼ 0.05

25 g glucose: t ¼ 3.44, P < 0.01. n.s; effects after 10 g and 50 g glucose 25 g glucose: t ¼ 2.27, P < 0.05; n.s. effects after 10 g and 50 g glucose Dgl-plac ¼ 0.75, n.s.

Results

Nutrition ReviewsV Vol. 73(2):92–105

R

97

N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo N ¼ 21 patients with mild and very mild AD, 71.5 6 8.5 y; N ¼ 14 age- and sex-matched controls, 73.5 6 4.7 y; 50 g glucose vs. placebo

N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo N ¼ 11 elderly patients; 67.4 y (range 58–77 y)b; 50 g glucose vs. placebo

Allen et al. (1996)26 Craft et al. (1992)20

Manning et al. (1990)23 Hall et al. (1989)24

N ¼ 20; 68.8 6 6 y (range 60–80 y); 25 g glucose vs. placebo N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo

n.s. n.s. n.s. Dgl-plac ¼ 3.42, P < 0.001 Healthy: Dgl-plac ¼ 0.2; AD: Dglplac ¼ 1.0; treatment, n.s. Healthy: Dgl-plac ¼ 0.0; AD: Dglplac ¼ 0.8; treatment, n.s. Healthy: Dgl-plac ¼ 0.6; AD: Dgl-plac ¼ 0.4; treatment, n.s. Dgl-plac ¼ 0.06, n.s. n.s.

Spatial span backward (WMS-III) Visual memory span forward (WMS-R) Visual memory span backward (WMS-R) Rey/Taylor figure test, delayed Pattern recall immediate

Computerized semantic verification task accuracy, easy þ hard Categorical verification response time, easy þ hard Category fluency

Category fluency, easy and difficult

Verbal fluency, easy and difficult letters

Verbal fluency

Rey/Taylor complex figure test Visual memory test (WMS-R)

Pattern recall recognition

Easy: Dgl-plac ¼ 1.0, n.s.; difficult: Dgl-plac ¼ 0.9, n.s. Easy: Dgl-plac ¼ 2.6, n.s.; difficult: Dgl-plac ¼ 1.9, n.s. Easy: Dgl-plac ¼ 0.13, n.s.; difficult: Dgl-plac ¼ 0.08, n.s. Easy: Dgl-plac ¼ 29, n.s.; difficult: Dgl-plac ¼ 36, n.s. Dgl-plac ¼ 2.9, n.s.

Dgl-plac ¼ 1.4, n.s.

n.s. n.s. n.s. n.s.

Rey/Taylor complex figure test delayed recall Spatial span forward (WMS-III) Spatial span backward (WMS-III) Spatial span forward (WMS-III)

Pattern recall delayed

n.s.

Results

Rey/Taylor complex figure test immediate recall

Cognitive test

Verbal fluency Dgl-plac ¼ 1.68, P < 0.01 Boston naming test Dgl-plac ¼ 0.14, n.s. N ¼ 23 patients with AD; 82 y (range 68–94 y); 75 g Priming: word-stem completion task, Dgl-plac ¼ 1.63, P ¼ 0.002 Manning et al. (1993)19 glucose vs. placebo recognition Priming: word-stem completion task, Dgl-plac ¼ 0.52, n.s. completion Abbreviations: Dgl-plac, difference in performance after glucose and placebo drink; AD, Alzheimer’s disease; ADAS, A´lzheimer’s disease assessment scale; GR, glucose regulation; MCI, mild cognitive impairment; n.s., no significant differences between glucose and placebo drink; PAL, paired associate learning; RAVLT, Rey auditory verbal learning test; RBMT, Rivermead behavioral memory test; WMS-II, Wechsler memory scale second edition; WMS-III, Wechsler memory scale third edition; WAIS-III, Wechsler adult intelligence scale third edition; WMS-R, Wechsler memory scale, revised. a Fourteen young participants (30 6 5 y) were included in this study, but only the results for older participants are shown in the table. b Twelve young participants (20 y, range, 18–23 y) were included in this study, but only the results for older participants are shown in the table.

Allen et al. (1996)26

Riby et al. (2004)12

Riby et al. (2006)11

N ¼ 43; 78 6 8 y (range > 65 y); 50 g glucose, 100 g sucrose vs. placebo N ¼ 13 elderly patients; 68 6 5.9a; 25 g glucose vs. placebo

N ¼ 15; 62.3 6 6.5 y (range  55 y); 50 g glucose vs. placebo

Messier et al. (1997)17

Semantic memory/verbal fluency Van der Zwaluw et al. (2014)27

N ¼ 57; 71.9 6 7.2 y (range 55–84 y); 50 g glucose vs. placebo

N ¼ 93; 70.1 6 8.3 y (range 55–88 y); 50 g glucose vs. placebo

Population description: N, age [mean 6 standard deviation (range)], and study design

Messier et al. (2003)13

Visual memory Messier et al. (2010)9

Reference

Table 1. Continued

which the spatial or temporal context of learning has been lost, also did not improve after glucose intake. One study showed significant improvements after glucose intake on verbal fluency26 and another study showed improvements on a word-stem completion task19; however, these effects can also be a result of a general improvement in information processing, which may have resulted in a quicker response. An explanation for the lack of effect of glucose may be that the abilities for verbal reasoning and semantic memory are not heavily affected by normal aging.28 Two studies included younger participants in addition to elderly persons,11,24 and one showed a more pronounced effect of glucose in the elderly compared with the younger participants.24 The studies that investigated the differences between healthy older adults and cognitively impaired older adults showed mixed results. One study showed a difference between early-stage AD and healthy elderly participants with respect to the relationship between glucose administration and glucose recovery. In healthy participants, episodic memory improved in individuals with better glucose recovery, while in people with poor recovery, memory was impaired. This pattern was reversed in the AD patients.20 In another study, the enhancing effects of glucose were not more pronounced in patients with mild cognitive impairment compared with healthy elderly persons.10 In summary, based on the results of 19 studies, it may be concluded that a glucose load selectively enhances episodic memory performance, but results on other memory functions are inconclusive. In general, it seems that glucose ingestion was found to be more effective with sensitive cognitive tests that had a certain level of task complexity, although the effects of glucose may be limited to a certain extent. GLUCOSE AND NONMEMORY COGNITIVE FUNCTIONS IN ELDERLY PEOPLE Research on the influence of glucose on cognitive functions other than memory is relatively scarce and only 14 such studies were identified for this review. The tests performed in these studies were divided into the following cognitive domains: information-processing speed, executive function, attention, visual/spatial function, and other functions9,10,12–15,17,19,20,22,23,26,27,29 (Table 2). Seven studies showed a positive effect of glucose on various tasks in different cognitive domains.14,17,19,20,26,27,29 In three studies, information-processing speed and executive functioning were improved when measured with different parts of the trail-making test, the letter symbol digit test, or the Stroop color word test.14,27,29 In one study, the improvements in performance after glucose ingestion were only seen in men.14 Glucose 98

improved divided attention, measured by a computerized dual-reaction time task,29 but episode-watching, another attention test, did not improve. Visual/spatial function was determined with a facial recognition task, Rey/Taylor figure test, figural fluency, or a one-feature target-detection task. Three studies observed glucoseenhancing effects,19,20,26 although one of these studies only showed improvement in participants with AD.20 AD patients also improved their performance on an orientation task after a glucose load.19 Poor b-cell function was associated with greater improvements in the trail-making test, whereas participants with better b-cell function performed worse.15 Similar improvements in information-processing speed occurring only in participants with poor glucose regulation and not in those with better regulation were found in two other studies. 17, 27 Due to the limited number of studies and the variety of tests covering different cognitive domains, it is not possible to draw any conclusions regarding a possible facilitating effect of glucose on domains other than memory. The higher-order executive functions, which are primarily controlled processes such as activation, inhibition, and switching, are influenced by normal aging and require more mental effort. Glucose may mediate the processes, but more research in larger samples is needed to replicate the results. FRUCTOSE, SUCROSE, AND COGNITIVE PERFORMANCE As with glucose, fructose is a monosaccharide; together with glucose, it forms sucrose. In contrast to glucose, however, fructose cannot cross the blood-brain barrier,30 it does not raise blood glucose levels, and it is directly metabolized by the liver. This can indicate that mechanisms other than raised glucose levels are responsible for enhancing cognition, and these are probably of a peripheral nature.31, 32 Only two studies were found that investigated the effects of sucrose on cognitive functions in an adult human population.27,33 One showed that after ingestion of a sucrose drink, elderly participants performed better on speed of information-processing tasks compared with those who drank a placebo.27 Another study showed that sucrose in combination with nicotine may be beneficial for performance on a continuous performance task in young adults.33 Studies performed in rats showed that fructose can improve memory performance, although extrapolating results from animal studies to humans must be done with caution. In a series of rat experiments by Messier and White,31 both glucose and fructose enhanced memory with the same dose; Rodriguez et al.34 showed that peripherally injected fructose may affect cognitive Nutrition ReviewsV Vol. 73(2):92–105 R

Table 2 Summary of studies investigating the effect of glucose on other cognitive functions in elderly people. Reference

Population description: N; age [mean 6 standard deviation (range)]; and study design Information-processing speed N ¼ 43; 78 6 8 y (range > 65 Van der Zwaluw et al. y); 50 g glucose, 100 g (2014)27 sucrose vs. placebo Gagnon et al. (2010)29 Messier et al. (2010)9 Riby et al. (2004)12 Messier et al. (2003)13 Kaplan et al. (2001)14 Messier et al. (1997)17

Allen et al. (1996)26 Manning et al. (1990)23 Executive function Van der Zwaluw et al. (2014)27 Gagnon et al. (2010)29 Kaplan et al. (2001)14 Kaplan et al. (2000)15

Allen et al. (1996)26 Attention Van der Zwaluw et al. (2014)27 Gagnon et al. (2010)29 Riby et al. (2009)10

N ¼ 44; 67.7 6 5 y (range 60–80 y); 50 g glucose vs. placebo N ¼ 93; 70.1 6 8.3 y (range 55–88 y); 50 g glucose vs. placebo N ¼ 20; 68.8 6 6 y (range 60–80 y); 25 g glucose vs. placebo N ¼ 57; 71.9 6 7.2 y (range 55–84 y); 50 g glucose vs. placebo N ¼ 22; 71.2 6 1.3 y (range 61–79 y); 50 g glucose vs. fat, protein, and placebo N ¼ 15; 62.3 6 6.5 y (all55 y); 50 g glucose

Cognitive tests

Results

Stroop reading and color naming Letter digit substitution test TAP flexibility, letters TAP flexibility, digits Compound scores TMT A Stroop reading Stroop color naming Digit symbol coding (WAIS-III) Symbol search (WAIS-III)

Dgl-plac ¼ 0.9, n.s. Dgl-plac ¼ 1.1, P ¼ 0.04 Dgl-plac ¼ 4, n.s. Dgl-plac ¼ 11, n.s. Dgl-plac ¼ 0.1, n.s. F(1, 41) ¼ 6.81, P < 0.05 F(1,41) ¼ 3.64, n.s. n.s. n.s. n.s.

Digit symbol substitution test (WAIS-III)

Dgl-plac ¼ 1.5, n.s.

Digit symbol coding (WAIS-III) Symbol search (WAIS-III)

n.s. n.s.

TMT A

P ¼ 0.02 in men

Digit symbol coding (WAIS-R) Cancellation H test

N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo

TMT A Grooved pegboard Finger oscillation test

n.s. Improved by glucose, but not in men with a good glucose regulation Dgl-plac ¼ 9.4, n.s. Dgl-plac ¼ 1.2, n.s. Dgl-plac ¼ 1.72, n.s.

N ¼ 43; 78 6 8 y (all > 65 y); 50 g glucose, 100 g sucrose vs. placebo N ¼ 44; 67.7 6 5 y (range 60–80 y); 50 g glucose vs. placebo N ¼ 22; 71.2 6 1.3 y (range 61–79 y); 50 g glucose vs. fat, protein, and placebo N ¼ 20; 72.3 6 1.4 y (range 60–82 y); 50 g glucose vs. mashed potatoes, barley, and placebo

Stroop interference TAP flexibility Compound scores TMT B ratio [(B-A)/A] Stroop inhibition Stroop switching TMT A þ B

Dgl-plac ¼ 2.3, n.s. Dgl-plac ¼ 27, n.s. Dgl-plac ¼ 0.02, n.s. F(1, 41) ¼ 0.15, n.s. F(1, 39) ¼ 4.61, P < 0.05 F(1, 41) ¼ 10.47, P < 0.01 P ¼ 0.02 in men

TMT B

N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo

TMT B

n.s. overall, but carbohydrate intake improved performance in those with poor b-cell function and impaired in those with better b cell function Dgl-plac ¼ 15.1, n.s.

N ¼ 43; 78 6 8 y (all > 65 y); 50 g glucose, 100 g sucrose vs. placebo N ¼ 44; 67 6 5 y (range 60–80 y); 50 g glucose vs. placebo N ¼ 24 patients with MCI, 73 6 5.4 y; N ¼ 24 healthy elderly patients, 71 6 5.6 y; 25 g glucose vs. placebo

TAP alertness, simple RT TAP alertness, cued RT

Dgl-plac ¼ 6, n.s. Dgl-plac ¼ 10, n.s.

Computerized dual task–RT Computerized dual task–accuracy SART hit rate

F(1, 38) ¼ 8.49, P < 0.01 F(1, 38) ¼ 4.61, P < 0.05 MCI: Dgl-plac ¼ 0.03; healthy: Dgl-plac ¼ 0.02, n.s. MCI: Dgl-plac ¼ 0.03; healthy: Dgl-plac ¼ 0.00, n.s. MCI: Dgl-plac ¼ 0.04; healthy: Dgl-plac ¼ -0.01, n.s.

SART reaction time SART false-alarm rates

(Continued)

Nutrition ReviewsV Vol. 73(2):92–105 R

99

Table 2. Continued Reference Kaplan et al. (2001)14 Kaplan et al. (2000)15

Allen et al. (1996)26 Visual/spatial function Messier et al. (2010)9 Allen et al. (1996)26

Craft et al. (1992)20

Manning et al. (1990)23

Population description: N; age [mean 6 standard deviation (range)]; and study design N ¼ 22; 71.2 6 1.3 y (range 61–79 y); 50 g glucose vs. fat, protein, and placebo N ¼ 20; 72.3 6 1.4 y (range 60–82 y); 50 g glucose vs. mashed potatoes, barley, and placebo N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo N ¼ 93; 70.1 6 8.3 y (range 55–88 y); 50 g glucose vs. placebo N ¼ 28; 73 y (range 61–87 y); 50 g glucose vs. placebo

N ¼ 21 patients with mild and very mild AD, 71.5 6 8.5 y; N ¼ 14 age- and sexmatched controls, 73.5 6 4.7 y; 50 g glucose vs. placebo N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo

Cognitive tests

Results

Episode watching (sustained attention)

n.s.

Episode watching (sustained attention)

n.s.

Dichotic listening

Dgl-plac ¼ 0.15, n.s.

Rey/Taylor complex figure test copy

n.s.

Meier visual test

Dgl-plac ¼ 0.79, n.s.

Rey/Taylor complex figure test, copy Figural fluency

Dgl-plac ¼ 0.74, n.s.

One-feature target detection and localization task

Healthy: Dgl-plac ¼ 0.4; AD: Dglplac ¼ 3.7, in AD significant improvement after glucose

Two-feature target detection and localization task Letter cancellation test

Healthy: Dgl-plac ¼ 2.36; AD: Dgl-plac ¼ 0.58, n.s. Dgl-plac ¼ 4.29, n.s.

Dgl-plac ¼ 1.43, P < 0.05

Other Riby et al. (2004)12

N ¼ 20; 68.8 6 6 y (range Mental control test (WMS-III) Dgl-plac ¼ 0.8, n.s. 60–80 y); 25 g glucose vs. placebo Randt memory test–orientation Dgl-plac ¼ 0.91, P ¼ ¼ 0.045 Manning et al. (1993)19 N ¼ 23 patients with AD, 82 y (range 68–94 y); 75 g glucose vs. placebo N ¼ 10; 67.6 y (range 60–82 y). Ammons quick test–intelligence n.s. Parsons and Gold 10, 25, and 50 g glucose vs. (1992)22 placebo Ammons quick test–intelligence Dgl-plac ¼ 2.00, n.s. Manning et al. (1990)23 N ¼ 17; 73 y (range 62–84 y); 50 g glucose vs. placebo Abbreviations: Dgl-plac, difference in performance after glucose and placebo drink; AD, Alzheimer’s disease; MCI, mild cognitive impairment; n.s., no significant differences between glucose and placebo drink; RT, reaction time; SART, sustained attention to response task; TAP, test for attentional performance; TMT A, trail-making test part A; TMT B, trail making test part B; WAIS-III, Wechsler adult intelligence scale third edition; WAIS-R, Wechsler adult intelligence scale revised; WMS-II, Wechsler memory scale second edition; WMS-III, Wechsler memory scale third edition; WMS-R, Wechsler memory scale, revised.

