CognatiQ® (Coffee fruit extract)

“Natural Brain Performance”

Overview

• CognatiQ®, is a natural, non-stimulant patented coffee fruit extract (Coffea arabica) for brain performance
• According to the supplier, the patented and sustainable path rescues and preserves the coffee fruit, keeps it from the waste stream, and concentrates its unique and potent phytonutrients shown to support better brain performance
• CognatiQ® is soluble and efficacious at a low dose of 100 mg, making it versatile in a variety of delivery formats and market solutions
• CognatiQ® holds 4 published human clinical studies, shown to significantly increase levels of a key neuroprotein (BDNF) vital to learning, memory, and higher thinking. Within these studies, the mechanism of action has been suggested. This is unique as most research starts with animal or cell culture studies to initiate its potential health effects.
• Country of origin: India
• Proposed shelf life of 2 years
• GRAS status
• CognatiQ® is nonGMO, gluten free, free of allergens, and contains no artificial or synthetic ingredients

REASON FOR USE IN FORMULA (BDNF overview)

Brain-derived neurotrophic factor (BDNF) is a neurotrophin, a type of protein active in the brain as well as the central and peripheral nervous systems. BDNF was discovered in 1982, and since then, it has several documented roles in the development and maintenance of bodily brain functions. (Reyes Izquierdo, 2013) (Binder, 2004)

BDNF has been studied for its part in neuroplasticity, which means, this vital neuroprotein helps your nervous system respond and adapt to changing conditions of the body and the environment. Furthermore, BDNF supports the survival of existing neurons and promotes the growth, regeneration and creation of new neurons and synapses, a process known as neurogenesis. (Calabrese, 2014) (Lu, 2014) (Rossi, 2006)

BDNF, an important contributor to neuroplasticity and neurogenesis, makes it a key player in the body’s ability to maintain short- and long-term memory formation and execution.

In recent years, the search for new compounds, from natural sources, capable of modulating BDNF has been increasingly explored. One such botanical, coffee fruit extract under the brand CognatiQ®, has become a clinically validated approach to increasing BDNF levels, and improving cognitive performance fast and over time. (Reyes Izquierdo, 2013) ((Reyes Izquierdo, 2013 (follow up)) (Robinson, 2019.) (Robinson, 2021.)

Composition & Dosing

Coffee fruit extract (Coffea arabica) providing a minimum of 40% chlorogenic acids, 15% 5-caffeoylquinic acid, 2% caffeine

100 mg provides 40 mg of chlorogenic acids, 15 mg 5-caffeoylquinic acid, and 2 mgs of caffeine (CognatiQ-F01060 Spec)

What is special about CognatiQ®?

CognatiQ®, is a non-stimulant clinically validated ingredient that increases BDNF levels shown in human research. It’s 40% chlorogenic acid, minimal caffeine content, and its unique polyphenol profile makes it a more effective extract compared to others. (Reyes Izquierdo, 2013) (CognatiQ-F01060 Spec)

And here’s why:

Per the supplier: their coffee fruit products are unique to the industry in that they utilize the whole fruit, skin, pulp and bean in making their products. Historically when coffee fruit is harvested, the bean is separated from the fruit and the fruit is discarded because it spoils quickly. By using the whole fruit, they are reducing a waste stream but also harnessing the benefits of the coffee fruit’s unique polyphenol profile.

In the current literature, caffeine has been known to affect BDNF protein levels in normal animals. While administration during adulthood or old age increased BDNF, caffeine intake at high doses in early life downregulated the neurotrophin concentration. Caffeine’s effect on BDNF levels in humans have yet to be elucidated. (Sangiovanni, 2017.)

A clinical study investigated the effects of three different coffee fruit extracts with varying amounts of caffeine (.7%, 72.8%, 2%). All but one coffee fruit extract (CognatiQ®) increased BDNF in the blood suggesting that the effect might be related to the amount of procyanidins/the unique coffee polyphenol profile rather than to caffeine. (Sangiovanni, 2017) (Reyes Izquierdo, 2013) (Robinson, 2021)

Natural Medicines Database Safety, Effectiveness & Interaction Analysis

• Only provides an in-depth monograph for coffee.
• Does not provide a detailed section on whole coffee fruit extract; therefore, further research was conducted on the safety of coffee fruit extract.

