Improvement of cognitive performance by a nutraceutical formulation: Underlying mechanisms revealed by laboratory studies.

Cognitive decline, decrease in neuronal function and neuronal loss that accompany normal aging and dementia are the result of multiple mechanisms, many of which involve oxidative stress. Herein, we review these various mechanisms and identify pharmacological and non-pharmacological approaches, including modification of diet, that may reduce the risk and progression of cognitive decline. The optimal degree of neuronal protection is derived by combinations of, rather than individual, compounds. Compounds that provide antioxidant protection are particularly effective at delaying or improving cognitive performance in the early stages of Mild Cognitive Impairment and Alzheimer's disease. Laboratory studies confirm alleviation of oxidative damage in brain tissue. Lifestyle modifications show a degree of efficacy and may augment pharmacological approaches. Unfortunately, oxidative damage and resultant accumulation of biomarkers of neuronal damage can precede cognitive decline by years to decades. This underscores the importance of optimization of dietary enrichment, antioxidant supplementation and other lifestyle modifications during aging even for individuals who are cognitively intact.

Beneficial and Deleterious Impact of a Nutritional Supplementation for Inhibition of Proliferation of Neuroblastoma in Culture.

Neuroblastoma, a cancer of the sympathetic nervous system, primarily affects infants and children ≤10 yr of age. High-risk neuroblastoma is associated with low survival rates and increased risks of treatment-related side-effects. Therefore, effective treatments that increase survival and reduce adverse side-effects are crucial. Cucurbitacin E (CucE), a nutritional supplement shown to have potential as an alternative to chemotherapy, was investigated for potential impact on neuroblastoma alone and in combination with the standard chemotherapeutic agent, paclitaxel, (PAC). CucE and PAC each inhibited proliferation of murine neuroblastoma cells in culture. Combined treatment with CucE and PAC also induced morphological differentiation. However, both differentiation and antiproliferative effects were reversible. Consequently, while nutritional supplementation represents a potential therapeutic approach toward treatment of cancer, certain nutritional/chemotherapeutic combinations may induce transient rather than permanent effects. Transient inhibition of proliferation by nutritional supplementation could inadvertently protect carcinogenic cells from toxicity otherwise induced by a chemotherapeutic agent. Combinatorial treatments involving nutritional supplements should therefore be utilized with caution.

Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer's Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study.

Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer's disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.

A Nutritional Formulation for Cognitive Performance in Mild Cognitive Impairment: A Placebo-Controlled Trial with an Open-Label Extension.

Thirty-four individuals with mild cognitive impairment were randomized for 6 months to a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or indistinguishable placebo, followed by a 6-month open-label extension in which all individuals received NF. The NF cohort improved in the Dementia Rating Scale (DRS; effect size >0.7) and maintained baseline performance in CLOX-1. The placebo cohort did not improve in DRS and declined in CLOX-1, but during the open-label extension improved in DRS and ceased declining in CLOX-1. These findings extend prior studies of NF efficacy for individuals without cognitive impairment and with Alzheimer's disease.

Nutritional supplementation for Alzheimer's disease?

PURPOSE OF REVIEW: Evidence for the benefit of nutrition in Alzheimer's disease continues to accumulate. Many studies with individual vitamins or supplements show marginal, if any, benefit. However, new findings with combinatorial formulations demonstrate improvement in cognitive performance and behavioral difficulties that accompany Alzheimer's disease. Herein, we review some of the most recent clinical advances and summarize supportive preclinical studies. RECENT FINDINGS: We present novel positive effects on Alzheimer's disease derived from diet, trace elements, vitamins and supplements. We discuss the inherent difficulty in conducting nutritional studies because of the variance in participants' nutritional history, versus pharmacological interventions in which participants are naive to the intervention. We examine the evidence that epigenetics play a role in Alzheimer's disease and how nutritional intervention can modify the key epigenetic events to maintain or improve cognitive performance. SUMMARY: Overall consideration of the most recent collective evidence suggests that the optimal approach for Alzheimer's disease would seem to combine early, multicomponent nutritional approaches (a Mediterranean-style diet, multivitamins and key combinatorial supplements), along with lifestyle modifications such as social activity and mental and physical exercise, with ultimate addition of pharmacological agents when warranted.

