Lower brain and blood nutrient status in Alzheimer's disease: Results from meta-analyses.

INTRODUCTION: Alzheimer's disease (AD) patients are at risk of nutritional insufficiencies because of physiological and psychological factors. Recently, we showed the results of the meta-analyses indicating lower plasma levels of vitamins A, B12, C, E, and folate in AD patients compared with cognitively intact elderly controls (controls). Now, additional and more extensive literature searches were performed selecting studies which compare blood and brain/cerebrospinal fluid (CSF) levels of vitamins, minerals, trace elements, micronutrients, and fatty acids in AD patients versus controls. METHODS: The literature published after 1980 in Cochrane Central Register of Controlled Trials, Medline, and Embase electronic databases was systematically analyzed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines to detect studies meeting the selection criteria. Search terms used are as follows: AD patients, Controls, vitamins, minerals, trace elements, micronutrients, and fatty acids. Random-effects meta-analyses using a linear mixed model with correction for age differences between AD patients and controls were performed when four or more publications were retrieved for a specific nutrient. RESULTS: Random-effects meta-analyses of 116 selected publications showed significant lower CSF/brain levels of docosahexaenoic acid (DHA), choline-containing lipids, folate, vitamin B12, vitamin C, and vitamin E. In addition, AD patients showed lower circulatory levels of DHA, eicosapentaenoic acid, choline as phosphatidylcholine, and selenium. CONCLUSION: The current data show that patients with AD have lower CSF/brain availability of DHA, choline, vitamin B12, folate, vitamin C, and vitamin E. Directionally, brain nutrient status appears to parallel the lower circulatory nutrient status; however, more studies are required measuring simultaneously circulatory and central nutrient status to obtain better insight in this observation. The brain is dependent on nutrient supply from the circulation, which in combination with nutrient involvement in AD-pathophysiological mechanisms suggests that patients with AD may have specific nutritional requirements. This hypothesis could be tested using a multicomponent nutritional intervention.

The medical food Souvenaid affects brain phospholipid metabolism in mild Alzheimer's disease: results from a randomized controlled trial.

BACKGROUND: Synaptic dysfunction contributes to cognitive impairment in Alzheimer's disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer's disease. METHODS: Thirty-four drug-naive patients with mild Alzheimer's disease (Mini Mental State Examination score ≥20) were enrolled in this exploratory, double-blind, randomized controlled study. Before and after 4-week intervention with Souvenaid or an isocaloric control product, phosphorus and proton magnetic resonance spectroscopy (MRS) was performed to assess surrogate measures of phospholipid synthesis and breakdown (phosphomonoesters [PME] and phosphodiesters [PDEs]), neural integrity (N-acetyl aspartate), gliosis (myo-inositol), and choline metabolism (choline-containing compounds [tCho]). The main outcome parameters were PME and PDE signal intensities and the PME/PDE ratio. RESULTS: MRS data from 33 patients (60-86 years old; 42% males; Souvenaid arm n = 16; control arm n = 17) were analyzed. PME/PDE and tCho were higher after 4 weeks of Souvenaid compared with control (PME/PDE least squares [LS] mean difference [95% CI] 0.18 [0.06-0.30], p = 0.005; tCho LS mean difference [95% CI] 0.01 [0.00-0.02], p = 0.019). No significant differences were observed in the other MRS outcome parameters. CONCLUSIONS: MRS reveals that Souvenaid affects brain phospholipid metabolism in mild Alzheimer's disease, in line with findings in preclinical studies. TRIAL REGISTRATION: Netherlands Trial Register, NTR3346 . Registered on 13 March 2012.

Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer's Disease.

Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors' effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer's disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

Nutrients required for phospholipid synthesis are lower in blood and cerebrospinal fluid in mild cognitive impairment and Alzheimer's disease dementia.

