Treatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukansan in clinical practice

The efficacy and safety of the kampo medicine Yokukansan (YKS, TJ-54) in the treatment of behavioral and psychological symptoms of dementia (BPSD) were investigated in patients with Alzheimer's disease (AD) in an open-label study. This study included 26 patients who had been diagnosed as having AD and were not treated with donepezil hydrochloride. These patients were administered YKS (7.5 g/day) for four weeks to investigate the changes in neuropsychological test results and care burden in the period from the start to completion of the study treatment. The Neuropsychiatric Inventory (NPI) was used for evaluation of BPSD, the Mini-Mental State Examination (MMSE) for evaluation of cognitive functions, the Zarit burden interview for evaluation of the caregiver's burden, Disability Assessment of Dementia (DAD) for evaluation of activities of daily living (ADL) and Self-Rating Depression Scale (SDS) for evaluation of the caregiver's depression. No significant change was seen in MMSE and DAD after four weeks of treatment, but the mean NPI total score decreased significantly. Furthermore, among the NPI subscales, a statistically significant decrease in score was not seen, however, a clinically significant decrease was seen in terms of hallucinations, agitation, anxiety, irritability or abnormal behavior. No significant changes were seen in caregiver's burden after four weeks of treatment. No serious adverse reactions to YKS were observed. The results of this study suggested that YKS may be an effective and well-tolerated drug in the treatment of BPSD in AD patients.     

Impact of donepezil hydrochloride on the care burden of family caregivers of patients with Alzheimer's disease

Background: To evaluate the impact of donepezil hydrochloride on the care burden on family members of patients with Alzheimer's disease (AD). At present, donepezil is the only drug approved for the treatment of AD in Japan. Although the care burden on primary caregivers of AD patients comprises both physical and psychological burdens and donepezil is recognized to improve cognitive dysfunction and associated symptoms, there are few data on the effects of the drug on the care burden. Methods: Of the uninstitutionalized AD patients who visited a dementia clinic between June 2008 and May 2009 with their primary family caregivers, 416 subjects who satisfied the enrollment criteria were registered for the study. All participants provided informed consent. Assessment included changes in scores on the Japanese version of the Zarit Caregiver Burden Interview (J‐ZBI) and the Mini‐Mental State Examination (MMSE), as well as the presence of behavioral and psychological symptoms of dementia (BPSD). Caregivers answered the questionnaires at baseline and after 12 weeks treatment with donepezil (starting dose 3 mg, p.o., once daily, followed by 5 mg after 1 or 2 weeks). Results: There were significant changes in mean scores on the J‐ZBI (?1.9 ± 9.5; P < 0.01) and MMSE (+0.9 ± 2.9; P < 0.01) from baseline to Week 12, without significant correlation between these two scores. In patients with BPSD, there was a significant decrease in J‐ZBI scores over the 12 weeks (P = 0.013); in contrast, in patients without BPSD, the decrease in the J‐ZBI score did not reach statistical significance (P = 0.418). Conclusions: The results indicate that donepezil improves cognitive function and some of the BPSD. As a possible consequence of improvements in BPSD, donepezil may also reduce caregivers' burden.     

Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer's disease

Objective

The aim of this study was to investigate the effects of yokukansan (YKS) on the behavioral and psychological symptoms of dementia (BPSD) in elderly patients with Alzheimer's disease (AD).

Methods

Fifteen patients with AD (mean age: 80.2 ± 4.0 years) participated in the study. The Mini-Mental State Examination (MMSE) was used for the assessment of cognitive function. BPSD were evaluated using the Neuropsychiatric Inventory (NPI). The Barthel Index was used for the assessment for the activities of daily living (ADL). The treatment with YKS along with sulpiride, a dopamine D₂ selective antipsychotic, was performed for 12 weeks.

Results

Fourteen patients completed the trial. After the 12 weeks of treatment with YKS, significant improvement of the mean NPI score was observed while no significant improvement was observed in the control group. The average dose of sulpiride at the end of the present study was less in the YKS group than in the control group. The MMSE results did not change either in the YKS group or in the control group. The Barthel Index did not significantly change either in the YKS group or in the control group. No serious adverse effects were noted.

