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

Now just ask your competent? doctor how much of WCCE is in normal coffee grounds(Folgers or Mountain House). Or do you need to buy the supplement separately? 

Or does your doctor already have protocols that deliver the needed amounts of BDNF? Or is your doctor already incompetent in that need already?

• BDNF (172 posts to April 2011)

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

Jennifer L. Robinson,^1,2,3,4,5,* Julio A. Yanes,^1,2,3,4 Meredith A. Reid,^2,3,4,5 Jerry E. Murphy,¹ Jessica N. Busler,^1,2,3,4 Petey W. Mumford,⁶ Kaelin C. Young,^6,7 Zbigniew J. Pietrzkowski,⁸ Boris V. Nemzer,⁹ John M. Hunter,⁹ and Darren T. Beck^4,7

Rui F. M. Silva, Academic Editor

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Abstract

Bioactive plant-based compounds have shown promise as protective agents across multiple domains including improvements in neurological and psychological measures. Methodological challenges have limited our understanding of the neurophysiological changes associated with polyphenol-rich supplements such as whole coffee cherry extract (WCCE). In the current study, we (1) compared 100 mg of WCCE to a placebo using an acute, randomized, double-blind, within-subject, cross-over design, and we (2) conducted a phytochemical analysis of WCCE. The primary objective of the study was to determine the neurophysiological and behavioral changes that resulted from the acute administration of WCCE. We hypothesized that WCCE would increase brain-derived neurotrophic factor (BDNF) and glutamate levels while also increasing neurofunctional measures in cognitive brain regions. Furthermore, we expected there to be increased behavioral performance associated with WCCE, as measured by reaction time and accuracy. Participants underwent four neuroimaging scans (pre- and post-WCCE and placebo) to assess neurofunctional/metabolic outcomes using functional magnetic resonance imaging and magnetic resonance spectroscopy. The results suggest that polyphenol-rich WCCE is associated with decreased reaction time and may protect against cognitive errors on tasks of working memory and response inhibition. Behavioral findings were concomitant with neurofunctional changes in structures involved in decision-making and attention. Specifically, we found increased functional connectivity between the anterior cingulate and regions involved in sensory and decision-making networks. Additionally, we observed increased BDNF and an increased glutamate/gamma-aminobutyric acid (GABA) ratio following WCCE administration. These results suggest that WCCE is associated with acute neurophysiological changes supportive of faster reaction times and increased, sustained attention.

Keywords: functional magnetic resonance imaging, spectroscopy, 7T, polyphenols, nutraceuticals

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1. Introduction

Recent studies have demonstrated the promising effects of bioactive phytochemicals (e.g., polyphenols) on cardiovascular and endocrine health outcomes [1,2,3,4]. As such, an increasingly intriguing line of inquiry is whether materials with high contents of these compounds may also have effects on neurophysiological and psychological measures. Preliminary evidence suggests that polyphenols may have effects in these domains, particularly in aging populations [4,5,6,7]. Whole coffee cherry extract (WCCE), is a proprietary, safe [8], powdered extract of whole coffee cherries from Coffea arabica with high levels of polyphenols and substantially low (<2%) levels of caffeine (for a detailed composition profile, please see Table 1 of the study by Reyes-Izquierdo et al. (2013b) [9]). WCCE has been previously associated with increased serum concentrations of both circulating and exosomal brain-derived neurotrophic factor (BDNF), in addition to increased alertness and decreased fatigue [4,9,10,11,12]. BDNF is a protein synthesized in neurons and other types of cells, and it is associated with a range of neural (e.g., plasticity) [13,14,15,16] and psychological processes [17,18,19,20]. As such, BDNF may represent an important target for identifying the pathophysiological mechanisms underlying observed behavioral or cognitive effects associated with WCCE (and possibly other polyphenol-rich materials). However, there is a need for comprehensive studies that simultaneously assess cognition and neurophysiological measures in order to better understand such mechanisms [4,5].

Because of the observed beneficial effects of WCCE in the extant literature that are commensurate with evidence from other polyphenol-rich materials [7,21,22] and in light of the mounting evidence suggesting that polyphenols have neurotrophic effects [23,24,25,26], it is important to consider the chemical properties of WCCE that may drive the mechanisms involved in such effects. Recently, the phytochemical profile of WCCE was determined by a high-resolution non-targeted mass spectrometry approach (Figure 1) [27]. Importantly, one of the most abundant and widely distributed polyphenols in plants are chlorogenic acids, which are well-known for their antioxidant, anti-inflammatory, anti-hypertensive, and therapeutic properties [28,29,30]. Coffee is remarkably rich with chlorogenic acids and other polyphenols. These naturally occurring phytonutrients are concentrated during the WCCE extraction process (please see Table 1). In this study, we extended the chemical profiling of WCCE to include the antioxidant potential, as determined by five separate assays.

