Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

AIMS: We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD). METHODS: The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aß42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis. RESULTS: We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. In vivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. In vitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both in vivo and in vitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway. CONCLUSIONS: PA is expected to provide a valuable candidate for new drug development for AD in the future.

B vitamins and prevention of cognitive decline and incident dementia: a systematic review and meta-analysis.

CONTEXT: Elevation of homocysteine (Hcy) levels is well-established as a risk factor for dementia, yet controversy exists regarding whether B-vitamin-mediated reduction of homocysteine levels can benefit cognitive function. OBJECTIVE: To investigate whether B vitamin supplementation can reduce the risk of cognitive decline and incident dementia. DATA SOURCES: The PubMed, EMBASE, Cochrane Library, and Web of Science were systematically searched for articles published from the inception dates to March 1, 2020. Randomized controlled trials (RCT) were included if B vitamins were supplied to investigate their effect on the rate of cognitive decline. Cohort studies investigating dietary intake of B vitamins and the risk of incident dementia were eligible. Cross-sectional studies comparing differences in levels of B vitamins and Hcy were included. DATA EXTRACTION: Two reviewers independently performed data extraction and assessed the study quality. DATA ANALYSIS: Random-effect or fixed-effect models, depending on the degree of heterogeneity, were performed to calculate mean differences (MDs), hazard ratios (HRs), and odds ratios (ORs). RESULTS: A total of 95 studies with 46175 participants (25 RCTs, 20 cohort studies, and 50 cross-sectional studies) were included in this meta-analysis. This meta-analysis supports that B vitamins can benefit cognitive function as measured by Mini-Mental State Examination score changes (6155 participants; MD, 0.14, 95%CI 0.04 to 0.23), and this result was also significant in studies where placebo groups developed cognitive decline (4211 participants; MD, 0.16, 95%CI 0.05 to 0.26), suggesting that B vitamins slow cognitive decline. For the > 12 months interventional period stratum, B vitamin supplementation decreased cognitive decline (3814 participants; MD, 0.15, 95%CI 0.05 to 0.26) compared to placebo; no such outcome was detected for the shorter interventional stratum (806 participants; MD, 0.18, 95%CI -0.25 to 0.61). In the non-dementia population, B vitamin supplementation slowed cognitive decline (3431 participants; MD, 0.15, 95%CI 0.04 to 0.25) compared to placebo; this outcome was not found for the dementia population (642 participants; MD, 0.20, 95%CI -0.35 to 0.75). Lower folate levels (but not B12 or B6 deficiency) and higher Hcy levels were significantly associated with higher risks of dementia (folate: 6654 participants; OR, 1.76, 95%CI 1.24 to 2.50; Hcy: 12665 participants; OR, 2.09, 95%CI 1.60 to 2.74) and cognitive decline (folate: 4336 participants; OR, 1.26, 95%CI 1.02 to 1.55; Hcy: 6149 participants; OR, 1.19, 95%CI 1.05 to 1.34). Among the population without dementia aged 50 years and above, the risk of incident dementia was significantly decreased among individuals with higher intake of folate (13529 participants; HR, 0.61, 95%CI 0.47 to 0.78), whereas higher intake of B12 or B6 was not associated with lower dementia risk. CONCLUSIONS: This meta-analysis suggests that B vitamin supplementation is associated with slowing of cognitive decline, especially in populations who received early intervention and intervention of long duration; the study also indicates that higher intake of dietary folate, but not B12 or B6, is associated with a reduced risk of incident dementia in non-dementia aged population. Given the prevalence of dementia cases in many countries with aging populations, public health policies should be introduced to ensure that subgroups of the population at risk have an adequate B vitamin status.

Strategies for the use of Ginkgo biloba extract, EGb 761® , in the treatment and management of mild cognitive impairment in Asia: Expert consensus.

