Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

OBJECTIVE: To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). METHODS: 142 DIAD mutation carriers received either gantenerumab SC (n = 52), solanezumab IV (n = 50), or placebo (n = 40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, ß-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. RESULTS: Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR] = 9.1, confidence interval [CI][1.2, 412.3]; p = 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR = 5.0, CI[1.0, 30.4]; p = 0.055), as were individuals with microhemorrhage at baseline (OR = 13.7, CI[1.2, 163.2]; p = 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. INTERPRETATION: In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-ß monoclonal antibodies in dominantly inherited Alzheimer's disease.

PURPOSE: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-ß (Aß) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aß monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aß radiotracers were used. To study the consequences of using different Aß radiotracers to measure Aß clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aß monoclonal antibodies. METHODS: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aß PET imaging. RESULTS: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aß radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aß radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aß radiotracers were used versus trials where only one Aß radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. CONCLUSION: Gantenerumab treatment induces longitudinal changes in Aß PET, and the absolute rates of these longitudinal changes differ significantly between Aß radiotracers. These differences were not seen in the placebo arm, suggesting that Aß-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aß radiotracers. Our results suggest converting Aß PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aß PET biomarker data and, if feasible, use a single radiotracer for the best results. TRIAL REGISTRATION: ClinicalTrials.gov NCT01760005. Registered 31 December 2012. Retrospectively registered.

Comparison of the Quick Mild Cognitive Impairment (Qmci) screen to the Montreal Cognitive Assessment (MoCA) in an Australian geriatrics clinic.

INTRODUCTION: The Montreal Cognitive Assessment (MoCA) accurately differentiates mild cognitive impairment (MCI) from mild dementia and normal controls (NC). While the MoCA is validated in multiple clinical settings, few studies compare it with similar tests also designed to detect MCI. We sought to investigate how the shorter Quick Mild Cognitive Impairment (Qmci) screen compares with the MoCA. METHODS: Consecutive referrals presenting with cognitive complaints to a teaching hospital geriatric clinic (Fremantle, Western Australia) underwent a comprehensive assessment and were classified as MCI (n = 72) or dementia (n = 109). NC (n = 41) were a sample of convenience. The Qmci and MoCA were scored by trained geriatricians, in random order, blind to the diagnosis. RESULTS: Median Qmci scores for NC, MCI and dementia were 69 (+/-19), 52.5 (+/-12) and 36 (+/-14), respectively, compared with 27 (+/-5), 22 (+/-4) and 15 (+/-7) for the MoCA. The Qmci more accurately identified cognitive impairment (MCI or dementia), area under the curve (AUC) 0.97, than the MoCA (AUC 0.92), p = 0.04. The Qmci was non-significantly more accurate in distinguishing MCI from controls (AUC 0.91 vs 0.84, respectively = 0.16). Both instruments had similar accuracy for differentiating MCI from dementia (AUC of 0.91 vs 0.88, p = 0.35). At the optimal cut-offs, calculated from receiver operating characteristic curves, the Qmci (≤57) had a sensitivity of 91% and specificity of 93% for cognitive impairment, compared with 87% sensitivity and 80% specificity for the MoCA (≤23). CONCLUSION: While both instruments are accurate in detecting MCI, the Qmci is shorter and arguably easier to complete, suggesting that it is a useful instrument in an Australian geriatric outpatient population. Copyright © 2016 John Wiley & Sons, Ltd.

Habitual exercise levels are associated with cerebral amyloid load in presymptomatic autosomal dominant Alzheimer's disease.

INTRODUCTION: The objective of this study was to evaluate the relationship between self-reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers. METHODS: In 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self-reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aß42, and CSF tau levels was evaluated using linear regression. RESULTS: No differences in brain amyloid load, CSF Aß42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels. DISCUSSION: Our findings indicate a relationship exists between self-reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.

The inter-rater reliability of the Risk Instrument for Screening in the Community.

