A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease

Narasimhalu K, Effendy S, Sim CH, Lee JM, Chen I, Hia SB, Xue HL, Corrales MP, Chang HM, Wong MC, Chen CP, Tan EK. A randomized controlled trial of rivastigmine in patients with cognitive impairment no dementia because of cerebrovascular disease.
Acta Neurol Scand: 2010: 121: 217–224.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objectives – The safety and efficacy of early acetylcholinesterase inhibitors therapy in patients with cognitive impairment no dementia (CIND) after a cerebrovascular accident have not been examined. In this study, we investigated the safety and efficacy of rivastigmine in cognition, particularly executive function in patients with CIND because of cerebrovascular disease. Methods – This study was a 24‐week, double‐blind, randomized, placebo‐controlled trial of ischemic stroke patients seen at a tertiary hospital who had cognitive impairment no dementia because of cerebrovascular disease. The intervention was either rivastigmine or placebo up to 9 mg/day. The primary outcome of interest was mean change from baseline in the Ten‐Point Clock Drawing and Color Trails 1 and 2. Results – Fifty patients were randomized into rivastigmine (n = 25) and placebo (n = 25) arms. Patients in the rivastigmine group showed statistically significant improvement (1.70 vs 0.13, P = 0.02) on the animal subtask of the verbal fluency measure compared with placebo. There was also a trend (non‐significant) towards improvement in Color Trails II. Conclusions – In this pilot study, we demonstrated that rivastigmine was well tolerated in patients with CIND because of cerebrovascular disease and may potentially improve executive functioning.     

Effects of working memory training in patients with Parkinson's disease without cognitive impairment: A randomized controlled trial

ObjectiveTo determine the feasibility and evaluate effects of a computerized working memory (WM) training (WMT) in patients with Parkinson's Disease (PD) on cognitive and clinical outcomes.Methods76 patients with PD without cognitive impairment were randomized to either the WMT group (n = 37), who participated in a 5-week adaptive WMT, or a passive waiting-list control group (CG, n = 39). Patients underwent clinical and neuropsychological examination at baseline, after training, and at 3-months follow-up, with verbal WM and non-verbal WM as primary outcomes. Outcome assessors were blinded for group allocation.ResultsAll WMT participants completed the training successfully and reported high levels of motivation for and satisfaction with the training. Repeated-measures, linear mixed-effects models revealed positive training effects for the WMT group compared to the CG in verbal working memory with a small relative effect size 0.39 [95%CI 0.05; 0.76] for the 3-months follow-up only. No other reliable training effects in cognitive and clinical variables were found for either point of time.ConclusionsIn this randomized controlled trial, WMT was feasible and yielded some evidence for 3-months follow-up training gains in patients with PD. WMT might be an effective intervention to prevent cognitive decline in this patient group, however, more longitudinal studies with longer follow-up periods and more sensitive assessment tools will have to proof this concept.Trial registrationGerman Clinical Trials Register (DRKS00009379).     

无痴呆型血管性认知障碍患者执行功能损害特征分析

目的探讨无痴呆型血管性认知障碍（VCIND）患者执行功能损害的特征。方法采用语义与语音流畅试验、数字符号编码测验、连线测验、画钟测验和Stroop色词测验对43例VCIND患者和35名性别、年龄和文化程度相匹配的正常对照进行测试。结果与正常对照组相比,VCIND组患者计时类测验明显低于正常对照组（P＜0.01）,计分类测验中数字符号编码测验、语义与语音流畅试验低于正常对照组（P＜0.01）,其中Stroop色词测验计分（P＜0.05）。与正常对照组比较,VCIND组画钟测验评分无统计学意义（P〉0.05）。结论VCIND患者执行功能损害主要表现为转换障碍、工作记忆损害、知觉运动与信息处理速度减慢。     

