Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation

Annie M Racine; Rebecca L Koscik; Christopher R Nicholas; Lindsay R Clark; Ozioma C Okonkwo; Jennifer M Oh; Ansel T Hillmer; Dhanabalan Murali; Todd E Barnhart; Tobey J Betthauser; Catherine L Gallagher; Howard A Rowley; N Maritza Dowling; Sanjay Asthana; Barbara B Bendlin; Kaj Blennow; Henrik Zetterberg; Cynthia M Carlsson; Bradley T Christian; Sterling C Johnson

doi:10.1016/j.dadm.2015.11.006

Cerebrospinal fluid ratios with Aβ42 predict preclinical brain β-amyloid accumulation

Alzheimers Dement (Amst). 2016:2:27-38. doi: 10.1016/j.dadm.2015.11.006.

Authors

Annie M Racine¹, Rebecca L Koscik², Christopher R Nicholas³, Lindsay R Clark⁴, Ozioma C Okonkwo³, Jennifer M Oh³, Ansel T Hillmer⁵, Dhanabalan Murali⁶, Todd E Barnhart⁷, Tobey J Betthauser⁷, Catherine L Gallagher³, Howard A Rowley⁸, N Maritza Dowling³, Sanjay Asthana⁹, Barbara B Bendlin⁹, Kaj Blennow¹⁰, Henrik Zetterberg¹¹, Cynthia M Carlsson³, Bradley T Christian¹², Sterling C Johnson¹³

Affiliations

¹ Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Neuroscience Training Program, University of Wisconsin-Madison, USA, Madison, WI 53705; Neuroscience and Public Policy Program, University of Wisconsin-Madison, USA, Madison, WI 53705; Institute on Aging, University of Wisconsin-Madison, USA, Madison, WI 53706.
² Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
³ Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
⁴ Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
⁵ Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705.
⁶ Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI, 53719.
⁷ Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
⁸ Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Department of Radiology, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
⁹ Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705.
¹⁰ Institute of Neurology, University College London, London, UK.
¹¹ Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Institute of Neurology, University College London, London, UK.
¹² Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705; Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI, 53719.
¹³ Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, USA, Madison WI 53705; Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, USA, Madison, WI 53705; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, USA, Madison, WI 53705.

Abstract

Introduction: Biomarkers are urgently needed for the critical yet understudied preclinical stage of Alzheimer's disease (AD).

Methods: CSF collection, [C-11]PiB amyloid imaging, and MRI were acquired in n=104 cognitively healthy adults enriched with risk for sporadic AD. Image-derived cerebral β-amyloid (Aβ) burden, measured concurrently and longitudinally, was regressed on CSF measures of Aβ, neural injury, and inflammation, as well as ratios with Aβ₄₂. Linear mixed effects regression was used to model the effect of the CSF measures that predicted longitudinal brain amyloid accumulation on longitudinal cognitive decline, measured by memory test scores.

Results: At baseline, Aβ₄₂/Aβ₄₀ and all CSF ratios to Aβ₄₂ were associated with PiB binding in AD-vulnerable regions. Longitudinally, Aβ₄₂/Aβ₄₀ and ratios of total tau, phosphorylated-tau, neurofilament light protein, and monocyte chemoattractant protein-1 to Aβ₄₂ were associated with increased β-amyloid deposition over two years, predominantly in lateral parietal and temporal cortex. However, these CSF ratios were not significantly associated with cognitive decline, and the effect seems to be largely driven by Aβ₄₂ in the denominator.

Discussion: These results corroborate previous findings that t-tau/Aβ₄₂ and p-tau/Aβ₄₂ are the strongest candidate biomarkers during the preclinical timeframe. They support a framework in which neural injury and amyloid deposition are likely occurring simultaneously. It may be that neurodegenerative processes influence progressive amyloid accumulation, even in the preclinical time frame. CSF biomarkers for non-specific axonal injury and inflammation may provide more information at more advanced stages of the preclinical time course.

Keywords: Alzheimer’s disease; Aβ42; MCP-1; NFL; PET; PiB; YKL-40; amyloid; biological parametric mapping; biomarkers; cerebrospinal fluid; linear mixed effects; preclinical AD; tau.

Abstract

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