Oral Tau Aggregation Inhibitor for Alzheimer's Disease: Design, Progress and Basis for Selection of the 16 mg/day Dose in a Phase 3, Randomized, Placebo-Controlled Trial of Hydromethylthionine Mesylate.

BACKGROUND: Hydromethylthionine mesylate is a tau aggregation inhibitor shown to have exposure-dependent pharmacological activity on cognitive decline and brain atrophy in two completed Phase 3 trials in mild/moderate Alzheimer's disease (AD). OBJECTIVES: The present report summarises the basis for selection of 16 mg/day as monotherapy as the optimal treatment regime and the design rationale of a confirmatory Phase 3 trial (LUCIDITY). DESIGN: The trial comprises a 12-month double-blind, placebo-controlled phase followed by a 12-month modified delayed-start open-label treatment phase. SETTING: 76 clinical research sites in North America and Europe. PARTICIPANTS: 545 patients with probable AD or MCI-AD in the final version of the protocol. INTERVENTION: Participants were assigned randomly to receive hydromethylthione mesylate at doses of 16 mg/day, 8 mg/day or placebo at a 4:1:4 ratio during the double-blind phase. All participants in the open-label phase receive the 16 mg/day dose. MEASUREMENTS: Co-primary clinical outcomes are the 11-item Alzheimer's Disease Assessment Scale (ADAS-cog11) and the 23-item Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23). Secondary biomarker measures include whole-brain atrophy and temporal lobe 18F-fluorodeoxyglucose positron emission tomography. RESULTS: 446 participants are expected to complete the 12-month placebo-controlled phase in March 2022. CONCLUSIONS: If the primary end points are met, the data will provide confirmatory evidence of the clinical and biomarker benefits of hydromethylthionine mesylate in minimal to moderate AD. As low-dose oral hydromethylthionine mesylate is simple to use clinically, does not cause amyloid-related imaging abnormalities and has a benign safety profile, it would likely improve AD management.

Study of the use of antidepressants for depression in dementia: the HTA-SADD trial--a multicentre, randomised, double-blind, placebo-controlled trial of the clinical effectiveness and cost-effectiveness of sertraline and mirtazapine.

OBJECTIVE: Depression is common in dementia, causing considerable distress and other negative impacts. Treating it is a clinical priority, but the evidence base is sparse and equivocal. This trial aimed to determine clinical effectiveness of sertraline and mirtazapine in reducing depression 13 weeks post randomisation compared with placebo. DESIGN: Multicentre, parallel-group, double-blind placebo-controlled randomised controlled trial of the clinical effectiveness of sertraline and mirtazapine with 13- and 39-week follow-up. SETTING: Nine English old-age psychiatry services. PARTICIPANTS: A pragmatic trial. Eligibility: probable or possible Alzheimer's disease (AD), depression (4+ weeks) and Cornell Scale for Depression in Dementia (CSDD) score of 8+. EXCLUSIONS: clinically too critical (e.g. suicide risk); contraindication to medication; taking antidepressants; in another trial; and having no carer. INTERVENTIONS: (1) Sertraline; (2) mirtazapine; and (3) placebo, all with normal care. Target doses: 150 mg of sertraline or 45 mg of mirtazapine daily. OUTCOME: CSDD score. Randomisation: Allocated 1 : 1 : 1 through Trials Unit, independently of trial team. Stratified block randomisation by centre, with randomly varying block sizes; computer-generated randomisation. Blinding: Double blind: medication and placebo identical for each antidepressant. Referring clinicians, research workers, participants and pharmacies were blind. Statisticians blind until analyses completed. RESULTS: Numbers randomised: 326 participants randomised (111 placebo, 107 sertraline and 108 mirtazapine). OUTCOME: Differences in CSDD at 13 weeks from an adjusted linear-mixed model: mean difference (95% CI) placebo-sertraline 1.17 (-0.23 to 2.78; p = 0.102); placebo-mirtazapine 0.01 (-1.37 to 1.38; p = 0.991); and mirtazapine-sertraline 1.16 (-0.27 to 2.60; p = 0.112). HARMS: Placebo group had fewer adverse reactions (29/111, 26%) than sertraline (46/107, 43%) or mirtazapine (44/108, 41%; p = 0.017); 39-week mortality equal, five deaths in each group. CONCLUSIONS: This is a trial with negative findings but important clinical implications. The data suggest that the antidepressants tested, given with normal care, are not clinically effective (compared with placebo) for clinically significant depression in AD. This implies a need to change current practice of antidepressants being the first-line treatment of depression in AD. From the data generated we formulated the following recommendations for future work. (1) The secondary analyses presented here suggest that there would be value in carrying out a placebo-controlled trial of the clinical effectiveness and cost-effectiveness of mirtazapine in the management of Behavioural and Psychological Symptoms of Dementia. (2) A conclusion from this study is that it remains both ethical and essential for trials of new medication for depression in dementia to have a placebo arm. (3) Further research is required to evaluate the impact that treatments for depression in people with dementia can have on their carers not only in terms of any impacts on their quality of life, but also the time they spend care-giving. (4) There is a need for research into alternative biological and psychological therapies for depression in dementia. These could include evaluations of new classes of antidepressants (such as venlafaxine) or antidementia medication (e.g. cholinesterase inhibitors). (5) Research is needed to investigate the natural history of depression in dementia in the community when patients are not referred to secondary care services. (6) Further work is needed to investigate the cost modelling results in this rich data set, investigating carer burden and possible moderators to the treatment effects. (7) There is scope for reanalysis of the primary outcome in terms of carer and participant CSDD results.

