Sequential Therapy Based on Evolvement of Patterns: A New Model for Treatment of Alzheimer's Disease.

In order to solve the problem of long-term (>9 months) efficacy in the treatment of Alzheimer's disease (AD) by conventional therapy (CT), a staged and multiply-targeted sequential therapy based on the evolvement of patterns (STEP) was developed. Its main innovations include: (1) the time order of evolution of patterns defined by Chinese medicine (CM) in AD was found, that is, "the orderly pattern evolution starting from Shen (Kidney) deficiency, progressing to phlegm, stasis and fire, and worsening to severe toxin as well as functional collapse"; (2) the cascade hypothesis of Shen deficiency in AD and its sequential therapy based on Shen-reinforcing was proposed, that is, "reinforcing Shen in the early stage and throughout the whole process, resolving phlegm, activating blood and purging fire in the middle stage, detoxifying and replenishing vitality to stop the collapse in the advanced stage", and through meta-analysis, clinical drug use was optimized, thus the leap from "inferential selection" to "evidence-based selection" was realized; (3) the STEP regimen combined with CT maintained cognitive and behavioral stability in AD patients for at least 12 months, with cognitive enhancement and behavioral synergy after 9 months, and cognitive benefit was superior to CT at 9, 12, 15, 18, 21, and 24 months, respectively. The 2-year cognitive improvement rate was increased by 25.64% (P=0.020) and the cognitive deterioration rate was decreased by 48.71% (P=0.000). Among them, the cognitive and functional benefits of Shen-reinforcing therapy for very early AD (350 cases) for 1 year were better than the placebo (P<0.001), and the dementia conversion rate was reduced by 8.85% (P=0.002). The behavioral symptomatic relief of patients with vascular dementia received fire-purging therapy (540 cases) was superior to those received CT (P=0.016). These data suggested that the STEP regimen has synergistic effects on CTs at least in terms of cognitive benefit, and the earlier the use, the greater the benefit will have. Therefore, the STEP regimen should be considered as one of the clinical options, particularly for the dearth of effective pharmaceutical or immunological interventions that are currently available for AD.

Effect of GAPT extract on expression of tau protein and its phosphorylation related enzymes in hippocampal neurons of APPV717I transgenic mice.

OBJECTIVE: To investigate the effect of GAPT, an extract mixture from Radix Ginseng, Rhizoma Acor tatarinowii, Radix Polygalae and Radix Curcuma (containing ingredient of turmeric), etc. on expression of tau protein and its phosphorylation related enzyme in hippocampal neurons of APPV717I transgenic mice. METHODS: Sixty three-month-old APPV717I transgenic mice were randomly divided into model group, donepezil group [0.92 mg/(kg•d)], the low, medium and high dosage of GAPT groups [0.075, 0.15, 0.30 g/(kg•d), 12 in each group], and 12 three-month-old C57BL/6J mice were set as a normal control group, treatments were administered orally once a day respectively, and both the normal group and model group were given 0.5% sodium carboxymethyl cellulose solution. Immunohistochemistry (IHC) and Western blot analysis were used to detect the expression of total tau protein (Tau-5), cyclin-dependent kinase 5 (CDK5) and protein phosphatase 2A (PP2A) in hippocampal neurons of experimental mice after 8-month drug administration (11 months old). RESULTS: In the model group, the expression of Tau-5 and CDK5 were increased, whereas the expression of PP2A was decreased in hippocampal neurons, which were signifificantly different compared with that in the normal group (all P<0.01). IHC test indicated the number and area of either Tau-5 or CDK5 positive cells were decreased with a dose-depended way in GAPT groups, and an increase of PP2A. Compared with the model group, the changes were signifificant in GAPT groups (P<0.05 or P<0.01). Similar results were shown by Western blot. CONCLUSION: GAPT could attenuate abnormal hyperphosphorylation of tau protein in hippocampal neurons of APPV717I transgenic mice via inhibiting the expression of CDK5 and activating the expression of PP2A.

Effects of Chinese medicine for promoting blood circulation and removing blood stasis in treating patients with mild to moderate vascular dementia: a randomized, double-blind and parallel-controlled trial.

