Combination of intensive cognitive rehabilitation and donepezil therapy in Alzheimer's disease (AD)

Acetylcholinesterase inhibitors (AchEIs) are extensively used in Alzheimer's disease (AD) while reality orientation therapy (ROT) is a cognitive rehabilitation indicated for mentally deteriorated patients. We aimed to evaluate the efficacy of the combination of donepezil with an intensive ROT with active participation of the caregiver. Patients with AD (n = 100, mean age 78.4 ± 4.3 years) initiated treatment with donepezil, 5 mg/day; 62 of them underwent a 3-week, daily ROT and physical reactivation training with the caregiver (Group A); 38 participants received only donepezil therapy (Group B). All subjects were tested for cognitive and functional abilities at baseline, at the end of the training program, and after 2 months of follow-up. There was a significant improvement in mini-mental state examination (MMSE) score (p < 0.001) and the AD assessment scale-cognitive (ADAS-Cog) subscale (p < 0.001), without changes in impaired activity of daily living (ADL) and instrumental ADL (IADL) after intensive ROT training in Group A. MMSE was maintained after 2 months in-home ROT continuation. There were no significant changes in MMSE in drug-only treated patients (Group B) after 3 weeks, with a non-significant tendency to improvement in ADAS-Cog. Our results suggest benefit of an intensive ROT program in dementia patients receiving donepezil that seems to be maintained as far as ROT is continued by the caregiver.     

多奈哌齐治疗阿尔茨海默病的远期疗效观察

目的 观察多奈哌齐治疗阿尔茨海默病(AD)的远期疗效和安全性. 方法 86例AD患者随机分为对照组43例和治疗组43例.对照组运用茴拉西坦、尼莫地平、银杏叶片进行常规治疗,治疗组在常规治疗的基础上每日加服多奈哌齐l0 mg.以简易智能状态检查量表(MMSE)、AD评估量表认知分量表(ADAS-cog)、日常生活能力量表(ADL)、总体衰退量表(GDS)等评分作为主要评价指标,比较两组患者在治疗前与治疗3、6、12、18、24、30、36、42、48、54、60、66和72个月后的认知能力、精神状况、日常生活能力的情况. 结果 与对照组比较,治疗组患者MMSE、ADAS-cog、GDS评分在3个月以后、ADL评分在6个月以后优于对照组,差异有统计学意义(t=2.361,-2.198,-1.790和-2.420;P＜0.05或P＜0.01);12个月时与对照组相比最显著(均P＜0.01),36个月以后各项指标继续减退,到72个月时,治疗组与对照组相比,MMSE高出7.5分,ADAS-cog优于20.3分,ADL优于19.5分,GDS优于1.4分(均P＜0.01).与治疗前比较,治疗组患者MMSE、ADAS cog、GDS评分在治疗3、6、12、18和24个月时差异有统计学意义(P＜0.05或P＜0.01);ADL评分在6、12、18、24和30个月时差异有统计学意义(P＜0.05或P＜0.01);ADAS-cog和GDS评分在24个月以后、MMSE和ADL在30个月以后差异无统计学意义(P＞0.05). 结论 多奈哌齐治疗AD的远期疗效满意,安全可靠,可有效减缓AD患者认知功能和总体功能衰退进程.     

Cognitive profiles and response to donepezil treatment in Alzheimer's disease patients

Background:   The aim of this study was to determine whether there are certain characteristic neuropsychological profiles, assessed by the Mini-Mental State Examination (MMSE) at baseline, which predict donepezil treatment response.
Methods:   A total of 112 consecutive outpatients with Alzheimer's disease (AD) were treated with donepezil for 3–4 months. Multiple regression analysis was performed to estimate the relative contributions of individual subscales at baseline to the MMSE change (study point – baseline). To identify the characteristic patterns in cognitive deficits of patients with AD who responded to donepezil therapy, the subscales of the MMSE at baseline of responders and non-responders were compared.
Results:   Multiple regression analysis revealed that lower scores on attention and calculation, and language function, and a higher scale on orientation (date) are related to an improvement of the MMSE. When an improvement of 4 or more points on the MMSE score was defined as a significant response, responders scored significantly lower than non-responders on attention and calculation, whereas non-responders scored significantly lower than responders on memory.
Conclusion:   Our results suggest that individual differences in patterns of neuropsychological impairments may partly contribute to the diversity of the response to donepezil treatment. Although further studies with more detailed neuropsychological tests are needed to confirm our results, the MMSE may add to the prediction of response to donepezil treatment in patients with AD.     