A Phase II Randomized Clinical Trial of a Nutritional Formulation for Cognition and Mood in Alzheimer's Disease.

BACKGROUND: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer's disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. OBJECTIVE: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. METHODS: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer's Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for 3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. RESULTS: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. CONCLUSIONS: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior.

Has prenatal folate supplementation established an at-risk population for age-related cognitive decline?

Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system throughout life. Maternal folate supplementation during pregnancy has reduced developmental disorders of the nervous system, but may have also fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals may harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. An increased association of such polymorphisms has been detected in individuals with autism. Prenatal nutritional supplementation may have inadvertently established latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.

Synergistic inhibition of synaptic signaling in cortical cultures by subcytotoxic levels of oligomerized amyloid-ß and iron: alleviation by zinc.

Iron exacerbates amyloid-ß (Aß) toxicity, while zinc alleviates it. We examined the impact of these metals on Aß-induced signaling inhibition. Murine embryonic cortical neurons on multi-electrode arrays received 0.1 µM FeCl2 0.1 µM zinc acetate and/or 10 nM oligomerized Aß(1-42). No toxicity was observed. Spontaneous signaling was not altered by iron or Aß individually, but was inhibited by both. Zinc did not impact signaling alone, but prevented inhibition by iron plus Aß. Aß can be detected years before cognitive decline. Subcytotoxic iron levels may potentiate Aß-induced impairment of synaptic activity during these early stages; zinc supplementation may alleviate this potentiation.

Lifetime requirement of the methionine cycle for neuronal development and maintenance.

PURPOSE OF REVIEW: Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system. One critical pathway is the methionine cycle, in which folate and B12 convert homocysteine to methionine, which is in turn converted to S-adenosyl methionine (SAM; the major methyl donor). As a consequence of methylation, however, SAM is converted to the neurotoxin homocysteine and must be excreted or drawn back into the methionine cycle, which requires additional folate and B12. Dietary or genetic folate deficiency impairs this cycle, leading to developmental disorders, including those of the nervous system. RECENT FINDINGS: Folate and SAM exert profound epigenetic effects via DNA and histone methylation. Maternal supplementation during pregnancy has fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. Herein, we consider the potential link of failure to meet this additional requirement to early and age-related cognitive compromise. SUMMARY: Compromises in the methionine cycle can manifest as a spectrum of disorders throughout life. These considerations underscore how prenatal nutritional supplementation can alleviate developmental disorders by inadvertently establishing latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.

Positive argument for debate in J Neural Transmission: Alzheimer's disease: are we intervening too late? Yes, by years if not decades.

The ongoing debate as to whether we are or are not early enough in treatment for Alzheimer's disease presents distinct vantage points. Points expressed range from stressing the need for early preventive measures to highlighting the failure of "alternative" therapies, and concluding that we are unfortunately doing all that we can at present. Herein, we stress the worth of nutritional intervention, and review why such studies are often inherently compromised. We conclude that considerable education is needed to advance lifestyle modifications early enough to obtain their optimal effect, and instead of positioning "classical" interventions against "alternative" interventions, the combinations of both may impart maximal benefit. The introduction of novel detection methods at the earliest indications of cognitive impairment may provide a window of opportunity for initiation of preventative approaches.

Nutrition and dementia: are we asking the right questions?

Alzheimer's disease (AD) has no cure or nullifying pharmacological interventions. Nutritional supplementation represents a systemic approach that in some studies has provided benefit and has augmented pharmacological approaches. However, additional studies report no benefit of supplementation. We review herein how studies of nutrition on dementia, including those combining nutrition and dementia, are inherently compromised. We also review studies with mice, which demonstrate that nutritional supplementation can alleviate multiple genetic risk factors for AD. An individual diagnosed with AD has by definition undergone considerable cognitive decline; anticipating restoration/maintenance of cognitive performance following nutritional supplementation alone may be misdirected. Nutrition declines in aging, and even more so in AD. While optimization of nutrition should ideally be initiated well before any cognitive decline, we present evidence that the systemic benefit alone of nutritional supplementation at the very minimum warrants initiation along with pharmacological intervention.

Dietary supplementation with S-adenosyl methionine delayed amyloid-ß and tau pathology in 3xTg-AD mice.