Predicting risk of adverse healthcare outcomes is important to enable targeted delivery of interventions. The Risk Instrument for Screening in the Community (RISC), designed for use by public health nurses (PHNs), measures the 1-year risk of hospitalisation, institutionalisation and death in community-dwelling older adults according to a five-point global risk score: from low (score 1,2) to medium (3) to high (4,5). We examined the inter-rater reliability (IRR) of the RISC between student PHNs (n=32) and expert raters using six cases (two low, medium and high-risk), scored before and after RISC training. Correlations increased for each adverse outcome, statistically significantly for institutionalisation (r=0.72 to 0.80, p=0.04) and hospitalisation (r=0.51 to 0.71, p<0.01) but not death. Training improved accuracy for low-risk but not all high-risk cases. Overall, the RISC showed good IRR, which increased after RISC training. That reliability fell for some high-risk cases suggests that the training programme requires adjustment to improve IRR further.

Predicting Outcomes in Frail Older Community-Dwellers in Western Australia: Results from the Community Assessment of Risk Screening and Treatment Strategies (CARTS) Programme.

Understanding risk factors for frailty, functional decline and incidence of adverse healthcare outcomes amongst community-dwelling older adults is important to plan population-level health and social care services. We examined variables associated with one-year risk of institutionalisation, hospitalisation and death among patients assessed in their own home by a community-based Aged Care Assessment Team (ACAT) in Western Australia. Frailty and risk were measured using the Clinical Frailty Scale (CFS) and Risk Instrument for Screening in the Community (RISC), respectively. Predictive accuracy was measured from the area under the curve (AUC). Data from 417 patients, median 82 ± 10 years, were included. At 12-month follow-up, 22.5% (n = 94) were institutionalised, 44.6% (n = 186) were hospitalised at least once and 9.8% (n = 41) had died. Frailty was common, median CFS score 6/9 ± 1, and significantly associated with institutionalisation (p = 0.001), hospitalisation (p = 0.007) and death (p < 0.001). Impaired activities of daily living (ADL) measured on the RISC had moderate correlation with admission to long-term care (r = 0.51) and significantly predicted institutionalisation (p < 0.001) and death (p = 0.01). The RISC had the highest accuracy for institutionalisation (AUC 0.76). The CFS and RISC had fair to good accuracy for mortality (AUC of 0.69 and 0.74, respectively), but neither accurately predicted hospitalisation. Home assessment of community-dwelling older patients by an ACAT in Western Australia revealed high levels of frailty, ADL impairment and incident adverse outcomes, suggesting that anticipatory care planning is imperative for these patients.

The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases.

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.

Deferiprone in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target. Objective: To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD. Design, Setting, and Participants: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff. Interventions: Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months. Main Outcomes and Measures: The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis). Results: Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (ß for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; ß for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%). Conclusions: These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD. Trial Registration: ClinicalTrials.gov Identifier: NCT03234686.

The AUstralian multidomain Approach to Reduce dementia Risk by prOtecting brain health With lifestyle intervention study (AU-ARROW): A study protocol for a single-blind, multi-site, randomized controlled trial.

INTRODUCTION: The Finnish Geriatric Intervention Study (FINGER) led to the global dementia risk reduction initiative: World-Wide FINGERS (WW-FINGERS). As part of WW-FINGERS, the Australian AU-ARROW study mirrors aspects of FINGER, as well as US-POINTER. METHOD: AU-ARROW is a randomized, single-blind, multisite, 2-year clinical trial (n = 600; aged 55-79). The multimodal lifestyle intervention group will engage in aerobic exercise, resistance training and stretching, dietary advice to encourage MIND diet adherence, BrainHQ cognitive training, and medical monitoring and health education. The Health Education and Coaching group will receive occasional health education sessions. The primary outcome measure is the change in a global composite cognitive score. Extra value will emanate from blood biomarker analysis, positron emission tomography (PET) imaging, brain magnetic resonance imaging (MRI), and retinal biomarker tests. DISCUSSION: The finalized AU-ARROW protocol is expected to allow development of an evidence-based innovative treatment plan to reduce cognitive decline and dementia risk, and effective transfer of research outcomes into Australian health policy. Highlights: Study protocol for a single-blind, randomized controlled trial, the AU-ARROW Study.The AU-ARROW Study is a member of the World-Wide FINGERS (WW-FINGERS) initiative.AU-ARROW's primary outcome measure is change in a global composite cognitive score.Extra significance from amyloid PET imaging, brain MRI, and retinal biomarker tests.Leading to development of an innovative treatment plan to reduce cognitive decline.

