Peripheral vascular responses to acetylcholine as a predictive tool for response to cholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: Cholinesterase inhibitors remain the first line therapy for people with mild to moderate Alzheimer's disease (AD). Response is modest and difficult to predict from pre-treatment characteristics. We hypothesise that skin vascular response to iontophoresis of acetylcholine, which is partly determined by the level of cholinesterase activity, may be a pre-treatment measure that could predict response to therapy. METHODS: Twenty-four people with probable AD underwent iontophoresis of acetylcholine to the volar surface of the forearm skin prior to treatment with a cholinesterase inhibitor. The peak skin vascular response and the resolution to baseline levels were measured using laser Doppler perfusion imaging. Response to treatment was assessed after 6 months using criteria from the National Institute for Health and Care Excellence (NICE) and iontophoresis with acetylcholine was repeated. Blindness between clinical and laboratory assessments was maintained. RESULTS: Fourteen out of twenty-four people responded to treatment using NICE criteria. By comparison to non-responders, responders to treatment had a faster resolution to baseline from acetylcholine-induced vasodilation prior to treatment, which slowed with treatment. In this pilot study there was a high level of accuracy in the classification of response using this variable. No baseline cognitive or functional measures discriminated end-point responders from non-responders. CONCLUSION: Cholinesterase inhibitors are well tolerated but the number of people with adverse effects would be reduced if it was possible to predict response. The role of vasodilator response to acetylcholine and recovery as a potential biomarker for efficacy of treatment should now be evaluated and may possibly be of relevance in stratifying samples for interventional studies in AD and other forms of dementia. We feel that a more definitive study is now justified.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Prediction of general hospital admission in people with dementia: cohort study.

BACKGROUND: People with dementia are extremely vulnerable in hospital and unscheduled admissions should be avoided if possible. AIMS: To identify any predictors of general hospital admission in people with dementia in a well-characterised national prospective cohort study. METHOD: A cohort of 730 persons with dementia was drawn from the Scottish Dementia Research Interest Register (47.8% female; mean age 76.3 years, s.d. = 8.2, range 50-94), with a mean follow-up period of 1.2 years. RESULTS: In the age- and gender-adjusted multivariable model (n = 681; 251 admitted), Neuropsychiatric Inventory score (hazard ratio per s.d. disadvantage 1.21, 95% CI 1.08-1.36) was identified as an independent predictor of admission to hospital. CONCLUSIONS: Neuropsychiatric symptoms in dementia, measured using the Neuropsychiatric Inventory, predict non-psychiatric hospital admission of people with dementia. Further studies are merited to test whether interventions to reduce such symptoms might reduce unscheduled admissions to acute hospitals.

What motivates patients and carers to participate in dementia studies?

AIM: The aim of this study was to explore what motivates people to participate in dementia research. METHOD: Three focus groups, attended by carers and people with dementia who had already volunteered to take part in dementia research, were used to explore motivation. Their thoughts and feelings about brain tissue donation were also explored. An adaptation of the participation chain model was used. A fourth focus group was given a supplementary questionnaire examining use of resources. Focus group content was analysed using a content analysis approach to identify themes. FINDINGS: Individualistic motivations included increased confidence and a chance to have a say. Collectivistic motivations included 'helping through being part of something bigger'. Mobilisation (catalysing) issues included a desire for change, and 'being asked'. In response to the questionnaire participants identified that they would have taken part regardless of any tangible benefits, with all saying that they would not have been put off by any of the costs. CONCLUSION: Participants in these focus groups were keen to be involved in dementia research and discounted any potential costs to themselves. They highlighted that being asked was an important factor in engaging them in dementia research.

Does the Addenbrooke's Cognitive Examination-revised add to the Mini-Mental State Examination in established Alzheimer disease? Results from a national dementia research register.

