Neural Mechanism of Shentai Tea Polyphenols on Cognitive Improvements for Individuals with Subjective Cognitive Decline: A Functional Near-Infrared Spectroscopy Study

Abstract

Background:

A growing awareness about non-pharmacological intervention for cognitively impaired individuals may represent an alternative therapeutic approach that is actively accepted by patients with very early stage of Alzheimer’s disease. Understanding the neural basis of non-pharmacological intervention is a crucial step toward wide use for patients with cognitive disorders.

Objective:

To investigate the underlying neural mechanism of shentai tea polyphenols in subjects with subjective cognitive decline (SCD) using functional near-infrared spectroscopy (fNIRS).

Methods:

A total number of 36 patients with SCD participated in the study and received supplementation with shentai tea polyphenols for three months. All participants underwent a series of tests on neuropsychological function and fNIRS assessment during n-back tasks at baseline and follow-up.

Results:

After intervention with shentai tea polyphenols in SCD, increased cerebral activity was observed in left dorsolateral prefrontal cortex (DLPFC), left premotor cortex (PMC), left primary somatosensory cortex (PSC), right inferior frontal gyrus (IFG), and premotor cortex (PMC). Moreover, shentai tea polyphenols intervention of three months significantly improved SCD subjects’ cognitive functions (memory, language, and subjective cognitive ability) and depression condition. We further found that the improvement of Hamilton Depression Rating Scale and Auditory Verbal Learning Test-recognition scores had positive correlations with increased brain activity in right IFG and left DLPFC, respectively.

Conclusion:

This study provides new evidence that the frontal cortex was found to be specifically activated after non-pharmacological intervention of shentai tea polyphenols in SCD, which may be associated with cognitive enhancement and mental wellbeing. These findings provide important implications for the selection of shentai tea polyphenols interventions for SCD.

Keywords

Functional near-infrared spectroscopy non-pharmacological intervention shentai tea polyphenols subjective cognitive decline

INTRODUCTION

Subjective cognitive decline (SCD) is characterized by a self-perception of decline in cognitive performance without objective impairment in neuropsychological tests [1]. Longitudinal studies of SCD individuals with amyloidopathy showed a higher risk of progressing to mild cognitive impairment (MCI) in 40%of individuals and a future decline to dementia in 62%of individuals within 3 years [1]. Therefore, SCD is regarded as the early clinical manifestation in the Alzheimer’s disease (AD) continuum. The management of patients with dementia is a major challenge. Given no effective therapy to date for AD, the stage of SCD have been proposed as an “window of opportunity” for AD prevention and management [2]. A growing interest in non-pharmacological approaches aimed at cognitive enhancement pointed toward the individuals with SCD due to its characteristic of high safety. Previous surveys showed that most elderly people prefer functional foods to improve memory and cognitive condition [3, 4]. However, little evidence is available regarding the underlying brain mechanism of functional foods.

Shentai tea polyphenols, a kind of functional foods, are natural compounds extracted from plant foods. The existing literatures showed shentai tea polyphenols have almost no toxic side effects and long-term intake is safe for participants [5 –7]. Shentai tea polyphenols contain several effective active ingredients including Ginsenoside, tea polyphenols, and oligopeptides. Studies of animal models have reported that these active ingredients improved cognitive function by modulating a number of neurotransmitter systems and regulating amyloid-β amyloidogenesis [8 –10]. Currently, the effect of shentai tea polyphenols on cognitive function in individuals with SCD remains unclear. More importantly, the neuronal mechanisms underlying cognitive plasticity are not fully characterized.

Functional near-infrared spectroscopy (fNIRS) can sensitively measure the concentrations changes of oxygen (HbO) and de-oxygen hemoglobin (HbR) of cerebral active response to different levels of cognitive tasks [11]. Importantly, fNIRS maps human brain function and brain activation patterns by imaging local changes in hemoglobin concentrations caused by cerebral blood flow response to neural activity. Several studies demonstrated that docosahexaenoic acid could facilitate neurovascular coupling via modulation of the cholinergic system. It was suggested that the enhanced cognitive performance after functional foods intervention may be associated with improved cerebral blood flow [12, 13]. Thus, fNIRS provides a useful tool for monitoring cerebral blood flow and brain activation changes.