BACKGROUND: Mild cognitive impairment (MCI) is a neurocognitive state between normal cognitive aging and dementia, with evidence of neuropsychological changes but insufficient functional decline to warrant a diagnosis of dementia. Individuals with MCI are at increased risk for progression to dementia; and an appreciable proportion display neuropsychiatric symptoms (NPS), also a known risk factor for dementia. Cerebrovascular disease (CVD) is thought to be an underdiagnosed contributor to MCI/dementia. The Ginkgo biloba extract, EGb 761® , is increasingly being used for the symptomatic treatment of cognitive disorders with/without CVD, due to its known neuroprotective effects and cerebrovascular benefits. AIMS: To present consensus opinion from the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) regarding the role of EGb 761® in MCI. MATERIALS & METHODS: The ASCEND Group reconvened in September 2019 to present and critically assess the current evidence on the general management of MCI, including the efficacy and safety of EGb 761® as a treatment option. RESULTS: EGb 761® has demonstrated symptomatic improvement in at least four randomized trials, in terms of cognitive performance, memory, recall and recognition, attention and concentration, anxiety, and NPS. There is also evidence that EGb 761® may help delay progression from MCI to dementia in some individuals. DISCUSSION: EGb 761® is currently recommended in multiple guidelines for the symptomatic treatment of MCI. Due to its beneficial effects on cerebrovascular blood flow, it is reasonable to expect that EGb 761® may benefit MCI patients with underlying CVD. CONCLUSION: As an expert group, we suggest it is clinically appropriate to incorporate EGb 761® as part of the multidomain intervention for MCI.

Stroke in China: advances and challenges in epidemiology, prevention, and management.

With over 2 million new cases annually, stroke is associated with the highest disability-adjusted life-years lost of any disease in China. The burden is expected to increase further as a result of population ageing, an ongoing high prevalence of risk factors (eg, hypertension), and inadequate management. Despite improved access to overall health services, the availability of specialist stroke care is variable across the country, and especially uneven in rural areas. In-hospital outcomes have improved because of a greater availability of reperfusion therapies and supportive care, but adherence to secondary prevention strategies and long-term care are inadequate. Thrombolysis and stroke units are accepted as standards of care across the world, including in China, but bleeding-risk concerns and organisational challenges hamper widespread adoption of this care in China. Despite little supporting evidence, Chinese herbal products and neuroprotective drugs are widely used, and the increased availability of neuroimaging techniques also results in overdiagnosis and overtreatment of so-called silent stroke. Future efforts should focus on providing more balanced availability of specialised stroke services across the country, enhancing evidence-based practice, and encouraging greater translational research to improve outcome of patients with stroke.

Illumination with 630 nm Red Light Reduces Oxidative Stress and Restores Memory by Photo-Activating Catalase and Formaldehyde Dehydrogenase in SAMP8 Mice.

AIMS: Pharmacological treatments for Alzheimer's disease (AD) have not resulted in desirable clinical efficacy over 100 years. Hydrogen peroxide (H2O2), a reactive and the most stable compound of reactive oxygen species, contributes to oxidative stress in AD patients. In this study, we designed a medical device to emit red light at 630 ± 15 nm from a light-emitting diode (LED-RL) and investigated whether the LED-RL reduces brain H2O2 levels and improves memory in senescence-accelerated prone 8 mouse (SAMP8) model of age-related dementia. RESULTS: We found that age-associated H2O2 directly inhibited formaldehyde dehydrogenase (FDH). FDH inactivity and semicarbazide-sensitive amine oxidase (SSAO) disorder resulted in endogenous formaldehyde (FA) accumulation. Unexpectedly, excess FA, in turn, caused acetylcholine (Ach) deficiency by inhibiting choline acetyltransferase (ChAT) activity in vitro and in vivo. Interestingly, the 630 nm red light can penetrate the skull and the abdomen with light penetration rates of ∼49% and ∼43%, respectively. Illumination with LED-RL markedly activated both catalase and FDH in the brains, cultured cells, and purified protein solutions, all reduced brain H2O2 and FA levels and restored brain Ach contents. Consequently, LED-RL not only prevented early-stage memory decline but also rescued late-stage memory deficits in SAMP8 mice. INNOVATION: We developed a phototherapeutic device with 630 nm red light, and this LED-RL reduced brain H2O2 levels and reversed age-related memory disorders. CONCLUSIONS: The phototherapy of LED-RL has low photo toxicity and high rate of tissue penetration and noninvasively reverses aging-associated cognitive decline. This finding opens a promising opportunity to translate LED-RL into clinical treatment for patients with dementia. Antioxid. Redox Signal. 00, 000-000.

Reduction of Endogenous Melatonin Accelerates Cognitive Decline in Mice in a Simulated Occupational Formaldehyde Exposure Environment.

