Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients

Alzheimer’s Disease Neuroimaging Initiative

doi:10.1002/alz.13765

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients

Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.

METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.

RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).

DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter.

HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

Original language	English
Pages (from-to)	2980-2989
Number of pages	10
Journal	Alzheimer's & dementia : the journal of the Alzheimer's Association
Volume	20
Issue number	4
DOIs	https://doi.org/10.1002/alz.13765
Publication status	Published - Apr 2024

Bibliographical note

Funding

We are grateful to the diverse participants who contribute to our research. The Meta VCI Map consortium is supported by Vici Grant 918.16.616 from ZonMw to G.J.B. This study was supported by a Veni grant (project9150162010055) from ZonMW to J.M.B. C.D.C., E.F.F., and P.M.M. were supported by NIA P30 AG10129, P30 AG072972 and U01 AG024904. ADNI data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ACE was funded by Alzheimer Nederland. PRODEM was supported by the Austrian Science Fund (FWF grants KLI523, P30134, and I2889-B31). The YOAD study was funded by Alzheimer's Research UK (ARUK-Network 2012-6-ICE). The Harmonization study is supported by the National Medical Research Council of Singapore (MOH-000707-00). We are grateful to the diverse participants who contribute to our research. The Meta VCI Map consortium is supported by Vici Grant 918.16.616 from ZonMw to G.J.B. This study was supported by a Veni grant (project9150162010055) from ZonMW to J.M.B. C.D.C., E.F.F., and P.M.M. were supported by NIA P30 AG10129, P30 AG072972 and U01 AG024904. ADNI data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH\u201012\u20102\u20100012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol\u2010Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann\u2010La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ACE was funded by Alzheimer Nederland. PRODEM was supported by the Austrian Science Fund (FWF grants KLI523, P30134, and I2889\u2010B31). The YOAD study was funded by Alzheimer's Research UK (ARUK\u2010Network 2012\u20106\u2010ICE). The Harmonization study is supported by the National Medical Research Council of Singapore (MOH\u2010000707\u201000). F.B. is supported by the NIHR biomedical research center at UCLH and reports the following: steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC, and Prothena; consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, and Combinostics; research agreements with Merck, Biogen, GE Healthcare, and Roche; co\u2010founder and shareholder of Queen Square Analytics Ltd. M.D. received honoraria for lectures from Bayer Vital and Sanofi Genzyme and reports the following: consultant for Hovid Berhad and Roche Pharma, member of scientific advisory board for Biogen. R.W.P. received honoraria from GE Healthcare and is co\u2010lead of Neurofilament light consortium. C.H.S. is supported by an Alzheimer's Society Fellowship and is a scientific advisor to BrainKey. V.V. is supported by JPND\u2010funded E\u2010DADS project (ZonMw project #733051106). The remaining authors have nothing to disclose. Author disclosures are available in the Supporting Information .

Funders	Funder number
Northern California Institute for Research and Education
Alzheimer's Association
BioClinica
University of Southern California
National Institute of Biomedical Imaging and Bioengineering
AbbVie
Alzheimer Nederland
Biogen
National Institutes of Health
Alzheimer's Disease Neuroimaging Initiative
Araclon Biotech
DOD ADNI
Alzheimer's Drug Discovery Foundation
ZonMw	project9150162010055, 733051106
Austrian Science Fund	I2889‐B31, I 2889, P 30134, KLI 523
Alzheimer’s Research UK	ARUK‐Network 2012‐6‐ICE
National Institute on Aging	P30 AG072972, U01 AG024904, P30 AG10129
National Medical Research Council	MOH‐000707‐00
U.S. Department of Defense	W81XWH‐12‐2‐0012

Keywords

Humans
Female
Middle Aged
Aged
Aged, 80 and over
Male
White Matter/pathology
Arteriolosclerosis/pathology
Amyloid beta-Peptides/metabolism
Dementia/pathology
Magnetic Resonance Imaging

Access to Document

10.1002/alz.13765

Persistent URL (handle)

Persistent link

Cite this

@article{44a4f789ab3d4e59b73d696611dc5feb,

title = "Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients",

abstract = "INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3\% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and A{\ss}42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and A{\ss}42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).DISCUSSION: Vascular risk factors and A{\ss}42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and A{\ss}42 pathology affect the brain's white matter.HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.",

keywords = "Humans, Female, Middle Aged, Aged, Aged, 80 and over, Male, White Matter/pathology, Arteriolosclerosis/pathology, Amyloid beta-Peptides/metabolism, Dementia/pathology, Magnetic Resonance Imaging",

author = "Biesbroek, \{J Matthijs\} and Mirthe Coenen and Charles DeCarli and Fletcher, \{Evan M\} and Maillard, \{Pauline M\} and Frederik Barkhof and Josephine Barnes and Thomas Benke and Chen, \{Christopher P L H\} and Peter Dal-Bianco and Anna Dewenter and Marco Duering and Christian Enzinger and Michael Ewers and Exalto, \{Lieza G\} and Nicolai Franzmeier and Saima Hilal and Edith Hofer and Koek, \{Huiberdina L\} and Maier, \{Andrea B\} and McCreary, \{Cheryl R\} and Papma, \{Janne M\} and Paterson, \{Ross W\} and Pijnenburg, \{Yolande A L\} and Anna Rubinski and Reinhold Schmidt and Schott, \{Jonathan M\} and Slattery, \{Catherine F\} and Smith, \{Eric E\} and Sudre, \{Carole H\} and Steketee, \{Rebecca M E\} and Teunissen, \{Charlotte E\} and \{van den Berg\}, Esther and \{van der Flier\}, \{Wiesje M\} and Narayanaswamy Venketasubramanian and Vikram Venkatraghavan and Vernooij, \{Meike W\} and Wolters, \{Frank J\} and Xu Xin and Kuijf, \{Hugo J\} and Biessels, \{Geert Jan\} and \{Alzheimer{\textquoteright}s Disease Neuroimaging Initiative\}",