Safety data

• The GRAS Evaluation dossier – (Gras Notice 868, Coffee fruit extract)
• Three genotoxicity studies, three short term oral toxicity studies, and a 90-day dietary toxicity study were included in this review. A tolerance of 8800 mg/kg BW per day was shown in female rats. Male rats tolerated up to 4000 mg/kg/ BW per day and approximately 2100 mg/kg BW per day of whole powder or water extract in the diet. No adverse events were seen in the 90-day study. (Heimbach JT et al (2010) Safety studies on products from whole coffee fruit. Food Chem Toxicol 48, 2517–2525.)

Research summary:

CognatiQ Preclinical data (MOA): researchers did not conduct preclinical data on coffee fruit and its effects on BDNF; however, with the high safety profile of coffee/coffee fruit, the literature available on BDNF, and the ability to measure BDNF in human studies was considered sufficient substantiation.

BDNF research:

• Rossi, 2006. Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment.
• Lu, 2014. BDNF and synaptic plasticity, cognitive function, and dysfunction.
• Calabrese, 2014. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity.

Human Studies (using CognatiQ material)

• Reyes Izquierdo, 2013. Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor in healthy subjects.
• Reyes Izquierdo, 2013 (follow up). Stimulatory effect of whole coffee fruit concentrate powder on plasma levels of total and exosomal BDNF in healthy subjects: An acute within-subject clinical study.
• Robinson, 2019. Cognitive short- and long-term effects of coffee cherry extract in older adults with mild cognitive decline.
• Robinson, 2021. Neurophysiological effects of whole coffee cherry extract in older adults with subjective cognitive impairment: A randomized, double-blind, placebo-controlled, cross-over pilot study.

Totality of the evidence: this search criteria was PubMed, targeted search criteria for all data (note, this type of search does not bring up every branded ingredient study as most are not open access)

• BDNF = 31,591 results with no filters or specified search criteria
• Coffee fruit extract = 432 results with no filters or specified search criteria
• Coffee fruit extract + BDNF = 3 results with no filters or specified search criteria

Human studies

Reyes Izquierdo, 2013. Modulatory effect of coffee fruit extract on plasma levels of brain-derived neurotrophic factor (BDNF) in healthy subjects

Purpose: To assess the effect of whole coffee fruit concentrate (WCFC), green coffee caffeine powder (N677), grape seed extract powder (N31) and green coffee bean extract powder (N625) on blood levels of BDNF.

Population: 25 healthy fasted subjects aged between 18 and 55 years with a BMI between 18-25kg/m2

Treatment: Fasted subjects consumed a single, 100 mg dose of each material given in the morning

• Four polyphenol-rich fruit extracts were tested in healthy subjects and these extracts contained varying amounts of caffeine.
• In follow-up studies performed under the same experimental conditions, five additional participants received WCFC, chlorogenic acid or water as vehicle (no treatment group).
• As WCFC contains high amounts of chlorogenic acid, it was hypothesized that this specific polyphenolic acid may cause an increase in blood level of BDNF. Consequently, we administered 50 mg of chlorogenic acid as a single dose to five healthy subjects.

Design: Randomized placebo-controlled study (no blinding)

• Subjects fasted for 12 hours prior to the first blood collection.

Composition: WCFC supplied by Futureceuticals, see table 1 for further info **The percentage of caffeine was within each tested compound, rather than an absolute mass of caffeine.

• N677 – Green coffee caffeine powder (72.8% caffeine)
• N625 – green coffee bean extract powder (2% caffeine)
• N31 – grape seed extract powder (caffeine free)
• WCFC – Whole Coffee fruit concentrate powder (0.7% caffeine), CognatiQ material
• Placebo – (silicon dioxide)

Measurements: plasma levels of BDNF collected at time zero and at 30-minute intervals, up to 120 minutes. BDNF levels were compared with a reference standard curve and each subject was normalized to their own value measured at time zero (T0). Peak levels of plasma BDNF for each patient were used for comparisons. Plasma BDNF levels at 60 minutes after treatment were compared to baseline.