Individuals afflicted with occupational formaldehyde (FA) exposure often suffer from abnormal behaviors such as aggression, depression, anxiety, sleep disorders, and in particular, cognitive impairments. Coincidentally, clinical patients with melatonin (MT) deficiency also complain of cognitive problems associated with the above mental disorders. Whether and how FA affects endogenous MT metabolism and induces cognitive decline need to be elucidated. To mimic occupational FA exposure environment, 16 healthy adult male mice were exposed to gaseous FA (3 mg/m³) for 7 consecutive days. Results showed that FA exposure impaired spatial memory associated with hippocampal neuronal death. Biochemical analysis revealed that FA exposure elicited an intensive oxidative stress by reducing systemic glutathione levels, in particular, decreasing brain MT concentrations. Inversely, intraperitoneal injection of MT markedly attenuated FA-induced hippocampal neuronal death, restored brain MT levels, and reversed memory decline. At tissue levels, injection of FA into the hippocampus distinctly reduced brain MT concentrations. Furthermore, at cellular and molecular levels, we found that FA directly inactivated MT in vitro and in vivo. These findings suggest that MT supplementation contributes to the rescue of cognitive decline, and may alleviate mental disorders in the occupational FA-exposed human populations.

The Effects of Acupuncture at Real or Sham Acupoints on the Intrinsic Brain Activity in Mild Cognitive Impairment Patients.

Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Acupuncture at different acupoints could exert different modulatory effects on the brain network. However, whether acupuncture at real or sham acupoints can produce different effects on the brain network in MCI or AD patients remains unclear. Using resting-state fMRI, we reported that acupuncture at Taixi (KI3) induced amplitude of low-frequency fluctuation (ALFF) change of different brain regions in MCI patients from those shown in the healthy controls. In MCI patients, acupuncture at KI3 increased or decreased ALFF in the different regions from those activated by acupuncture in the healthy controls. Acupuncture at the sham acupoint in MCI patients activated the different brain regions from those in healthy controls. Therefore, we concluded that acupuncture displays more significant effect on neuronal activities of the above brain regions in MCI patients than that in healthy controls. Acupuncture at KI3 exhibits different effects on the neuronal activities of the brain regions from acupuncture at sham acupoint, although the difference is only shown at several regions due to the close distance between the above points.

Rationale and design of a multicenter, phase 2 clinical trial to investigate the efficacy of traditional Chinese medicine SaiLuoTong in vascular dementia.

BACKGROUND: Vascular dementia (VaD) is the second most prevalent type of dementia among the aged, for whom limited pharmacologic options are available so far. SaiLuoTong capsule is a modern traditional Chinese medicine formula, which has been demonstrated to improve cognition of VaD by the reports of animal experiments and preliminary clinical trial. However, evaluation of this therapy in randomized multicenter trials is needed. In this article, we present the rationale and design of the SaiLuoTong in Vascular Dementia Study. METHODS: This phase 2 clinical trial of SaiLuoTong among patients with mild-to-moderate VaD is a 26-week, multicenter, randomized, double-blind, placebo-controlled study with a subsequent 26-week, open-label extension. After a 4-week placebo run-in period, participants are centrally randomized (1:1:1) to 3 groups: group A receives SaiLuoTong 360 mg per day for 52 weeks; group B receives SaiLuoTong 240 mg per day for 52 weeks; group C (the control group) are further randomly assigned to 2 groups in a 1:1 ratio and receives placebo during the double-blind phase, then SaiLuoTong 360 mg per day or SaiLuoTong 240 mg per day during the extension phase. The primary outcome measures include the VaD assessment scale cognitive subscale and the Alzheimer Disease Cooperative Study-clinical global impression of change. Safety measures include body weight, vital signs, electrocardiography, laboratory tests, and records of adverse events. Assuming an attrition rate of 20%, at least 372 patients are required to obtain a statistical power of 80%. RESULTS: The first patient was enrolled into the study in April 2012 and the completion of the study is expected in September 2014. CONCLUSIONS: The rigorous methodology of the study will hopefully move forward the scientific evaluation of traditional Chinese medicine in treatment of VaD. The results of the present study will provide high-quality evidence on the effect of SaiLuoTong in patients with VaD and has the potential to establish a novel therapeutic approach for this disorder.

A Randomized Trial of Chinese Diaoshi Jifa on Treatment of Dizziness in Meniere's Disease.