The current study aimed to investigate the effect of three months’ supplementation with shentai tea polyphenols on cerebral activity in SCD using fNIRS, as well as the relationship between brain functional activity changes and neuropsychological performance. This study will provide new evidence for the underlying brain mechanism of non-pharmacological intervention of shentai tea polyphenols in individuals with SCD. More importantly, the preliminary results could lay a foundation for further double-blinded placebo-controlled study.

METHODS

This was a longitudinal pretest–posttest study, carried out at the Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China. Research activities involved in this study were conducted in accordance with the ethical standards of the Helsinki Declaration. This study was approved by the Medical Research Ethics Committee and Institutional Review Board of Xuanwu Hospital in the Capital Medical University (ID: [2019]088) and registered on ClinicalTrials.gov (Identifier: NCT04279418). The scheme of the current trial is described in Fig. 1.

Fig. 1

Flow chart of the study.

Participants and procedure

Participants with SCD in this study were from the Sino-Longitudinal Cognitive Impairment and Dementia Study (SILCODE), from April to September in 2019 [14]. They were recruited mainly through memory clinics, referrals from general physicians, or informants. The inclusion criteria were as follows: 1) 50–79 years old, right-handed, and Han Chinese subjects; 2) presence of self-perceived persistent cognitive decline compared with previous normal status (unrelated to an acute event); and 3) continuous concerns associated with memory over 6 months; 4) normal range in cognitive tests and failure to meet the criteria for MCI after being adjusted for age, sex, and years of education [15]. The exclusion criteria included: 1) allergic to ginseng, fish, or green tea; 2) have taken other functional foods in past 6 months; 3) history of digestive tract diseases, or dysfunction in digestion and absorption; 4) history of major depression, anxiety, stroke, traumatic brain injury, carbon monoxide poisoning, general anesthesia and schizophrenia; 5) other neurological conditions (e.g. brain tumors, Parkinson’s disease, encephalitis, or epilepsy), or systemic disorders (e.g. thyroid dysfunction, severe anemia, HIV or syphilis) that could cause cognitive decline; 6) moderate and severe white matter degeneration, multiple lacunar infraction, space occupying lesion and encephalomalacia, which are confirmed by MRI. We recruited 300 participants and 71 participants fulfilled the inclusion criteria and a total of 36 participants who agreed to accept intervention completed the baseline assessments and subsequently received shentai tea polyphenols. Post-test data were collected after intervention and the average time from baseline data collection until finishing follow-up data collection lasted no more than 6 months.

Intervention

36 participants were assigned to receive shentai tea polyphenols for 90 days, two tablets, two times a day after breakfast and dinner. The main components of shentai tea polyphenols (Zhenao Brain Gold Guard capsule, 300 mg/pill, G20130093, China) included: ginsenoside (6.8 g/100 g), green tea polyphenols (6.3 g/100 g), and oligopeptides (14.8 g/100 g). All participants were asked to maintain their dietary habits during the time of intervention. In order to ensure the compliance of participants, researchers closely monitored all participants’ intake throughout the trial.

Assessments

Measures assessed at baseline were summarized in Table 1: 1) demographic information including age, gender, years of education, history of hypertension, hyperlipidemia, and diabetes; 2) apolipoprotein E (APOE) ɛ4 genotype. 3) neuropsychological assessments; and 4) fNIRS assessments. Data collected at follow-up included neuropsychological assessments and fNIRS assessments. All clinical data were collected by experienced neurologists.

