Use of serum insulin-like growth factor-I levels to predict psychiatric non-response to donepezil in patients with Alzheimer's disease.

OBJECTIVE: Insulin-like growth factor-I (IGF-I) deficiency may be involved in cognitive deficits seen with aging and in neurodegenerative diseases such as Alzheimer's disease (AD). This study was aimed at investigating whether non-responder to donepezil could be predicted using decreased serum levels of IGF-I in AD patients. DESIGN: This study involved 106 elderly subjects: 50 patients with AD and 56 age-matched controls without dementia. In patients with AD, donepezil was given orally 3 mg/day for 4 weeks and 5 mg/day for another 12 weeks. AD patients were divided into responders and non-responders based on the changes in mini-mental state examination (MMSE) scores before and 16 weeks after treatment with donepezil. Serum levels of IGF-I and atherogenic biomarkers were determined. RESULTS: Before treatment with donepezil, there was a significant positive correlation between serum IGF-I levels and the MMSE scores in all subjects. Serum IGF-I levels and the MMSE scores were significantly lower in AD patients than in non-demented controls and were the lowest in non-responders to donepezil. Atherogenic biomarkers (LDL cholesterol, triglycerides, lipoprotein(a), lipid peroxide, apolipoprotein E, and glucose levels) did not differ significantly among these groups. On multiple logistic regression, non-responders to donepezil showed decreased serum IGF-I levels <110 ng/ml and MMSE scores <15 points before treatment. CONCLUSIONS: These findings suggest that decreased levels of serum IGF-I combined with MMSE scores before treatment could predict non-responders to donepezil among AD patients, which may be a simple and practical method for selecting patients expected to show a response to treatment.     

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.     

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.     

Economic evaluation of donepezil for the treatment of Alzheimer's disease in Canada.

BACKGROUND: Donepezil is a new drug recently approved in the United States and Canada for the treatment of Alzheimer's disease (AD). We estimated the cost-effectiveness of donepezil 5 mg daily as an adjunct to usual care in the management of persons with mild-to-moderate AD defined as a Mini-Mental Health State Examination (MMSE) score in the range 10 to 26. METHODS: Treatment effect data as MMSE change-over-baseline scores were obtained from a 30-week placebo-controlled trial of donepezil. MMSE scores beyond observed trial data were estimated using a Markov model with 10 cycles of 24 weeks based on the placebo MMSE progression observed in the trial. Data from AD subjects in the Canadian Study of Health and Aging were used to estimate costs of nursing home care, community services, medications, and caregiver time as a function of MMSE score. A clinic-based cohort study from Alberta was used to estimate the distribution of AD patients by MMSE score presenting for treatment. The effectiveness measure for the economic model was expected time (over 5 years) spent with nonsevere AD (MMSE > or = 10). RESULTS: Over 5 years of treatment, donepezil is predicted to reduce health care costs by CA$929 per patient but increase caregiver time costs by CA$48 per patient for an overall cost saving to society of CA$882 per patient. Patients not receiving donepezil are predicted to spend 2.21 years of the 5 years in nonsevere AD compared with 2.41 years for treated patients (a gain of just over 2 months). Sensitivity analysis reveals that cost savings per patient increase if more AD patients are assumed to survive to 5 years; however, if donepezil treatment continues when patients' MMSE score falls below 10, the incremental cost is higher for treatment at CA$1554 per patient. CONCLUSION: Based on the limited available data, our model predicts that the use of donepezil for mild-to-moderate AD in Canada is associated with lower 5-year costs and less time spent with severe AD when compared with the alternative of usual care with no donepezil therapy. As more reliable long-term data become available, these predictions should be confirmed and/or updated.     

Donepezil provides greater benefits in mild compared to moderate Alzheimer's disease: Implications for early diagnosis and treatment

We assessed the cognitive and functional outcomes of donepezil treatment in mild versus moderate Alzheimer's disease (AD) patients. We performed a 6-month prospective, observational, multicenter study of the progression of cognitive and functionality abilities in a large sample patients with AD who initiated treatment with donepezil in monotherapy. According to baseline mini mental state examination (MMSE), patients were divided in two groups: mild AD (MMSE ≥ 21) and moderate AD (MMSE < 21). Patients were evaluated with the memory alteration test (M@T) and the Alzheimer's disease functional assessment and change scale (ADFACS) at baseline and at 6 months. A total of 403 patients finished the study (mild AD = 152; moderate AD = 251). The MMSE total score and M@T score remained stable at 6 months in the whole sample, with MMSE memory domain and M@T free and cued recall domains improving significantly from baseline. Total ADFACS, instrumental (IADL) and basic activities of daily living (BADL) got significantly worse, with the worsening being significantly greater in the moderate AD group. Significant differences between the groups favoring mild AD were observed for MMSE memory, orientation and language domains, M@T temporal orientation and semantic memory domains, and for IADL. We concluded that in AD patients on donepezil, cognition remains stable at 6 months. The beneficial effect of donepezil treatment, in terms of cognition and functionality, is greater for mild than for moderate AD.     

