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The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment.

ABSTRACT: The objective of this study was to evaluate the A/T/N biomarker scheme in relation with brain atrophy patterns in individuals with mild cognitive impairment (MCI). Of the 154 participants with MCI, 74 progressed to AD within 36-months, and 80 remained stable. In addition, 101 cognitively healthy participants and 102 participants with AD were included. The A/T/N classification was assessed with cerebrospinal fluid markers. Each individual was rated as either positive (abnormal) or negative (normal) on each biomarker. Brain atrophy was assessed with visual ratings from magnetic resonance imaging. None of the individuals with MCI progressed to AD if they had a negative "A" biomarker in conjunction with minimal atrophy. In contrary, several individuals with MCI progressed to AD if they had a positive "A" biomarker in conjunction with minimal atrophy. Numerous individuals with MCI showed inconsistency in the neurodegeneration domain ("N") regarding t-tau and atrophy. The assessment of the A/T/N classification scheme in addition with brain atrophy patterns in MCI, increases the knowledge of the clinical trajectories and the variability within the neurodegeneration domain. This emphasises that individuals with MCI display heterogeneous longitudinal patterns closely connected to their biomarker profiles, which could have important clinical implications.

SUBMITTER: Ekman U

PROVIDER: S-EPMC5976713 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment.

Ekman Urban U Ferreira Daniel D Westman Eric E

Scientific reports 20180530 1

The objective of this study was to evaluate the A/T/N biomarker scheme in relation with brain atrophy patterns in individuals with mild cognitive impairment (MCI). Of the 154 participants with MCI, 74 progressed to AD within 36-months, and 80 remained stable. In addition, 101 cognitively healthy participants and 102 participants with AD were included. The A/T/N classification was assessed with cerebrospinal fluid markers. Each individual was rated as either positive (abnormal) or negative (norma ...[more]

PMID: 29849029

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Project description:Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N=139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N=17) and healthy controls (N=4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology.

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.

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The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment.

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The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment.

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