Conclusions

Twelve weeks of the YKS treatment significantly improved BPSD with less antipsychotics in elderly patients with AD. The YKS treatment did not cause any cognitive decline or ADL decline and no serious adverse effects were noted. The present study suggests that YKS is beneficial for the treatment of BPSD and that it can possibly reduce the doses of antipsychotics required for the treatment of BPSD. Further studies with larger patient populations using a double-blind placebo-controlled design should be performed.     

Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan,a traditional Japanese medicine

Background: This multicentre open‐label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies. Methods: Sixty‐three dementia with Lewy bodies patients with probable BPSD (M : W, 30 : 33; mean age, 78.2 ± 5.8 years) were enrolled and treated with YKS for 4 weeks. Results: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P < 0.001) and Zarit Burden Interview‐Japanese edition tests (mean decrease, 3.6 points; P= 0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time‐dependent significant improvement was observed in the Neuropsychiatric Inventory score (n= 23; mean decrease, 14.4; P < 0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview‐Japanese edition (n= 22; mean decrease, 8.2; P < 0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini‐Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (<3.5 mEq/L) was present in four patients (6%) at the study endpoint. Worsening of extrapyramidal symptoms was not observed. Conclusion: YKS improved BPSD in dementia with Lewy bodies patients and caregiver burden scores without deterioration in cognitive function. YKS is useful for the treatment of delusions and hallucinations in BPSD.     

The Behavioral Effects of Combination Therapy of Memantine and Acetylcholinesterase Inhibitors Compared with Acetylcholinesterase Inhibitors Alone in Patients with Moderate Alzheimer’s Dementia: A Double-Blind Randomized Placebo-Controlled Trial

Objective This study aimed to investigate treatment effects of combination therapy of memantine and acetylcholinesterase inhibitors (AchEIs) compared with AchEIs alone on behavioral and psychological symptoms of dementia (BPSD) in patients with moderate Alzheimer’s dementia (AD). Methods This was a 12-week, double-blind, randomized, placebo-controlled trial. A total of 148 patients with moderate AD participated in this study. Mini-Mental State Examination, Neuropsychiatric Inventory (NPI), Clinician’s Interview-Based Impression of Change plus caregiver input, Gottfries–Bråne–Steen Scale, and Zarit Burden Interview were used as assessment scales. Results There were no significant differences in age, sex, or education between AChEIs alone and combination groups. The combination group showed significantly more improvement of NPI-disinhibition score (0.76±2.15) than the AChEIs alone group (-0.14±1.71) after 12 weeks. Conclusion Our findings suggest that the combination therapy of memantine and AchEIs might be a beneficial option for reducing disinhibition symptoms of patients with moderate AD compared with AchEIs alone. We believe that clinicians need to consider additional memantine treatment when patients with moderate AD complain disinhibition symptom. A larger clinical trial is needed to further determine the efficacy and advantages of such combination therapy of memantine and AchEIs for treating BPSD of patients with moderate AD.     

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.     

阿尔茨海默病照料者的负担及相关因素研究

目的探讨影响阿尔茨海默病（AD）患者照料者负担的相关因素。方法选择来自记忆障碍门诊的不同严重程度AD患者及其照料者各190例,收集人口学资料,用Zarit照料者负担问卷评估照料者负担;用简易智力状态检查（MMSE）、日常生活能力量表（ADL）、神经精神科问卷（NPI）、临床痴呆严重度评定量表（CDR）评估患者的认知损害程度、日常生活能力、精神行为症状及疾病的严重程度,进行一系列相关分析。结果照料者负担Zarit评分6-47分,平均（21.73±8.02）分,Zarit分值与MMSE、ADL、NPI评分及病程的相关系数r值分别为-0.428、0.495、0.59及0.283（P〈0.01）。女性Zarit值（24.28±8.44）分高于男性（19.91±7.2）分（t=3.83,P〈0.01）。结论阿尔茨海默病照料者负担与患者认知损害的严重程度、病程、日常生活能力、是否合并精神行为异常及照料者性别有关。     

Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease

Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.     

