Craig W. Ritchie

Rapid Restoration of Cognition in Alzheimer's Transgenic Mice with 8-Hydroxy Quinoline Analogs Is Associated with Decreased Interstitial Aβ

As a disease-modifying approach for Alzheimers disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

The incidence of delirium associated with orthopedic surgery: a meta-analytic review

BACKGROUND The aim of this study was to perform a systematic review and meta-analysis of the literature regarding the incidence of delirium following orthopedic surgery. METHODS Relevant papers were sourced from online databases and gray literature. Included studies used a validated diagnostic method to measure the incidence of delirium in a prospective sample of adult/elderly orthopedic patients. Data were subject to meta-analysis after stratification by type of surgery (elective v. emergency) and inclusion/exclusion of pre-existing cognitive impairment. A funnel plot assessed for publication bias. RESULTS 26 publications reported an incidence of postoperative delirium of 4-53.3% in hip fracture samples and 3.6-28.3% in elective samples. Significant heterogeneity was evident, and this persisted despite stratification. Hip fracture was associated with a higher risk of delirium than elective surgery both when the cognitively impaired were included in the sample (random effects pooled estimate = 21.7% [95% CI = 14.6-28.8] vs. 12.1% [95% CI = 9.6-14.6]), and when the cognitively impaired were excluded (random effects pooled estimate = 25% [95% CI = 15.7-34.7] vs. 8.8% [95% CI = 4.1-13.6]). The funnel plot showed a deficit of small studies showing low risk and large studies showing high risk. In eight hip fracture studies, the proportion of delirium cases with a preoperative onset ranged from 34 to 92%. CONCLUSIONS Delirium occurs more commonly with hip fracture than elective surgery, and frequently has a preoperative onset when associated with trauma. Recommendations are made with the aim of standardizing future research in order to further explore and reduce the heterogeneity and possible publication bias observed.

Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology:

The British Association for Psychopharmacology coordinated a meeting of experts to review and revise its previous 2011 guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A–D, with A having the strongest evidence base (from randomised controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and both structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography and single photon emission computerised tomography) brain imaging can improve diagnostic accuracy in particular situations (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for cognition in mild to moderate Alzheimer’s disease (A), memantine for moderate to severe Alzheimer’s disease (A) and combination therapy (cholinesterase inhibitors and memantine) may be beneficial (B). Drugs should not be stopped just because dementia severity increases (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E, nutritional supplements and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer’s disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (both Parkinson’s disease dementia and dementia with Lewy bodies), and memantine may be helpful (A). No drugs are clearly effective in vascular dementia, though cholinesterase inhibitors are beneficial in mixed dementia (B). Early evidence suggests multifactorial interventions may have potential to prevent or delay the onset of dementia (B). Though the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition in those with or at high risk of Alzheimer’s disease are in progress. Though results of pivotal studies in early (prodromal/mild) Alzheimer’s disease are awaited, results to date in more established (mild to moderate) Alzheimer’s disease have been equivocal and no disease modifying agents are either licensed or can be currently recommended for clinical use.

A systematic review of the scientific evidence for the efficacy of a palliative care approach in advanced dementia

BACKGROUND Patients with dementia often receive poor end-of-life care, with inadequate pain control and without access to the palliative care services that patients with cancer are offered. This has been identified as an area of need in recent UK. Government reports and by the Alzheimers Society (UK). Our objective was to perform a systematic review of the scientific literature regarding the efficacy of a palliative care model in patients with dementia. METHODS A systematic review was carried out to identify controlled trials that investigated the efficacy of palliative care in patients with dementia. Data sources included were Medline, EMBASE, PsycINFO, CINAHL, British Nursing Index, AMED, Cochrane Database of Systematic Reviews, Web of Science, Cochrane Central Register of Controlled Trials, International Standard Randomised Controlled Trial register, the NHS Economic Evaluation Database and the System for Information on Grey Literature in Europe. Other data was sourced from hand searches of papers identified on electronic databases and review articles. RESULTS The search identified 30 review articles, but only four papers were eligible for full appraisal and only two of these met the full criteria for inclusion. These papers gave equivocal evidence of the efficacy for a palliative model of care in dementia. CONCLUSION Despite the increased interest in palliative care for patients with dementia there is currently little evidence on which to base such an approach. This may in part be due to the ethical difficulties surrounding such research, prognostic uncertainty in clinicians and the lack of clear outcome measures for patients who are unable to express their needs or wishes. Further systematic research is urgently needed to educate an important and developing area of clinical practice.

