title: Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation.
abstract: Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ- in all three ROIs and in Aβi compared to Aβ- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Annie M
authors.initials: AM
authors.lastname: Racine
authors.affiliation: Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Adluru
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705, USA ; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53719, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Christian
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Ozioma C
authors.initials: OC
authors.lastname: Okonkwo
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oh
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Cleary
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Birdsill
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison, WI 53719, USA.
authors.forename: Ansel T
authors.initials: AT
authors.lastname: Hillmer
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Dhanabalan
authors.initials: D
authors.lastname: Murali
authors.affiliation: Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Gallagher
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Carlsson
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rowley
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: N Maritza
authors.initials: NM
authors.lastname: Dowling
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
authors.affiliation: Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI 53705, USA ; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA ; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D056324:Diffusion Tensor Imaging / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D064847:Multimodal Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D066127:White Matter / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides
keywords: AD risk; ANCOVA, Analysis of Covariance; ANTs, Advanced Normalization Tools; APOE4, apolipoprotein E gene ε4; Alzheimer's disease; Amyloid imaging; Aβ+, amyloid positive; Aβi, amyloid indeterminate; Aβ−, amyloid negative; BET, Brain Extraction Tool; Cingulum–CC, cingulum adjacent to corpus callosum; Cingulum–HC, hippocampal cingulum (projecting to medial temporal lobe); DTI, Diffusion Tensor Imaging; DTI-TK, Diffusion Tensor Imaging Toolkit; DVR, distribution volume ratio; Da, axial diffusivity; Dr, radial diffusivity; FA, fractional anisotropy; FH, (parental) family history; FSL, FMRIB Software Library; FUGUE, FMRIB's utility for geometrically unwarping EPIs; FWE, family wise error; GM, gray matter; HARDI, high angular resolution diffusion imaging; ICBM, International Consortium for Brain Mapping; MD, mean diffusivity; PCC, posterior cingulate cortex; PIB, Pittsburgh compound B; PRELUDE, phase region expanding labeler for unwrapping discrete estimates; RAVLT, Rey Auditory Verbal Learning Test; SPM, Statistical Parametric Mapping; TMT, Trail Making Test; WASI, Wechsler Abbreviated Scale of Intelligence; WM, white matter; WRAP, Wisconsin Registry for Alzheimer's Prevention; WRAT, Wide Range Achievement Test; White matter