White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease

Seonjoo Lee, Molly E. Zimmerman, Atul Narkhede, Sara E. Nasrabady, Giuseppe Tosto, Irene B. Meier, Tammie L.S. Benzinger, Daniel S. Marcus, Anne M. Fagan, Nick C. Fox, Nigel J. Cairns, David M. Holtzman, Virginia Buckles, Bernardino Ghetti, Eric McDade, Ralph N. Martins, Andrew J. Saykin, Colin L. Masters, John M. Ringman, Stefan Fӧrster & 12 others Peter R. Schofield, Reisa A. Sperling, Keith A. Johnson, Jasmeer P. Chhatwal, Stephen Salloway, Stephen Correia, Clifford R Jr. Jack, Michael Weiner, Randall J. Bateman, John C. Morris, Richard Mayeux, Adam M. Brickman

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. Discussion Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

Original languageEnglish (US)
Article numbere0195838
JournalPLoS One
Volume13
Issue number5
DOIs
StatePublished - May 1 2018

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Cerebral Amyloid Angiopathy
amyloid
Alzheimer disease
Amyloid
Alzheimer Disease
mutation
Mutation
Magnetic resonance imaging
blood vessels
Pathology
cerebrovascular disorders
White Matter
testing
Blood Vessels
Cerebrovascular Disorders
Testing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Lee, S., Zimmerman, M. E., Narkhede, A., Nasrabady, S. E., Tosto, G., Meier, I. B., ... Brickman, A. M. (2018). White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease. PLoS One, 13(5), [e0195838]. https://doi.org/10.1371/journal.pone.0195838

White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease. / Lee, Seonjoo; Zimmerman, Molly E.; Narkhede, Atul; Nasrabady, Sara E.; Tosto, Giuseppe; Meier, Irene B.; Benzinger, Tammie L.S.; Marcus, Daniel S.; Fagan, Anne M.; Fox, Nick C.; Cairns, Nigel J.; Holtzman, David M.; Buckles, Virginia; Ghetti, Bernardino; McDade, Eric; Martins, Ralph N.; Saykin, Andrew J.; Masters, Colin L.; Ringman, John M.; Fӧrster, Stefan; Schofield, Peter R.; Sperling, Reisa A.; Johnson, Keith A.; Chhatwal, Jasmeer P.; Salloway, Stephen; Correia, Stephen; Jack, Clifford R Jr.; Weiner, Michael; Bateman, Randall J.; Morris, John C.; Mayeux, Richard; Brickman, Adam M.

In: PLoS One, Vol. 13, No. 5, e0195838, 01.05.2018.

Research output: Contribution to journalArticle

Lee, S, Zimmerman, ME, Narkhede, A, Nasrabady, SE, Tosto, G, Meier, IB, Benzinger, TLS, Marcus, DS, Fagan, AM, Fox, NC, Cairns, NJ, Holtzman, DM, Buckles, V, Ghetti, B, McDade, E, Martins, RN, Saykin, AJ, Masters, CL, Ringman, JM, Fӧrster, S, Schofield, PR, Sperling, RA, Johnson, KA, Chhatwal, JP, Salloway, S, Correia, S, Jack, CRJ, Weiner, M, Bateman, RJ, Morris, JC, Mayeux, R & Brickman, AM 2018, 'White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease', PLoS One, vol. 13, no. 5, e0195838. https://doi.org/10.1371/journal.pone.0195838
Lee, Seonjoo ; Zimmerman, Molly E. ; Narkhede, Atul ; Nasrabady, Sara E. ; Tosto, Giuseppe ; Meier, Irene B. ; Benzinger, Tammie L.S. ; Marcus, Daniel S. ; Fagan, Anne M. ; Fox, Nick C. ; Cairns, Nigel J. ; Holtzman, David M. ; Buckles, Virginia ; Ghetti, Bernardino ; McDade, Eric ; Martins, Ralph N. ; Saykin, Andrew J. ; Masters, Colin L. ; Ringman, John M. ; Fӧrster, Stefan ; Schofield, Peter R. ; Sperling, Reisa A. ; Johnson, Keith A. ; Chhatwal, Jasmeer P. ; Salloway, Stephen ; Correia, Stephen ; Jack, Clifford R Jr. ; Weiner, Michael ; Bateman, Randall J. ; Morris, John C. ; Mayeux, Richard ; Brickman, Adam M. / White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease. In: PLoS One. 2018 ; Vol. 13, No. 5.
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abstract = "Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21{\%} of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. Discussion Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.",
author = "Seonjoo Lee and Zimmerman, {Molly E.} and Atul Narkhede and Nasrabady, {Sara E.} and Giuseppe Tosto and Meier, {Irene B.} and Benzinger, {Tammie L.S.} and Marcus, {Daniel S.} and Fagan, {Anne M.} and Fox, {Nick C.} and Cairns, {Nigel J.} and Holtzman, {David M.} and Virginia Buckles and Bernardino Ghetti and Eric McDade and Martins, {Ralph N.} and Saykin, {Andrew J.} and Masters, {Colin L.} and Ringman, {John M.} and Stefan Fӧrster and Schofield, {Peter R.} and Sperling, {Reisa A.} and Johnson, {Keith A.} and Chhatwal, {Jasmeer P.} and Stephen Salloway and Stephen Correia and Jack, {Clifford R Jr.} and Michael Weiner and Bateman, {Randall J.} and Morris, {John C.} and Richard Mayeux and Brickman, {Adam M.}",
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T1 - White matter hyperintensities and the mediating role of cerebral amyloid angiopathy in dominantly-inherited Alzheimer’s disease

