Design of the DYNAMO study: a multi-center randomized controlled trial to investigate the effect of pre-thickened oral nutritional supplements in nursing home residents with dysphagia and malnutrition (risk).

BACKGROUND: Oropharyngeal Dysphagia (OD) and malnutrition are frequently reported conditions in nursing home residents, and are often interrelated. Best care for dysphagic residents with, or at risk of, malnutrition should target adequate nutritional intake and the safety and efficacy of swallowing. The effect of oral nutritional supplements (ONS) suitable for nursing home residents with concurrent OD and malnutrition (risk) on nutritional status has not been investigated before. The current study aims to investigate the effect of daily use of a range of pre-thickened ONS on the body weight of nursing home residents with OD and malnutrition (risk) compared to standard OD and nutritional care. METHODS / DESIGN: The DYNAMO study is a randomized, controlled, multi-center, open label trial with two parallel groups. Study participants will be recruited in nursing homes of several care organizations in the south of the Netherlands. Study duration is 12 weeks. Residents in the control group will receive standard OD and nutritional care, and residents in the test group will receive standard OD and nutritional care with extra daily supplementation of pre-thickened ONS. The main outcome parameter is the difference in body weight change between the control and test groups. An a priori estimation of the required sample size per group (control / test) totals 78. Other outcome parameters are differences in: nutritional intake, health-related quality of life, OD-specific quality of life, activities of daily living, vital signs, and blood nutrient and metabolite levels. DISCUSSION: Regular ONS could address the nutritional needs of nursing home residents with malnutrition (risk), but might be too thin and unsafe for residents with OD. Pre-thickened ONS is suitable for residents with OD. It offers the advantage of being a ready-to-use amylase-resistant product available in several consistencies which are able to increase swallowing efficacy and safety. The DYNAMO study is the first to investigate the effects of pre-thickened ONS on nutritional status in nursing home residents with concurrent OD and malnutrition (risk). TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR NL7898. Registered 24 July 2019, https://www.trialregister.nl/trial/7898.

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.

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.

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.

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.

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.

Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats.

BACKGROUND: Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE-N-methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT plays an important role in the transport of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) from the liver to plasma and possibly other tissues. We hypothesized that if B-vitamin supplementation enhances PEMT activity, then supplementation could also increase the concentration of plasma levels of PUFAs such as DHA. To test this hypothesis, we determined the effect of varying the combined dietary intake of these three B-vitamins on plasma DHA concentration in rats. METHODS: In a first experiment, plasma DHA and plasma homocysteine concentrations were measured in rats that had consumed a B-vitamin-poor diet for 4 weeks after which they were either continued on the B-vitamin-poor diet or switched to a B-vitamin-enriched diet for another 4 weeks. In a second experiment, plasma DHA and plasma homocysteine concentrations were measured in rats after feeding them one of four diets with varying levels of B-vitamins for 4 weeks. The diets provided 0% (poor), 100% (normal), 400% (enriched), and 1600% (high) of the laboratory rodent requirements for each of the three B-vitamins. RESULTS: Plasma DHA concentration was higher in rats fed the B-vitamin-enriched diet than in rats that were continued on the B-vitamin-poor diet (P = 0.005; experiment A). Varying dietary B-vitamin intake from deficient to supra-physiologic resulted in a non-linear dose-dependent trend for increasing plasma DHA (P = 0.027; experiment B). Plasma DHA was lowest in rats consuming the B-vitamin-poor diet (P > 0.05 vs. normal, P < 0.05 vs. enriched and high) and highest in rats consuming the B-vitamin-high diet (P < 0.05 vs. poor and normal, P > 0.05 vs. enriched). B-vitamin deficiency significantly increased plasma total homocysteine but increasing intake above normal did not significantly reduce it. Nevertheless, in both experiments plasma DHA was inversely correlated with plasma total homocysteine. CONCLUSION: These data demonstrate that dietary folate, vitamin B-12, and vitamin B-6 intake can influence plasma concentration of DHA.

Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets.

Choline is an important component of the human diet and is required for the endogenous synthesis of choline-containing phospholipids, acetylcholine and betaine. Choline can also be synthesised de novo by the sequential methylation of phosphatidylethanolamine to phosphatidylcholine. Vitamins B6, B12 and folate can enhance methylation capacity and therefore could influence choline availability not only by increasing endogenous choline synthesis but also by reducing choline utilisation. In the present experiment, we determined whether combined supplementation of these B vitamins affects plasma choline concentration in a rat model of mild B vitamin deficiency which shows moderate increases in plasma homocysteine. To this end, we measured plasma choline and homocysteine concentrations in rats that had consumed a B vitamin-poor diet for 4 weeks after which they were either continued on the B vitamin-poor diet or switched to a B vitamin-enriched diet for another 4 weeks. Both diets contained recommended amounts of choline. Rats receiving the B vitamin-enriched diet showed higher plasma choline and lower plasma homocysteine concentrations as compared to rats that were continued on the B vitamin-poor diet. These data underline the interdependence between dietary B vitamins and plasma choline concentration, possibly via the combined effects of the three B vitamins on methylation capacity.

A specific blend of intact protein rich in aspartate has strong postprandial glucose attenuating properties in rats.

Three studies were carried out to help define an optimal protein blend for use in a nutritional product for diabetic patients. To this end, we tested the effects of coinfusions of combinations of different types of carbohydrates and proteins on the postprandial glycemic plasma response in healthy rats. Expt. 1 compared the effects of administering different forms of soy protein (intact protein, its hydrolysate, or an equivalent amount of the same amino acids), all in combination with a fixed amount of glucose (Glu), on postprandial Glu and insulin plasma concentrations. Intact soy protein (SI) had stronger insulinogenic properties compared with its hydrolysate but was equally potent in reducing the postprandial Glu response. In Expt. 2, we compared the effect of replacing 50% of the SI with the whey-derived protein alpha-lactalbumin when coingested with maltodextrin as the carbohydrate source. Only the specific aspartate-rich blend of SI and alpha-lactalbumin significantly improved the postprandial Glu response. In Expt. 3, we studied the effect of using the blend of SI and alpha-lactalbumin combined with a slowly digestible carbohydrate. The protein blend was still capable of significantly decreasing the postprandial Glu response even when a slow-release carbohydrate source was included. Combining this aspartate-rich protein blend with a slow-release carbohydrate might therefore lead to a low-glycemic nutritional product beneficial for dietary management in diabetic patients.