Clinical study on decreasing occurance of Alzheimer's Disease through intervention on amnestic Mild Cognitive Impairment with Di-Huang-Yi-Zhi formula in Shigatse, Tibet

doi:10.21203/rs.3.rs-80949/v1

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Clinical study on decreasing occurance of Alzheimer's Disease through intervention on amnestic Mild Cognitive Impairment with Di-Huang-Yi-Zhi formula in Shigatse, Tibet

https://doi.org/10.21203/rs.3.rs-80949/v1

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Background

Mild cognitive impairment (MCI) is generally considered a transitional stage between normal aging and AD dementia. This study aimed to analyze the efficacy of Di-Huang-Yi-Zhi (DHYZ) formula in treating amnestic Mild Cognitive Impairment (aMCI) for the patients in high altitude area (Qinghai Tibet Plateau).

Method:

A total of 106 patients in Shigatse, Tibet were randomly allocated into two groups. One group were to receive DHYZ decoction (150 ml each time, twice a day), the other group were to have aniracetam capsule (200 mg each time, three times a day) ,with 53 patients in each group. Changes in neuropsychological scales including mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), the Barthel Index for activities of daily living (ADL) and TCM symptoms were detected during a 12-month treatment period. After one year follow-up, the conversion rate of AD was observed.

Result

There was no significant difference between the two groups in baseline characteristics and scale scores (P > 0.05). Compared with the aniracetam group, the DHYZ group showed statistically higher MMSE and MoCA score and lower TCM score at the 9-month and 12-month. In addition, the ADAS-Cog and ADL scores in DHYZ group at 12-month were lower than that in the aniracetam control group. After one year follow-up, the conversion rate of AD in DHYZ group was 10% (5/50), and aniracetam group was 15.69% (8/51). The conversion rate of AD in DHYZ group was significantly lower than that in aniracetam group.

Conclusion

DHYZ formula can improve the cognition behavior and global function of patients with aMCI, it can also delay the conversion to AD. This is represents a new treatment option for the patients.

Neurology

Amnestic Mild Cognitive Impairment

Alzheimer's Disease

Conversion rate

Di-Huang-Yi-Zhi (DHYZ) formula

Plateau area

Alzheimer’s disease (AD) is the most common cause of late-onset dementia, accounting for 60–80% of the cases [1]. Nearly half of the person aged 85 years and older have late onset AD and the prevalence will quadruple by mid-century worldwide [1, 2]. Mild cognitive impairment (MCI) is generally considered a transitional stage between normal aging and AD dementia [3], which represents worse memory or other cognitive functions than that would be expected for a person’s age and may evolve into AD ultimately [3]. MCI can be roughly classified as amnestic MCI (aMCI)-subjects have a poor performance on neuropsychological tests of episodic memory, and non-amnestic MCI-subjects have a poor performance on neuropsychological tests covering cognitive domains other than memory [4]. Predominant memory impairment is the hallmark of aMCI, and subjects with aMCI are at high risk to develop AD dementia [5].

MCI has become a common target for secondary prevention of AD nowadays. Early diagnosis and treatment for MCI are considered important and necessary for AD prevention. A great effort has been made on exploring individual compounds capable of slowing down cognitive decline in subject with MCI in the past 10–15 years, however, none of these agents have been proved effective. Because of the insufficient evidence, there is no recommended pharmacological treatment for MCI.

The pathogenesis of AD is complex and multifactorial, including both genetic and environmental risk factors [5–7]. A set of synergistic pharmacological interventions that interact with multiple targets such as Aβ/tau pathology, abnormal inflammation and cholinergic pathways may be effective in prevention and treatment of AD. There is a long history for Traditional Chinese Medicine (TCM) in preventing and treating cognitive impairment [8]. TCM formula will not only focus on improving symptoms but also on restoring and maintaining the body homeostasis. The precept of TCM is very similar to the rationality of modern multi-targeted therapeutics [9]. Currently, several TCM formulas such as intelligent Decoction has been applied for many centuries and are still prescribed by Chinese medical physicians to patients with cognitive impairment.