脑小血管病患者伴发非痴呆血管性认知功能损害情况及尼莫地平疗效的研究

目的探讨脑小血管病(cerebral small vessel disease,SVD)不同亚型伴发非痴呆血管性认知功能损害的情况,评价尼莫地平对SVD的疗效。方法选择SVD患者118例,包括52例腔隙灶脑梗死(LI)和66例白质疏松(WML)患者。分别将LI组和WML组患者随机分组为治疗组(基础治疗加尼莫地平治疗)和对照组(基础治疗),进行6个月治疗。治疗前后对所有患者采用蒙特利尔认知评估量表(MoCA)、简易智能状态检查表(MMSE)、语义分类流畅测验(动物)、Stroop测验(计算错误数)、画钟试验、积木测验、数字广度顺背测验、数字符号测验、逻辑记忆亚测验和再生亚测验进行认知功能评价,并比较各组患者治疗前后认知功能评分。结果治疗前,LI组患者语义分类流畅测验(动物)、数字符号测验、逻辑记忆亚测验、视觉再生亚测验、MoCA、MMSE评分显著高于WML组患者,Stroop测验得分显著低于WML组患者。经过6个月治疗后,LI组和WML组患者中的对照组治疗前后各项认知功能评分均没有统计学差异(P>0.05)。LI组患者中治疗组MoCA、画钟试验和数字广度顺背测验得分升高,Stroop测验得分下降(均P<0.05);WML组患者中治疗组MoCA、MMSE、画钟试验、数字广度顺背测验和视觉再生亚测验得分升高,Stroop测验得分下降(均P<0.05)。结论 SVD两个亚型伴发非痴呆血管性认知功能损害情况不同,LI患者损害程度比WML患者轻。尼莫地平治疗可较好的改善患者的执行功能、视空间结构能力和注意力。     

A primary study of diffusion tensor imaging-based histogram analysis in vascular cognitive impairment with no dementia

Purpose

This study performed diffusion tensor imaging (DTI) histogram analysis and voxel-based analysis (VBA) to detect white matter (WM) damage in patients with vascular cognitive impairment with no dementia (VCIND) and to determine correlations between DTI histogram-derived measures and cognitive dysfunction in these patients.

Materials and methods

Among patients with subcortical ischemic vascular disease, 18 patients with VCIND were selected along with 18 age- and sex-matched cognitive-normal subjects. Both groups underwent magnetic resonance and DTI scans, and fractional anisotropy (FA) changes in VBA between the two groups were assessed. Further, mean diffusivity (MD) and FA histograms of WM and normal-appearing WM (NAWM) in each subject were evaluated.

Results

Compared to control, the VCIND group showed lower FA values throughout the brain. FA and MD histogram patterns of WM and NAWM were significantly different between the groups. Significant differences were found in all DTI histogram-derived measures, except in the mean FA peak height of WM and mean MD peak location of NAWM. Neuropsychological results (z-scores) were found to be significantly correlated with mean FA peak location, average MD, mean MD peak location of WM, and mean FA peak height, average MD, mean MD peak location of NAWM.

Conclusions

Results of VBA and diffusion tensor imaging-based histogram analysis suggest that VCIND patients have more severe damage in WM and NAWM than the control. Thus, the severity of damage in WM and NAWM may be related with cognitive dysfunction in VCIND patients, and DTI histogram analysis can help in further understanding VCIND.     

Abnormal functional connectivity in patients with vascular cognitive impairment, no dementia: a resting-state functional magnetic resonance imaging study

The functional connectivity (FC) method was used to investigate the changes in the resting state of patients with vascular cognitive impairment, no dementia (VCIND). Resting-state functional magnetic resonance images (fMRIs) were acquired from 16 patients with subcortical ischemic vascular disease (SIVD) who fulfilled the criteria for VCIND, as well as 18 age- and sex-matched subjects with SIVD with no cognitive impairment (control group). Posterior cingulate cortex connectivity was gathered by investigating synchronic low-frequency fMRI signal fluctuations with a temporal correlation method. Compared with the control group, the patients showed FC decrease in the left middle temporal gyrus, the left anterior cingulate/left middle frontal gyrus, the right caudate, the right middle frontal gyrus, and the left medial frontal gyrus/paracentral lobule. There were also some regions that showed increased connectivity. These regions included the right inferior temporal gyrus, the left middle temporal gyrus, the left precentral gyrus, and the left superior parietal lobule. Our findings revealed the change in resting-state patterns of neuronal activity in patients with VCIND. This change may be caused by subcortical white matter lesions that destroyed direct and indirect fiber tract connectivity across the cerebral white matter and influenced the cortical FC and hypoperfusion resulted from small vascular disease. The results of the increased connectivity may be evoked by the compensatory recruitment and plasticity mechanism. Our findings suggest that the simplicity and noninvasiveness of this method makes it a potential tool to help thoroughly understand the pathogenesis of VCIND.     

