Research Paper
Rationale and clinical data supporting nutritional intervention in Alzheimer’s disease S. Engelborghs1, C. Gilles2, A. Ivanoiu3, M. Vandewoude4 1
Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium and Memory Clinic and Department of Neurology, ZNA Hoge Beuken and Middelheim, Antwerp, Belgium, 2 Geriatrics Department and Memory Clinic, Centre Hospitalier de l’Ardenne-Vivalia, Libramont, Belgium, 3 Department of Neurology, Saint Luc University Hospital, and Institute of Neuroscience, Catholic University of Louvain, Brussels, Belgium, 4Department of Geriatrics, ZNA St. Elisabeth, University of Antwerp, Antwerp, Belgium Adequate nutrition plays an important role in the maintenance of cognitive function, particularly during aging. Malnutrition is amongst the risk factors for developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Epidemiological studies have associated deficiencies in some nutrients with a higher risk of cognitive dysfunction and/or AD. Cognitive decline in AD is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources. As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors (mainly uridine monophosphate, choline and omega-3 fatty acids) to make the phospholipids required to build neuronal membranes may have beneficial effects on synaptic degeneration in AD. In addition, B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Despite this, no randomized controlled trial has hitherto provided evidence that any single nutrient has a beneficial effect on cognition or lowers the risk for AD. However, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders like AD leading to synaptic degeneration. Here we review the clinical evidence for supplementation, based on a multi-target approach with a focus on key nutrients with a proposed role in synaptic dysfunction. Based on preclinical evidence, a nutrient mixture, SouvenaidH (Nutricia N.V., Zoetermeer, The Netherlands) was developed. Clinical trials with SouvenaidH have shown improved memory performance in patients with mild AD. Further clinical trials to evaluate the effects of nutritional intervention in MCI and early dementia due to AD are on-going. Keywords: Nutrition, Alzheimer’s disease, Docosahexaenoic acid, Vitamin B, Folic acid
Introduction Alzheimer’s disease (AD) places a huge burden on society due to the medical and societal costs associated with treating and caring for patients with cognitive impairment. The key pathological features of AD include the accumulation of amyloid b and hyperphosphorylated tau,1 which are the principal components of the neuropathological hallmarks of AD, senile plaques and neurofibrillary tangles. Together with oxidative stress, elevated homocysteine and mitochondrial and vascular dysfunction, these changes are thought to lead to membrane disruption and synaptic loss. Among the different pathological
Correspondence to: S. Engelborghs, Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Universiteitsplein 1, BE–2610 Antwerp, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551213Z.0000000006
markers, synaptic loss shows the closest correlation with cognitive decline.2,3 At present, it is not possible to directly measure in vivo synaptic activity or loss, but fluorine-18 fluorodeoxyglucose positron emission tomography does allow the visualisation of glucose metabolism as a marker for synaptic activity.4 Evidence from this technique shows that a reduction in glucose metabolism in specific brain areas is present from the earliest stages of the disease process.5 It has long been known that cognitive function can be influenced by nutrition.6 High body mass index during middle age has been associated with an increased risk of dementia in old age and mild calorie restriction has been shown to delay age-related cortical atrophy. The Mediterranean diet, which is rich in vegetables, antioxidants and polyunsaturated
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fatty acids (PUFA), is associated with a lower risk of mild cognitive impairment (MCI)7 and AD.8 In the elderly, malnutrition and weight loss are also indicators of faster progression in AD. Patients with early-stage AD are more likely to be deficient in specific nutrients, and a low intake of omega-3 fatty acids is associated with increased risk of MCI and AD.9 This is unsurprising, as the brain is made up of 60% fat, 20% of which is omega-3 (v-3) and omega-6 (v-6) essential fatty acids. In particular, the production and maintenance of neural membranes is vital for synapse formation and function and requires provision of numerous nutrients in the diet, including v-3 and v-6 PUFA. Here we review the preclinical and clinical studies investigating the potential of specific nutritional components to affect neuronal membrane formation and composition, synaptic formation/function and cognitive performance.
Role of specific nutrients in AD Preclinical and epidemiological studies have implicated many nutrients in AD, including those related to neuronal membranes and synaptic function. However, the evidence for the effectiveness of supplementation with individual nutrients in AD is conflicting. The outcomes of published, randomized, double-blind studies of individual nutrients are summarized in Table 1.10–28 PUFA including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Synapses consist of neuronal membranes that are composed of phospholipid bilayers embedded with cholesterol and sphingolipids.29 Of the phospholipids that make up neuronal membranes and are needed for optimum receptor functioning, phosphatidylcholine is the most abundant. Choline, uridine and docosahexaenoic acid (DHA), all precursors to phosphatidylcholine, are also required for brain phosphatide synthesis. Dietary intake of eicosapentaenoic acid (EPA) and DHA is associated with global grey matter volume and increased cognitive performance in healthy elderly subjects.30 Furthermore, preclinical studies have suggested that a diet rich in PUFA could have a beneficial effect against the pathology of AD.31 Several studies have investigated this effect of dietary supplementation with EPA and DHA, in both healthy subjects and patients with MCI or mild to moderate AD. The quality of these studies varies, as do the number of participants and the duration of treatment. A recent Cochrane review analyzed the randomized, double-blind studies in which PUFA supplements were given to healthy older subjects, limiting the review to larger studies of >6 months duration.32 Three studies met the criteria and
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together involved over 4000 subjects.10–12 The metaanalysis concluded that there was no benefit of fishoil supplementation in healthy older people, but that longer studies may be needed to detect a signal. The on-going EPOCH trial is investigating effects of DHA and EPA in 391 cognitively healthy older adults over 18 months and has completed enrolment.33 Further studies have investigated the effects in subjects with MCI, dementia or age-related cognitive impairments. Again, the results have been mixed, but the largest, longest study found no effect of DHA supplementation on cognitive decline.18 Uridine and choline Uridine and choline are precursors for the phosphatides in synaptic membranes and therefore crucial to synaptic function. As with PUFAs, a variety of evidence pointed to a role for uridine and choline in cognitive enhancement. Rodent studies found that supplementing diet with uridine plus DHA enhanced dendritic spine levels and cognitive performance,34 and a biomarker study looking at cerebrospinal fluid from patients with AD identified increased cysteine and decreased uridine as the best combination to predict mild AD (mini-mental state examination [MMSE] .22) with specificity and sensitivity over 75%.35 However, no randomized, blinded clinical trials exploring the effect of uridine or choline, alone, or in combination, on cognition have been reported. The nutrient combination CognitexH (Life ExtensionH, Fort Lauderdale, FL, USA), which contains uridine-5 monophosphate, alpha-glyceryl phosphorylcholine, phosphatidylserine and pregnenolone, has been assessed in a 12-week, open-label trial of 30 elderly patients with subjective memory complaints and may improve cognitive performance,36 but this requires replication in a double-blind, placebo-controlled study. Folic acid and other B vitamins Homocysteine is cytotoxic and is usually transported out of cells into the plasma, so high plasma levels of homocysteine reflect high intracellular concentrations. High plasma homocysteine levels have been associated with higher risk of AD and brain atrophy in both patients with AD37 and the healthy elderly.38 Folic acid and B vitamins such as B6 and B12 regulate levels of homocysteine, which is biosynthesized from methionine by the removal of the terminal C-methyl group and can be recycled into methionine or converted into cysteine with the aid of B vitamins that act as co-enzymes. Epidemiological studies have shown that low levels of folic acid or vitamin B6 predict cognitive decline in elderly subjects,39 which may be due to their action as co-factors to enhance
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fatty acids (PUFA), is associated with a lower risk of mild cognitive impairment (MCI)7 and AD.8 In the elderly, malnutrition and weight loss are also indicators of faster progression in AD. Patients with early-stage AD are more likely to be deficient in specific nutrients, and a low intake of omega-3 fatty acids is associated with increased risk of MCI and AD.9 This is unsurprising, as the brain is made up of 60% fat, 20% of which is omega-3 (v-3) and omega-6 (v-6) essential fatty acids. In particular, the production and maintenance of neural membranes is vital for synapse formation and function and requires provision of numerous nutrients in the diet, including v-3 and v-6 PUFA. Here we review the preclinical and clinical studies investigating the potential of specific nutritional components to affect neuronal membrane formation and composition, synaptic formation/function and cognitive performance.