Development of interventions for the secondary prevention of Alzheimer's dementia: the European Prevention of Alzheimer's Dementia (EPAD) project

Alzheimers dementia affects more than 40 million people worldwide with substantial increases in prevalence anticipated. Interventions that either modify risk or reduce the development of early disease could delay the onset of dementia or reduce the rate of cognitive and functional decline. The European Prevention of Alzheimers Dementia (EPAD) is a public-private consortium, funded by the Innovative Medicines Initiative, designed to increase the likelihood of successful development of new treatments for the secondary prevention of Alzheimers dementia. EPAD will help with testing of different agents in this pre-dementia population through four components: improvement of access to existing cohorts and registries, development of the EPAD Registry of approximately 24,000 people who might be at increased risk of developing Alzheimers dementia, establishment of the EPAD Longitudinal Cohort Study of 6000 people at any one time, and establishment of an adaptive, proof-of-concept trial including 1500 participants at any given time. The need for EPAD and its key design elements are described, and we discuss EPAD in relation to similar projects in progress. These parallel efforts reflect the need for a coordinated, worldwide battle against dementia, in which EPAD will play a crucial role.

Metal-protein attenuating compounds and Alzheimer's disease

Since the description of the amyloid plaque in the pathology of Alzheimer’s disease, one of the main focuses of research has been the role of the amyloid precursor protein metabolite amyloid-β, which is the constituent protein of plaque. Affecting the production, aggregation or clearance of this protein may well have a modifying effect on disease progression. Although available therapies for Alzheimer’s disease may interact with amyloid-β in vivo, no conspicuous disease-modifying effect has been demonstrated in clinical trials with these drugs. Drugs whose primary target is not the rectification of the neurotransmitter deficits associated with Alzheimer’s disease but rather the life cycle of amyloid-β are currently being developed with varying degrees of success. Of these drugs, the metal-protein attenuating compounds have currently the most encouraging clinical data supporting their use. Clioquinol is an example from this class, which has recently shown encouraging efficacy from early clinical evaluation in the absence of any compelling evidence of subacute myelopathic optic neuritis, which has been associated with this drug’s use in Japanese populations. This article will discuss the scientific rationale behind the use of metal-protein attenuating compounds in Alzheimer’s disease and summarise the available clinical trial data.

Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses

BACKGROUND Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimers disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimers disease. METHODS In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimers Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimers disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. FINDINGS Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue donepezil and start memantine, and 73 (25%) to continue donepezil and start memantine. 162 (55%) patients underwent nursing home placement within 4 years of randomisation, with similar numbers for all groups (36 [49%] in patients who continued donepezil without memantine, 42 [58%] who discontinued donepezil without memantine, 41 [54%] who discontinued donepezil and started memantine, and 43 [59%] who continued donepezil and started memantine). We noted significant (p=0·010) heterogeneity of treatment effect over time, with significantly more nursing home placements in the combined donepezil discontinuation groups during the first year (hazard ratio 2·09 [95% CI 1·29-3·39]) than in the combined donepezil continuation groups, and no difference during the next 3 years (0·89 [0·58-1·35]). We noted no effect of patients starting memantine compared with not starting memantine during the first year (0·92 [0·58-1·45]) or the next 3 years (1·23 [0·81-1·87]). INTERPRETATION Withdrawal of donepezil in patients with moderate-to-severe Alzheimers disease increased the risk of nursing home placement during 12 months of treatment, but made no difference during the following 3 years of follow-up. Decisions to stop or continue donepezil treatment should be informed by potential risks of withdrawal, even if the perceived benefits of continued treatment are not clear. FUNDING Medical Research Council and UK Alzheimers Society.