OBJECTIVE: To evaluate how much the Addenbrooke's Cognitive Examination-revised (ACE-R) improves the estimate of cognitive ability from the Mini-Mental State Examination (MMSE) in people with Alzheimer disease (AD). METHODS: We examined itemized data in people with AD who were on the Scottish Dementia Research Interest Register drawn from eight centres across Scotland, covering 75% of the Scottish population. ACE-R items that comprise the MMSE and those that did not (non-MMSE items) were summed separately. We residualized MMSE total on non-MMSE total and vice versa to derive a measure of the variance unique to each. RESULTS: Five hundred and one (258 male, 243 female) participants, mean age 75.7 (range 52-94) years were on the register, of whom 329 (160 men, 169 women) had AD. Of those with AD, 309 had a mean MMSE of 20.5 and mean ACE-R of 57.5 measured with Pearson r = 0.92 between MMSE and ACE-R totals, and the regression equation ACE-R score = 3.0 × MMSE - 4.1. The unique non-MMSE items score correlated with ACE-R total r = 0.40 (16% of ACE-R variance). CONCLUSIONS: The ACE-R and MMSE total scores are highly correlated. In this clinical sample of people with established AD, for an MMSE score of 24, the predicted ACE-R score was 67.9 with 95% confidence intervals of 61.6-75.4. The extra non-MMSE ACE-R items improve estimates of cognitive ability by 16%.

Fifteen year comparison of antipsychotic use in people with dementia within hospital and nursing home settings: sequential cross-sectional study.

OBJECTIVE: The use of antipsychotics to treat people with behavioural and psychological symptoms associated with dementia is controversial, especially in long-stay settings. We assessed the relationship between behaviour, function and antipsychotic use in people with dementia in a long-stay psychiatric unit and designated elderly mentally ill (EMI) nursing homes over a 15-year period. METHOD: Sequential cross-sectional studies assessing twelve behaviours and seven measures of function for each patient. Antipsychotic and antidepressant use was obtained from current prescription records. RESULTS: Regular antipsychotic use in hospital fell between 1990 and 1998. In 1998 use in nursing homes was significantly greater than in hospital, and increased between 1998 and 2005. Noisiness/verbal aggression (NVA) was the only behaviour more commonly associated with regular antipsychotic use over that timescale. Those with low levels of core symptoms (p = 0.021) and high dependency patients (p = 0.001) were more likely to be receiving regular antipsychotics in nursing homes than in hospital. Depression was not treated well even when identified. CONCLUSION: Compared to a long-stay hospital setting, antipsychotic drug use for people with dementia in nursing homes has risen and become less systematic. This cannot be explained by increasing core behaviour symptoms or differences in physical dependency.

A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease.

OBJECTIVES: (1) to assess the effect of 1 mg folic acid supplementation of cholinesterase inhibitors (ChI) in a 6 month double-blind placebo-controlled study of patients with Alzheimer's Disease (AD) and (2) to assess whether outcome measures were affected by changes in homocysteine levels. METHOD: Fifty-seven consecutive outpatients with probable AD were treated concurrently with a ChI and either folic acid or placebo. None had conditions or medication known to interfere with folate metabolism. Fasting folate and homocysteine levels were measured prior to commencing ChI and 6 months later. Response was categorised using criteria of the National Institute of Clinical Excellence (NICE). RESULTS: Twelve males and 29 females completed treatment (mean age 76.27 SD 6.23 years, Mini-Mental State Examination (MMSE) 23.49 SD 3.53, baseline homocysteine 18.39 SD 4.62 micromoles per litre). 23 received folic acid and 18 placebo. There were no significant baseline differences or use of individual ChI between the two arms. After 6 months a significant difference was seen in the change from baseline in combined Instrumental Activities of Daily Living and Social Behaviour scores between arms (folate+1.50 (SD 5.32) vs placebo -2.29 (SD 6.16) (p=0.03) but not change in MMSE scores. Sixteen of 23 subjects receiving folic acid and 7/18 placebo subjects were classified as NICE responders (p=0.05). CONCLUSION: This pilot double blind study suggests that response to ChI in patients with AD may be improved by the use of folic acid. The relationship between any change in homocysteine levels and response to treatment is discussed.

