Comparative efficacy of various exercise interventions on sleep in patients with cognitive impairment: a systematic review and meta-analysis.

Background: Sleep disturbances are an early indicator of cognitive impairment and exacerbate its progression. While pharmacological treatments for sleep disorders exist, their side-effect profile includes an increased risk of falls and the potential to exacerbate cognitive impairment. Non-pharmacological treatments such as physical exercise should be considered. However, uncertainties persist. We aimed to assess the potential benefits of exercise interventions on sleep in patients with cognitive impairment and determine the specific effects of various exercise modalities. Materials and methods: A systematic search was performed on seven databases for eligible studies published before Nov 2022. Randomized controlled trials of exercise for patients with cognitive impairment (mild cognitive impairment and Alzheimer's disease) were included. All analyses were conducted using RevMan version 5.4. Meta-analysis and The Grading of Recommendations Assessment Development and Evaluations (GRADE) quality ratings were performed on sleep quality and objective sleep data. Results: A total of 8 randomized controlled trials were included with a sample size of 486 subjects. For patients with cognitive impairment, physical exercise had a beneficial effect on sleep quality [MD = -3.55 (-5.57, -1.32), Z = 3.13, p = 0.002] and total sleep time [MD = 33.77 (23.92, 43.62), Z = 6.72, P < 0.00001]. No improvement was found in sleep efficiency and nocturnal awakening time. Subgroup analysis showed that multi-component exercise produced superior results. Conclusion: Physical exercise may improve sleep quality and total sleep time for patients with cognitive impairment. Multi-component exercise designed individually is more effective. Large-scale randomized controlled trials with objective sleep outcome measurements are warranted.Clinical trial registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022377221.

Systematic review: clinical characteristics of anti-N-methyl-D-aspartate receptor encephalitis.

Background: The number of reported cases of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has gradually increased since its discovery in 2007, while there are no uniform treatment guidelines. Objective: To summarize the clinical characteristics of patients with anti-NMDAR encephalitis and to analyze the factors affecting the disease prognosis. Methods: A systematic analysis of medical records was conducted, and PubMed, Embase, and Cochrane Library were searched from January 1, 2011, to December 31, 2021. Data were extracted, analyzed, and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Results: This study included 472 case reports. Most patients had prodromal symptoms of about 2 weeks, including psychiatric symptoms (53.2%), flu-like symptoms (51.5%), and seizures (23.9%), among others. Poor prognoses were associated with patients who had autonomic instability (p = 0.010), central hypoventilation (p = 0.014), and ICU support (p = 0.002). Patients with a higher age of onset were more likely to develop central hypoventilation (OR 1.024, CI 1.006-1.042, p = 0.009), cognitive impairment (OR 1.023, CI 1.009-1.037, p = 0.001), and memory impairment (OR 1.034, CI 1.017-1.050, p < 0.001), whereas patients with a lower age were more likely to have seizures (OR 0.979, CI 0.965-0.993, p = 0.003). In this study, 97.0% of patients received immunotherapy, with the most commonly used treatment regimen being intravenous methylprednisolone (IVGC) and intravenous immunoglobulin (IVIG). When compared with other treatment regimens, the IVGC+IVIG regimen (p < 0.001) resulted in better prognoses. Conclusion: When encountering patients with fever, headache, and initial psychiatric symptoms of unknown etiology, clinicians should test their CSF for antibodies to distinguish autoimmune encephalitis. Patients with autonomic instability, central hypoventilation, and ICU support had poorer prognoses. Clinicians should be aware that older patients are more likely to develop central hypoventilation, cognitive impairment, and memory impairment, while younger patients are more likely to develop seizures. The IVGC+IVIG treatment regimen has better prognoses than others. This study includes case reports, which have obvious selection bias, and there are no unified standards to measure the severity of the disease. Therefore, in the future, larger samples and randomized controlled trials are needed to evaluate the efficacy of different treatment regimens.

