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

Article type: Research Article

Authors: Melah, Kelsey E.^a | Lu, Sharon Yuan-Fu^b | Hoscheidt, Siobhan M.^a | Alexander, Andrew L.^b | Adluru, Nagesh^b | Destiche, Daniel J.^b | Carlsson, Cynthia M.^a | Zetterberg, Henrik^{c; d} | Blennow, Kaj^c | Okonkwo, Ozioma C.^{a; e} | Gleason, Carey E.^{a; f} | Dowling, N. Maritza^{a; g} | Bratzke, Lisa C.^h | Rowley, Howard A.ⁱ | Sager, Mark A.^e | Asthana, Sanjay^{a; f} | Johnson, Sterling C.^{a; e; f} | Bendlin, Barbara B.^{a; e; *}

Affiliations: [a] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [b] Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA | [c] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [d] UCL Institute of Neurology, Queen Square, London, UK | [e] Wisconsin Alzheimer’s Institute, School of Medicine and Public Health, Madison, WI, USA | [f] Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [g] Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [h] School of Nursing, Wisconsin School of Medicine and Public Health, Madison, WI, USA | [i] Department of Neuroradiology, School of Medicine and Public Health, Madison, WI, USA

Correspondence: [*] Correspondence to: Barbara B. Bendlin, PhD, J5/1M, Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. Tel.: +1 608 265 2483; E-mail: [email protected].

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. Conclusion:Inflammation may play a role in neural damage in preclinical AD.

Keywords: Alzheimer’s disease, cerebrospinal fluid proteins, diffusion tensor imaging, inflammation,

DOI: 10.3233/JAD-150897

Journal: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 873-886, 2016