title: Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease.
abstract: BACKGROUND
  The immune response in Alzheimer's disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown.
  
  
  OBJECTIVE
  To determine whether neuroinflammation exacerbates neural damage in preclinical AD.
  
  
  METHODS
  We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI.
  
  
  RESULTS
  Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus.
  
  
  CONCLUSIONS
  Inflammation may play a role in neural damage in preclinical AD.
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Melah
authors.affiliation: Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.
authors.forename: Sharon Yuan-Fu
authors.initials: SY
authors.lastname: Lu
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Hoscheidt
authors.affiliation: Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.
authors.forename: Nagesh
authors.initials: N
authors.lastname: Adluru
authors.affiliation: Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Destiche
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Carlsson
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|UCL Institute of Neurology, Queen Square, London, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Ozioma C
authors.initials: OC
authors.lastname: Okonkwo
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Carey E
authors.initials: CE
authors.lastname: Gleason
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: N Maritza
authors.initials: NM
authors.lastname: Dowling
authors.affiliation: School of Nursing, Wisconsin School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Bratzke
authors.affiliation: Department of Neuroradiology, School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rowley
authors.affiliation: Wisconsin Alzheimer's Institute, School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sager
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
authors.forename: Sterling C
authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, School of Medicine and Public Health, Madison, WI, USA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Bendlin
mesh_terms: D054392:Adipokines / Q000134:cerebrospinal fluid; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid; D000071451:Chitinase-3-Like Protein 1; D056324:Diffusion Tensor Imaging; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D037102:Lectins / Q000134:cerebrospinal fluid; D008297:Male; D017628:Microglia / Q000473:pathology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D066127:White Matter / Q000473:pathology*; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D054392:Adipokines; D016229:Amyloid beta-Peptides; D015415:Biomarkers; C111835:CCL2 protein, human; C084533:CHI3L1 protein, human; D018932:Chemokine CCL2; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; cerebrospinal fluid proteins; diffusion tensor imaging; inflammation
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