Verbal repetition in patients with Alzheimer's disease who receive donepezil

BACKGROUND: Current outcome measures for Alzheimer's disease (AD) drugs have been criticized as insufficiently patient-centred. One commonly unmeasured goal of patients and caregivers is verbal repetition. OBJECTIVES: We examined how often reducing repetition (of questions, statements or stories) was set as treatment goal, whether and when it responded, and how change in repetition correlated with change in other domains. METHODS: This is a secondary analysis of the open-label Atlantic Canada Alzheimer's Disease Investigation of Expectations study of donepezil for mild-moderate AD in 100 community-dwelling people. Goal Attainment Scaling, an individualized account of the goals of treatment, was the primary outcome measure. RESULTS: Reducing repetition was a treatment goal in 46%, who were not systematically different from others. Of 18 patients in whom repetition improved for 9 months, 83% (15) showed a response at 3 months. Early (3-month) response correlated best with the overall level of goal attainment (r = 0.74) and changes in leisure activities (r = 0.69) and social interactions (r = 0.68) compared with changes in cognition (r = 0.44) or behaviour (r = 0.11). Correlations with the ADAS-Cog and MMSE change scores remained only modest (at 12 months = -0.25 and 0.19, respectively). Correlations with the CIBIC-Plus were higher (-0.47 at 3 months and -0.43 at 12 months). CONCLUSION: Diminution of repetition is common, and appears to mark response to cholinesterase inhibition in some patients. Responders generally also show improved cognition and function, perhaps as an aspect of improved executive function.     

Facework,social politeness and the Alzheimer's patient

A recent paper by (Temple et al., 1999) investigating the politeness abilities of Alzheimer's sufferers has suggested that the sufferers they worked with were capable of employing politeness strategies towards their interlocutor. Given that politeness, according to (Brown and Levinson, 1987) revolves around face and that attending to another person's face requires the ability to take the other's role or perspective, Temple et al.'s findings would seem to contradict the findings of (Hamilton, 1988) who made the claim that Alzheimer's sufferers are unable to take the role of the other. Our proposal is that a more sophisticated view of politeness is required in identifying what the Alzheimer's patient is capable of. A refinement of the notion of politeness would also allow us to reconcile these two views. This refinement may be usefully achieved through employing the subdivision made by (Janney and Arndt, 1992) who propose that social politeness be distinguished from tact. In this approach, it is tact that involves facework while social politeness is more conventionalized or routinized. The distinction between tact and social politeness allows us to recognise certain politeness behaviours as not involving facework. Applying this distinction to our data, we find that our subject does engage in social politeness but, as one would expect from Hamilton's assumptions, she does not appear to be able to attend to the face of her interlocutors with much show of tact. However, in relation to facework, whilst she does not demonstrate much awareness of the need to protect the other's face, she does, in fact, engage with some sophistication in saving her own face. In this paper, we aim to examine not whether Alzheimer's Disease sufferers have the ability to be polite or not but which aspects of politeness remain after other aspects appear to have been lost.     

灯盏生脉胶囊联合盐酸多奈哌齐治疗阿尔茨海默病的临床研究

目的 观察灯盏生脉胶囊联合盐酸多奈哌齐对阿尔茨海默病患者认知功能、日常生活能力及安全性的影响。方法 将98例阿尔茨海默病患者随机分为治疗组与对照组各49例; 对照组给予每日口服盐酸多奈哌齐5 mg/次,1次/d,治疗组在对照组的基础上口服灯盏生脉胶囊0.36 g/次,3次/d; 比较2组患者治疗前与治疗3、6月后认知功能评分(MMSE、ADAS-cog)、日常生活能力评分(ADAS-ADL)、血清一氧化氮(NO)、内皮素(ET)水平及不良反应发生率。结果 治疗6月后治疗组MMSE评分为(21.85±2.58)分,对照组为(20.48±2.23)分(P<0.05); 治疗3、6月后治疗组ADAS-cog评分为(45.48±5.94)、(41.57±5.10)分,对照组为(48.69±6.23)、(414.24±5.53)分(P<0.05); 治疗3、6月后治疗组ADAS-ADL评分为(43.91±4.25)、(47.57±3.86),对照组为(41.77±4.44)分、(44.46±5.18)分(P<0.05); 治疗3、6月后治疗组NO水平为(41.95±7.62)、(37.89±5.93)μmol/L,对照组为(45.28±6.68)、(41.55±7.92)μmol/L(P<0.05); 治疗3、6月后治疗组ET水平为(140.48±22.94)、(132.04±10.08)ng/L,对照组为(152.08±17.39)、(143.91±17.60)ng/L(P<0.05); 2组药物不良反应主要有恶心、失眠、头痛、乏力、头晕、腹泻、皮疹,治疗组和对照组药物不良反应发生率分别为20.41%和14.28%(P>0.05)。结论 灯盏生脉胶囊联合盐酸多奈哌齐可提高阿尔茨海默病患者认知功能及日常生活能力,减少神经毒性物质NO、ET的生成,且安全性较好     