Statistically significant results:

• First experiment
• WCFC increased BDNF levels in subjects by an average of 137% with respect to baseline compared to placebo. (N677 showed an increase of 42% but was non-significant, N625 did not cause a significant increase, N31 increased BDNF levels in plasma by 30% but was non-significant)
• Second experiment
• WCFC increased BDNF levels in subjects by an average of 148%; however, blood levels in the untreated group were not statistically changed (15% increase by average)
• Pooling all ten subjects from the two studies, treatment with 100 mg of WCFC caused a 143% increase in BDNF plasma levels at 60 minutes compared to baseline.
• Results from chlorogenic experiment
• On its own, chlorogenic acid did not increase blood level of BDNF in a statistically significant manner, suggesting that this substance may not be the sole reason for WCFC’s ability to increase BDNF.

Conclusion: Caffeine has been previously reported to increase BDNF levels. N677 is mostly comprised of caffeine, yet caused only a modest increase in plasma BDNF levels. The most profound effects were observed after treatment with WCFC, although this extract contains only 0.7% caffeine by weight. It is suggested that WCFC’s unique polyphenol profile, especially the procyanidins, is associated with the significant increases in BDNF levels. The present work suggests this unique profile has the ability to increase plasma BDNF levels and, perhaps, to a larger extent than caffeine itself.

Limitations: small sample size – researchers indicated a sample of 40 subjects would likely be needed to reach statistical power of 80%. Results for the other extracts should be interpreted with caution. Larger groups are needed to verify results. However, the result of this power analysis does not diminish the statistical significance of WCFC on plasma BDNF levels. No detail was given outlining the delivery format of consumption.

Strengths: healthy subjects, 5 arm study. To minimize confounding effects, all subjects remained in the testing facility during experimentation to avoid the possibility of blood BDNF increase due to physical activity and exercise. In addition, all subjects were tested during the same time of day to minimize any differences in blood BDNF due to diurnal effect.

Adverse events: none reported

Safety evaluation: was not performed in this study

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: Mexico
• Sample size
• Adult population

Notes: Since a 34% reduction in BDNF levels were seen with placebo, A second experiment was performed to verify the reproducibility of the effect of WCFC on BDNF and to test the effect of extended fasting (untreated control) on the baseline level of BDNF in blood.

Reyes-Izquierdo, 2013 (follow up). Stimulatory Effect of Whole Coffee Fruit Concentrate Powder on Plasma Levels of Total and Exosomal Brain-Derived Neurotrophic Factor in Healthy Subjects: An Acute Within-Subject Clinical Study

Purpose: To confirm and further investigate Reyes 2013 previous study results that showed ingestion of 100 mg single dose of whole coffee fruit concentrate (WCFC) increased blood levels of BDNF

Population: Twenty healthy subjects with ages ranging from 25 to 35 participated in this study

• All study subjects were generally healthy and did not use any type of medication or supplement for a period of 15 days prior to the start of the study.
• BMI between 18.5 and 24.9 kg/m2

Treatment: All fasted and resting subjects received placebo on Day 1, 100 mg of WCFC on Day 2, and a cup of freshly brewed coffee on Day 3. Placebo was given in a capsule, no information provided delivery format of WCFC.

Design: A single dose, placebo-controlled, within-subject crossover study given in the morning

• Subjects fasted for 12 hours prior to collection
• After the within-subject crossover study, one participant at random received an additional dose of WCFC to determine exosomal BDNF levels.

Composition: WCFC supplied by Futureceuticals

• WCFC – refer to previous study (caffeine content 0.7%)
• Coffee – prepared in a Platinum B70 Keurig® brewer, contained 130 mg caffeine

Measurements:

• Plasma BDNF and serum exosome levels (used to determine exosomal BDNF levels) were measured at time zero and at 30-minute intervals, up to 120 minutes. As previously described [1], BDNF levels were compared to a reference standard curve and each subject was normalized to their own value measured at time zero (T0). Results from each group were pooled and standard error of the mean was used for each separate analysis.
• Lactate and glucose measurements

Statistically significant results:

• Treatment with WCFC resulted in a statistically significant increase in plasma BDNF compared to placebo (p = 0.0073) or coffee (p = 0.0219) during first 60 minutes. A single 100 mg dose of capsulated WCFC increased plasma BDNF by 91% at 60 minutes and 66% at 120 minutes compared to baseline.
• In a one subject, clinical case experiment, WCFC increased serum BDNF by 54% and exosomal BDNF by 206%. This data requires further investigation.
• WCFC appears to be a stimulator of endogenous BDNF release from cells

Conclusion: A single dose of WCFC nearly doubles the amount of BDNF in the blood after 60 minutes with sustained effects for at least two hours after treatment. All presented results justify further clinical investigation of WCFC as a tool to manage BDNF-dependent health conditions. It has been reported for the first time (in one subject) that blood-circulating BDNF may exist as both free BDNF and contained within exosomes.