INTRODUCTION: Synaptic membrane formation depends on nutrients that fuel metabolic pathways for the synthesis of constituent phospholipids. Consequently, insufficient availability of such nutrients may restrict membrane formation and contribute to synaptic dysfunction in Alzheimer's disease (AD). We assessed whether blood and cerebrospinal fluid (CSF) concentrations of nutrients related to phospholipid synthesis differ among patients with AD, mild cognitive impairment (MCI), and control subjects. METHODS: Concentrations of uridine, choline, folate, homocysteine, and other related metabolites were analyzed in paired blood and CSF samples from subjects selected from the Amsterdam Dementia Cohort with AD (n = 150; age, 66 ± 7 years; 37% female), MCI (n = 148; age, 66 ± 8 years; 37% female), and control subjects (n = 148; age, 59 ± 8 years; 38% female). RESULTS: Age- and gender-adjusted analysis of variance revealed different concentrations of circulating uridine, choline, and folate and CSF uridine, folate, and homocysteine (all P < .05) among the three diagnostic groups. Post hoc pairwise comparison showed that subjects with AD had lower CSF uridine, plasma choline and higher CSF homocysteine concentrations, whereas subjects with MCI had lower plasma and CSF uridine, serum and CSF folate, and higher CSF homocysteine concentrations compared with control subjects (all P < .05), with differences ranging from -11 to +22%. DISCUSSION: AD and MCI patients have lower levels of nutrients involved in phospholipid synthesis. The current observations warrant exploration of the application of nutritional strategies in the early stages of AD.

Dietary Crude Lecithin Increases Systemic Availability of Dietary Docosahexaenoic Acid with Combined Intake in Rats.

Crude lecithin, a mixture of mainly phospholipids, potentially helps to increase the systemic availability of dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), such as docosahexaenoic acid (DHA). Nevertheless, no clear data exist on the effects of prolonged combined dietary supplementation of DHA and lecithin on RBC and plasma PUFA levels. In the current experiments, levels of DHA and choline, two dietary ingredients that enhance neuronal membrane formation and function, were determined in plasma and red blood cells (RBC) from rats after dietary supplementation of DHA-containing oils with and without concomitant dietary supplementation of crude lecithin for 2-3 weeks. The aim was to provide experimental evidence for the hypothesized additive effects of dietary lecithin (not containing any DHA) on top of dietary DHA on PUFA levels in plasma and RBC. Dietary supplementation of DHA-containing oils, either as vegetable algae oil or as fish oil, increased DHA, eicosapentaenoic acid (EPA), and total n-3 PUFA, and decreased total omega-6 PUFA levels in plasma and RBC, while dietary lecithin supplementation alone did not affect these levels. However, combined dietary supplementation of DHA and lecithin increased the changes induced by DHA supplementation alone. Animals receiving a lecithin-containing diet also had a higher plasma free choline concentration as compared to controls. In conclusion, dietary DHA-containing oils and crude lecithin have synergistic effects on increasing plasma and RBC n-3 PUFA levels, including DHA and EPA. By increasing the systemic availability of dietary DHA, dietary lecithin may increase the efficacy of DHA supplementation when their intake is combined.

Meta-analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability.

INTRODUCTION: Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-ß appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. METHODS: We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. RESULTS: Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. DISCUSSION: The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.

A nutrient combination designed to enhance synapse formation and function improves outcome in experimental spinal cord injury.

Spinal cord injury leads to major neurological impairment for which there is currently no effective treatment. Recent clinical trials have demonstrated the efficacy of Fortasyn® Connect in Alzheimer's disease. Fortasyn® Connect is a specific multi-nutrient combination containing DHA, EPA, choline, uridine monophosphate, phospholipids, and various vitamins. We examined the effect of Fortasyn® Connect in a rat compression model of spinal cord injury. For 4 or 9 weeks following the injury, rats were fed either a control diet or a diet enriched with low, medium, or high doses of Fortasyn® Connect. The medium-dose Fortasyn® Connect-enriched diet showed significant efficacy in locomotor recovery after 9 weeks of supplementation, along with protection of spinal cord tissue (increased neuronal and oligodendrocyte survival, decreased microglial activation, and preserved axonal integrity). Rats fed the high-dose Fortasyn® Connect-enriched diet for 4 weeks showed a much greater enhancement of locomotor recovery, with a faster onset, than rats fed the medium dose. Bladder function recovered quicker in these rats than in rats fed the control diet. Their spinal cord tissues showed a smaller lesion, reduced neuronal and oligodendrocyte loss, decreased neuroinflammatory response, reduced astrocytosis and levels of inhibitory chondroitin sulphate proteoglycans, and better preservation of serotonergic axons than those of rats fed the control diet. These results suggest that this multi-nutrient preparation has a marked therapeutic potential in spinal cord injury, and raise the possibility that this original approach could be used to support spinal cord injured patients.