Efficacy of a high dosage of donepezil for Alzheimer's disease as examined by single‐photon emission computed tomography imaging

Background: The efficacy of donepezil 10 mg/day against Alzheimer's disease (AD) was examined, with a primary focus on changes in cerebral blood flow (CBF) as determined by single‐photon emission computed tomography imaging. Methods: The subjects were 24 outpatients who had been diagnosed with probable AD, which had progressed to advanced AD. Mini‐Mental State Examination and Alzheimer's Disease Assessment Scale (ADAS) scores were determined before and after the donepezil dosage increase. ^99mTc‐ethylcysteinate dimer single‐photon emission computed tomography was performed to evaluate changes in CBF. Then, a comparative study evaluated changes after the donepezil dosage increased. Results: After the donepezil dosage increase, adverse effects associated with gastrointestinal symptoms were observed in one patient, and irritability was observed in three. The average Mini‐Mental State Examination score changed from15.25 ± 6.24 to 14.67 ± 6.07; significant changes were not observed. Seventeen subjects were evaluated with the Alzheimer's Disease Assessment Scale‐cognitive subscale. After the dosage increase, the average subscale score decreased from 24.52 ± 13.39 to 21.56 ± 9.14, and significant improvement was observed (P= 0.021). With respect to changes in the CBF, the values of all three indicators decreased after the higher dosage increased CBF. However, no significant differences were observed in CBF. Analysis performed after the donepezil dosage increase revealed significant increases in CBF in the right occipital and temporal lobes, left temporal lobe, right parietal lobe, and both parts of the posterior cerebellum. Conclusion: Increasing the donepezil dosage from 5 mg/day to 10 mg/day is effective for the treatment of AD.     

A computed tomography study of Alzheimer's disease by regional volumetric and parenchymal density measurements

Summary Seventeen patients with clinically diagnosed Alzheimer's disease and 13 healthy age-matched controls were studied by means of computed tomography (CT). To assess cerebral atrophy, regional volumetric measurements and parenchymal density measurements were performed. The results indicate that: (1) Alzheimer patients show diffuse cerebral atrophy in the early stage; (2) the evaluation of lobar atrophy by means of CT is useful for the clinical diagnosis of Alzheimer's disease; (3) the evaluation of parenchymal density by means of CT is not as sensitive as the evaluation of lobar atrophy.     

Cost-effectiveness analysis of donepezil for mild to moderate Alzheimer's disease in Taiwan

BACKGROUND: Donepezil is a drug used for treatment in patients with Alzheimer's disease (AD). Information regarding the cost-effectiveness of this medication was previously rare in Asia. We used techniques of decision analysis and economic evaluation in conjunction with available local epidemiological and clinical data on costs of mild to moderate AD to assess the cost-effectiveness of donepezil in Taiwan. METHODS: A four-state Markov model was built to simulate the disease progression of AD patients. Local transition probabilities and costs of different stages were from the studies published earlier. RESULTS: Over a 5-year span, donepezil treatment for mild or moderate AD patients is predicted to result in the gain of 0.505 QALYs when comparing to usual care, while at the same time reducing the cost by US$7,691. The incremental cost was US$3,647 from the payer perspective; thus, the incremental cost-effectiveness ratio was estimated to be US$7,226 when considering only the medical expenditures. CONCLUSIONS: Under some assumptions, donepezil treatment might be a cost saving strategy for mild to moderate AD patients in Taiwan from a societal perspective. It is inconclusive from the payer's part since we still lack a consensus for judging the cost-effectiveness of a new health care technology.     