Limitations: small sample size, placebo was given in a capsule, no information provided on delivery format of WCFC.

Strengths: Follow up study to confirm previous results; the effect was not seen with freshly brewed coffee over the same time, a control that was not tested previously.

Adverse events: none reported

Safety evaluation: glucose was monitored for hypoglycemia

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: Mexico
• Sample size
• Adult population

Notes: Researcher’s were interested in determining whether treatment with WCFC increases only free BDNF levels in the blood or whether exosomal BDNF levels change as well. Caution should be used when expressing these results as only 1 participant was included in the analysis.

Exosomes: extracellular vesicles generated by all cells, that carry genetic information and proteins to cells throughout your body, creating paths for communication between cells.

**The results of the Reye’s studies are preliminary data that suggest the mechanism of action of the coffee fruit extract on cognitive performance. Further studies below conclude these findings. **

Reed, 2018. Acute Low and Moderate Doses of a Caffeine-Free Polyphenol-Rich Coffeeberry Extract Improve Feelings of Alertness and Fatigue Resulting from the Performance of Fatiguing Cognitive Tasks

Purpose: To evaluate the influence of acute consumption of a polyphenol-rich, non-caffeinated coffeeberry extract on performance of a series of fatiguing cognitive tasks, motivation to do the cognitive tasks, and mood state responses in healthy adults

Population: 30 healthy adults completed the full protocol, average age of 24.6 years

• Underwent a screening that included a practice battery not only ensured understanding of the instructions and testing procedures but also was used to exclude those potential participants who were unable or unwilling to perform adequately on the cognitive tests.

Treatment: Consumed one of four beverages (labeled A, B, C, and D on the bottles)

Design: A randomized, double-blind, placebo-controlled, cross-over design.

• A treatment containing 75 mg caffeine was used as a positive control to document participants’ responsiveness to an established psychostimulant.
• Enrolled subjects completed a serious of 4 testing visits and consumed a beverage during each session.
• A block randomization was used to participants consumed beverages in one of eight possible orders (ABCD, ADCB, BADC, BDCA, CADB, CBAD, DABC, or DCBA)
• The 24-h history questionnaires and previous meal logs to avoid confounding factors

Composition: All four beverage conditions contained a base liquid of water, sucralose, acesulfame potassium, preservatives, colors, and flavors.

• A – placebo, contained no added caffeine or coffeeberry extract
• B – positive control, contained 75 mg caffeine
• C – 100 mg coffeeberry extract, no caffeine
• D – 300 mg coffeeberry extract, no caffeine
• *Note, the specific coffee extract contains 51% chlorogenic acid, 17% 5-caffeoylquinic acid, 3.8% trigonelline, and 1.6% caffeine. This is not CognatiQ material and differences in composition should be considered when discussing study results.

Procedure & Measurements:

• Subjects were testing with a 50-55 min baseline testing battery. Following baseline testing, subjects were given their beverage and asked to consume fully within 10 minutes. This was followed by a 60-min quiet rest phase, to allow sufficient time for the beverages to become bioactive. Post treatment, 1 testing was completed, followed by a 15-min break. Finally, participants completed post treatment 2 testing. Testing visits lasted for approximately 4-4.5 hours each.
• Participants seated in a chair at a computer screen (measured for distance) in the testing chamber. The cognitive demand battery was delivered. The mental and physical state energy and fatigue scales were added to the CDB as was a measure of the degree of motivation to perform the cognitive tests. See Page 6 of study for details.
• Word Presentation recall test (memory)
• Picture Presentation recall test (memory)
• Serial 3 s Subtraction task – (speed and accuracy test)
• Serial 7s Subtraction task – (speed and accuracy test)
• Rapid Visual Information Processing (RVIP) – (reaction time and accuracy test)
• Mental Fatigue, Alertness, and Motivation Visual Analogue Scales (VAS) – (subjective test)
• Mental and Physical State Energy and Fatigue Scales (EFS-State Scales) – (subjective test)
• Bond-Lader Scale – (Subjective mood test)
• Delayed Word Call – (write down as many words shown earlier)
• Delayed Word Recognition – (respond yes or no to the 30 words shown but ½ were decoys and not shown earlier – test of reaction time and recall)
• Delayed Picture Recognition - (respond yes or no to the 30 pictures shown but ½ were decoys and not shown earlier – test of reaction time and recall)
• Motivation to Perform Cognitive Tasks- (subjective motivation test)