DHYZ formula is composed of 7 kinds of Chinese herbal medicines, such as Shudi, Yizhiren, Shichangpu, etc. It has the functions of tonifying kidney ,filling essence, dredging collaterals and detoxifying the body DHYZ has been proved to have anti-aging effect in the early stage of Alzheimer's disease, including regulating cell cycle related proteins, preventing brain oxidative damage, regulating the activities of central neurotransmitter chat and ache(regulating the activities of chat and ache in the central nervous system), inhibiting the abnormal phosphorylation of tau protein, and inhibiting PC12 cell apoptosis induced by glutamate [10–17]. In addition, we have intervened in patients with PD, MCI and VCIND, which proves that DHYZ is effective and safe [18–23]. Therefore, we take aneracetam as a positive control drug to observe the effect of DHYZ, hoping to provide a new treatment for delaying the development of AD.

Due to high altitude, anoxia, cold and other natural environment factors inplateau area, itis easy to cause poor cerebral blood supply and metabolic dysfunction, which willeasily leads to cognitive impairment and develop AD. In addition to traffic inconvenience in the plateau, lack of knowledge of dementia and medical resources, we should pay more attention to the cognitive impairment in plateau area.

At present, there are few studies and reports on mild cognitive impairment in plateau area. In order to provide evidence for the prevention and treatment of aMCI in plateau area as well as delay the development of dementia, this study analyzed the characteristics of cognitive impairment and the therapeutic effect of TCM in aMCI patients in Shigatse, Tibet.

Study design

This is a prospective, open-label and randomized study to assess the efficacy of DHYZ formula in treating patients with aMCI. Patients who admitted at the Integrated TCM & Western Medicine Department, Shigatse people's Hospital between July 2017 and July 2018 were enrolled.

Participants

Patients who visited our institution due to subjective memory complaints and diagnosed as aMCI based on criteria establish by National Institute on Aging and Alzheimer’s Association(NIA-AA)(2011) were recruited. Other inclusion criteria were as follows: 1) aged between 50 and 80 years; 2) mini-Mental State Examination (MMSE) score of 24–30, 17-item Hamilton depression scale score ≤ 12, and Hachinski Ischaemic Score (HIS) ≤ 4; 3) sufficient vision and auditory ability and sufficient mental state to complete the neuropsychiatric assessments. Patients were excluded if they had one of the following exclusion criteria: 1) dementia; 2) cerebrovascular disease; 3) within the last two years, had psychiatric disorders including depression and schizophrenia or had a history of alcoholism, drug abuse or drug addiction based on Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV); ( 3) drug abuse or drug addiction based on DSM-IV diagnostic and Statistical Manual of mental disorders (DSM-IV) within the past two years with mental illness, including depression and schizophrenia, or with a history of alcohol abuse;)4)other neuropsychological disorders that may affect cognitive functions; 5) hydrocephalus, cerebral tumor, progressive supranuclear palsy, epilepsia, subdural hematomas, disseminated sclerosis or other cerebral diseases.

Drug and Treatment

DHYZ formula contains 15 g Shudi (Radix Rehmanniae Preparata), 15 g Danshen (Salviae Miltiorrhizae Radix), 6 g Yizhiren (Alpinia oxyphylla), 9 g Shichangpu (Rhizoma Acorigraminei), 9 g Fushen (Indian Bread with Pine), 9 g Shanzhuyu (Cornus officinalis) and 3 g Guijiajiao (Tortoise-shell glue). Aniracetam capsules were provided by Luo Xing Pharmaceutical Co. Ltd (H20059460, Shandong, China).

Eligible patients were randomly allocated into treatment group (DHYZ) and control group (Aniracetam) at a ratio of 1:1 by using a computer-generated procedure.

Patients in the DHYZ group took DHYZ decoction (150 ml each time, twice a day). Patients in the aniracetam group were administered orally aniracetam capsule (two capsules each time, 100 mg/capsule, three times a day). Patients were treated with DHYZ decoction or aniracetam for 12 months.

