Modeling grey matter atrophy as a function of time, aging or cognitive decline show different anatomical patterns in Alzheimer's disease

Ellen Dicks, Lisa Vermunt, Wiesje M van der Flier, Pieter Jelle Visser, Frederik Barkhof, Philip Scheltens, Betty M Tijms, Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy.

METHODS: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology.

RESULTS: Using time or aging as predictors, amyloid abnormal participants annually declined -1.29 ± 0.08 points and - 0.28 ± 0.03 points respectively on the MMSE and -12.23 ± 0.47 cm3 and -8.87 ± 0.34 respectively in total GM volume (p < .001). For the time and age models atrophy was widespread and preclinical and prodromal AD showed similar atrophy patterns. Comparing prodromal AD to AD dementia, AD dementia showed faster atrophy mostly in temporal lobes as modeled with time, while prodromal AD showed faster atrophy in mostly frontoparietal areas as modeled with age (pFDR < 0.05). Modeling change in GM volume as a function of decline on MMSE, slopes were less steep compared to those based on time and aging (-4.1 ± 0.25 cm3 per MMSE point decline; p < .001) and showed steeper atrophy for prodromal AD compared to preclinical AD in the right inferior temporal gyrus (p < .05) and compared to AD dementia mostly in temporal areas (pFDR < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced.

CONCLUSION: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.

Original languageEnglish
JournalNeuroImage: Clinical
Volume22
DOIs
Publication statusE-pub ahead of print - 19 Mar 2019

Cite this

@article{4b98ff2becbe46a3868f4ef96d8e52c2,
title = "Modeling grey matter atrophy as a function of time, aging or cognitive decline show different anatomical patterns in Alzheimer's disease",
abstract = "BACKGROUND: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy.METHODS: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology.RESULTS: Using time or aging as predictors, amyloid abnormal participants annually declined -1.29 ± 0.08 points and - 0.28 ± 0.03 points respectively on the MMSE and -12.23 ± 0.47 cm3 and -8.87 ± 0.34 respectively in total GM volume (p < .001). For the time and age models atrophy was widespread and preclinical and prodromal AD showed similar atrophy patterns. Comparing prodromal AD to AD dementia, AD dementia showed faster atrophy mostly in temporal lobes as modeled with time, while prodromal AD showed faster atrophy in mostly frontoparietal areas as modeled with age (pFDR < 0.05). Modeling change in GM volume as a function of decline on MMSE, slopes were less steep compared to those based on time and aging (-4.1 ± 0.25 cm3 per MMSE point decline; p < .001) and showed steeper atrophy for prodromal AD compared to preclinical AD in the right inferior temporal gyrus (p < .05) and compared to AD dementia mostly in temporal areas (pFDR < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced.CONCLUSION: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.",
author = "Ellen Dicks and Lisa Vermunt and {van der Flier}, {Wiesje M} and Visser, {Pieter Jelle} and Frederik Barkhof and Philip Scheltens and Tijms, {Betty M} and {Alzheimer's Disease Neuroimaging Initiative}",
note = "Copyright {\circledC} 2019 The Authors. Published by Elsevier Inc. All rights reserved.",
year = "2019",
month = "3",
day = "19",
doi = "10.1016/j.nicl.2019.101786",
language = "English",
volume = "22",
journal = "NeuroImage: Clinical",
issn = "2213-1582",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Modeling grey matter atrophy as a function of time, aging or cognitive decline show different anatomical patterns in Alzheimer's disease

AU - Dicks, Ellen

AU - Vermunt, Lisa

AU - van der Flier, Wiesje M

AU - Visser, Pieter Jelle

AU - Barkhof, Frederik

AU - Scheltens, Philip

AU - Tijms, Betty M

AU - Alzheimer's Disease Neuroimaging Initiative

N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2019/3/19

Y1 - 2019/3/19

N2 - BACKGROUND: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy.METHODS: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology.RESULTS: Using time or aging as predictors, amyloid abnormal participants annually declined -1.29 ± 0.08 points and - 0.28 ± 0.03 points respectively on the MMSE and -12.23 ± 0.47 cm3 and -8.87 ± 0.34 respectively in total GM volume (p < .001). For the time and age models atrophy was widespread and preclinical and prodromal AD showed similar atrophy patterns. Comparing prodromal AD to AD dementia, AD dementia showed faster atrophy mostly in temporal lobes as modeled with time, while prodromal AD showed faster atrophy in mostly frontoparietal areas as modeled with age (pFDR < 0.05). Modeling change in GM volume as a function of decline on MMSE, slopes were less steep compared to those based on time and aging (-4.1 ± 0.25 cm3 per MMSE point decline; p < .001) and showed steeper atrophy for prodromal AD compared to preclinical AD in the right inferior temporal gyrus (p < .05) and compared to AD dementia mostly in temporal areas (pFDR < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced.CONCLUSION: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.

AB - BACKGROUND: Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy.METHODS: We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3-5] scans per individual over 2 [1.6-4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology.RESULTS: Using time or aging as predictors, amyloid abnormal participants annually declined -1.29 ± 0.08 points and - 0.28 ± 0.03 points respectively on the MMSE and -12.23 ± 0.47 cm3 and -8.87 ± 0.34 respectively in total GM volume (p < .001). For the time and age models atrophy was widespread and preclinical and prodromal AD showed similar atrophy patterns. Comparing prodromal AD to AD dementia, AD dementia showed faster atrophy mostly in temporal lobes as modeled with time, while prodromal AD showed faster atrophy in mostly frontoparietal areas as modeled with age (pFDR < 0.05). Modeling change in GM volume as a function of decline on MMSE, slopes were less steep compared to those based on time and aging (-4.1 ± 0.25 cm3 per MMSE point decline; p < .001) and showed steeper atrophy for prodromal AD compared to preclinical AD in the right inferior temporal gyrus (p < .05) and compared to AD dementia mostly in temporal areas (pFDR < 0.05). Associations with time, aging and MMSE remained when accounting for these effects in the other models, suggesting that all measures explain part of the variance in GM atrophy. Repeating analyses in amyloid normal individuals, effects for time and aging showed similar widespread anatomical patterns, while associations with MMSE were largely reduced.CONCLUSION: Effects of time, aging and MMSE all explained variance in GM atrophy slopes within individuals. Associations with MMSE were weaker than those for time or age, but specific for amyloid pathology. This suggests that at least some of the atrophy observed in time or age models may not be specific to AD.

U2 - 10.1016/j.nicl.2019.101786

DO - 10.1016/j.nicl.2019.101786

M3 - Article

VL - 22

JO - NeuroImage: Clinical

JF - NeuroImage: Clinical

SN - 2213-1582

ER -