Table 1

Demographic and neuropsychological characteristics at baseline

Parameter	SCD (n = 36)
Age (y)	63.41±7.26
Gender (male/female)	7/15
Education level (y)	12.59±2.89
APOE ɛ4 carriers (%)	5 (22.73%)
History of hypertension (±)	8/14
History of hyperlipidemia (±)	11/11
History of diabetes (±)	3/19
SCD-Q9	4.48±1.46
HAMD	7.27±7.30
HAMA	7.82±7.07
AVLT-DR	7.14±2.03
AVLT-R	22.45±1.77
STT-A	52.91±16.41
STT-B	130.50±25.11
AFT	20.05±4.85
BNT	24.45±3.26
MoCA-B	25.95±2.66
MES	89.91±10.88
PSQI	6.00±3.44
RBDSQ	1.32±1.67
ESS	6.32±6.27

APOE ɛ4, APOE apolipoprotein E; SCD-Q9, SCD questionnaire 9; HAMD, Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale; AVLT-DR, Auditory Verbal Learning Test-delay recall; AVLT-R, Auditory Verbal Learning Test-recognition; STT-A, Shape Trails Test Parts A; STT-B, Shape Trails Test Parts B; AFT, Animal Fluency Test; BNT, Boston Naming Test; MoCA-B, Montreal Cognitive Assessment Basic Version; BNT, Boston Naming Test; PSQI, Pittsburgh Sleep Quality Index; RBDSQ, REM Sleep Behavior Disorder Screening Questionnaire; ESS, Epworth Sleepiness Scale.

Neuropsychological assessments

To evaluate the changes of neuropsychological symptoms of participants, we carried on a neuropsychological battery that measures cognitive function in the domains of memory, language and executive function [14]. Auditory Verbal Learning Test-HuaShan version (AVLT-H) has been widely used in routine clinical practice and research associated with AD and other neurodegenerative disorders. AVLT-delay recall (AVLT-DR) and AVLT-recognition (AVLT-R) were the two measures to reflect memory domain. Animal Fluency Test (AFT) and 30-item Boston Naming Test (BNT)were administered to assess language. Shape Trails Test Parts A (STT-A) and B (STT-B) were administered to assess executive function. In addition, all subjects were administered the Montreal Cognitive Assessment Basic Version (MoCA-B) and SCD questionnaire 9 (SCD-Q9) to assess global cognitive function and subjective cognitive performance. And we also used Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Scale (HAMA), Pittsburgh Sleep Quality Index (PSQI), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), and Epworth Sleepiness Scale (ESS) to evaluate mood and sleep quality of all subjects.

Functional near-infrared spectroscopy data acquisition

A multiple-channel fNIRS system (Huichuang, China) was used to measure the concentrations of HbO and HbR during n-back tasks at baseline and post-intervention [16]. fNIRS data from individual channels were acquired at two different wavelengths (690 and 830 nm) with a sampling rate of 17 Hz. The fNIRS scanning was conducted in a dimly lit room with a 54-channel array of optode (Fig. 2), which was generated by 24 light emitters and 16 optical detectors. The sources and detectors were alternately placed on each participant’s right and left hemispheres with an interoptode distance of 3 cm. The fNIRS data preprocessing was implemented in Homer2 [17]. The raw data were first converted to the changes in optical density. Then, principal component analysis (PCA) was performed to eliminate the global noise and the spline method was used to correct the detected motion [18]. Subsequently, a bandpass filter ranged from 0.01 to 0.3 Hz was employed to eliminate the high frequency and low frequency noise. Finally, the HbO and HbR concentrations were calculated by using the modified Beer–Lambert law [19]. The HbO signal was primarily analyzed for the present study due to its superior signal-to-noise in the correlation with regional cerebral blood flow [20].

Fig. 2

Distribution of measurement channels on brain cortex.

Primary and secondary outcomes

The aim of this study was to explore the brain effects and neural mechanism of shentai tea polyphenols in SCD individuals. Therefore, the cerebral hemodynamic changes were selected as the primary outcome. We also aimed to evaluate changes in cognitive performance, mood and sleep quality as the secondary outcome, which is measured by the neuropsychological battery.

Statistical analyses

Paired t-test was used to analyze changes in working memory task-induced activation and neuropsychological performance after intervention. Correlation analysis was performed between the significant changes in activation and all neuropsychological test scores. Spearman correlation was used to access their relationship. Data were analyzed using IBM SPSS Statistics 26.0. A value of p < 0.05 was considered statistically significant.

