title: Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging.
abstract: Brain changes associated with Alzheimer's disease (AD) begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter) include diffusion tensor imaging (DTI) and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years) from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI) model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF) biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD). AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI.
authors.affiliation: Lieutenant, Medical Service Corp, United States Navy, Falls Church, Virginia, United States of America.|Department of Medical Physics, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States of America.|Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Radiology and Radiologic Sciences, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America.
authors.forename: Andrew R
authors.identifier: http://orcid.org/0000-0001-9254-8142
authors.initials: AR
authors.lastname: Hoy
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Martina
authors.initials: M
authors.lastname: Ly
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Carlsson
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Ozioma C
authors.initials: OC
authors.lastname: Okonkwo
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.|UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Department of Medical Physics, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, United States of America.|Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, Wisconsin, United States of America.|Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, United States of America.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Geriatric Research Education and Clinical Center, William S. Middleton Memorial Veteran's Hospital, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Disease Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D066127:White Matter / Q000473:pathology*