Peripheral Blood and Cerebrospinal Fluid Levels of YKL-40 in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

The pathogenesis associated with Alzheimer's disease (AD) is particularly complicated, and early diagnosis and course monitoring of the disease are not ideal based on the available core biomarkers. As a biomarker closely related to neuroinflammation, YKL-40 provides a potential scalable approach in AD, but its association remains controversial and inconclusive with AD. We conducted this study to assess the utility of YKL-40 levels in peripheral blood and cerebrospinal fluid (CSF) of AD patients and healthy controls (HCs) by meta-analysis. We systematically searched and screened relevant trials for comparing YKL-40 levels between AD patients and HCs in PubMed, Embase, Cochrane, and Web of Science, with a search deadline of 14 March 2023 for each database. A total of 17 eligible and relevant studies involving 1811 subjects, including 949 AD patients and 862 HCs, were included. The results showed that YKL-40 levels in the peripheral blood of AD patients and HCs did not possess significant differences. Subgroup analysis showed YKL-40 significantly differed in plasma (SMD = 0.527, 95%CI: [0.302, 0.752]; p = 0.000), but did not in serum. In the case of comparison with HCs, YKL-40 was significantly higher in CSF of AD patients (SMD = 0.893, 95%CI: [0.665, 1.121]; p = 0.000). Besides that, when we performed a combined analysis of total YKL-40 in both peripheral blood and CSF, overall YKL-40 concentrations were also significantly increased among AD patients (SMD = 0.608, 95%CI: [0.272, 0.943]; p = 0.000). YKL-40 provides support and rationale for the neuroinflammatory pathogenesis of AD. The significance of CSF levels of YKL-40 for early screening of AD is definite. Plasma levels of YKL-40 also appear to assist in discriminating AD patients from HCs, which facilitates early screening and monitoring of the natural course of AD.

An AS-qPCR-based method for the detection of Alzheimer's disease-related SNPs.

Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases in the world and has a strong genetic predisposition. At present, there is still no effective method for the early diagnosis and prevention of AD. Accumulating evidence shows the association of several loci with AD risk, such as apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 (TOMM40). However, for routine disease diagnosis in clinics, genotype detection methods based on gene sequencing technology are time-consuming and excessively costly. Thus, in this study, we developed a high-sensitivity, low-cost, and convenient single nucleotide polymorphism (SNP) detection assay method based on allele-specific quantitative polymerase chain reaction (AS-qPCR) technology, which can be used to determine the SNP genotype in APOE and TOMM40. A total of 40 patients were recruited from the outpatient department of the memory clinic of Dongzhimen Hospital, Beijing University of Chinese Medicine. The SNP detection assay method includes three steps. First, positive plasmids with different genotypes (TT/CC/TC) in APOE rs429358, rs7412, and TOMM40 rs11556505 were prepared. Second, 3'-T/3'-C primers were designed to amplify these positive plasmids for each SNP site. Finally, we calculated the log10 of the copy number ratio for each positive plasmid, and the genotype interpretation interval was established. Based on this method, we investigated whether the SNPs in 40 patients could be accurately calculated using AS-qPCR technology. The accuracy of SNP detection was verified by PCR-Pooling sequencing. The results showed that SNP genotypes assessed by AS-qPCR technology corresponded perfectly to the results obtained by conventional DNA sequencing. We have developed a genotype detection method for AD based on AS-qPCR, which can be performed easily, rapidly, accurately, and at low cost. The method will contribute to the early diagnosis of patients with late-onset Alzheimer's and the detection of large clinical samples in the future.

Peripheral high levels of CRP predict progression from normal cognition to dementia: A systematic review and meta-analysis.