Statistically significant results:

• 100 mg of coffee berry extract beverages significantly attenuated perceptions of increased mental fatigue and decreased alertness resulting from the completion of the fatiguing cognitive tasks
• At time 3, 100 mg of coffee berry extract beverage performed better word recall compared to the placebo
• Claims:
• 100 mg of coffee berry extract beverage was shown to improve memory recall, reduce self-reported mental fatigue and decreased alertness after completion of 9 cognitive tasks
• Helps support memory, recall, and focus
• Serial 3 s Subtraction task – (speed and accuracy test)
• Supports less fatigue and decreased alertness after completion of multiple cognitive tasks
• Helps exert mental energizing effects on the brain 1-2 hours post ingestion

Conclusion: Beverages containing low (100 mg) and moderate (300 mg) amounts of a polyphenol-rich, non-caffeinated coffeeberry extract significantly attenuate both increases in self-reported fatigue and decreases in self-reported alertness resulting from the completion of a series of fatiguing cognitive tasks.

Limitations: Sufficient screening but small sample size that completed the full protocol, different material of coffee extract was used. The strengths listed below (eating, exercise, sleep) can also be a limitation since it was self-reported data. Results may not be generalized since the group was mainly college aged and graduate students. Does not specify the exact time of day testing was started.

Strengths: randomized, placebo controlled 4 arm study, participants underwent a screening prior to being enrolled that would help make sure they had the ability and understanding to perform the cognitive tests. Subjects were required to provide info on their eating prior to testing to and avoid fasting (ensure subjects ate similarly to avoid confounding factors) and to avoid any after or morning caffeine consumption, to avoid moderate to vigorous physical activity and to achieve a typical night of sleep prior to each visit.

Adverse events: No adverse events were observed by the investigators or reported by the participants that could be attributed to beverage consumption.

Safety evaluation: not evaluated

Potential disclosures:

• This study did not use CognatiQ material – the material used in the present study is referred to as CFE2 and has a slightly different composition
• Coffee extract was given orally in a beverage
• Study site – Athens, Georgia
• Sample size
• Young adult population

Notes: The specific coffee extract contains 51% chlorogenic acid, 17% 5-caffeoylquinic acid, 3.8% trigonelline, and 1.6% caffeine. This is not CognatiQ material, although minor, differences in composition should be considered when discussing study results. Results for the 300 mg was provided in the study but not reported in the above analysis.

Robinson, 2019. Cognitive short- and long-term effects of coffee cherry extract (CCE) in older adults with mild cognitive decline.

Purpose: To examine CCE’s influence on cognitive performance in older adults with mild cognitive decline

Population: 71 adults with mild cognitive decline completed the study

• Healthy BMI range
• Aged between 55 and 65 years
• Subjected were assessed by the Spanish-translated Montreal Cognitive Assessment scale
• MoCA score between 18-25
• These criteria were chosen to assure inclusion of individuals of advanced age who scored within the desired MoCA range but who were otherwise generally healthy.

Treatment: Encapsulated format taken twice per day, once in the morning, and once in the evening

• A) Placebo at both ingestion time points (Placebo-Placebo) = 0 CCE
• B) CCE in the morning followed by placebo in the evening (CCE-Placebo) = 100 mg total CCE
• C) Placebo in the morning followed by CCE in the evening (Placebo-CCE) = 100 mg total CCE
• D) CCE in the morning followed by CCE in the evening (CCE-CCE) = 200 mg total CCE

Design: A randomized, double-blind, placebo-controlled 4-arm study, a 28-day regimen

• Participants were instructed to take the first capsule on an empty stomach, 15–30 minutes before a meal, and the second capsule at bedtime, at least 1-hour after their last meal and 30–45 minutes before their bedtime for maximum absorption, and to control for chronotherapeutic effects
• Randomized by gender

Composition: CCE supplied by Futureceuticals, CCE = 100 mg of Coffee cherry extract, Placebo = 100 mg capsule of micro-cellulose

Measurements: Participants engaged in a cognitive challenge that involved working memory processes. Participants were assessed every 7 days for 4 weeks.