Role of specific nutrients in AD Preclinical and epidemiological studies have implicated many nutrients in AD, including those related to neuronal membranes and synaptic function. However, the evidence for the effectiveness of supplementation with individual nutrients in AD is conflicting. The outcomes of published, randomized, double-blind studies of individual nutrients are summarized in Table 1.10–28 PUFA including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Synapses consist of neuronal membranes that are composed of phospholipid bilayers embedded with cholesterol and sphingolipids.29 Of the phospholipids that make up neuronal membranes and are needed for optimum receptor functioning, phosphatidylcholine is the most abundant. Choline, uridine and docosahexaenoic acid (DHA), all precursors to phosphatidylcholine, are also required for brain phosphatide synthesis. Dietary intake of eicosapentaenoic acid (EPA) and DHA is associated with global grey matter volume and increased cognitive performance in healthy elderly subjects.30 Furthermore, preclinical studies have suggested that a diet rich in PUFA could have a beneficial effect against the pathology of AD.31 Several studies have investigated this effect of dietary supplementation with EPA and DHA, in both healthy subjects and patients with MCI or mild to moderate AD. The quality of these studies varies, as do the number of participants and the duration of treatment. A recent Cochrane review analyzed the randomized, double-blind studies in which PUFA supplements were given to healthy older subjects, limiting the review to larger studies of >6 months duration.32 Three studies met the criteria and
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together involved over 4000 subjects.10–12 The metaanalysis concluded that there was no benefit of fishoil supplementation in healthy older people, but that longer studies may be needed to detect a signal. The on-going EPOCH trial is investigating effects of DHA and EPA in 391 cognitively healthy older adults over 18 months and has completed enrolment.33 Further studies have investigated the effects in subjects with MCI, dementia or age-related cognitive impairments. Again, the results have been mixed, but the largest, longest study found no effect of DHA supplementation on cognitive decline.18 Uridine and choline Uridine and choline are precursors for the phosphatides in synaptic membranes and therefore crucial to synaptic function. As with PUFAs, a variety of evidence pointed to a role for uridine and choline in cognitive enhancement. Rodent studies found that supplementing diet with uridine plus DHA enhanced dendritic spine levels and cognitive performance,34 and a biomarker study looking at cerebrospinal fluid from patients with AD identified increased cysteine and decreased uridine as the best combination to predict mild AD (mini-mental state examination [MMSE] .22) with specificity and sensitivity over 75%.35 However, no randomized, blinded clinical trials exploring the effect of uridine or choline, alone, or in combination, on cognition have been reported. The nutrient combination CognitexH (Life ExtensionH, Fort Lauderdale, FL, USA), which contains uridine-5 monophosphate, alpha-glyceryl phosphorylcholine, phosphatidylserine and pregnenolone, has been assessed in a 12-week, open-label trial of 30 elderly patients with subjective memory complaints and may improve cognitive performance,36 but this requires replication in a double-blind, placebo-controlled study. Folic acid and other B vitamins Homocysteine is cytotoxic and is usually transported out of cells into the plasma, so high plasma levels of homocysteine reflect high intracellular concentrations. High plasma homocysteine levels have been associated with higher risk of AD and brain atrophy in both patients with AD37 and the healthy elderly.38 Folic acid and B vitamins such as B6 and B12 regulate levels of homocysteine, which is biosynthesized from methionine by the removal of the terminal C-methyl group and can be recycled into methionine or converted into cysteine with the aid of B vitamins that act as co-enzymes. Epidemiological studies have shown that low levels of folic acid or vitamin B6 predict cognitive decline in elderly subjects,39 which may be due to their action as co-factors to enhance
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Walker et al. 201224
Ford et al. 201023
Durga et al. 2007 FACIT22
Vitamin B/folic acid Eussen et al. 200621
Freund-Levi et al. 200620
Quinn et al. 201018 Chiu et al. 200819
Stough et al. 201217
6 months, plus 6 months open label
18 months 24 weeks
90 days
271 subjects with MCI, aged >70 years
900 adults aged 60–64 years with depressive symptoms
24 months
2 years
195 older persons with mild vitamin 24 weeks B deficiency living freely and living in care facility houses aged >70 years 818 healthy men and women with raised 3 years plasma homocysteine Age 50–70 years 299 men with hypertension, aged >75 years 2 years
174 patients with mild–moderate AD
50 subjects aged .65 years with MCI 74 healthy participants aged 45–77 years 295 patients with mild–moderate AD 46 patients with MCI or mild–moderate AD
Sinn et al. 201216 6 months
12 weeks
25 elderly subjects with MCI
Rondanelli et al. 201215
DHA improved memory and DHA-treated subjects had a significantly better change in memory then placebo-treated subjects DHAzmelatoninztryptophan combination improved several measures of cognitive function
No decline in cognitive function in either treatment or placebo arm No effect of dietary doses of v-3 fatty acids on global cognitive decline in coronary heart disease patients DHA improved memory function in healthy older adults with age-related cognitive decline
No effect on cognitive performance
Conclusion
100 mg Folic acid 0.8 mg vitamin B6 20 mg vitamin B12 0.5 mg
Folic acid, 2 mg Vitamin B6, 25 mg Vitamin B12, 400 mg Folic acid 400 mg, vitamin B12
Folic acid 0.8 mg/day
Vitamin B12, 1 mg, with or without folic acid, 0.4 mg/day
Treatment slowed the rate of brain atrophy in patients with MCI.
Supplementation improved immediate and delayed memory performance compared with placebo
Vitamin B12 administered alone or in combination with folic acid showed no improvements in cognitive function in older persons Improved performance on tests that measure information-processing speed and memory, domains that are known to decline with age No difference in change in cognitive performance from baseline to 24 months with vitamin treatment vs placebo
Daily: DHA (720 mg), EPA (286 mg), vitamin E (16 mg), soy phospholipids (160 mg), melatonin (5 mg), tryptophan (95 mg) EPA, 1.67 g/day DHA, but not EPA, improved verbal fluency DHA, 1.55 g/day HiDHAH (252 mg DHA, 60 mg EPA, No significant effects on cognitive function 10 mg vitamin E) DHA 2 g/day No effect of DHA on rate cognitive decline Omega-3 PUFA Treatment group showed improvement in ADAS-cog compared with placebo, in patients with 1.8 g/day MCI but not AD DHA 1.7 g No effect of DHA/EPA on rate of cognitive decline, EPA 0.6 g but positive effects were observed in a subset of patients with very mild AD (MMSE .27)
DHA, 430 mg plus EPA, 150 mg/day
12 months
Fish oil 1800 or 400 mg/day 200 mg EPA plus 500 mg DHA EPA–DHA 400 mg/day or a-linolenic acid 2 g/day, or EPA plus a-linolenic acid DHA, 900 mg/day
40 months
24 months
26 weeks
Mean follow-up Nutrient
6 months
OPAL
302 cognitive healthy subjects aged >65 years 867 cognitively healthy adults, aged 70–79 years 2911 cognitively healthy adults aged 60–80 years
Subjects
Yurko-Mauro et al. 2010 MIDAS13 185 subjects with a Logical Memory (WMS III) baseline score .1 SD below younger adult mean, aged .55 years 36 elderly subjects with MCI Lee et al. 201214
Geleijnse et al.12
Dangour et al. 2010
11
EPA/DHA Van de Rest et al. 200810
Study
Table 1 Randomized, double-blind trials of individual nutritional supplements on cognitive performance
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Note: AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s disease assessment scale-cognitive; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; FACIT, Folic Acid and Carotid Intima-Media Thickness; MCI, mild cognitive impairment; MIDAS, Memory Improvement with DHA Study; MMSE, mini-mental state examination; OPAL, Older People And n-3 Long-chain polyunsaturated fatty acids study; PUFA, polyunsaturated fatty acids; SD, standard deviation; WMS, Wechsler memory scale.
Vitamin E did not reduce the rate of cognitive decline Subjects in the supplementation group experienced more rapid decline in MMSE
Vitamin E had no effect on rate of progression to AD
Vitamin E 1.5 g/day plus donepezil 10 mg Vitamin E 600 IU every other day Vitamin E 800 IU/day Vitamin C 500 mg/day a-lipoic acid 900 mg/day Coenzyme Q 400 mg, 3x daily 3 years
769 subjects with MMSE 24–30 55–90 6377 healthy US women aged >65 years 66 subjects with mild–moderate AD
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Vitamin C and E Petersen et al. 200526
Mean follow-up Nutrient Subjects Study
Table 1 Continued 20
Patients with higher baseline homocysteine levels who received active treatment experienced a greater reduction in atrophy than placebo
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endogenous precursor synthesis via the regeneration of methyl groups, thereby affecting the availability of precursors and potentially synaptogenesis. Paradoxically though, high levels of folic acid have also been associated with especially rapid cognitive decline40 and the results from interventional studies are conflicting (Table 1).10–28 In subjects with no signs of cognitive decline, supplementation with folic acid had no effect on cognitive performance.21,23 However, in some specific patient groups, such as patients with elevated homocysteine levels22 or patients with depressive symptoms,24 folic acid and vitamin B6 and B12 supplementation produced positive cognitive effects, and in combination they were shown to slow the rate of brain atrophy in patients with MCI.25 Vitamins C and E The brain is particularly sensitive to damage by reactive oxygen species, which are produced by mitochondria. Preclinical evidence suggests that a diet rich in antioxidants, such as vitamins C and E, can inhibit production of amyloid b or prevent cognitive dysfunction in animals.41 However, of the three double-blind, placebo-controlled trials that have been reported, two showed no effect of vitamin E supplementation on cognitive function26,27 and the third found a faster cognitive decline in the intervention than the placebo group,28 suggesting that vitamin E supplementation is not an effective intervention for age-related cognitive decline or mild AD. In conclusion, the results of interventional trials with single nutrients have not demonstrated conclusive evidence for preventing cognitive decline in healthy older subjects, or for preventing loss or restoring function in patients with mild to moderate AD.
Role of nutrient combinations in AD Synaptic loss shows the closest correlation with cognitive health in AD. Synapses are part of the neuronal membrane, which is being continuously remodelled, so adequate availability of the nutritional precursors (mainly uridine monophosphate, choline and v-3fatty acids) of the phospholipids required to build neuronal membranes might have beneficial effects on synaptic degeneration in AD. In addition, as B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders with synaptic degeneration, such as AD.
