Mixed model of repeated measures versus slope models in Alzheimer’s disease clinical trials

Randomized clinical trials of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) typically assess intervention efficacy with measures of cognitive or functional assessments repeated every six months for one to two years. The Mixed Model of Repeated Measures (MMRM), which assumes an "unstructured mean" by treating time as categorical, is attractive because it makes no assumptions about the shape of the mean trajectory of the outcome over time. However, categorical time models may be over-parameterized and inefficient in detecting treatment effects relative to continuous time models of, say, the linear trend of the outcome over time. Mixed effects models can also be extended to model quadratic time effects, although it is questionable whether the duration and interval of observations in AD and MCI studies is sufficient to support such models. Furthermore, it is unknown which of these models are most robust to missing data, which plagues AD and MCI studies. We review the literature and compare estimates of treatment effects from four potential models fit to data from five AD Cooperative Study (ADCS) trials in MCI and AD.     

Is there a rationale for including only patients already being treated with acetylcholinesterase inhibitors in a prodromal AD trial?

Prodromal AD clinical trial methodology is advancing rapidly. It is now possible to more accurately identify MCI patients with underlying AD pathology at an earlier stage of the disease through the use of amyloid imaging and CSF biomarkers. Measurement of decline in these early stage clinical trials using continuous clinical and cognitive outcome measures is conceptually more appealing and adds greater efficiency compared to the classical outcome of "conversion" to dementia used in prior MCI clinical trials. Nevertheless, the fact that many prodromal AD patients who are likely to be recruited to these early stage studies are not taking acetylcholinesterase inhibitors at the time of enrollment, but are poised to start taking them over a multi-year period of follow-up, is a potential confound that needs to be addressed.     

Designing clinical trials for early (pre-dementia) Alzheimer’s disease: Determining the appropriate population for treatment

Treatments that are designed to reduce Alzheimer’s disease (AD) pathology may be most useful when given to subjects prior to a diagnosis of AD using current diagnostic criteria. These earlier patients may have early cognitive losses consistent with mild cognitive impairment (MCI) or may be completely asymptomatic. Screening and treatment programs for other disease states have been explored previously; these include cholesterol screening for cardiovascular disease, genetic screening for Huntington’s disease and screening for some types of cancer. Cancer screening and treatment programs have been developed for colon cancer, breast cancer and prostate cancer. Screening programs for these other disease states are briefly reviewed and are compared to preliminary modeling data describing a hypothetical screening and treatment program for AD. While primary prevention based on screening of asymptomatic individuals using biomarkers has broad appeal, secondary prevention employing treatment of patients with MCI may be more easily implemented.     

Vascular risk factors, alcohol intake, and cognitive decline

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer’s disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.     

Validation of the neurobehavioral cognitive status examination and the Rivermead Behavioural Memory Test in investigations of dementia

The aim of this retrospective study was to validate two commonly used instruments, Cognistat and the Rivermead Behavioural Memory Test, RBMT, for detection of MCI and mild dementia. Two different diagnosis groups, mild cognitive impairment (MCI) and Alzheimer's disease combined with mixed dementia representing mild dementia (MD), were compared with a group of patients who did not receive a diagnosis of dementia. All patients were assessed at a specialized outpatient memory clinic in a university hospital in Sweden using the Mini Mental State Examination (MMSE), Cognistat, and RBMT. Sensitivity, specificity, predictive value, and likelihood ratio were calculated for the tests. The Cognistat and RBMT have moderate validity in the detection of MCI and mild dementia. On their own, none of the tests used is sufficient for diagnosing MCI or mild dementia. A combination of the Cognistat and RBMT provides additional information in early stage dementia; in this regard the RBMT is better than the Cognistat, which also has other limitations. The RBMT can be helpful for distinguishing between MCI and mild dementia. There is a need for a more sensitive screening test to capture early cognitive impairment related to patients' occupational performance and problems in daily life.     

Lap Time Variability From a 400-m Walk Is Associated With Future Mild Cognitive Impairment and Alzheimer's Disease