OBJECTIVE: Several cross-sectional studies have demonstrated a relationship between inflammation and dementia. Uncertainty exists over the ability of C-reactive protein (CRP), one of the most investigated markers of inflammation, to predict the progression of normal cognition to dementia. A systematic review and meta-analysis were performed to assess whether high peripheral levels of CRP are associated with cognitive impairment and whether CRP is a risk factor for predicting progression from normal cognition to cognitive decline or dementia. METHODS: Literature published before November 2022 was retrieved from PubMed, Embase, and Web of Science. Prospective cohort studies that employed recognized evaluation instruments to assess global cognitive function or used accepted diagnostic criteria to ascertain dementia were selected. Subgroup analysis was conducted on specific cognitive domains and causes of dementia (i.e., Alzheimer's disease and vascular dementia). Odds ratios (ORs) and hazard ratios (HRs) were extracted and merged to facilitate data analysis. A random-effects model was used for the meta-analysis and a descriptive analysis of the data that could not be merged was conducted. RESULTS: A total of 13 articles (14 cohort studies) were included for meta-analysis and six articles were included for descriptive analysis. The results showed that high CRP levels were not related to future cognitive decline (OR = 1.115; 95 % CI: 0.830-1.497; p = 0.469) but were associated with an increased risk of conversion to dementia. (HR = 1.473; 95 % CI: 1.037-2.090; p = 0.0394). This association persisted after full adjustment for potential covariates, with an OR of 1.044 (95 % CI:0.767-1.421, p = 0.785) for cognitive decline and an HR of 1.429 (95 % CI:1.088-1.876, p = 0.010) for dementia. The subgroup analysis showed that a higher level of CRP was related to a decline in visual-spatial ability (OR = 1.402, 95 % CI: 1.045-1.882, p = 0.024) and the risk of conversion to vascular dementia (total effect size of OR and HR = 2.769, 95 % CI: 1.586-4.83, p = 0.000). CONCLUSIONS: Higher CRP levels as an indicator of chronic systemic inflammation cannot predict future cognitive decline but may indicate a higher risk of conversion to dementia.

Polygala tenuifolia and Acorus tatarinowii in the treatment of Alzheimer's disease: a systematic review and meta-analysis.

Background: The complexity of Chinese medicine treatment for Alzheimer's disease (AD) utilizing a multi-herb therapy makes the evidence in current studies insufficient. Herb pairs are the most fundamental form of multi-herb formulae. Among the Chinese herbal formulas for AD treatment, Polygala tenuifolia (PT) and Acorus tatarinowii (AT) appeared as the most commonly used herbal pairs in combination. Objective: The aim of this study is to evaluate the clinical efficacy and safety of the combination of PT and AT in the treatment of AD. Methods: We systematically searched and screened randomized controlled trials of pairing PT and AT for the treatment of AD patients in eight databases with a search deadline of June 26, 2023. Authors, year of publication, title, and basic information such as subject characteristics (age, sex, and race), course of disease, control interventions, dose, and treatment duration were extracted from the screened studies. Primary outcomes assessed included mini-mental state examination (MMSE), activities of daily living (ADL), and AD assessment scale-cognitive subscale (ADAS-cog), while secondary outcomes included efficiency and adverse events. The quality of the included studies was assessed using the Cochrane risk of bias tool. The mean difference with 95% confidence intervals (MD [95% CI]) and risk ratio (RR) was selected as the effect size, and the data were analyzed and evaluated using RevMan 5.4 and Stata 16. Results: A total of sixteen eligible and relevant studies involving 1103 AD participants were included. The combination of PT and AT plus conventional drugs was superior to single conventional drugs in MMSE [MD = 2.57, 95%CI: (1.44, 3.69); p < 0.00001; I 2 = 86%], ADL [MD = -3.19, 95%CI: (-4.29, -2.09); p < 0.00001; I 2 = 0%], and ADAS-cog scores [MD = -2.09, 95%CI: (-3.07, -1.10); p < 0.0001; I 2 = 0%]. The combination of PT and AT plus conventional drugs had a significantly more favorable benefit in clinical effectiveness [RR = 1.27, 95%CI: (1.12, 1.44); p = 0.0002; I 2 = 0%]. Adverse events were not increased with the combination of PT and AT plus conventional drugs compared to conventional drugs [RR = 0.65, 95%CI: (0.35, 1.19); p = 0.16; I 2 = 0%]. The experimental group treated with the combination of PT and AT alone for AD was comparable in MMSE, ADL, and ADAS-cog scores compared with the control group treated with single conventional drugs. Conclusion: Compared to single conventional drugs, the combination of PT and AT may be used as an alternative therapy to improve global cognition and functioning in AD, and the combination of PT and AT as adjunctive therapy appears to produce a better therapeutic response to AD in terms of efficacy without increasing the risk of adverse events. However, the very low to low quality of available evidence limits confidence in the findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023444156.