RESULTS

Demographic characteristics

During the study period, 36 participants completed the three-month intervention of shentai tea polyphenols and follow-up. The demographic and neuropsychological characteristics of the participates were shown in Table 1.

Changes of regional brain activity after intervention

Compared to baseline, a significant increase in the oxy-Hb change occurred in right inferior frontal gyrus (IFG, ch54) during 1-back and 2-back task after intervention. Furthermore, during performing 3-back task, the participants exhibited a significant oxy-Hb increase in left dorsolateral prefrontal cortex (DLPFC, ch4), left premotor cortex (PMC, ch8 and ch9), left primary somatosensory cortex (PSC, ch13), right IFG (ch51 and54), and right PMC (ch44 and 49). These activation regions after intervention were mapped on the brain surface (Fig. 3). The details were shown in Table 2.

Fig. 3

Comparison of concentrations of HbO between baseline and post-intervention under each task. Colors indicate concentrations of HbO. L, left hemisphere; R, right hemisphere.

Table 2

Brain regions with increased activity after intervention

tasks	Brain regions	BA	ch	t value	df	p
1-back	R-IFG	45	54	2.12	21	0.046
2-back	R-IFG	45	54	2.6	21	0.017
3-back	L-DLPFC	9	4	2.29	21	0.032
3-back	L-PMC	6	8	2.62	21	0.016
3-back	L-PMC	6	9	2.59	21	0.017
3-back	L-PSC	3	13	2.31	21	0.031
3-back	R-IFG	45	51	2.67	21	0.014
3-back	R-IFG	45	54	2.29	21	0.033
3-back	R-PMC	6	44	2.49	21	0.021
3-back	R-PMC	6	49	2.81	21	0.011

L, left hemisphere; R, right hemisphere; IFG, right inferior frontal gyrus; DLPFC, dorsolateral prefrontal cortex; PMC, premotor cortex; PSC, primary somatosensory cortex; PMC, premotor cortex; BA, Brodmann Area; ch, channel.

Changes of neuropsychological scores after intervention

Three-month intervention of shentai tea polyphenols enhanced significantly the scores in AVLT-DR, AFT, and BNT, as well as significantly decreased the scores in SCD-Q9 and HAMD. These differences suggested an improvement in memory, language, subjective cognitive performance, and mental state of participants. The results of neuropsychological tests are showed in Table 3.

Table 3

Changes of neuropsychological tests after intervention

	Baseline	Post-intervention	p
SCD-Q9	4.48 (1.46)	3.23 (2.18)	0.041^*
HAMD	7.27 (7.30)	5.55 (4.93)	0.037^*
HAMA	7.82 (7.07)	7.23 (6.93)	0.356
AVLT-DR	7.14 (2.03)	7.82 (2.44)	0.044^*
AVLT-R	22.45 (1.77)	22.91 (1.44)	0.378
STT-A	52.91 (16.41)	51.55 (17.05)	0.737
STT-B	130.50 (25.11)	124.00 (33.68)	0.311
AFT	20.05 (4.85)	21.55 (4.54)	0.029^*
BNT	24.45 (3.26)	25.64 (2.79)	0.006^*
MoCA-B	25.95 (2.66)	26.55 (2.34)	0.163
PSQI	6.00 (3.44)	6.55 (3.53)	0.361
RBDSQ	1.32 (1.67)	1.00 (1.27)	0.382
ESS	6.32 (6.27)	6.77 (5.36)	0.622

SCD-Q9, SCD questionnaire 9; HAMD, Hamilton Depression Rating Scale; HAMA, Hamilton Anxiety Rating Scale; AVLT-DR, Auditory Verbal Learning Test-delay recall; AVLT-R, Auditory Verbal Learning Test-recognition; STT-A, Shape Trails Test Parts A; STT-B, Shape Trails Test Parts B; AFT, Animal Fluency Test; BNT, Boston Naming Test; MoCA-B, Montreal Cognitive Assessment Basic Version; BNT, Boston Naming Test; PSQI, Pittsburgh Sleep Quality Index; RBDSQ, REM Sleep Behavior Disorder Screening Questionnaire; ESS, Epworth Sleepiness Scale.