Safety, tolerability, and efficacy of PBT2 in Huntington's disease: a phase 2, randomised, double-blind, placebo-controlled trial

BACKGROUND PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntingtons disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntingtons disease. METHODS In this 26-week, randomised, double-blind, placebo-controlled trial, adults (≥25 years old) with early-stage to mid-stage Huntingtons disease were randomly assigned (1:1:1) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests (Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test) and scores on eight individual cognitive tests (the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with ClinicalTrials.gov, NCT01590888. FINDINGS Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg (n=36), PBT2 100 mg (n=38), or placebo (n=35) at 19 research centres in Australia and the USA. 32 (89%) individuals on PBT2 250 mg, 38 (100%) on PBT2 100 mg, and 34 (97%) on placebo completed the study. Six serious adverse events (acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntingtons disease) occurred in five participants in the PBT2 250 mg group, three (fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntingtons disease) occurred in two participants in the PBT2 100 mg group, and one (increasing aggression) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntingtons disease, as unrelated to study drug. 32 (89%) participants on PBT2 250 mg, 30 (79%) on PBT2 100 mg, and 28 (80%) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg (least-squares mean 0·02, 95% CI -0·10 to 0·14; p=0·772) nor PBT2 250 mg (0·07, -0·05 to 0·20; p=0·240) significantly improved the main composite cognition Z score between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group (17·65 s, 0·65-34·65; p=0·042) but not in the 100 mg group (0·79 s improvement, -15·75 to 17·32; p=0·925); neither dose significantly improved cognition on the other tests. INTERPRETATION PBT2 was generally safe and well tolerated in patients with Huntingtons disease. The potential benefit on executive function will need to be confirmed in a larger study. FUNDING Prana Biotechnology Limited.

Detecting cognitive changes in preclinical Alzheimer's disease: A review of its feasibility

Significant progress has been made in characterizing the biological changes occurring in preclinical Alzheimers disease (AD). Cognitive dysfunction has been viewed, however, as a late‐stage phenomenon, despite increasing evidence that changes may be detected in the decades preceding dementia. In the absence of comprehensive evidence‐based guidelines for preclinical cognitive assessment, longitudinal cohort and neuroimaging studies have been reviewed to determine the temporal order and brain biomarker correlates of specific cognitive functions. Episodic memory decline was observed to be the most salient cognitive function, correlating with high levels of amyloid deposition and hypoconnectivity across large‐scale brain networks. Prospective studies point to early decline in both episodic and semantic memory processing as well as executive functions in the predementia period. The cognitive tests have, however, been principally those used to diagnose dementia. New procedures are required which target more finely the medial temporal lobe subregions first affected by clinically silent AD pathology.

Recommended cognitive outcomes in preclinical Alzheimer's disease: Consensus statement from the European Prevention of Alzheimer's Dementia project

The Horizon 2020/IMI European Prevention of Alzheimers Dementia (EPAD) project will undertake large‐scale proof‐of‐concept trials in predementia Alzheimers disease (AD). Within EPAD, the monitoring of cognitive trajectories in the preclinical period will constitute a central outcome measure; however, there are currently no clear guidelines as to how this should be achieved as most measures have been developed for the period around dementia diagnosis. The EPAD Scientific Advisory Group for Clinical and Cognitive Outcomes identified appropriate cognitive measures based on a literature search covering both cognitive correlates of preclinical brain changes from imaging studies and cognitive changes observed over time in nondementia population cohorts developing incident dementia. These measures were evaluated according to the following criteria: validity, coherence with biomarker changes, psychometric properties, cross‐cultural suitability, availability of alternative forms, and normative data limited practice effects. The resulting consensus statement provides recommendations for both future drug trials and research into preclinical Alzheimers disease.