• Montreal Cognitive Assessment Scale (screening)
• 6-item Cognitive Impairment Test (6-CIT) (screening)
• To assess the effectiveness of CCE in preventing mental fatigue and increasing processing speed and accuracy, researchers performed a cognitive challenge that combined a simple mathematical calculation (a basic addition operation) and a common working memory task, the n-back. The n-back is a robust cognitive task in which participants must recall a stimulus “n” trial prior to the current trial. For this study, we used an n = 1, meaning that participants had to recall the previous answer. See page 6 of study for further detail. Total time to complete test was also recorded. 2 test blocks were given before the testing block.
• All assessments were performed in the morning and prior to taking their study capsules
• The main variables were differences between day 7 and baseline, and day 28 and baseline, in reaction times, and in the number of blocks attempted prior to successful completion of a cognitive challenge testing block
• Measure of “accuracy” defined as the # of failed blocks participants attempted prior to successful completion

Statistically significant results:

• At D7, reductions in reaction time were statistically significant for two of the three CCE groups, with improvements of 27.09% (CCE-Placebo), and 25.26% (CCE-CCE). These increased to 32.05%, and 41.25%, respectively, by D28. (Total time to complete each task was improved, a measure of processing speed)
• By D28, CCE groups showed improved accuracy by 34.62% (CCE-Placebo), 16.67% (Placebo-CCE), and 36.90% (CCE-CCE) but were *not* statistically significant compared to placebo.

Conclusion: These results suggest CCE, when taken in the morning or twice per day, is associated with improvements in reaction times (processing speed) and trends toward indications of improved accuracy in older adults. These observations suggest CCE may help increase processing speed, sustained attention and focus.

Limitations: not a completely pure randomization, relatively small sample size despite the large screening. No dietary or exercise restrictions

Strengths: 4-arm study, large screening of 671 potential subjects, minimized potential confounding factors by elimination participants on medications

Adverse events: none reported

Safety evaluation: not performed

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: Mexico – all subjects of Mexican descent
• Older adult population

Notes: The three CCE study arms were designed to investigate whether there might be different effects of a morning dose versus an evening dose of CCE, given natural biological rhythms, and also to see whether 200 mg total CCE per day may have additional effects.

Robinson, 2021. Neurophysiological Effects of Whole Coffee Cherry Extract in Older Adults with Subjective Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Pilot Study

Purpose: To determine the neurophysiological and behavioral changes from the acute administration of whole coffee cherry extract (WCCE) in older adults with subjective cognitive impairment. Researchers We hypothesized that WCCE would be associated with increased BDNF, improved cognitive function as measured by accuracy and reaction time during behavioral challenges, and changes in glutamate (increases) and GABA (decreases) compared to the placebo. Given the latter hypothesis, they also anticipated increased glutamate and glutamine ratios with GABA.

Population: 12 subjects recruited; 8 subjects completed the study with an average age of 60 years

• Screened using logical memory section of the Wechsler Memory Scale IV, the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) scale
• Aside from memory complaints and memory difficulties, participants were healthy per the exclusion criteria
• 4 dropouts due to discomforts in the scanner

Treatment: 100 mg of WCCE (NeuroFactor®) in capsules or silica oxide capsules, identical in appearance to WCCE, served as the placebo. Each capsule contained 100 mg of material. Design: An acute, randomized, double-blind, within-subject, cross-over design and 2) phytochemical analysis of WCCE

• Following initial screening and informed consent, basic demographic information was collected and neurocognitive assessments were administered (i.e., MMSE, CDR, and WMS). All participants fasted prior to the MRI study session.
• All MRI sessions were conducted in the morning
• Due to the length of the study session, participants were allowed to eat a small breakfast item between scans. This was held consistent for both sessions for all participants
• Additionally, participants were asked to refrain from alcohol, caffeine, heavy exercise, and tobacco for at least 18 h prior to their scanning sessions.