Outcomes measures

During a treatment of 12 months(during a 12 months of treatment) and 1 year’s follow-up, the efficacy of DHYZ formula were mainly assessed in terms of cognition, behavior and global function by neuropsychological scales including MMSE (China) [24] and Montreal cognitive assessment (MoCA) [25], Assessment Scale-Cognitive Subscale (ADAS-Cog) [26] and the activities of daily living (ADL) scales [27]. In addition, we also evaluated the efficacy by using the TCM syndrome score scale established by the Guideline principle of clinical research on mild cognitive impairment (protocol) [28]. All scale detections were conducted by two independent experts who were unaware of the study design and grouping. If there was any discrepancy, a third expert would re-evaluate the results.

Safety

Before and after treatment, routine examinations (blood, urine, stool, liver and kidney function, electrocardiogram) were performed in both groups.

Statistical Analysis

Quantitative data were presented as mean ± SD, while qualitative data were expressed by number (percentage). Paired and independent sample t-tests were used for intra-group and inter-group comparisons in demographic characteristics and efficacy measurements, respectively. All statistical analyses were performed using the SPSS (SPSS, Chicago, IL, USA; version 19.0). P values less than 0.05 were considered statistically significant.

The balance between groups was analyzed before treatment. Before and after treatment, the curative effect of the two groups were statistically and significantly tested, and the index changes were significantly tested.

Subjects characteristics at baseline

A total of 106 aMCI cases were enrolled in this study and randomly allocated to the DHYZ group (n=53) and Aniracetam group (n=53). The average age of patients in the Aniracetam group was 69.62 ± 4.95 years, and that of DHYZ group was 67.66 ± 5.26 years. There was no significant difference between the two groups in age (P = 0.058), MMSE (P = 0.827), MoCA (P = 0.951), ADAS-Cog (P = 0.847), ADL (P = 0.865) or TCM before treatment (P = 0.874) (Table 1 and Table 3).

Efficacy outcomes

Table 1 shows the results of several neuropsychological scale tests，including MMSE, MoCA, ADAS-Cog and ADL before and during the 12-month treatment period.

In terms of MMSE, there was no significant difference in the Aniracetam group compared with baseline value (P > 0.05). However, the MMSE was significantly improved by DHYZ after treated for 6 months (24.46±1.11 after 6 months, 25.06±1.36 after 9 months and 25.68±1.33 after 12 months versus 24.04±1.24 at baseline; P = 0.049, < 0.001 and < 0.001, respectively). Compared with the Aniracetam group, statistically higher MMSE score in the DHYZ group were observed at the 9-(25.68±1.33 versus 23.88±1.55, P < 0.001) and 12-month timepoints (24.04±1.24 versus 23.74±1.70, P < 0.001).

In terms of MoCA, there was no difference in the Aniracetam group compared with baseline value (P > 0.05). However, improved MoCA were detected following DHYZ treatment at the 9-and 12-month timepoints (24.06±1.79 and 24.68±1.56 versus 22.90±1.63 at baseline, P < 0.001). Compared with the Aniracetam group, statistically higher MoCA score in the DHYZ group were observed at the 9- (24.06±1.79 versus 22.68±2.03, P < 0.001) and 12-month timepoints (24.68±1.56 versus 22.38±1.92, P < 0.001).

In terms of ADAS-Cog, there was no difference in the Aniracetam group compared with baseline value at the 3-, 6- or 9-month timepoints (P > 0.05), while the ADAS-Cog score was even higher at the 12-month timepoint (23.82±9.01 versus 20.56±4.24, P < 0.001), indicating a worse performance of Aniracetam. In the DHYZ group, significantly lower ADAS-Cog score was observed at the 12-month timepoint (17.58±3.99 versus 20.36±5.93, P < 0.001). The value also had statistically prominent difference when compared with the Aniracetam group (P < 0.001).

