Cerebrospinal fluid tau, Aβ, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration

Michael L Alosco; Yorghos Tripodis; Nathan G Fritts; Amanda Heslegrave; Christine M Baugh; Shannon Conneely; Megan Mariani; Brett M Martin; Samuel Frank; Jesse Mez; Thor D Stein; Robert C Cantu; Ann C McKee; Leslie M Shaw; John Q Trojanowski; Kaj Blennow; Henrik Zetterberg; Robert A Stern

doi:10.1016/j.jalz.2018.05.004

Cerebrospinal fluid tau, Aβ, and sTREM2 in Former National Football League Players: Modeling the relationship between repetitive head impacts, microglial activation, and neurodegeneration

Alzheimers Dement. 2018 Sep;14(9):1159-1170. doi: 10.1016/j.jalz.2018.05.004. Epub 2018 Jul 23.

Authors

Michael L Alosco¹, Yorghos Tripodis², Nathan G Fritts³, Amanda Heslegrave⁴, Christine M Baugh⁵, Shannon Conneely³, Megan Mariani³, Brett M Martin⁶, Samuel Frank⁷, Jesse Mez¹, Thor D Stein⁸, Robert C Cantu⁹, Ann C McKee¹⁰, Leslie M Shaw¹¹, John Q Trojanowski¹¹, Kaj Blennow¹², Henrik Zetterberg¹³, Robert A Stern¹⁴

Affiliations

¹ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
² Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA.
⁴ Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK.
⁵ Interfaculty Initiative in Health Policy, Harvard University, Boston, MA, USA.
⁶ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Data Coordinating Center, Boston University School of Public Health, Boston, MA, USA.
⁷ Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁸ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Departments of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA; VA Boston Healthcare System, U.S. Department of Veteran Affairs, Jamaica Plain, MA, USA; Department of Veterans Affairs Medical Center, Bedford, MA, USA.
⁹ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Concussion Legacy Foundation, Boston, MA, USA; Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA; Department of Neurosurgery, Emerson Hospital, Concord, MA, USA.
¹⁰ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Departments of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA; VA Boston Healthcare System, U.S. Department of Veteran Affairs, Jamaica Plain, MA, USA; Department of Veterans Affairs Medical Center, Bedford, MA, USA.
¹¹ Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
¹³ Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute at UCL, London, UK; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
¹⁴ Boston University Alzheimer's Disease Center and Boston University CTE Center, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Neurosurgery, Boston University School of Medicine, Boston, MA, USA; Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA, USA. Electronic address: bobstern@bu.edu.

Abstract

Introduction: Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid β_1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy.

Methods: Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau₁₈₁, amyloid β_1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI.

Results: No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P = .041), and higher sTREM2 levels were associated with higher t-tau concentrations (P = .009).

Discussion: In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.

Keywords: Alzheimer's disease; Aβ; Cerebrospinal fluid; Chronic traumatic encephalopathy; Concussion; Microglial activation; Repetitive head impacts; Subconcussive; sTREM2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / cerebrospinal fluid*
Biomarkers / cerebrospinal fluid
Chronic Traumatic Encephalopathy / cerebrospinal fluid*
Chronic Traumatic Encephalopathy / pathology
Football / injuries*
Humans
Male
Membrane Glycoproteins / cerebrospinal fluid*
Microglia / pathology
Middle Aged
Nerve Degeneration / cerebrospinal fluid
Nerve Degeneration / pathology
Receptors, Immunologic
tau Proteins / cerebrospinal fluid*

Substances

Amyloid beta-Peptides
Biomarkers
MAPT protein, human
Membrane Glycoproteins
Receptors, Immunologic
TREM2 protein, human
tau Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding