Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review.

In mild cognitive impairment (MCI) due to Alzheimer disease (AD), also known as prodromal AD, there is evidence for a pathologic shortage of uridine, choline, and docosahexaenoic acid [DHA]), which are key nutrients needed by the brain. Preclinical and clinical evidence shows the importance of nutrient bioavailability to support the development and maintenance of brain structure and function in MCI and AD. Availability of key nutrients is limited in MCI, creating a distinct nutritional need for uridine, choline, and DHA. Evidence suggests that metabolic derangements associated with ageing and disease-related pathology can affect the body's ability to generate and utilize nutrients. This is reflected in lower levels of nutrients measured in the plasma and brains of individuals with MCI and AD dementia, and progressive loss of cognitive performance. The uridine shortage cannot be corrected by normal diet, making uridine a conditionally essential nutrient in affected individuals. It is also challenging to correct the choline shortfall through diet alone, because brain uptake from the plasma significantly decreases with ageing. There is no strong evidence to support the use of single-agent supplements in the management of MCI due to AD. As uridine and choline work synergistically with DHA to increase phosphatidylcholine formation, there is a compelling rationale to combine these nutrients. A multinutrient enriched with uridine, choline, and DHA developed to support brain function has been evaluated in randomized controlled trials covering a spectrum of dementia from MCI to moderate AD. A randomized controlled trial in subjects with prodromal AD showed that multinutrient intervention slowed brain atrophy and improved some measures of cognition. Based on the available clinical evidence, nutritional intervention should be considered as a part of the approach to the management of individuals with MCI due to AD, including adherence to a healthy, balanced diet, and consideration of evidence-based multinutrient supplements.

The Trajectory from Mood to Obesity.

PURPOSE OF REVIEW: To describe and explain the relationships between mood disturbances and the development of obesity. RECENT FINDINGS: That depression, anxiety, PTSD, or severe stresses can promote obesity as a side-effect of the drugs used to treat them, or through "carbohydrate craving" to enhance brain serotonin synthesis and alleviate dysphoria by consuming foods that are rich in both carbohydrates and fats. That seasonal affective disorder and severe PMS can independently cause patients to overconsume foods rich in both carbohydrates and fats. The obesity caused by drugs or mood disorders associated with "carbohydrate craving" leading to excess calorie intake can be suppressed by dietary measures.

Synapse formation in the brain can be enhanced by co-administering three specific nutrients.

The memory impairments of early Alzheimer's disease [AD] are thought to result from a deficiency in synapses within the hippocampus and related brain regions. This deficiency could result from an acceleration in synapse turnover - perhaps caused by an endogenous neurotoxin like A-beta oligomers - or from a decrease in the production of the synaptic membrane needed to form new synapses. An AD-associated decrease in synaptogenesis almost certainly does occur, inasmuch as major decreases are also observed in the numbers of hippocampal dendritic spines, the immediate cytologic precursor of glutamatergic synapses. The syntheses of new dendritic spines and synapses can, however, be increased by concurrently raising brain levels of three circulating nutrients - uridine, omega-3 fatty acids docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA), and choline. This could provide an additional strategy for restoring synapses and thereby memory. The three nutrients are rate-limiting precursors in the Kennedy Cycle, the pathway which forms the phosphatides that are the major component of synaptic membranes. Uridine also increases the production of synaptic proteins, the other major membrane constituent, and the outgrowth of neurites. Hence administering the three nutrients accelerates synapse formation. These actions of uridine are largely mediated by uridine triphosphate (UTP), which can be released as a neurotransmitter from presynaptic terminals and can then activate P2Y2 receptors. The UTP in neurons can also be converted to cytidylyl triphosphate, CTP, the intermediate utilized in the Kennedy Cycle.

Connectomics and other novel methods for examining neural systems.

Novel approaches for studying the brain and relating its activities to mental phenomena have come into use during the past decade (Bargmann, 2015). These include both new laboratory methods - involving, among others, generation of isolated cells which retain neuronal characteristics in vivo; the selective stimulation of neurons by light in vivo; and direct electrical stimulation of specific brain regions to restore a system's balance of excitation and inhibition - and a new organizing principle, "connectomics", which recognizes that networks, and not simply a key nucleus or region, underlie most brain functions and malfunctions. Its application has already improved our comprehension of how the brain normally functions and our ability to help patients with such poorly treated neurologic and psychiatric diseases as Alzheimer's disease.