Balance on the Brain: a randomised controlled trial evaluating the effect of a multimodal exercise programme on physical performance, falls, quality of life and cognition for people with mild cognitive impairment-study protocol.

INTRODUCTION: Exercise and physical activity have been shown to improve cognition for people living with mild cognitive impairment (MCI). There is strong evidence for the benefits of aerobic exercise and medium evidence for participating in regular strength training for people with MCI. However, people living with MCI fall two times as often as those without cognitive impairment and the evidence is currently unknown as to whether balance training for people with MCI is beneficial, as has been demonstrated for older people without cognitive impairment. The aim of this study is to determine whether a balance-focused multimodal exercise intervention improves balance and reduces falls for people with MCI, compared with a control group receiving usual care. METHODS AND ANALYSIS: This single blind randomised controlled trial (Balance on the Brain) will be offered to 396 people with MCI living in the community. The multimodal exercise intervention consists of two balance programmes and a walking programme to be delivered by physiotherapists over a 6-month intervention period. All participants will be followed up over 12 months (for the intervention group, this involves 6-month intervention and 6-month maintenance). The primary outcomes are (1) balance performance and (2) rate of falls. Physical performance, levels of physical activity and sedentary behaviour, quality of life and cognition are secondary outcomes. A health economic analysis will be undertaken to evaluate the cost-effectiveness of the intervention compared with usual care. ETHICS AND DISSEMINATION: Ethics approval has been received from the South Metropolitan Health Service Human Research Ethics Committee (HREC), Curtin University HREC and the Western Australia Department of Health HREC; and approval has been received to obtain data for health costings from Services Australia. The results will be disseminated through peer-review publications, conference presentations and online platforms. TRIAL REGISTRATION NUMBER: ACTRN12620001037998; Australian New Zealand Clinical Trials Registry (ANZCTR).

Efficacy of probucol on cognitive function in Alzheimer's disease: study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA study).

INTRODUCTION: Preclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid beta (Aß) in the peripheral circulation is causally related to the development of Alzheimer's disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-Aß compromise the brain microvasculature, resulting in extravasation and retention of the lipoprotein-Aß moiety. The latter results in an inflammatory response and neurodegeneration ensues. Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-Aß secretion, concomitant with maintaining blood-brain-barrier function, suppressing neurovascular inflammation and supporting cognitive function. This protocol details the probucol in Alzheimer's study, a drug intervention trial investigating if probucol has potential to attenuate cognitive decline, delay brain atrophy and reduce cerebral amyloid burden in patients with mild-to-moderate AD. METHODS AND ANALYSIS: The study is a phase II, randomised, placebo-controlled, double-blind single-site clinical trial held in Perth, Australia. The target sample is 314 participants with mild-to-moderate AD. Participants will be recruited and randomised (1:1) to a 104-week intervention consisting of placebo induction for 2 weeks followed by 102 weeks of probucol (Lorelco) or placebo. The primary outcome is changed in cognitive performance determined via the Alzheimer's Disease Assessment Scales-Cognitive Subscale test between baseline and 104 weeks. Secondary outcomes measures will be the change in brain structure and function, cerebral amyloid load, quality of life, and the safety and tolerability of Lorelco, after a 104week intervention. ETHICS AND DISSEMINATION: The study has been approved by the Bellberry Limited Human Research Ethics Committee (approval number: HREC2019-11-1063; Version 4, 6 October 2021). Informed consent will be obtained from participants prior to any study procedures being performed. The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12621000726853).

Early identification of frailty: Developing an international delphi consensus on pre-frailty.

BACKGROUND: Frailty is associated with a prodromal stage called pre-frailty, a potentially reversible and highly prevalent intermediate state before frailty becomes established. Despite being widely-used in the literature and increasingly in clinical practice, it is poorly understood. OBJECTIVE: To establish consensus on the construct and approaches to diagnose and manage pre-frailty. METHODS: We conducted a modified (electronic, two-round) Delphi consensus study. The questionnaire included statements concerning the concept, aspects and causes, types, mechanism, assessment, consequences, prevention and management of pre-frailty. Qualitative and quantitative analysis methods were employed. An agreement level of 70% was applied. RESULTS: Twenty-three experts with different backgrounds from 12 countries participated. In total, 70 statements were circulated in Round 1. Of these, 52.8% were accepted. Following comments, 51 statements were re-circulated in Round 2 and 92.1% were accepted. It was agreed that physical and non-physical factors including psychological and social capacity are involved in the development of pre-frailty, potentially adversely affecting health and health-related quality of life. Experts considered pre-frailty to be an age-associated multi-factorial, multi-dimensional, and non-linear process that does not inevitably lead to frailty. It can be reversed or attenuated by targeted interventions. Brief, feasible, and validated tools and multidimensional assessment are recommended to identify pre-frailty. CONCLUSIONS: Consensus suggests that pre-frailty lies along the frailty continuum. It is a multidimensional risk-state associated with one or more of physical impairment, cognitive decline, nutritional deficiencies and socioeconomic disadvantages, predisposing to the development of frailty. More research is needed to agree an operational definition and optimal management strategies.