The correlation between improvement of neuropsychological scores and the increased cerebral activity

Spearman correlation test showed a significant positive correlation between the increased scores of AVLT-R and the mean oxy-Hb increases in left DLPFC during the 3-back task. Moreover, there was also a positive correlation between decreased scores of HAMD and the mean oxy-Hb increases in right IFG during the 3-back task (see Table 4).

Table 4

Correlation between increased activitys in brain regions and alterations of neuropsychological scores

Brain regions	AVLT-DR	AVLT-R	HAMD	AFT	BNT
1-back R-IFG(ch 54)	r = 0.234	r = 0.087	r = 0.293	r = –0.032	r = 0.374
	p = 0.294	p = 0.700	p = 0.186	p = 0.887	p = 0.086
2-back R-IFG(ch 54)	r = 0.182	r = 0.001	r = 0.288	r = –0.293	r = 0.292
	p = 0.418	p = 0.996	p = 0.193	p = 0.186	p = 0.187
3-back L-DLPFC(ch 4)	r = 0.056	r = 0.461	r = 0.175	r = 0.098	r = 0.211
	p = 0.805	p = 0.031^*	p = 0.436	p = 0.663	p = 0.345
3-back L-PMC(ch 8)	r = 0.052	r = 0.145	r = –0.013	r = 0.011	r = –0.114
	p = 0.817	p = 0.520	p = 0.956	p = 0.960	p = 0.613
3-back L-PMC(ch 9)	r = 0.093	r = 0.088	r = 0.014	r = 0.306	r = –0.087
	p = 0.680	p = 0.698	p = 0.950	p = 0.166	p = 0.699
3-back L-PSC(ch13)	r = 0.058	r = 0.093	r = –0.017	r = 0.281	r = 0.053
	p = 0.799	p = 0.680	p = 0.940	p = 0.206	p = 0.815
3-back R-IFG(CH 51)	r = 0.005	r = 0.264	r = 0.363	r = –0.076	r = 0.107
	p = 0.982	p = 0.236	p = 0.097	p = 0.738	p = 0.637
3-back R-IFG(ch54)	r = 0.190	r = 0.235	r = 0.547	r = 0.027	r = 0.185
	p = 0.396	p = 0.292	p = 0.008^*	p = 0.905	p = 0.411
3-back R-PMC (ch44)	r = 0.062	r = –0.078	r = 0.249	r = –0.072	r = –0.312
	p = 0.785	p = 0.729	p = 0.263	p = 0.750	p = 0.158
3-back R-PMC(ch 49)	r = 0164	r = 0.048	r = 0.194	r = –0.303	r = 0.058
	p = 0.467	p = 0.832	p = 0.387	p = 0.170	p = 0.811

DISCUSSION

The present study revealed that the right IFG activity was increased during 1-back and 2-back tasks in subjects with SCD after intervention with shentai tea polyphenols. With increasing difficulty of cognitive tasks, more brain regions (left DLPFC, left PMC, left PSC, and right PMC) exhibited significantly enhanced activities. Furthermore, we observed a positive correlation between the mean oxy-Hb increases in left DLPFC and the increased scores of AVLT-R, as well as between the mean oxy-Hb increases in right IFG and decreased score of HAMD. Exploring the brain mechanism of shentai tea polyphenols intervention provided the important theoretical evidence for a promising interventional approach for SCD.