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Note: AD, Alzheimer’s disease; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; MAVIS, mineral and vitamin intervention study; MMSE, mini-mental state examination; NTB, neuropsychological test battery; SU.FOL.OM3, supplementation with folate, vitamins B12 and/or omega-3 fatty acids; SU.VI.MAX, supplementation in vitamins and mineral antioxidants.
SouvenaidH 24 weeks Scheltens et al. 2012 (Souvenir II)67
Scheltens et al. 2010 (Souvenir I)66
225 subjects with probable AD (MMSE 20–26) 259 drug-naive patients with mild AD
8 years’ treatment followed by 6 years’ treatment-free 12 weeks
Folate 0.56 mg, vitamin B6 3 mg, B12 0.02 mg or EPA/DHA 600 mg, or both Vitamin C 120 mg, B carotene 6 mg, vitamin E 30 mg, selenium 100 mg and zinc 20 mg/day SouvenaidH 4 years
1748 subjects with history of myocardial infarction, aged 45–80 years 4447 healthy French adults aged 45–60 years at baseline
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Kesse-Guyot et al. 2011 SU.VI.MAX65
McNeill et al. 2007 MAVIS63
Andreeva et al. 2011 SU.FOL.OM364
1 year
6 months
220 healthy, free-living women aged 60–91 years 910 healthy men and women aged >65 years Wolters et al. 2005
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No evidence for beneficial effect of supplementation on cognitive function Possible beneficial effects in those at higher risk of nutritional deficiency No significant effect of supplementation on cognitive function, although evidence of beneficial effects in some subgroups was observed Improved episodic memory after supplementation Improved verbal memory only in subjects who were nonsmokers or had low vitamin C concentrations at baseline SouvenaidH improved delayed verbal recall compared with placebo Increase in NTB memory domain z-score in active vs control group
Episodic memory was significantly improved following supplementation No effect on cognitive performance
Multivitamin, mineral and herb supplement (Swisse Men’s UltiviteH) Multivitamin providing 11 vitamins and 2 minerals Multivitamin providing 11 vitamins and 5 minerals at 50–210% of UK reference nutrient intake 8 weeks 51 men aged 50–74 years Harris et al. 201261
62
Nutrient Mean follow-up Subjects Multivitamin/combination approaches
Table 2 Randomized, double-blind trials of combinations of nutritional supplements on cognitive performance
Preclinical evidence A number of studies have shown that levels of membrane phospholipids and their precursors can be increased by administration of uridine, DHA or EPA, and choline, both in vitro and in vivo.42,43 Studies in rats have shown that dietary B-vitamin supplementation increased concentrations of plasma choline44 and DHA45 compared with rats deficient in vitamin D. However, unlike DHA and EPA, the v-6 PUFA arachidonic acid administered orally to gerbils did not promote membrane synthesis.46 The largest effects on levels of brain phospholipids have been seen with combined administration of DHA and/or uridine monophosphate to gerbils and rats consuming choline-containing diets.46–52 A combination of PUFAs, vitamins and minerals was more effective at promoting neurite outgrowth in a neuroblastoma cell model than each of the nutrients alone53 and co-administration of uridine, EPA/DHA and choline increased dendritic spine density in the hippocampus of adult gerbils to a greater extent than when given without uridine.51 Dendritic spine formation is considered to be the precursor to formation of new synaptic connections in the adult brain54 and enhances cognitive function.49,50 Diets supplemented with choline, uridine monophosphate and DHA also lead to elevation in levels of synaptic proteins, such as syntaxin-3, PSD-95 and synapsin-1, markers of synaptogenesis.46 In animal models of AD, dietary enrichment with a combination of several precursors and cofactors (UMP, v-3 PUFAs, choline, folate, vitamin B12, vitamin B6, phospholipids and antioxidants) increased neuronal membrane phosphatidylcholine synthesis,55 where the effects of individual nutrients have been inconsistent. Some studies demonstrated reductions in Ab levels with DHA supplementation in transgenic mouse models31 and Ab pre-infused rats,56 but other studies showed no effect of v-3 PUFAs on Ab levels.57 Oral uridine monophosphate and/or DHA supplementation enhanced learning and memory in normal gerbils; the largest effects occurred when DHA and UMP were supplemented in combination.50 Tests of spatial learning and memory in both normal rats and animals with chronic cerebral hypo-perfusion showed improved outcomes with combined administration of PUFAs, choline, B vitamins, phospholipids, antioxidants and other nutrients compared with these nutrients alone.58,59 The specific nutrient combination FortasynH Connect includes DHA, EPA, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium and was hypothesized to enhance synapse formation and function. In in vivo studies, FortasynH Connect prevented the Ab-induced
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reduction in exploratory activity in rats infused with Ab55 and decreased Ab levels in a transgenic mouse model of AD, where supplementation with DHA or UMP, alone and in combination, was less effective.60 Clinical evidence The results of clinical trials of combined nutritional supplements are summarized in Table 2.61–67 One interventional study of a multivitamin and mineral supplement (Swisse Men’s UltiviteH, Swisse Vitamins Pty Ltd, Melbourne, Australia), given to 51 men aged 50–74 years for 8 weeks, showed a benefit on cognitive performance,61 but two larger, longer studies of combination supplements (220 healthy women aged >60 years, 6 months of treatment, and 910 healthy men and women aged >65 years, 1 year of treatment) did not find any conclusive evidence of a benefit.62,63 The nutritional intervention SouvenaidH (Nutricia N.V., Zoetermeer, The Netherlands), which contains the specific nutrient combination FortasynH Connect, has currently been assessed in two randomized controlled trials. The first was a double-blind, placebo-controlled, multi-country, proof-of-concept study (Souvenir I study, Dutch Trial Register number ISRCTN72254645) involving 225 drug-naive patients with mild AD (MMSE 20–26).66 After 12 weeks of once-daily treatment, a significant improvement in the co-primary endpoint of delayed verbal recall was observed in patients who had received active treatment.66 SouvenaidH was also found to be very well tolerated with a high level of treatment adherence (.90%). These data provided the first indication that the hypothesis behind the development of FortasynH Connect and SouvenaidH may be true. However, no biomarkers of synaptic activity or connectivity were measured to further validate this hypothesis. To extend and confirm these findings, a follow-up study (Souvenir II) was conducted. The Souvenir II study was a 24-week, randomized, placebo-controlled, double-blind, parallel-group, multi-country, trial to assess the efficacy and tolerability of
SouvenaidH in drug-naive patients with mild AD (MMSE 2563, Dutch Trial Registration number NTR1975). The primary endpoint was memory performance and a significant improvement was reported with SouvenaidH (P50.023 for a positive trajectory of active intervention versus placebo; as assessed by the memory domain z-score of a neuropsychological test battery [NTB], Table 3).67 However, a treatment effect on functional ability or executive function was not established (P.0.05; Table 3).67 Similar to the proof-of-concept study, SouvenaidH was well tolerated with adverse events consistent with those expected in an elderly population with mild AD. In addition, Souvenir II employed techniques to assess the impact of treatment on synaptic function and connectivity. The encephalographic signal reflects synchronous activity of many synapses and is therefore representative of underlying synaptic function.68 Souvenir II demonstrated that treatment with SouvenaidH increased peak frequency and functional connectivity in the delta band over the 24-week treatment period, suggesting preserved or even enhanced synaptic function in the active group. This was the first evidence that the cognitive benefits of a nutritional intervention may be related to improved synaptic function. A further randomized, controlled study of SouvenaidH, the US S-Connect study, enrolled 527 patients with mild to moderate AD to assess the effects of 24 weeks of once-daily SouvenaidH on cognitive performance. Preliminary results showed that both the placebo and SouvenaidH groups showed a modest increase in Alzheimer’s Disease Assessment Scale-cognitive scores over the duration of the study, with no difference between treatment groups at Week 2469 Another randomized, controlled study of SouvenaidH is currently in progress: the 2-year LipiDiDiet study recruited 300 patients with prodromal AD, measuring memory performance of the modified NTB and secondary measures of progression to AD, cognitive performance and functional abilities (Alzheimer’s Disease Cooperative Study–
Table 3 Descriptive statistics for the neuropsychological test battery outcomes from the randomized, controlled, Souvenir II study investigating the impact of the nutritional supplement SouvenaidH on memory and cognitive function in patients with mild AD67
NTB memory domain z-score Change baseline – Week 24 24-week outcome trajectory NTB executive function domain z-score Change baseline – Week 24 24-week outcome trajectory NTB total composite z-score Change baseline – Week 24 24-week outcome trajectory Note: NTB: Neuropsychological test battery.
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Control (n5129)
Active (n5130)
P-value
0.111 (0.463) [103]
0.202 (0.395) [103]
0.090 0.023
0.006 (0.323) [99]
0.048 (0.333) [93]
0.386 0.686
0.035 (0.286) [89]
0.120 (0.278) [83]
0.035 0.053
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activities of daily living, depression). Results from LipiDiDiet will add to the available evidence for SouvenaidH in patients with mild AD.
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Conclusion The importance of nutrition in AD is clear, but translating the preclinical and epidemiological data into clinical benefits has been challenging and dietary supplementation with individual nutrients has produced inconclusive or negative results. However, results from trials with SouvenaidH show that a combination approach to nutritional intervention has the potential to improve memory performance and could become part of the management regimen in early AD. Clinical trials in MCI due to AD are ongoing.
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Acknowledgements Editorial assistance with the first draft of this review article was provided by Veronica Porkess PhD, of Fishawack Communications Ltd, funded by Nutricia Advanced Medical Nutrition.