Determinants of burden in those who care for someone with dementia.

OBJECTIVES: Caregiver burden is a key measure in caregiver research and is frequently used as a baseline measure in intervention studies. Previous research has found numerous factors associated with caregiver burden such as the relationship quality between carer and patient, the patient's cognitive ability, behavioural and psychological symptoms displayed by the patient, caregiver gender, adverse life events to name a few. Many studies have investigated these factors singularly however current thought suggests a multi-factorial role and inter-dependence of these factors. Based on this it was decided to investigate factors associated with caregiver burden using a multiple regression analysis in order to ascertain the predictive quality of these factors of caregiver burden. METHOD: Cross-sectional study using validated measures of a patient's cognitive ability, ability to carry out day-to-day tasks and behavioural and psychological symptoms. Caregiver outcomes used are caregiver burden, relationship quality, caregiver confidence, experience of adverse life events, neuroticism, age and gender. Interviews and questionnaires were carried out on 74 patients diagnosed with dementia and their main caregivers from the Midlands of England. RESULTS: Multiple regression analysis showed that caregiver overload, carer-patient relationship quality, the experience of adverse life events, caregiver gender, caregivers' level of neuroticism, caregiver role captivity and the level of caregiver confidence accounted for over 80% of the variance in caregiver burden. CONCLUSION: These results confirm previous correlational research on caregiver burden. Furthermore, due to the use of multiple regression analysis the findings also show factors that are clear predictors of caregiver burden and we offer possible suggestions from these findings on future clinical practice interventions on caregiver burden.

Aspirin in Alzheimer's disease (AD2000): a randomised open-label trial.

BACKGROUND: Cardiovascular risk factors and a history of vascular disease can increase the risk of Alzheimer's disease (AD). AD is less common in aspirin users than non-users, and there are plausible biological mechanisms whereby aspirin might slow the progression of either vascular or Alzheimer-type pathology. We assessed the benefits of aspirin in patients with AD. METHODS: 310 community-resident patients who had AD and who had no potential indication or definite contraindication for aspirin were randomly assigned to receive open-label aspirin (n=156; one 75-mg enteric-coated tablet per day, to continue indefinitely) or to avoid aspirin (n=154). Primary outcome measures were cognition (assessed with the mini-mental state examination [MMSE]) and functional ability (assessed with the Bristol activities of daily living scale [BADLS]). Secondary outcomes were time to formal domiciliary or institutional care, progress of disability, behavioural symptoms, caregiver wellbeing, and care time. Patients were assessed at 12-week intervals in the first year and once each year thereafter. Analysis of the primary outcome measures was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN96337233. FINDINGS: Patients had a median age of 75 years; 156 patients had mild AD, 154 had moderate AD, and 18 had concomitant vascular dementia. Over the 3 years after randomisation, in patients who took aspirin, mean MMSE score was 0.10 points higher (95% CI -0.37 to 0.57; p=0.7) and mean BADLS score was 0.62 points lower (-1.37 to 0.13; p=0.11) than in patients assigned to aspirin avoidance. There were no obvious differences between the groups in any other outcome measurements. 13 (8%) patients on aspirin and two (1%) patients in the control group had bleeds that led to admission to hospital (relative risk=4.4, 95% CI 1.5-12.8; p=0.007); three (2%) patients in the aspirin group had fatal cerebral bleeds. INTERPRETATION: Although aspirin is commonly used in dementia, in patients with typical AD 2 years of treatment with low-dose aspirin has no worthwhile benefit and increases the risk of serious bleeds.