Background. Meniere's disease is characterized by refractory dizziness and hearing disturbance. We aimed to investigate the efficacy and tolerance of Diaoshi Jifa, a Chinese hand skill for treating dizziness in Meniere's disease. Methods. An open-labeled, randomized, controlled intervention trial was conducted. Twenty-seven patients diagnosed with Meniere's disease were randomly allocated to control group or experimental group. Both groups were assessed by DHI (dizziness handicap inventory (DHI)) questionnaire score before and within 24 hours of receiving treatment, respectively. Results. Twenty-six participants completed the study, and no adverse event was reported due to Diaoshi Jifa treatment. The difference in the DHI scores between baseline and posttreatment reached significant difference in both groups (63.88 ± 19.94 versus 10.25 ± 9.77 and 54.36 ± 17.97 versus 49.6 ± 20.50). Significant difference in DHI scores was observed between the two groups after treatment (10.25 ± 9.77 versus 49.6 ± 20.50). Further investigation of DHI subscales in the experimental group revealed significant improvement posttreatment in the physical domain, functional domain, and emotional domain. Although higher rate of improvement in the emotional domain compared to physical or functional domains was found, the difference was not statistically significant. Conclusions. Diaoshi Jifa might be a fast, effective, and well-tolerated method for alleviating dizziness in Meniere's disease.

[Post-marketing clinical study of traditional Chinese medicine--lessons learned from comprehensive evaluation of Fufang Zaoren capsule].

By comprehensive review and analysis of post-marketing clinical research on the efficacy and safety,we concluded that Fufang Zaoren capsule has certain therapeutic effects for insomnia, although current clinical research design needs improving. The post-marketing clinical studies also showed that it causes several adverse reactions at the recommended doses, such as chills, fever, dizziness, nausea, shortness of breath, chest tightness and palpitations, whereas high doses of Fufang Zaoren capsule can cause delayed extrapyramidal symptoms. Health Canada government website also prompted the L-tetrahydropalmatine in Fufang Zaoren capsule caused liver damage in pregnant women. The authors summarized the risk points, factors and risk control in the clinical use of Fufang Zaoren capsule and also present their perspective on the research status, existing problems and corresponding countermeasures in the post-marketing clinical re-evaluation of traditional Chinese medicine.

The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease.

We previously described an association between Alzheimer's disease (AD) and a single-nucleotide polymorphism -980C/G (rs3754048) in the promoter of the anterior pharynx-defective-1a (APH-1A) gene. Here, we examine the potential of this -980C/G polymorphism to affect APH-1A transcription and confer a risk of AD. We validated the presence of APH-1A promoter polymorphism -980C/G in other two Chinese cohort sets (450 AD and 450 controls). Subsequently, we measured APH-1A mRNA and protein levels and γ-secretase activity in C or G allele carriers. Finally, we examined the polymorphism's transcriptional function using a dual-luciferase reporter assay and also tracked transcription factor binding to the variant promoter sequence with electrophoretic mobility shift assays (EMSAs). We found that the APH-1A levels and γ-secretase activity were higher in individuals carrying allele G. The G allele increased APH-1A transcriptional activity significantly in both N2A cells and HEK293 cells. The EMSA revealed an increased binding of the transcription factor Yin Yang 1 (YY1) to allele G. Overexpression of YY1 resulted in an activation of the APH-1A promoter (2.7-fold). Specific YY1 siRNA led to decreases in APH-1A promoter activity and mRNA and protein levels. Our data indicate that the APH-1A promoter polymorphism -980C/G might alter the binding ability of YY1 transcription factor, resulting in an increased level of APH-1A and γ-secretase activity. These factors further facilitated ß-amyloid (Aß) 42 generation and ultimately modified patients' susceptibility to AD. The involvement of transcription factor YY1 might be a novel mechanism for the development of AD.

[Correlation analysis on changes between cognitive ability and brain fMRI after acupoint thread embedding in Alzheimer's disease patients].