S-adenosyl methionine (SAM) contributes to multiple pathways in neuronal homeostasis, several of which are compromised in age-related neurodegeneration and Alzheimer's disease. Dietary supplementation of transgenic mice with SAM maintained acetylcholine levels, cognitive performance, oxidative buffering capacity, and phosphatase activity, and reduced aggression, calcium influx, endogenous PS-1 expression, γ-secretase activity, and levels of amyloid-ß (Aß) and phospho-tau. Herein, we examined whether or not SAM could delay neuropathology in 3xTg-AD mice, which harbor mutant genes for human AßPP, PS-1 and tau. Mice received a standard AIN-76 diet with or without SAM (100 mg/kg diet) for 1 month commencing at 10 months of age or for 3 months commencing at 12.5 months of age; mice were sacrificed and examined for Aß and tau neuropathology at 11 and 15.5 months of age, respectively. SAM supplementation reduced hippocampal intracellular AßPP/Aß and phospho-tau immunoreactivity to a similar extent at both sampling intervals. Supplementation reduced the number of extracellular Aß deposits by 80% (p < 0.01) at 11 months of age after 1 month of treatment but only by 24% (p < 0.34) at 15.5 months of age after 3 months of treatment. As anticipated, neurofibrillary tangles were not observed in mice at these young ages; however, supplementation reduced levels of phospho-tau and caspase-cleaved tau within Sarkosyl-insoluble preparations in mice at 15.5 months of age. These limited analyses indicate that SAM can modulate the time course of AD neuropathology, and support further long-term analyses.

Environmental enrichment can prevent cognitive decline induced by dietary oxidative challenge.

Alzheimer's disease encompasses multiple risk factors; convergence may be necessary for clinical manifestation. Mice received a complete diet or one lacking folate and vitamin E and containing iron as a pro-oxidant, in a standard environment (SE) or a large cage containing objects to stimulate exploration/activity (enriched environment; EE). Mice declined in maze navigation on the deficient versus complete diet in the SE but not the EE. Mice on the complete diet demonstrated superior performance in the EE versus SE. The EE reduced brain lipid and protein oxidation. These findings suggest that maintaining nutrition and activity may delay age-related cognitive decline.

Apple juice improved behavioral but not cognitive symptoms in moderate-to-late stage Alzheimer's disease in an open-label pilot study.

Preclinical studies demonstrate that apple juice exerts multiple beneficial effects including reduction of central nervous system oxidative damage, suppression of Alzheimer's disease (AD) hallmarks, improved cognitive performance, and organized synaptic signaling. Herein, we initiated an open-label clinical trial in which 21 institutionalized individuals with moderate-to-severe AD consumed 2 4-oz glasses of apple juice daily for 1 month. Participants demonstrated no change in the Dementia Rating Scale, and institutional caregivers reported no change in Alzheimer's Disease Cooperative Study (ADCS)-Activities of Daily Living (ADL) in this brief study. However, caregivers reported an approximate 27% (P < .01) improvement in behavioral and psychotic symptoms associated with dementia as quantified by the Neuropsychiatric Inventory, with the largest changes in anxiety, agitation, and delusion. This pilot study suggests that apple juice may be a useful supplement, perhaps to augment pharmacological approaches, for attenuating the decline in mood that accompanies progression of AD, which may also reduce caregiver burden.

Dietary supplementation with S-adenosyl methionine delays the onset of motor neuron pathology in a murine model of amyotrophic lateral sclerosis.

The full range of causative factors in Amyotrophic lateral sclerosis (ALS) remains elusive, but oxidative stress is recognized as a contributing factor. Mutations in Cu/Zn superoxide dismutase 1 (SOD-1), associated with familial ALS, promote widespread oxidative damage. Mice-expressing G93A mutant human SOD-1 mice display multiple pathological changes characteristic of ALS and are therefore useful for therapeutic development. Dietary supplementation with S-adenosyl methionine (SAM) has provided multiple neuroprotective effects in mouse models of age-related cognitive pathology. We examined herein whether SAM supplementation could affect the course of motor neuron pathology in mice-expressing mutant human SOD-1. SAM delayed disease onset by 2-3 weeks. SAM also delayed hallmarks of neurodegeneration in these mice and in ALS, including preventing loss of motor neurons, and reducing gliosis, SOD-1 aggregation, protein carbonylation, and induction of antioxidant activity. SAM did not increase survival time. These preliminary findings, using a single concentration of SAM, suggest that SAM supplementation maybe useful as part of a comprehensive therapeutic approach for ALS.