ObjectivesTo determine whether the trajectory of preclinical lap time variability from a 400-m walk differentiates participants with future mild cognitive impairment (MCI)/Alzheimer's disease (AD) from matched controls.DesignA case-control retrospective study embedded in a large longitudinal cohort study, the Baltimore Longitudinal Study of Aging (BLSA).SettingIn the BLSA, participants were scheduled for clinical visits, including mobility and cognitive assessments. Data reported here were collected between April 2007 and September 2017 (average follow-up 5.2 ± 2.4 years).Participants67 participants developed MCI/AD and 134 age- and sex-matched controls remained cognitively normal.MeasurementsDiagnoses of MCI and AD were adjudicated at a consensus conference. The rate of change in lap time variability between MCI/AD cases prior to symptom onset and controls were compared using mixed effects linear regression, and adjusted for baseline executive function, memory, gait speed, and changes in gait speed.ResultsCompared to controls, eventual MCI/AD cases had a greater rate of increase in lap time variability prior to symptom onset (β = 0.59, P = .009). This association was independent of baseline cognition, gait speeds at baseline or change over time from a 6-m or 400-m walk.Conclusion/ImplicationsIndependent of other early indicators and gait slowing, a greater rate of increase in lap time variability from a 400-m walk differentiates individuals who eventually develop MCI/AD from controls, suggesting that early pathology affects the automaticity of walking. Lap time variability can be assessed during routine clinical practice over time and might help identify individuals at risk for future MCI/AD.     

Evolving early (pre-dementia) Alzheimer’s disease trials: Suit the outcomes to the population and study design

Assuming that some cases of Alzheimer’s disease (AD) could be prevented or delayed, prevention trials will be developed for this neurodegenerative condition. Initially, stakeholders will have to agree about the definition of prevention—true primary prevention, meaning the prevention of AD neuropathological changes; the prevention of clinical signs and symptoms that often augur AD; or preventing the progression of signs and symptoms to full-blown dementia. True primary prevention trials will have to rely completely upon neuroimaging or biomarker outcomes that reflect AD pathology. On the other hand, trials designed to prevent signs and symptoms of dementia will require researchers to agree on the phenomenology that would constitute an unequivocal endpoint: cognitive worsening on one or more measure compared to a normative group; development of Mild cognitive impairment (MCI); or development of Alzheimer’s dementia. Prevention trials utilizing any of these outcomes in the general public will be large, will have to utilize low risk public health interventions, and might therefore have only a small impact (treatment effect size), especially if the studies are too short or the study populations are too diverse. An alternative to interventions aimed at the general public would be any attempt to prevent signs and symptoms of dementia in individuals thought to be at an increased risk for clinical dementia. These trials could try to reduce the development of signs and symptoms of dementia in cognitively normal subjects, or they could try to prevent progression from some form of Mild Cognitive Impairment to AD, or they could have the more subtle goal of reducing the accumulation of subclinical deficits in MCI subjects. If the populations for these trials are limited to individuals who have abnormal laboratory and neuroimaging studies associated with AD neuropathology, the results will not generalize to biomarker-negative, at risk individuals, who are likely to constitute the majority of any clinically relevant study population. Outcome measures for each study design will depend upon the characteristics of the study.     

Temporal association patterns and dynamics of amyloid-β and tau in Alzheimer’s disease

The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer’s disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β_1?42 (Aβ_1?42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ_1?42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20–62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers Aβ_1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of Aβ_1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (? 2.35 pg/mL/year), compared to minimal loss relative to AD onset (? 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Quantitative trajectories are likely to be of use in clinical trial design, as they allow for a more detailed insight into the effectiveness of treatments designed to delay development of biological disease.     

The advanced activities of daily living: A tool allowing the evaluation of subtle functional decline in mild cognitive impairment

Objectives

Assessment of advanced activities of daily living (a-ADL) can be of interest in establishing the diagnosis of Alzheimer’s disease (AD) in an earlier stage, since these activities demand high cognitive functioning and are more responsive to subtle changes. In this study we tested a new a-ADL tool, developed according to the International Classification of Functioning, Disability and Health (ICF). The a-ADL tool is based on the total number of activities performed (TNA) by a person and takes each subject as his own reference. It distinguishes a total Disability Index (a-ADL-DI), a Cognitive Disability Index (a-ADL-CDI), and a Physical Disability Index (a-ADL-PDI), with lower score representing more independency. We explored whether these indices allow distinction between cognitively healthy persons, patients with Mild Cognitive Impairment (MCI) and patients with mild AD.

Methods

Participants were on average 80 years old (SD 4.6; 66–90), were community dwelling, and were diagnosed as (1) cognitively healthy subjects (n=26); (2) patients with MCI (n = 17), or (3) mild AD (n = 25), based upon extensive clinical evaluation and a set of global, cognitive, mood and functional assessments. The a-ADL-tool was not part of the clinical evaluation.

Results

The a-ADL-CDI was significantly different between the three groups (p<.01). The a-ADL-DI was significantly different between MCI and AD (p<.001). The tool had good psychometrical properties (inter-rater reliability; agreement between patient and proxy; correlations with cognitive tests). Although the sample size was relatively small, ROC curves were computed for the a-ADL-DI and a-ADL-CDI with satisfactory and promising results.