Effects of Souvenaid on plasma micronutrient levels and fatty acid profiles in mild and mild-to-moderate Alzheimer's disease.

INTRODUCTION: Circulating levels of uridine, selenium, vitamins B12, E and C, folate, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been shown to be lower in patients with Alzheimer's disease (AD) than in healthy individuals. These low levels may affect disease pathways involved in synapse formation and neural functioning. Here, we investigated whether, and to what extent, circulating levels of micronutrients and fatty acids can be affected by oral supplementation with Souvenaid (containing a specific nutrient combination), using data derived from three randomized clinical trials (RCT) and an open-label extension (OLE) study with follow-up data from 12 to 48 weeks. METHODS: Subjects with mild (RCT1, RCT2) or mild-to-moderate AD (RCT3) received active or control product once daily for 12-24 weeks or active product during the 24-week OLE following RCT2 (n = 212-527). Measurements included plasma levels of B vitamins, choline, vitamin E, selenium, uridine and homocysteine and proportions of DHA, EPA and total n-3 long-chain polyunsaturated fatty acids in plasma and erythrocytes. Between-group comparisons were made using t tests or non-parametric alternatives. RESULTS: We found that 12-24-week active product intake increased plasma and/or erythrocyte micronutrients: uridine; choline; selenium; folate; vitamins B6, B12 and E; and fatty acid levels of DHA and EPA (all p < 0.001). In the OLE study, similar levels were reached in former control product/initial active product users, whereas 24-week continued active product intake showed no suggestion of a further increase in nutrient levels. CONCLUSIONS: These data show that circulating levels of nutrients known to be decreased in the AD population can be increased in patients with mild and mild-tomoderate AD by 24-48-week oral supplementation with Souvenaid. In addition, to our knowledge, this is the first report of the effects of sustained dietary intake of uridine monophosphate on plasma uridine levels in humans. Uptake of nutrients is observed within 6 weeks, and a plateau phase is reached for most nutrients during prolonged intake, thus increasing the availability of precursors and cofactors in the circulation that may be used for the formation and function of neuronal membranes and synapses in the brain.

Specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats.

Fortasyn Connect (FC) is a specific nutrient combination designed to target synaptic dysfunction in Alzheimer's disease by providing neuronal membrane precursors and other supportive nutrients. The aim of the present study was to investigate the effects of FC on hippocampal cholinergic neurotransmission in association with its effects on synaptic membrane formation in aged rats. Eighteen-month-old male Wistar rats were randomized to receive a control diet for 4 weeks or an FC-enriched diet for 4 or 6 weeks. At the end of the dietary treatments, acetylcholine (ACh) release was investigated by in vivo microdialysis in the right hippocampi. On completion of microdialysis studies, the rats were sacrificed, and the left hippocampi were obtained to determine the levels of choline, ACh, membrane phospholipids, synaptic proteins, and choline acetyltransferase. Our results revealed that supplementation with FC diet for 4 or 6 weeks, significantly enhanced basal and stimulated hippocampal ACh release and ACh tissue levels, along with levels of phospholipids. Feeding rats the FC diet for 6 weeks significantly increased the levels of choline acetyltransferase, the presynaptic marker Synapsin-1, and the postsynaptic marker PSD-95, but decreased levels of Nogo-A, a neurite outgrowth inhibitor. These data show that the FC diet enhances hippocampal cholinergic neurotransmission in aged rats and suggest that this effect is mediated by enhanced synaptic membrane formation. These data provide further insight into cellular and molecular mechanisms by which FC may support memory processes in Alzheimer's disease.

A nutritional approach to ameliorate altered phospholipid metabolism in Alzheimer's disease.

Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer's disease (AD) within 2-3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.

Differences in nutritional status between very mild Alzheimer's disease patients and healthy controls.