Dietary deficiency increases presenilin expression, gamma-secretase activity, and Abeta levels: potentiation by ApoE genotype and alleviation by S-adenosyl methionine.

Apolipoprotein E4 (ApoE4) is a risk factor for Alzheimer's disease (AD). Whether this risk arises from a deficient function of E4 or the lack of protection provided by E2 or E3 is unclear. Previous studies demonstrate that deprivation of folate and vitamin E, coupled with dietary iron as a pro-oxidant, for 1 month displayed increased presenilin 1 (PS-1) expression, gamma-secretase, and Abeta generation in mice lacking ApoE (ApoE-/- mice). While ApoE-/- mice are a model for ApoE deficiency, they may not reflect the entire range of consequences of E4 expression. We therefore compared herein the impact of the above deficient diet on mice expressing human E2, E3, or E4. As folate deficiency is accompanied by a decrease in the major methyl donor, S-adenosyl methionine (SAM), additional mice received the deficient diet plus SAM. E2 was more protective than murine ApoE or E3 and E4. Surprisingly, PS-1 and gamma-secretase were over-expressed in E3 to the same extent as in E4 even under a complete diet, and were not alleviated by SAM supplementation. Abeta increased only in E4 mice maintained under the complete diet, and was alleviated by SAM supplementation. These findings suggest dietary compromise can potentiate latent risk factors for AD.

Dietary deficiency in folate and vitamin E under conditions of oxidative stress increases phospho-tau levels: potentiation by ApoE4 and alleviation by S-adenosylmethionine.

Prior studies link dietary deficiency and genetic risk factors for Alzheimer's disease (AD). In the present report, mice expressing human apolipoprotein E4 (associated with increased risk of AD) and apolipoprotein E3 were subjected to a diet lacking folate and vitamin E, and containing iron as a pro-oxidant. Consistent with prior studies, E4 mice displayed more phospho-tau than E3 mice prior to dietary challenge. The deficient diet increased phospho-tau in E4 but not E3 mice, which was prevented by S-adenosyl methionine supplementation. Since neurofibrillary tangles are comprised of phospho-tau, investigation of the impact of dietary deficiency and S-adenosyl methionine supplementation on neurofibrillary tangle formation are warranted.

Dietary supplementation with a combination of alpha-lipoic acid, acetyl-L-carnitine, glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to murine brain and improves cognitive performance.

Alzheimer disease has a complex etiology composed of nutritional and genetic risk factors and predispositions. Moreover, genetic risk factors for cognitive decline may remain latent pending age-related decline in nutrition, suggesting the potential importance of early nutritional intervention, including preventative approaches. We hypothesized that a combination of multiple nutritional additives may be able to provide neuroprotection. We demonstrate herein that dietary supplementation with a mixture of ALA, ALCAR, GPC, DHA, and PS reduced reactive oxygen species in normal mice by 57% and prevented the increase in reactive oxygen species normally observed in mice lacking murine ApoE when maintained on a vitamin-free, iron-enriched, oxidative-challenge diet. We further demonstrate that supplementation with these agents prevented the marked cognitive decline otherwise observed in normal mice maintained on this challenge diet. These findings add to the growing body of research indicating that key dietary supplementation may delay the progression of age-related cognitive decline.

Dietary supplementation with apple juice decreases endogenous amyloid-beta levels in murine brain.

Folate deficiency has been associated with age-related neurodegeneration. We demonstrate herein that dietary deficiency in folate and vitamin E, coupled pro-oxidant stress induced by dietary iron, increased amyloid-beta (Abeta) levels in normal adult mice. This increase was potentiated by apolipoprotein E (ApoE) deficiency as shown by treatment of transgenic mice homozygously lacking murine ApoE. Dietary supplementation with apple juice concentrate in drinking water alleviated the increase in Abeta for both mouse genotypes. These findings provide further evidence linking nutritional and genetic risk factors for age-related neurodegeneration, and underscore that dietary supplementation may be useful to augment therapeutic approaches.