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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.
J Alzheimers Dis. 2016; 50(3):873-86.JA

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.

Authors+Show Affiliations

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.Waisman Laboratory for Brain Imaging and Behavior, Madison, WI, USA.Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.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.Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.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.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.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.School of Nursing, Wisconsin School of Medicine and Public Health, Madison, WI, USA.Department of Neuroradiology, School of Medicine and Public Health, Madison, WI, USA.Wisconsin Alzheimer's Institute, School of Medicine and Public Health, Madison, WI, USA.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.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26836182

Citation

Melah, Kelsey E., et al. "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." Journal of Alzheimer's Disease : JAD, vol. 50, no. 3, 2016, pp. 873-86.
Melah KE, Lu SY, Hoscheidt SM, et al. 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. J Alzheimers Dis. 2016;50(3):873-86.
Melah, K. E., Lu, S. Y., Hoscheidt, S. M., Alexander, A. L., Adluru, N., Destiche, D. J., Carlsson, C. M., Zetterberg, H., Blennow, K., Okonkwo, O. C., Gleason, C. E., Dowling, N. M., Bratzke, L. C., Rowley, H. A., Sager, M. A., Asthana, S., Johnson, S. C., & Bendlin, B. B. (2016). 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. Journal of Alzheimer's Disease : JAD, 50(3), 873-86. https://doi.org/10.3233/JAD-150897
Melah KE, et al. 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. J Alzheimers Dis. 2016;50(3):873-86. PubMed PMID: 26836182.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Melah,Kelsey E, AU - Lu,Sharon Yuan-Fu, AU - Hoscheidt,Siobhan M, AU - Alexander,Andrew L, AU - Adluru,Nagesh, AU - Destiche,Daniel J, AU - Carlsson,Cynthia M, AU - Zetterberg,Henrik, AU - Blennow,Kaj, AU - Okonkwo,Ozioma C, AU - Gleason,Carey E, AU - Dowling,N Maritza, AU - Bratzke,Lisa C, AU - Rowley,Howard A, AU - Sager,Mark A, AU - Asthana,Sanjay, AU - Johnson,Sterling C, AU - Bendlin,Barbara B, PY - 2016/2/3/entrez PY - 2016/2/3/pubmed PY - 2016/11/1/medline KW - Alzheimer’s disease KW - cerebrospinal fluid proteins KW - diffusion tensor imaging KW - inflammation SP - 873 EP - 86 JF - Journal of Alzheimer's disease : JAD JO - J Alzheimers Dis VL - 50 IS - 3 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/26836182/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_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-150897 DB - PRIME DP - Unbound Medicine ER -