functioning. In another study, a combination of fructose and glucose was found to have less of an effect on memory than a single dose of one of these monosaccharides.35 This might be a result of the hepatic output of glucose, which may be attenuated when both fructose and glucose are administered.36 White37 observed an effect of fructose only after a higher dose (2 g/kg) and not after a smaller dose (100 mg/kg), whereas in two other studies, an improvement was seen after 100 mg/kg.34,35 Due to the limited number of human studies and the equivocal results of rat studies, no conclusions can 100

be drawn about the effects of fructose and sucrose on cognitive functions in older humans. METHODOLOGICAL ISSUES Study design All but one study29 used a repeated-measures design to minimize the influence of substantial variability in the memory functions of elderly people on test scores; this is probably the most optimal study design for this Nutrition ReviewsV Vol. 73(2):92–105 R

research area, which focuses on acute effects. To counteract the risk of learning effects in such a design, the order of test drinks was, in most instances, counterbalanced and parallel versions of cognitive tests sensitive for learning effects were used. Despite these measures, it is possible that other types of interindividual variability among the participants, such as glucose recovery abilities, stress, sex, and baseline performance, may have influenced the results.15 The majority of studies were done in the morning, after an overnight fast, in order to control for circadian rhythm; however, this calls into question the actual effects of a glucose load in daily life.12 While a glucose-enhancing effect has been demonstrated in younger adults after only 2 h of fasting,38 this has not yet been investigated in the elderly. Neuropsychological testing Various neurocognitive tests were used in the studies evaluated, and the number of different tests within a study was sometimes large, which may have increased the risk of chance findings. Nevertheless, the effect of glucose on episodic memory was seen in most of the studies, indicating that glucose may be beneficial for improving episodic memory. It has been discussed that the level of task difficulty can influence the observed effect of glucose, and an often-mentioned assumption is that tasks have to be difficult in order for a glucose effect to be observed. Supporting this assumption are results in which performance on delayed recall tasks profited more from glucose than performance on immediate recall tasks.10,14,23 However, Riby et al.11 observed the opposite, with a beneficial effect found for the easier task only, and not for the task with more demanding conditions. The authors suggested that an individual’s cognitive capacity is limited when conditions are too demanding and that glucose is not able to counteract these demands. Nonetheless, the term “cognitively demanding” has not been clearly defined, as both duration and task complexity play a role. Test conditions and glucose dose All of the studies included in this review used glucose dissolved in water compared with a placebo solution (250 ml) containing saccharine, aspartame, or a combination of artificial sweeteners. Cognitive testing started around 5–15 minutes after ingestion. Drinks were matched for sweetness and taste by adding a lemon or orange flavor to the beverage. Because it is assumed that artificial sweeteners do not alter blood glucose levels, it was also assumed that they would not affect cognition. However, small effects of saccharin on several brain regions have been shown,39 which can be explained by Nutrition ReviewsV Vol. 73(2):92–105 R

the effect of taste on memory processes, as activated taste receptors produce small amounts of insulin.32,40 No difference on cognitive functioning was found, however, when a saccharin solution was compared with water.41 In one study performed in young adults, a beneficial effect of glucose was observed only when participants were told that they received the glucose drink and not when they were told they drank the placebo.42 One discrepancy among the studies was the dosage of glucose used; in most studies, the glucose drinks contained either 25 g or 50 g of glucose, but in one study, a dose of 10 g (no effect) was used22 and in another 75 g was used (which was beneficial in AD patients).19 For memory function, all studies using a 25 g dose of glucose showed a positive effect on episodic memory (n¼4 studies), 10–12,22 whereas 6 of the 14 studies that used a 50 g dose showed a positive effect.14,16,21,23,24,26 In the nonmemory cognitive domains, the opposite was shown; no facilitating effects were found in the studies that used a 25 g dose of glucose (n¼3),10,12,22 whereas the majority of studies that used a 50 g dose of glucose showed effects on different cognitive functions (7 of 11 studies).14,17,19,20,26,27,29 It is plausible that the optimum dose of glucose differs for different cognitive functions. For example, in rats it has been shown that each brain region has a different level of extracellular glucose.43,44 Moreover, glucose transporters are not homogeneously distributed throughout the brain; this may suggest that the effects of glucose vary among brain regions.45–47 Brain regions may also vary in the degree to which glucose metabolism increases to maximum capacity.48 Furthermore, because every individual has a different body weight, the amount of glucose per kilogram body weight is different, which may, at least partially, explain the different results.38 Dose-response studies in young and older adults showed that the effect of glucose follows an inverted U-shaped dose-response function, with 25 g indicated as the most optimum dose22,38,49; this is comparable to findings from a rat study.50 The optimum blood glucose concentration for facilitating memory is between 8 and 10 mmol/L and around 8.9 mmol/L in healthy elderly people. In patients with AD, higher concentrations are probably warranted to induce an enhancing effect of glucose. Craft et al.18 showed that 75 g of glucose was needed to reach an optimal blood glucose level of 225 mg/dL (12.5 mmol/L). The optimal dose of glucose may also depend on peripheral glucose regulation, but results are inconclusive. The different findings may be explained by the most frequently used method, i.e., a median split to divide the study population into those who recover better and those who recover more poorly from glucose. This is based on the study population and not on a reference value. Therefore, reliable determination of poor glucose 101

regulators classified as such in a different study population has been questioned. Nevertheless, possible explanations for the effect of glucose regulation are present for the two glucose recovery conditions. The improvements for the better regulators could be explained by the fact that good glucose regulation is needed in order for the extra glucose to be used in an effective way. Insulin sensitivity is probably also better and may, consequently, have effects on the brain. On the other hand, people with relatively poor glucose regulation perform worse on cognitive tests and, thus, have more room for improvement.1 POSSIBLE MECHANISMS FOR THE EFFECT OF GLUCOSE ON COGNITIVE FUNCTIONS Glucose enters the brain through the blood–brain barrier by using GLUT1 glucose transporters, which are located in the endothelial cells of blood vessels.51 A concentration gradient drives glucose to the extracellular fluid of the brain; therefore, extracellular glucose levels fluctuate with blood glucose levels, whereas intracellular levels are more controlled.52 Only a limited amount of glucose is stored as glycogen in astrocytes but not in neurons.53,54 When a deficit of neuronal glucose occurs, lactate, which is derived from glycogen, goes from the astrocytes to the extracellular fluid to the neurons, where it can be used as an energy substrate. This drive of lactate is dependent on the level of adenosine triphosphate (ATP) within the neuron; low levels of ATP increase the transport.32 Several possible neurochemical systems underlying the glucose-facilitating effect on cognition have been implicated. Proposed mechanisms are primarily based on the rationale that glucose is needed as a metabolic substrate for physiological mechanisms in both central and peripheral processes, such as ion pumps involved in neurotransmission, cell mechanisms, and for synthesis of the neurotransmitters serotonin, noradrenalin, glutamate, gamma-aminobutyric acid, and acetylcholine (ACh).43 A proposed general mechanism is that the supply of extra glucose prevents depletion of brain glucose levels when a cognitive task is performed.55 Because of the brain’s limited storage capacity for glucose, a continuous peripheral supply of glucose is necessary.56 Increased neural activity is associated with increased use of glucose in localized brain areas,44 which results in a decrease of glucose in extracellular brain areas after a task is learned. More difficult tasks may lead to greater depletion of stored glucose, and the supply of extra glucose may counteract these depletion effects, especially when astrocytes cannot deliver enough lactate. Recently, it has been suggested that the effects of glucose on cognitive 102