note = "{\textcopyright} 2024 The Authors. Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2024",

month = apr,

doi = "10.1002/alz.13765",

language = "English",

volume = "20",

pages = "2980--2989",

journal = "Alzheimer's \& dementia : the journal of the Alzheimer's Association",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients. / Alzheimer’s Disease Neuroimaging Initiative.
In: Alzheimer's & dementia : the journal of the Alzheimer's Association, Vol. 20, No. 4, 04.2024, p. 2980-2989.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities

T2 - A multicenter study in 3132 memory clinic patients

AU - Biesbroek, J Matthijs

AU - Coenen, Mirthe

AU - DeCarli, Charles

AU - Fletcher, Evan M

AU - Maillard, Pauline M

AU - Barkhof, Frederik

AU - Barnes, Josephine

AU - Benke, Thomas

AU - Chen, Christopher P L H

AU - Dal-Bianco, Peter

AU - Dewenter, Anna

AU - Duering, Marco

AU - Enzinger, Christian

AU - Ewers, Michael

AU - Exalto, Lieza G

AU - Franzmeier, Nicolai

AU - Hilal, Saima

AU - Hofer, Edith

AU - Koek, Huiberdina L

AU - Maier, Andrea B

AU - McCreary, Cheryl R

AU - Papma, Janne M

AU - Paterson, Ross W

AU - Pijnenburg, Yolande A L

AU - Rubinski, Anna

AU - Schmidt, Reinhold

AU - Schott, Jonathan M

AU - Slattery, Catherine F

AU - Smith, Eric E

AU - Sudre, Carole H

AU - Steketee, Rebecca M E

AU - Teunissen, Charlotte E

AU - van den Berg, Esther

AU - van der Flier, Wiesje M

AU - Venketasubramanian, Narayanaswamy

AU - Venkatraghavan, Vikram

AU - Vernooij, Meike W

AU - Wolters, Frank J

AU - Xin, Xu

AU - Kuijf, Hugo J

AU - Biessels, Geert Jan

AU - Alzheimer’s Disease Neuroimaging Initiative

PY - 2024/4

Y1 - 2024/4

N2 - INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter.HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

AB - INTRODUCTION: White matter hyperintensities (WMH) are associated with key dementia etiologies, in particular arteriolosclerosis and amyloid pathology. We aimed to identify WMH locations associated with vascular risk or cerebral amyloid-β1-42 (Aβ42)-positive status.METHODS: Individual patient data (n = 3,132; mean age 71.5 ± 9 years; 49.3% female) from 11 memory clinic cohorts were harmonized. WMH volumes in 28 regions were related to a vascular risk compound score (VRCS) and Aß42 status (based on cerebrospinal fluid or amyloid positron emission tomography), correcting for age, sex, study site, and total WMH volume.RESULTS: VRCS was associated with WMH in anterior/superior corona radiata (B = 0.034/0.038, p < 0.001), external capsule (B = 0.052, p < 0.001), and middle cerebellar peduncle (B = 0.067, p < 0.001), and Aß42-positive status with WMH in posterior thalamic radiation (B = 0.097, p < 0.001) and splenium (B = 0.103, p < 0.001).DISCUSSION: Vascular risk factors and Aß42 pathology have distinct signature WMH patterns. This regional vulnerability may incite future studies into how arteriolosclerosis and Aß42 pathology affect the brain's white matter.HIGHLIGHTS: Key dementia etiologies may be associated with specific patterns of white matter hyperintensities (WMH). We related WMH locations to vascular risk and cerebral Aβ42 status in 11 memory clinic cohorts. Aβ42 positive status was associated with posterior WMH in splenium and posterior thalamic radiation. Vascular risk was associated with anterior and infratentorial WMH. Amyloid pathology and vascular risk have distinct signature WMH patterns.

KW - Humans

KW - Female

KW - Middle Aged

KW - Aged

KW - Aged, 80 and over

KW - Male

KW - White Matter/pathology

KW - Arteriolosclerosis/pathology

KW - Amyloid beta-Peptides/metabolism

KW - Dementia/pathology

KW - Magnetic Resonance Imaging

UR - https://www.scopus.com/pages/publications/85191238408

UR - https://www.scopus.com/inward/citedby.url?scp=85191238408&partnerID=8YFLogxK

U2 - 10.1002/alz.13765

DO - 10.1002/alz.13765

M3 - Article

C2 - 38477469

SN - 1552-5260

VL - 20

SP - 2980

EP - 2989

JO - Alzheimer's & dementia : the journal of the Alzheimer's Association

JF - Alzheimer's & dementia : the journal of the Alzheimer's Association

IS - 4

ER -

Amyloid pathology and vascular risk are associated with distinct patterns of cerebral white matter hyperintensities: A multicenter study in 3132 memory clinic patients

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this