Assessment of the effects of AZD3480 on cognitive function in patients with schizophrenia

AZD3480 is a selective agonist of α4β2 central neuronal nicotinic receptors (NNRs). This study investigated its effects on cognition, relative to placebo, in 440 patients with stable schizophrenia who were taking a single atypical antipsychotic medication and who were active cigarette smokers. Mean age was 41 (range 19 to 55) years and the majority of patients (88%) had a diagnosis of paranoid schizophrenia. Patients were randomized to one of 3 doses of AZD3480: 5 mg, 20 mg, and 35/100 mg (depending on CYP2D6 metabolic status), or to placebo. Treatment was given once daily for 12 weeks. The primary outcome measure was change in cognitive function from baseline to Week 12, as measured by IntegNeuro computerized test battery of cognitive function scores. Secondary outcome measures included assessment of functional capacity (University of California at San Diego Performance Based Skills Assessment [UPSA2]) and adaptive function (Social Functioning Scale [SFS]). AZD3480 failed to improve cognition relative to placebo in this population of patients or in subpopulations defined by disposition, metabolic status, antipsychotic treatment, age, age of illness onset, and sex. Likewise, no improvement relative to placebo was observed in either the SFS measure of adaptive functioning or the UPSA2 measure of functional capacity. AZD3480 was generally well tolerated in the population studied.     

Reviews: Effects of transdermal rivastigmine on ADAS-cog items in mild-to-moderate Alzheimer's disease

Alzheimer's disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD.     

Domain-specific improvement of cognition on memantine in patients with Alzheimer's disease treated with rivastigmine

OBJECTIVE: Cholinergic therapy is used in mild-to-moderate Alzheimer's disease (AD) and antiglutamatergic therapy in moderate-to-severe AD. Global scales, as commonly used in clinical trials, blur specifics of disease progression and drug effects. The objective was to assess combination therapy of rivastigmine plus memantine by specific neuropsychological tests in patients with mild-to-moderate AD. METHODS: 12-week-short multicenter open-label pilot study. Ninety patients with mild-to-moderate AD already on stable medication with rivastigmine (3-6 mg b.i.d.) additionally received memantine for 12 weeks. Subscales of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE) and additional neuropsychological tests (e.g. span tasks, semantic fluency) were assessed. RESULTS: The scores in the ADAS-cog memory subscale, the MMSE score, and digit span and semantic fluency significantly improved on combination therapy. CONCLUSION: Memory improvement was correlated with ADAS-cog memory score at baseline and inversely with age at onset of treatment. The data suggest that improvement on combination therapy results from an improvement of attention/executive function with secondary memory improvement, which will need to be confirmed in a subsequent double-blind study on a larger number of patients.     

Uncinate fasciculus-correlated cognition in Alzheimer's disease: a diffusion tensor imaging study by tractography

Background: Neuroimaging studies show increased diffusivity and decreased anisotropy in Alzheimer's disease (AD) patients by diffusion tensor imaging (DTI). Previous reports have analyzed a correlation with cognitive function and DTI parameters, but their results are inconsistent. A reason for this might be a region of interest (ROI) method, used to calculate parameters for DTI, because this method has various usages of how to place a ROI and includes summations of values for various neuronal fiber tracts, resulting in contamination of unintended fibers. To improve the instability with ROI placement, a tractography‐based method might be useful. Our coworker reported decreased fractional anisotropy (FA) and increased apparent diffusion coefficient (ADC) of uncinate fasciculus (UF) in patients with AD by tractography. To confirm whether DTI parameter values are related to severity of cognitive function in patients with AD, we measured mean diffusion anisotropy and diffusivity of coregistered voxels along the tracking lines (i.e. tract of interest) of UF. Methods: The subjects were 30 patients with probable AD (NINCDS‐ADRDA criteria). Assessment of cognitive function was carried out according to the Mini‐Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale‐cognitive component‐Japanese version (ADAS‐Jcog). A 1.5‐T clinical magnetic resonance unit was used to obtain diffusion tensor images. Diffusion tensors were computed and fiber‐tract maps were created using ‘dTV II’ DTI software developed by Masutani et al. We measured mean FA and ADC values along the bilateral UF. Results: FA values were positively correlated with MMSE score (r= 0.67) and were negatively correlated with ADAS‐Jcog score (r=?0.62), while ADC values were negatively correlated with MMSE score (r=?0.58) and were positively correlated with ADAS‐Jcog score (r= 0.59). Conclusion: FA and ADC values might reflect the severity of cognitive dysfunction. The tract‐of‐interest method might be a useful tool for objectively evaluating DTI parameters in AD.     