Effect of hearing aids on cognitive functions in middle-aged and older adults with hearing loss: A systematic review and meta-analysis.

Objective: The study aimed to examine the effects of hearing aids on cognitive function in middle-aged and older adults with hearing loss. Data sources and study selection: PubMed, Cochrane Library, and Embase were searched for studies published before 30 March 2022. Randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) were included in the search. Restriction was set on neither types, severity, or the time of onset of hearing impairment nor cognitive or psychiatric statuses. Data extraction and synthesis: Two independent reviewers extracted data and assessed the study quality of RCTs. Cognitive function outcomes were descriptively summarized and converted to standardized mean difference (SMD) in the meta-analysis. Meta-analysis was conducted in RCTs. Sub-group analyses were conducted by cognitive statuses, psychiatric disorders, and cognitive domains. Results: A total of 15 studies met the inclusion criteria, including five RCTs (n = 339) and 10 NRSIs (n = 507). Groups were classified as subjects without dementia or with normal global cognition, subjects with AD or dementia, and subjects with depressive symptoms. For subjects without dementia, improvements were found in global cognition, executive function, and episodic memory. For subjects with depressive symptoms, improvements were found in immediate memory, global cognition, and executive function. No improvement was found in subjects with AD or dementia. In total, four RCTs were included in the meta-analysis. For subjects without dementia (SMD = 0.11, 95% confidence interval [CI]: -0.15-0.37) and those with AD, no significant effect was found (SMD = -0.19, 95% CI: -0.65-0.28). For subjects without dementia, no significant effect was found in language (SMD = 0.14, 95% CI: -0.30-0.59) or general executive function (SMD = -0.04, 95% CI: -0.46-0.38). Further sub-group analysis found no significant effect in executive function (SMD = -0.27, 95% CI: -0.72-0.18) or processing speed (SMD = -0.02, 95% CI: -0.49-0.44). Conclusion: Hearing aids might improve cognitive performance in domains such as executive function in subjects without dementia. The effects on subjects with depressive symptoms remained unclear. No improvement was found in subjects with AD or dementia. Long-term RCTs and well-matched comparison-group studies with large sample sizes are warranted. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022349057.

Plasma ß-amyloid, tau, neurodegeneration biomarkers and inflammatory factors of probable Alzheimer's disease dementia in Chinese individuals.