Positron emission tomography and pathological evidence of response to neoadjuvant therapy in adenocarcinoma of the esophagus

SUMMARY.  Our aim was to determine if fluorodeoxyglucose positron emission tomography (FDG-PET) could be correlated with a pathological response in patients with esophageal adenocarcinoma receiving neoadjuvant chemotherapy and/or chemoradiation therapy. Patients with resectable, histologically proven adenocarcinoma of the esophagus were entered in the study. Preoperative chemotherapy comprised two cycles of cisplatin and 5-fluorouracil. Radiation therapy commenced with the second cycle on day 22. FDG-PET images were obtained pre-treatment and on completion of intended neo-adjuvant treatment. Quantification was achieved by the calculation of both standardized uptake values (SUV) and tumor/liver ratios (TLR). Evidence of histopathological response was identified according to the Mandard tumor regression scoring system. There were 45 patients, 22 receiving neoadjuvant chemotherapy and 23 chemoradiation therapy. Forty patients underwent surgical resection. Seven patients (16%) had a histopathological response. The mean percentage change in SUV in the histological responders group was –56.8% (SD 29) and in the non-responders –27.8% (SD 32.1) ( P =  0.035). The mean percentage change in TLR was –49.1% (SD 44.8) in the responders and in the non-responders –27.3% (SD 31.3) ( P =  0.128). There was no difference between the two methods of assessment, however there was less variation with SUV. There was no correlation between the FDG-PET response and the histopathological response. Presently an FDG-PET scan performed 3–6 weeks after neoadjuvant therapy for adenocarcinoma of the esophagus should not be used as a marker of the potential result of the treatment. The optimal timing of a second FDG-PET remains unclear.     

Health-related quality of life before, during and after combination therapy with interferon and ribavirin in unselected Swedish patients with chronic hepatitis C

OBJECTIVE: To study the relationship between health-related quality of life (HRQOL) and mode of acquisition, treatment discontinuations, drop in haemoglobin levels and treatment outcome in patients with chronic hepatitis C (CHC). MATERIAL AND METHODS: Consecutive unselected Swedish patients with CHC completed the SF-36 questionnaire before, during and after treatment with interferon and ribavirin. Results. At baseline, HRQOL was reduced in all SF-36 subscales in our patients (n=147) as compared with the general Swedish population. Former intravenous drug users (IVDUs) scored significantly lower in social function (p=0.03) and mental health (p=0.03) than patients who had acquired their infection from blood transfusions (PTH). A decline of >40 points in HRQOL from baseline to week 12 was noticed in the role limitations-physical (RP) score for the IVDU and PTH groups (p<0.0001 and 0.001, respectively). Patients with a >or=20% fall in haemoglobin levels at treatment week 12 had a significantly poorer RP (p=0.006) and role limitations-emotional score (p<0.02) than patients with a <10% fall. Early treatment dropouts had significantly lower HRQOL scores at baseline than adherent patients. At follow-up, sustained viral responders had significantly higher scores than non-responders. CONCLUSIONS: Swedish outpatients with CHC have a marked reduction in their HRQOL as compared to the general population. Therapy reduces HRQOL most substantially in those with a marked reduction in haemoglobin. Early dropouts from therapy have significantly lower HRQOL scores at baseline than adherent patients, and sustained viral responders improve their HRQOL significantly more than non-responders.     