performance are mediated by the control of metabolic substrates by astrocytes.54 Under normal conditions, glucose is taken up by astrocytes to form glycogen. During learning or a cognitive task, glycogenolysis and production of lactate are induced by activation of membrane receptors on astrocytes. Glucose is then primarily taken up by astrocytes rather than neurons.57 This may indicate that lactate from astrocytes provides an extra energy substrate in addition to glucose.54,58 An important brain area that relates to glucosefacilitating effects is the hippocampus. This is a key structure in learning and memory modulation and is especially important in mediating episodic memory function. As discussed above, performance on episodic memory has been found to benefit the most from glucose ingestion. When learning a new task, hippocampal activity increases, and extra glucose can help sustain hippocampal activity, which may lead to better storage of new memories.59 Hippocampal extracellular glucose levels fluctuate depending on cognitive demands55; as shown in rats, levels decrease during memory tasks and these changes appear to be larger in older rats.60 A functional magnetic resonance imaging study in patients with schizophrenia showed that glucose ingestion was associated with greater parahippocampal activation during verbal encoding.61 These results indicate that the medial temporal region may be involved in memory facilitation due to glucose. In the hippocampus, another possible mechanism can be identified; the neurotransmitter ACh is produced in the hippocampus and is part of the cholinergic system, which is a neurotransmitter system involved in the regulation of memory and learning.62 The release of ACh is regulated, in part, by glucose availability. In rat studies, a relationship between glucose availability and brain ACh levels has been shown; intrahippocampal and intraseptal glucose injections increased ACh release and improved alternation scores in rats.63,64 In highly demanding situations, such as difficult memory tasks, increased glucose levels may enhance the production of acetyl coenzyme A, thereby facilitating the production of ACh.65 ACh also plays a role in prefrontal lobe functioning66; as such, the increase in ACh following a glucose load may explain the possible effects of glucose on executive function and attention.67 Insulin receptors are found throughout the brain, although not homogeneously, with higher concentrations of receptors in, among other locations, the hippocampus.68,69 This indicates another possible site of action of glucose intake because of a glucose-mediated secretion of insulin. Insulin can enter the brain by receptor-mediated transport at the blood–brain barrier. Via insulin receptors, insulin may be important in memory formation by activating specific signaling Nutrition ReviewsV Vol. 73(2):92–105 R

pathways that may modulate synaptic plasticity, density, and neurogenesis.70,71 It has been shown that intranasal infusion with insulin improves memory in patients with AD.72 Under euglycemic hyperinsulinemic conditions, insulin has been shown to improve verbal memory and selective attention.73 However, when an oral glucose load is given, it is difficult to discriminate between the possible mechanism of the glucose-mediated insulin secretion and the effects of pure glucose because of the close relationship between an increase in glucose levels and a subsequent increase in insulin levels. Another possible mechanism of glucose facilitation is via ATP-sensitive potassium channels, which seem to be sensitive to glucose metabolism. Glucose needs to be present in order for intraneuronal ATP levels to increase, which results in depolarization of neurons. This again mediates the release of neurotransmitters (as explained by Stefani and Gold74), which can then alter cognitive performance. The action of glucose seems to occur not only in the central nervous system but also in the peripheral nervous system.43 Peripheral mechanisms might travel via the gut hormone cholecystokinin and its receptors in the celiac ganglion.15,32 In addition, glucose may also affect cognition via the liver, where a mechanism may send a neural signal to the central nervous system, via stimulation of the vagus nerve, in order to influence the physiological processes that underlie memory.32 Findings in vagotomized rats substantiate that there is a peripheral mechanism as well; L-glucose, which does not cross the blood–brain barrier, enhanced task performance in healthy rats but not in vagotomized rats.75 This may also explain the possible effects of fructose, which does not cross the blood–brain barrier but has been shown to enhance memory in rats. The metabolite pyruvate, a common metabolite of glucose and fructose, may be a key in the mechanism of improving memory.35 A substantial amount of pyruvate can cross the blood–brain barrier. In the brain, pyruvate undergoes reversible carboxylation and can then act as an energy substrate for neurons in case of energy deficiency.76 The facilitating effects of glucose on memory and, partially, on other cognitive functions have been shown in younger and older populations, but the effects seem to be more pronounced in the elderly.24 Underlying causes of aging can be changes in neuron components in a structural, chemical, or electrical manner.56 Moreover, neuroendocrine regulation may be changed, such that key hormones involved in memory storage are disturbed and age-related impairments in glucose metabolism occur.51 Circulating blood glucose levels increase with age, while overall cerebral glucose metabolism and insulin sensitivity decrease. Aged rats showed a larger decrease in extracellular hippocampal glucose Nutrition ReviewsV Vol. 73(2):92–105 R