Background: Plasma-derived ß-amyloid, tau, and neurodegeneration (ATN) biomarkers can accurately diagnose Alzheimer's disease (AD) and predict its progression. Few studies have investigated the relationship between plasma biomarkers and changes in plasma inflammatory markers in clinically diagnosed AD. Methods: Seventy-four participants were recruited, including 30 mild-to-moderate AD dementia patients and 44 normal controls (NC). All participants underwent neuropsychological testing and blood sampling for biomarker testing. AD was clinically diagnosed according to the National Institute on Aging-Alzheimer's Association (NIA-AA) core criteria and required age-mismatched hippocampal atrophy. We performed Single Molecule Array (Simoa), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA), to examine plasma ATN markers, including ß-amyloid (Aß) 40, Aß42, p-tau181, total (t)-tau, neurofilament protein light chain (NfL), and inflammatory factors (TNF-α, IL-1ß, IL-6, and IL-8). Results: The level of the plasma Aß42/Aß40 ratio was significantly declined and the levels of the plasma p-tau181, NfL and TNF-α were significantly higher in the AD group than the NC group, but there was no significant difference in the levels of plasma t-tau, IL-1ß, IL-6, and IL-8 between the AD and NC groups. The levels of plasma p-tau181, NfL, Aß42/Aß40 ratio, and TNF-α were all associated with impairments in multiple cognitive domains. Among them, the plasma Aß42/Aß40 ratio, and the p-tau181 and TNF-α levels were associated with impairments in global cognition, memory, and visuospatial abilities, but not with executive function, only plasma NfL level was associated with executive function. Plasma NfL showed higher diagnostic performance in AD than in NC individuals (AUC = 0.833). A combined diagnostic prediction model of plasma Aß42/Aß40 ratio, p-tau 181, and NfL had the highest value than each factor alone (AUC = 0.902),with a sensitivity and specificity of 0.867 and 0.886, respectively. Conclusion: The levels of plasma ATN biomarkers (Aß42/Aß40 ratio, p-tua181, and NfL) were significantly changed in clinically diagnosed AD patients and they all associated with different domains of cognitive impairment. Plasma ATN biomarkers better differentiate mild-to-moderate AD dementia from NC when they are incorporated into diagnostic models together rather than individually. Plasma ATN biomarkers have the potential to be a screening tool for AD. However, the expression of inflammatory factors in AD patients requires further research.

Plasma repressor element 1-silencing transcription factor levels are decreased in patients with Alzheimer's disease.

BACKGROUND: Repressor element 1-silencing transcription (REST)/neuron-restrictive silencer factor is considered a new therapeutic target for neurodegenerative disorders such as Alzheimer's disease (AD). However, the relationship between AD and REST remains unclear. This study aimed to 1) examine plasma REST levels and REST gene levels in AD patients and 2) further explore the pathological relationships between REST protein levels and cognitive decline in clinical conditions, including medial temporal lobe atrophy. METHODS: Participants (n = 252, mean age 68.95 ± 8.78 years) were recruited in Beijing, China, and then divided into a normal cognition (NC) group (n = 89), an amnestic mild cognitive impairment (aMCI) group (n = 79), and an AD dementia group (n = 84) according to diagnostic criteria. All participants underwent neuropsychological assessments, laboratory tests, and neuroimaging scans (magnetic resonance imaging) at baseline. Plasma REST protein levels and the distribution of REST single nucleotide polymorphisms (SNPs) were compared among the three groups. Correlations between cognitive function, neuro-imaging results, and REST levels were determined by a multivariate linear regression analysis. RESULTS: The plasma REST levels in both the NC group (430.30 ± 303.43)pg/ml and aMCI group (414.27 ± 263.39)pg/ml were significantly higher than that in the AD dementia group (NC vs AD dementia group, p = 0.034; aMCI vs AD dementia group, p = 0.033). There was no significant difference between the NC and aMCI groups (p = 0.948). No significant difference was found among the three groups regarding the genotype distribution (rs2227902 and rs3976529 SNPs) of the REST gene. The REST level was correlated with the left medial temporal lobe atrophy index (r = 0.306, p = 0.023). After 6 months of follow-up, the REST level in the NC group was positively correlated with the change in the Mini-Mental State Examination score (r = 0.289, p = 0.02). CONCLUSION: The plasma REST protein level is decreased in AD dementia patients, which is associated with memory impairment and left temporal lobe atrophy and may have potential value for clinical diagnosis of AD dementia.

The Correlation Between Olfactory Test and Hippocampal Volume in Alzheimer's Disease and Mild Cognitive Impairment Patients: A Meta-Analysis.

