A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

INTRODUCTION: This study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild-to-moderate Alzheimer's disease (AD) on background donepezil 10 mg/day. METHODS: A randomized, double-blind, placebo-controlled 4-week safety study of HTL0018318 with up-titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition. RESULTS: Treatment-emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7-21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post-dose, HTL0018318-related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up-titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints. DISCUSSION: HTL0018318 was well tolerated in mild-to-moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.

Determining clinically meaningful decline in preclinical Alzheimer disease.

OBJECTIVE: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify ß-amyloid (Aß)-related decline. METHODS: In 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aß status and longitudinal changes across multiple cognitive domains and assessed interactions between Aß and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect. RESULTS: Cognitively unimpaired Aß+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aß to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aß+ groups declined consistently on cognitive composite measures. CONCLUSIONS: A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aß status were inconsistent and not readily generalizable.

Association of ß-Amyloid and Apolipoprotein E ε4 With Memory Decline in Preclinical Alzheimer Disease.

Importance: Older age, high levels of ß-amyloid (Aß), and the presence of the apolipoprotein E (APOE) ε4 allele are risk factors for Alzheimer disease (AD). However, the extent to which increasing age, Aß, and ε4 are associated with memory decline remains unclear, and the age at which memory decline begins for Aß-positive ε4 carriers and noncarriers has not been determined. Objective: To determine the association of age, Aß level, and APOE ε4 with memory decline in a large group of cognitively healthy older adults. Design, Setting, and Participants: This longitudinal observational study included cognitively healthy older adults (age >60 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study from March 31, 2006, through March 31, 2017; of 1583 individuals enrolled, 1136 refused or were excluded owing to other criteria (eg, having mild cognitive impairment or AD). Participants underwent Aß imaging in research clinics in Perth and Melbourne and more than 72 months of follow-up (at 18-month intervals). The association of age with memory was fitted to a quadratic model. Age was treated as a continuous, time-dependent variable. Exposures: ß-Amyloid imaging using positron emission tomography, genotyping for APOE ɛ4, and longitudinal neuropsychological assessments of episodic memory during the 72-month follow-up. Main Outcomes and Measures: Episodic memory composite score. Results: Of the 447 participants, 203 (45.4%) were men and 244 (54.6%) were women; mean (SD) age was 72.5 (6.6) years. Equal proportions of female participants were observed in each Aß-ɛ4 group (24 of 51 Aß-positive ε4 noncarriers [47.1%] ; 35 of 64 Aß-negative ε4 carriers [54.7%]; 40 of 72 Aß-positive ε4 carriers [55.6%]; and 145 of 260 Aß-negative ε4 noncarriers [55.8%]). Adults with Aß findings (mean [SD] age, 74.4 [6.8] years) were approximately 4 years older than those negative for Aß (mean [SD] age, 69.8 [6.1] years). Memory decline diverged significantly from Aß-negative ɛ4 noncarriers at an earlier age in Aß-positive ɛ4 carriers (64.5 years) than in Aß-positive ɛ4 noncarriers (76.5 years), such that by 85 years of age, Aß-positive ε4 carriers performed approximately 1.5 SD units worse on the episodic memory composite than Aß-negative ε4 noncarriers and approximately 0.8 SD units worse than Aß-positive ε4 noncarriers. Memory performance of Aß-negative ɛ4 carriers did not differ from that of the Aß-negative ɛ4 noncarriers (estimate [SE], 0.001 [0.001]; t = 0.526; P = .77). Conclusions and Relevance: Prior work has shown that Aß and ε4 combine to influence memory decline in nondemented older adults. Results of this study indicate that increasing age may further exacerbate these effects. The estimates provided may be used to determine the risk of memory decline associated with Aß and ε4 at each age.

Massed versus spaced visuospatial memory in cognitively healthy young and older adults.

