Introduction

Convincing evidence implies that degenerative disorders manifesting as slow, progressive loss of brain function are associated with specific physiologic changes, alterations in functional signaling pathways and risk factors that cumulatively impair normal neuronal function. ₁ It is noteworthy that clinical symptoms are generally present before frank neuronal loss is observed. This suggests the presence of a window of opportunity for reversal, or slowing, of the process or for potential functional enhancement. ₂

Based on this type of observation, many individuals currently use alternative therapies for a range of conditions including brain health. The safety and efficacy of these products are rarely substantiated. This creates a confusing marketplace for consumers seeking such approaches.

The present clinical trial was conducted to evaluate the efficacy of a combination of nutrients on parameters of cognitive function in an aging but otherwise cognitively healthy group of humans. One group of subjects took a placebo product and one group took an active product for a three-month period. Depression and anxiety scales and two panels that tested various mental functions were administered at baseline and after three months in both groups. Inter-group comparisons were studied as a function of time.

Material and Methods

Participants

Subjects were recruited from the general population of Bangor, Maine. Telephone interviews were used to screen potential participants. They then had an on-site interview with a registered nurse. At their initial visit with the nurse, each potential subject answered questions about medical history, medications, current medical conditions and therapy, dietary supplement use, habits, work environment and living conditions.

Mild chronic medical conditions, such as treated hypertension, were permitted. Excluded conditions are listed in Table 1.

Table 1: Medically Excluded Conditions

• Severe cardiovascular, hepatic, renal or pulmonary disease

• Insulin-dependent diabetes

• Prevalent cancer

• Immune dysfunction

• Head or spinal injury

• Mental illness

• Excessive alcohol intake (*7 drinks per week) or addiction

• Women who were nursing, pregnant, or attempting to become pregnant

Allowed medication for pre-existing conditions was not discontinued. Attempts were made to exclude the use of medications that impacted cognitive function. These medications are listed in Table 2. Their use precluded participation in the clinical trial.

Figure 1

Table 2: Excluded Categories of Medication

Study participants were between 35 and 70 years of age. The mean age was 46.6 years and two-thirds of the subjects were between 40 and 60 years of age. This is considered middle age and represents a period of life when certain aspects of cognitive processing decline. All those included had the ability to tolerate the product or placebo and completed compliance testing. After reading and signing the consent form, subjects were informed how to report adverse events and were randomized according to protocol. The clinical study was reviewed and approved by the Asentral Human Institutional Review Board in Salisbury, Massachusetts. Subjects were treated equally and were free to withdraw from the study at any time. Baseline characteristics were not significantly different. Data are shown in Table 3.

Figure 2

Table 3: Baseline Characteristics*

Experimental design and procedures

A three-month, double-blind, fixed-dose, placebo-controlled, randomized, parallel-group experimental design was used. Individuals meeting inclusionary criteria were randomly assigned to either the placebo or active product group in an enrollment ratio of 2:3, respectively. The active product and the placebo were similar in appearance, number, smell and taste. Ingredients for the active product are listed in Table 4. The placebo consisted of cellulose.

Figure 3

Table 4: Ingredients in One Day Dosing of Active Product

Antioxidants

Beta carotene, alpha carotene, lutein, zeaxanthin, cryptoxanthin, Gingko biloba, green tea, vinpocetine, bilberry, grape seed, maritime pine bark, lycopene, resveratrol

Antireductants

Choline, inositol, trimethylglycine
Calcium modulators
Taurine
Cholinergic neuromodulators
DMAE (dimethylaminoethanol), Huperzine A
Cellular energizers
Creatine, alpha ketoglutarate, N-acetyl L-tyrosine, acetyl L-carnitine, PABA, glutamine, L-pyroglutamic acid
Phosphatidyl serine
Soy bean oil
Modulators of glycosaminoglycans
Chondroitin, glucosamine
Insulin sensitizers
Vanadium

Mitochondrial cofactors

Acetyl L-carnitine, alpha lipoic acid, coenzyme Q10
Neurotrophins
Soy isoflavones

*Based upon a 2000 calorie diet

To assess treatment changes, enrolled participants were administered the following series of standardized neuropsychological tests during pretreatment baseline evaluations, and again, after three months of randomized treatment: Vigil Continuous Performance Test (Vigil); California Verbal Learning Test-version II (CVLT-II); and Beck Depression and Anxiety Scales.

Noncompliance was defined as a deviation of greater than 10 percent from the optimum treatment regimen. Adverse events and protocol compliance were assessed at each biweekly contact period, at the end of the study and on an as-needed basis.

Statistical methods

Results

After obtaining informed consent, 43 subjects who met the inclusion criteria and were assessed as being able to comply with the test protocol were randomized (26 and 17 in the treatment and placebo groups, respectively). Of these 43, there were 2 who failed to complete the trial. Loss-to-follow-up was the reason for dropout. Thus, the data from 41 subjects are included in the trial; 25 in the treatment group and 16 in the placebo group.

Baseline cognitive status of the study population was not statistically different between groups. (Data not shown.) The subjects reported no serious adverse events. Mild nausea was noted in 6 of the subjects on product and 5 on placebo. This was transitory in all cases and did not require removal from the trial..

One of the primary outcomes, summarized in Table 5, was from the computerized version of the Vigil Continuous Performance Test. The active product produced an improvement (Z=0.55) which was significant (p*0.01) in commission error (extra hits) testing.

Figure 4

Table 5: Vigil: Mean Differences of Z Scores (Age and Gender-Adjusted) from Baseline (a positive mean number indicates improvement)

The second set of outcomes came from the California Verbal Learning (CVLT-II) tool. The primary responses are shown in Table 6.