Competing Interests
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All authors were consultants for Nutricia.
References 1 Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res. 2011;1415:136– 48. 2 DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. 3 Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59:1118–9. 4 de Wilde MC, Kamphuis PJ, Sijben JW, Scheltens P. Utility of imaging for nutritional intervention studies in Alzheimer’s disease. Eur J Pharmacol. 2011;668Suppl 1: S59–69. 5 Mosconi L, McHugh PF. FDG- and amyloid-PET in Alzheimer’s disease: is the whole greater than the sum of the parts? Q J Nucl Med Mol Imaging. 2011;55:250–64. 6 Grantham-McGregor S. Chronic undernutrition and cognitive abilities. Hum Nutr Clin Nutr. 1984;38:83–94. 7 Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66:216–25. 8 Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006;59:912–21. 9 Phillips MA, Childs CE, Calder PC, Rogers PJ. Lower omega-3 fatty acid intake and status are associated with poorer cognitive function in older age: A comparison of individuals with and without cognitive impairment and Alzheimer’s disease. Nutr Neurosci. 2012. [Epub ahead of print]. 10 van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Dullemeijer C, Olderikkert MG, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71:430–8. 11 Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, et al. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr. 2010;91:1725–32. 12 Geleijnse JM, Giltay EJ, Kromhout D. Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimers Dement. 2012;8:278–87. 13 Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, et al. Beneficial effects of docosahexaenoic
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acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6:456–64. Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, doubleblind, placebo-controlled trial. Psychopharmacology (Berl). 2013;225:605–12. Rondanelli M, Opizzi A, Faliva M, Mozzoni M, Antoniello N, Cazzola R, et al. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutr Neurosci. 2012;15:46–54. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107:1682–93. Stough C, Downey L, Silber B, Lloyd J, Kure C, Wesnes K, et al. The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population. Neurobiol Aging. 2012;33:824 e1–3. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304:1903–11. Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1538–44. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxe´n-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402–8. Eussen SJ, de Groot LC, Joosten LW, Bloo, RJ, Clarke, R, Ueland, PM, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84:361–70. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208–16. Ford AH, Flicker L, Alfonso H, Thomas J, Clarnette R, Martins R, et al. Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology. 2010;75:1540–7. Walker JG, Batterham PJ, Mackinnon AJ, Jorm AF, Hickie I, Fenech M, et al. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in communitydwelling older adults with depressive symptoms–the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012;95:194–203. Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5:e12244. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–88. Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006;166:2462–8. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, et al. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012;69:836–41. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9:112–24. Titova OE, Sjogren P, Brooks SJ, Kullberg J, Ax E, Kilander L, et al. Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly. Age (Dordr). 2013;35:1495–505. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, et al. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25:3032–40.
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32 Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2012;6:CD005379. 33 Danthiir V, Burns NR, Nettelbeck T, Wilson C, Wittert G. The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: a randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults. Nutr J. 2011;10:117. 34 Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging. 2009;13:189–97. 35 Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, et al. Metabolite profiling of Alzheimer’s disease cerebrospinal fluid. PLoS One. 2012;7:e31501. 36 Richter Y, Herzog Y, Eyal I, Cohen T. Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial. J Diet Suppl. 2011;8:158–68. 37 Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008;29:S143– 72. 38 Sachdev PS, Valenzuela M, Wang XL, Looi JC, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology. 2002;58:1539–41. 39 Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med. 2005;118:161–7. 40 Morris MS, Selhub J, Jacques PF. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study. J Am Geriatr Soc. 2012;60:1457–64. 41 Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev. 2012;2012:914273. 42 Wurtman RJ, Cansev M, Sakamoto T, Ulus IH. Use of phosphatide precursors to promote synaptogenesis. Annu Rev Nutr. 2009;29:59–87. 43 Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5’-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005;1058:101–8. 44 van Wijk N, Watkins CJ, Bo¨hlke M, Maher TJ, Hageman RJ, Kamphuis PJ, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 2012;107:1408–12. 45 van Wijk N, Watkins CJ, Hageman RJ, Sijben JC, Kamphuis PG, Wurtman RJ, et al. Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats. Nutr Metab (Lond). 2012;9:49. 46 Cansev M, Wurtman RJ. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience. 2007;148:421–31. 47 Cansev M, Marzloff G, Sakamoto T, Ulus IH, Wurtman RJ. Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009;31:181–92. 48 Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ. Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson’s disease. Neurosci Res. 2008;62:206–9. 49 Holguin S, Huang Y, Liu J, Wurtman R. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008;191:11–6. 50 Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. 2008;22:3938–46. 51 Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5’-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50–9. 52 Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff G. Synaptic proteins and phospholipids are increased
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in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006;1088:83–92. Shrivastava R, Vincent B, Gobron S, Cucuat N, John GW. Evidence for growth-promoting effects of omega n-3 fatty acids alone and in combination with a specific vitamin and mineral complex in rat neuroblastoma cells. Nutr Neurosci. 2005;8:317– 21. Arellano JI, Espinosa A, Fairen A, Yuste R, DeFelipe J. Nonsynaptic dendritic spines in neocortex. Neuroscience. 2007;145:464–9. de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM. Neuroprotective effects of a specific multi-nutrient intervention against Abeta42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327–39. Hashimoto M, Hossain S, Agdul H, Shido O. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid beta-infused rats relates to the decreases of amyloid beta and cholesterol levels in detergent-insoluble membrane fractions. Biochim Biophys Acta. 2005;1738:91–8. Arendash GW, Jensen MT, Salem N, Jr, Hussein N, Cracchiolo J, Dickson A, et al. A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer’s transgenic mice. Neuroscience. 2007;149:286–302. de Wilde MC, Farkas E, Gerrits M, Kiliaan AJ, Luiten PG. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion. Brain Res. 2002;947:166–73. de Wilde MC, Hogyes E, Kiliaan AJ, Farkas T, Luiten PG, Farkas E. Dietary fatty acids alter blood pressure, behavior and brain membrane composition of hypertensive rats. Brain Res. 2003;988:9–19. Broersen LM, Kuipers AA, Balvers M, van Wijk N, Savelkoul PJ, de Wilde MC, et al. A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AbetaPPswe/PS1dE9 mice. J Alzheimers Dis. 2013;33:177–90. Harris E, Macpherson H, Vitetta L, Kirk J, Sali A, Pipingas A. Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial. Hum Psychopharmacol. 2012;27:370– 7. Wolters M, Hickstein M, Flintermann A, Tewes U, Hahn A. Cognitive performance in relation to vitamin status in healthy elderly German women-the effect of 6-month multivitamin supplementation. Prev Med. 2005;41:253–9. McNeill G, Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutr J. 2007;6:10. Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L, Hercberg S, Galan P. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Am J Clin Nutr. 2011;94:278–86. Kesse-Guyot E, Fezeu L, Jeandel C, Ferry M, Andreeva V, Amieva H, et al. French adults’ cognitive performance after daily supplementation with antioxidant vitamins and minerals at nutritional doses: a post hoc analysis of the Supplementation in Vitamins and Mineral Antioxidants (SU.VI.MAX) trial. Am J Clin Nutr. 2011;94:892–9. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, et al. Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial. Alzheimers Dement. 2010;6:1–10e1. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, et al. Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis. 2012;31:225–36. Siegel M, Donner TH, Engel AK. Spectral fingerprints of largescale neuronal interactions. Nat Rev Neurosci. 2012;13:121–34. Shah R, Kamphuis P, Leurgans S, Swinkels S, Sadowsky C, Bongers A, Rappaport S, Quinn J, Wieggers R, Bennett D, Scheltens P. SouvenaidH as an add-on intervention in patients with mild to moderate Alzheimer’s disease using Alzheimer’s disease medication: results from a randomized, controlled, double-blind study (S-Connect). CtAD, San Diego, November 2011; J Nutr Health Aging 2011;15 (Suppl 1) S30 (Abstract P38).