Post‐marketing survey of donepezil hydrochloride in Japanese patients with Alzheimer's disease with behavioral and psychological symptoms of dementia (BPSD)

Background: To investigate the efficacy and safety of donepezil hydrochloride (Aricept^®; Eisai Co., Ltd, Tokyo, Japan), we conducted a post‐marketing survey in Japanese patients with Alzheimer's disease (AD) who also had behavioral and psychological symptoms of dementia (BPSD), such as hallucinations/delusions, wandering, and aggression, which cause the greatest burden on caregivers. Methods: A prospective, centrally registered investigation was conducted through regular clinical settings with patients diagnosed as mild to moderate AD presenting with hallucinations/delusions, wandering, and/or aggression. The treatment period was 12 weeks and no restrictions were placed on concomitant medications. Results: The BPSD improvement rates at last‐observation‐carried‐forward (LOCF) were 60.1% for hallucinations/delusions, 59.6% for wandering, and 65.6% for aggression. For all symptoms, improvement rates increased with the duration of the treatment period. The BPSD deterioration rates at LOCF were 1.3% for hallucinations/delusions, 3.4% for wandering, and 1.6% for aggression. Assessment of cognitive function with both the revised Hasegawa Dementia Scale (HDS‐R) and Mini‐Mental State Examination (MMSE) indicated significant improvements after treatment. There were significant differences in the changes in HDS‐R scores between patients whose hallucinations/delusions or wandering were improved and patients whose symptoms were not improved. Moreover, the data suggested a possible correlation between changes in hallucinations/delusions and HDS‐R scores, changes in hallucinations/delusions and MMSE scores, and changes in wandering and MMSE scores. Patients in whom BPSD improved also demonstrated a greater improvement in cognitive function compared with patients in whom no improvement in BPSD was noted. Nursing burden on caregivers at LOCF showed 3.6% for ‘No burden’, 54.1% for ‘Burden decreased’, and 4.5% for ‘Burden increased.’ There was an increase in the combined ratio of ‘No burden’ and ‘Burden decreased’ in proportion with prolonged treatment period. Patients with improved BPSD had a significantly greater ratio (88.5–94.4%) of ‘No burden’ plus ‘Burden decreased’ than those patients in whom no improvement in BPSD was noted. Conclusions: These results suggest that donepezil not only improves the cognitive dysfunction of AD patients, but may also relieve BPSD in these patients. Treatment with donepezil was also found to alleviate the burden of caregivers for approximately 60% of patients. Moreover, the results indicate that donepezil is unlikely to trigger potential risks of excessive deterioration of BPSD, which would result in a heavier burden of nursing care.     

Patients with Lewy body dementia use more resources than those with Alzheimer's disease

OBJECTIVES: The purpose of this study was to compare resource use and costs in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) and to assess determinants of costs of care in DLB. METHOD: Thirty-four patients with DLB were included in a cross-sectional study. The patients were matched with respect to age, gender and Mini Mental State Examination (MMSE) score to 34 patients with AD. Both groups were examined using Resource Utilisation in Dementia (RUD Lite), MMSE and the Neuropsychiatric inventory (NPI). The DLB patients were additionally examined using the Disability Assessment for Dementia Scale (DAD). RESULTS: Costs of care in patients suffering from DLB was on average 348,000 SEK (37,500 euro) per year compared to 169,000 SEK (18,200 euro) in the AD group (p < 0.001). Within the DLB group, care costs correlated significantly (r(c) = 2.77, p < 0.001) with dependency in instrumental activities of daily living measured with DAD, whereas MMSE and NPI were not significantly correlated to resource use in the DLB group. CONCLUSIONS: DLB patients use more resources, and are more costly than AD patients. Dependency in instrumental activities of daily living is strongly correlated to resource use in DLB patients.     

Successful treatment with Yokukansan for behavioral and psychological symptoms of Parkinsonian dementia

Objective

To evaluate the efficacy and safety of Yokukansan, a traditional Chinese herbal medicine, for treating behavioral and psychological symptoms of dementia (BPSD) in patients with Parkinson disease (PD; n = 7) and those with PD with dementia (PDD; n = 7).

Background

BPSD are often seen in patients with senile dementia and have serious deleterious effects on the lives of patients and caregivers. Recent studies indicate that the traditional Chinese herbal medicine Yokukansan may be safe and beneficial for the treatment of BPSD patients.