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aß targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

Screening for cognitive impairment in an Australian aged care assessment team as part of comprehensive geriatric assessment.

Accurate detection of mild cognitive impairment (MCI) is important to stratify and address risk. Yet, few short cognitive screening instruments are validated for this. . In Australia, all clients referred to an Aged Care Assessment Team (ACAT) receive comprehensive geriatric assessment (CGA) including the Standardized Mini-Mental State Examination (SMMSE). We compared the accuracy of the quick mild cognitive impairment (Qmci) screen to the SMMSE in 283 participants: 195 with dementia, 47 with MCI, and 41 with subjective cognitive decline (SCD) in an Australian community-based ACAT. Both had similar accuracy in identifying dementia, AUC of 0.86 for the Qmci versus 0.93 for the SMMSE (p = 0.10), but the Qmci was more accurate than the SMMSE in differentiating MCI from SCD, AUC of 0.84 versus 0.71, respectively, p = 0.046. These suggest that the new, short (3-5 min) Qmci screenis appropriate for use in an ACAT or other units conducting CGA.

Selecting a Bedside Cognitive Vital Sign to Monitor Cognition in Hospital: Feasibility, Reliability, and Responsiveness of Logical Memory.

Although there is a high prevalence of delirium and cognitive impairment among hospitalised older adults, short, reliable cognitive measures are rarely used to monitor cognition and potentially alert healthcare professionals to early changes that might signal delirium. We evaluated the reliability, responsiveness, and feasibility of logical memory (LM), immediate verbal recall of a short story, compared to brief tests of attention as a bedside "cognitive vital sign" (CVS). Trained nursing staff performed twice-daily cognitive assessments on 84 clinically stable inpatients in two geriatric units over 3-5 consecutive days using LM and short tests of attention and orientation including months of the year backwards. Scores were compared to those of an expert rater. Inter-rater reliability was excellent with correlation coefficients for LM increasing from r = 0.87 on day 1 to r = 0.97 by day 4 (p < 0.0001). A diurnal fluctuation of two points from a total of 30 was deemed acceptable in clinically stable patients. LM scores were statistically similar (p = 0.98) with repeated testing (suggesting no learning effect). All nurses reported that LM was feasible to score routinely. LM is a reliable measure of cognition showing diurnal variation but minimal learning effects. Further study is required to define the properties of an ideal CVS test, though LM may satisfy these.

Reducing inappropriate prescribing for older adults with advanced frailty: A review based on a survey of practice in four countries.

The management of medications in persons with frailty presents challenges. There is evidence of inappropriate prescribing and a lack of consensus among healthcare professionals on the judicious use of medications, particularly for patients with more severe frailty. This study reviews the evidence on the use of commonly prescribed pharmacological treatments in advanced frailty based on a questionnaire of prescribing practices and attitudes of healthcare professionals at different stages in their careers, in different countries. A convenience sample of those attending hospital grand rounds in Ireland, Canada and Australia/New Zealand (ANZ) were surveyed on the management of 18 medications in advanced frailty using a clinical vignette (man with severe dementia, Clinical Frailty Scale 7/9). Choices were to continue or discontinue (stop now or later) medications. In total, 298 respondents from Ireland (n = 124), Canada (n = 110), and ANZ (n = 64) completed the questionnaire, response rate 97%, including 81 consultants, 40 non-consultant hospital doctors, 134 general practitioners and 43 others (nurses, pharmacists, and medical students). Most felt that statins (88%), bisphosphonates (77%) and cholinesterase inhibitors (76%) should be discontinued. Thyroid replacement (88%), laxatives (83%) and paracetamol (81%) were most often continued. Respondents with experience in geriatric, palliative and dementia care were significantly more likely to discontinue medications. Age, gender and experience working in nursing homes did not contribute to the decision. Reflecting the current literature, there was no clear consensus on inappropriate prescribing, although respondents preferentially discontinued medications for secondary prevention. Experience significantly predicted the number and type discontinued, suggesting that education is important in reducing inappropriate prescribing for people in advanced states of frailty.

