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Abstract

Objective:

To estimate whole-brain microinfarct burden from microinfarct counts in routine postmortem examination.

Methods:

We developed a simple mathematical method to estimate the total number of cerebral microinfarcts from counts obtained in the small amount of tissue routinely examined in brain autopsies. We derived estimates of total microinfarct burden from autopsy brain specimens from 648 older participants in 2 community-based clinical-pathologic cohort studies of aging and dementia.

Results:

Our results indicate that observing 1 or 2 microinfarcts in 9 routine neuropathologic specimens implies a maximum-likelihood estimate of 552 or 1,104 microinfarcts throughout the brain. Similar estimates were obtained when validating in larger sampled brain volumes.

Conclusions:

The substantial whole-brain burden of cerebral microinfarcts suggested by even a few microinfarcts on routine pathologic sampling suggests a potential mechanism by which these lesions could cause neurologic dysfunction in individuals with small-vessel disease. The estimation framework developed here may generalize to clinicopathologic correlations of other imaging-negative micropathologies.

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Supplementary Material

File (1358.pdf)
File (appendix_e-1.pdf)
File (estimating_cerebral_microinfarct.pdf)

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Information & Authors

Information

Published In

Neurology®
Volume 80Number 15April 9, 2013
Pages: 1365-1369
PubMed: 23486880

Publication History

Received: August 6, 2012
Accepted: November 13, 2012
Published online: March 13, 2013
Published in print: April 9, 2013

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Disclosure

M.B. Westover, M.T. Bianchi, and C. Yang report no disclosures. J.A. Schneider contributed data used in this work from the Funding for the Religious Orders Study and the Rush Memory and Aging Project, which were supported by grants from the National Institute on Aging (R01 AG15819, R01 AG17917, P30 AG10161, and K08 AG00849). S.M. Greenberg is funded by R01AG026484 from the NIH. Go to Neurology.org for full disclosures.

Study Funding

Supported by a grant from the NIH (R01 AG026484).