In terms of ADL, there were significant improvement in the Aniracetam group compared with baseline value at the 3-, 9- and 12-month timepoints (23.60±1.69 after 3 months, 23.30±1.85 after 9 months, 22.96±1.89 after 12 months versus 24.04±1.76 at baseline; P = 0.016, 0.009 and < 0.001, respectively). In the DHYZ group, significant improvement was detected since treated for 3 months (23.44±1.84 after 3 months, 23.28±1.93 after 6 months, 22.58±1.86 after 9 months and 21.7±1.43 after 12 months versus 23.98±1.76 at baseline; P = 0.001, < 0.001, < 0.001, and < 0.001, respectively). Although improvement in terms of ADL score was both detected in the Aniracetam group and DHYZ group, the value in the DHYZ group at 12-month timepoint was notably lower than that in the Aniracetam control group (P < 0.001).

Table 2 shows the results of several neuropsychological scale tests including MMSE, MoCA, ADAS-Cog and ADL after treatment and 1 year follow-up

After 1 year follow-up, there was no significant change in MMSE and ADAS-Cog scores between the two groups. The MoCA was significantly improved by DHYZ (24.68±1.56 after 12 months versus 25.03±2.06 1 year follow-up; P = 0.029). ADL scores in the DHYZ group (21.7±1.43 after 12 months versus 20.66±1.58 1 year follow-up; P < 0.001) and Aniracetam group (22.96±1.89 after 12 months versus 22.07±2.38 1 year follow-up; P = 0.011) were both significant improved. Compared with the Aniracetam group, statistically lower ADL score in the DHYZ group (P < 0.001).

Table 3 shows the results of TCM symptom scores before therapy and during the 12-month treatment period.

In terms of TCM (Table 3), there were significant improvement in the Aniracetam compared with baseline value since treated for 3 months (11.82±2.58, 11.34±2.65, 10.84±2.61 and 10.18±2.39 after 3, 6, 9 and 12 months versus 12.60±2.60 at baseline; Ps < 0.001). In the DHYZ group, significant improvement was detected since treated for 6 months (10.88±2.68, 9.18±2.78 and 7.52±2.54 after 6, 9 and 12 months versus 12.68±2.43 before treatment; Ps < 0.001). Although improvement in terms of TCM score was both determined in the Aniracetam group and DHYZ group, the values in the DHYZ group at 9- and 12-month timepoints were markedly lower than that in the placebo control group (P = 0.003 and < 0.001, respectively).

Table 4 shows the results of TCM symptom scores after treatment and 1 year follow-up. After 1 year follow-up, there was no significant change in TCM symptom scores in the Aniracetam group. While the TCM symptom scores was significantly improved by DHYZ (7.52±2.54 after 12 months versus 6.31±2.18 1 year follow-up; P < 0.001).

Exclusion and drop-out

One female patient and two male patients in DHYZ group were excluded due to poor compliance and failure to take medication as required; two female patients in Aniracetam group were excluded due to poor compliance, failure to take medicine on time and regular follow-up, so the final statistical results were: 50 cases in DHYZ group and 51 cases in Aniracetam group. After 1 year follow-up, no one was lost, so the final statistical results were: 50 in DHYZ group and 51 in Aniracetam group.

Conversion rate

After 1 year follow-up, 13 patients in the two groups were found to be transformed into AD, 5 in the DHYZ group, with a conversion rate of 10%, and 8 in the Aniracetam group, with a conversion rate of 15.69%. 13 patients had significant decline in memory, calculation and orientation. In daily life, they need help in cooking, taking medicine, financing and so on.

MCI is considered an intermediary stage between normal aging and AD. Nowadays, the diagnosis of MCI mainly relies on objective measures such as MMSE and ADAS-cog scores. We designed this study to assess the effects of DHYZ formula on brain activation and behavioral performance as measured by these operational criteria. We hope to provide a treatment option for early detection and early intervention of aMCI, delay or prevent the occurrence and development of AD, and give full play to the advantages of traditional Chinese medicine.

