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Souvenaid is the name of a medical nutrition formulation, presented as a drink, that has been studied for potential use in the dietary management of early Alzheimer’s disease.[1] Randomised controlled trials have shown that Souvenaid improves memory in subjects with early Alzheimer’s disease.[2][3]

Souvenaid was developed by Advanced Medical Nutrition division of Nutricia and contains a patented combination of nutrients, referred to under the trademark Fortasyn Connect™.[4] Souvenaid was designed to support synapse formation and function[1] in early Alzheimer’s disease.

Development of Souvenaid concept

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Souvenaid is the result of research by investigators from the Massachusetts Institute of Technology (MIT), and other international groups being conducted since 2002. Much of the research was led by MIT Professor Richard Wurtman.[2]

The concept of Souvenaid is based on the fact that loss of synapses is one of the hallmarks of Alzheimer’s disease and that this hallmark correlates best with memory impairment.[5][6][7] There is evidence in the scientific literature that individuals with this condition may lack adequate levels of nutrients important for the formation of new synapses in order to compensate for the experienced loss.[8][9][10][11][12][13][14] Souvenaid has been studied in pre-clinical and clinical studies.

Pre-clinical Trials

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Researchers demonstrated in pre-clinical models that by increasing the supply of certain nutrients,[15][16][17] the synthesis of phospholipids and neuronal membranes can be increased.[17][18][19][20] Those nutrients were also shown to increase dendritic spines, synaptic proteins and neurite outgrowth,[20][21][22][23] all prerequisites for synapse formation, as well as neurotransmission.[21][24][25][26] The greatest effects were observed when combinations of nutrients were used.[18][22][23][24] Administration of specific nutrients was also shown to improve learning and memory in preclinical models.[27][28][29][30][31][32] These research findings provided the scientific rationale for the formulation of Souvenaid.[1]

Clinical Trials of Souvenaid

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Early Alzheimer’s disease

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Souvenaid has been tested in two randomised, controlled, double-blind clinical trials in early Alzheimer’s disease (AD).[2][3] In both studies, Souvenaid was compared with a matched isocaloric, isonitrogenous control drink in mild AD subjects who had not received drug therapy for Alzheimer’s disease.

The ‘Souvenir I’ study included 225 subjects with mild Alzheimer’s disease (mean MMSE score 23.9) enrolled at sites in The Netherlands, Germany, Belgium, UK and USA. Results were published in 2010 in the journal Alzheimer’s & Dementia by Philip Scheltens and colleagues.[2] The trial showed that daily Souvenaid for 12 weeks significantly improved the co-primary endpoint of delayed verbal memory, measured using the standard Wechsler Memory Scale-revised (WMS-r). There was no difference between Souvenaid and the control drink on the modified 13-item Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), the other co-primary endpoint.

The ‘Souvenir II’ study included 259 subjects with mild Alzheimer’s disease (mean MMSE score 25.0) enrolled in sites in The Netherlands, Germany, France, Belgium, Italy and Spain. Results were first presented by Philip Scheltens at the fourth congress ‘Clinical Trials on Alzheimer’s Disease (CtAD)’ in San Diego in November 2011.[3] The study showed that during 24 weeks, Souvenaid significantly improved the predefined primary endpoint of memory, measured by the memory domain of a Neuropsychological Test Battery (NTB). No significant intervention effect was observed on the NTB executive function domain, a secondary endpoint of the study.

Souvenaid was well tolerated in both studies involving subjects with drug-naïve early Alzheimer’s disease.[2][3] There was no difference in the incidence of adverse events between Souvenaid and the control drink. The trials were funded by Nutricia.

Mild-to-moderate Alzheimer’s disease

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‘S-Connect’ was a 24-week randomised, controlled, double-blind study conducted in 48 centres in the USA in 527 subjects with mild-to-moderate Alzheimer’s disease (MMSE score 14–24). All subjects were on stable use of acetylcholinesterase inhibitors and/or N-methyl d-aspartate (NMDA) receptor antagonist. Results were first presented by Dr Raj Shah at the fourth congress ‘Clinical Trials on Alzheimer’s Disease (CtAD)’ in San Diego in November 2011.[33] There was no difference in the primary efficacy endpoint of ADAS-cog between Souvenaid and control groups. No group differences in adverse event rates were seen between Souvenaid and the control drink. The trial was funded by Nutricia.

Prodromal Alzheimer’s disease

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‘LipiDiDiet’ is a randomised, controlled trial [34] conducted by the European LipiDiDiet Consortium and funded by the EU FP7 project LipiDiDiet, (Grant Agreement N° 211696). The study is designed to evaluate the effects of Souvenaid in subjects with prodromal Alzheimer’s disease defined by the Dubois criteria[35] over a study period of 24 months. The primary endpoint is cognitive performance during 24 months of intervention as measured by a modified version of the NTB.[36] Secondary endpoints include progression to Alzheimer’s disease, cognitive performance, functional abilities, occurrence of depressive symptoms, plasma biomarkers, brain atrophy rates on magnetic resonance imaging (MRI), nutritional parameters, tolerability and safety. As of May 2012, the study is still ongoing.