Background: Previous studies have reported that olfactory identification deficits may be the earliest clinical features of Alzheimer's disease (AD). However, the association between odor identification and hippocampal atrophy remains unclear. Objective: This meta-analysis quantified the correlation between odor identification test scores and hippocampal volume in AD. Method: A search of the PUBMED, EMBASE, and WEB OF SCIENCE databases was conducted from January 2003 to June 2020 on studies with reported correlation coefficients between olfactory identification score and hippocampal volume in patients with amnestic AD or mild cognitive impairment (MCI). The quality of the studies was assessed using the Newcastle-Ottawa quality assessment scale (NOS). Pooled r-values were combined and computed in R studio. Results: Seven of 627 original studies on AD/MCI using an olfactory identification test (n = 902) were included. A positive correlation was found between hippocampal volume and olfactory test scores (r = 0.3392, 95% CI: 0.2335-0.4370). Moderator analysis showed that AD and MCI patients were more profoundly correlated than normal controls (AD: r = 0.3959, 95% CI: 0.2605-0.5160; MCI: r = 0.3691, 95% CI: 0.1841-0.5288; NC: r = 0.1305, 95% CI: -0.0447-0.2980). Age difference and patient type were the main sources of heterogeneity in this analysis. Conclusion: The correlation appears to be more predominant in the cognitive disorder group (including MCI and AD) than in the non-cognitive disorder group. Age is an independent factor that affects the severity of the correlation during disease progression. The mildness of the correlation suggests that olfactory tests may be more accurate when combined with other non-invasive examinations for early detection. Systematic Review Registration: https://inplasy.com/, identifier INPLASY202140088.

Assessment of the Psychological Burden Among Family Caregivers of People Living with Alzheimer's Disease Using the Zarit Burden Interview.

BACKGROUND: In China, family caregivers play a major role in caring for people living with Alzheimer's disease (PLWAD), but little is known about the burden this creates. OBJECTIVE: This study aimed to investigate the burden among family caregivers of PLWAD and the factors influenced it. METHODS: Family caregivers of PLWAD were recruited from a hospital in China from January 2018 to July 2018. All data were collected online using the Chinese version of the Zarit Burden Interview (ZBI), and the participants' sociodemographic and caregiving details were obtained. T-tests and Kruskal-Wallis H (K) tests were used to compare ZBI scores between groups. Factors related to the caregiver psychological burden were analyzed using multiple linear regression analysis. RESULTS: A total of 300 participants were assessed, of which 213 (71.00%) were female. More than half of the caregivers were the patient's daughter (51.0%, n = 153). The average ZBI score of the caregivers was 43.05 (13.42). The level of burden was influenced by age, the relationship of the caregiver to the patient, the severity of AD, the caregiver's retirement status, the income level of the caregiver, and the caring time. Regression analysis showed that retired caregivers were more likely to have higher levels of burden and that burden increased with AD severity. CONCLUSION: Most family caregivers of PLWAD have a considerable caregiver psychological burden. The findings increase the understanding of factors that influence family caregiver burden, and pave the way for potential interventions, such as social support and caregiver empowerment, to reduce their burden.

Clinical Features and Therapeutic Effects of Anti-leucine-rich Glioma Inactivated 1 Encephalitis: A Systematic Review.