Methods

We treated 7 PD and 7 PDD patients for 4 weeks with Yokukansan and observed them without Yokukansan for 4 weeks. Changes in behavioral and psychological symptoms were evaluated every 4 weeks according to the Neuropsychiatric Inventory (NPI) scale.

Results

Significant improvements in behavioral and psychological symptoms, particularly in the incidence and duration of hallucinations, were observed in most PD and PDD patients after 4 weeks of Yokukansan treatment. No significant changes were observed in the laboratory tests, cognitive function, activities of daily living, or parkinsonism.

Conclusion

Our results suggest that Yokukansan improves BPSD in both PD and PDD patients without worsening their cognitive function, ability to perform activities of daily living, or parkinsonism.     

Memantine in behavioral variant frontotemporal dementia: negative results

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.     

The effects of behavioral and psychological symptoms on caregiver burden in frontotemporal dementia,Lewy body dementia,and Alzheimer's disease: clinical experience in China

Background and aims: Caregivers of individuals with neurodegenerative diseases, including frontotemporal dementia (FTD), Lewy body dementia (DLB), and Alzheimer's disease (AD), experience high levels of psychological and physical stress, likely due to behavioral and psychological symptoms of dementia (BPSD). This study is the first to simultaneously evaluate the effects of BPSD on caregiver burden in these three types of dementia.

Method: A total of 214 dementia patients, including probable FTD (n = 82), DLB (n = 22), and AD (n = 110), as well as their primary caregivers, were assessed using psychological inventories and cognitive evaluation. The FTD group was further divided into the three established clinical variants: behavioral variant frontotemporal dementia (bvFTD, n = 51), non-fluent variant primary progressive aphasia (nfvPPA, n = 15), and semantic variant primary progressive aphasia (svPPA, n = 16). Cognitive impairment and neuropsychiatric symptoms were assessed using the Mini Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test, and Neuropsychiatric Inventory (NPI), respectively. Caregiver burden was assessed using the Zarit Burden Inventory (ZBI).

Results: FTD patients had higher NPI and ZBI scores than DLB and AD patients, whose scores were similar. Logistic regression analysis revealed that the factors influencing caregiver burden for each group were: FTD: total NPI scores, agitation, and aberrant motor behavior; bvFTD: total NPI scores; DLB: total NPI scores; and AD: total NPI scores, onset age, apathy, and ADL. Caregivers of bvFTD patients had the highest levels of burden, which were significantly greater than for caregivers of nfvPPA, svPPA, DLB, and AD patients.

Conclusion: BPSD was highly correlated with emotional burden in caregivers of FTD, DLB, and AD patients. The highest burden was observed in bvFTD caregivers.     

Investigation of the short- and long-term effects of donepezil on cognitive function in Alzheimer's disease

Background: Donepezil is effective in maintaining cognitive function in patients with mild to moderate Alzheimer's disease (AD). However, not all patients respond to donepezil. In the present study, we examined the short‐ and long‐term effects of donepezil on cognitive function after 2 years treatment. Methods: The present retrospective study was performed on 122 AD outpatients who had been taking donepezil for ≥1 year. All subjects underwent periodic examination of cognitive function (Mini‐Mental State Examination (MMSE), Rorschach Cognitive Index (RCI)) and clinical evaluation on the Clinical Dementia Rating (CDR); first before starting treatment and then at 4‐month intervals after initiation of donepezil. Patients were divided into three groups: (i) MG, the ‘maintained’ group, in which the global CDR score was maintained during treatment; (ii) DeG, the ‘declined’ group, in which the global CDR score increased; and (iii) DrG, the drop out group, who discontinued the treatment. Changes in scores on the MMSE and RCI were compared before treatment and at 4‐month intervals within each group. In addition, over each 4‐month period, MMSE and RCI scores were compared between the three groups. Furthermore, to investigate the condition of effective treatment, the reasons why donepezil treatment was discontinued in the DrG were examined. Results: The most frequent reason for discontinuation was the appearance of behavioral and psychiatric symptoms of dementia (BPSD), which were more frequently observed in the DrG. Although depression and/or disinclination were more frequent in the MG, hyperactivity was more frequent in the DeG and DrG. Before treatment, patients in the DrG exhibited significantly lower scores on the MMSE than did patients in the MG and DeG. Upon examination 4 months after starting treatment, patients in the MG showed cognitive improvement on the MMSE and RCI, whereas those in the DeG showed cognitive deterioration on the MMSE. Conclusion: The results of the present study suggest that when a short‐term beneficial effect of the donepezil on cognitive functions is seen, long‐term effect may also be expected at 2 years. Periodic clinical evaluation and examination of cognitive function is indispensable for effective donepezil treatment.     