How Anticholinergic Drugs Might Promote Alzheimer's Disease: More Amyloid-ß and Less Phosphatidylcholine.

Drugs that block muscarinic cholinergic neurotransmission in the brain can, as a consequence, increase the formation of amyloid-ß, and decrease brain levels of phosphatidylcholine (by slowing its synthesis and accelerating its turnover). Both of these effects might cause a decrease in brain synapses, as characterizes and probably underlies the memory disorder of early Alzheimer's disease.

Biomarkers in the diagnosis and management of Alzheimer's disease.

Traditionally Alzheimer's disease (AD) has been diagnosed and its course followed based on clinical observations and cognitive testing, and confirmed postmortem by demonstrating amyloid plaques and neurofibrillary tangles in the brain. But the growing recognition that the disease process is ongoing, damaging the brain long before clinical findings appear, has intensified a search for biomarkers that might allow its very early diagnosis and the objective assessment of its responses to putative treatments. At present at least eight biochemical measurements or scanning procedures are used as biomarkers, usually in panels, by neurologists and others. The biochemical measurements are principally of amyloid proteins and their A-beta precursors, or of tau proteins. Brain atrophy can be assessed by means of structural magnetic resonance imaging (sMRI), and decreased blood flow and metabolism can be estimated by functional magnetic resonance imaging (fMRI). [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) is used to measure the brain's energy utilization and to infer synaptic number. Impaired connectivity between brain regions is indicated by diffusion tensor imaging (DTI), while magnetic resonance spectroscopy (MRS) provides metabolic markers of diminished cell number. Additional proposed biomarkers utilize electroencephalography (EEG) and magnetoencephalography (MEG) for quantifying impairments in connectivity. Genetic analyses illustrate the heterogeneity of disease processes that can cause cognitive impairment syndromes. Recent observations awaiting confirmation suggest that levels of some plasma phospholipids can also be biomarkers of AD and that reductions in these levels can enable the accurate prediction that a cognitively normal individual will go on to develop MCI or AD within 2 years.

Evidence for the existence of pyrimidinergic transmission in rat brain.

The uridine nucleotides uridine-5'-triphosphate (UTP) and uridine-5'-diphosphate (UDP) have previously been identified in media from cultured cells. However, no study to date has demonstrated their presence in brain extracellular fluid (ECF) obtained in vivo. Using a novel method, we now show that UTP and UDP, as well as uridine, are detectable in dialysates of striatal ECF obtained from freely-moving rats. Intraperitoneal (i.p.) administration of uridine or exposure of striatum to depolarizing concentrations of potassium chloride increases extracellular uridine, UTP and UDP, while tetrodotoxin (TTX) decreases their ECF levels. Uridine administration also enhances cholinergic neurotransmission which is accompanied by enhanced brain levels of diacylglycerol (DAG) and inositol trisphosphate (IP3) and blocked by suramin, but not by PPADS (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) or MRS2578 suggesting a possible mediation of P2Y2 receptors activated by UTP. These observations suggest that uridine, UTP and UDP may function as pyrimidinergic neurotransmitters, and that enhancement of such neurotransmission underlies pharmacologic effects of exogenous uridine on the brain.

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.

A nutrient combination that can affect synapse formation.

Brain neurons form synapses throughout the life span. This process is initiated by neuronal depolarization, however the numbers of synapses thus formed depend on brain levels of three key nutrients-uridine, the omega-3 fatty acid DHA, and choline. Given together, these nutrients accelerate formation of synaptic membrane, the major component of synapses. In infants, when synaptogenesis is maximal, relatively large amounts of all three nutrients are provided in bioavailable forms (e.g., uridine in the UMP of mothers' milk and infant formulas). However, in adults the uridine in foods, mostly present at RNA, is not bioavailable, and no food has ever been compelling demonstrated to elevate plasma uridine levels. Moreover, the quantities of DHA and choline in regular foods can be insufficient for raising their blood levels enough to promote optimal synaptogenesis. In Alzheimer's disease (AD) the need for extra quantities of the three nutrients is enhanced, both because their basal plasma levels may be subnormal (reflecting impaired hepatic synthesis), and because especially high brain levels are needed for correcting the disease-related deficiencies in synaptic membrane and synapses.