Characteristics of MRI features in Alzheimer's disease patients predicting response to donepezil treatment

We attempted to investigate whether morphological features as shown on magnetic resonance imaging (MRI) predict response to donepezil treatment in patients with Alzheimer's disease (AD). Sixty-three patients with AD were divided into responders (n = 16) and non-responders (n = 47) based on the changes in the MMSE score between baseline and endpoint. Atrophy of the substantia innominata was more pronounced in responders than non-responders. Although no significant difference in the medial temporal lobe atrophy between responders and non-responders was found, magnetization transfer ratios (MTRs) of the hippocampus and parahippocampus, indicators of structural damage, in the non-responder group were significantly reduced compared to those in the responder group. There were no significant differences in the severity of white matter lesions between the two groups. Logistic regression analysis revealed that the overall discrimination rate was 81%, with 85% of non-responders and 69% of responders, through measurement of the thickness of the substantia innominata and MTR of the hippocampus and parahippocampus. These results suggest that AD patients who show more severe cholinergic dysfunction and less severe structural damage of the hippocampus and parahippocampus as shown on MRI are likely to respond to donepezil treatment.     

Prevalence of neuropsychiatric syndromes in Alzheimer's disease (AD)

This study aimed to estimate the prevalence and explore the multidimensional complexity of the neuropsychiatric syndromes of AD. Neuropsychiatric symptoms and syndromes of 216 subjects with probable and possible AD diagnosed by NINCDS-ADRDA criteria were evaluated by the Korean version of behavior rating scale for dementia (BRSD-K). The prevalence rate of six neuropsychiatric syndromes (depressive symptoms, inertia, vegetative symptoms, irritability/aggression, behavioral dysregulation, psychotic symptoms) and comorbid neuropsychiatric syndromes were calculated according to the Clinical Dementia Rating scale. To investigate the relationship among neuropsychiatric syndromes, logistic regression analyses were performed. About 95% of patients with AD had one or more neuropsychiatric symptoms and syndromes during the past month. Among the neuropsychiatric syndromes, irritability/aggression (76.2%) was the most frequent, followed by apathy (72.3%) and depressive symptoms (68.0%). About 90% of the subjects had one or more comorbid neuropsychiatric syndromes. The mean numbers of comorbid neuropsychiatric syndromes were significantly varied according to the severity of disease (p < 0.05). Depressive symptoms were significantly associated with vegetative symptoms and irritability/aggression (p < 0.05). Inertia and psychotic symptoms were significantly associated with vegetative symptoms and behavioral dysregulation, respectively (p < 0.05). This study demonstrated that neuropsychiatric syndromes of AD were highly prevalent and involved complex relationships among them.     

Topography of cortical thinning areas associated with hippocampal atrophy (HA) in patients with Alzheimer's disease (AD)

Prior studies have shown that patients with AD have decreased functional or structural connectivity between the hippocampus and other brain areas. To the best of our knowledge, however, there have been no studies investigating the topography of cortical thinning areas and correlations with HA using surface based morphometry of three-dimensional (3D) T1-weighted magnetic resonance (MR) images. Cortical thickness was measured using SBM, and hippocampal volume was measured using an automated method, in 219 patients with AD and 54 subjects with no cognitive impairment (NCI). A partial correlation model was used in analysis of cortical thinning related to HA. Cortical thinning areas related to HA were found mostly within areas associated with polysynaptic or direct pathways of the hippocampus, a finding consistent with the disconnection hypothesis. Therefore, the cortical atrophy related to HA in patients with AD may represent disrupted cortical brain networks in connection with HA. However, since the topography of HA-related cortical thinning in groups with Clinical Dementia Ratings (CDR) of 0.5 and 1 corresponded to the stages I-II and III-IV of Braak and Braak staging, respectively, we could not exclude the possibility of the "concomitant hypothesis," i.e. that these areas are affected concomitantly with the hippocampus.     