A shared decision-making communication training program for physicians treating fibromyalgia patients: effects of a randomized controlled trial

OBJECTIVE: Fibromyalgia syndrome (FMS) is a condition of chronic widespread pain that is difficult to control and is associated with strains in physician-patient interaction. Shared decision making (SDM) can be a potential solution to improve interaction. We evaluated the effects of an SDM intervention, including an SDM communication training program for physicians, in a randomized controlled trial with FMS patients. The main objective was to assess whether SDM improves the quality of physician-patient interaction from patients' perspective. METHODS: Patients were randomized to either an SDM group or an information-only group. The SDM group was treated by physicians trained in SDM communication and had access to a computer-based information package; the information-only group received only the information package and was treated by standard physicians. All patients were offered the same evidence-based treatment options for FMS. Patients were assessed with questionnaires on physician-patient interaction (main outcome criteria) and decisional processes. Physicians filled out a questionnaire on interaction difficulties. Assessment took place immediately after the initial consultation. RESULTS: Data from 85 FMS patients (44 in the SDM group and 41 in the information-only group) were analyzed. The mean age was 49.9 years (S.D.=10.2), and 91.8% of patients were female. The quality of physician-patient interaction was significantly higher in the SDM group than in the information-only group (P<.001). We found no differences in secondary outcome measures. CONCLUSIONS: SDM with FMS patients might be a possible means to achieve a positive quality of physician-patient interaction. A specific SDM communication training program teaches physicians to perform SDM and reduces frustration in patients.     

Mild cognitive impairment has similar alterations as Alzheimer's disease in gut microbiota

ObjectiveGut microbiota changes before the onset of Alzheimer's disease (AD) and the alterations could be detected in the stage of mild cognitive impairment (MCI). The findings might offer diagnostic biomarkers before the onset of dementia.BackgroundAD is the most common cause of dementia, and MCI is the predementia state. Recent studies suggest the alterations in the gut microbial communities associated with AD, whereas the microbiota in MCI before the onset of dementia has not been discovered and characterized in humans.New/Updated HypothesisWe hypothesize that the dysbiosis happens in the MCI stage. Patients with AD and MCI have decreased microbial diversity, and changes in gut microbiota could be detected for early detection of AD. In our preliminary study, we identified differences between AD and normal controls in 11 genera from the feces and 11 genera from the blood. No difference in genera between AD and MCI was detected. Using the diagnostic model from fecal samples with all different genera input, 93% (28 in 30) of patients with MCI could be identified correctly.Major Challenges for the HypothesisThe diagnosis of MCI and AD in the study was based on symptoms and neuroimaging, and AD biomarkers should be included for precise diagnosis in further validating studies. Besides, as the microbiota changes longitudinally, their relationship with the progress of dementia needs to be studied in the prospective studies.Linkage to Other Major TheoriesEscherichia was observed increased at genus level in both fecal and blood samples from AD and MCI. For AD biomarker, postmortem brain tissue from patients with AD showed lipopolysaccharides and gram-negative Escherichia coli fragments colocalize with amyloid plaque. In this way, the amyloid pathogenesis for AD would be triggered during MCI by gut microbiota shifting. Besides, systemic inflammatory reactions caused by compounds secreted by bacteria may impair the blood-brain barrier and promote neuroinflammation and/or neurodegeneration. Furthermore, abnormal metabolites caused by microbial gene functions have an impact on neurodegeneration.     

Disease progression in vascular cognitive impairment: cognitive, functional and behavioural outcomes in the Consortium to Investigate Vascular Impairment of Cognition (CIVIC) cohort study

BACKGROUND AND PURPOSE: Empirical studies to clarify the outcomes in Vascular Cognitive Impairment (VCI) are needed. We compared cognitive, functional, and behavioural outcomes in patients with VCI to patients with no cognitive impairment (NCI), and Alzheimer's disease (AD). METHODS: Secondary analysis of the Consortium to Investigate Vascular Impairment of Cognition (CIVIC), a multi-centre Canadian memory clinic 30-month cohort study. RESULTS: Of 1347 patients, 938 were eligible for follow-up, of whom 239 (24.5%) were lost and 29 (3%) had died. Of the remaining 697 patients, 125 had NCI, 229 had VCI, and 343 had AD at baseline. Compared to people with NCI, of whom 20-40% showed progression based on cognitive and functional measures, those with VCI were more likely to progress (50-65%), as were people with AD (50-80%) (p<0.01). More people with VCI showed progression of affective symptoms (30%) than those with NCI (12%) or AD (15% p<0.01). Progression of impaired judgment (rated clinically) in VCI (15%) was similar to AD (11%) but more common than in NCI (4%, p<0.01). CONCLUSIONS: Most people with VCI show readily detectable progression by 30 months. Depressive symptoms were more common and more progressive in VCI than in Alzheimer's disease, whereas clinical evidence of progressive executive dysfunction was common in both AD and VCI.     

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project

IntroductionLarge variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways.MethodsGenome Research at Fundacio ACE ([email protected]) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, [email protected] series were meta-analyzed with additional genome-wide association study data sets.ResultsWe classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444.DiscussionThe regulation of vasculature is a prominent causal component of probable AD. [email protected] meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.     