小剂量多奈哌齐联合美金刚治疗老年性痴呆的疗效及安全性

目的观察多奈哌齐联合美金刚治疗老年性痴呆患者认知功能和行为能力的改善作用及安全性。方法将30例老年性痴呆患者随机分为多奈哌齐对照组和多奈哌齐联合美金刚试验组。疗程16周,每4周随访1次,评估简易精神状态量表(MMSE);治疗16周后进行有效性评估:采用阿尔茨海默病评定量表的认知分量表(ADAS-Cog)评定患者认知功能;采用临床医生访谈时对病情变化的印象补充量表(CIBIC-Plus)评价患者总体功能变化情况;采用神经精神科问卷(NPI)了解患者精神行为症状的变化;采用日常生活能力量表(ADL)了解患者日常功能情况。结果 29例患者完成最后随访,对照组MMSE,ADAS-Cog,CIBIC-Plus,NPI,ADL评分治疗前后比较有统计学意义(P<0.05);试验组MMSE,ADAS-Cog,CIBIC-Plus,NPI,ADL评分治疗前后比较有统计学意义(P<0.05);治疗前两组各量表评分比较无统计学意义;治疗16周后,两组比较,试验组较对照组患者NPI评分明显下降(P<0.05),表现在脱抑制和激越等情绪方面;CIBIC-Plus总体功能变化实验组较对照组好转明显(P<0.05),余各项评分两组间无显著性差异(P>0.05)。结论多奈哌齐及多奈哌齐联合美金刚治疗老年性痴呆均有效,后者更优于前者,尤其对情绪方面的阳性症状控制较好,且具有良好的安全性和耐受性。     

Behavioral and psychological symptoms of dementia characteristic of mild Alzheimer patients

In order to clarify the characteristics of Behavioral and Psychological Symptoms of Dementia (BPSD) in patients with mild Alzheimer's disease (AD), BPSD among the severities of Clinical Dementia Rating (CDR) in 74 patients with AD were compared using the Neuropsychiatric inventory (NPI). The result, when compared between mild (CDR = 0.5, 1) and moderate or severe (CDR = 2, 3) AD, was a significant difference in frequency of euphoria, disinhibition and aberrant motor behavior, but no significant difference was found in frequency of delusions, hallucinations, agitation, dysphoria, anxiety, apathy and irritability. In addition, a significant difference was found in the mean scores of the composite score for euphoria, apathy, disinhibition and aberrant motor behavior, but no significant difference was found in the mean scores of the composite score for delusions, hallucinations, agitation, dysphoria, anxiety and irritability. That is, the mild AD groups (CDR 0.5 or 1) had delusions, hallucinations, agitation, dysphoria, anxiety, apathy and irritability as frequently as the moderate or severe AD groups (CDR 2 or 3), and had the equivalent level of composite scores to the moderate or severe AD groups (CDR 2 or 3) in delusion, hallucination, agitation, dysphoria, anxiety and irritability. Therefore, it was supposed that psychotic symptoms (delusion, hallucination) and emotional symptoms (agitation, dysphoria, anxiety, irritability) are important BPSD in patients with mild AD as well as those with moderate or severe AD, and there are needs for health, welfare and medical services for these symptoms.     