Composition: WCCE supplied by Futureceuticals (as NeuroFactor) – see table 1 for full list of polyphenol compounds expressed in mg/g. Std. extract at a min of 40% chlorogenic acid

• Total Chlorogenic acid 42.6%
• Trigonelline 23.37%
• Caffeine 1.8%

Measurements:

• Participants underwent four neuroimaging scans (pre- and post-WCCE and placebo) to assess neurofunctional/metabolic outcomes using functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS)
• Blood levels of BDNF were taken upon arriving and 90 minutes following the ingestion of the study material (just prior to post-ingestion MRI scan)
• Participants completed all scanning tasks and were escorted out of the scanning environment to the lounge area, where they immediately ingested either WCCE or the placebo. Following a designated 90-min wait time, another blood draw was conducted, and the scanning procedure was repeated.
• Participants were then dismissed and returned after 72 h to repeat the entire protocol with the alternate test substance. – Based on research that shows polyphenols are metabolized fully within a 72 hr time frame.
• Go/no-go task was used to assess inhibitory responses. Stimuli were presented in a continuous stream, and participants were asked to perform a binary decision on each stimulus (e.g., is the stimulus in an alternating pattern with the previous stimulus?). The task was designed to have more ‘go’ than ‘no-go’ trials, enticing the participant into a pattern of responses, thus making the ‘no-go’ trials more difficult in populations with poor impulse control
• Accuracy and reaction time, were recorded by the E-Prime stimulus presentation software using a block task set up. This task reliably activates regions of the prefrontal cortex (PFC), including the middle frontal gyrus, the inferior frontal gyrus, and the anterior cingulate. These regions are implicated in cognitive control and response inhibition, making this an ideal task for examining the effects of WCCE on cognitive function.
• To assess the effectiveness of CCE in preventing mental fatigue and increasing processing speed and accuracy, researchers performed a cognitive challenge that combined a simple mathematical calculation (a basic addition operation) and a common working memory task, the n-back. The n-back is a robust cognitive task in which participants must recall a stimulus “n” trial prior to the current trial.
• For both cognitive tasks, accuracy, defined as the number of correct responses, and reaction time, measured in ms, were recorded by the E-Prime (https://pstnet.com/products/e-prime/) stimulus presentation software.

Statistically significant results:

• BDNF significantly increased after a single dose administration of WCCE
• These results suggest WCCE may increase the efficiency of pivotal regions of the brain that contribute to cognition.
• WCCE decreased reaction time and may protect against cognitive errors on tasks of working memory and response inhibition.
• Behavioral findings were related with neurofunctional changes in structures involved in decision-making and attention.
• Behaviorally, WCCE resulted in an approximately four times greater reduction in reaction time during the n-back task compared to the placebo.

Conclusion: Advanced neuroimaging techniques were used to identify neurophysiological changes associated with the acute consumption of WCCE. The data demonstrated neurophysiological changes with behavioral improvements. To the researcher’s knowledge, this represents the first comprehensive study of its kind assessing multi-level outcomes employing a rigorous double-blind, randomized, within-subjects crossover design. WCCE is associated with acute neurophysiological changes supportive of faster reaction times and increased, sustained attention.

Limitations: Small sample size; researchers note, though the sample size may be considered small in the context of traditional fMRI studies, it should be noted that recent research has suggested that within-subjects designs may substantially improve power, given that larger group-based designs may not detect important differences in individual variability

Strengths: Cross over design. Performing fMRI and MRS at high field strengths (e.g., 7 Tesla (7T)) offers significant advantages such as an increased signal-to-noise that allows for more sensitive assessments. Likewise, using high field strengths also affords better spectral resolution, providing more robust and accurate

measurements of glutamate and glutamine. Furthermore, the utilization of a within-subjects design allows for the control of individual variability, which has recently been considered an important and necessary step toward understanding brain dynamics, favoring smaller samples with greater density of measurement.

Adverse events: none reported

Safety evaluation: not performed

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: Auburn University, AL in the United States
• Sample size
• Older adult population

Notes: To the researcher’s knowledge, this represents the first comprehensive study of its kind assessing multi-level outcomes employing a rigorous double-blind, randomized, within-subjects crossover design

Final thoughts: A total of 5 studies are summarized above. Coffee fruit extract has been studied in young and older adults across 3 studies with positive cognitive outcomes showcasing this ingredient can be useful for a wide range of demographics. 2 out of the 3 studies used the CognatiQ material. Although Reed, 2018 provided a slightly different coffee berry extract composition to participants, results were consistent with the other 2 studies performed with CognatiQ. 2 studies confirm the mechanism of action in humans using the CognatiQ material.