Search

Alzheimer’s Disease (AD) is the leading cause of dementia. Epidemiological studies suggest that AD is linked with poor status of nutrients including DHA, B-vitamins and the vitamins E and C. Ongoing neurodegeneration, particularly synaptic loss, leads to the classical clinical features of AD namely, memory impairment, language deterioration, and executive and visuospatial dysfunction. The main constituents of neural and synaptic membranes are phospholipids. Supplemenation of animals with three dietary precursors of phospholipids namely, DHA, uridine monophosphate and choline, results in increased levels of brain phospholipids, synaptic proteins, neurite outgrowth, dendritic spines formation (i.e. the anatomical precursors of new synapses) and an improvement in learning and memory. Other nutrients act as co-factors in the synthesis pathway of neuronal membranes. For example B-vitamins are involved in methylation processes, thereby enhancing the availability of choline as a synaptic membrane precursor. A multi-nutrient concept that includes these nutrients may improve membrane integrity, thereby influencing membrane-dependent processes such as receptor function and amyloid precursor protein (APP) processing, as shown by reduced amyloid production and amyloid β plaque burden, as well as toxicity. Together, these insights provided the basis for the development of a medical food for patients with AD, Souvenaid®, containing a specific combination of nutrients (Fortasyn™ Connect) and designed to enhance synapse formation in AD. The effect of Souvenaid on memory and cognitive performance was recently assessed in a proof-of-concept study, SOUVENIR I, with 212 drug-naïve mild AD patients (MMSE 20-26). This proof-of-concept study demonstrated that oral nutritional supplementation with Souvenaid® for 12 weeks improves memory in patients with mild AD. To confirm and extend these findings, we have designed and initiated three additional studies. Two of these studies will be completed in 2011; Souvenir II, a 24-week European study, with 259 drug-naïve mild AD patients (MMSE≥20) and S-Connect, another 24-week study, with 527 mild-tomoderate AD patients (MMSE 14-24) using AD medication conducted in the US. The third is the EU-funded LipiDiDiet study, a 24-month study, which will enrol 300 people with prodromal AD to assess the effect on memory performance.

The inherited metabolic disease phenylketonuria (PKU) is characterized by increased concentrations of phenylalanine in the blood and brain, and as a consequence neurotransmitter metabolism, white matter, and synapse functioning are affected. A specific nutrient combination (SNC) has been shown to improve synapse formation, morphology and function. This could become an interesting new nutritional approach for PKU. To assess whether treatment with SNC can affect synapses, we treated PKU mice with SNC or an isocaloric control diet and wild-type (WT) mice with an isocaloric control for 12 weeks, starting at postnatal day 31. Immunostaining for post-synaptic density protein 95 (PSD-95), a post-synaptic density marker, was carried out in the hippocampus, striatum and prefrontal cortex. Compared to WT mice on normal chow without SNC, PKU mice on the isocaloric control showed a significant reduction in PSD-95 expression in the hippocampus, specifically in the granular cell layer of the dentate gyrus, with a similar trend seen in the cornus ammonis 1 (CA1) and cornus ammonis 3 (CA3) pyramidal cell layer. No differences were found in the striatum or prefrontal cortex. PKU mice on a diet supplemented with SNC showed improved expression of PSD-95 in the hippocampus. This study gives the first indication that SNC supplementation has a positive effect on hippocampal synaptic deficits in PKU mice. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-β 1-42 (Aβ42) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aβ42-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 AβPPswe/PS1dE9 mouse model with endogenous Aβ 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 Aβ levels and amyloid plaque burden in the hippocampus of AβPP/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 AβPP/PS1 mice, confirm and extend our previous findings in the Aβ42 infusion model and favor the combined administration of relevant nutrients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7). [ABSTRACT FROM AUTHOR]

The effect of supplementation with the omega 3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β1-42 (Aβ42) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dose-dependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ42 levels and resulted in a 4-8 fold decrease in extracellular prostaglandin E2 (PGE2) levels. Tocopherol, which was added to DHA to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ42 and PGE2 levels when given alone. The addition of selective COX-2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE2 release, but did not inhibit Aβ42 secretion, and even significantly increased Aβ42 production in this cell system. Together, the present data show that, whereas both DHA and COX-2 inhibitors may reduce PGE2 production, only DHA in the presence of tocopherol significantly reduced Aβ42 production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ42 secretion through membrane-related, but not PGE2-related mechanisms. [ABSTRACT FROM AUTHOR]

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-β 1-42 (Aβ(42)) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aβ(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 AβPP(swe)/PS1(dE9) mouse model with endogenous Aβ 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 Aβ levels and amyloid plaque burden in the hippocampus of AβPP/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 AβPP/PS1 mice, confirm and extend our previous findings in the Aβ(42) infusion model and favor the combined administration of relevant nutrients.

Neurodegenerative disorders, and dementia in particular, have been shown to have a cerebrovascular pathogenic component often in the form of reduced cerebral blood flow. The debate whether such a reduced brain perfusion is a primary trigger or a secondary symptom in the neuropathological progression of dementia has not been conclusively decided yet. However, compelling experimental evidence has been collected to demonstrate an initiating role of reduced cerebral blood flow in neurodegenerative processes. Along these lines, experimental cerebral hypoperfusion in rodents was shown to impair spatial learning and to generate neuronal damage and associated gliosis in sensitive brain regions like the hippocampus and frontoparietal cortex. Since suboptimal cerebral blood supply was thus identified as a potential trigger of cognitive decline, the improvement of cerebral blood flow in cognitive disorders has emerged as an alternative treatment to moderate the symptoms and to delay the onset of advanced dementia. Various drugs, such as cholinergic compounds, hemorheologic agents and vascular smooth muscle relaxants, have already been tested in some instances for their efficacy to increase brain perfusion. In this respect, both clinical and preclinical trials delivered positive data. Furthermore, not only the treatment but also the prevention of the development of cognitive deficiency can target the cerebrovascular system. For this purpose, long-chain polyunsaturated fatty acids derived from fish oil (also known as n-3 PUFAs) have been considered as dietary supplements. These fatty acids appeared particularly effective in the prevention of hypertension-associated vascular pathology. The present review provides an overview of the actions of these compounds focusing on cerebral blood flow, neurodegeneration and cognitive decline.