Longitudinal patterns of unawareness of memory deficits in mild Alzheimer's disease

Aim:   Patients with Alzheimer's disease (AD) frequently demonstrate impaired awareness of their cognitive difficulties. However, less is known about the longitudinal progression of this phenomenon. We examined the longitudinal evolution of unawareness in patients with mild AD to determine whether impaired awareness progresses with cognitive decline.
Methods:   Based on Mini-Mental State Examination (MMSE) score changes after a 1-year follow up, 39 patients were regarded as the stabilized group and 19 patients were regarded as the non-stabilized group. The unawareness of memory impairment was evaluated with a standardized questionnaire system based on the Everyday Memory Checklist (EMC). The EMC scores for the patient's own rating, the caregivers' rating and the unawareness score, defined as the difference between these (caregiver rating – patient rating), were analyzed.
Results:   Although unawareness scores were similar in the two groups at the initial examination, they were significantly higher in the non-stabilized group than in the stabilized group at the follow up examination. There was a significant and negative correlation between change in unawareness score and change in MMSE score over time ( r  = −0.56, P  < 0.0001).
Conclusion:   Our results indicated that impaired awareness progressed with cognitive decline. The EMC may be a simple and useful tool for the monitoring of progression in patients with AD.     

Development of elderly diabetes burden scale for elderly patients with diabetes mellitus

Background:   The purpose of the present paper was to validate an elderly diabetes burden scale (EDBS) and to assess its correlates in elderly patients with diabetes mellitus.
Methods:   Comprehensive questionnaires about both diabetes-specific and non-specific quality of life (QOL) were given by an interviewer to 455 elderly diabetic patients aged > 65 years. To assess diabetes-specific QOL, the EDBS was developed. The internal consistency and test–retest reliability of the EDBS were assessed. The validity of the EDBS was assessed with the correlation with the Philadelphia Geriatric Center morale scale, the mini-mental state examination (MMSE) and diabetic complications, treatment of diabetes, hemoglobin (Hb) A1c, frequency of hypoglycemia, and socioeconomic factors.
Results:   Factor analysis of the 23 items on EDBS produced six reliable components (Cronbach's α): symptom burden (0.55), dietary restrictions (0.89), social burden (0.89), worry about diabetes (0.85), treatment dissatisfaction (0.85), and burden by tablets or insulin (0.77). It was found that the EDBS and its six subscales had good test–retest reliability ( r  = 0.94–0.99). However, the EDBS correlated significantly with the morale scale but not with MMSE, suggesting convergent and discriminant validity. The high scores of some subscales and total EDBS were significantly associated with high HbA1c level, frequency of hypoglycemia, and insulin therapy, showing construct validity. Multivariate analyses revealed that hyperglycemia, frequency of hypoglycemia, insulin treatment, the presence of microangiopathy, and low positive social support were independently associated with increased elderly diabetes burden scores.
Conclusion:   The EDBS is a simple but reliable and valid measure of diabetic-specific QOL in elderly people with diabetes mellitus.     

Cognitive function among physically independent very old people in an urban Japanese community

Background:   A study was conducted to clarify the characteristics of cognitive function among physically independent very old people dwelling in an urban community in Japan.
Methods:   Five hundred and thirteen old-old (aged 75–84 years) and 168 oldest-old (aged 85–100 years) adults participated. We carried out the Mini-Mental State Examination (MMSE) for measuring cognitive functions in the elderly. Age-related differences in the total score and subscale scores of the MMSE were analyzed by sex using ancova , controlling for education, vision and hearing problems.
Results:   Mean MMSE scores for old-old and oldest-old men were 27.5 and 25.9, respectively, and those for old-old and oldest-old women were 27.8 and 25.0, respectively. Age-related differences in the MMSE total score between the old-old and oldest-old were observed in both sexes, suggesting that overall cognitive functions continue to decline over time in very old age. Age-related differences between the old-old and oldest-old in items measuring, registration, calculation and delayed recall were observed in both sexes, and also in those assessing time orientation, place orientation, delayed recognition, writing sentences, and copying figures were observed in women.
Conclusion:   These findings suggest that the faculties are those most sensitive to normal aging among very old individuals. There were no age group differences in five items: reverse spelling, naming objects, repeating a sentence, listening and obeying, and reading and obeying.     