The effect of the apolipoprotein E gene polymorphisms and haplotypes on behavioural and psychological symptoms in probable Alzheimer's disease.

BACKGROUND: Patients with Alzheimer's disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer's disease has been demonstrated. Several studies have investigated whether the exon 4 epsilon2/epsilon3/epsilon4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results. OBJECTIVE: We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene. METHODS: Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD. RESULTS: We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A-491T with irritability, T-427C with agitation/aggression and appetite disturbances, and T-219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings. CONCLUSIONS: Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.

Proxy completion of EQ-5D in patients with dementia.

There are measurement difficulties associated with the assessment of health-related quality of life (HRQL) in older people with dementia. The use of proxies is a commonly employed approach to overcome such problems. The research reported in this paper sought to identify, specifically for the EuroQol EQ-5D HRQL instrument, whether construct validity is greater for 'family caregivers' or 'clinicians' as two alternative sources of proxy information for patients with a diagnosis of dementia. This involved the exploration of the strength of the associations between clinical measures of illness severity and EQ-5D data. The data appear to reveal a pattern suggesting that the viewpoint of the proxy (i.e., clinician or family caregiver) is important. The findings suggest that the data provided by clinicians (when compared to data from carers) had higher construct validity for the more observable dimensions of the EQ-5D instrument (i.e., 'mobility' and 'self-care'). Conversely, the data from family carers had higher construct validity for the less observable dimensions (i.e., 'usual activities' and 'anxiety/depression'). Previous research on proxy provision of HRQL data has tended to focus on trying to identify a single proxy. The results of this study suggest that using carefully matched sets of measures and assessment perspectives may produce more valid EQ-5D health state descriptions.

Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial.

BACKGROUND: Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? METHODS: 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. FINDINGS: Cognition averaged 0.8 MMSE (mini-mental state examination) points better (95% CI 0.5-1.2; p<0.0001) and functionality 1.0 BADLS points better (0.5-1.6; p<0.0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0.4) or progression of disability (58% vs 59% at 3 years; p=0.4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0.97 (95% CI 0.72-1.30; p=0.8); the relative risk of progression of disability or entering institutional care was 0.96 (95% CI 0.74-1.24; p=0.7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. INTERPRETATION: Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than cholinesterase inhibitors are needed for Alzheimer's disease.

Thiamine for Wernicke-Korsakoff Syndrome in people at risk from alcohol abuse.