Blood amyloid levels and risk of dementia in the Ginkgo Evaluation of Memory Study (GEMS): A longitudinal analysis

IntroductionBoth high or low plasma amyloid levels have been associated with risk of dementia in nondemented subjects.MethodsWe examined baseline plasma β-amyloid (Aβ) levels in relationship to incident dementia during a period of 8.5 years in 2840 subjects age >75 years; 2381 were cognitively normal (CN) and 450 mild cognitive impairment.ResultsIncreased plasma Aβ1-40 and Aβ1-42 levels were associated with gender (women), age, low education, creatinine levels, history of stroke, and hypertension. CN participants who developed dementia had lower levels of Aβ1-42 and Aβ1-42/Aβ1-40 ratio compared with those who did not. Aβ levels did not predict dementia in mild cognitive impairment participants.DiscussionThere was an inverse association between Aβ1-42 and Aβ1-42/Aβ1-40 ratio to risk of dementia in CN participants. Cerebral and cardiovascular disease and renal function are important determinants of increased Aβ levels and must be considered in evaluations of relationship of plasma Aβ and subsequent risk of dementia.     

不同浓度A型肉毒毒素治疗偏侧面肌痉挛疗效观察:一项多中心随机双盲交叉设计临床试验

研究背景目前有关A型肉毒毒素治疗偏侧面肌痉挛注射浓度的各项研究报道不尽相同,其疗效及药物不良反应发生率亦差异较大,且很少有随机对照临床试验。本研究拟评价两种不同浓度A型肉毒毒素治疗偏侧面肌痉挛的疗效及安全性。方法选择4所医疗单位共80例偏侧面肌痉挛患者,随机以高浓度(50 U/ml)和低浓度(25 U/ml)局部注射A型肉毒毒素,复发后采取高、低浓度交叉再注射,分析两组疗效和药物不良反应发生率。结果两种Α型肉毒毒素浓度治疗偏侧面肌痉挛均有效(P=0.000)。不同治疗顺序疗效及药物起效时间比较差异无统计学意义(均P>0.05),但高浓度组疗效持续时间更长(P=0.000);治疗后8天至3个月两组Cohen分级下降值差异无统计学意义(P=0.863),治疗4、5个月时两组Cohen分级下降值差异有统计学意义(均P=0.000);治疗时间超过6个月时,两组Cohen分级下降值相近(P=0.515)。治疗期间高浓度组药物不良反应发生率高于低浓度组(P=0.000),且持续时间更长(P=0.000);但两组总体不良反应程度轻微,不经特殊处理均可自愈,无一例出现药物过敏或全身性中毒反应。结论 A型肉毒毒素局部注射治疗偏侧面肌痉挛安全有效,高浓度重复注射间隔时间更长,患者针刺疼痛感降低,经济负担减轻,但药物不良反应相对明显且持续时间更长。     

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment

IntroductionUnlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel.MethodsFifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later.ResultsBrain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention.DiscussionA dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.     

The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: A randomized,double‐blind,placebo‐controlled,multicenter study

Cognitive impairment can occur at all stages of Parkinson's disease. Rasagiline is a selective monoamine oxidase type‐B inhibitor that enhances central dopaminergic transmission. Dopamine is thought to be involved in certain cognitive processes such as working memory. We assessed the effects of rasagiline on cognitive deficits in cognitively impaired, nondemented patients with Parkinson's disease. This was a randomized, double‐blind, placebo‐controlled prospective study. Patients with Parkinson's disease receiving stable dopaminergic treatment were assigned to receive rasagiline 1 mg/day or placebo for 3 months. Patients were eligible if they had impairment in 2 of 4 cognitive domains (attention, executive functions, memory, visuospatial functions) in the screening neuropsychological tests, yet did not fulfill criteria for Parkinson's disease dementia. Fifty‐five patients were randomized; 48 patients completed the study. Patients in the rasagiline group showed significant improvement in digit span–backward compared with the placebo group (P = .04), with trends favoring rasagiline in digit span total and digit‐ordering tests. Verbal fluency total score showed a significant difference in favor of rasagiline (P = .038), with trends favoring rasagiline in semantic fluency test and Stroop spontaneous corrections. The composite cognitive domain Z scores revealed a significant difference in favor of rasagiline compared with placebo in the attentional Z score (P < .005). There were no significant differences between the 2 groups in the other cognitive tests or cognitive domain Z scores. The monoamine oxidase type‐B inhibitor rasagiline may exert beneficial effects on certain aspects of attention and executive functions in nondemented patients with Parkinson's disease with cognitive impairment. © 2011 Movement Disorder Society