Anticholinergic drug use and risk of mortality for people with dementia in Northern Ireland.

OBJECTIVE: Anticholinergic burden refers to the cumulative effect of medications which contain anticholinergic properties. We assessed how anticholinergic burden and different types of anticholinergic medications influence mortality rates among people with dementia in Northern Ireland. Our secondary aim was to determine what demographic characteristics predict the anticholinergic burden of people with dementia. METHODS: Data were extracted from the Enhanced Prescribing database for 25,418 people who were prescribed at least one dementia management medication between 2010 and 2016. Information was also extracted on the number of times each available anticholinergic drug was prescribed between 2010 and 2016, allowing the calculation of an overall anticholinergic burden. Cox proportional hazard models were used to determine how anticholinergic burden influenced mortality whilst multilevel model regression determined what demographic characteristics influence overall anticholinergic burden. RESULTS: Of the 25,418 people with dementia, only 15% (n = 3880) had no anticholinergic burden. Diazepam (42%) and risperidone (18%) were the two most commonly prescribed drugs. Unadjusted Cox proportional hazard models indicated that higher anticholinergic burden was associated with significantly higher mortality rates in comparison to people with dementia who had no anticholinergic burden (HR = 1.59: 95% CI = 1.07-2.36). In particular, urological (HR = 1.20: 95% CI = 1.05-1.38) and respiratory (HR = 1.17: 95% CI = 1.08-1.27) drugs significantly increased mortality rates. People with dementia living in areas with low levels of deprivation had significantly lower anticholinergic burden (HR=-.39: 95% CI=-.47:-30). CONCLUSIONS: Reducing anticholinergic burden is essential for people with dementia. Further research should address the unfavourable prognosis of people living with dementia in highly deprived areas.

Dementia.

Dementia is a clinical diagnosis requiring new functional dependence on the basis of progressive cognitive decline. It is estimated that 1.3% of the entire UK population, or 7.1% of those aged 65 or over, have dementia. Applying these to 2013 population estimates gives an estimated number of 19,765 people living with dementia in Northern Ireland. The clinical syndrome of dementia can be due to a variety of underlying pathophysiological processes. The most common of these is Alzheimer's disease (50-75%) followed by vascular dementia (20%), dementia with Lewy bodies (5%) and frontotemporal lobar dementia (5%). The clinical symptoms and pathophysiological processes of these diseases overlap significantly. Biomarkers to aid diagnosis and prognosis are emerging. Acetylcholinesterase inhibitors and memantine are the only medications currently licensed for the treatment of dementia. The nature of symptoms mean people with dementia are more dependent and vulnerable, both socially and in terms of physical and mental health, presenting evolving challenges to society and to our healthcare systems.

Cause of death in Alzheimer's disease: a cohort study.

BACKGROUND: Reporting of cause of death in patients with Alzheimer's disease (AD) has changed over the past few decades but concerns persist over the accuracy of death certificate completion in this setting. OBJECTIVES: To examine the causes of death in AD and examine how this compares with those affecting the normal population. METHODS: Death certificates were obtained for 85 AD patients and 52 control subjects from a cohort of 396 participants. Underlying causes of death and other conditions mentioned on the death certificates of the AD patients were analysed and compared with the Northern Ireland population age-and-sex adjusted mortality rates and subsequently to the death certificates of control subjects. RESULTS: AD and pneumonia were causes of significant excess mortality and the most common underlying causes of death in the AD patient group (23.53 and 17.65%, respectively). When compared with the control subjects, AD and gastrointestinal diseases were found to be more prevalent. AD was recorded on 63.5% of death certificates of AD subjects who died during follow-up. CONCLUSION: The cause of death documented for AD patients may be affected by the physician's knowledge of the patient or reflects the approach to management of patients with end-stage dementia.

Effect of apolipoprotein E and butyrylcholinesterase genotypes on cognitive response to cholinesterase inhibitor treatment at different stages of Alzheimer's disease.

Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

Executive functioning in Alzheimer's disease and vascular dementia.

OBJECTIVE: To compare performance of patients with mild-moderate Alzheimer's disease (AD) and vascular dementia (VaD) on tests of executive functioning and working memory. METHODS: Patients with AD (n = 76) and VaD (n = 46) were recruited from a memory clinic along with dementia free participants (n = 28). They underwent specific tests of working memory from the Cognitive Drug Research (CDR) battery and pen and paper tests of executive function including CLOX 1 & 2, EXIT25 and a test of verbal fluency (COWAT). All patients had a CT brain scan which was independently scored for white matter change/ischaemia. RESULTS: The AD and VaD groups were significantly impaired on all measures of working memory and executive functioning compared to the disease free group. There were no significant differences between the AD and VaD groups on any measure. Z-scores confirmed the pattern of impairment in executive functioning and working memory was largely equivalent in both patient groups. Small to moderate correlations were seen between the MMSE and the neurocognitive scores in both patient groups and the pattern of correlations was also very similar in both patient groups. CONCLUSIONS: This study demonstrates sizeable executive functioning and working memory impairments in patients with mild-moderate AD and VaD but no significant differences between the disease groups.