Some studies have reported the impact of functional foods on brain function alterations in healthy adults. Jackson et al. revealed an increased hemodynamic response in the prefrontal cortex following supplementation with docosahexaenoic acid-rich fish oil in healthy young adults [21 –23]. In addition, a cross-sectional study had found that increased level of subjective cognitive complaints was associated with significantly lower task-related blood oxygen level dependent response in the right IFG, which implied that right IFG appeared to play an important role in regulating cognition [24]. Konagai et al. reported an increased concentration of oxygenated hemoglobin in the DLPFC in healthy older adults during performance of a cognitive task (2-back task) following supplementation with krill oil containing n-3 polyunsaturated fatty acids. Consistent with the studies of healthy adults, increasing right IFG and left DLPFC activity were observed in subjects with SCD following three months’ supplementation with shentai tea polyphenols in the present study. It is also worth mentioning that only right IFG were observed the enhanced activity during performance of tasks with lower difficulty (1-back and 2-bak tasks). With more difficult tasks (3-back tasks), the participants showed a significant increased activity in right IFG, left DLPFC, left PMC, left PSC, and right PMC. The results suggested that three months’ supplementation with shentai tea polyphenols may improve brain compensatory response and cognitive reserve ability.

The latest study indicated that individuals with SCD have exhibited minor deficits in memory, executive function, and language abilities [25]. The intervention measures of preventing them converting to AD represents the greatest challenge. Our study found that not only subjective cognitive enhancement, but also the objective cognitive performances (memory and language abilities) and HAMD scores were improved after shentai tea polyphenols intervention. Further, we analyzed the relationship between improved neuropsychological scores and cerebral hemodynamics. The results showed that improved performances in memory and depression, were associated with increased activities in left DLPFC and in right IFG, respectively. Frontal cortex is an important brain region contributing to emotion, memory, language, attention, decision-making, and executive function [26 –29]. Previous findings have suggested that abnormal differences in the regional spontaneous neuronal activity of the right inferior frontal orbital gyrus were associated with dysfunctional patterns of the corresponding brain circuits during rest in depression patients [22]. Moreover, the orbitofrontal cortex can influence mood and behavior via right IFG. As one key brain region of frontoparietal network, left DLPFC has been proven to be associated with memory processing [30]. A study applying transcranial direct current stimulation to left DLPFC found improved working memory performance in both healthy and clinical participants [31]. Of note, a significant association between improved scores of AVLT-R and increased activity in left DLPFC was found in the present study, but we did not observe the statistical difference of AVLT-R scores after three-month intervention compare to the baseline. On the one hand, three months’ supplementation is still a relatively short time for observing obvious cognitive improvements. On the other hand, AVLT is not sensitive measure to investigate the mild changes. Besides, the limited sample size should be taken into consideration with respect to interpretation of the results. Further research is needed to draw any firm conclusions.

Shentai tea polyphenols contained several active ingredients including ginsenoside, tea polyphenols, and oligopeptides. Ginsenoside had been reported to benefit neurons by increasing the activities of antioxidant enzymes and decreasing the level of lipid peroxidation. Ginsenoside can also prevent mitochondrial decay and the lipofuscin accumulation as well. Moreover, tea polyphenol and peptide were considered to invoke cellular activities related to neuro-protective effects by regulating hippocampal cAMP-response element binding protein signaling cascade and brain derived neurotrophic factor [8 , 33]. Therefore, ginsenoside, green tea polyphenols, and oligopeptides may increase cerebral activity and improve cognitive function through the above neuro-protective effects.

Several limitations in this study must be mentioned. First, our present study was based on a single centered and small sample study. Future multicenter studies with larger sample sizes are needed. Second, although this self-contrasted study showed significant effects on brain activities with shentai tea polyphenols intervention, the results need to be replicated by randomized double-blinded placebo-controlled clinical trial. Finally, more than three months’ supplementation with shentai tea polyphenols should be explored in the future investigations.

In conclusion, three-month intervention with shentai tea polyphenols enhanced cerebral hemodynamical response in right IFG, left DLPFC, left PMC, left PSC, and right PMC to n-back tasks in individuals with SCD, as well as the memory, language, subjective cognitive function, and depression condition. The present study may positively contribute to the underlying neural mechanism of shentai tea polyphenols in subjects with SCD. The preliminary open-label study provided the essential basis to further explore the efficacy, feasibility, and safety of shentai tea polyphenols in individuals with SCD and dementia.

Footnotes

ACKNOWLEDGMENTS

The authors thank all participants and their families for their involvement and cooperation.

Authors’ disclosures available online ().

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