BACKGROUND: Autopsy studies suggest that Wernicke-Korsakoff Syndrome (WKS) is not a rare disorder, particularly in individuals who abuse alcohol. Thiamine has been established as the treatment of choice for over 50 years, but there is uncertainty about appropriate dosage and duration. Current practice guidelines are based on case reports and clinical experience. OBJECTIVES: To determine the quality of evidence for the efficacy of thiamine in preventing and treating the manifestations of WKS as a consequence of alcohol excess, and if so in which form it should be given, at what dose and for how long. SEARCH STRATEGY: Trials were identified from the latest updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 3 February 2003 using the terms "(thiamin* or aneurin*) and (Korsakoff* or Wernicke* or alcohol*). The CDCIG Specialized register contains up-to-date records from all major health care databases (Medline, Embase, PsycInfo, Cinahl and others) as well as from many trials databases. SELECTION CRITERIA: All randomized trials in which treatment with thiamine or thiamine-containing products was administered and compared with alternative interventions for people with, or at risk of developing, WKS secondary to alcohol abuse. DATA COLLECTION AND ANALYSIS: All abstracts were independently inspected by two reviewers (ED & PB) and relevant papers were retrieved and assessed for methodological quality using Cochrane Reviewers' Handbook criteria. MAIN RESULTS: Two studies were identified that met the inclusion criteria, but only one contained sufficient data for quantitative analysis. Ambrose (2001) randomized participants (n=107) to one of five doses of intramuscular thiamine and measured outcomes after 2 days of treatment. We compared the lowest dose (5mg/day) with each of the other four doses. There was a significant difference in favour of the 200mg/day compared with the 5 mg/day dose in the number of trials taken to reach criterion on a delayed alternation test (MD -17.90, 95% CI -35.4 to -0.40, p=0.04). No significant differences emerged in comparing the other doses with 5 mg/day. The pattern of results did not present a simple dose-response relationship. The study had methodological shortcomings in design and the presentation of results that limited further analysis. REVIEWER'S CONCLUSIONS: There is insufficient evidence from randomized controlled clinical trials to guide clinicians in the dose, frequency, route or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse.

EQ-5D in patients with dementia: an investigation of inter-rater agreement.

BACKGROUND: There are difficulties in obtaining health-related quality of life (HRQL) data from patients with dementia due to variation in their cognitive ability, degree of insight and capacity to make judgments. The use of proxies is one solution. OBJECTIVES: To examine the inter-rater agreement of patient and proxy completion of the EuroQol EQ-5D instrument (EQ-5D). RESEARCH DESIGN: The EQ-5D instrument was completed separately by patients, their caregivers and a physician. Assessment of inter-rater agreement involved comparison of self-completed (patient) and proxy-completed (caregiver and physician) responses for each dimension of EQ-5D, using a weighted kappa score. Three key hypotheses were tested. (1) Interrater agreement would be stronger between patient and caregiver than between patient and physician. (2) Interrater agreement would be stronger on the 'observable' and objective dimensions of EQ-5D. (3) Interrater agreement between patient and proxies would be stronger for patients with earlier dementia. SUBJECTS: The sample comprised 64 patients with a range of dementia severity. MEASURES: The EQ-5D health state classification system and visual analogue scale were used to assess HRQL. Global severity of dementia was determined using the Clinical Dementia Rating Scale. RESULTS: The principal finding of this study was that responses to EQ-5D questions were highly variable across the three raters such that none of the three hypotheses were strongly supported. CONCLUSIONS: The data provide some support for the use of EQ-5D when interviewer administered. However, there are serious concerns regarding the validity of patient self-rated HRQL data obtained in this study and uncertainty exists regarding who the appropriate proxy should be, as different groups of proxies provide different results. It was not clear whether caregivers or physicians represent better proxies. Further research should focus on the comparison of caregivers and physicians as proxies.

Olfactory identification is impaired in clinic-based patients with vascular dementia and senile dementia of Alzheimer type.

AIMS: It is now well established that there are abnormalities in the sense of smell in patients suffering from Alzheimer's disease (AD). They have both raised olfactory thresholds and impaired odour identification. The situation in vascular dementia is unclear. We used the University of Pennsylvania Smell Identification Test (UPSIT), a 40-item, forced choice, cued, 'scratch-and- sniff' test, to examine olfactory identification in vascular dementia and to determine whether it would differentiate the disorder from AD and normal elderly. METHODS: We investigated three matched subject groups: 13 people having a Cambridge Examination for Mental Disorders in the Elderly (CAMDEX) diagnosis of definite senile dementia of Alzheimer type, 13 having a CAMDEX diagnosis of definite vascular dementia and 13 non-cognitively impaired controls. The subjects were then tested with the UPSIT in their own home by an independent blind researcher to see if the test could distinguish the different diagnostic groups in this setting. RESULTS: The median UPSIT score was 30 (out of a maximum of 40) for controls, 12 for the vascular group and 15 for the AD group. The difference was significant (p = 0.05) between both demented groups and the normal controls. Similarly there was a significant difference in the UPSIT score between the AD group and controls (p = 0.001) and between the vascular dementia group and controls (p = 0.001), but there was no significant difference between the AD group and the vascular dementia group. The UPSIT score correlated strongly with the degree of cognitive impairment as measured by the CAMCOG (r(s) = 0.683, p = 0.01) CONCLUSIONS: Patients with vascular dementia had a similar degree of olfactory impairment to those with AD. The UPSIT successfully differentiated between dementia patients and normal elderly British subjects tested in their own homes. The UPSIT did not differentiate between those with AD and vascular dementia.