BACE1 polymorphisms do not influence platelet membrane beta-secretase activity or genetic susceptibility for Alzheimer's disease in the Northern Irish population.

Beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer's disease (AD). BACE1 is a protease that catalyses APP cleavage at the beta-secretase site. We evaluated all common and putatively functional polymorphisms in the genomic region encompassing BACE1 for an association with AD, and for functional effects on platelet beta-secretase activity. Tag SNPs (n = 10) derived from phase II of the International HapMap Project, and a nonsynonymous variant, were successfully genotyped in 901 Caucasian individuals from Northern Ireland using Sequenom iPLEX and TaqMan technologies. APOE genotyping was performed by PCR-RFLP. Platelet membrane beta-secretase activity was assayed in a subset of individuals (n = 311). Hardy-Weinberg equilibrium was observed for all variants. Evidence for an association with AD was observed with multi-marker haplotype analyses (P = 0.01), and with rs676134 when stratified for APOE genotype (P = 0.02), however adjusting for multiple testing negated the evidence for association of this variant with AD. chi(2) analysis of genotype and allele frequencies in cases versus controls for individual SNPs revealed no evidence for association (5% level). No genetic factors were observed that significantly influenced platelet membrane beta-secretase activity. We have selected an appropriate subset of variants suitable for comprehensive genetic investigation of the BACE1 gene. Our results suggest that common BACE1 polymorphisms and putatively functional variants have no significant influence on genetic susceptibility to AD, or platelet beta-secretase activity, in this Caucasian Northern Irish population.

Platelet beta-secretase activity is increased in Alzheimer's disease.

beta-Secretase activity is the rate-limiting step in Abeta peptide production from amyloid precursor protein. Abeta is a major component of Alzheimer's disease (AD) cortical amyloid plaques. beta-Secretase activity is elevated in post mortem brain tissue in AD. The current study investigated whether beta-secretase activity was also elevated in peripheral blood platelets. We developed a novel fluorimetric beta-secretase activity assay to investigate platelets isolated from individuals with AD (n=86), and age-matched controls (n=115). Platelet membrane beta-secretase activity (expressed as initial rate) varied over fourfold between individuals, raising important questions about in vivo regulation of this proteolytic activity. Nonetheless, we identified a significant 17% increase in platelet membrane beta-secretase activity in individuals with AD compared to controls (p=0.0003, unpaired t-test). Platelet membrane beta-secretase activity did not correlate with mini-mental state examination (MMSE) score in the AD group (mean MMSE=17.7, range 1-23), indicating that the increase did not occur as a secondary result of the disease process, and may even have preceded symptom onset.

Alpha7 nicotinic acetylcholine receptor gene and reduced risk of Alzheimer's disease.

BACKGROUND: Sporadic Alzheimer's disease (AD) is a common disabling disease of complex aetiology for which there are limited therapeutic options. We sought to investigate the role of the alpha7 nicotinic acetylcholine receptor gene (CHRNA7) in influencing risk of AD in a large population. CHRNA7 is a strong candidate gene for AD for several reasons: (1) its expression is altered differentially in the AD brain; (2) it interacts directly with beta amyloid peptide (Abeta(42)); and (3) agonist activation induces several neuroprotective pathways. METHODS: In this study we used a genetic haplotype approach to assess the contribution of common variation at the CHRNA7 locus to risk of AD. Fourteen single nucleotide polymorphisms (SNPs) were genotyped in 764 AD patients and 314 controls. RESULTS: Three blocks of high linkage disequilibrium (LD) and low haplotype diversity were identified. The block 1 TCC haplotype was significantly associated with reduced odds of AD (p = 0.001) and was independent of apolipoprotein E (APOE) status. Individual SNPs were not associated with risk for AD. CONCLUSIONS: We conclude that genetic variation in CHRNA7 influences susceptibility to AD. These results provide support for the development of alpha7nAChR agonists or modulators as potential drug treatments for AD. Further work is necessary to replicate the findings in other populations.

Elevated platelet beta-secretase activity in mild cognitive impairment.

