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.

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).