Catatonia, autism, and ECT.

We describe the clinical presentation, course, and treatment response of a 14-year-old boy with catatonic stupor. This patient, with a preexisting diagnosis of autism, displayed mutism, akinesia, and an extreme level of rigidity, waxy flexibility, posturing, including the psychological pillow, facial grimacing, and other involuntary movements of his upper extremities. In addition he had symptoms suggestive of a depressive disorder as well as some non-specific psychotic symptoms. Intravenous injection of sodium amytal failed to resolve any motor symptoms, although he showed a good response to the zolpidem test. A course of electroconvulsive therapy (ECT) caused dramatic and sustained relief of catatonic stupor without a change in the symptoms of autism. The presentation of catatonia in autism and the use of ECT in children are discussed, and the available literature reviewed. This is the first description of the use of ECT in the treatment of catatonia coinciding with autism and we confirm its efficacy.

A comparison of semantic memory in vascular dementia and dementia of Alzheimer's type.

OBJECTIVE: To determine whether semantic memory is impaired in vascular dementia and to assess the utility of semantic memory measures in differentiating vascular dementia from dementia of Alzheimer's type (DAT). DESIGN: Case-control study. PATIENTS: Ten patients with Cambridge Mental Disorders in the Elderly (CAMDEX) diagnosis of 'definite' mild or moderate vascular dementia (mean age 77) were individually matched with 10 patients with a CAMDEX diagnosis of 'definite' DAT on the basis of age, education, sex, premorbid IQ (as measured by the National Adult Reading Test) and performance on the Cambridge Cognitive Examination (CAMCOG). In addition, 10 age, sex and education matched volunteer or relative controls were assessed. OUTCOME MEASURES: A detailed semantic memory test battery consisting of five subtests: category fluency, picture naming, picture sorting, word-picture matching and generation of verbal definitions. RESULTS: Compared to normal controls, both patient groups were impaired on all subtests of the semantic battery with the exception of the word-picture matching test. No differences were found between the vascular dementia and DAT groups on any of the measures. CONCLUSIONS: Impairment of semantic memory is a feature of both vascular dementia and DAT. Tests of semantic memory appear, therefore, of little value in differentiating between these two major causes of dementia. Further work is required to determine whether the nature of the processing deficit is the same in these conditions.

Semantic memory is impaired in schizophrenia.

Memory is emerging as a key area of neuropsychological deficit in schizophrenia, with evidence suggesting that the impairment is restricted to long-term memory. Semantic memory, the component of long-term memory containing stored representations of the meanings of words and knowledge about the world, was examined in 46 schizophrenic patients and 40 normal controls using a recently devised battery of tests. Evidence of semantic memory impairment was found which was wide ranging and substantial; in some cases it approached the levels seen in a group of 22 patients with mild-to-moderate Alzheimer's disease. Both group analysis and a more detailed examination of two single cases suggested that semantic memory impairment represents a disproportionate and possibly specific neuropsychological deficit in schizophrenia.

Bioavailability of griseofulvin from a novel capsule formulation.

The in vivo availability of griseofulvin from a novel formulation has been compared with the micronized powder. The formulation technique involves the conversion of the hydrophobic surface of the drug to a hydrophilic one by treatment with a film forming polymer. This enhances the wettability of the power, and increases its dissolution rate. The results of the in vivo study show the formulation technique has increased the rate and extent of bioavailability of griseofulvin when compared with the non-treated powder.