盐酸美金刚与盐酸多奈哌齐治疗阿尔茨海默病疗效对比

目的比较盐酸美金刚与盐酸多奈哌齐治疗阿尔茨海默病(AD)的有效性和安全性。方法将72例AD患者随机分为2组:美金刚组36例给予盐酸美金刚片20mg/d,多奈哌齐组36例给予盐酸多奈哌齐10mg/d,2组疗程均为6个月。2组患者治疗前和治疗3个月、6个月后均采用简易智能精神状态检查量表(MMSE)和AD评定量表的认知次级量表(ADAS-cog)评价患者认知功能、精神行为及痴呆严重程度。结果经治疗3个月、6个月后,2组患者MMSE、ADAS-cog评分均较治疗前明显好转(P<0.05或P<0.01);治疗3个月、6个月后,2组患者MMSE、ADAS-cog评分比较差异无统计学意义(均P>0.05);美金刚组的不良反应发生率低于多奈哌齐组(χ2=4.5714,P>0.05)。结论盐酸美金刚与盐酸多奈哌齐均能显著改善AD患者的认知功能、日常生活能力和人格情感障碍,两药疗效无明显差异,且盐酸美金刚具有良好的安全性。     

Potential treatment effects of donepezil not detected in Alzheimer's disease clinical trials: a physician survey

OBJECTIVES: Clinical trials of the cholinesterase inhibitor donepezil have used standard psychometric tools to evaluate treatment efficacy. These trials, however, appear not to capture clinically demonstrable, but otherwise unmeasured, beneficial treatment effects. We sought to identify and categorize clinically recognizable effects of donepezil treatment in Alzheimer's disease. METHODS: A list of potential effects was developed using clinical trials data and the experience of an expert panel. These were incorporated in a questionnaire, which was tested with a focus group, revised and then used in a postal survey of physicians. Data were classified by cognitive domain, and reviewed by a second panel. RESULTS: Items that were most often rated as being improved were related to frontal systems function, including attentional capacity and initiative. Behavioral symptoms that were among the highest rated items were apathy, mood, and agitation. The top two other items were social interactions and involvement in domestic activities. Of the top ten symptomatic treatment effects, only four appeared to be readily identified by current standard measures. CONCLUSIONS: Physicians recognize as important several treatment effects that are not well captured by current standard measures. New methods are needed to capture such effects, which also have the potential to offer insight into the neurobiology of the human cholinergic system.     

Transcribing discourse: interactions with Alzheimer's disease

This paper illustrates the use of a 'discourse line' in transcribing spoken interaction between a person with Alzheimer's disease, and a visitor. Discourse is here interpreted as a metacategory, or an analytic level of interaction. We view transcribing as an integral part of 'doing discourse', and use two sub-layers of the discourse line, dedicated to speech acts and conversation analysis, respectively. The prosody and voice layer is used to show the analysis of a speaker's use of a specific voice quality in discourse terms.     

Deterioration in donepezil-induced PR prolongation after a coadministration of memantine in a patient with Alzheimer's disease

The side effects and interaction of memantine and donepezil hydrochloride when used concomitantly are currently unknown. We encountered a case of a 77-year-old female with Alzheimer's disease in which the concomitant use of memantine exacerbated the prolonged electrocardiogram PR interval which appeared while donepezil hydrochloride was being orally administered. In terms of the cardiac circulation system side effects caused by donepezil hydrochloride and memantine, bradycardia has been reported. However, clinicians should be also aware of PR prolongation associated with the concomitant use of donepezil and memantine.     

