The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study.

BACKGROUND: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS: 179 drug-naïve mild AD patients who participated in the Souvenir II study. INTERVENTION: Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION: Dutch Trial Register NTR1975.

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.

Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.

Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer's disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohen's d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

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.

Can nutrients prevent or delay onset of Alzheimer's disease?

Age-related changes in nutritional status can play an important role in brain functioning. Specific nutrient deficiencies in the elderly, including omega-3 fatty acids, B-vitamins, and antioxidants among others, may exacerbate pathological processes in the brain. Consequently, the potential of nutritional intervention to prevent or delay cognitive impairment and the development of Alzheimer's disease (AD) is a topic of growing scientific interest. This review summarizes epidemiological studies linking specific nutritional deficiencies to mild cognitive impairment (MCI), as well as completed and ongoing nutritional studies in prevention of MCI and AD. Processes that underlie AD pathogenesis include: membrane/synaptic degeneration, abnormal protein processing (amyloid-beta, tau), vascular risk factors (hypertension, hypercholesterolemia), inflammation, and oxidative stress. Consideration of mechanistic evidence to date suggests that several nutritional components can effectively counteract these processes, e.g., by promoting membrane formation and synaptogenesis, enhancing memory/behavior, improving endothelial function, and cerebrovascular health. The literature reinforces the need for early intervention in AD and suggests that multi-nutritional intervention, targeting multiple aspects of the neurodegenerative process during the earliest possible phase in the development of the disease, is likely to have the greatest therapeutic potential.

The potential role of nutritional components in the management of Alzheimer's Disease.

Epidemiological evidence linking nutrition to the incidence and risk of Alzheimer Disease is rapidly increasing. The specific nutritional deficiencies in Alzheimer patients may suggest a relative shortage of specific macro- and micronutrients. These include omega-3 fatty acids, several B-vitamins and antioxidants such as vitamins E and C. Recent mechanistic studies in cell systems and animal models also support the idea that nutritional components are able to counteract specific aspects of the neurodegenerative and pathological processes in the brain. In addition, it has been shown that several nutritional components can also effectively stimulate membrane formation and synapse formation as well as improve behavior and cerebrovascular health. The suggested synergy between nutritional components to improve neuronal plasticity and function is supported by epidemiological studies as well as experimental studies in animal models. The ability of nutritional compositions to stimulate synapse formation and effectively reduce Alzheimer Disease neuropathology in these preclinical models provides a solid basis to predict potential to modify the disease process, especially during the early phases of Alzheimer Disease.