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September 01, 2020; 95 (9) Article

Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans

Carrie B. Peltz, Kimbra Kenney, Jessica Gill, Ramon Diaz-Arrastia, Raquel C. Gardner, Kristine Yaffe
First published June 22, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010087
Carrie B. Peltz
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Kimbra Kenney
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Jessica Gill
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Ramon Diaz-Arrastia
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Raquel C. Gardner
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Kristine Yaffe
From San Francisco Veterans Affairs Health Care System (C.B.P., R.C.G., K.Y.), CA; Northern California Institute for Research and Education (C.B.P.), San Francisco; Uniformed Services University of the Health Sciences (K.K.), Rockville; NIH (J.G.), Bethesda, MD; Department of Neurology (R.D.-A.), University of Pennsylvania, Philadelphia; and Departments of Neurology (R.C.G., K.Y.), Psychiatry (K.Y.), and Epidemiology and Biostatistics (K.Y.), University of California, San Francisco.
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Citation
Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans
Carrie B. Peltz, Kimbra Kenney, Jessica Gill, Ramon Diaz-Arrastia, Raquel C. Gardner, Kristine Yaffe
Neurology Sep 2020, 95 (9) e1126-e1133; DOI: 10.1212/WNL.0000000000010087

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Abstract

Objective To determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI).

Methods We enrolled 155 veterans from 2 veterans' retirement homes: 90 without TBI and 65 with TBI history. Participants were further separated into CogI groups: controls (no TBI, no CogI), n = 60; no TBI with CogI, n = 30; TBI without CogI, n = 30; and TBI with CogI, n = 35. TBI was determined by the Ohio State University TBI Identification Method. CogI was defined as impaired cognitive testing, dementia diagnosis, or use of dementia medication. Blood specimens were enriched for CNS-derived exosomes. Proteins (neurofilament light [NfL], total tau, glial fibrillary acidic protein [GFAP], α-synuclein, β-amyloid 42 [Aβ42], and phosphorylated tau [p-tau]) and cytokines (tumor necrosis factor–α [TNF-α], interleukin-6 [IL-6], and interleukin-10) were measured using ultrasensitive immunoassays.

Results Veterans were, on average, 79 years old. In participants with TBI history, 65% had mild TBI; average time from most recent TBI was 37 years. In adjusted analyses, the TBI and CogI groups differed on CNS-enriched exosome concentration of p-tau, NfL, IL-6, TNF-α (all p < 0.05), and GFAP (p = 0.06), but not on Aβ42 or other markers. Adjusted area under the curve (AUC) analyses found that all significantly associated biomarkers combined separated TBI with/without CogI (AUC, 0.85; 95% confidence interval [CI], 0.74–0.95) and CogI with/without TBI (AUC, 0.88; 95% CI, 0.77–0.99).

Conclusions Increased levels of blood-based, CNS-enriched exosomal biomarkers associated with TBI and CogI can be detected even decades after TBI.

Classification of evidence This study provides Class II evidence that in veterans with a history of TBI, CNS-enriched exosome concentration of p-tau, NfL, IL-6, and TNF-α are associated with CogI.

Glossary

α-syn=
α-synuclein;
Aβ42=
β-amyloid 42;
AD=
Alzheimer disease;
AUC=
area under the curve;
AVLT=
Auditory Verbal Learning Test;
CI=
confidence interval;
CogI=
cognitive impairment;
CTE=
chronic traumatic encephalopathy;
GFAP=
glial fibrillary acidic protein;
IL-6=
interleukin-6;
IL-10=
interleukin-10;
LOC=
loss of consciousness;
MMSE=
Mini-Mental State Examination;
mTBI=
mild traumatic brain injury;
NfL=
neurofilament light;
NINDS=
National Institute of Neurologic Disorders and Stroke;
OSU-TBI-ID=
Ohio State University TBI Identification Method;
p-tau=
phosphorylated tau;
ROC=
receiver operating characteristic;
TBI=
traumatic brain injury;
TNF-α=
tumor necrosis factor–α;
WAIS-R=
Wechsler Adult Intelligence Scale–Revised

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Class of Evidence: NPub.org/coe

  • Received September 30, 2019.
  • Accepted in final form February 27, 2020.
  • © 2020 American Academy of Neurology
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Letters: Rapid online correspondence

  • Author response: Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans
    • Carrie B. Peltz, Research Associate, San Francisco Veterans Affairs Health Care System
    • Kristine Yaffe, Scola Endowed Chair and Vice Chair, Professor of Psychiatry, Neurology and Epidemiology, University of California, San Francisco
    Submitted July 28, 2020
  • Reader response: Blood biomarkers of traumatic brain injury and cognitive impairment in older veterans
    • Thomas Wisniewski, MD, Director of the NYU Alzheimer’s Disease Research Center, New York University School of Medicine
    • Silvia Fossati, MD, Associate Director Alzheimer’s Center at Temple, Temple University (Philadelphia)
    Submitted July 23, 2020
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