Rationale and clinical data supporting nutritional intervention in Alzheimer’s disease S. Engelborghs1, C. Gilles2, A. Ivanoiu3, M. Vandewoude4 1
Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium and Memory Clinic and Department of Neurology, ZNA Hoge Beuken and Middelheim, Antwerp, Belgium, 2 Geriatrics Department and Memory Clinic, Centre Hospitalier de l’Ardenne-Vivalia, Libramont, Belgium, 3 Department of Neurology, Saint Luc University Hospital, and Institute of Neuroscience, Catholic University of Louvain, Brussels, Belgium, 4Department of Geriatrics, ZNA St. Elisabeth, University of Antwerp, Antwerp, Belgium Adequate nutrition plays an important role in the maintenance of cognitive function, particularly during aging. Malnutrition is amongst the risk factors for developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Epidemiological studies have associated deficiencies in some nutrients with a higher risk of cognitive dysfunction and/or AD. Cognitive decline in AD is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources. As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors (mainly uridine monophosphate, choline and omega-3 fatty acids) to make the phospholipids required to build neuronal membranes may have beneficial effects on synaptic degeneration in AD. In addition, B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Despite this, no randomized controlled trial has hitherto provided evidence that any single nutrient has a beneficial effect on cognition or lowers the risk for AD. However, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders like AD leading to synaptic degeneration. Here we review the clinical evidence for supplementation, based on a multi-target approach with a focus on key nutrients with a proposed role in synaptic dysfunction. Based on preclinical evidence, a nutrient mixture, SouvenaidH (Nutricia N.V., Zoetermeer, The Netherlands) was developed. Clinical trials with SouvenaidH have shown improved memory performance in patients with mild AD. Further clinical trials to evaluate the effects of nutritional intervention in MCI and early dementia due to AD are on-going. Keywords: Nutrition, Alzheimer’s disease, Docosahexaenoic acid, Vitamin B, Folic acid
Introduction Alzheimer’s disease (AD) places a huge burden on society due to the medical and societal costs associated with treating and caring for patients with cognitive impairment. The key pathological features of AD include the accumulation of amyloid b and hyperphosphorylated tau,1 which are the principal components of the neuropathological hallmarks of AD, senile plaques and neurofibrillary tangles. Together with oxidative stress, elevated homocysteine and mitochondrial and vascular dysfunction, these changes are thought to lead to membrane disruption and synaptic loss. Among the different pathological
Correspondence to: S. Engelborghs, Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Universiteitsplein 1, BE–2610 Antwerp, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551213Z.0000000006
markers, synaptic loss shows the closest correlation with cognitive decline.2,3 At present, it is not possible to directly measure in vivo synaptic activity or loss, but fluorine-18 fluorodeoxyglucose positron emission tomography does allow the visualisation of glucose metabolism as a marker for synaptic activity.4 Evidence from this technique shows that a reduction in glucose metabolism in specific brain areas is present from the earliest stages of the disease process.5 It has long been known that cognitive function can be influenced by nutrition.6 High body mass index during middle age has been associated with an increased risk of dementia in old age and mild calorie restriction has been shown to delay age-related cortical atrophy. The Mediterranean diet, which is rich in vegetables, antioxidants and polyunsaturated
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fatty acids (PUFA), is associated with a lower risk of mild cognitive impairment (MCI)7 and AD.8 In the elderly, malnutrition and weight loss are also indicators of faster progression in AD. Patients with early-stage AD are more likely to be deficient in specific nutrients, and a low intake of omega-3 fatty acids is associated with increased risk of MCI and AD.9 This is unsurprising, as the brain is made up of 60% fat, 20% of which is omega-3 (v-3) and omega-6 (v-6) essential fatty acids. In particular, the production and maintenance of neural membranes is vital for synapse formation and function and requires provision of numerous nutrients in the diet, including v-3 and v-6 PUFA. Here we review the preclinical and clinical studies investigating the potential of specific nutritional components to affect neuronal membrane formation and composition, synaptic formation/function and cognitive performance.
Role of specific nutrients in AD Preclinical and epidemiological studies have implicated many nutrients in AD, including those related to neuronal membranes and synaptic function. However, the evidence for the effectiveness of supplementation with individual nutrients in AD is conflicting. The outcomes of published, randomized, double-blind studies of individual nutrients are summarized in Table 1.10–28 PUFA including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Synapses consist of neuronal membranes that are composed of phospholipid bilayers embedded with cholesterol and sphingolipids.29 Of the phospholipids that make up neuronal membranes and are needed for optimum receptor functioning, phosphatidylcholine is the most abundant. Choline, uridine and docosahexaenoic acid (DHA), all precursors to phosphatidylcholine, are also required for brain phosphatide synthesis. Dietary intake of eicosapentaenoic acid (EPA) and DHA is associated with global grey matter volume and increased cognitive performance in healthy elderly subjects.30 Furthermore, preclinical studies have suggested that a diet rich in PUFA could have a beneficial effect against the pathology of AD.31 Several studies have investigated this effect of dietary supplementation with EPA and DHA, in both healthy subjects and patients with MCI or mild to moderate AD. The quality of these studies varies, as do the number of participants and the duration of treatment. A recent Cochrane review analyzed the randomized, double-blind studies in which PUFA supplements were given to healthy older subjects, limiting the review to larger studies of >6 months duration.32 Three studies met the criteria and
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together involved over 4000 subjects.10–12 The metaanalysis concluded that there was no benefit of fishoil supplementation in healthy older people, but that longer studies may be needed to detect a signal. The on-going EPOCH trial is investigating effects of DHA and EPA in 391 cognitively healthy older adults over 18 months and has completed enrolment.33 Further studies have investigated the effects in subjects with MCI, dementia or age-related cognitive impairments. Again, the results have been mixed, but the largest, longest study found no effect of DHA supplementation on cognitive decline.18 Uridine and choline Uridine and choline are precursors for the phosphatides in synaptic membranes and therefore crucial to synaptic function. As with PUFAs, a variety of evidence pointed to a role for uridine and choline in cognitive enhancement. Rodent studies found that supplementing diet with uridine plus DHA enhanced dendritic spine levels and cognitive performance,34 and a biomarker study looking at cerebrospinal fluid from patients with AD identified increased cysteine and decreased uridine as the best combination to predict mild AD (mini-mental state examination [MMSE] .22) with specificity and sensitivity over 75%.35 However, no randomized, blinded clinical trials exploring the effect of uridine or choline, alone, or in combination, on cognition have been reported. The nutrient combination CognitexH (Life ExtensionH, Fort Lauderdale, FL, USA), which contains uridine-5 monophosphate, alpha-glyceryl phosphorylcholine, phosphatidylserine and pregnenolone, has been assessed in a 12-week, open-label trial of 30 elderly patients with subjective memory complaints and may improve cognitive performance,36 but this requires replication in a double-blind, placebo-controlled study. Folic acid and other B vitamins Homocysteine is cytotoxic and is usually transported out of cells into the plasma, so high plasma levels of homocysteine reflect high intracellular concentrations. High plasma homocysteine levels have been associated with higher risk of AD and brain atrophy in both patients with AD37 and the healthy elderly.38 Folic acid and B vitamins such as B6 and B12 regulate levels of homocysteine, which is biosynthesized from methionine by the removal of the terminal C-methyl group and can be recycled into methionine or converted into cysteine with the aid of B vitamins that act as co-enzymes. Epidemiological studies have shown that low levels of folic acid or vitamin B6 predict cognitive decline in elderly subjects,39 which may be due to their action as co-factors to enhance
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fatty acids (PUFA), is associated with a lower risk of mild cognitive impairment (MCI)7 and AD.8 In the elderly, malnutrition and weight loss are also indicators of faster progression in AD. Patients with early-stage AD are more likely to be deficient in specific nutrients, and a low intake of omega-3 fatty acids is associated with increased risk of MCI and AD.9 This is unsurprising, as the brain is made up of 60% fat, 20% of which is omega-3 (v-3) and omega-6 (v-6) essential fatty acids. In particular, the production and maintenance of neural membranes is vital for synapse formation and function and requires provision of numerous nutrients in the diet, including v-3 and v-6 PUFA. Here we review the preclinical and clinical studies investigating the potential of specific nutritional components to affect neuronal membrane formation and composition, synaptic formation/function and cognitive performance.