Studies have shown that the occurrence of AD is related to many factors, including apoptosis, oxidative stress, mitochondrial dysfunction, inflammatory response and energy metabolism disorder. According to TCM, prescriptions used to treat AD clinically composes of complex variety of many different herbs, which is very similar to the concept of modern multi-targeted therapeutics. TCM believes that the clinical prescription for AD is composed of a variety of traditional Chinese medical herbs, which is very similar to the concept of modern multi-target treatment. Each TCM formula comprises several herbs with different functions that will work synergistically at multiple targets of a complicated disease. DHYZ is a seven-herbs formula, such as Shudi, Danshen,Yizhiren༌Shichangpu༌Fushen༌Shanzhuyu and Guijiajiao.

Shudi(Radix Rehmanniae Preparata)has warm nature and return to liver and kidney meridians. It has the effect of nourishing yin and blood, benefiting essence and filling marrow. Danshen༈Salviae Miltiorrhizae Radix༉ is bitter in taste and cold in nature. It has the functions of activating blood circulation and regulating menstruation, removing blood stasis and relieving pain, cooling blood and eliminating carbuncle, clearing heart and removing (removing pathogenic factors), nourishing blood and calming nerves. Shichangpu (Rhizoma Acorigraminei) is bitter in taste and warm in nature. It has the functions of moistening and appetizing stomach, opening orifices, clearing phlegm, refreshing mind and improving intelligence. Guijiajiao༈Tortoise-shell glue༉ is slightly cold in nature. It can nourish yin and Yang, strengthen kidney and bone, nourish blood and heart. Fushen༈Indian Bread with Pine༉is mild in nature, and has functions of calming heart, calming mind and benefiting water. Yizhiren༈Alpinia oxyphylla༉is a kind of medicine. It has a pungent taste and warm nature. It can enter the spleen and kidney meridians. It can benefit the spleen and stomach, take saliva solution and warm the kidney. These herbs play the role of tonifying kidney and filling essence, resolving phlegm and dredging collaterals.

TCM has a long history in the treatment of AD in China. Based on thousands of years of medical practice, TCM has accumulated rich theories and abundant valuable experience in the prevention and treatment of AD [8]. Although there is no clear description of MCI in traditional Chinese medicine, memory and cognitive impairment related to AD are found in ancient Chinese medical literature. A classic work of Chinese Medicine “Huang Di Nei Jing” said, “The brain is the sea of marrow” and “kidney stores essence to generate marrow” [29]. The kidney essence, which is the energy from the kidney can produce cerebral marrow, spinal cord, and bone marrow, thus to nourish the brain and maintain the physiological functions of the brain. The insufficient kidney essence can directly reduce the generation of cerebral marrow, leading to various symptoms such as dizziness and amnesia. In addition, the disorder of memory and cognition should be attributed to brain defects caused by phlegm obstruction according to TCM therapy. Besides kidney essence deficiency, phlegm dampness and turbidity orifice obstruction are also important pathological features of AD [30]. The static phlegm turbidity would make the sea of marrow turbid, and hinder the movement of original qi, thus leading to insufficient nourishment of brain. As a result, dementia will arise [30].

In TCM, AD is considered holistic. Although the pathological site of AD is in the brain, this disease is believed to be highly correlated to the abnormal functions of other organs including the kidney, liver, heart and spleen. Thus, kidney essence deficiency and phlegm stasis become the important pathogenesis for AD on TCM. The seven-herbs formula DHYZ was created based on the abundant academic experience of the old medicine. DHYZ formula is established to strengthen the spleen and tonify the kidney, and get rid of phlegm and stasis, which is supposed to improve memory and cognition in AD or MCI patients. The results from our study confirmed the efficacy of DHYZ formula in treating MCI.

As there are few reports on the prevention and treatment of MCI in plateau area, this study is of great significance for early detection and intervention of MCI patients in plateau area. The number of cases in this study is not large, mainly concentrated in Shigatse City and surrounding counties, not covering some distant counties, which may have some limitations on the conclusion.

In the future work, we will increase the number of patients and include more people from different counties and townships, and provide a better basis for the prevention and intervention of TCM in plateau area.

