Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Sep 12;9(1):73.
doi: 10.1186/s13195-017-0299-x.

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

Mara Ten Kate  1   2 , Frederik Barkhof  3   4 , Pieter Jelle Visser  5   6 , Charlotte E Teunissen  7 , Philip Scheltens  5 , Wiesje M van der Flier  5   8 , Betty M Tijms  5
Affiliations

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

Mara Ten Kate et al. Alzheimers Res Ther. .

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 < 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)).

Conclusions: In 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.

Keywords: Alzheimer’s disease; Magnetic resonance imaging; Mild cognitive impairment; survival analysis.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by the VU University Medical Centre institutional ethics committee. All subjects gave written informed consent for their clinical data to be used for research purposes.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Brain regions predicting clinical progression in subjects with MCI. Hazard ratio for progression to dementia associated with lower residual gray matter volume depicted at each voxel. Residual gray matter volumes were standardized prior to analysis. R right, L left (Color figure online)
Fig. 2
Fig. 2
Brain regions predicting clinical progression in amyloid-positive and amyloid-negative subjects. Left panel: significant voxels predicting time to progression to dementia in amyloid-positive subjects. Right panel: significant voxels predicting time to progression to dementia in amyloid-negative subjects. Depicted are hazard ratios for progression to dementia, associated with lower residual gray matter volume. R right, L left (Color figure online)
See this image and copyright information in PMC

References

    1. Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild cognitive impairment to dementia in clinic- vs community-based cohorts. Arch Neurol. 2009;66:1151–7. doi: 10.1001/archneurol.2009.106. - DOI - PMC - PubMed
    1. Mitchell J, Arnold R, Dawson K, Nestor PJ, Hodges JR. Outcome in subgroups of mild cognitive impairment (MCI) is highly predictable using a simple algorithm. J Neurol. 2009;256:1500–9. doi: 10.1007/s00415-009-5152-0. - DOI - PubMed
    1. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:270–9. doi: 10.1016/j.jalz.2011.03.008. - DOI - PMC - PubMed
    1. Jack CR, Wiste HJ, Lesnick TG, Weigand SD, Knopman DS, Vemuri P, et al. Brain β-amyloid load approaches a plateau. Neurology. 2013;80:890–6. doi: 10.1212/WNL.0b013e3182840bbe. - DOI - PMC - PubMed
    1. Villain N, Chételat G, Grassiot B, Bourgeat P, Jones G, Ellis KA, et al. Regional dynamics of amyloid-β deposition in healthy elderly, mild cognitive impairment and Alzheimer’s disease: a voxelwise PiB–PET longitudinal study. Brain. 2012;135:2126–39. doi: 10.1093/brain/aws125. - DOI - PubMed

MeSH terms