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

INTRODUCTION: Quantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design. METHODS: Pittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally. RESULTS: Global amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers. DISCUSSION: Although the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers.

Luteinizing hormone levels are positively correlated with plasma amyloid-beta protein levels in elderly men.

Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated with increased risk of cognitive decline and developing dementia. Compared to controls, men with Alzheimer's disease (AD) have been shown to have lower serum testosterone levels and higher serum luteinizing hormone (LH) levels. As serum free testosterone concentration is negatively correlated with LH in older men, the independent contributions of these hormones to the pathogenesis of AD warrants further clarification. To explore this notion, we measured plasma amyloid-beta (Abeta), serum testosterone, serum LH and other biochemical parameters in 40 cognitively normal elderly men. Multiple linear regression analysis revealed that serum LH concentration is the only parameter that significantly correlates with plasma Abeta levels in these men (r=0.5, p=0.041). These results suggest that increased serum LH concentration, rather than lower serum free testosterone, is associated with the accumulation of Abeta in plasma. Larger, longitudinal human studies are needed to determine the significance of LH in the pathogenesis of AD.

Interaction between testosterone and apolipoprotein E epsilon4 status on cognition in healthy older men.

CONTEXT: Reduced testosterone levels have been implicated as a potential causative factor in cognitive decline with older age. Men who possess the apolipoprotein E (APOE) epsilon4 allele have an increased risk of developing Alzheimer's disease; however, no studies have examined whether the influence of testosterone on cognition in healthy older men may be modulated by this genetic predisposition. OBJECTIVE: The objective of the study was to investigate the association between serum testosterone concentrations and cognitive performance in healthy older men, taking into account APOE epsilon4 status. DESIGN: This was a cross-sectional study conducted from 2003 to 2004. SETTING: The study population consisted of community-dwelling males residing in Perth, Western Australia. PARTICIPANTS: Healthy men over 55 yr, free of cognitive impairment and dementia (n = 45), were included in the study. MAIN OUTCOME MEASURES: Participants had fasting early morning blood samples for testosterone and SHBG and were assessed for mood as well as indices of general cognition, verbal and visual memory, executive functioning, working memory, and attention. RESULTS: There was a significant interaction between calculated free testosterone (FT) and APOE epsilon4 on general cognition (P = 0.01) and executive functioning, working memory, and attention (P < 0.01). Higher levels of FT were associated with better general cognition in non-epsilon4 carriers (P = 0.01). By contrast, in epsilon4 carriers higher FT levels were associated with lower scores on tests of executive functioning, working memory, and attention (P = 0.02). In men at increased risk for Alzheimer's disease, higher testosterone levels were not associated with better cognitive function. CONCLUSIONS: Cross-sectional and prospective studies of testosterone and cognition in older men should take into account APOE epsilon4 status.

Inspection time in non-demented older adults with mild cognitive impairment.

The aim of this study was to examine inspection time (IT) performance in older adults with mild cognitive impairment (MCI), who are at higher risk of developing further cognitive decline or dementia. IT is described as an index of speed of informational intake. IT correlates with measures of fluid intelligence and is possibly a marker for the integrity of the cholinergic system of the brain. IT may therefore be useful in aiding the diagnosis of early-stage progressive cognitive impairment. The current study compares IT in 28 people with MCI to 28 age, gender and education-matched controls. The computer-based, visual IT task required participants to discriminate between two visual stimuli that were presented for brief periods. Participants' IT performance was compared to their performance on cognitive and memory tasks. Group comparison showed that participants with MCI performed significantly worse on IT than controls and was not affected by years of education. In combination with other clinical, neuropsychological and biological tests, IT may be a useful assessment tool for improving the identification of older adults at risk for clinically relevant cognitive decline.