Conclusion

The a-ADLCDI and a-ADL-DI might offer a useful contribution to the identification and follow up of patients with mild cognitive disorders in an older population.     

ApoE4 Is Associated with Lower Body Mass,Particularly Fat Mass,in Older Women with Cognitive Impairment

A lower body mass is associated with the progression of Alzheimer’s disease (AD) and the risk of mortality in patients with AD; however, evidence of genetic determinants of decreased body mass in cognitively impaired older adults is limited. We therefore investigated the genetic effect of APOE-ε4 on body composition in older adults with mild cognitive impairment (MCI) and early-to-moderate-stage AD. A total of 1631 outpatients (aged 65–89 years) with MCI and early-to-moderate-stage AD were evaluated for the association between body composition and APOE-ε4 status. After adjusting for covariates, including cognitive function evaluated with the Mini-Mental State Examination, the presence of the APOE-ε4 was associated with lower weight (β = −1.116 ± 0.468 kg per presence, p = 0.017), fat mass (β = −1.196 ± 0.401 kg per presence, p = 0.003), and percentage of body fat (β = −1.700 ± 0.539% per presence, p = 0.002) in women but not in men. Additionally, the impact of APOE-ε4 on measures of body composition in women was more remarkable in MCI than in AD patients. The presence of the APOE-ε4 allele was associated with lower fat mass, particularly in women with MCI, independent of cognitive decline.     

Efficacy and Safety of Sesame Oil Cake Extract on Memory Function Improvement: A 12-Week,Randomized, Double-Blind,Placebo-Controlled Pilot Study

The goal of treatment for mild cognitive impairment (MCI) is to reduce the existing clinical symptoms, delay the progression of cognitive impairment and prevent the progression to Alzheimer’s disease (AD). At present, there is no effective drug therapy for AD treatment. However, early intake of dietary supplements may be effective in alleviating and delaying the MCI. This study aims to evaluate the effects of sesame oil cake extract (SOCE) supplementation on cognitive function in aged 60 years or older adults with memory impairment. A total of 70 subjects received either SOCE (n = 35) or placebo (n = 35) for 12 weeks based on random 1:1 assignment to these two groups. Cognitive function was evaluated by a computerized neurocognitive function test (CNT), and changes in the concentrations of plasma amyloid β (Aβ) proteins and urine 8-OHdG (8-hydroxy-2′-deoxyguanosine) were investigated before and after the experiment. Verbal learning test index items of the CNT improved markedly in the SOCE group compared to the placebo group (p < 0.05). Furthermore, plasma amyloid-β (1–40) and amyloid-β (1–42) levels in the SOCE group decreased significantly compared to that in the placebo group (p < 0.05). There was no statistically significant difference in urine 8-OHdG between the two groups (p > 0.05). Collectively, intake of SOCE for 12 weeks appears to have a beneficial effect on the verbal memory abilities and plasma β-amyloid levels of older adults with memory impairment.     

Estimation of bivariate measurements having different change points, with application to cognitive ageing.

Longitudinal studies of ageing make repeated observations of multiple measurements on each subject. Change point models are often used to model longitudinal data. We demonstrate the use of Bayesian and profile likelihood methods to simultaneously estimate different change points in the longitudinal course of two different measurements of cognitive function in subjects in the Bronx Aging Study who developed Alzheimer's disease (AD). Analyses show that accelerated memory decline, as measured by Buschke Selective Reminding, begins between seven and eight years before diagnosis of AD, while decline in performance on speeded tasks as measured by WAIS Performance IQ begins slightly more than two years before diagnosis, significantly after the decline in memory.     

Homocysteine and mild cognitive impairment: Are these the tools for early intervention in the dementia spectrum?

Dementia, being a neurodegenerative disease, has devastating consequences not just for the ailing but also for the carers as it has a tremendous negative impact on the quality of life. The pathophysiology of dementia commences far earlier than its diagnosis. Mild cognitive impairment (MCI) is a stage prior to definite dementia. The progression from MCI to dementia is insidious with no definite demarcation, thus making diagnosis clinically difficult at an early stage. This paper attempts to throw light on the epidemiology, risk factors and the aetiopathogenesis of MCI. It further attempts to elaborate on the rate of conversion of MCI to definite dementia and the factors influencing the same. Many established as well as probable, modifiable as well as non-modifiable risk factors influence the progress of MCI to definite dementia. Homocysteine, a sulphur containing amino-acid has been identified as a probable risk factor for the dementia spectrum. Various existing clinical evidences and biological plausibility towards probable link between homocysteine and dementia are discussed in this paper. B vitamin mediated homocysteine reduction and cognitive outcomes demonstrate mixed results. This review attempts to evaluate hyperhomocysteinaemia and MCI as a brain risk marker and assess their potential for future research with a view to attempt early intervention.     