during training compared with younger rats.60,77 Also, extracellular glucose levels in the hippocampal areas are lower in older compared with younger rats77; this may explain, at least in part, why the effect of glucose is larger in elderly people. Furthermore, insulin receptors in the brain may change due to aging and might play a role in memory formation.78 Mechanisms suggested to explain the glucoseenhancing effects of a rise in blood glucose levels have been contradicted by some study results. Kaplan et al. investigated the effects of other nutrients in addition to glucose on cognition and showed that protein14 and barley,15 both of which have low glycemic indexes, also improved cognition. Blood glucose levels rose minimally, and it was suggested that the supply of energy may be more important for the enhancement of cognitive functions, pointing to other possible evolutionary mechanisms. Furthermore, Manning et al.21 showed a beneficial effect of glucose at a 24-h delayed recall, when glucose levels were at normal levels. This indicates that once a memory has been formed, it outlasts the acute effects of glucose on the brain. CONCLUSION This review discussed the effects of glucose load on various cognitive functions in healthy elderly people and in individuals with mild cognitive impairment and AD. Based on the studies included, it can be concluded that glucose may improve episodic memory in elderly people. For other cognitive domains, however, the beneficial effect is doubtful, with only a few studies demonstrating beneficial effects. The limited number of studies on domains other than memory is surprising given that attention-related functions and higher executive functions are particularly likely to decline as people age.79 Nevertheless, it is possible that glucose has domain-specific actions and may, thus, only slightly improve functions other than episodic memory. Fructose and sucrose might also improve cognitive performance; however, most of the available evidence was derived from studies in rats, and there have been few investigations in humans. This review of the available literature focused on studies of the effects of glucose on cognitive performance in the elderly because it is assumed that elderly people have more room for cognitive improvement than younger individuals and might, therefore, derive greater benefit from glucose. Furthermore, it has been suggested that elderly people have different nutritional needs because their brain metabolic rate is different from that of younger adults.56 Also, dysfunction of the neurons that contain ACh, especially in the hippocampus, as a result of aging supports interest in determining the ability of glucose to enhance cognition in older individuals.66 103

A 2011 review showed that these effects exist not only in older populations but also in younger individuals, leading the authors to conclude that glucose can have beneficial effects in both populations.1 In younger populations, the research focus has been primarily on episodic memory, and glucose was found to improve memory performance, especially when there was a divided-attention condition such as dual tasking.1 Glucose may also have an effect on nonmemory functions, but the tasks administered have to be challenging in order for an effect to be observed. In a study performed with both elderly and younger participants, the facilitating effect of glucose was more pronounced in the older adults,24 but contradictory results were found in a meta-analysis that showed a smaller effect size in older adults than in younger adults.12 However, the authors recommended that the effects be treated with caution, as the studies in both populations were heterogeneous and more effect sizes were available from studies of younger populations.12 By focusing solely on the elderly in the current review, it was possible to discuss the results extensively, and by showing the broad spectrum of neuropsychological tests that were conducted, there was a unique opportunity to look at the results of all the cognitive functions examined. In conclusion, a glucose load seems to improve episodic memory in elderly people, but limited evidence is available for the effects of glucose on other cognitive domains. Because the effects of fructose and sucrose on cognitive functioning have rarely been studied, no conclusions about their effects can be made. It is difficult to make recommendations for the regular dietary use of pure glucose, sucrose, or products that contain large amounts of added sugars, however, due to the negative long-term health effects of their consumption, as stated in the 2010 Dietary Guidelines forAmericans.80 In addition, a recent draft report by the World Health Organization proposes that the guidelines for free sugar use be reconsidered, since limiting the consumption of free sugars may reduce the risk of obesity and dental caries.81 For difficult memory tasks, extra glucose might be useful for improving performance. While a quick rise in glucose levels may be beneficial in the short term, over the long term, stable glucose levels are warranted. The expansive and reliable effects of glucose on cognitive functions in older adults suggest that studies of glucose and derived ways to augment brain metabolism may be useful in the search for cognitive enhancers, particularly for enhancement of these functions in elderly people. To get a more complete picture, future research should focus on gaining a better understanding of the mechanism behind the effects of glucose and sucrose on cognitive performance; this would also be useful for gaining an understanding of 104

the related neurological processes. Neuroimaging studies will be of great use for determining the specific brain regions involved in the enhancing effects of glucose, whereas animal models can be useful for untangling different mechanisms of neuronal functions.

Acknowledgments The authors thankfully acknowledge Richelle Kosse for her work in preparing the literature search for this review. Funding: Knowledge Centre Sugar & Nutrition (Baarn, the Netherlands) commissioned this work and partly nanced the preparation of this manuscript. The sponsor had no role in the design, performance, or approval of the manuscript. Declaration of interest: The authors have no relevant interests to declare.

REFERENCES 1.

2. 3. 4. 5. 6.

7.

8.

9. 10.

11.

12. 13. 14.

15.

16. 17. 18.