Impact of history or onset of chronic medical conditions on higher-level functional capacity among older community-dwelling Japanese adults

Background:   Many studies have examined the impact of chronic medical conditions on the age-related decline in basic activities of daily living (BADL) and the instrumental activities of daily living (IADL), but less is known concerning the influence of chronic disease on physical, cognitive, social, and economic aspects of higher-level functional capacity.
Methods:   Subjects comprised 793 and 725 persons aged 65–84 years, living in an urban and a rural Japanese community, respectively. A baseline interview established any history of chronic medical conditions. Four years later, a second interview again assessed chronic disease, and higher-level functional capacity was evaluated using the Tokyo Metropolitan Institute of Gerontology (TMIG) Index of Competence.
Results:   Multiple logistic regression analysis revealed that declines in total score and/or any of three subscales of the TMIG Index of Competence were significantly associated with a history of chronic disease, the onset of visual impairment and the development of hearing impairment, even after controlling for the subject's age, gender, educational attainment, and baseline TMIG Index of Competence. Episodes of stroke were significantly associated with declines in IADL. Hypertension, diabetes mellitus, and heart disease were also significantly associated with a decrease in functional competence, although each affected a different subscale of the TMIG Index of Competence.
Conclusions:   The present results underline the importance of controlling chronic medical conditions through a physically active lifestyle and an appropriate medical regimen in order to limit the age-related decline in functional capacity.     

Association between insulin resistance and cognitive function in elderly diabetic patients

Background:   Recently, cognitive impairment in elder diabetic subjects has sparked considerable interest. Insulin resistance (IR) is one of the central pathologies in diabetes mellitus, and several studies have shown that IR is associated with cognitive impairment in non-diabetic elderly subjects. However, the involvement of IR in cognitive dysfunction in the diabetic elderly has remained to be elucidated.
Methods:   In the current study we measured IR with the euglycemic insulin clamp technique, and assessed cognitive function in 13 elderly diabetic patients (mean age, 69.1 ± 4.4). Several tests to assess cognitive function including Mini-Mental State Examination (MMSE) were performed, and clinical indices were evaluated. IR was evaluated by metabolic clearance rates (MCR).
Results:   The Spearman's rank correlation coefficient between MCR and MMSE scores was 0.587 ( P  = 0.035). When subjects were divided into two groups at the median MCR (5.0 mL/kg/min), the lower MCR (high IR) group ( n  = 5) had significantly lower MMSE scores than the higher group ( n  = 8). The Spearman's rank correlation coefficient was –0.641 ( P  = 0.018) between hs-CRP and MMSE scores. When subjects were divided into two groups at the median of high-sensitivity C-reactive protein (hs-CRP) (594.0 µg/dL), the higher hs-CRP group ( n  = 6) had significantly lower MMSE scores than the lower group ( n  = 7).
Conclusion:   The current study shows that higher IR measured with the euglycemic insulin clamp technique and higher hs-CRP is associated with lower MMSE scores in non-demented diabetic elderly patients.     

Rapid loss of hepatitis C virus genotype 1b from serum in patients receiving a triple treatment with telaprevir (MP-424), pegylated interferon and ribavirin for 12 weeks

Aim:  To evaluate the efficacy and safety of the triple treatment with telaprevir (MP-424), pegylated interferon (PEG-IFN) and ribavirin during 12 weeks on-treatment.
Methods:  The triple treatment was given to 20 patients with chronic hepatitis C who had been infected with hepatitis C virus (HCV)-1b in high viral load (median: 6.8 log IU/mL [range: 5.5–7.2]), with a median age of 54 years (range: 36–65 years). They were followed for early dynamics of HCV RNA in serum during 12 weeks and side-effects.
Results:  HCV RNA levels decreased by 4.8 logs by 7 days and 5.5 logs by 14 days. HCV RNA disappeared in 50% (10/20) at 2 weeks, 79% (15/19) at 4 weeks, 88% (14/16) at 6 weeks, 94% (15/16) at 8 weeks and 100% (13/13) at 12 weeks. HCV RNA disappeared equally frequently in 10 treatment-naive patients, six non-responders to IFN monotherapy and four non-responders to PEG-IFN and ribavirin. It was no different in the patients with and without amino acid substitutions reducing the response to IFN. The treatment was withdrawn in seven (35%) patients, mostly due to reduced hemoglobin of less than 8.5 g/dL, of whom six (86%) remained clear of HCV RNA at 12 weeks.
Conclusion:  HCV RNA was lost from serum rapidly and universally in patients infected with HCV-1b in high viral loads by the triple treatment. Because an early loss of HCV RNA correlates with high rates of sustained virological response (SVR), it would increase SVR substantially, and merit the patients who have not responded to previous therapies.     

Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults

OBJECTIVES: To examine whether use of vitamins C or E alone or in combination was associated with lower incidence of dementia or Alzheimer's disease (AD).
DESIGN: Prospective cohort study.
SETTING: Group Health Cooperative, Seattle, Washington.
PARTICIPANTS: Two thousand nine hundred sixty-nine participants aged 65 and older without cognitive impairment at baseline in the Adult Changes in Thought study.
MEASUREMENTS: Participants were followed biennially to identify incident dementia and AD diagnosed according to standard criteria. Participants were considered to be users of vitamins C or E if they self-reported use for at least 1 week during the month before baseline.
RESULTS: Over a mean follow-up±standard deviation of 5.5±2.7 years, 405 subjects developed dementia (289 developed AD). The use of vitamin E was not associated with dementia (adjusted hazard ratio (HR)=0.98, 95% confidence interval (CI)=0.77–1.25) or with AD (HR=1.04; 95% CI=0.78–1.39). No association was found between vitamin C alone (dementia: HR=0.90, 95% CI=0.71–1.13; AD: HR=0.95, 95% CI=0.72–1.25) or concurrent use of vitamin C and E (dementia: HR=0.93, 95% CI=0.72–1.20; AD: HR=1.00, 95% CI=0.73–1.35) and either outcome.
CONCLUSION: In this study, the use of supplemental vitamin E and C, alone or in combination, did not reduce risk of AD or overall dementia over 5.5 years of follow-up.     

The response to short-term intensive insulin therapy in type 2 diabetes

Aim: Although a short course of intensive insulin therapy (IIT) can improve beta-cell function and glycaemic control in most patients with newly diagnosed type 2 diabetes (T2DM), the impact of this intervention in diabetes of longer duration has not been carefully studied. Thus, we sought to evaluate the effect of short-term IIT in patients with established T2DM.
Methods: Thirty-four patients, with diabetes of mean 5.9 ± 6.6 years duration, underwent 4–8 weeks of IIT, with 4-h meal test administered at baseline and at 1 day post-IIT. A positive clinical response was defined as fasting glucose < 7.0 mmol/l off any antidiabetic therapy at the latter test.
Results: A positive response was achieved in 68% (n = 23) of the subjects. At baseline meal test, the responders had lower glucose levels than the non-responders from 120 to 240 min (all timepoints p ≤ 0.0008) and higher late incremental area-under-the-C-peptide-curve (AUC_Cpep), particularly from 60 to 150 min (all p < 0.005). Beta-cell function (ratio of AUC_Cpep to AUC_gluc divided by HOMA-IR) was similar between the groups at baseline (median 54.1 vs. 51.3, p = 0.62) but after IIT was significantly higher in the responders (109.3 vs. 57.4, p = 0.009). At baseline, the strongest predictors of the change in beta-cell function were glucose levels between 180 and 240 min (all r = −0.5, p = 0.005) and incremental AUC_Cpep from 120 to 180 min (all r ≥ 0.66, p ≤ 0.0001), both reflecting late-phase insulin secretion.
Conclusions: The clinical response to short-term IIT is variable, consistent with the heterogeneity of T2DM. However, preserved late-phase insulin secretion may identify those patients who can benefit from this intervention with improved beta-cell function.     

A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting

OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.     

Albumin, Apolipoprotein E-ɛ4 and Cognitive Decline in Community-Dwelling Chinese Older Adults

OBJECTIVES: To examine the association between serum albumin and cognitive impairment and decline in community-living older adults.
DESIGNS: Population-based cohort study, followed up to 2 years; serum albumin, apolipoprotein E (APOE)-ɛ4, and cognitive impairment measured at baseline and cognitive decline (≥2-point drop in Mini-Mental State Examination (MMSE) score). Odds ratios were controlled for age, sex, education, medical comorbidity, hypertension, diabetes mellitus, cardiac disease, stroke, smoking, alcohol drinking, depression, APOE-ɛ4, nutritional status, body mass index, anemia, glomerular filtration rate, and baseline MMSE.
SETTINGS: Local area whole population.
PARTICIPANTS: One thousand six hundred sixty-four Chinese older adults aged 55 and older.
RESULTS: The mean age of the cohort was 66.0±7.3, 65% were women, mean serum albumin was 42.3±3.1 g/L, and mean MMSE score was 27.2±3.2. Lower albumin tertile was associated with greater risk of cognitive impairment in cross-sectional analysis (low, odds ratio (OR)=2.30, 95% confidence interval (CI)=1.31–4.03); medium, OR=1.59, 95% CI=0.88–2.88) versus high ( P for trend=.002); and with cognitive decline in longitudinal analyses: low, OR=1.73, 95% CI=1.18–2.55; medium, OR=1.32, 95% CI=0.89–1.95, vs high ( P for trend=.004). In cognitively unimpaired respondents at baseline (MMSE≥24), similar associations with cognitive decline were observed ( P for trends <.002). APOE-ɛ4 appeared to modify the association, due mainly to low rates of cognitive decline in subjects with the APOE-ɛ4 allele and high albumin.
CONCLUSION: Low albumin was an independent risk marker for cognitive decline in community-living older adults.     