Hypertension, white matter change and response to cholinesterase inhibitors in Alzheimer's disease.

BACKGROUND: Cholinesterase inhibitors are used to treat mild to moderate Alzheimer's disease. Their role in patients with concurrent cerebrovascular disease has been less well studied, and the influence of vascular risk factors on response to treatment is uncertain. We investigated the effect of hypertension and white matter lesions (WML) on response. METHODS: A retrospective sample of 160 consecutive out-patients who had blood pressure measured and the presence or absence of WML recorded at baseline and who completed six months treatment with a cholinesterase inhibitor was studied. Subjects scored either zero or one on the Modified Hachinski Ischaemic Scale. Subjects were assessed using the Mini-Mental State Examination (MMSE), the Digit Symbol Substitution test (DSST) and both the Instrumental Activities of Daily Living (IADL) and Social Behaviour (SB) sub-scales of the Nurses Observation Scale for Geriatric Patients (NOSGER). RESULTS: 43.9% of the total study population were classified as good responders using our criteria. Neither the presence of hypertension nor the presence of WML alone influenced outcome. However, there was a statistically significant interaction between blood pressure and WML on outcome variables on multiple analysis of variance (MANOVA) (F(4, 139) = 5.60, p < 0.0005). Subjects with both hypertension and WML deteriorate to a significantly greater extent in IADL and SB scores than any other group (p < 0.05 in each case). This effect could not be explained by age or by smoking status. CONCLUSION: Our results support the hypothesis that there is an interaction between hypertension and WML that adversely influences functional change during cholinesterase inhibitor treatment. Our results are a contrast to suggestions that subjects with vascular disease show a better response to cholinesterase inhibitors. We recommend careful exploration of factors that may influence outcome.

Current smoking and response to cholinesterase inhibitor therapy in Alzheimer's disease.

Current smoking has been suggested as predicting poor response to cholinesterase inhibitor treatment. This observational study compares response in subjects with NINCDS-ADRDA 'probable' Alzheimer's disease who are current smokers and subjects who are non-smokers. Smoking status was not associated with response. Smokers were significantly more likely to improve Digit Symbol Substitution Test (DSST) scores following treatment. In non-smokers, improvement from baseline DSST scores was associated with good response but this was not the case in smokers. The change in the DSST is in keeping with smokers having increased numbers of nicotinic receptors. In smokers, the lack of association between improvement in DSST scores and good response may be representative of inhibitory properties of cigarette smoke that are unrelated to nicotine.

Association of a salivary acetylcholinesterase with Alzheimer's disease and response to cholinesterase inhibitors.

OBJECTIVES: A decrease in cholinergic activity is a key event in the biochemistry of Alzheimer's disease (AD). The aim of the study was to investigate the expression levels of markers of cholinergic function in saliva, which is a readily accessible body fluid that can be obtained from subjects with minimal distress. DESIGN AND METHODS: Salivary samples were obtained from people with NINCDS-ARDRA "probable" Alzheimer's disease and age- and sex-matched controls. Salivary acetylcholinesterase enzyme (AChE) activity was determined colorometrically. RESULTS: Robust AChE catalytic activity was detected in the saliva samples that was stable for up to 6 h at room temperature following the provision of the salivary sample. The activity of the enzyme was significantly lower in people with AD than in age-matched controls. In addition, there were significant differences in activity between those who responded to acetylcholinesterase inhibitor (AChE-I) therapy and those who did not. CONCLUSIONS: Salivary enzyme activity may therefore prove to be a useful marker of central cholinergic activity.

Memantine (Ebixa) in the later stages of dementia.

Memantine is the first agent licensed for the treatment of moderate to severe Alzheimer's disease. It is an N-methyl D-aspartate (NMDA) receptor antagonist which reduces glutamatergic excitotoxicity. Benefits are seen in cognitive, functional and global measures in both outpatients and nursing home residents. Prospective health economic benefits have been reported.