BACKGROUND: Studies on the systemic availability of nutrients and nutritional status in Alzheimer's disease (AD) are widely available, but the majority included patients in a moderate stage of AD. OBJECTIVE: This study compares the nutritional status between mild AD outpatients and healthy controls. METHODS: A subgroup of Dutch drug-naïve patients with mild AD (Mini-Mental State Examination (MMSE) ≥20) from the Souvenir II randomized controlled study (NTR1975) and a group of Dutch healthy controls were included. Nutritional status was assessed by measuring levels of several nutrients, conducting the Mini Nutritional Assessment (MNA®) questionnaire and through anthropometric measures. RESULTS: In total, data of 93 healthy cognitively intact controls (MMSE 29.0 [23.0-30.0]) and 79 very mild AD patients (MMSE = 25.0 [20.0-30.0]) were included. Plasma selenium (p < 0.001) and uridine (p = 0.046) levels were significantly lower in AD patients, with a similar trend for plasma vitamin D (p = 0.094) levels. In addition, the fatty acid profile in erythrocyte membranes was different between groups for several fatty acids. Mean MNA screening score was significantly lower in AD patients (p = 0.008), but not indicative of malnutrition risk. No significant differences were observed for other micronutrient or anthropometric parameters. CONCLUSION: In non-malnourished patients with very mild AD, lower levels of some micronutrients, a different fatty acid profile in erythrocyte membranes and a slightly but significantly lower MNA screening score were observed. This suggests that subtle differences in nutrient status are present already in a very early stage of AD and in the absence of protein/energy malnutrition.

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

Brain imaging and human nutrition: which measures to use in intervention studies?

Throughout the life span, the brain is a metabolically highly active organ that uses a large proportion of total nutrient and energy intake. Furthermore, the development and repair of neural tissue depend on the proper intake of essential structural nutrients, minerals, and vitamins. Therefore, what we eat, or refrain from eating, may have an important impact on our cognitive ability and mental performance. Two of the key areas in which diet is thought to play an important role are in optimizing neurodevelopment in children and in preventing neurodegeneration and cognitive decline during aging. From early development to aging, brain imaging can detect structural, functional, and metabolic changes in humans and modifications due to altered nutrition or to additional nutritional supplementation. Inclusion of imaging measures in clinical studies can increase understanding with regard to the modification of brain structure, metabolism, and functional endpoints and may provide early sensitive measures of long-term effects. In this symposium, the utility of existing brain imaging technologies to assess the effects of nutritional intervention in humans is described. Examples of current research showing the utility of these markers are reviewed.

Brain imaging and human nutrition: which measures to use in intervention studies?

The present review describes brain imaging technologies that can be used to assess the effects of nutritional interventions in human subjects. Specifically, we summarise the biological relevance of their outcome measures, practical use and feasibility, and recommended use in short- and long-term nutritional studies. The brain imaging technologies described consist of MRI, including diffusion tensor imaging, magnetic resonance spectroscopy and functional MRI, as well as electroencephalography/magnetoencephalography, near-IR spectroscopy, positron emission tomography and single-photon emission computerised tomography. In nutritional interventions and across the lifespan, brain imaging can detect macro- and microstructural, functional, electrophysiological and metabolic changes linked to broader functional outcomes, such as cognition. Imaging markers can be considered as specific for one or several brain processes and as surrogate instrumental endpoints that may provide sensitive measures of short- and long-term effects. For the majority of imaging measures, little information is available regarding their correlation with functional endpoints in healthy subjects; therefore, imaging markers generally cannot replace clinical endpoints that reflect the overall capacity of the brain to behaviourally respond to specific situations and stimuli. The principal added value of brain imaging measures for human nutritional intervention studies is their ability to provide unique in vivo information on the working mechanism of an intervention in hypothesis-driven research. Selection of brain imaging techniques and target markers within a given technique should mainly depend on the hypothesis regarding the mechanism of action of the intervention, level (structural, metabolic or functional) and anticipated timescale of the intervention's effects, target population, availability and costs of the techniques.

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD.

A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AßPPswe/PS1dE9 mice.