多奈哌齐与他克林治疗阿尔茨海默病的对照研究

目的：验证多奈哌齐治疗阿尔茨海默病（AD）的安全性及有效性。方法：对61例AD患者进行多奈哌齐和他克林的多中心开放，对照治疗，其中多奈哌齐组33例（5mg/d)，他克林组28例（平均100mg/d）；共治疗12 ，应用简易精神状态检查（MMSE），日常生活能力量表（ADL）评定临床疗效。用副反应量表（TESS）评定副反应，结果：多奈哌齐组治疗总有效率为70％，显效率为51％，他克林组分别为68％和46％，起效时间均在治疗第4周末，两组间差异无显著性（X^2值分别为0．023和0．011，P＞0．05）。组间比较，多奈哌齐组和他克林组治疗前后MMSET评分及加分离，ADL评分及减分率的羞匀无显著性（P＞0．05），多奈哌齐组的不良反应较他克林组显著少而轻（X^2＝7．79，P＜0．01），仅有6例患者存在轻度的恶心或食欲减退，结论：多奈哌齐能有效治疗AD，且不良反应少而轻微。     

Cost‐effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO‐AD trial)

Objective

Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild‐to‐moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost‐effective for community‐dwelling, moderate‐to‐severe Alzheimer's disease patients.

Methods

Cost‐effectiveness analysis was based on a 52‐week, multicentre, double‐blind, placebo‐controlled, factorial clinical trial. A total of 295 community‐dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine.

Results

Continuing donepezil for 52 weeks was more cost‐effective than discontinuation, considering cognition, activities of daily living and health‐related quality of life. Starting memantine was more cost‐effective than donepezil discontinuation. Donepezil–memantine combined is not more cost‐effective than donepezil alone.

Conclusions

Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.     

What contribution can genetics make to predict the risk of Alzheimer's disease?

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although its etiology remains incompletely understood, genetic variants are important contributors. The prediction of AD risk through individual genetic variants is an important topic of research that may have individual and societal consequences when preventive treatments will become available. However, the genetic substratum of AD is heterogeneous. In addition to the extremely rare and fully penetrant pathogenic variants of the PSEN1, PSEN2 or APP genes causing autosomal dominant AD, a large spectrum of risk factors have been identified in complex forms, including the common risk factor APOE?4, which is associated with a moderate-to-high risk, common polymorphisms associated with a modest individual risk, and a plethora of rare variants in genes like SORL1, TREM2 or ABCA7 with moderate to high-magnitude effect. Understanding how these genetic factors contribute to AD risk in a given individual, in additional to non-genetic factors, remains a challenge. Over the last 10 years, age-related penetrance curves have progressively incorporated advances in the knowledge of AD genetics, from APOE to common polygenic components and, currently, SORL1 rare variants, which represents an important step towards precision medicine in AD. In this review, we present the complex genetic architecture of AD and we expose the prediction of AD risk according to its underlying genetic component.     

A randomized, placebo-controlled study of the efficacy and safety of sertraline in the treatment of the behavioral manifestations of Alzheimer's disease in outpatients treated with donepezil

OBJECTIVE: To examine the safety and efficacy of sertraline augmentation therapy in the treatment of behavioral manifestations of Alzheimer's disease (AD) in outpatients treated with donepezil. METHODS AND MATERIALS: Patients with probable or possible AD, and a Neuropsychiatric Inventory (NPI) total score >5 (with a severity score > or =2 in at least one domain), were treated with donepezil (5-10 mg) for 8 weeks, then randomly assigned to 12 weeks of double-blind augmentation therapy with either sertraline (50-200 mg) or placebo. Primary efficacy measures were the 12-item Neuropsychiatric Inventory (NPI) and the Clinical Global Impression Improvement (CGI-I) and Severity (CGI-S) scales. RESULTS: 24 patients were treated with donepezil+sertraline and 120 patients with donepezil+placebo. There were no statistically significant differences at endpoint on any of the three primary efficacy measures. However, a linear mixed model analysis found modest but statistically significantly greater improvements in the CGI-I score on donepezil+sertraline. Moreover, in a sub-group of patients with moderate-to-severe behavioral and psychological symptoms of dementia, 60% of patients on sertraline vs 40% on placebo (p = 0.006) achieved a response (defined as > or = 50% reduction in a four-item NPI-behavioral subscale). One adverse event (diarrhea) was significantly (p < 0.05) more common in the donepezil+sertraline group compared to the donepezil+placebo group. CONCLUSION: Sertraline augmentation was well-tolerated in this sample of AD outpatients. In addition, post hoc analyses demonstrated a modest but statistically significant advantage of sertraline over placebo augmentation in mixed model analyses and a clinically and statistically significant advantage in a subgroup of patients with moderate-to-severe behavioral and psychological symptoms of dementia.