BACKGROUND/AIMS: We have recently reported that platelet activity of the rate-limiting enzyme for beta-amyloid peptide production is elevated in established Alzheimer's disease. Laboratory investigation of the very early stages of dementia provides an opportunity to investigate pathological mechanisms before advanced disease hinders interpretation. Mild cognitive impairment (MCI) exists prior to obvious dementia, and is associated with increased risk of conversion to overt disease. METHODS: We developed and used a fluorimetric assay to quantify platelet membrane beta-secretase activity in 52 patients with MCI and 75 controls. RESULTS: Platelet membrane beta-secretase activity was 24% higher in individuals with MCI compared to controls (p = 0.001, unpaired t test with Welch correction). CONCLUSION: Elevated platelet beta-secretase activity in subjects with MCI is an area for further study in relation to the etiology and diagnosis of MCI.

Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease.

Several lines of evidence indicate that the Abeta peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Abeta is generated by cleavage of the Met-Asp bond at position 671-672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called beta-secretase. Two 'beta-secretase' proteases have been identified: BACE (beta-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/beta-secretase activity in brain regions affected by the disease. We have demonstrated that robust beta-secretase activity is also detectable in platelets that contain APP and release Abeta. This review considers the current evidence for alterations in beta-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

Behavioural and psychological syndromes in Alzheimer's disease.

OBJECTIVES: The origins of behavioural and psychological symptoms of dementia are still poorly understood. By focusing on piecemeal behaviours as opposed to more robust syndrome change valid biological correlates may be overlooked. Our understanding of BPSD via the identification of neuropsychiatric syndromes. METHODS: We recruited 435 subjects from old age psychiatry and elderly care memory outpatient clinics fulfilling the criteria for diagnosis of probable Alzheimer's disease. Behavioural and psychological symptoms were assessed using the Neuropsychiatric Inventory. Principal components factor analysis was carried out on the composite scores of the 12 symptom domains to identify behavioural syndromes (factors). Results were confirmed by performing three different rotations: Varimax, Equamax and Quartimax. RESULTS: Four factors were identified (which accounted for 57% of the variance): 'affect' factor-depression/dysphoria, anxiety, irritability/lability and agitation/aggression; 'physical behaviour' factor-apathy, aberrant motor behaviour, sleep disturbance and appetite/eating disturbance; 'psychosis' factor-delusions and hallucinations; 'hypomania' factor-disinhibition and elation/euphoria. These groups were unchanged when different methods of rotation were used. CONCLUSIONS: We report novel observations that agitation/aggression/irritability cluster within a depressive symptom factor and apathy is found within a physical behaviour factor.

Apolipoprotein E e4 allele influences aggressive behaviour in Alzheimer's disease.

The rising number of people with cognitive impairment is placing health care budgets under significant strain. Dementia related behavioural change is a major independent risk factor for admission to expensive institutional care, and aggressive symptoms in particular are poorly tolerated by carers and frequently precipitate the collapse of home coping strategies. Aggressive change may result from known genetic risk factors for Alzheimer's disease (AD) and therefore accompany conventional markers such as apolipoprotein E (ApoE). We tested this hypothesis in 400 moderately to severely affected AD patients who were phenotyped for the presence of aggressive or agitated behaviour during the month prior to interview using the Neuropsychiatric Inventory with Caregiver Distress. The proportion of subjects with aggression/agitation in the month prior to interview was 51.8%. A significantly higher frequency of the e4 allele was found in individuals recording aggression/agitation in the month prior to interview (chi2 = 6.69, df = 2, p = 0.03). The additional risk for aggression/agitation conferred by e4 was also noted when e4 genotypes were compared against non-e4 genotypes (chi2 = 5.45, df = 1, p = 0.02, OR = 1.60, confidence interval (CI) 1.06 to 2.43). These results indicate that advanced Alzheimer's disease patients are at greater risk of aggressive symptoms because of a genetic weakness in apolipoprotein E.

A 6-month open-label study of the effectiveness and tolerability of galantamine in patients with Alzheimer's disease.