Smith MA, Riby LM, van Eekelen JAM, et al. Glucose enhancement of human memory: a comprehensive research review of the glucose memory facilitation effect. Neurosci Biobehav Rev. 2011;35:770–783. Nilsson LG. Memory function in normal aging. Acta Neurol Scand Suppl. 2003;179: 7–13. Salthouse TA. Speed and knowledge as determinants of adult age differences in verbal tasks. J Gerontol. 1993;48:P29–P36. Kuhl DE, Metter EJ, Riege WH, et al. The effect of normal aging on patterns of local cerebral glucose utilization. Ann Neurol. 1984;15 (Suppl):S133–S137. Cunnane S, Nugent S, Roy M, et al. Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition. 2011;27:3–20. Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol. 2004;26: 1044–1080. Brands AM, Van den Berg E, Manschot SM, et al. A detailed profile of cognitive dysfunction and its relation to psychological distress in patients with type 2 diabetes mellitus. J Int Neuropsychol Soc. 2007;13:288–297. Gagnon C, Greenwood CE, Bherer L. Glucose regulation is associated with attentional control performances in nondiabetic older adults. J Clin Exp Neuropsychol. 2011;33:972–981. Messier C, Tsiakas M, Gagnon M, et al. Effect of age and glucoregulation on cognitive performance. J Clin Exp Neuropsychol. 2010;32:809–821. Riby LM, Marriott A, Bullock R, et al. The effects of glucose ingestion and glucose regulation on memory performance in older adults with mild cognitive impairment. Eur J Clin Nutr. 2009;63:566–571. Riby LM, McMurtrie H, Smallwood J, et al. The facilitative effects of glucose ingestion on memory retrieval in younger and older adults: is task difficulty or task domain critical? Brit J Nutr. 2006;95:414–420. Riby LM, Meikle A, Glover C. The effects of age, glucose ingestion and glucoregulatory control on episodic memory. Age Ageing. 2004;33:483–487. Messier C, Tsiakas M, Gagnon M, et al. Effect of age and glucoregulation on cognitive performance. Neurobiol Aging. 2003;24:985–1003. Kaplan RJ, Greenwood CE, Winocur G, et al. Dietary protein, carbohydrate, and fat enhance memory performance in the healthy elderly. Am J Clin Nutr. 2001;74: 687–693. Kaplan RJ, Greenwood CE, Winocur G, et al. Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates. Am J Clin Nutr. 2000;72:825–836. Manning CA, Stone WS, Korol DL, et al. Glucose enhancement of 24-h memory retrieval in healthy elderly humans. Behav Brain Res. 1998;93:71–76. Messier C, Gagnon M, Knott V. Effect of glucose and peripheral glucose regulation on memory in the elderly. Neurobiol Aging. 1997;18:297–304. Craft S, Dagogo-Jack SE, Wiethop BV, et al. Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. Behav Neurosci. 1993;107:926–940.

Nutrition ReviewsV Vol. 73(2):92–105 R

19.

20. 21.

22. 23. 24.

25.

26. 27.

28. 29.

30. 31.

32. 33. 34.

35.

36. 37.

38.

39. 40. 41.

42. 43. 44.

45. 46. 47.

48.

49.

Manning CA, Ragozzino ME, Gold PE. Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer’s type. Neurobiol Aging. 1993;14:523–528. Craft S, Zallen G, Baker LD. Glucose and memory in mild senile dementia of the Alzheimer type. J Clin Exp Neuropsychol. 1992;14:253–267. Manning CA, Parsons MW, Gold PE. Anterograde and retrograde enhancement of 24-h memory by glucose in elderly humans. Behav Neural Biol. 1992;58: 125–130. Parsons MW, Gold PE. Glucose enhancement of memory in elderly humans: an inverted-U dose-response curve. Neurobiol Aging. 1992;13:401–404. Manning CA, Hall JL, Gold PE. Glucose effects on memory and other neuropsychological tests in elderly humans. Psychological Science. 1990;1:307–311. Hall JL, Gonder-Frederick LA, Chewning WW, et al. Glucose enhancement of performance on memory tests in young and aged humans. Neuropsychologia. 1989; 27:1129–1138. Knott V, Messier C, Mahoney C, et al. Glucose and glucoregulatory modulation of memory scanning, event-related potentials and EEG in elderly subjects. Neuropsychobiology. 2001;44:156–166. Allen JB, Gross AM, Aloia MS, et al. The effects of glucose on nonmemory cognitive functioning in the elderly. Neuropsychologia. 1996;34:459–465. Van der Zwaluw NL, Van de Rest O, Kessels RP, et al. Short-term effects of glucose and sucrose on cognitive performance and mood in elderly people. J Clin Exp Neuropsychol. 2014;36:517–527. Alwin DF, McCammon RJ. Aging, cohorts, and verbal ability. J Gerontol B Psychol Sci Soc Sci. 2001;56(Suppl):S151–S161. Gagnon C, Greenwood CE, Bherer L. The acute effects of glucose ingestion on attentional control in fasting healthy older adults. Psychopharmacology (Berl). 2010; 211:337–346. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Physiol. 1971;221:1629–1639. Messier C, White NM. Memory improvement by glucose, fructose, and two glucose analogs: a possible effect on peripheral glucose transport. Behav Neural Biol. 1987;48:104–127. Messier C. Glucose improvement of memory: a review. Eur J Pharmacol. 2004;490: 33–57. Harte CB, Kanarek RB. The effects of nicotine and sucrose on spatial memory and attention. Nutr Neurosci. 2004;7:121–125. Rodriguez WA, Horne CA, Mondragon AN, et al. Comparable dose-response functions for the effects of glucose and fructose on memory. Behav Neural Biol. 1994; 61:162–169. Rodriguez WA, Horne CA, Padilla JL. Effects of glucose and fructose on recently reactivated and recently acquired memories. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:1285–1317. Mayes PA. Intermediary metabolism of fructose. Am J Clin Nutr. 1993;58 (Suppl): 754S–765S. White NM. Peripheral and central memory enhancing actions of glucose. In: RCA Frederickson, JL McGaugh, DL Felten, eds. Peripheral Signalling of the Brain: role in Neural–Immune Interactions, Learning and Memory. Toronto: Hogrefe and Huber; 1991. p. 421–443. Sunram-Lea SI, Owen L, Finnegan Y, et al. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults. J Psychopharmacol. 2011;25:1076–1087. Kobayakawa T, Ogawa H, Kaneda H, et al. Spatio-temporal analysis of cortical activity evoked by gustatory stimulation in humans. Chem Senses. 1999;24:201–209. Bellisle F, Louis-Sylvestre J, Demozay F, et al. Reflex insulin response associated to food intake in human subjects. Physiol Behav. 1983;31:515–521. Messier C. The absence of effect of glucose on memory is associated with low susceptibility to the amnestic effects of scopolamine in a strain of mice. Behav Brain Res. 1998;96:47–57. Green MW, Taylor MA, Elliman NA, et al. Placebo expectancy effects in the relationship between glucose and cognition. Br J Nutr. 2001;86:173–179. Greenwood CE. Dietary carbohydrate, glucose regulation, and cognitive performance in elderly persons. Nutr Rev. 2003;61 (Suppl):S68–S74. McNay EC, McCarty RC, Gold PE. Fluctuations in brain glucose concentration during behavioral testing: dissociations between brain areas and between brain and blood. Neurobiol Learn Mem. 2001;75:325–337. Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012;75: 762–777. Duelli R, Kuschinsky W. Brain glucose transporters: relationship to local energy demand. News Physiol Sci. 2001;16:71–76. Duelli R, Staudt R, Duembgen L, et al. Increase in glucose transporter densities of Glut3 and decrease of glucose utilization in rat brain after one week of hypoglycemia. Brain Res. 1999;831:254–262. Hope C, Seiss E, Dean PJ, et al. Consumption of glucose drinks slows sensorimotor processing: double-blind placebo-controlled studies with the Eriksen flanker task. Front Hum Neurosci. 2013;7:651. Riby LM. The impact of age and task domain on cognitive performance: a meta-analytic review of the glucose facilitation effect. Brain Impairment. 2004;5: 145–165.