Constructing classification boundaries in the memory clinic: negotiating risk and uncertainty in constituting mild cognitive impairment

Determining the boundaries around processes of ‘normal’ ageing and pathological cognitive deterioration associated with Alzheimer's disease (AD) is a difficult process, complicated further by the expansion of the disease category to include mild cognitive impairment (MCI). MCI is a label used to identify individuals with the symptoms of cognitive deterioration not attributable to ‘normal ageing’ but deemed to be ‘at risk’ of developing AD despite clinical uncertainty around whether individuals will go on to develop the condition in the future. Drawing on qualitative data gathered across an out-patient memory service, this article examines practitioners’ accounts of the complexity associated with constructing the boundaries around MCI, AD and age in the clinic. Practitioners utilise uncertainty by classifying patients with MCI to keep them on for review to account for the possibility that patients may go on to develop AD but they also recognise the difficulty in predicting future progression to AD. Negotiating classification boundaries in the clinic is, however, not only about managing uncertainty regarding potential future risk but also about navigating the wider social and political context in which ageing and cognitive deterioration intersect, and are constructed and managed.     

Analysis of longitudinal data in an Alzheimer's disease clinical trial

Evidence of delayed progression is the primary mechanism for demonstrating therapeutic efficacy in clinical trials in Alzheimer's disease. In the major trials of therapeutic treatment of AD, to date, measures based on clinical judgement and cognitive performance, instead of mortality, have been used as the primary response measures. There is good reason for this since the course of the disease is quite long, and AD trials designed around mortality would require either very large sample sizes or very long follow-up in order to have adequate power. However, the evaluation of progression in AD using clinical markers is subject to a number of challenges often found in longitudinal databases, for example, missing data, floor and ceiling effects and non-linearity. Unfortunately, few of these issues are being addressed in the typical analysis of progression data. This paper explores these analytic issues in the context of the recently completed Alzheimer's Disease Cooperative Study trial of vitamin E and Selegeline in moderate AD patients.     

A combination of galantamine and memantine modifies cognitive function in subjects with amnestic MCI

Objectives

Mild cognitive impairment (MCI) is etiologically heterogeneous, and a substantial proportion of MCI subjects will develop different dementia disorders. One subtype of this syndrome, amnestic MCI, occurs preferentially but not exclusively in prodromal AD and is characterized by defined deficits of episodic memory.

Design, setting and participants

For a 2-year, double-blinded, placebo-controlled study MCI patients, presenting with an amnestic syndrome but not necessarily based on presumed prodromal AD were randomized.

Intervention

Patients received (a) a combination of 16 mg galantamine plus 20 mg memantine, or (b) 16 mg galantamine alone or (c) placebo.

Measurements

The primary objective was to explore the differential impact of these interventions on the progression to dementia and on cognitive changes as measured by the ADAScog.

Results

After recruitment of 232 subjects, the trial was halted before reaching the planned sample size, because safety concerns arose in other studies with galantamine in MCI. This resulted in a variable treatment duration of 2?C52 weeks. The statistical analysis plan was amended for studying cognitive effects of discontinuing the study medication, which was done separately for galantamine and memantine, and under double-blind conditions. There was one death, no unexpected severe adverse events, and no differences of severe adverse events between the treatment arms. The cognitive changes on the ADAScog were not different among the groups. Only for the subgroup of amnestic MCI with presumed AD etiology, a significant improvement of ADAScog score over placebo before the discontinuation of medication was observed, while amnestic MCI presumably due to other etiologies showed no cognitive changes with broad variation. Cognitive improvement was numerically larger in the combination treatment group than under galantamine alone. Patients who received placebo declined as expected. Discontinuation of galantamine, either as part of the combination regimen or as mono treatment, resulted in a transient decline of the ADAScog score in amnestic MCI of presumed AD etiology, while discontinuation of Memantine did not change the cognitive status.

Conclusion

In an interrupted trial with amnestic MCI subjects the combination of galantamine plus memantine were generally well tolerated. In the subgroup of MCI subjects with presumed AD etiology, a cognitive benefit of a short-term combination treatment of galantamine plus memantine was observed, and cognitive decline occurred after discontinuation of galantamine.     