Role of specific nutrients in AD Preclinical and epidemiological studies have implicated many nutrients in AD, including those related to neuronal membranes and synaptic function. However, the evidence for the effectiveness of supplementation with individual nutrients in AD is conflicting. The outcomes of published, randomized, double-blind studies of individual nutrients are summarized in Table 1.10–28 PUFA including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) Synapses consist of neuronal membranes that are composed of phospholipid bilayers embedded with cholesterol and sphingolipids.29 Of the phospholipids that make up neuronal membranes and are needed for optimum receptor functioning, phosphatidylcholine is the most abundant. Choline, uridine and docosahexaenoic acid (DHA), all precursors to phosphatidylcholine, are also required for brain phosphatide synthesis. Dietary intake of eicosapentaenoic acid (EPA) and DHA is associated with global grey matter volume and increased cognitive performance in healthy elderly subjects.30 Furthermore, preclinical studies have suggested that a diet rich in PUFA could have a beneficial effect against the pathology of AD.31 Several studies have investigated this effect of dietary supplementation with EPA and DHA, in both healthy subjects and patients with MCI or mild to moderate AD. The quality of these studies varies, as do the number of participants and the duration of treatment. A recent Cochrane review analyzed the randomized, double-blind studies in which PUFA supplements were given to healthy older subjects, limiting the review to larger studies of >6 months duration.32 Three studies met the criteria and
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together involved over 4000 subjects.10–12 The metaanalysis concluded that there was no benefit of fishoil supplementation in healthy older people, but that longer studies may be needed to detect a signal. The on-going EPOCH trial is investigating effects of DHA and EPA in 391 cognitively healthy older adults over 18 months and has completed enrolment.33 Further studies have investigated the effects in subjects with MCI, dementia or age-related cognitive impairments. Again, the results have been mixed, but the largest, longest study found no effect of DHA supplementation on cognitive decline.18 Uridine and choline Uridine and choline are precursors for the phosphatides in synaptic membranes and therefore crucial to synaptic function. As with PUFAs, a variety of evidence pointed to a role for uridine and choline in cognitive enhancement. Rodent studies found that supplementing diet with uridine plus DHA enhanced dendritic spine levels and cognitive performance,34 and a biomarker study looking at cerebrospinal fluid from patients with AD identified increased cysteine and decreased uridine as the best combination to predict mild AD (mini-mental state examination [MMSE] .22) with specificity and sensitivity over 75%.35 However, no randomized, blinded clinical trials exploring the effect of uridine or choline, alone, or in combination, on cognition have been reported. The nutrient combination CognitexH (Life ExtensionH, Fort Lauderdale, FL, USA), which contains uridine-5 monophosphate, alpha-glyceryl phosphorylcholine, phosphatidylserine and pregnenolone, has been assessed in a 12-week, open-label trial of 30 elderly patients with subjective memory complaints and may improve cognitive performance,36 but this requires replication in a double-blind, placebo-controlled study. Folic acid and other B vitamins Homocysteine is cytotoxic and is usually transported out of cells into the plasma, so high plasma levels of homocysteine reflect high intracellular concentrations. High plasma homocysteine levels have been associated with higher risk of AD and brain atrophy in both patients with AD37 and the healthy elderly.38 Folic acid and B vitamins such as B6 and B12 regulate levels of homocysteine, which is biosynthesized from methionine by the removal of the terminal C-methyl group and can be recycled into methionine or converted into cysteine with the aid of B vitamins that act as co-enzymes. Epidemiological studies have shown that low levels of folic acid or vitamin B6 predict cognitive decline in elderly subjects,39 which may be due to their action as co-factors to enhance
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Smith et al. 201025
Walker et al. 201224
Ford et al. 201023
Durga et al. 2007 FACIT22
Vitamin B/folic acid Eussen et al. 200621
Freund-Levi et al. 200620
Quinn et al. 201018 Chiu et al. 200819
Stough et al. 201217
6 months, plus 6 months open label
18 months 24 weeks
90 days
271 subjects with MCI, aged >70 years
900 adults aged 60–64 years with depressive symptoms
24 months
2 years
195 older persons with mild vitamin 24 weeks B deficiency living freely and living in care facility houses aged >70 years 818 healthy men and women with raised 3 years plasma homocysteine Age 50–70 years 299 men with hypertension, aged >75 years 2 years
174 patients with mild–moderate AD
50 subjects aged .65 years with MCI 74 healthy participants aged 45–77 years 295 patients with mild–moderate AD 46 patients with MCI or mild–moderate AD
Sinn et al. 201216 6 months
12 weeks
25 elderly subjects with MCI
Rondanelli et al. 201215
DHA improved memory and DHA-treated subjects had a significantly better change in memory then placebo-treated subjects DHAzmelatoninztryptophan combination improved several measures of cognitive function
No decline in cognitive function in either treatment or placebo arm No effect of dietary doses of v-3 fatty acids on global cognitive decline in coronary heart disease patients DHA improved memory function in healthy older adults with age-related cognitive decline
No effect on cognitive performance
Conclusion
100 mg Folic acid 0.8 mg vitamin B6 20 mg vitamin B12 0.5 mg
Folic acid, 2 mg Vitamin B6, 25 mg Vitamin B12, 400 mg Folic acid 400 mg, vitamin B12
Folic acid 0.8 mg/day
Vitamin B12, 1 mg, with or without folic acid, 0.4 mg/day
Treatment slowed the rate of brain atrophy in patients with MCI.
Supplementation improved immediate and delayed memory performance compared with placebo
Vitamin B12 administered alone or in combination with folic acid showed no improvements in cognitive function in older persons Improved performance on tests that measure information-processing speed and memory, domains that are known to decline with age No difference in change in cognitive performance from baseline to 24 months with vitamin treatment vs placebo
Daily: DHA (720 mg), EPA (286 mg), vitamin E (16 mg), soy phospholipids (160 mg), melatonin (5 mg), tryptophan (95 mg) EPA, 1.67 g/day DHA, but not EPA, improved verbal fluency DHA, 1.55 g/day HiDHAH (252 mg DHA, 60 mg EPA, No significant effects on cognitive function 10 mg vitamin E) DHA 2 g/day No effect of DHA on rate cognitive decline Omega-3 PUFA Treatment group showed improvement in ADAS-cog compared with placebo, in patients with 1.8 g/day MCI but not AD DHA 1.7 g No effect of DHA/EPA on rate of cognitive decline, EPA 0.6 g but positive effects were observed in a subset of patients with very mild AD (MMSE .27)
DHA, 430 mg plus EPA, 150 mg/day
12 months
Fish oil 1800 or 400 mg/day 200 mg EPA plus 500 mg DHA EPA–DHA 400 mg/day or a-linolenic acid 2 g/day, or EPA plus a-linolenic acid DHA, 900 mg/day
40 months
24 months
26 weeks
Mean follow-up Nutrient
6 months
OPAL
302 cognitive healthy subjects aged >65 years 867 cognitively healthy adults, aged 70–79 years 2911 cognitively healthy adults aged 60–80 years
Subjects
Yurko-Mauro et al. 2010 MIDAS13 185 subjects with a Logical Memory (WMS III) baseline score .1 SD below younger adult mean, aged .55 years 36 elderly subjects with MCI Lee et al. 201214
Geleijnse et al.12
Dangour et al. 2010
11
EPA/DHA Van de Rest et al. 200810
Study
Table 1 Randomized, double-blind trials of individual nutritional supplements on cognitive performance
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Note: AD, Alzheimer’s disease; ADAS-cog, Alzheimer’s disease assessment scale-cognitive; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; FACIT, Folic Acid and Carotid Intima-Media Thickness; MCI, mild cognitive impairment; MIDAS, Memory Improvement with DHA Study; MMSE, mini-mental state examination; OPAL, Older People And n-3 Long-chain polyunsaturated fatty acids study; PUFA, polyunsaturated fatty acids; SD, standard deviation; WMS, Wechsler memory scale.
Vitamin E did not reduce the rate of cognitive decline Subjects in the supplementation group experienced more rapid decline in MMSE
Vitamin E had no effect on rate of progression to AD
Vitamin E 1.5 g/day plus donepezil 10 mg Vitamin E 600 IU every other day Vitamin E 800 IU/day Vitamin C 500 mg/day a-lipoic acid 900 mg/day Coenzyme Q 400 mg, 3x daily 3 years
769 subjects with MMSE 24–30 55–90 6377 healthy US women aged >65 years 66 subjects with mild–moderate AD
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Vitamin C and E Petersen et al. 200526
Mean follow-up Nutrient Subjects Study
Table 1 Continued 20
Patients with higher baseline homocysteine levels who received active treatment experienced a greater reduction in atrophy than placebo
Nutrition in Alzheimer’s disease
Conclusion
Engelborghs et al.
endogenous precursor synthesis via the regeneration of methyl groups, thereby affecting the availability of precursors and potentially synaptogenesis. Paradoxically though, high levels of folic acid have also been associated with especially rapid cognitive decline40 and the results from interventional studies are conflicting (Table 1).10–28 In subjects with no signs of cognitive decline, supplementation with folic acid had no effect on cognitive performance.21,23 However, in some specific patient groups, such as patients with elevated homocysteine levels22 or patients with depressive symptoms,24 folic acid and vitamin B6 and B12 supplementation produced positive cognitive effects, and in combination they were shown to slow the rate of brain atrophy in patients with MCI.25 Vitamins C and E The brain is particularly sensitive to damage by reactive oxygen species, which are produced by mitochondria. Preclinical evidence suggests that a diet rich in antioxidants, such as vitamins C and E, can inhibit production of amyloid b or prevent cognitive dysfunction in animals.41 However, of the three double-blind, placebo-controlled trials that have been reported, two showed no effect of vitamin E supplementation on cognitive function26,27 and the third found a faster cognitive decline in the intervention than the placebo group,28 suggesting that vitamin E supplementation is not an effective intervention for age-related cognitive decline or mild AD. In conclusion, the results of interventional trials with single nutrients have not demonstrated conclusive evidence for preventing cognitive decline in healthy older subjects, or for preventing loss or restoring function in patients with mild to moderate AD.
Role of nutrient combinations in AD Synaptic loss shows the closest correlation with cognitive health in AD. Synapses are part of the neuronal membrane, which is being continuously remodelled, so adequate availability of the nutritional precursors (mainly uridine monophosphate, choline and v-3fatty acids) of the phospholipids required to build neuronal membranes might have beneficial effects on synaptic degeneration in AD. In addition, as B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders with synaptic degeneration, such as AD.
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Note: AD, Alzheimer’s disease; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; MAVIS, mineral and vitamin intervention study; MMSE, mini-mental state examination; NTB, neuropsychological test battery; SU.FOL.OM3, supplementation with folate, vitamins B12 and/or omega-3 fatty acids; SU.VI.MAX, supplementation in vitamins and mineral antioxidants.
