Xuekai Zhang

Herbal therapy: a new pathway for the treatment of Alzheimer's disease

It has been a clinical challenge to treat Alzheimers disease (AD). In the present commentary we discuss whether herbal therapy could be a novel treatment method for AD on the basis of results from clinical trials, and discuss the implications for potential therapy for AD pathophysiology. There is evidence to suggest that single herbs or herbal formulations may offer certain complementary cognitive benefits to the approved drugs. The current evidence supporting their use alone, however, is inconclusive or inadequate owing to many methodological limitations. Herbal mixtures may have advantages with multiple target regulation compared with the single-target antagonist in the view of traditional Chinese medicine. Several clinical trials using herbal mixtures are being conducted in China and will hopefully show promising results for treating AD in the near future.

A combination extract of Renshen (Panax Ginseng), Yinyanghuo (Herba Epimedii Brevicornus), Yuanzhi (Radix Palygalae) and Jianghuang (Rhizoma Curcumae Longae) decreases glycogen synthase kinase 3β expression in brain cortex of APPV717I transgenic mice

OBJECTIVE To investigate the neuroprotective mechanism of combination extract of Renshen (Panax Ginseng), Yinyanghuo (Herba Epimedii Brevicornus), Yuanzhi (Radix Palygalae) and Jianghuang (Rhizoma Curcumae Longae) (GEPT) in treating Alzheimers disease on the target of glycogen synthase kinase 3beta (GSK-3beta). METHODS Three-month-old APPV7171 transgenic mice were randomly divided into ten groups (n = 12 per group) and intragastrically administrated vehicle or medicines: APP group was given 0.5% CMC, donepezil group was given donepezil (APP + D group) (0.92 mg/kg(-1) x day(-1)), and GEPT groups were given small dose of GEPT (APP+Gs group) (0.075 g/ kg(-1) x day(-1)), medium dose (APP+Gm group) (0.15 g/ kg(-1) day(-1)), and large dose (APP+GI group) (0.30 g/ kg(-1) x day(-1)) for 4 or 8 months, respectively. Three-month-old C57BL/6J mice as vehicle controls (n=12) were given 0.5% CMC for 4 or 8 months as well. The GSK-3beta expression in the cortex of 7- and 11-month-old APPV7171 transgenic mice with and without GEPT or donepezil treatment and normal C57BL/6J mice were measured via Western blotting and Immunohistochemistry. RESULTS Immunohistochemistry analysis showed significant increase of GSK-3beta in the cerebral cortex of 7-month-old APP group (compare to control group P = 0.003), while the GSK-3beta expression of donepezil or GEPT group were all significantly decreased (Donepezil vs APP: P = 0.041; GI vs APP: P = 0.049; Gm vs APP: P = 0.029; Gh vs APP: P = 0.036). Western blot analysis showed similar results. The densitometric measures of GSK-3beta in APP mice increased significantly as compared with the control group (P = 0.008). And the GSK-3beta expression in donepezil and GEPT groups were all decreased. There was significant difference between Gh group or donepezil group and the control group (P = 0.05). Similar findings were shown in the 11-month-old mice in each group, except for greater decrease of GSK-3beta in the GEPT group. CONCLUSION GEPT can effectively decrease the level of GSK-3beta expression in the brain cortex of APPV7171 transgenic mice, and such effect is more significant in 11-month-old mice. This partially explains the neuroprotecting mechanism of GEPT in preventing and treating of AD.

Expression of one important chaperone protein, heat shock protein 27, in neurodegenerative diseases

IntroductionMany neurodegenerative diseases are characterised by accumulations of misfolded proteins that can colocalise with chaperone proteins (for example, heat shock protein 27 (HSP27)), which might act as modulators of protein aggregation.MethodsThe role of HSP27 in the pathogenesis of neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and motor neuron disease (MND) was investigated. We used immunohistochemical and Western blot analysis to determine the distribution and amount of this protein in the frontal and temporal cortices of diseased and control subjects.ResultsHSP27 immunostaining presented as accumulations of granules within neuronal and glial cell perikarya. Patients with AD and FTLD were affected more often, and showed greater immunostaining for HSP27, than patients with MND and controls. In FTLD, there was no association between HSP27 and histological type. The neuropathological changes of FTLD, AD and MND were not immunoreactive to HSP27. Western blot analysis revealed higher HSP27 expression in FTLD than in controls, but without qualitative differences in banding patterns.ConclusionsThe pattern of HSP27 immunostaining observed may reflect the extent of ongoing neurodegeneration in affected brain areas and is not specific to FTLD, AD or MND. It may represent an accumulation of misfolded, damaged or unwanted proteins, awaiting or undergoing degradation.

A NEW AGE-BASED CUTOFF OF VISUAL RATING SCALES IN MRI: IMPROVING THE DIAGNOSTIC ACCURACY OF AD IN A CHINESE POPULATION

Background: We investigated the diagnostic accuracy of various white matter hyperintensities(WMH) indexes and DTI measures for diagnosing Alzheimer’s dementia(AD) and compared their impacts on global cognition according to the diagnosis of cognitive status. Methods:Sociodemographic data, neuropsychological tests, 3 Tesla brain MRIs including DTI of 388 subjects(149 cognitive normal(CN), 106 mild cognitive impairment(MCI), 133 AD) were used. The WMHs were segmented automatically using automated monospectral segmentation method forWMHs using FLAIR MRIs. The WMH indexes using Fazekas classification, modified Fazekas classification, 3-dimensional smoothness index, texture index, and combined WMH indexed were examined. Fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity of each white matter tract based on JHU ICBM-DTI-81 White-Matter Labels atlas were calculated as DTI measures. Discriminant analysis for classifying CN, MCI, and AD and Receiver Operating Characteristic(ROC) Curve analysis for diagnosing AD were performed. Stepwise linear regression analysis was performed to examine the impacts of WMH indexes and DTI measures on Mini-Mental State Examination(MMSE) score according to the diagnosis. Results: 50.4% for Fazekas classification, 54.0% for modified Fazekas, 60.3% for smoothness index, 59.2% for texture index, 63.5% for combined WMH index, 96.1% for DTI measures, and 96.6% for DTI+WMH index were correctly classified by discriminant analysis. AUCs for diagnosing Alzheimer’s dementia were 0.740 for combinedWMH index, and 1.000 for DTImeasures. Texture indexes based on T1(CN), texture indexes based on FLAIR(MCI) and only DTI measures(AD) were included for stepwise linear regression model with highest R squared value for MMSE score. Conclusions: DTI measures showed superiority for classifying CN/MCI/AD and diagnosing AD than any WMH indexes. However, in CN and MCI groups, the texture index better explained the global cognitive function than the DTI measures. A replication of the results is needed through an independent sample, and the relationship between WHMs, DTI measures, and cognitive function needs to be clarified through longitudinal studies. Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(2015R1D1A1A01059251) and grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant no. HI09C1379).

ADDING CHINESE HERBAL MEDICINE TO CONVENTIONAL THERAPY BRINGS COGNITIVE BENEFITS TO PATIENTS WITH ALZHEIMER’S DISEASE: A TWO-YEAR STUDY

or 10 mg/kg or a titration regimen up to 10 mg/kg [average expected dose, 5.3 mg/kg at 52 weeks]) or placebo once every 4 weeks for 52 weeks in a staggered, ascending-dose design. Randomization in fixed-dose arms was stratified by ApoE4 status (carrier/noncarrier). Baseline to week 54 change in CDR-sum of boxes (CDR-SB) score was an exploratory endpoint. This post hoc analysis assessed cognitive and functional domains of the CDR at the week 54 visit in the overall study population and a subpopulation of patients with early AD defined by CDR global score, 0.5; CDR memory domain score, 0.5; and MMSE score, 24. Results:A total of 196 patients were randomized and dosed in PRIME. In the overall study population, the baseline means for CDR-SB, cognitive domain scores, and functional domain scores were 3.17, 2.00, and 1.17, respectively. At week 54, the adjusted mean changes for the cognitive domain scores were 0.93 (placebo), 0.94 (1 mg/kg), 0.72 (3 mg/kg), 0.49 (6 mg/kg), 0.30 (10 mg/kg), and 0.64 (titration regimen). For functional domain scores, the corresponding adjusted mean changes were 0.91, 0.81, 0.67, 0.62, 0.32, and 0.10. A subanalysis of patients with early AD was consistent with findings from the overall study population. Conclusions: This interim post hoc analysis suggests an effect of aducanumab on both cognitive and functional CDR domain scores at week 54 in the overall study population and in a subset with early AD.

Early detection of amnestic mild cognitive impairment from normal cognition or dementia by neurometabolites of the brain with magnetic resonance spectroscopy in a chinese population

large group of cognitively normal (CN), individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: 324 CN, 502 individuals with MCI, and 182 with AD were selected from the Alzheimer’s Disease Neuroimaging Initiative database. We included participants only if [18F] florbetapir positron emission tomography (PET), conducted within 3 month of a clinical and cognitive assessment visits, and APOE genotype information is available. To determine main effects and interactions of APOE ε4 and Ab burden on the scores, a series of 2 X 2 analysis of covariance, with age, gender, and education as covariates, was performed. Results: The influence of APOE ε4 status and Ab positivity on cognitive function, clinical severity, and functional status were minimal in CN and AD. In MCI, main effect of APOE ε4 was dominantly observed in executive function, with ε4 carriers exhibiting poorer performances. Ab positivity had no influence over this association. Main effect of Ab positivity was significant in global cognition, memory, and visuospatial ability, with MCI individuals of high Ab burden exhibiting poorer performances. However no single measure of the executive function domain was influenced by Ab positivity (Figure). Interactive effects of Ab positivity and APOE ε4 status were found in the measures of global cognition, verbal recognition memory, and clinical severity. Conclusions:We provided further evidence that APOE ε4 and Ab plays independent and interactive roles in cognitive functions from the large sample of CN, MCI, and AD. In MCI, the influences of APOE ε4and Ab burden status on executive and non-executive functions were found in a manner of dissociable pattern.

The differential diagnosis of amnestic mild cognitive impairment and Alzheimer's disease dementia by hippocampal volume measurement with MR in a chinese population

Figure 2. The correlation between bilateral hippocampal volume and MMSE scores of all subjects. Yeo Jin Kim, Hee Jin Kim, Jae-Hyun Park, Sung Tae Kim, Kyung Han Lee, Jong Min Lee, Jin San Lee, Duk L. Na, Sang Won Seo, Samsung Medical Center, Seoul, South Korea; Hanyang University, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea. Contact e-mail: sangwonseo@empal.com

THE PROTECTIVE EFFECTS OF GEPT ON HIPPOCAMPAL NEURONS AND SYNAPSES OF APP/PS1 TRANSGENIC MICE

Background:Mid-life obesity can increase the risk for developing dementia later in life, particularly Alzheimer’s disease (AD), and experimental diet-induced obesity increases AD-like pathology and/or behavioural deficits in transgenic mouse models of AD. However, most of these experimental studies assess the effect of high fat diet (HFD) in male mice only, and effects in female mice are less clear. Moreover, our previous work has shown that HFD also affects memory in healthy controls and that this effect is gender dependent.Resveratrol (RSV) has recently showed to improve health and life span of mice on a HFD and to improve learning and memory in both aged and AD mice, effects that are thought to be due to its anti-oxidant and/or anti-inflammatory properties. However until now no studies have been done taking into account both AD and co-morbidities (obesity). Therefore, the aim of this study was to test the effect of RSV in female 3xTgADmice fed with a HFD.Methods:Groups of female 3xTgAD and control (Non-Tg) mice w ere maintained on a control (12% fat) or a HFD (60% fat) for 12 months with or without RSV supplementation in the drinking water (5 mg/Kg/day). Body weight (BW) was monitored weekly. Behaviour was assessed at 12 months of treatment using the open-field and Y-maze spontaneous alternation tests. Epididymal fat, brown adipose tissue (BAT) and liver weight were measured after culling.Results: RSV did not affect BW in female 3xTgADmice fed a HFD but a decrease in weight gain was observed in Non-Tg HFD animals. HFD increased epididymal fat and BAT weight in both Non-Tg and 3xTgAD mice, and RSV reversed this effect only in Non-Tg mice. HFD also elevated liver weight in Non-Tg mice, which was reversed by RSV. RSV had no effect on behaviour or memory in both groups. Conclusions: These results suggest that RSV is able to reverse metabolic changes induced by the HFD in female Non-Tg mice but not in 3xTgAD animals, with no effect on behaviour in either. In conclusion, the effect of a HFD on memory is not affected by RSV and therefore is unlikely to be due to changes in oxidative stress and/or inflammation.

GEPT extract prevents beta-amyloid-deposition–induced synaptic dysfunction in APPV717I transgenic mice, possibly by adjusting the expression of CaMKII and CaN

reproducible AD defects, and positions CVNmouse as the most complete AD model available.Methods:Wild-type and CVNmice were studied starting at age of 3 months. Behavioral battery included Open field, Barnesmaze, Radial arm water maze, and Contextual fear conditioning. At 3,6,9 and 12 months of age, tissue were collected for biochemical analysis. Immunohistochemical stainings for Ab1-40 and microglia were performed, and neuronal number was evaluated by CFV histological staining. MRI volumetric as well as spectroscopic (1H-MRS) analyses were performed.Results:CVNmice exhibited significant age-dependent behavioral deficits in Barnes maze, Radial arm water maze and Contextual fear conditioning. Robust biochemical changes, including increased number of dense amyloid plaques in hippocampus, thalamus and cortex, and increased levels of insoluble Ab subtypes were evident. Significant inflammatory response detected by Iba-1 and CD45 immunoreactive microglia was heavily condensed around the plaques in all brain regions studied. The number of viable neurons in hippocampus was significantly decreased in aged animals. In 1H-MRS several translational AD-related metabolic changes were detected. Conclusions: The new CVN mouse provides a more complete tool to study novel therapies targeted for treatment of AD. Several desired AD-related end-points are present in this mouse line making it a valuable model for drug development.