Use of biomarkers and imaging to assess pathophysiology, mechanisms of action and target engagement

Multidisciplinary basic research led to an evolving knowledge of the molecular pathogenesis of Alzheimer’s disease (AD). These advances have been translated into defined therapeutic concepts and distinct classes of compounds with putative disease-modifying effects that are now being tested in clinical trials. There is a growing consensus that disease-modifying treatments may be most effective when commenced early in the course and progression of AD pathophysiology, before amyloid deposition and neurodegeneration become too widespread. Biological indicators of pathophysiological mechanisms are required to chart and identify AD in the prodromal phase or, preferably, in asymptomatic individuals. Biomarkers are becoming even more important, owing to the challenges in demonstrating efficacy of candidate-drugs that hit pathophysiological targets using clinical and cognitive outcomes in early AD trials with limited duration. Currently, there is emerging consensus that advances in therapeutic strategies for AD that delay predefined milestones or slow the cognitive and disease progression would considerably decrease the expanding global burden of the disease. To effectively test preventive compounds for AD and bring therapy to affected individuals as early as possible there is an urgent need for a concerted collaboration among worldwide academic institutions, industry, and regulatory bodies with the aim of establishing networks for the identification and qualification of multi-modal biological disease markers.     

Functional evaluation distinguishes MCI patients from healthy elderly people — The ADCS/MCI/ADL scale

Patients with MCI may present minor impairments in activities of daily living (ADL). The main objective of this work was to evaluate the ability of two versions of the Alzheimer's Disease Cooperative Study / Activities of Daily Living scale adapted for MCI patients (ADCS/MCI/ADL18 and ADCS/MCI/ADL24) to distinguish patients with MCI from healthy control subjects. Participants were 60 years or older and community dwelling: 31 control subjects, 30 aMCI patients and 33 AD patients. A protocol of neuropsychological tests, global evaluation scales, functional scales, and depressive symptoms assessment was used. Activities of balancing the cheque book, using a telephone, going shopping, taking medication regularly, finding objects, talking about current events, watching television, initiating complex activities, keeping appointments or meetings, reading, getting around outside the home and driving a car were impaired in aMCI patients. The ADCS/MCI/ADL24 scale was better than the ADCS/MCI/ADL18 scale in distinguishing aMCI patients from healthy controls (sensitivity=0.87, specificity=0.87, ROC c=0.887, cut-off point=52/53). The detection of initial functional changes with appropriate scales may contribute to the early diagnosis of MCI and the development of targeted interventions to improve everyday function or prolong independence.     

Pathological correlates of cognitive decline in Alzheimer's disease

Although Alzheimer's disease (AD) has been investigated for more than 100 years, it was not until the 60s that quantitative measures of the disease progression and severity in relation to function and neuropathology were made by Blessed and his colleagues. With the increasing understanding of the pathological changes of AD that take place, there is growing interest in identifying which pathological marker most reliably predicts the dementia and the cognitive profile. Markers of pathology that have been investigated include senile plaques, neurofibrillary tangles, synaptic loss, and neurochemical changes. Many clinical measures have been evaluated as well including Clinical Dementia Rating, Mini Mental State Examination, and Functional Assessment Staging as ways of both predicting the presence of pathological changes of AD as well as correlating with the specific measures of pathology. Accumulation of neuropathology appears to correlate with functional, global, and cognitive decline as people progress through AD. This review will summarize evidence of which neuropathological change correlates robustly with cognitive decline and which cognitive index predicts pathological changes in AD. In general, tangles and synaptic loss are better correlates of cognitive decline and correlate better.     

瑞典斯德哥尔摩市社区人群老年痴呆和阿尔茨海默病的危险因素队列研究

目的探讨老年痴呆和阿尔茨海默病（AD）的危险因素。方法在6年问（1991-1996年）对斯德哥尔摩市一个社区非痴呆老年人群（n=1301，年龄≥75岁）进行两次随访检查，并按照美国老年精神病协会制订的DSM—Ⅲ—R标准诊断随访期间痴呆和AD新发病例。研究对象在基线调查时对有关因素暴露情况系经问卷调查、临床检查和查阅住院病例登记资料库等方法确定。采用Cox比例风险模型对资料进行统计分析。结果随访期间共有350例被诊断为痴呆，包括260例AD患者。多因素分析结果显示，痴呆和AD发病的危险因素有年龄大、文化程度低、认知功能损害、体力活动障碍、低舒张压、糖尿病、缺血性心脏病和携带APOEa4基因。脑卒中和心房纤维颤动亦能增加痴呆的危险性，而服用抗高血压药物则可降低痴呆和AD发病的危险性。结论某些人口统计学因素、认知和体力功能障碍、血管性疾病及遗传易感性是老年痴呆和AD的重要危险因素；使用抗高血压药物及控制高血压相关的血管性疾病可能会降低痴呆发病的危险性。