References

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  1. ^ a b c Sijben JWC, de Wilde MC, Wieggers R, Groenendijk M, Kamphuis PJGH. A multi nutrient concept to enhance synapse formation and function: science behind a medical food for Alzheimer’s disease. OCL 2011;18:267-270. doi : 10.1684/ocl.2011.0410
  2. ^ a b c d e Scheltens P, Kamphuis PJ, Verhey FR, Olde Rikkert MG, Wurtman RJ, Wilkinson D, Twisk JW, Kurz A. Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial. Alzheimers Dement. 2010;6:1-10.e1. PMID 20129316.
  3. ^ a b c d Scheltens P, Twisk J, Blesa R, Scarpini E, Von Arnim C, Bongers A, Harrison J, Swinkels S, De Deyn P, Wieggers R, Vellasi B, Kamphuis P. Souvenaid® improves memory in drug-naïve patients with mild Alzheimer’s disease: results from a randomized, controlled, double-blind study (Souvenir II) CtAD, San Diego, November 2011; J Nutr Health Aging 2011;15 (Suppl 1) S13 (Abstract LB3)
  4. ^ http://souvenaid.nutricia.com/clinical-trial-programme.html
  5. ^ Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-80. PMID 1789684.
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  8. ^ Glasø M, Nordbø G, Diep L, Bøhmer T. Reduced concentrations of several vitamins in normal weight patients with late-onset dementia of the Alzheimer type without vascular disease. J Nutr Health Aging. 2004;8:407-13. PMID 15359361.
  9. ^ Köseoglu E, Karaman Y. Relations between homocysteine, folate and vitamin B12 in vascular dementia and in Alzheimer disease. Clin Biochem. 2007;40:859-63. PMID 17532313.
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  12. ^ Ravaglia G, Forti P, Maioli F, Bianchi G, Martelli M, Talerico T, Servadei L, Zoli M, Mariani E. Plasma amino acid concentrations in patients with amnestic mild cognitive impairment or Alzheimer disease. Am J Clin Nutr. 2004;80:483-8. PMID 15277174.
  13. ^ Corrigan FM, Van Rhijn AG, Ijomah G, McIntyre F, Skinner ER, Horrobin DF, Ward NI. Tin and fatty acids in dementia. Prostaglandins Leukot Essent Fatty Acids. 1991;43:229-38. PMID 1946550.
  14. ^ Corrigan FM, Horrobin DF, Skinner ER, Besson JA, Cooper MB. Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content. Int J Biochem Cell Biol 1998;30:197-207. PMID 9608673.
  15. ^ van Wijk N, Watkins CJ, Böhlke M, Maher TJ, Hageman RJ, Kamphuis PJ, Broersen LM, Wurtman RJ. 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. PMID 21917195.
  16. ^ 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. PMID 16126180.
  17. ^ a b Ulus IH, Watkins CJ, Cansev M, Wurtman RJ. Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cell Mol Neurobiol. 2006;26:563-77. PMID 16636900.
  18. ^ a b Wurtman RJ, Ulus IH, Cansev M, Watkins CJ, Wang L, Marzloff G. Synaptic proteins and phospholipids are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Res. 2006;1088:83-92. PMID 16631143.
  19. ^ 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. PMID 17683870; PMC 2048660.
  20. ^ a b 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. PMID 17950710; PMC 2140951.
  21. ^ a b Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5'-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27:137-45. PMID 16055952.
  22. ^ a b Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 Neuroscience. 2005;134:207-14. Erratum in: Neuroscience. 2005;135:657. PMID 15939540.
  23. ^ a b 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. PMID 19145070.
  24. ^ a b Farkas E, de Wilde MC, Kiliaan AJ, Meijer J, Keijser JN, Luiten PG. Dietary long chain PUFAs differentially affect hippocampal muscarinic 1 and serotonergic 1A receptors in experimental cerebral hypoperfusion. Brain Res. 2002;954:32-41. PMID 12393230.
  25. ^ Wang L, Albrecht MA, Wurtman RJ. Dietary supplementation with uridine-5'-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Res. 2007;1133:42-8. PMID 17184749; PMC 1852434.
  26. ^ Savelkoul PJ, Janickova H, Kuipers AA, Hageman RJ, Kamphuis PJ, Dolezal V, Broersen LM. A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro. J Neurochem. 2012;120:631-40. doi: 10.1111/j.1471-4159.2011.07616.x. PMID 22146060.
  27. ^ Holguin S, Martinez J, Chow C, Wurtman R. Behav Brain Res 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. PMID 18606862; PMC 2574024.
  28. ^ Teather LA, Wurtman RJ. Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. J Nutr. 2006;136:2834-7. PMID 17056809.
  29. ^ 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. PMID 14519522.
  30. ^ 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. PMID 12176157.
  31. ^ De Bruin NM, Kiliaan AJ, De Wilde MC, Broersen LM. Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiol Learn Mem. 2003;80:63-79. PMID 12737935.
  32. ^ de Wilde MC, Penke B, van der Beek EM, Kuipers AA, Kamphuis PJ, Broersen LM. Neuroprotective effects of a specific multi-nutrient intervention against Aβ42-induced toxicity in rats. J Alzheimers Dis. 2011;27:327-39. PMID 21811020.
  33. ^ Shah R, Kamphuis P, Leurgans S, Swinkels S, Sadowsky C, Bongers A, Rappaport S, Quinn J, Wieggers R, Bennett D, Scheltens P. Souvenaid® 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)
  34. ^ Freund-Levi Y, Visser PJ, Kivipelto M, Wieggers RL, Hartmann T, Soinnen H. The LipiDiDiet study: rationale and study design. CtAD, San Diego, November 2011; J Nutr Health Aging 2011;15 (Suppl 1) S32 (Abstract P42)
  35. ^ Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P. Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010;9:1118-27. PMID 20934914.
  36. ^ Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials. Arch Neurol. 2007;64:1323-9. PMID 17846273.
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