Background: Clinical presentations and treatment programs about anti-leucine-rich glioma inactivated 1 (LGI1) encephalitis still remain incompletely understood. Objective: This study analyzed the clinical features and therapeutic effects of anti-LGI1 encephalitis. Methods: PubMed, EMBASE, and the Cochrane Library were searched to identify published English and Chinese articles until April 2021. Data were extracted, analyzed, and recorded in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 80 publications detailing 485 subjects matched our inclusion criteria. Short-term memory loss (75.22%), faciobrachial dystonic seizures (FBDS) (52.53%), other seizures excluding FBDS (68.48%), psychiatric symptoms (57.67%), and sleep disturbances (34.30%) were the most frequently described symptoms in anti-LGI1 encephalitis. Hyponatremia (54.90%) was the most common hematologic examination change. The risk of incidence rate of malignant tumors was higher than in healthy people. The positive rate of anti-LGI1 in serum (99.79%) was higher than CSF (77.38%). Steroids (93.02%), IVIG (87.50%), and combined use (96.67%) all had a high remission rate in the initial visit. A total of 35 of 215 cases relapsed, of which 6/35 (17.14%) did not use first-line treatment, and 21 (60.00%) did not maintain long-term treatment. Plasma exchange (PE) could be combined in severe patients, immunosuppressant could be used for refractory patients or for recurrence and using an anti-epileptic drug to control seizures may benefit cognition. Conclusions: Short-term memory loss, FBDS, psychiatric symptoms, and hyponatremia were key features in identifying anti-LGI1 encephalitis. Serum and CSF antibody tests should be considered in diagnosis criteria. Steroids with IVIG should be recommended, PE was combined for use in severe patients, immunosuppressant therapy might improve outcomes if recurrence or progression occurred, and control seizures might benefit cognition. The useful ways to reduce relapse rate were early identification, clear diagnosis, rapid treatment, and maintaining long-term treatment. The follow-up advice was suggested according to the research of paraneoplastic syndrome, and concern about tumors was vital as well.

Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial.

BACKGROUND AND PURPOSE: Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT). METHODS: A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician's Interview-based Impression of Change-plus caregiver information (CIBIC-plus). RESULTS: A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found. CONCLUSIONS: TZ and donepezil could bring symptomatic benefit for mild to moderate VaD. Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1.

Increased substantia nigra echogenicity correlated with visual hallucinations in Parkinson's disease: a Chinese population-based study.

As a noninvasive technique, transcranial sonography (TCS) of substantia nigra (SN) has gradually showed its effectiveness not only in diagnosis but also in understanding clinical features of Parkinson's Disease (PD). This study aimed to further evaluate TCS for clinical diagnosis of PD, and to explore the association between sonographic manifestations and visual hallucinations (VH). A total of 226 subjects including 141 PD patients and 85 controls were recruited. All participants received TCS. A series of rating scales to evaluate motor and non-motor symptoms were performed in PD patients. Results showed that 172 subjects were successfully assessed by TCS. The area of SN was greater in PD patients than that in controls (P < 0.001). As receiver-operating characteristic (ROC) curve analysis showed, the best cutoff value for the larger SN echogenicity size was 23.5 mm2 (sensitivity 70.3%, specificity 77.0%). Patients with VH had larger SN area (P = 0.019), as well as higher Non-Motor Symptoms Scale (NMSS) scores (P = 0.018). Moreover, binary logistic regression analysis indicated that SN hyperechogenicity (odds ratio = 4.227, P = 0.012) and NMSS scores (odds ratio = 0.027, P = 0.042) could be the independent predictors for VH. In conclusion, TCS can be used as an auxiliary diagnostic tool for Parkinson's disease. Increased SN echogenicity is correlated with VH in Parkinson's disease, possibly because the brain stem is involved in the mechanism in the onset of VH. Further studies are needed to confirm these findings.

Chinese herbal medicine Qinggongshoutao for the treatment of amnestic mild cognitive impairment: A 52-week randomized controlled trial.