DHYZ formula can significantly improve the memory and cognitive ability of patients with aMCI in Shigatse, Tibet, enhance the quality of life, and delay the transformation process to AD. More importantly, it can provide experience for the prevention and control of AD in plateau area.

aMCI: amnestic Mild Cognitive Impairment; AD:Alzheimer's disease; DHYZ:Di-Huang-Yi-Zhi; TCM:Traditional Chinese medicine; MMSE:mini-mental state examination; MoCA:Montreal cognitive assessment; ADAS-Cog:Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADL:the Barthel Index for activities of daily living; SD:standard deviation

Acknowledgements

Not applicable.

Ethic approval and consent to participate

The present study was approved by Chinese Clinical Trial Registry (ChiCTR), ChiCTR2000028893. The written informed consent was obtained from each participant after an adequate explanation for the study purpose, procedures, possible risks and discomforts.

Funding

This study was supported by the Project of Shanghai Municipal Science and Technology Commission, Research on the correlation between amnestic mild cognitive impairment characteristics and TCM Syndrome Types in Shigatse, Tibet (19695840100).

Availability of data and materials

Please contact corresponding authors for data requests.

Authors’ contributions

CG conceived and designed the study, LMZ and TS contributes to clinical data collection and data analysis; HMA, XCY, and JWY participated the study. All authors read and approved the final manuscript.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Table 1. Changes in MMSE, MOCA, ADAS-Cog and ADL scores before and after treatment at different timepoints.

Table 2. Changes in MMSE, MOCA, ADAS-Cog and ADL scores after treatment and 1 year follow-up

	Aniracetam (n=51)		DHYZ (n=50)
	12 months	1 year follow-up	12 months	1 year follow-up
MMSE	23.74±1.70	23.61±1.89	25.68±1.33	25.52±2.11
MoCA	22.38±1.92	22.29±2.03	24.68±1.56	25.03±2.06^*#
ADAS-Cog	23.82±9.01	24.03±9.88	17.58±3.99	17.97±4.23
ADL	22.96±1.89	22.07±2.38^*	21.7±1.43	20.66±1.58^*#

Notes: Data were presented as mean ± standard deviation (S.D.). ^*P < 0.05, compared with the same group at baseline, ^#P < 0.05 compared with the Aniracetam group at different timepoints.

MMSE: mini-mental state examination; MoCA: Montreal cognitive assessment; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive Subscale; ADL: activity of daily living.

Table 3. Changes in TCM symptom scores before and after treatment at different timepoints.

Group	Time	TCM score
Aniracetam (n=51)	Baseline	12.60±2.60
	3 months	11.82±2.58^*
	6 months	11.34±2.65^*
	9 months	10.84±2.61^*
	12 months	10.18±2.39^*
DHYZ (n=50)	Baseline	12.68±2.43
	3 months	11.82±2.63
	6 months	10.88±2.68^*
	9 months	9.18±2.78^*^#
	12 months	7.52±2.54^*^#

Notes: Data were presented as mean ± standard deviation (S.D). ^*P < 0.05, compared with the same group at baseline, ^#P < 0.05 compared with the placebo control group at different timepoints.

TCM: Traditional Chinese Medicine.

Table 4. Changes in TCM symptom scores after treatment and 1 year follow-up

Group	Time	TCM score
Aniracetam (n=51)	12 months	10.18±2.39
	1 year follow-up	10.06±2.47
DHYZ (n=50)	12 months	7.52±2.54
	1 year follow-up	6.31±2.18^*^#

Notes: Data were presented as mean ± standard deviation (S.D). ^*P < 0.05, compared with the same group at baseline, ^#P < 0.05 compared with the placebo control group at different timepoints.

TCM: Traditional Chinese Medicine.

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Clinical study on decreasing occurance of Alzheimer's Disease through intervention on amnestic Mild Cognitive Impairment with Di-Huang-Yi-Zhi formula in Shigatse, Tibet

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Abstract

Background

Method:

Result

Conclusion

Background

Methods

Study design

Participants

Drug and Treatment

Outcomes measures

Safety

Statistical Analysis

Results

Subjects characteristics at baseline

Efficacy outcomes

Exclusion and drop-out

Conversion rate

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

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