SouvenaidH 24 weeks Scheltens et al. 2012 (Souvenir II)67
Scheltens et al. 2010 (Souvenir I)66
225 subjects with probable AD (MMSE 20–26) 259 drug-naive patients with mild AD
8 years’ treatment followed by 6 years’ treatment-free 12 weeks
Folate 0.56 mg, vitamin B6 3 mg, B12 0.02 mg or EPA/DHA 600 mg, or both Vitamin C 120 mg, B carotene 6 mg, vitamin E 30 mg, selenium 100 mg and zinc 20 mg/day SouvenaidH 4 years
1748 subjects with history of myocardial infarction, aged 45–80 years 4447 healthy French adults aged 45–60 years at baseline
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Kesse-Guyot et al. 2011 SU.VI.MAX65
McNeill et al. 2007 MAVIS63
Andreeva et al. 2011 SU.FOL.OM364
1 year
6 months
220 healthy, free-living women aged 60–91 years 910 healthy men and women aged >65 years Wolters et al. 2005
Nutrition in Alzheimer’s disease
No evidence for beneficial effect of supplementation on cognitive function Possible beneficial effects in those at higher risk of nutritional deficiency No significant effect of supplementation on cognitive function, although evidence of beneficial effects in some subgroups was observed Improved episodic memory after supplementation Improved verbal memory only in subjects who were nonsmokers or had low vitamin C concentrations at baseline SouvenaidH improved delayed verbal recall compared with placebo Increase in NTB memory domain z-score in active vs control group
Episodic memory was significantly improved following supplementation No effect on cognitive performance
Multivitamin, mineral and herb supplement (Swisse Men’s UltiviteH) Multivitamin providing 11 vitamins and 2 minerals Multivitamin providing 11 vitamins and 5 minerals at 50–210% of UK reference nutrient intake 8 weeks 51 men aged 50–74 years Harris et al. 201261
62
Nutrient Mean follow-up Subjects Multivitamin/combination approaches
Table 2 Randomized, double-blind trials of combinations of nutritional supplements on cognitive performance
Preclinical evidence A number of studies have shown that levels of membrane phospholipids and their precursors can be increased by administration of uridine, DHA or EPA, and choline, both in vitro and in vivo.42,43 Studies in rats have shown that dietary B-vitamin supplementation increased concentrations of plasma choline44 and DHA45 compared with rats deficient in vitamin D. However, unlike DHA and EPA, the v-6 PUFA arachidonic acid administered orally to gerbils did not promote membrane synthesis.46 The largest effects on levels of brain phospholipids have been seen with combined administration of DHA and/or uridine monophosphate to gerbils and rats consuming choline-containing diets.46–52 A combination of PUFAs, vitamins and minerals was more effective at promoting neurite outgrowth in a neuroblastoma cell model than each of the nutrients alone53 and co-administration of uridine, EPA/DHA and choline increased dendritic spine density in the hippocampus of adult gerbils to a greater extent than when given without uridine.51 Dendritic spine formation is considered to be the precursor to formation of new synaptic connections in the adult brain54 and enhances cognitive function.49,50 Diets supplemented with choline, uridine monophosphate and DHA also lead to elevation in levels of synaptic proteins, such as syntaxin-3, PSD-95 and synapsin-1, markers of synaptogenesis.46 In animal models of AD, dietary enrichment with a combination of several precursors and cofactors (UMP, v-3 PUFAs, choline, folate, vitamin B12, vitamin B6, phospholipids and antioxidants) increased neuronal membrane phosphatidylcholine synthesis,55 where the effects of individual nutrients have been inconsistent. Some studies demonstrated reductions in Ab levels with DHA supplementation in transgenic mouse models31 and Ab pre-infused rats,56 but other studies showed no effect of v-3 PUFAs on Ab levels.57 Oral uridine monophosphate and/or DHA supplementation enhanced learning and memory in normal gerbils; the largest effects occurred when DHA and UMP were supplemented in combination.50 Tests of spatial learning and memory in both normal rats and animals with chronic cerebral hypo-perfusion showed improved outcomes with combined administration of PUFAs, choline, B vitamins, phospholipids, antioxidants and other nutrients compared with these nutrients alone.58,59 The specific nutrient combination FortasynH Connect includes DHA, EPA, uridine-mono-phosphate, choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium and was hypothesized to enhance synapse formation and function. In in vivo studies, FortasynH Connect prevented the Ab-induced
Conclusion
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21
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reduction in exploratory activity in rats infused with Ab55 and decreased Ab levels in a transgenic mouse model of AD, where supplementation with DHA or UMP, alone and in combination, was less effective.60 Clinical evidence The results of clinical trials of combined nutritional supplements are summarized in Table 2.61–67 One interventional study of a multivitamin and mineral supplement (Swisse Men’s UltiviteH, Swisse Vitamins Pty Ltd, Melbourne, Australia), given to 51 men aged 50–74 years for 8 weeks, showed a benefit on cognitive performance,61 but two larger, longer studies of combination supplements (220 healthy women aged >60 years, 6 months of treatment, and 910 healthy men and women aged >65 years, 1 year of treatment) did not find any conclusive evidence of a benefit.62,63 The nutritional intervention SouvenaidH (Nutricia N.V., Zoetermeer, The Netherlands), which contains the specific nutrient combination FortasynH Connect, has currently been assessed in two randomized controlled trials. The first was a double-blind, placebo-controlled, multi-country, proof-of-concept study (Souvenir I study, Dutch Trial Register number ISRCTN72254645) involving 225 drug-naive patients with mild AD (MMSE 20–26).66 After 12 weeks of once-daily treatment, a significant improvement in the co-primary endpoint of delayed verbal recall was observed in patients who had received active treatment.66 SouvenaidH was also found to be very well tolerated with a high level of treatment adherence (.90%). These data provided the first indication that the hypothesis behind the development of FortasynH Connect and SouvenaidH may be true. However, no biomarkers of synaptic activity or connectivity were measured to further validate this hypothesis. To extend and confirm these findings, a follow-up study (Souvenir II) was conducted. The Souvenir II study was a 24-week, randomized, placebo-controlled, double-blind, parallel-group, multi-country, trial to assess the efficacy and tolerability of
SouvenaidH in drug-naive patients with mild AD (MMSE 2563, Dutch Trial Registration number NTR1975). The primary endpoint was memory performance and a significant improvement was reported with SouvenaidH (P50.023 for a positive trajectory of active intervention versus placebo; as assessed by the memory domain z-score of a neuropsychological test battery [NTB], Table 3).67 However, a treatment effect on functional ability or executive function was not established (P.0.05; Table 3).67 Similar to the proof-of-concept study, SouvenaidH was well tolerated with adverse events consistent with those expected in an elderly population with mild AD. In addition, Souvenir II employed techniques to assess the impact of treatment on synaptic function and connectivity. The encephalographic signal reflects synchronous activity of many synapses and is therefore representative of underlying synaptic function.68 Souvenir II demonstrated that treatment with SouvenaidH increased peak frequency and functional connectivity in the delta band over the 24-week treatment period, suggesting preserved or even enhanced synaptic function in the active group. This was the first evidence that the cognitive benefits of a nutritional intervention may be related to improved synaptic function. A further randomized, controlled study of SouvenaidH, the US S-Connect study, enrolled 527 patients with mild to moderate AD to assess the effects of 24 weeks of once-daily SouvenaidH on cognitive performance. Preliminary results showed that both the placebo and SouvenaidH groups showed a modest increase in Alzheimer’s Disease Assessment Scale-cognitive scores over the duration of the study, with no difference between treatment groups at Week 2469 Another randomized, controlled study of SouvenaidH is currently in progress: the 2-year LipiDiDiet study recruited 300 patients with prodromal AD, measuring memory performance of the modified NTB and secondary measures of progression to AD, cognitive performance and functional abilities (Alzheimer’s Disease Cooperative Study–
Table 3 Descriptive statistics for the neuropsychological test battery outcomes from the randomized, controlled, Souvenir II study investigating the impact of the nutritional supplement SouvenaidH on memory and cognitive function in patients with mild AD67
NTB memory domain z-score Change baseline – Week 24 24-week outcome trajectory NTB executive function domain z-score Change baseline – Week 24 24-week outcome trajectory NTB total composite z-score Change baseline – Week 24 24-week outcome trajectory Note: NTB: Neuropsychological test battery.
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Control (n5129)
Active (n5130)
P-value
0.111 (0.463) [103]
0.202 (0.395) [103]
0.090 0.023
0.006 (0.323) [99]
0.048 (0.333) [93]
0.386 0.686
0.035 (0.286) [89]
0.120 (0.278) [83]
0.035 0.053
Engelborghs et al.
activities of daily living, depression). Results from LipiDiDiet will add to the available evidence for SouvenaidH in patients with mild AD.
14
Conclusion The importance of nutrition in AD is clear, but translating the preclinical and epidemiological data into clinical benefits has been challenging and dietary supplementation with individual nutrients has produced inconclusive or negative results. However, results from trials with SouvenaidH show that a combination approach to nutritional intervention has the potential to improve memory performance and could become part of the management regimen in early AD. Clinical trials in MCI due to AD are ongoing.
15
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Acknowledgements Editorial assistance with the first draft of this review article was provided by Veronica Porkess PhD, of Fishawack Communications Ltd, funded by Nutricia Advanced Medical Nutrition.
Competing Interests
19
20
All authors were consultants for Nutricia.