Authors

Affiliations & Disclosures

M. Brandon Westover, MD, PhD
From the Hemorrhagic Stroke Research Program (M.B.W., M.T.B., S.M.G.), Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston; and Rush Alzheimer's Disease Center (C.Y., J.A.S.), Department of Pathology, Rush University Medical Center, Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Matt T. Bianchi, MD, PhD
From the Hemorrhagic Stroke Research Program (M.B.W., M.T.B., S.M.G.), Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston; and Rush Alzheimer's Disease Center (C.Y., J.A.S.), Department of Pathology, Rush University Medical Center, Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
I have a patent pending on a portable sleep monitoring device. There have been no royalties, and there is no licensing agreement in place (pursuant to the question below about future rights). The device is unrelated to this manuscript.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
1) Center for Integration of Medicine and Innovative Technology: Pilot Grant 2) Harvard Medical School: Clinical Investigator Training Program Fellowship 3) Harvard Catalyst: KL2 training fellowship
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Chunhui Yang, MD, PhD
From the Hemorrhagic Stroke Research Program (M.B.W., M.T.B., S.M.G.), Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston; and Rush Alzheimer's Disease Center (C.Y., J.A.S.), Department of Pathology, Rush University Medical Center, Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Julie A. Schneider, MD, MS
From the Hemorrhagic Stroke Research Program (M.B.W., M.T.B., S.M.G.), Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston; and Rush Alzheimer's Disease Center (C.Y., J.A.S.), Department of Pathology, Rush University Medical Center, Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
1. served on scientific advisory board for GE Healthcare (2010) 2. served on scientific advisory board for Eli Lilly and Company (2011)
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
2005-current Journal Histochemistry and Cytochemistry (Monitoring editor) 2008-current International Journal of Clinical and Experimental Pathology (IJCEP, ISSN 1936-2625) (Editorial Board) 2010 Journal of Alzheimer's Disease (Associate Editor)
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Neuropathology consultant, AVID radiopharmaceuticals 2009-12
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
AVID radiopharmaceutical phase III clinical trial Neuropathologist 2010-2011
Research Support, Government Entities:
1.
1R01AG042210 (Schneider) 07/1/12- 06/30/17 Epidemiologic Study of TDP-43 Pathology in Aging and Dementia Major goal is to determine whether age-related TDP-43 pathology represents a separate pathologic process associated with a dementia syndrome with a distinct cognitive phenotype and specific genetic risk factors that are separate from AD. Role: Principal investigator R01NS078009 (Buchman) 9/15/12-6/30/17 NINDS The Clinical Profile of Parkinson's Disease (PD) Pathology. The overall goal is to characterize the clinical profile of PD pathology in older persons without a diagnosis of PD. Role: co-investigator R01AG043379 (Buchman) 9/30/12-8/31/17 NIA Brain and Spinal Cord Microvascular Pathology in Late-Life Motor Impairment The overall goal is to test the hypothesis that specific microvascular pathologies in the brain and spinal cord contribute to late-life motor impairment. U01AG016976 (Kukull/Montine) 7/1/12-6/30/13 NIA (Pilot) Optimization of Neuropathologic Assessment of Alzheimer's Disease; The overall goal is to optimize neuropathologic diagnosis of Alzheimer's disease for uniformity and accurancy across centers Role: Site Principal Investigator P30 AG10161 (Bennett) 9/30/91-6/30/16 Rush Alzheimer's Disease Core Center Major goals to provide core infrastructure support for research regarding aging/dementia/AD. Role: Associate Director, Core Leader: Neuropathology Core R01 AG031553 (Morris) 3/15/08 – 2/28/13 Epidemiologic Study of Brain Vitamin E, Diet, and Age-Related Neurologic Diseases; Major goal is analyze Vitamin E in brain, CSF, serum, and diet and compare to neuropathology and dementia. Role: Co-Principal Investigator R01 AG17917 (Bennett) 9/30/01-6/30/13 Epidemiologic Study of Neural Reserve and Neurobiology of Aging; Major goals are to identify structural bases of reserve and examine mechanisms risk factors lead to age-related functional impairment. Role: Co-Investigator R01 AG15819 (7/1/98 – 6/30/13 Risk Factors, Pathology and Clinical Expressions of AD The major goals of this project are to examine the pathologic mechanisms through which risk factors lead to clinical AD. Role: Co-investigator P01 AG14449 (Mufson) 9/1/97 – 3/31/13 Neurobiology of Mild cognitive impairment in the Elderly; The major goals are to identify neurobiologic substrates of mild cognitive impairment. Role: Co-investigator (Neuropathologist) R01AG033678-01 (Boyle) 9/15/2009 - 6/30/14 Epidemiologic study of impaired decision making in preclinical Alzheimer's disease. The overall goal of the proposed epidemiologic study is to examine the causes and consequences of impaired decision-making in old age. Role: Neuropathologist R01AG034374 (Boyle) 8/15/2009 -7/31/14 Characterizing the behavior profile of healthy cognitive aging. Goal is to use innovative statistical approaches to characterize the profile of healthy cognitive aging defined as age-related cognitive change not accounted for by the presence of common neuropathologies (i.e., Alzheimer's disease, cerebral infarcts, and the Lewy body diseases) or terminal decline. Role: Neuropathologist. P01 AG09466 (deToledo-Morrell) 4/1/1991-8/31/12 Anatomic, Physiologic, Cognitive Pathology of AD; major goals- to identify neurobiologic, radiologic, physiologic, cognitive markers with AD; Role: Co-Investigator; Neuropathologist, Administrative Core R01 AG36042 (Bennett) 9/15/09-8/31/14 Exploring the Role of the Brain Epigenome: Cognitive Decline and Life Experiences The goal of the study is to examine the relation of DNA methylation to cognitive decline and life experiences. Role: Neuropathologist R01 HL096944 (Levine) 9/1/09 – 6/30/13 Stroke and aPL: Community-Based Clinicopathologic Study The major goal of this project is to investigate the role and mechanisms of antiphospholipid antibodies (aPL) in the development of pathologically-proven ischemic brain infarction. Role: Neuropathologist R01AG040039 (Arvanitakis) 9/30/11-8/31/16 National Institute on Aging Vascular Cognitive and Motor Decline: Impact of aPL The major goal of this project is to investigate the role and mechanisms of antiphospholipid antibodies (aPL) in the development of cognitive and motor decline in aging. R01AG039478 (Arnold) 4/1/11-3/31/16 National Institute on Aging Targeted Proteomics of Resilient Cognition in Aging The major goal of the study is to identify candidate proteins and pathways that best confer cognitive resilience despite the accumulation of neurodegenerative disease pathology. Role: Neuropathologist R01AG036836 (DeJager) 9/15/11-8/31/15 National Institute on Aging Exploring the Role of the Brain Transcriptome in Cognitive Decline The major goal is to investigate the transcriptome of human brain tissue to identify molecular pathways that contribute to cognitive decline. Role: Neuropathologist
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Steven M. Greenberg, MD, PhD
From the Hemorrhagic Stroke Research Program (M.B.W., M.T.B., S.M.G.), Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston; and Rush Alzheimer's Disease Center (C.Y., J.A.S.), Department of Pathology, Rush University Medical Center, Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
Hoffman-Laroche, MRI Review Committee
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
1) VasCog 2011, travel reimbursement 2) New York Academy of Sciences 2012, travel reimbursement 3) Quebec Society of Vascular Sciences, travel reimbursement and honorarium 4) Cerebral Amyloid Angiopathy conference, travel reimbursement
Editorial Boards:
1.
Stroke, Editorial Board, 2010-present; Cerebrovascular Disease, Editorial Board, 2008-present; Neurology, Editorial Board, 2005-present; J Alzheimer's Disease and Other Dementias, Editorial Board, 2005-present
Patents:
1.
NONE
Publishing Royalties:
1.
1) UpToDate, Cerebral Amyloid Angiopathy 2) MedLink, Cerebral Amyloid Angiopathy
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NIH, PI, R01AG026484, 2005-2015; NIH, PI, R01NS070834, 2010-2015; NIH, PI, U10NS077360, 2011-2018
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence to Dr. Greenberg: [email protected]
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

Study concept and design: Drs. Westover, Bianchi, and Greenberg. Acquisition of data: Drs. Yang and Schneider. Analysis and interpretation of data: Drs. Westover, Bianchi, Schneider, Yang, and Greenberg. Drafting of the manuscript: Drs. Westover, Bianchi, and Greenberg. Critical revision of the manuscript for important intellectual content: Drs. Westover, Bianchi, Schneider, Yang, and Greenberg. Statistical analysis: Drs. Westover and Bianchi.

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