Diet is an important lifestyle factor implicated in the etiology of Alzheimer's disease (AD), but so far it is not fully elucidated to which nutrients the suggested protective effect of diet can be attributed. Recent evidence obtained in the amyloid-ß 1-42 (Aß(42)) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aß(42)-induced toxicity. FC comprises the nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid (DHA), eicosapentaenoic acid, uridine-mono-phosphate (UMP), choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium. In order to investigate whether the combined administration of these nutrients may also affect AD-like pathology, we now evaluated the effects of the FC diet intervention in the transgenic AßPP(swe)/PS1(dE9) mouse model with endogenous Aß production. In addition we evaluated the effects of diets containing the individual nutrients DHA and UMP and their combination in this model. Between the age of 3 and 6 months, FC diet decreased brain Aß levels and amyloid plaque burden in the hippocampus of AßPP/PS1 mice. The FC diet also reduced ongoing disintegrative degeneration in the neocortex, as indicated by Amino Cupric Silver staining. Although all three DHA-containing diets were equally effective in changing brain fatty acid profiles, diets differentially affected amyloid-related measures, indicating that effects of DHA may depend on its dietary context. The current data, showing that dietary enrichment with FC reduces AD-like pathology in AßPP/PS1 mice, confirm and extend our previous findings in the Aß(42) infusion model and favor the combined administration of relevant nutrients.

Utility of imaging for nutritional intervention studies in Alzheimer's disease.

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder and the leading cause of dementia, wherein synapse loss is the strongest structural correlate with cognitive impairment. Basic research has shown that dietary supply of precursors and co-factors for synthesis of neuronal membranes enhances the formation of synapses. Daily intake of a medical food containing a mix of these nutrients for 12 weeks in humans improved memory, measured as immediate and delayed verbal recall by the Wechsler Memory Scale-revised, in patients with very mild AD (MMSE 24-26). An improvement of immediate verbal recall was noted following 24 weeks of intervention in an exploratory extension of the study. These data suggest that the intervention may improve synaptic formation and function in early AD. Here we review emerging technologies that help identify changes in pathological hallmarks in AD, including synaptic function and loss of connectivity in the early stages of AD, before cognitive and behavioural symptoms are observable. These techniques include the detection of specific biomarkers in the cerebrospinal fluid, as well as imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid PET, structural/functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography (MEG) and electroencephalography (EEG). Such techniques can provide new insights into the functional and structural changes in the brain over time, and may therefore help to develop more effective AD therapies. In particular, nutritional intervention studies that target synapse formation and function may benefit from these techniques, especially FDG-PET and EEG/MEG employed in the preclinical or early stages of the disease.

Supplementation with a fish oil-enriched, high-protein medical food leads to rapid incorporation of EPA into white blood cells and modulates immune responses within one week in healthy men and women.

Immune modulatory effects of EPA and DHA are well described. However, these fatty acids must be effectively incorporated into cell membrane phospholipids to modify cell function. To address the absence of human data regarding short-term incorporation, the present study investigated the incorporation of EPA and DHA into white blood cells (WBC) at different time points during 1 wk of supplementation with a medical food, which is high in protein and leucine and enriched with fish oil and specific oligosaccharides. Additionally, the effects on ex vivo immune function were determined. In a single-arm, open label study, 12 healthy men and women consumed 2 × 200 mL of medical food providing 2.4 g EPA, 1.2 g DHA, 39.7 g protein (including 4.4 g L-leucine), and 5.6 g oligosaccharides daily. Blood samples were taken at d 0 (baseline), 1, 2, 4, and 7. Within 1 d of nutritional intervention, the percentage of EPA in phospholipids of WBC increased from 0.5% at baseline to 1.3% (P < 0.001). After 1 wk, the percentage of EPA rose to 2.8% (P < 0.001). Additionally, the production of proinflammatory cytokines in LPS-stimulated whole blood cultures was significantly increased within 1 wk. Nutritional supplementation with a fish oil-enriched medical food significantly increased the percentage of EPA in phospholipids of WBC within 1 wk. Simultaneously, ex vivo immune responsiveness to LPS increased significantly. These results hold promise for novel applications such as fast-acting nutritional interventions in cancer patients, which should be investigated in future studies.

Is it prudent to add n-3 long-chain polyunsaturated fatty acids to paediatric enteral tube feeding?