盐酸美金刚治疗阿尔茨海默病多中心随机对照临床试验

目的 盐酸多奈哌齐随机对照评估盐酸美金刚片（美金刚）治疗轻、中度阿尔茨海默病（AD）临床疗效和安全性。方法100例可能或很可能轻、中度AD患者随机接受美金刚或盐酸多奈哌齐治疗16周,每4周随访1次,8周评估采用Blessed-Roth量表,16周评估采用简易智能状态检查量表（MMSE）、Blessed-Roth量表和全面衰退量表（GDS）。结果两组分别自身前后比较差别均显示有统计学意义;GDS、Blessed-Roth量表基本生活习惯改变部分评分的自身前后比较,各个量表评分变化均数在两组之间的比较差异均无统计学意义。试验组不良反应率为6％。结论美金刚和盐酸多奈哌齐均能显著改善轻、中度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美金刚具有较好的安全性。     

Changes in cognitive functions of patients with dementia of the Alzheimer type following long-term administration of donepezil hydrochloride: Relating to changes attributable to differences in apolipoprotein E phenotype

Aim:   We conducted a study of changes in cognitive functions by long-term monitoring of dementia of Alzheimer type (DAT) patients to investigate the relationship between the progression of DAT symptoms and the presence of apolipoprotein (ApoE)4.
Methods:   The subjects consisted of 40 DAT patients who had been treated with donepezil for 3 years or more. The Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale – Cognitive Subscale Japanese version (ADAS-Jcog), were conducted annually. The patients were categorized into ApoE4⁺ and ApoE4^- groups. Changes in initial cognitive function assessment score (0 years) were then studied longitudinally at each stage of the observation period (1, 2, 3 years) (Wilcoxon's signed-rank test). Moreover, the scores at each time period were compared cross-sectionally between the two groups (Mann–Whitney U -test).
Results:   Significant decreases in MMSE scores were observed at the three time periods in both groups ( P  < 0.01) in the cross-sectional study. In the longitudinal study, the ApoE4⁺ group demonstrated a lower trend ( P  < 0.1) after 1 year only. Significantly poorer ADAS-Jcog scores were observed in the ApoE4⁺ group at the 3-year point both in the longitudinal and in the cross-sectional study ( P  < 0.05). For ADAS-Jcog sub-items, in the longitudinal study, orientation was demonstrated to be significantly poorer in the ApoE4⁺ group in the third year ( P  < 0.05).
Conclusion:   ApoE4 was suggested to not only be a risk factor for disease onset, but also a risk factor for exacerbation of symptoms with respect to long-term prognosis.     

Vitamin D treatment in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of clonal disturbances with defective cellular differentiation. Vitamin D3 (VD) analogues can act on the differentiation and maturity of different cell lines. We studied the effects of VD on a series of patients with MDS in an open-design trial. Nineteen patients, 12 men and seven women, with MDS were included. Patients were 74.8 ± 5.6 years (mean ± SD), seven had refractory anaemia with ringed sideroblasts, five had refractory anaemia, one had refractory anaemia with excess of blasts and six had chronic myelomonocytic leukaemia. All the patients were in a low to intermediate risk group. Mean follow-up period was 26.21 months, range 9–75. Responders were defined as follows: granulocyte or platelet count increase by 50%, or haemoglobin increase of 1.5 g/dl or transfusion needs decrease by 50%. The first five patients received 266 μg of calcifediol three times a week and the other 14 received calcitriol (0.25–0.75 μg/d). Response was observed in 11 patients. In the calcifediol-treated group, one case responded, three were non-responders, and one showed progression. In the calcitriol group, 10 were responders (two with major response), and four were non-responders. No correlation was observed between baseline levels of vitamin D metabolites and the presence of response. No hypercalcaemia was observed. Treatment with vitamin D3 metabolites could induce a long-standing response of the haematological disturbance in some low-intermediate risk MDS patients without inducing hypercalcaemia.