Figure 1

LC–MS base peak chromatogram (BPC) profile of whole coffee cherry extract (WCCE), adapted from the work of Nemzer and colleagues (under review) [27]. The major detected peaks were labelled with peak numbers ranging from 1 to 24, and the compounds corresponding to each peak are identified here: 1. gluconic acid; 2. quinic acid; 3. malic acid; 4. citric acid; 5. 2-hydroxyglutaric acid; 6. 3-O-caffeoylquinic acid (3-CQA); 7. protocatechualdehyde; 8. 3- coumaroylquinic acid (3-CoQA); 9. 5-CQA; 10. 3-feruloylquinic acid (3-FQA); 11. 4-CQA; 12. caffeic acid; 13. 5-CoQA; 14. 4-CoQA; 15. 5-FQA; 16. 4-FQA; 17. quinic acid-glucoside-R*; 18. 3-dicaffeoylquinic acid (3-DiCQA); 19. 5-DiCQA; 20. 4-DiCQA; 21. 3-Caffeoyl-5-FQA; 22. valeroylquinic acid (VQA) diglucoside-R*; 23. caffeoyl tryptophan; and 24. dimethylcaffeic acid. Other compounds identified in WCCE in the positive ion mode include pantothenic acid, trigonelline, choline, and glycerophosphocholine derivatives. Figure adapted from the work of Nemzer et al. (under review) [27]. A listing of the typical polyphenols found in WCCE can be found in Table 1.

Table 1

List of polyphenol compounds in WCCE, expressed in mg/g ± SD. Table adapted from the work of Nemzer et al. (under review) [27].

Polyphenol	mg/g
3-O-Caffeoylquinic acid	41.3 ± 8.4
5-p-coumaroylquinic acid	0.4 ± 0.1
5-O-Caffeoylquinic acid	134.6 ± 16.7
3-Feruloylquinic acid	7 ± 1.2
4-O-Caffeoylquinic acid	74.9 ± 11.1
p-coumaroylquinic acid	0.6 ± 0.1
p-coumaroylquinic acid	2.5 ± 0.5
4-Feruloylquinic acid	8.4 ± 1.7
5-Feruloylquinic acid	38.1 ± 6.3
3-O-Caffeoylquinic lactone	7.8 ± 1.2
4-O-Caffeoylquinic lactone	3.8 ± 0.6
3,4-O-Dicaffeoylquinic acid	37.6 ± 7.3
3,5-O-Dicaffeoylquinic acid	12.1 ± 2.2
4,5-O-Dicaffeoylquinic acid	47.2 ± 7.8
3-O-Feruloyl-4-Caffeoylquinic acid	0.9 ± 0.2
3-O-Caffeoy-4-Feruloylquinic acid	3.3 ± 0.6
3-O-Feruloyl-5-Caffeoylquinic acid	0.2 ± 0
3-O-Caffeoy-5-Feruloylquinic acid	1.1 ± 0.3
4-O-Feruloyl-5-Caffeoylquinic acid	0.7 ± 0.2
4-O-Caffeoy-5-Feruloylquinic acid	3.4 ± 0.7
Total CGA	425.8 ± 63.9
Trigonelline	33.78 ± 5.2
Caffeine	18.2 ± 3.3

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Interestingly, mild cognitive impairment (MCI) is associated with a reduced BDNF level [18,31]. MCI represents an intermediate stage between the expected cognitive decline of normal aging and the more serious decline of dementia. MCI is marked by problems with memory, language, thinking, and judgment that are greater than normal age-related changes. Given that earlier studies reported that WCCE may stimulate increases in BDNF [9,11], one remaining question was whether WCCE, potentially through increases in BDNF, could acutely improve cognitive function or provide protective effects in older adults who may be on the verge of or have MCI. To this end, BDNF has been associated with such changes via its effects on N-methyl-D-aspartate-type (NMDA) receptors [32,33,34]. Furthermore, recent evidence suggests that the long-term administration of WCCE has cognitive effects in such a population in as little as seven days and persisting for 28 days [35]. Thus, understanding the acute neurophysiological effects may provide critical mechanistic information.

Though acute, observable changes may be associated with BDNF, it is also plausible that underlying pathophysiological mechanisms may be related to some other, as-yet unidentified, neural process(es). Unfortunately, even when solely considering BDNF, methodological limitations have led to a dearth of evidence to suggest, define, support, or explain the complex and dynamic mechanistic possibilities. For example, hippocampal BDNF messenger ribonucleic acid (mRNA) expression largely depends on the neuronal excitation/inhibition balance [36], rendering it difficult to elucidate underlying mechanisms. To our knowledge, no previous study has examined neurotransmitters (e.g., glutamate and/or gamma-aminobutyric acid (GABA) concentrations) or neurometabolics concurrent with changes in BDNF levels. Therefore, the purpose of this study was to implement a comprehensive, multi-modal investigation to assess (1) the quantitative profiles of various phenolics inherent in WCCE, (2) the antioxidant properties of WCCE, and (3) the effects of WCCE in older adults on neurofunctional and neurometabolic processes while concurrently measuring associated acute cognitive and behavioral effects.

In this pilot study, representing the first of its kind, we leveraged a randomized, double-blind, placebo-controlled, within-subjects crossover design to assess the neurophysiological, neurofunctional, and cognitive effects of acute WCCE administration. Contributing to the novelty of this study, we employed advanced ultra-high field, high-resolution (i.e., submillimeter) functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques to identify the neurofunctional and neurometabolic changes, respectively, of the acute administration of WCCE. 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 [37,38,39]. Likewise, using high field strengths also affords better spectral resolution, providing more robust and accurate measurements of glutamate and glutamine [40,41]. 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 [42,43,44,45,46,47,48]. We also report a complementary analysis outlining the antioxidant potential of WCCE across five separate assays. 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, we also anticipated increased glutamate and glutamine ratios with GABA.

 

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