INTRODUCTION: This randomized, double-blind trial aimed to test effect of a Chinese herbal medicine, Qinggongshoutao (QGST) pill, on the cognition and progression of amnestic mild cognitive impairment (aMCI). METHODS: Patients with aMCI were randomly assigned to receive QGST, Ginkgo biloba extract, or placebo for 52 weeks. The primary outcome measures were progression to possible or probable Alzheimer's disease (AD) and change in Alzheimer's Disease Assessment Scale-cognitive subscale scores; secondary outcome measures included assessments for cognition and function. RESULTS: Total 350 patients were enrolled, possible or probable AD developed in 10. There were significant differences in the probability of progression to AD in the QGST group (1.15%) compared with placebo group (10%). There was significant difference in Alzheimer's Disease Assessment Scale-cognitive subscale scores in favor of QGST over the placebo group. Secondary outcome measure (Mini-Mental State Examination) also showed benefit in QGST at end point. DISCUSSION: In patients with aMCI, QGST showed lower AD progression rate than placebo at 8.85%, and may have benefit on global cognition.

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.

A new age-related cutoff of medial temporal atrophy scale on MRI improving the diagnostic accuracy of neurodegeneration due to Alzheimer's disease in a Chinese population.

BACKGROUND: Visual rating scales are still the most popular tools in assessing atrophy degrees of whole brain and lobes. However, the false negative rate of the previous cutoff score of visual rating scales was relatively high for detecting dementia of Alzheimer's type (DAT). This study aimed to evaluate the diagnostic value of new cutoffs of visual rating scales on magnetic resonance imaging for discriminating DAT in a Chinese population. METHODS: Out of 585 enrolled subjects, 296 participants were included and diagnosed as normal cognition (NC)(n = 87), 138 diagnosed as amnestic mild cognitive impairment (aMCI), and 71 as dementia of Alzheimer's type (DAT). Receiver operating characteristic (ROC) curve analyses were used to calculate the diagnostic value of visual rating sales (including medial temporal atrophy (MTA), posterior atrophy rating scale (PA),global cortical atrophy scale (GCA) and medial temporal-lobe atrophy index (MTAi))for detecting NC from DAT . RESULTS: Scores of MTA correlated to age and Mini-mental state examination score. When used to detect DAT from NC, the MTA showed highest diagnostic value than other scales, and when the cutoff score of 1.5 of MTA scale, it obtained an optimal sensitivity (84.5%) and specificity (79.1%) respectively, with a 15.5% of false negative rate. Cutoff scores and diagnostic values were calculated stratified by age. For the age ranges 50-64, 65-74, 75-84 years, the following cut-offs of MTA should be used, ≥1.0(sensitivity and specificity were 92.3 and 68.4%), ≥1.5(sensitivity and specificity were 90.4 and 85.2%), ≥ 2.0(sensitivity and specificity were 70.8 and 82.3%) respectively. All of the scales showed relatively lower diagnostic values for discriminating aMCI from NC. CONCLUSIONS: The new age-based MTA cutoff showed better diagnostic accuracy for detecting DAT than previous standard, the list of practical cut-offs proposed here might be useful in clinical practice.

The influence of GAPT extraction on synapse loss of APPswe/PS1dE9 transgenic mice via adjusting Bcl-2/Bax balance.

INTRODUCTION: The degeneration of memory-focused synapses play important roles in Alzheimer's disease (AD) pathogenesis, while it is not well known how ß amyloid interferes neuron apoptosis and how a herbal combination GAPT influence synapse loss and neuronal apoptosis pathways of APP/PS1 transgenic mice. METHODS: Three-month and six-month APPswe/PS1dE9 transgenic mice were used. Spatial and memory ability were measured by Morris Water Maze, Neuron and synapse number were assessed by electron microscope; Aß, Bcl-2/Bax were determined by immunohistochemistry and western blot. RESULTS: APP/PS1 mice not only had increased Aß accumulation, impaired memory performance, less synapse number, and much more necrosed neurons, but also had significant reduction in the Bcl-2/Bax ratio. However, GAPT and donepezil showed improved memory performance, less Aß accumulation, increased neuron and synapse number, as well as restored balance of Bcl-2/Bax. DISCUSSION: GAPT may improve cognitive functions via both reducing Aß deposition and restoring Bcl-2/Bax balance of neuron.