BACKGROUND: The present study examined the effect of massed versus spaced learning trials on 24-hour delayed recall for a visuospatial learning task. To determine the utility of measuring the incremental benefit of spaced training as a cognitive assay that may be useful in early clinical trials, we used a within-subject crossover design, with two small samples (typical sample sizes for phase I clinical trials). METHODS: Young adults and cognitively healthy older adults without significant physical, neurological, or psychiatric illness were trained on a visuospatial paired-associate learning task under a massed condition (learning trials were presented in immediate succession) and a spaced condition (learning trials were presented with 15-minute intertrial delays). RESULTS: Statistically significant differences between training conditions on the visuospatial task, such that young adult participants performed better on delayed recall after spaced training, were identified. Large effect sizes for young and older adults on this task suggest meaningful differences between training conditions, reflecting the expected "spacing effect." The role of amyloid aggregation was also considered for a subset of participants; as amyloid levels increased, the benefit of spaced training decreased, suggesting that the effect of this training paradigm is modulated by disease burden. CONCLUSIONS: The utility of this paradigm as a potential assay for phase I proof-of-concept trials, targeting molecular mechanisms that are central to the encoding and consolidation of new learning, is discussed.

A web-based normative data tool for assessing cognitive performance in healthy older Australians.

A decline in cognition greater than expected with ageing and accompanied by subjective cognitive concerns or functional changes may be indicative of a dementing disorder. The capacity to correctly identify cognitive decline relies on comparisons with normative data from a suitably matched healthy reference group with relatively homogeneous demographic features. Formal assessment of cognition is usually performed by specialist neuropsychologists trained in administration and interpretation of psychometric tests. With a scarcity of normative data from large cohorts of older adults, Australian neuropsychologists commonly use representative data from small international studies. Data from 727 healthy older Australians participating in the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing have been used to create a normative dataset. A web-based calculator was developed to simplify the time-consuming process of comparing cognitive performance scores with these representative data.

Preexisting cognitive impairment in patients scheduled for elective coronary artery bypass graft surgery.

BACKGROUND: An accurate assessment of the prevalence of cognitive impairment in patients scheduled for coronary artery bypass graft (CABG) surgery is necessary if valid assumptions regarding cognitive change are to be made. Such an assessment requires the use of a healthy control group free of cardiovascular disease. METHODS: In a retrospective observational study, 349 patients scheduled for CABG surgery underwent neuropsychological testing. We compared the results with those from a group of 170 healthy controls without cardiovascular disease and containing more female patients who were matched for age and IQ score. Cognitive impairment was defined as test scores > or =2 sd less than the controls on two or more of the seven tests. RESULTS: The CABG surgery patients performed significantly worse than the control group on all tests except the Grooved Pegboard test (nondominant). When analyzed by group, performance on the verbal learning test was the most impaired. Cognitive impairment was present in 122 (35%) of CABG surgery patients before their procedure. Prior myocardial infarction, age, and IQ were independent predictors of cognitive impairment. CONCLUSIONS: Cognitive impairment is prevalent in patients presenting for CABG surgery. Impaired cognition before surgery must be considered when assessing the effects of CABG surgery on cognitive performance.

Examination of the use of cognitive domains in postoperative cognitive dysfunction after coronary artery bypass graft surgery.

BACKGROUND: Cognitive domain summary scores have been used to examine postoperative cognitive dysfunction in a number of influential studies. To successfully examine cognitive dysfunction in this way, the domains need to be consistent during the assessment time points or the results are distorted. The current study examines two methods of determining cognitive domains and examines their temporal stability during serial cognitive assessments after coronary artery bypass graft surgery. METHODS: Two hundred and four coronary artery bypass graft patients and 80 matched healthy control subjects 55 years or older completed a battery of neuropsychological assessments at baseline and at 7 days and 3 months. Domains were determined in two ways. The first was based on precedence, and neuropsychological tests were allocated to commonly attributed cognitive domains. The second method was to conduct principal components analysis to statistically determine the domains at each time. The stability of these factors was then assessed over time by conducting repeated analysis. RESULTS: There were discrepancies between the two methods used to determine decline, and among the factors in the control and surgical groups. Stability with time was not evident as the factors varied within the groups. CONCLUSIONS: The assessment of postoperative cognitive dysfunction would be best served by the use of individual test results with efforts made to minimize false-positive classification as the extracted cognitive domains do not appear to be temporally consistent, and were sample specific.