Dataset Information

Progression to dementia in memory clinic patients with mild cognitive impairment and normal ?-amyloid.

ABSTRACT: BACKGROUND:Determination of ?-amyloid (A?) positivity and likelihood of underlying Alzheimer's disease (AD) relies on dichotomous biomarker cut-off values. Individuals with mild cognitive impairment (MCI) and A? within the normal range may still have a substantial risk of developing dementia, primarily of Alzheimer type. Their prognosis, as well as predictors of clinical progression, are not fully understood. The aim of this study was to explore the associations of cerebrospinal fluid (CSF) biomarkers (A?42, total tau, phosphorylated tau) and other characteristics, including modifiable vascular factors, with the risk of progression to dementia among patients with MCI and normal CSF A?42. METHODS:Three hundred eighteen memory clinic patients with CSF and clinical data, and at least 1-year follow-up, were included. Patients had normal CSF A?42 levels based on clinical cut-offs. Cox proportional hazard models with age as time scale and adjusted for sex, education, and cognition (Mini-Mental State Examination) were used to investigate predictors of progression to dementia and Alzheimer-type dementia. Potential predictors included CSF biomarkers, cognitive performance (verbal learning and memory), apolipoprotein E (APOE) ?4 genotype, medial temporal lobe atrophy, family history of dementia, depressive symptoms, and vascular factors, including the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) risk score. Predictive performance of patient characteristics was further explored with Harrell C statistic. RESULTS:Lower normal A?42 and higher total tau and phosphorylated tau were associated with higher dementia risk, and the association was not driven by A?42 values close to cut-off. Additional predictors included poorer cognition, APOE ?4 genotype, higher systolic blood pressure, and lower body mass index, but not the CAIDE dementia risk score. A?42 individually and in combination with other CSF biomarkers improved the risk prediction compared to age and cognition alone. Medial temporal lobe atrophy or vascular factors did not increase the predictive performance. CONCLUSIONS:Possibility of underlying AD pathology and increased dementia risk should not be ruled out among MCI patients with CSF A?42 within the normal range. While cut-offs may be useful in clinical practice to identify high-risk individuals, personalized risk prediction tools incorporating continuous biomarkers may be preferable among individuals with intermediate risk. The role of modifiable vascular factors could be explored in this context.

SUBMITTER: Rosenberg A

PROVIDER: S-EPMC6896336 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid.

Rosenberg Anna A Solomon Alina A Jelic Vesna V Hagman Göran G Bogdanovic Nenad N Kivipelto Miia M

Alzheimer's research & therapy 20191205 1

<h4>Background</h4>Determination of β-amyloid (Aβ) positivity and likelihood of underlying Alzheimer's disease (AD) relies on dichotomous biomarker cut-off values. Individuals with mild cognitive impairment (MCI) and Aβ within the normal range may still have a substantial risk of developing dementia, primarily of Alzheimer type. Their prognosis, as well as predictors of clinical progression, are not fully understood. The aim of this study was to explore the associations of cerebrospinal fluid (C ...[more]

PMID: 31805990

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Project description:BackgroundAmyloid pathology in subjects with mild cognitive impairment (MCI) is an important risk factor for progression to dementia due to Alzheimer's disease. Predicting the onset of dementia is challenging even in the presence of amyloid, as time to progression varies considerably among patients and depends on the onset of neurodegeneration. Survival analysis can account for variability in time to event, but has not often been applied to MRI measurements beyond singular predefined brain regions such as the hippocampus. Here we used a voxel-wise survival analysis to identify in an unbiased fashion brain regions where decreased gray matter volume is associated with time to dementia, and assessed the effects of amyloid on these associations.MethodsWe included 276 subjects with MCI (mean age 67?±?8, 41% female, mean Mini-Mental State Examination 26.6?±?2.4), baseline 3D T1-weighted structural MRI, baseline cerebrospinal fluid (CSF) biomarkers, and prospective clinical follow-up. We fitted for each voxel a proportional Cox hazards regression model to study whether decreased gray matter volume predicted progression to dementia in the total sample, and stratified for baseline amyloid status.ResultsDementia at follow-up occurred in 122 (44%) subjects over an average follow-up period of 2.5?±?1.5 years. Baseline amyloid positivity was associated with progression to dementia (hazard ratio 2.4, p?<?0.001). Within amyloid-positive subjects, decreased gray matter volume in the hippocampal, temporal, parietal, and frontal regions was associated with more rapid progression to dementia (median (interquartile range) hazard ratio across significant voxels 1.35 (1.32-1.40)). Repeating the analysis in amyloid-negative subjects revealed similar patterns (median (interquartile range) hazard ratio 1.76 (1.66-1.91)).ConclusionsIn subjects with MCI, both abnormal amyloid CSF and decreased gray matter volume were associated with future progression to dementia. The spatial pattern of decreased gray matter volume associated with progression to dementia was consistent for amyloid-positive and amyloid-negative subjects.

Project description:BackgroundAccording to the amyloid, tau, neurodegeneration research framework classification, amyloid and tau positive (A+T+) mild cognitive impairment (MCI) individuals are defined as prodromal Alzheimer disease. This study was designed to compare the clinical and biomarker features between A+T+MCI individuals who progressed to progressive MCI (pMCI) and those who remained stable MCI (sMCI), and to identify relevant baseline clinical biomarker and features that could be used to predict progression to dementia within 2 years.MethodsWe stratified 197 A+T+MCI individuals into pMCI (n = 64) and sMCI (n = 133) over 2 years. Demographics and cognitive assessment scores, cerebrospinal fluid (CSF), and neuroimaging biomarkers (18F-florbetapir positron emission tomography mean standardized uptake value ratios [SUVR] and structural magnetic resonance imaging [MRI]) were compared between pMCI and sMCI at baseline, 12- and 24-month follow-up. Logistic regression models then were used to evaluate clinical baseline and biomarker features that predicted dementia progression in A+T+MCI.ResultspMCI individuals had higher mean 18F-florbetapir SUVR, CSF total-tau (t-tau), and p-tau181P than those in sMCI individuals. pMCI individuals performed poorer in cognitive assessments, both global and domain specific (memory, executive, language, attention, and visuospatial skills) than sMCI. At baseline, there were significant differences in regions of interest of structural MRI between the two groups, including bilateral amygdala, hippocampus and entorhinal, bilateral inferior lateral ventricle, left superior and middle temporal, left posterior and caudal anterior cingulate (P < 0.05). Baseline CSF t-tau levels and cognitive scores of Montreal cognitive assessment, functional assessment questionnaire, and everyday cognition by the patient's study partner language domain could predict progression to dementia in A+T+MCI within 2 years.ConclusionsIn future clinical trials, specific CSF and cognitive measures that predict dementia progression in A+T+MCI might be useful risk factors for assessing the risk of dementia progression.

Project description:BACKGROUND:Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum. OBJECTIVE:To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes. METHODS:Patient-level longitudinal data from the National Alzheimer's Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon. RESULTS:Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy. CONCLUSION:Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.

Dataset Information

Progression to dementia in memory clinic patients with mild cognitive impairment and normal ?-amyloid.

Publications

Progression to dementia in memory clinic patients with mild cognitive impairment and normal β-amyloid.

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