Nutritional support, as complete enteral tube feeding, is needed by many paediatric patients and must provide sufficient nutrients for normal growth and development. Enteral feeds contain the parent essential fatty acids, linoleic acid and α-linolenic acid, but often do not contain n-3 long-chain polyunsaturated fatty acids. Available data suggest that biosynthesis of eicosapentaenoic acid and docosahexaenoic acid from α-linolenic acid is low in humans and varies between individuals. Long-term enteral feeding with formulae devoid of eicosapentaenoic acid and docosahexaenoic acid may result in low levels in plasma and tissues, potentially affecting immune and neurological function. Currently there is insufficient evidence to define the quantitative eicosapentaenoic acid and docosahexaenoic acid requirements for healthy children, or those with various disease states. Nevertheless, it appears prudent to supply children on long-term enteral nutrition with a dietary source of eicosapentaenoic acid and docosahexaenoic acid. A reasonable approach would be to provide amounts matching intakes of healthy children complying with the advice to consume 1-2 portions of oily fish per week. Further studies are needed to investigate the effects of different amounts of eicosapentaenoic acid and/or docosahexaenoic acid in enteral nutrition on polyunsaturated fatty acid status and the functional and clinical consequences in children.

Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease.

The balance of intake of n-6 and n-3 PUFA, and consequently their relative incorporation into immune cells, is important in determining the development and severity of immune and inflammatory responses. Some disorders characterised by exaggerated inflammation and excessive formation of inflammatory markers have become among the most important causes of death and disability in man in modern societies. The recognition that long-chain n-3 PUFA have the potential to inhibit (excessive) inflammatory responses has led to a large number of clinical investigations with these fatty acids in inflammatory conditions as well as in healthy subjects. The present review explores the presence of dose-related effects of long-chain n-3 PUFA supplementation on immune markers and differences between healthy subjects and those with inflammatory conditions, because of the important implications for the transfer of information gained from studies with healthy subjects to patient populations, e.g. for establishing dose levels for specific applications. The effects of long-chain n-3 PUFA supplementation on ex vivo lymphocyte proliferation and cytokine production by lymphocytes and monocytes in healthy subjects have been studied in twenty-seven, twenty-five and forty-six treatment cohorts respectively, at intake levels ranging from 0.2 g EPA+DHA/d to 7.0 g EPA+DHA/d. Most studies, particularly those with the highest quality study design, have found no effects on these immune markers. Significant effects on lymphocyte proliferation are decreased responses in seven of eight cohorts, particularly in older subjects. The direction of the significant changes in cytokine production by lymphocytes is inconsistent and only found at supplementation levels > or =2.0 g EPA+DHA/d. Significant changes in inflammatory cytokine production by monocytes are decreases in their production in all instances. Overall, these studies fail to reveal strong dose-response effects of EPA+DHA on the outcomes measured and suggest that healthy subjects are relatively insensitive to immunomodulation with long-chain n-3 PUFA, even at intake levels that substantially raise their concentrations in phospholipids of immune cells. In patients with inflammatory conditions cytokine concentrations or production are influenced by EPA+DHA supplementation in a relatively large number of studies. Some of these studies suggest that local effects at the site of inflammation might be more pronounced than systemic effects and disease-related markers are more sensitive to the immunomodulatory effects, indicating that the presence of inflamed tissue or 'sensitised' immune cells in inflammatory disorders might increase sensitivity to the immunomodulatory effects of long-chain n-3 PUFA. In a substantial number of these studies clinical benefits related to the inflammatory state of the condition have been observed in the absence of significant effects on immune markers of inflammation. This finding suggests that condition-specific clinical end points might be more sensitive markers of modulation by EPA+DHA than cytokines. In general, the direction of immunomodulation in healthy subjects (if any) and in inflammatory conditions is the same, which indicates that studies in healthy subjects are a useful tool to describe the general principles of immunomodulation by n-3 PUFA. However, the extent of the effect might be very different in inflammatory conditions, indicating that studies in healthy subjects are not particularly suitable for establishing dose levels for specific applications in inflammatory conditions. The reviewed studies provide no indications that the immunomodulatory effects of long-chain n-3 PUFA impair immune function or infectious disease resistance. In contrast, in some conditions the immunomodulatory effects of EPA+DHA might improve immune function.