BACKGROUND: Vascular dementia (VaD) is the second common subtype of dementia after Alzheimer's disease. However, there is still a lack of medication that demonstrates clinically relevant symptomatic improvement. Static blood obstructing the brain is the main Chinese medicine syndrome of VaD. OBJECTIVE: To evaluate the effects of Chinese medicine for promoting blood circulation and removing blood stasis in patients with mild to moderate VaD. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: In this 12-week randomized, double-blind, parallel-controlled trial, a total of 48 patients with mild to moderate VaD were enrolled between March 2009 and December 2010. All the patients entered a two-week placebo run-in period followed by a 12-week treatment with Chinese medicine for promoting blood circulation and removing blood stasis (n=24) or placebo (n=24), respectively. The placebo tablets have the identical taste and appearance as the Chinese medicine tablets. MAIN OUTCOME MEASURES: The primary outcome measure was the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog); the secondary outcome measures included the Activities of Daily Living (ADL) and the Mini-Mental State Examination (MMSE). RESULTS: The Chinese medicine group showed a slight deterioration of 0.25 points and the placebo group showed a deterioration of 2.35 points from baseline by the ADAS-cog, and there was a significant difference between the two groups (P=0.027). The ADL and the MMSE showed no significant difference from baseline in both groups. Adverse events were rare in both groups. CONCLUSION: The Chinese medicine for promoting blood circulation and removing blood stasis may improve cognition and it is safe and well tolerated.

[Correlation between cognitive functions and syndromes of traditional Chinese medicine in vascular cognitive impairment].

OBJECTIVE: To investigate the correlation between cognitive function and the Chinese medicine syndrome characteristics of vascular cognitive impairment (VCI). METHODS: A total of 774 subjects (age from 41 to 87 years old) from Beijing of China accepted neuropsychological assessments and differentiation of Chinese medicine syndromes. The mini-mental state examination (MMSE) and clinic dementia rating (CDR) were used to access the global cognitive function; the Hachinski ischemia scale (HIS) and the Hamilton depression scale (HAMD) were used for differential diagnosis; the ability of daily living (ADL) scale was used to assess the ability of daily living; the clock drawing test was used to access the executive function; the investigation of syndrome manifestations and the syndrome differentiation scale of vascular dementia (SDSVD) were used for diagnosis of syndrome manifestations. According to the diagnostic criteria of vascular cognitive impairment, subjects were subgrouped as normal cognition (NC) group and VCI group, and then the correlation between the cognitive functions and Chinese medicine syndromes was analyzed. RESULTS: The correlation between cognitive scales and Chinese medical syndrome: in the VCI group, the syndrome of phlegm turbid blocking upper orifices showed negative correlation with the scores of MMSE and CDT (r=-0.525, r=-0.321, P=0.000, P=0.001), and the ADL demonstrated positive correlation to the syndrome (r=0.424, P=0.000). The correlation between cognitive function and Chinese medical syndrome: the phlegm turbid blocking upper orifices was closely correlated with the total orientation, time orientation and place orientation (r=-0.451, r=-0.448, r=-0.392, P=0.001, P=0.000, P=0.004); instant word recall and delayed word recall were closely correlated with the syndrome of phlegm turbid blocking upper orifices (r=-0.355, r=-0.225, P=0.000, P=0.021); calculation/attention, language function and executive function had negative correlation to the syndrome of phlegm turbid blocking upper orifices (r=-0.379, r=-0.448, r=-0.321, P=0.000, P=0.000, P=0.013). The scores of orientation, calculation/attention, delayed word recall and language function in the patients with phlegm turbid blocking upper orifices were significantly lower than the patients with non-phlegm turbid blocking upper orifices (P<0.05). CONCLUSION: The syndrome of phlegm turbid blocking upper orifices is significantly correlated to the scores of MMSE and ADL, indicating that the phlegm turbid blocking upper orifices is related to the cognitive function and ability of daily living in the VCI patients. Treatment of the phlegm is important in the cognitive impairment in VCI patients.