Long-term cognitive benefits of donepezil in Alzheimer's disease: A retrospective comparison between 1994–1999 and 2000–2004

Objective:   In order to address an issue of how long Alzheimer's disease (AD) patients should receive donepezil, we estimated long-term effect of donepezil on cognition as well as its influential factors. We also evaluated the additional effect of cerebrospinal fluid (CSF)-tau protein levels on diagnosis.
Methods:   We compared cognitive changes between current (2000–2004) AD patients (donepezil users) and previous AD patients, seen by us 1994–1999, without receiving donepezil (non-donepezil users) by a mixed effect model. Cognition was assessed by Mini-Mental State Examination (MMSE) at 6-month intervals up to 24 months. Sensitivity analysis was performed exclusively on patients with high CSF-tau protein levels (CSF-tau >330 pg/mL) to minimize inaccuracies of the diagnosis
Results:   From 495 AD patients reviewed, 192 patients (120 donepezil users and 72 controls) were eligible. Estimated annual decline of MMSE was 1.2 points (95% confidence interval (95%CI), 0.9–1.5) in the donepezil users, whereas it was 2.8 points (95%CI, 2.1–3.6) in the control group. The difference was statistically significant ( P  < 0.001). The sensitivity analysis demonstrated that these declines were 1.2 (95%CI, 0.8–1.6) and 3.1 (95%CI, 2.3–3.9) points in the donepezil users and control groups, respectively.
Conclusions:   Long-term donepezil use for at least 2 years appeared to be beneficial in maintaining cognition in AD patients. As the cholinergic central nervous system consistently degenerates over time, long-term use of donepezil may be an appropriate therapy. Discontinuation of donepezil may not be recommended as far as patients are in a stable condition.     

Relationships between mood and estradiol (E2) levels in Alzheimer's disease (AD) patients

This study investigates the relationship between mood and estradiol (E2) levels and assesses the prevalence of mood symptoms in Alzheimer's disease (AD) patients compared to healthy elderly controls. Fifty-two AD patients (26 men, 23 estrogen non-using women and three estrogen-using women), mean age 76.2 years, were recruited and assessed with the Geriatric Depression Scale (GDS), a test of mood, and a radioimmunoassay measure of E2 levels at the time of testing. The AD patients were compared to a control group of age and gender-matched healthy elderly men and women estrogen-users and non-users. No differences were found between the AD patients and the controls in overall E2 levels, but, as expected, the women estrogen-users in both the AD and control groups had higher E2 levels than the men and the female estrogen non-users. Both groups of men had higher E2 levels than the estrogen non-using women. There was a significant negative correlation between E2 levels and GDS scores in the full sample, which was particularly strong in the estrogen-using women. This indicates that those subjects with higher E2 levels had less mood symptomatology. Overall, mood scores in the AD patients were higher than in the healthy controls, indicating higher levels of depressive symptomatology; the highest depression scores occurred in the AD women who were estrogen non-users. This suggests that depressive symptoms are common in AD patients, and that women with AD who are not taking estrogen replacement may be especially vulnerable to depression.     

Lifestyle versus ezetimibe plus lifestyle in patients with biopsy-proven non-alcoholic steatohepatitis (LISTEN): A double-blind randomised placebo-controlled trial

Background and aimsThe LISTEN trial (ClinicalTrial.gov accession: NCT01950884) is a phase IV 52 weeks double blind parallel randomized controlled trial that evaluated the effect of ezetimibe plus lifestyle and dietary intervention (eze) vs. lifestyle and dietary intervention alone (placebo) on progression and complications of non-alcoholic steatohepatitis (NASH) evaluated by liver histology.Methods and resultsForty patients with NASH ascertained by histology were randomly allocated on the two study groups and subjected to a follow-up of 52 weeks, when they underwent a second liver biopsy. Main composite end point (EP) was based on the histological improvement in the severity of NASH.Thirty patients completed the study, Eze treatment was not able to improve the primary EP in comparison with placebo, with and odds ratio of 1.029 (0.18–6.38), p = 0.974. Treatment emergent adverse events registered during the study were not more prevalent in the treatment arm.Conclusionsezetimibe administered on top of lifestyle and dietary modification failed to improve the histology of NASH in comparison with lifestyle and dietary modification alone.Trial accession numberClinicalTrial.gov: NCT01950884.