Improved cognition in Alzheimer's disease with short-term D-cycloserine treatment

OBJECTIVE: Glutamatergic neurotransmission is important for memory and cognition and is severely affected in Alzheimer's disease. D-Cycloserine exhibits partial agonist activity at the glycine site of N-methyl-D-aspartate subtype glutamate receptor, facilitating activation of the receptor and improving cognition and memory. METHOD: Seventeen patients with Alzheimer's disease received a three-phase, double-blind, placebo-controlled trial of 50 mg and 100 mg/day of D-cycloserine. RESULTS: D-Cycloserine was associated with significant improvement in scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (improvement of 3.0 points) when given at a dose of 100 mg/day. CONCLUSIONS: D-Cycloserine has cognitive benefits for patients with Alzheimer's disease.     

The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis

Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.     

Humour therapy in patients with late-life depression or Alzheimer's disease: a pilot study

BACKGROUND: Of the disabling disorders of the elderly, depression is the most common affective disorder and Alzheimer's disease (AD) the most common neurodegenerative disorder. Pharmacological treatment strategies for these disorders are often accompanied with severe side effects. Therefore non-pharmacological treatment strategies are of great importance. The aim of the present study was to investigate the impact of humour therapy on quality of life in patients with depression or AD. METHODS: Twenty patients with late-life depression and 20 patients with AD were evaluated. Ten patients in each group underwent a humour therapy group (HT) once in two weeks for 60 min in addition to standard pharmacotherapy, which was given as usual to the other group as standard therapy (ST). All patients completed a psychometric test battery at admission and before discharge from the clinic. RESULTS: The quality of life scores improved both in HT and ST groups for depressive patients but not for patients with AD irrespective of the therapy group. Depressive patients receiving HT showed the highest quality of life after treatment. In addition, patients with depression in both therapy groups showed improvements in mood, depression score, and instrumental activities of daily living. CONCLUSIONS: Although there was no significant effect of humour therapy comparing with standard therapy on quality of life, these findings suggest that humour therapy can provide an additional therapeutic tool. Further studies with higher frequently humour groups are required in order to investigate the impact of humour therapy in gerontopsychiatric treatment.     

Factors associated with mortality in patients with early-onset Alzheimer's disease: a five-year longitudinal study

To identify neuropsychiatric and somatic factors related to survival in early-onset Alzheimer's disease, we longitudinally studied 108 patients (35 male, 73 female) with early-onset Alzheimer's disease who were 46 to 64 years old at onset and 50 to 69 years old when diagnosed at our institution. A five-year follow-up, 30 patients had died. Pneumonia was the most common cause (73%), followed by malignancy (20%) and heart disease (7%). Kaplan-Meier survival curves showed a lower survival rate in patients with early-onset Alzheimer's disease than in age- and sex-matched life-table data in Japan. In Cox proportional hazards analysis, male gender, early disease onset, concurrent physical illness at time of diagnosis, and a low mini-mental state examination score increased the likelihood of death in patients with early-onset Alzheimer's disease. Our study confirmed that these patients have considerable excess mortality and a different pattern of cause of death than in the general population. Gender, age at onset, physical illness, and cognitive function strongly influenced survival. These factors may be predictors of mortality in patients with early-onset Alzheimer's disease that are useful in counseling patients and their families.     

Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer's disease: a pilot study

BACKGROUND: Vagus nerve stimulation (VNS) is an established treatment method for therapy-refractory epilepsy and, in Europe, for treatment-resistant depression also. Clinical and experimental investigations have also shown positive effects of VNS on cognition in epilepsy and depression. The purpose of the present pilot study was to investigate the effect of VNS on cognition in patients with Alzheimer's disease. METHOD: All the included patients (N = 10) met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for the diagnosis of Alzheimer's disease. Before the implantation of the vagus stimulator (NeuroCybernetic Prosthesis), the patients underwent neuropsychological tests (e.g., Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-cog] and Mini-Mental State Examination [MMSE]), computerized tomography of the brain, medical/neurologic and psychological examinations (status evaluation), and lumbar puncture with investigation of the cerebrospinal fluid. The presence of depressive symptoms was rated using the Montgomery-Asberg Depression Rating Scale. The VNS was initiated 2 weeks after the implantation, and the patients were followed up with regular investigations and tests over 6 months. Response was defined as improvement or absence of impairment in ADAS-cog and MMSE scores after 3 and 6 months. RESULTS: After 3 months of treatment, 7 of 10 patients were responders according to the ADAS-cog (median improvement of 3.0 points), and 9 of 10 patients were responders according to the MMSE (median improvement of 1.5 points). After 6 months of treatment, 7 patients were responders on the ADAS-cog (median improvement of 2.5 points), and 7 patients were responders on the MMSE (median improvement of 2.5 points). VNS was well tolerated, and its side effects were mild and transient. CONCLUSION: The results of this open-label pilot study suggest a positive effect of VNS on cognition in patients with Alzheimer's disease. Further studies are warranted.     