Figure 5

Table 6: CVLT-II: Mean Differences of Z Scores (Age and Gender-Adjusted) from Baseline (a positive mean number indicates improvement)

Among these five variables, a beneficial effect due to active product was seen in Total Response and Trial 1 with differences that were significant at p<0.01 and p<0.006, respectively. Learning Slope showed a difference between groups that represented a trend (p<0.085). No other CVLT-II variables were statistically different.

As depicted in Table 7, the third group of end points-the Beck Depression and Beck Anxiety scales-demonstrated improvements between the groups that were statistically significant at p<0.05 and p=0.009, respectively.

Figure 6

Table 7: Mood Rating Scales (a positive mean number indicates improvement)

Discussion

The Vigil test is the most popular clinic-based measure of sustained attention and vigilance. ₃ It has also been described as being the most sensitive measure for evaluating therapeutic efficacy in these domains. ₄ In the Vigil testing, all of the individual parameters were improved. The subjects on product were more alert than the group on placebo, missing far fewer of the target stimuli. They could also focus and sustain their attention better. The group on product gave fewer false-positive responses. This suggests they were better able to inhibit the impulse to respond inappropriately. This was statistically significant (p=0.01). The group on product had a tendency to respond more quickly, indicating greater activation and more efficient information processing. When evaluated for a 30-millisecond improvement in cognitive processing speed, those on product outperformed those on placebo by 30.4 percent (42.9 percent v. 12.5 percent, p=0.049).

Improvements of attention and impulsivity with psychostimulants are well documented. ₅ Attention, concentration and processing speed also respond to stimulant medications. Moderate effect sizes have been noted in various meta-analyses with Z-score improvements in the 0.3 to 0.5 range. ₆ In the present trial, the nutritional product produced an improvement in the commission rate parameter of Z=0.55 (p=0.01). The comparable improvements for hit rate, omissions and reaction rate were Z=0.49, Z=0.66 and Z=0.48, respectively.

Results on the CVLT-II Total Response score indicate overall cumulative learning (information that can be stored and retrieved from short-term storage, while being actively processed) was better for those on product. This difference was large (Z=0.65) and significant (p

The product group also showed improvements in the Beck Depression (4.31 +/- 6.2 vs 0.69 +/- 5.0, product vs placebo (p<0.05)) and Beck Anxiety (5.74 +/- 10.2 vs -2.44 +/- 8.0, product vs placebo (p<0.009)) scales. These improvements were not associated with any weight gain, a common occurrence associated with the use of antidepressant and antianxiety medications.

These benefits may be the result of several unique mechanisms. The brain was provided with a basic platform of micronutrient support. In addition, a collection of specific neuroprotectant agents was added as a second therapeutic tier designed to act synergistically with the basic nutrient foundation.

The intake in the average American diet of many of the essential micronutrients is suboptimal. ₇ Where there is one micronutrient deficiency, there is a significant likelihood of others. For example, in one study of rural, community-dwelling elderly less than 20 percent of the subjects consumed adequate levels of 16 out of 19 essential nutrients. ₈ These vary in degree from the inability to meet RDAs to frank deficiency states. When they persist, much metabolic damage may develop. ₉ Research indicates that deficiencies of iron; zinc; and the vitamins folate, B12, B6 and C can cause DNA damage, neuronal injury and mitochondrial decay. ₁₀ These common micronutrient deficiencies appear to damage cellular constituents by a mechanism similar to that which occurs upon exposure to radiation and many chemicals yet appears to be much more indolent. ₁₁ This may result in increased risk for cognitive dysfunction. In addition, folate, B6 or B12 deficiencies may contribute to homocysteine accumulation, a risk factor for vascular disease, Alzheimer's disease (AD) and neuropsychiatric disorders. ₁₂

An interesting component of this clinical trial involved improvement in mood parameters, depression and anxiety. Low folate levels and elevated plasma interleukin-6 (IL-6) levels have been associated with depression. ₁₃ A study in depressed but otherwise healthy men related pretreatment folate level to therapeutic response to fluoxetine. ₁₄ In another study in depressed adults with serum folate levels above 6 ng/ml who had previously shown inadequate antidepressant response, folinic acid (leucovorin) supplementation was associated with decline in depression scores. ₁₅ These insights support the contention that the relevance of folate to depression may extend beyond its more obvious role in reversing the sequelae of folate deficiency. ₁₆

The strengths of the study include its design, performance at a single center, compliance testing (requiring 90 percent supplement adherence rate) and administration of neuropsychological testing under the direct supervision of a board-certified neuropsychologist. A weakness of the study is the inability to attribute the success of the supplement to any one component.

The active product consisted of a combination of nutritional ingredients making it difficult, if not impossible, to determine which component was most responsible for the outcome. However, the intrinsic formulation of the product was based upon the ability of numerous nutrients to beneficially modulate an array of metabolic pathways and depended upon synergistic effects of the various components. Hence, the efficacy was more likely dependent upon modulation of many pathways rather than being related to any one specific pathway or single component.

In conclusion, the personal cost associated with suboptimal mental function is immeasurable. The financial burden is staggering. It is estimated that the economic impact of delaying the onset of Alzheimer's disease for merely six months would result in an annual savings of approximately $18 billion in the United States alone by the year 2050. ₁₇ Supplementation with nutrients of the type evaluated in this study suggests that it provides a beneficial impact upon brain health. It is inexpensive, makes biological sense, is simple to administer and would be expected to benefit those most at risk: the poor, young, elderly and medically infirm. Further collaboration among researchers, physicians, nutritionists, dieticians, teachers and parents is needed to help attain optimal brain health.

Acknowledgments

Correspondence to

James Blum, Ph. D. PMB 494 774 Mays Blvd., # 10 Incline Village, NV 89451 775 831-5965 jblum245@gmail.com