AU - Lee, Seonjoo

AU - Zimmerman, Molly E.

AU - Narkhede, Atul

AU - Nasrabady, Sara E.

AU - Tosto, Giuseppe

AU - Meier, Irene B.

AU - Benzinger, Tammie L.S.

AU - Marcus, Daniel S.

AU - Fagan, Anne M.

AU - Fox, Nick C.

AU - Cairns, Nigel J.

AU - Holtzman, David M.

AU - Buckles, Virginia

AU - Ghetti, Bernardino

AU - McDade, Eric

AU - Martins, Ralph N.

AU - Saykin, Andrew J.

AU - Masters, Colin L.

AU - Ringman, John M.

AU - Fӧrster, Stefan

AU - Schofield, Peter R.

AU - Sperling, Reisa A.

AU - Johnson, Keith A.

AU - Chhatwal, Jasmeer P.

AU - Salloway, Stephen

AU - Correia, Stephen

AU - Jack, Clifford R Jr.

AU - Weiner, Michael

AU - Bateman, Randall J.

AU - Morris, John C.

AU - Mayeux, Richard

AU - Brickman, Adam M.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. Discussion Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

AB - Introduction White matter hyperintensity (WMH) volume on MRI is increased among presymptomatic individuals with autosomal dominant mutations for Alzheimer’s disease (AD). One potential explanation is that WMH, conventionally considered a marker of cerebrovascular disease, are a reflection of cerebral amyloid angiopathy (CAA) and that increased WMH in this population is a manifestation of this vascular form of primary AD pathology. We examined whether the presence of cerebral microbleeds, a marker of CAA, mediates the relationship between WMH and estimated symptom onset in individuals with and without autosomal dominant mutations for AD. Participants and methods Participants (n = 175, mean age = 41.1 years) included 112 with an AD mutation and 63 first-degree non-carrier controls. We calculated the estimated years from expected symptom onset (EYO) and analyzed baseline MRI data for WMH volume and presence of cerebral microbleeds. Mixed effects regression and tests of mediation were used to examine microbleed and WMH differences between carriers and non-carriers and to test the whether the association between WMH and mutation status is dependent on the presence of microbleeds. Results Mutation carriers were more likely to have microbleeds than non-carriers (p<0.05) and individuals with microbleeds had higher WMH volume than those without (p<0.05). Total WMH volume was increased in mutation carriers compared with non-carriers, up to 20 years prior to EYO, after controlling for microbleed status, as we demonstrated previously. Formal testing of mediation demonstrated that 21% of the association between mutation status and WMH was mediated by presence of microbleeds (p = 0.03) but a significant direct effect of WMH remained (p = 0.02) after controlling for presence of microbleeds. Discussion Although there is some co-dependency between WMH and microbleeds, the observed increases in WMH among mutation carriers does not appear to be fully mediated by this marker of CAA. The findings highlight the possibility that WMH represent a core feature of AD independent of vascular forms of beta amyloid.

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