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Involvement of Nutrients in the Pathogenesis or Management of Alzheimer’s Disease


The three required compounds—uridine, an omega-3 polyunsaturated fatty acid such as DHA, and choline—are all normally present in the bloodstream and readily cross the blood–brain barrier.22


synaptogenesis. The nutrients are phosphatide precursors; in test animals they increase the production of synaptic membrane26 dendritic spines.27


and


Synaptic membrane is composed principally of phospholipids, including the phosphatides PC, phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI), and characteristic pre- and post-synaptic proteins. Conversion of the three circulating precursors to phosphatides is mediated by enzymes that have relatively low affinities for these substrates, and thus are unsaturated at the precursor concentrations normally present in the blood and brain. The choline in blood is obtained from various foods or is synthesized in the liver22


via a pathway that


requires methionine and thus is accelerated when vitamins B12, B6, and folic acid are administered.28 derives from hepatic synthesis.22


Circulating uridine, in humans, also Uridine is also present in most foods


in the form of RNA; however, there is no satisfactory evidence that this particular potential source of uridine can provide significant quantities of uridine to the circulation (in contrast to the uridine present as uridine monophosphate [UMP] in mothers’ milk and infant formulas).22


As


described above, DHA, an essential fatty acid, is obtained from dietary DHA and from the hepatic conversion of alpha-linolenic acid to DHA, a process described as disturbed in AD.19


Because the enzymes that


initiate the conversion of these compounds to PC are unsaturated, their activities are readily enhanced when their substrates are administered. Thus, administration of choline increases brain levels of its phosphorylated product phosphocholine; giving uridine (as UMP) increases brain levels of uridine triphosphate (UTP) and cytidine triphosphate (CTP); and giving DHA increases the proportion of diacylglycerol (DAG) molecules that contain this omega-3 fatty acid and thus are preferentially used for synthesizing phosphatides instead of triglycerides.22


The phosphocholine and CTP formed in the brains of animals given uridine plus choline then combine to form cytidine diphosphate (CDP)-choline, which in turn combines with DHA-containing DAG molecules to form PC. PE is similarly formed from this pathway, termed the ‘Kennedy Cycle’, except that phosphoethanolamine replaces phosphocholine; PS is formed by substituting a serine molecule for the choline in PC or ethanolamine in PE (‘base exchange’). Treatment of rats or gerbils with supplemental UMP, DHA, and choline for several weeks is associated with substantial increases in levels of PC per brain or per brain cell, as well as with roughly proportionate increases in the other phosphatides.26 Moreover, the effects of giving all three precursors tend to be greater than the sum of the effects of giving each separately. Animals so treated


1. Wurtman RJ, Non-nutritional uses of nutrients, Eur J Pharmacol, 2011;668:S10–S5.


2. Fernstrom JD, Wurtman RJ, Brain serotonin content: physiological dependence on plasma neutral amino acids, Science, 1971;174:1023–5.


3. Selkoe DJ, Alzheimer’s disease in a synaptic failure, Science, 2002;298:789–91.


4. 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(4):572–80.


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US NEUROLOGY


also exhibit significant improvements in memory functions, as assessed using the Morris water maze or T- or Y-mazes.24


Administration of the three phosphatide precursors also increases brain levels of pre- and post-synaptic proteins, including, for example, synapsin, synaptophysin, post-synaptic density protein-95 (PSD-95), and mGluR,22,26


as well as the numbers of hippocampal dendritic spines.27 These effects are due in part to an additional action of uridine: besides serving, indirectly, as a CTP precursor in cytidine-dependent phosphatide synthesis, uridine and its phosphorylated products (e.g., UTP) are also agonists for P2Y receptors on brain neurons, which promote neurite outgrowth29


and affect neuronal protein synthesis.22 These receptors,


parenthetically, are deficient in the parietal cortex of patients with AD.30 DHA, acting alone, also stimulates neurite outgrowth and dendritic spine formation somewhat, possibly by activating other receptors.


Existing techniques have not enabled the direct measurement of cortical or hippocampal synapse formation in animals receiving the three phosphatide precursors. However, the consensus among synaptologists seems to be that an increase in dendritic spines as produced by the precursors virtually always leads to an increase in synapses, i.e., more than 90 % of the time.7–9


In an initial clinical trial in which 110 drug-naive patients with very mild or mild AD received a medical food (Souvenaid®) containing the precursors and cofactors (e.g., vitamin B12, vitamin B6, folic acid) daily for twelve weeks and an equal number served as controls, those in the treated group—particularly those with very mild AD—exhibited a statistically significant improvement in memory compared with control subjects.25


Secondary outcomes tested, using NTB data, included executive function and the individual items that had been scored. A total of 91.9 % of the subjects completed the study, compliance was 97 %, and no differences were noted between the groups in the frequency of adverse events. Souvenaid again significantly improved the primary endpoint, memory performance (p=0.025). n


NINCDS-ADRDA criteria, Lancet Neurol, 2007;6:734–8.


7. Alvarez VA, Sabatini BL, Anatomical and physiological plasticity of dendritic spines, Annu Rev Neurosci, 2007;30:79–97.


8. Knobloch M, Mansuy IM, Dendritic spine loss and synaptic alterations in Alzheimer’s disease, Mol Neurobiol, 2008;37:73–82.


9. Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Impaired spine stability underlies plaque-related spine loss in an Alzheimer’s disease mouse model, Am J Pathol, 2007;171:1304–11.


10. Shankar GM, Li S, Mehta TH, et al., Amyloid-β protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat Med, 2008;14:837–42.


11. McDonald JM, Savva GM, Brayne C, et al., The presence of sodium dodecylsulphate-stable A-beta dimers is strongly associated with Alzheimer-type dementia, Brain, 2010;133:1328–41.


12. Crawford MA, Bazinet RP, Sinclair AJ, Fat intake and CNS functioning: ageing and disease, Ann Nutr Metab, 2009;55:202–28.


13. Quinn JF, Raman R, Thomas RG, et al., Docosahexaenoic acid supplementation and cognitive decline in alzheimer disease: A randomized trial, JAMA, 2010;304:1903–11.


14. Freund-Levi Y, Eriksdotter-Jönhagen M, Cederholm T, et al., Omega-3 fatty acid treatment in 174 patients with mild to moderate alzheimer disease: OmegAD Study: A randomized double-blind trial, Arch Neurol, 2006;53:1402–8.


15. Cunnane SC, Plourde M, Pifferi F, et al., Fish, Docosahexaenoic acid, and Alzheimer’s disease, Prog Lipid Res, 2009;48:239–56.


16. Brooksbank BW, Martinez M, Lipid abnormalities in the brain in adult Down’s Syndrome and Alzheimer’s disease, Mol Chem Neuropathol, 1989;11:157–85.


17. Söderberg M, Edlund C, Kristensson K, Dallner G, Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease, Lipids, 1991;26:421–5.


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Three additional large-scale trials are under way or have recently been completed; these also include measurements of biomarkers for assessing synaptic density (i.e., electroencephalography [EEG] and magnetoencephalography [MEG]). In one of these studies—designed to determine whether the findings of the initial trial could be confirmed—259 patients, also drug-naive and with early AD (mini-mental state examination [MMSE] = 25 + 2.8) received Souvenaid or placebo daily for 24 weeks, and the memory domain score of a neuropsychological test battery (NTB)—the primary outcome parameter—was measured initially and after 12 and 24 weeks.31


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