White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network

Seonjoo Lee, Fawad Viqar, Molly E. Zimmerman, Atul Narkhede, Giuseppe Tosto, Tammie L S Benzinger, Daniel S. Marcus, Anne M. Fagan, Alison Goate, Nick C. Fox, Nigel J. Cairns, David M. Holtzman, Virginia Buckles, Bernardino Ghetti, Eric McDade, Ralph N. Martins, Andrew Saykin, Colin L. Masters, John M. Ringman, Natalie S. RyanStefan Förster, Christoph Laske, Peter R. Schofield, Reisa A. Sperling, Stephen Salloway, Stephen Correia, Clifford Jack, Michael Weiner, Randall J. Bateman, John C. Morris, Richard Mayeux, Adam M. Brickman

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Objective White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. Methods The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. Interpretation Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.

Original languageEnglish (US)
Pages (from-to)929-939
Number of pages11
JournalAnnals of Neurology
Volume79
Issue number6
DOIs
StatePublished - Jun 1 2016

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Alzheimer Disease
Mutation
Magnetic Resonance Imaging
White Matter
Cerebrovascular Disorders
Occipital Lobe
Parietal Lobe
Age of Onset
Blood Vessels
Linear Models

ASJC Scopus subject areas

  • Medicine(all)
  • Neurology
  • Clinical Neurology

Cite this

Lee, S., Viqar, F., Zimmerman, M. E., Narkhede, A., Tosto, G., Benzinger, T. L. S., ... Brickman, A. M. (2016). White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network. Annals of Neurology, 79(6), 929-939. https://doi.org/10.1002/ana.24647

White matter hyperintensities are a core feature of Alzheimer's disease : Evidence from the dominantly inherited Alzheimer network. / Lee, Seonjoo; Viqar, Fawad; Zimmerman, Molly E.; Narkhede, Atul; Tosto, Giuseppe; Benzinger, Tammie L S; Marcus, Daniel S.; Fagan, Anne M.; Goate, Alison; Fox, Nick C.; Cairns, Nigel J.; Holtzman, David M.; Buckles, Virginia; Ghetti, Bernardino; McDade, Eric; Martins, Ralph N.; Saykin, Andrew; Masters, Colin L.; Ringman, John M.; Ryan, Natalie S.; Förster, Stefan; Laske, Christoph; Schofield, Peter R.; Sperling, Reisa A.; Salloway, Stephen; Correia, Stephen; Jack, Clifford; Weiner, Michael; Bateman, Randall J.; Morris, John C.; Mayeux, Richard; Brickman, Adam M.

In: Annals of Neurology, Vol. 79, No. 6, 01.06.2016, p. 929-939.

Research output: Contribution to journalArticle

Lee, S, Viqar, F, Zimmerman, ME, Narkhede, A, Tosto, G, Benzinger, TLS, Marcus, DS, Fagan, AM, Goate, A, Fox, NC, Cairns, NJ, Holtzman, DM, Buckles, V, Ghetti, B, McDade, E, Martins, RN, Saykin, A, Masters, CL, Ringman, JM, Ryan, NS, Förster, S, Laske, C, Schofield, PR, Sperling, RA, Salloway, S, Correia, S, Jack, C, Weiner, M, Bateman, RJ, Morris, JC, Mayeux, R & Brickman, AM 2016, 'White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network', Annals of Neurology, vol. 79, no. 6, pp. 929-939. https://doi.org/10.1002/ana.24647
Lee, Seonjoo ; Viqar, Fawad ; Zimmerman, Molly E. ; Narkhede, Atul ; Tosto, Giuseppe ; Benzinger, Tammie L S ; Marcus, Daniel S. ; Fagan, Anne M. ; Goate, Alison ; Fox, Nick C. ; Cairns, Nigel J. ; Holtzman, David M. ; Buckles, Virginia ; Ghetti, Bernardino ; McDade, Eric ; Martins, Ralph N. ; Saykin, Andrew ; Masters, Colin L. ; Ringman, John M. ; Ryan, Natalie S. ; Förster, Stefan ; Laske, Christoph ; Schofield, Peter R. ; Sperling, Reisa A. ; Salloway, Stephen ; Correia, Stephen ; Jack, Clifford ; Weiner, Michael ; Bateman, Randall J. ; Morris, John C. ; Mayeux, Richard ; Brickman, Adam M. / White matter hyperintensities are a core feature of Alzheimer's disease : Evidence from the dominantly inherited Alzheimer network. In: Annals of Neurology. 2016 ; Vol. 79, No. 6. pp. 929-939.
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abstract = "Objective White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. Methods The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5{\%}) with a mutation that results in AD and 115 (38.5{\%}) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. Interpretation Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.",
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T1 - White matter hyperintensities are a core feature of Alzheimer's disease

T2 - Evidence from the dominantly inherited Alzheimer network

AU - Lee, Seonjoo

AU - Viqar, Fawad

AU - Zimmerman, Molly E.

AU - Narkhede, Atul

AU - Tosto, Giuseppe

AU - Benzinger, Tammie L S

AU - Marcus, Daniel S.

AU - Fagan, Anne M.

AU - Goate, Alison

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

AU - Masters, Colin L.

AU - Ringman, John M.

AU - Ryan, Natalie S.

AU - Förster, Stefan

AU - Laske, Christoph

AU - Schofield, Peter R.

AU - Sperling, Reisa A.

AU - Salloway, Stephen

AU - Correia, Stephen

AU - Jack, Clifford

AU - Weiner, Michael

AU - Bateman, Randall J.

AU - Morris, John C.

AU - Mayeux, Richard

AU - Brickman, Adam M.

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N2 - Objective White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD. Methods The study comprised participants (n = 299; age = 39.03 ± 10.13) from the Dominantly Inherited Alzheimer Network, including 184 (61.5%) with a mutation that results in AD and 115 (38.5%) first-degree relatives who were noncarrier controls. We calculated the estimated years from expected symptom onset (EYO) by subtracting the affected parent's symptom onset age from the participant's age. Baseline MRI data were analyzed for total and regional WMH. Mixed-effects piece-wise linear regression was used to examine WMH differences between carriers and noncarriers with respect to EYO. Results Mutation carriers had greater total WMH volumes, which appeared to increase approximately 6 years before expected symptom onset. Effects were most prominent for the parietal and occipital lobe, which showed divergent effects as early as 22 years before estimated onset. Interpretation Autosomal-dominant AD is associated with increased WMH well before expected symptom onset. The findings suggest the possibility that WMHs are a core feature of AD, a potential therapeutic target, and a factor that should be integrated into pathogenic models of the disease.

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