盐酸美金刚治疗阿尔茨海默病的多中心随机对照研究

目的 与盐酸多奈哌齐对照评价盐酸荚金刚片治疗阿尔茨海默病(AD)的有效性和安全性.方法 241例AD患者(MMSE评分3-24分)随机分为2组,采用双盲双模拟的方法,埘照组给予盐酸多奈哌齐10 mg/d,试验组给予盐酸美金刚20 mg/d,疗程24周,分别在基线、第4、12和24周进行随访.主要疗效指标为印象变化(CIBIC-Plus)、AD评估量表-认知部分(ADAS-cog)和日常生活能力(ADL)量表,次要疗效指标为神经精神症状问卷(NPI)和MMSE.结果 207例患者完成试验,盐酸美金刚组和盐酸多奈哌齐组治疗24周后各量表评分均较基线有显著改善.盐酸美金刚组与盐酸多奈哌齐组相比较,各量表的评分变化分别为:CIBIC-Plus评分:3.4±0.8、3.5±0.8;ADAS-cog评分:-4.7±5.8、-4.6±6.5;ADL评分:-2.4±6.7、-2.2±5.3;NPI评分:-5.8±9.0、-3.1±8.5;MMSE评分:1.7±3.1、1.8±2.8;差异均无统计学意义.不良事件发生率盐酸多奈哌齐组41.88%,盐酸美金刚组30.58%.结论 盐酸美金刚作为治疗AD的新药,町以改善AD患者的总体功能、认知障碍、日常生活能力和精神行为症状,疗效与盐酸多奈哌齐相当,且具有良好的安全性和耐受性.     

Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study

AZD3480 is a selective agonist of the central α4β2 and α2β2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD ± 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58-85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25-26) indicated improvement versus placebo for AZD3480 20 mg (-1.4, 95% CI: -3.0; 0.2) and donepezil (-1.0, 95% CI: -2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating α4β2 receptors with NNRs in AD patients.     

Behavioral and psychological symptoms of dementia (BPSD) in dementia with Lewy bodies

Behavioral and psychological symptoms of dementia (BPSD) bother patients with dementia with Lewy bodies (DLB) and their families so frequently that early diagnosis of DLB before the appearance of prominent cognitive impairment is important. Because BPSD in DLB can be reduced or improved by early intervention, medical intervention is important. Of BPSD in DLB, vivid visual hallucinations and delusions are most important. Other visual cognitive impairments and sleep disturbances, including disorders in rapid eye movement (REM) sleep, are also frequently seen. Cholinesterase inhibitors, including donepezil chloride, are the first choice for the therapy of BPSD; Yokukansan (a type of Kanpo (traditional Chinese herbal) medicine) is the second choice. When neither treatment is effective, atypical antipsychotics, such as quetiapine, risperidone, and aripiprazol, may be used.     

Clinical profiles of late‐onset semantic dementia,compared with early‐onset semantic dementia and late‐onset Alzheimer's disease

Background: Semantic dementia (SD) has been recognized as a representative of dementia with presenile onset; however, recent epidemiological studies have shown that SD also occurs in the elderly. There have been few studies about the differences of clinical profiles between early‐onset SD (EO‐SD) and late‐onset SD (LO‐SD). Age‐associated changes in the brain might cause some additional cognitive and behavioural profiles of LO‐SD in contrast to the typical EO‐SD cases. The aim of the present study was to clarify the characteristics of neuropsychological, and behavioural and psychological symptoms of dementia (BPSD) profiles of LO‐SD patients observed in screening tests in comparison with EO‐SD patients and late‐onset Alzheimer's disease (LO‐AD) patients as controls. Methods: Study participants were LO‐SD (n = 10), EO‐SD (n = 15) and LO‐AD (n = 47). We examined the Mini‐Mental State Examination (MMSE), the Raven's Coloured Progressive Matrices (RCPM), the Short‐Memory Questionnaire (SMQ), the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Results: Both SD groups scored significantly lower than the LO‐AD patients in ‘naming’ of the MMSE. In the ‘construction’ score of the MMSE and the RCPM score, however, the LO‐SD patients as well as the LO‐AD patients were significantly lower than the EO‐SD patients. In the SMQ score, ‘euphoria’ and ‘disinhibition’ scores of the NPI, the SRI total and subscale scores, both SD groups were significantly higher, whereas in the ‘delusion’ score of the NPI, both SD groups were significantly lower than the LO‐AD patients. Conclusions: Visuospatial and constructive skills of LO‐SD patients might be mildly deteriorated compared with EO‐SD patients, whereas other cognitive and behavioural profiles of LO‐SD are similar to EO‐SD. Age‐associated changes in the brain should be considered when we diagnose SD in elderly patients.