Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings

Clifford R. Jack, Heather J. Wiste, Stephen D. Weigand, David S. Knopman, Michelle M. Mielke, Prashanthi Vemuri, Val Lowe, Matthew L. Senjem, Jeffrey L. Gunter, Denise Reyes, Mary M. Machulda, Rosebud Roberts, Ronald C. Petersen

Research output: Contribution to journalArticle

Abstract

We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

Original languageEnglish (US)
Pages (from-to)3747-3759
Number of pages13
JournalBrain
Volume138
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Amyloid
Amyloidosis
Biomarkers
Positron-Emission Tomography
Alzheimer Disease
Age Groups
Demography
Observational Studies
Cross-Sectional Studies
Research Personnel
Learning
Population

Keywords

  • Alzheimer's disease
  • amyloid and neurodegeneration
  • amyloid imaging
  • cognitive ageing
  • preclinical Alzheimer's disease

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Jack, C. R., Wiste, H. J., Weigand, S. D., Knopman, D. S., Mielke, M. M., Vemuri, P., ... Petersen, R. C. (2015). Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. Brain, 138(12), 3747-3759. https://doi.org/10.1093/brain/awv283

Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. / Jack, Clifford R.; Wiste, Heather J.; Weigand, Stephen D.; Knopman, David S.; Mielke, Michelle M.; Vemuri, Prashanthi; Lowe, Val; Senjem, Matthew L.; Gunter, Jeffrey L.; Reyes, Denise; Machulda, Mary M.; Roberts, Rosebud; Petersen, Ronald C.

In: Brain, Vol. 138, No. 12, 01.12.2015, p. 3747-3759.

Research output: Contribution to journalArticle

Jack, CR, Wiste, HJ, Weigand, SD, Knopman, DS, Mielke, MM, Vemuri, P, Lowe, V, Senjem, ML, Gunter, JL, Reyes, D, Machulda, MM, Roberts, R & Petersen, RC 2015, 'Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings', Brain, vol. 138, no. 12, pp. 3747-3759. https://doi.org/10.1093/brain/awv283
Jack CR, Wiste HJ, Weigand SD, Knopman DS, Mielke MM, Vemuri P et al. Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. Brain. 2015 Dec 1;138(12):3747-3759. https://doi.org/10.1093/brain/awv283
Jack, Clifford R. ; Wiste, Heather J. ; Weigand, Stephen D. ; Knopman, David S. ; Mielke, Michelle M. ; Vemuri, Prashanthi ; Lowe, Val ; Senjem, Matthew L. ; Gunter, Jeffrey L. ; Reyes, Denise ; Machulda, Mary M. ; Roberts, Rosebud ; Petersen, Ronald C. / Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings. In: Brain. 2015 ; Vol. 138, No. 12. pp. 3747-3759.
@article{c9bb50998980479384ad5788215bd00b,
title = "Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings",
abstract = "We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100{\%} at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.",
keywords = "Alzheimer's disease, amyloid and neurodegeneration, amyloid imaging, cognitive ageing, preclinical Alzheimer's disease",
author = "Jack, {Clifford R.} and Wiste, {Heather J.} and Weigand, {Stephen D.} and Knopman, {David S.} and Mielke, {Michelle M.} and Prashanthi Vemuri and Val Lowe and Senjem, {Matthew L.} and Gunter, {Jeffrey L.} and Denise Reyes and Machulda, {Mary M.} and Rosebud Roberts and Petersen, {Ronald C.}",
year = "2015",
month = "12",
day = "1",
doi = "10.1093/brain/awv283",
language = "English (US)",
volume = "138",
pages = "3747--3759",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Different definitions of neurodegeneration produce similar amyloid/neurodegeneration biomarker group findings

AU - Jack, Clifford R.

AU - Wiste, Heather J.

AU - Weigand, Stephen D.

AU - Knopman, David S.

AU - Mielke, Michelle M.

AU - Vemuri, Prashanthi

AU - Lowe, Val

AU - Senjem, Matthew L.

AU - Gunter, Jeffrey L.

AU - Reyes, Denise

AU - Machulda, Mary M.

AU - Roberts, Rosebud

AU - Petersen, Ronald C.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

AB - We recently demonstrated that the frequencies of biomarker groups defined by the presence or absence of both amyloidosis (A+) and neurodegeneration (N+) changed dramatically by age in cognitively non-impaired subjects. Our present objectives were to assess the consequences of defining neurodegeneration in five different ways on the frequency of subjects classified as N+, on the demographic associations with N+, and on amyloidosis and neurodegeneration (A/N) biomarker group frequencies by age. This was a largely cross-sectional observational study of 1331 cognitively non-impaired subjects aged 50-89 drawn from a population-based study of cognitive ageing. We assessed demographic associations with N+, and A/N biomarker group frequencies by age where A+ was defined by amyloid PET and N+ was defined in five different ways: (i) abnormal adjusted hippocampal volume alone; (ii) abnormal Alzheimer's disease signature cortical thickness alone; (iii) abnormal fluorodeoxyglucose positron emission tomography alone; (iv) abnormal adjusted hippocampal volume or abnormal fluorodeoxyglucose positron emission tomography; and (v) abnormal Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography. For each N+ definition, participants were assigned to one of four biomarker groups; A-N-, A+N-, A-N+, or A+N+. The three continuous individual neurodegeneration measures were moderately correlated (rs = 0.42 to 0.54) but when classified as normal or abnormal had only weak agreement (κ = 0.20 to 0.29). The adjusted hippocampal volume alone definition classified the fewest subjects as N+ while the Alzheimer's disease signature cortical thickness or abnormal fluorodeoxyglucose positron emission tomography definition classified the most as N+. Across all N+ definitions, N+ subjects tended to be older, more often male and APOE4 carriers, and performed less well on functional status and learning and memory than N- subjects. For all definitions of neurodegeneration, (i) the frequency of A-N- was 100% at age 50 and declined monotonically thereafter; (ii) the frequency of A+N- increased from age 50 to a maximum in the mid-70s and declined thereafter; and3 (iii) the frequency of A-N+ (suspected non-Alzheimer's pathophysiology) and of A+N+ increased monotonically beginning in the mid-50s and mid-60s, respectively. Overall, different neurodegeneration measures provide similar but not completely redundant information. Despite quantitative differences, the overall qualitative pattern of the A-N-, A+N-, A-N+, and A+N+ biomarker group frequency curves by age were similar across the five different definitions of neurodegeneration. We conclude that grouping subjects by amyloidosis and neurodegeneration status (normal/abnormal) is robust to different imaging definitions of neurodegeneration and thus is a useful way for investigators throughout the field to communicate in a common classification framework.

KW - Alzheimer's disease

KW - amyloid and neurodegeneration

KW - amyloid imaging

KW - cognitive ageing

KW - preclinical Alzheimer's disease

UR - http://www.scopus.com/inward/record.url?scp=84951033618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84951033618&partnerID=8YFLogxK

U2 - 10.1093/brain/awv283

DO - 10.1093/brain/awv283

M3 - Article

C2 - 26428666

AN - SCOPUS:84951033618

VL - 138

SP - 3747

EP - 3759

JO - Brain

JF - Brain

SN - 0006-8950

IS - 12

ER -