OBJECTIVE: To explore the mechanism of acupoint thread embedding (ATE) in treating Alzheimer's disease (AD) by means of brain functional magnetic resonance imaging (fMRI). METHODS: Twenty-six patients with mild to moderate AD were assigned to the tested group and the control group in pairing, 13 in each group. ATE was performed in patients of the tested group at Shenmen (HT7), Fenglong (ST40), Taixi (KI3) and Zusanli (ST36) acupoints, once every month for 6 times in total; but for patients of the control group only sham operation was done at the same acupoints. The correlation between cognitive ability and fMRI were assessed by comparing the scores of Mini-Mental State Examination (MMSE) and Alzhemer's Disease Assessment Scale-Cognitive section (ADAS-Cog), monitored at two time points, namely, in one week before starting treatment and 1 week after terminating 6-month treatment. Furthermore, fMRI was detected to obtain the data of the cerebral blood oxygen content before treatment and 6 months after completing the 6-month therapeutic course. Correlation analysis was conducted on the obtained data using software SPM. RESULTS: After treatment, changes of MMSE score significently increased in the test group (P < 0.01) and decreased in the control group (P < 0.01), and ADAS-Cog decreased in the test group (P < 0.01) and increased in the control group (P < 0.05), showing statistical significance between the two groups (P < 0.01, P < 0.05). The activated regions related with the change of MMSE were mainly inferior frontal gyrus, middle frontal gyrus, superior frontal gyrus, transverse temporal gyrus, on the left cerebrum and superior frontal gyrus, middle frontal gyrus, precentral gyrus, hippocampal gyrus, cingulate gyrus, postcentral gyrus, paracentral lobule on the right cerebrum; those related with change of ADAS-Cog were superior frontal gyrus, middle frontal gyrus, fusiform gyrus, inferior temporal gyrus, hippocampal gyrus on the left cerebrum, and superior frontal gyrus, middle frontal gyrus, precentral gyrus, fusiform gyrus, transverse temporal gyrus, postcentral gyrus, middle occipital gyrus on the right cerebrum. CONCLUSION: ATE could improve the cognitive ability of AD patients, its possible mechanism may be through the activation on the cognition related regions of frontal, temporal lobe and marginal system, as well as those of cerebellum.

[Clinical observation on catgut implantation at acupoint for treatment of Alzheimer's disease].

OBJECTIVE: To observe clinical therapeutic effect of catgut implantation at acupoint on Alzheimer's disease (AD). METHODS: Twenty-six cases with mild-moderate AD were divided into an acupoint catgut implantation group and a control group by sample-paired method. The acupoint catgut implantation group were treated with cat-gut implantation at Shenmen (HT 7), Zusanli (ST 36), Fenglong (ST 40) and Taixi (KI 3), and the control group with the same manipulation at the same acupoints with no catgut implanted, once each month, for 6 months. Mini-Mental State Examination (MMSE), Activity of Daily Living (ADL) and Alzheimer's Disease Assessment Scale-Cognitive Section (ADAS-Cog) scores were recorded before and after treatment and analyzed statistically. RESULTS: After treatment, the score of MMSE significantly increased (P < 0.01), the score of ADAS-Cog significantly decreased (P < 0.01) and the score of ADL did not significantly change in the acupoint catgut implantation group; compared with the control group, the score of MMSE in the acupoint catgut implantation significantly increased (P < 0.01), the score of ADAS-Cog significantly decreased (P < 0.05) and the score of ADL did not significantly change in the acupoint catgut implantation. CONCLUSION: Acupoint catgut implantation therapy increases cognitive function of the patient of AD, which provides a new therapeutic method for aged AD.

[Effects of acupuncture at Neiguan (PC 6) on human brain functional imaging in different functional states].

OBJECTIVE: To study on effects of acupuncture at a same point at physiological or pathological state on brain functional imaging. METHODS: Electroacupuncture was given at Neiguan (PC 6) of the healthy senile persons (normal group) and the patients of Alzheimer's disease (AD group), and they were scanned on a 1.5 T MRI scanner and the data of functional magnetic resonance imaging (fMRI) were analyzed by Statistical Parametric Mapping (SPM99). The functional imaging of different brain regions were obtained from both the healthy group and the AD group. RESULTS: Both the frontal lobe and the temporal lobe were activated in varying degrees by electroacupuncture at Neiguan (PC 6) in the healthy group. However, the frontal lobe, the temporal lobe and the cingulate gyrus as well as the cerebellum were activated in varying degrees and other brain regions were not activated by electroacupuncture at Neiguan (PC 6) in the AD group. CONCLUSION: Acupuncture at Neiguan (PC 6) can activate functions of different brain regions in the healthy group and the AD group, indicating that acupuncture at Neiguan (PC 6) has different effects on functional magnetic resonance imaging in different functional states.

[Effects of electroacupuncture at neiguan (PC 6) and Shenmen (HT 7) on brain functional imaging].

OBJECTIVE: To observe effect of electroacupuncture at Shenmen (HT 7) and Neiguan (PC 6) on brain functional imaging. METHODS: The technique of functional magnetic resonance imaging was used to observe the activated state in different brain regions caused by electroacupuncture. RESULTS: The frontal lobe was activated by electroacupuncture at Neiguan (PC 6) and the temporal lobe by Shenmen (HT 7). CONCLUSION: Electroacupuncture at different acupoints can activate different brain regions, which provides objective basis for treatment of intellectual impairment by electroacupuncture at Neiguan (PC 6) and Shenmen (HT 7).