The objective of this study was to assess the effectiveness and tolerability of galantamine in patients with mild-to-moderate Alzheimer's disease (AD) in everyday clinical practice. Patient selection was made on 36 sequential patients attending Belfast City Hospital Memory Clinic between December 2000 and June 2001. Patients were treated with galantamine for 6 months, starting from 4 mg twice daily increasing to 8 mg twice daily and then to 12 mg twice daily at 4-weekly intervals. Patients (25 females, 11 males), mean age 78 years (59-90), were diagnosed with probable AD and had a mini-mental state examination (MMSE) score of 10-26. Efficacy was assessed using the MMSE, neuropsychiatric inventory (NPI), neuropsychiatric inventory caregiver distress (NPI-D) scale and the Bristol activities of daily living (B-ADL) scale at baseline and after 3 and 6 months of treatment. Mean improvements were noted on all four measures of efficacy at 3 and 6 months; improvements were significant on the MMSE, NPI and NPI-D at 3 months and on the NPI-D at 6 months. Galantamine was overall well tolerated. The most common adverse events were gastrointestinal, particularly nausea. Four patients stopped treatment due to adverse events, and seven were stabilised on 8 mg twice daily as they were unable to tolerate the target dose. This naturalistic study confirms clinical trial data, which shows galantamine improves cognition and behavioural symptoms and is overall well tolerated.

DemTect: a new, sensitive cognitive screening test to support the diagnosis of mild cognitive impairment and early dementia.

OBJECTIVES: To design a new, highly sensitive psychometric screening to identify patients with mild cognitive impairment (MCI) and patients with dementia in the early stages of the disease. METHODS: Five tasks were included in the DemTect: a word list, a number transcoding task, a word fluency task, digit span reverse, and delayed recall of the word list. The normation was performed with 145 healthy control subjects (CG). Furthermore, 97 MCI patients and 121 patients with possible Alzheimer's disease (AD) were tested with the DemTect and the MMSE. Classification rates for both tests were analysed. RESULTS: On the basis of the CG data, age-dependant transformation algorithms for the DemTect subtests were defined, and an education correction was provided for the total transformed score. The patient groups scored significantly below the CG in both the DemTect and the MMSE. Compared to the MMSE, classification rates of the DemTect were superior for both the MCI and the AD group, with high sensitivities of 80% and 100%, respectively. CONCLUSIONS: The DemTect is short (8-10 minutes), easy to administer, and its transformed total score (maximum 18) is independent of age and education. The DemTect helps in deciding whether cognitive performance is adequate for age (13-18 points), or whether MCI (9-12 points) or dementia (8 points or below) should be suspected.

A retrospective study of the behavioural and psychological symptoms of mid and late phase Alzheimer's disease.

AIM: To document the behavioural and psychological symptoms in patients with a diagnosis of established Alzheimer's disease (AD) for at least 3 years. METHODS: Patients with a > or =3 year history of AD (NINCDS/ADRDA) were recruited from old age psychiatrist and elderly care memory clinics. Information regarding duration of symptoms and non-cognitive symptomatology was obtained during interview with a carer or next-of-kin who had contact with the patient at least 3 times a week and for at least 3 years. MMSE, FAST and NPI including caregiver distress, were used to assess cognition, function and behavioural/psychological disturbance respectively. With each non-cognitive symptom the carer was asked to estimate its onset. RESULTS: The mean age of patients was 77 years and duration of illness 87 months. Mean MMSE was 8/30 and FAST score 6d. Of the psychological symptoms occurring at any stage, depression (56%), delusions (55%) and anxiety (52%) were most common, with hallucinations, elation and disinhibition occurring less frequently. In general, behavioural changes were more common with apathy occurring in 88% of patients, motor behaviour in 70%, aggression in 66%, irritability and appetite changes in 60% and sleep disturbance in 54%. All symptoms except apathy became less common when the carer was asked if they were still present in the last month. Mean onset of psychological symptoms was 47 months. Mean onset of behavioural symptoms was 48 months. Behavioural disturbance seemed to cause more care-giver distress than psychological change. CONCLUSION: The results show behavioural and psychological symptoms in AD are common and distressing for carers. They appear to require a consistent period of neurodegeneration in order to emerge.

A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease.

This 12-week, multinational study compared the tolerability and cognitive effects of donepezil (up to 10 mg once daily) and rivastigmine (up to 6 mg twice daily) in 111 patients with mild to moderate Alzheimer's disease. Both medications were administered open label according to recommended dosing regimens from the respective product labelling available during the conduct of the study. More patients in the donepezil group (89.3%) completed the study compared with the rivastigmine group (69.1%; p=0.009), and 10.7% of the donepezil group and 21.8% of the rivastigmine group discontinued due to adverse events (AEs); 87.5% of donepezil-treated patients and 47.3% of rivastigmine-treated patients remained on the maximum approved dose of each drug at the last study visit. Both groups showed comparable improvements on the ADAS-cog administered by raters blind to study medication at weeks 4 and 12. Thus, using the recommended dosing schedules, donepezil was better tolerated with fewer discontinuations due to AEs, and both agents improved cognition to a similar extent.