Personalized medicine strategies for managing patients with parkinsonism and cognitive deficits.

Patients exhibiting the classic manifestations of parkinsonism - tremors, rigidity, postural instability, slowed movements and, sometimes, sleep disturbances and depression - may also display severe cognitive disturbances. All of these particular motoric and behavioral symptoms may arise from Parkinson's disease [PD] per se, but they can also characterize Lewy Body dementia [LBD] or concurrent Parkinson's and Alzheimer's diseases [PD & AD]. Abnormalities of both movement and cognition are also observed in numerous other neurologic diseases, for example Huntington's Disease and the frontotemporal dementia. Distinguishing among these diseases in an individual patient is important in "personalizing" his or her mode of treatment, since an agent that is often highly effective in one of the diagnoses (e.g., L-dopa or muscarinic antagonists in PD) might be ineffective or even damaging in one of the others. That such personalization, based on genetic, biochemical, and imaging-based biomarkers, is feasible is suggested by the numerous genetic abnormalities already discovered in patients with parkinsonism, Alzheimer's disease and Huntington's disease (HD) and by the variety of regional and temporal patterns that these diseases can produce, as shown using imaging techniques.

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.

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.

Non-nutritional uses of nutrients.

Nutrients are generally conceived as dietary substances which the body requires more-or-less continuously, within a particular dosage range, to protect against developing the characteristic syndromes that occur when they are deficient. However some nutrients - when given apart from their usual food sources or at higher doses than those obtained from the diet - can also exercise pharmacologic effects, particularly on the CNS. Some, like folic acid, can promote neuronal development; others, like the neurotransmitter precursors tryptophan, choline, and histidine, can modulate the rates at which their products are synthesized; yet others, like uridine and omega-3 fatty acids, can increase the production of synaptic membrane, and thus promote synaptogenesis. In order for the nutrient to produce such effects, its plasma levels must be allowed to increase substantially when larger amounts are consumed; an unsaturated or competitive system must exist for transporting the nutrient across the blood-brain barrier; and the enzymes that convert the nutrient to its pharmacologically-active form must also be unsaturated with substrate. Nutrient mixtures chosen for their pharmacologic effects (and general lack of serious side-effects) are presently used for ameliorating several conditions, and more such uses can be anticipated.

Nutritional modifiers of aging brain function: use of uridine and other phosphatide precursors to increase formation of brain synapses.

Brain phosphatide synthesis requires three circulating compounds: docosahexaenoic acid (DHA), uridine, and choline. Oral administration of these phosphatide precursors to experimental animals increases the levels of phosphatides and synaptic proteins in the brain and per brain cell as well as the numbers of dendritic spines on hippocampal neurons. Arachidonic acid fails to reproduce these effects of DHA. If similar increases occur in human brain, administration of these compounds to patients with diseases that cause loss of brain synapses, such as Alzheimer's disease, could be beneficial.

Fibromyalgia and the complex regional pain syndrome: similarities in pathophysiology and treatment.

Although the pain of fibromyalgia usually is not preceded by an injury to the involved tissue, whereas that of the complex regional pain syndrome usually starts at a site of prior trauma or surgery, both disorders may share a common mechanism-pathologic sensitization of brain mechanisms that integrate nociceptive signals-and both apparently respond to treatment with ketamine, an anesthetic-analgesic agent whose actions include blockade of N-methyl-D-aspartate receptors. Ketamine's widespread illegal use as a recreational agent probably precludes developing it as a general treatment of centrally mediated pain disorders; however, its efficacy suggests that related, to-be-discovered agents could be useful.

Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial.

OBJECTIVE: To investigate the effect of a medical food on cognitive function in people with mild Alzheimer's disease (AD). METHODS: A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale-revised, and the 13-item modified Alzheimer's Disease Assessment Scale-cognitive subscale at week 12. RESULTS: At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer's Disease Assessment Scale-cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer's disease Co-operative Study-Activities of Daily Living, Quality of Life in Alzheimer's Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated. CONCLUSIONS: Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.