Nutrition ReviewsV Vol. 73(2):92–105 R

50.

51. 52.

53. 54. 55.

56. 57.

58. 59. 60.

61.

62. 63.

64.

65.

66.

67. 68.

69. 70. 71.

72. 73. 74.

75.

76. 77. 78. 79.

80. 81.

Gold PE. Modulation of memory processing: enhancement of memory in rodents and humans. In: The Neuropsychology of Memory2nd ed. LR Squire, N. Butters, editor. New York: Guilford Press; 1992, 402-414. Convit A. Links between cognitive impairment in insulin resistance: an explanatory model. Neurobiol Aging. 2005;26 (Suppl 1):31–35. Seaquist ER, Damberg GS, Tkac I, et al. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes. 2001;50:2203–2209. Gold PE, Newman LA, Scavuzzo CJ, et al. Modulation of multiple memory systems: from neurotransmitters to metabolic substrates. Hippocampus. 2013;23:1053–1065. Gold PE. Regulation of memory—From the adrenal medulla to liver to astrocytes to neurons. Brain Res Bull. 2014;105:25–35. McNay EC, Fries TM, Gold PE. Decreases in rat extracellular hippocampal glucose concentration associated with cognitive demand during a spatial task. Proc Natl Acad Sci U S A. 2000;97:2881–2885. Korol DL, Gold PE. Glucose, memory, and aging. Am J Clin Nutr. 1998;67(Suppl): 764S–771S. Chuquet J, Quilichini P, Nimchinsky EA, et al. Predominant enhancement of glucose uptake in astrocytes versus neurons during activation of the somatosensory cortex. J Neurosci. 2010;30:15298–15303. Newman LA, Korol DL, Gold PE. Lactate produced by glycogenolysis in astrocytes regulates memory processing. PLoS One. 2011;6:e28427. Winocur G. Glucose-enhanced performance by aged rats on a test of conditional discrimination learning. Psychobiology. 1995;23:270–276. McNay EC, Gold PE. Age-related differences in hippocampal extracellular fluid glucose concentration during behavioral testing and following systemic glucose administration. J Gerontol A Biol Sci Med Sci. 2001;56:B66–B71. Stone WS, Thermenos HW, Tarbox SI, et al. Medial temporal and prefrontal lobe activation during verbal encoding following glucose ingestion in schizophrenia: a pilot fMRI study. Neurobiol Learn Mem. 2005;83:54–64. Benton D, Nabb S. Carbohydrate, memory, and mood. Nutr Rev. 2003;61(Suppl): S61–S67. Ragozzino ME, Unick KE, Gold PE. Hippocampal acetylcholine release during memory testing in rats: augmentation by glucose. Proc Natl Acad Sci U S A. 1996; 93:4693–4698. Ragozzino ME, Pal SN, Unick K, et al. Modulation of hippocampal acetylcholine release and spontaneous alternation scores by intrahippocampal glucose injections. J Neurosci. 1998;18:1595–1601. Messier C, Durkin T, Mrabet O, et al. Memory-improving action of glucose: indirect evidence for a facilitation of hippocampal acetylcholine synthesis. Behav Brain Res. 1990;39:135–143. Terry AV, Jr., Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther. 2003;306:821–827. Wallace TL, Bertrand D. Importance of the nicotinic acetylcholine receptor system in the prefrontal cortex. Biochem Pharmacol. 2013;85:1713–1720. Agrawal R, Gomez-Pinilla F. Metabolic syndrome in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J Physiol. 2012;590:2485–2499. Zhao WQ, Chen H, Quon MJ, et al. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol. 2004;490:71–81. Zhao WQ, Alkon DL. Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol. 2001;177:125–134. Steculorum SM, Solas M, Bruning JC. The paradox of neuronal insulin action and resistance in the development of aging-associated diseases. Alzheimers Dement. 2014;10 (1 Suppl):S3–S11. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70:440–448. Kern W, Peters A, Fruehwald-Schultes B, et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74:270–280. Stefani MR, Gold PE. Intra-septal injections of glucose and glibenclamide attenuate galanin-induced spontaneous alternation performance deficits in the rat. Brain Res. 1998;813:50–56. Talley CP, Clayborn H, Jewel E, et al. Vagotomy attenuates effects of L-glucose but not of D-glucose on spontaneous alternation performance. Physiol Behav. 2002; 77:243–249. Gonzalez SV, Nguyen NH, Rise F, et al. Brain metabolism of exogenous pyruvate. J Neurochem. 2005;95:284–293. Gold PE. Glucose and age-related changes in memory. Neurobiol Aging. 2005;26 (Suppl 1):60–64. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5:64–74. Belleville S, Chertkow H, Gauthier S. Working memory and control of attention in persons with Alzheimer’s disease and mild cognitive impairment. Neuropsychology. 2007;21:458–469. US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2010. Washington, DC: December 2010. World Health Organization. Draft guideline: sugars intake for adults and children http:// www.who.int/nutrition/sugars_public_consultation/en/2014 [accessed 11 April 2014].

105

Effects of glucose load on cognitive functions in elderly people.

Glucose is the main fuel for the brain, and manipulation of the glucose supply may consequently affect brain function. The present review was conducte...
188KB Sizes 1 Downloads 12 Views