Volume reduction in cerebral blood flow in patients with Alzheimer's disease: a sonographic study

Neuroimaging techniques such as PET and SPECT demonstrated a consistent reduction of cerebral blood flow (CBF) in Alzheimer's disease (AD). The aim of the study was to assess the potential role of ultrasonography for CBF measurement in AD patients and whether the CBF volume correlates positively with disease severity. Fifty patients who met the diagnostic criteria of probable AD (NINDS-ADRDA) were compared to 50 age-matched healthy elderly volunteers. The extracranial internal carotid arteries (ICAs) and the vertebral arteries (VAs) of the patients and controls were examined. Angle-corrected time-averaged flow velocity (TAV) and the diameter of the vessel were measured. Intravascular flow volumes were calculated as the product of TAV and the cross-sectional area of the circular vessel. CBF volume was calculated as the sum of flow volumes in the ICAs and VAs of both sides. All subjects underwent the MMSE. The mean global CBF (474.87 +/- 94.085 vs. 744.26 +/- 94.082 ml/min; p < 0.0001) was lower in AD patients than in healthy volunteers. A significant decline in global flow volumes (r = 0.48; p < 0.0007) with the degree of cognitive impairment was also present. The ability of ultrasonography to characterize flow decreases makes such a technique an attractive tool for the study of AD, for the evaluation of pharmacological therapies and, possibly, for early diagnosis.     

褪黑素对Alzheimer病模型大鼠认知功能和海马tau蛋白过度磷酸化的影响

目的 研究褪黑素(MT)对Alzheimer病(AD)模型大鼠认知功能和海马tau蛋白过度磷酸化的影响.方法 给大鼠海马内注射凝聚态β-淀粉样蛋白(Aβ)25-35制作AD模型;MT组大鼠从制模前7 d至制模后19 d每日腹腔注射MT,AD组大鼠制模后腹腔注射生理盐水;用Morris水迷宫试验检测大鼠的认知功能,银染法观察海马神经元形态,免疫组化法观察过度磷酸化tau蛋白的表达,并与正常对照组比较.结果 MT组大鼠Morris水迷宫试验结果明显好于AD组(均P＜0.001);海马CA1区磷酸化tau蛋白阳性细胞数(60.0±2.3)明显少于AD组(98.4±3.0)(P＜0.001),与正常对照组比较差异无统计学意义;海马CA1区神经元纤维形态较AD组规则.结论 MT可明显改善AD大鼠的认知功能,并且抑制海马tau蛋白的过度磷酸化.     

Associations between physical function,dual-task performance and cognition in patients with mild Alzheimer's disease

Objective: Alzheimer's disease (AD) causes a gradual decline in cognition, limitations of dual-tasking and physical function leading to total dependence. Hence, information about the interaction between physical function, dual-task performance and cognition may lead to new treatment strategies with the purpose of preserving function and quality of life.

The objective of this study was to investigate the associations between physical function, dual-task performance and cognition in community-dwelling patients with mild AD.

Methods: Baseline results from 185 participants (50–90 years old) in the single blinded multicenter RCT ‘ADEX’ (Alzheimer's disease: the effect of physical exercise) were used.

Assessments included tests of physical function: 400-m walk test, 10-m walk test, Timed Up and Go test and 30-s chair stand test; dual-task performance, i.e., 10-m walk while counting backwards from 50 or naming the months backwards; and cognition, i.e., Mini Mental State Examination, Symbol Digit Modalities Test, the Stroop Color and Word Test, and Lexical verbal fluency test.

Results: Results in the 30-s chair stand test correlated significantly with all tests of cognition (r = .208–.242) while the other physical function tests only randomly correlated with tests of cognition. Results in the dual-task counting backwards correlated significantly with results in all tests of cognition (r = .259–.388), which accounted for 7%–15% of the variation indicating that a faster time to complete dual-task performance was associated with better cognitive performance.

Conclusion: The evidence of the associations between physical function, dual-task performance and cognition is important when creating new rehabilitation interventions to patients with mild AD.     

Bingo vs. physical intervention in stimulating short-term cognition in Alzheimer's disease patients

Past research has shown that pharmacological measures can enhance cognitive and functional capacities for patients with Alzheimer's disease, but may result in unacceptable side effects. Investigations using nonpharmacological treatments are limited. This study evaluates the therapeutic effect of the game of Bingo as cognitive stimulation, versus daily physical activity, on short-term memory, concentration, word retrieval, and word recognition. Informed consent was obtained from the designated representatives of 50 subjects from six community adult day care centers on Long Island. The results show that cognitive stimulation enhanced performance on the Boston Naming Test and a Word List Recognition Task; physical intervention, however, did not reach statistical significance. Thus, a simple cognitive activity such as Bingo can be of great value to the daily management of Alzheimer's patients.