Dataset Information

Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment.

ABSTRACT:

Background

Amyloid 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.

Methods

We 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.

Results

Dementia 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?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.

SUBMITTER: Ten Kate M

PROVIDER: S-EPMC5596472 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment.

Ten Kate Mara M Barkhof Frederik F Visser Pieter Jelle PJ Teunissen Charlotte E CE Scheltens Philip P van der Flier Wiesje M WM Tijms Betty M BM

Alzheimer's research & therapy 20170912 1

<h4>Background</h4>Amyloid 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 br ...[more]

PMID: 28899429

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Project description:BackgroundIn patients with amyloid-positive mild cognitive impairment (MCI), neurodegenerative biomarkers such as medial temporal lobe atrophy (MTA) are useful to predict disease progression to dementia. Although posterior atrophy (PA) is a well-known neurodegenerative biomarker of Alzheimer's disease, little is known about PA as a predictor in patients with amyloid-positive MCI.MethodsWe included 258 patients with amyloid-positive MCI with at least one follow-up visit, and who had low cerebrospinal fluid (CSF) ?-amyloid1-42 concentration. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative study. We assessed PA and MTA on magnetic resonance imaging (MRI) using visual rating scales and retrospectively determined progression to dementia during the follow-up period of up to 3 years (median 24 months). The Cox proportional hazards model was used to analyze hazard ratios (HRs) of PA and MTA for disease progression. Additionally, subjects were divided into four groups according to brain atrophy pattern (no atrophy, MTA only, PA only, both MTA and PA), and HRs for disease progression were compared with the no atrophy reference group. Analyses were conducted with and without adjustment for CSF phosphorylated tau181p (p-tau) and baseline demographics.ResultsA total of 123 patients (47.7%) showed MTA and 174 patients (67.4%) showed PA. Of the total cohort, 139 cases (53.9%) progressed to dementia. PA and MTA were associated with an increased risk for progression to dementia (HR 2.244, 95% confidence interval (CI) 1.497-3.364, and HR 1.682, 95% CI 1.203-2.352, respectively). In the analysis according to atrophy pattern, HR (95% CI) for progression was 2.998 (1.443-6.227) in the MTA only group, 3.126 (1.666-5.864) in the PA only group, and 3.814 (2.045-7.110) in both MTA and PA group. These results remained significant after adjustment.ConclusionsIn patients with amyloid-positive MCI, PA could predict progression to dementia independently of MTA.

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: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 (CSF) biomarkers (Aβ42, 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 Aβ42. 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 Aβ42 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) ε4 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 Aβ42 and higher total tau and phosphorylated tau were associated with higher dementia risk, and the association was not driven by Aβ42 values close to cut-off. Additional predictors included poorer cognition, APOE ε4 genotype, higher systolic blood pressure, and lower body mass index, but not the CAIDE dementia risk score. Aβ42 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 Aβ42 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.

Dataset Information

Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment.

Background

Methods

Results

Publications

Amyloid-independent atrophy patterns predict time to progression to dementia in mild cognitive impairment.

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