References 1 Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer’s disease. Brain Res. 2011;1415:136– 48. 2 DeKosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol. 1990;27:457–64. 3 Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59:1118–9. 4 de Wilde MC, Kamphuis PJ, Sijben JW, Scheltens P. Utility of imaging for nutritional intervention studies in Alzheimer’s disease. Eur J Pharmacol. 2011;668Suppl 1: S59–69. 5 Mosconi L, McHugh PF. FDG- and amyloid-PET in Alzheimer’s disease: is the whole greater than the sum of the parts? Q J Nucl Med Mol Imaging. 2011;55:250–64. 6 Grantham-McGregor S. Chronic undernutrition and cognitive abilities. Hum Nutr Clin Nutr. 1984;38:83–94. 7 Scarmeas N, Stern Y, Mayeux R, Manly JJ, Schupf N, Luchsinger JA. Mediterranean diet and mild cognitive impairment. Arch Neurol. 2009;66:216–25. 8 Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol. 2006;59:912–21. 9 Phillips MA, Childs CE, Calder PC, Rogers PJ. Lower omega-3 fatty acid intake and status are associated with poorer cognitive function in older age: A comparison of individuals with and without cognitive impairment and Alzheimer’s disease. Nutr Neurosci. 2012. [Epub ahead of print]. 10 van de Rest O, Geleijnse JM, Kok FJ, van Staveren WA, Dullemeijer C, Olderikkert MG, et al. Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial. Neurology. 2008;71:430–8. 11 Dangour AD, Allen E, Elbourne D, Fasey N, Fletcher AE, Hardy P, et al. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr. 2010;91:1725–32. 12 Geleijnse JM, Giltay EJ, Kromhout D. Effects of n-3 fatty acids on cognitive decline: a randomized, double-blind, placebo-controlled trial in stable myocardial infarction patients. Alzheimers Dement. 2012;8:278–87. 13 Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, et al. Beneficial effects of docosahexaenoic
21
22
23 24
25
26 27 28
29 30
31
Nutrition in Alzheimer’s disease
acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010;6:456–64. Lee LK, Shahar S, Chin AV, Yusoff NA. Docosahexaenoic acid-concentrated fish oil supplementation in subjects with mild cognitive impairment (MCI): a 12-month randomised, doubleblind, placebo-controlled trial. Psychopharmacology (Berl). 2013;225:605–12. Rondanelli M, Opizzi A, Faliva M, Mozzoni M, Antoniello N, Cazzola R, et al. Effects of a diet integration with an oily emulsion of DHA-phospholipids containing melatonin and tryptophan in elderly patients suffering from mild cognitive impairment. Nutr Neurosci. 2012;15:46–54. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, et al. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr. 2012;107:1682–93. Stough C, Downey L, Silber B, Lloyd J, Kure C, Wesnes K, et al. The effects of 90-day supplementation with the omega-3 essential fatty acid docosahexaenoic acid (DHA) on cognitive function and visual acuity in a healthy aging population. Neurobiol Aging. 2012;33:824 e1–3. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304:1903–11. Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1538–44. Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun H, Faxe´n-Irving G, Garlind A, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006;63:1402–8. Eussen SJ, de Groot LC, Joosten LW, Bloo, RJ, Clarke, R, Ueland, PM, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84:361–70. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208–16. Ford AH, Flicker L, Alfonso H, Thomas J, Clarnette R, Martins R, et al. Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology. 2010;75:1540–7. Walker JG, Batterham PJ, Mackinnon AJ, Jorm AF, Hickie I, Fenech M, et al. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in communitydwelling older adults with depressive symptoms–the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012;95:194–203. Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5:e12244. Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med. 2005;352:2379–88. Kang JH, Cook N, Manson J, Buring JE, Grodstein F. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006;166:2462–8. Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, et al. Antioxidants for Alzheimer Disease: A Randomized Clinical Trial With Cerebrospinal Fluid Biomarker Measures. Arch Neurol. 2012;69:836–41. van Meer G, Voelker DR, Feigenson GW. Membrane lipids: where they are and how they behave. Nat Rev Mol Cell Biol. 2008;9:112–24. Titova OE, Sjogren P, Brooks SJ, Kullberg J, Ax E, Kilander L, et al. Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly. Age (Dordr). 2013;35:1495–505. Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, et al. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25:3032–40.
Acta Clinica Belgica
2014
VOL .
69
NO .
1
23
Engelborghs et al.
Nutrition in Alzheimer’s disease
32 Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev. 2012;6:CD005379. 33 Danthiir V, Burns NR, Nettelbeck T, Wilson C, Wittert G. The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: a randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults. Nutr J. 2011;10:117. 34 Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging. 2009;13:189–97. 35 Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, et al. Metabolite profiling of Alzheimer’s disease cerebrospinal fluid. PLoS One. 2012;7:e31501. 36 Richter Y, Herzog Y, Eyal I, Cohen T. Cognitex supplementation in elderly adults with memory complaints: an uncontrolled open label trial. J Diet Suppl. 2011;8:158–68. 37 Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008;29:S143– 72. 38 Sachdev PS, Valenzuela M, Wang XL, Looi JC, Brodaty H. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology. 2002;58:1539–41. 39 Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med. 2005;118:161–7. 40 Morris MS, Selhub J, Jacques PF. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study. J Am Geriatr Soc. 2012;60:1457–64. 41 Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev. 2012;2012:914273. 42 Wurtman RJ, Cansev M, Sakamoto T, Ulus IH. Use of phosphatide precursors to promote synaptogenesis. Annu Rev Nutr. 2009;29:59–87. 43 Cansev M, Watkins CJ, van der Beek EM, Wurtman RJ. Oral uridine-5’-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Res. 2005;1058:101–8. 44 van Wijk N, Watkins CJ, Bo¨hlke M, Maher TJ, Hageman RJ, Kamphuis PJ, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 2012;107:1408–12. 45 van Wijk N, Watkins CJ, Hageman RJ, Sijben JC, Kamphuis PG, Wurtman RJ, et al. Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats. Nutr Metab (Lond). 2012;9:49. 46 Cansev M, Wurtman RJ. Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience. 2007;148:421–31. 47 Cansev M, Marzloff G, Sakamoto T, Ulus IH, Wurtman RJ. Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Dev Neurosci. 2009;31:181–92. 48 Cansev M, Ulus IH, Wang L, Maher TJ, Wurtman RJ. Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson’s disease. Neurosci Res. 2008;62:206–9. 49 Holguin S, Huang Y, Liu J, Wurtman R. Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behav Brain Res. 2008;191:11–6. 50 Holguin S, Martinez J, Chow C, Wurtman R. Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB J. 2008;22:3938–46. 51 Sakamoto T, Cansev M, Wurtman RJ. Oral supplementation with docosahexaenoic acid and uridine-5’-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Res. 2007;1182:50–9. 52 Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff G. Synaptic proteins and phospholipids are increased
24
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VOL .
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53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68 69
in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006;1088:83–92. Shrivastava R, Vincent B, Gobron S, Cucuat N, John GW. Evidence for growth-promoting effects of omega n-3 fatty acids alone and in combination with a specific vitamin and mineral complex in rat neuroblastoma cells. Nutr Neurosci. 2005;8:317– 21. Arellano JI, Espinosa A, Fairen A, Yuste R, DeFelipe J. Nonsynaptic dendritic spines in neocortex. Neuroscience. 2007;145:464–9. de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM. Neuroprotective effects of a specific multi-nutrient intervention against Abeta42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327–39. Hashimoto M, Hossain S, Agdul H, Shido O. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid beta-infused rats relates to the decreases of amyloid beta and cholesterol levels in detergent-insoluble membrane fractions. Biochim Biophys Acta. 2005;1738:91–8. Arendash GW, Jensen MT, Salem N, Jr, Hussein N, Cracchiolo J, Dickson A, et al. A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer’s transgenic mice. Neuroscience. 2007;149:286–302. de Wilde MC, Farkas E, Gerrits M, Kiliaan AJ, Luiten PG. The effect of n-3 polyunsaturated fatty acid-rich diets on cognitive and cerebrovascular parameters in chronic cerebral hypoperfusion. Brain Res. 2002;947:166–73. de Wilde MC, Hogyes E, Kiliaan AJ, Farkas T, Luiten PG, Farkas E. Dietary fatty acids alter blood pressure, behavior and brain membrane composition of hypertensive rats. Brain Res. 2003;988:9–19. Broersen LM, Kuipers AA, Balvers M, van Wijk N, Savelkoul PJ, de Wilde MC, et al. A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AbetaPPswe/PS1dE9 mice. J Alzheimers Dis. 2013;33:177–90. Harris E, Macpherson H, Vitetta L, Kirk J, Sali A, Pipingas A. Effects of a multivitamin, mineral and herbal supplement on cognition and blood biomarkers in older men: a randomised, placebo-controlled trial. Hum Psychopharmacol. 2012;27:370– 7. Wolters M, Hickstein M, Flintermann A, Tewes U, Hahn A. Cognitive performance in relation to vitamin status in healthy elderly German women-the effect of 6-month multivitamin supplementation. Prev Med. 2005;41:253–9. McNeill G, Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutr J. 2007;6:10. Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L, Hercberg S, Galan P. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Am J Clin Nutr. 2011;94:278–86. Kesse-Guyot E, Fezeu L, Jeandel C, Ferry M, Andreeva V, Amieva H, et al. French adults’ cognitive performance after daily supplementation with antioxidant vitamins and minerals at nutritional doses: a post hoc analysis of the Supplementation in Vitamins and Mineral Antioxidants (SU.VI.MAX) trial. Am J Clin Nutr. 2011;94:892–9. Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, et al. Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial. Alzheimers Dement. 2010;6:1–10e1. Scheltens P, Twisk JW, Blesa R, Scarpini E, von Arnim CA, Bongers A, et al. Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis. 2012;31:225–36. Siegel M, Donner TH, Engel AK. Spectral fingerprints of largescale neuronal interactions. Nat Rev Neurosci. 2012;13:121–34. Shah R, Kamphuis P, Leurgans S, Swinkels S, Sadowsky C, Bongers A, Rappaport S, Quinn J, Wieggers R, Bennett D, Scheltens P. SouvenaidH as an add-on intervention in patients with mild to moderate Alzheimer’s disease using Alzheimer’s disease medication: results from a randomized, controlled, double-blind study (S-Connect). CtAD, San Diego, November 2011; J Nutr Health Aging 2011;15 (Suppl 1) S30 (Abstract P38).
