Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

Dara L Dickstein^#^{1

2}, Rita De Gasperi^#^{3

4}, Miguel A Gama Sosa^{3

4}, Georgina Perez-Garcia^{3

5}, Jennifer A Short⁴, Heidi Sosa^{3

4}, Gissel M Perez³, Anna E Tschiffely⁶, Kristen Dams-O'Connor^{5

7}, Mariel Y Pullman⁴, Karin Knesaurek⁸, Andrew Knutsen², Dzung L Pham², Lale Soleimani⁸, Barry D Jordan⁹, Wayne A Gordon⁷, Bradley N Delman⁸, Gleb Shumyatsky¹⁰, Pashtun-Poh Shahim^{2

11}, Steven T DeKosky¹², James R Stone¹³, Elaine Peskind^{14

15}, Kaj Blennow^{16

17}, Henrik Zetterberg^{16

17

18

19}, Steven A Chance²⁰, Mario Torso²⁰, Lale Kostakoglu⁸, Mary Sano^{3

4

21}, Patrick R Hof^{21

22

23}, Stephen T Ahlers⁶, Sam Gandy^{24

25

26

27

28

29

30}, Gregory A Elder^{31

32

33

34}

Affiliations

¹ Department of Pathology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
² Center for Neuroscience and Regenerative Medicine, Bethesda, MD, 20814, USA.
³ Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
⁴ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁵ Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁶ Department of Neurotrauma, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
⁷ Department of Rehabilitation and Physical Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁸ Department of Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
⁹ Burke Rehabilitation and Research, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA.
¹⁰ Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA.
¹¹ National Institute of Neurological Disorders and Stroke, NIH Neurological Institute, PO Box 5081, Bethesda, MD, 20824, USA.
¹² Department of Neurology, University of Florida, Gainesville, FL, 32611, USA.
¹³ Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VI, 2903, USA.
¹⁴ VA Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, WA, 98195, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
¹⁶ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
¹⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.
¹⁸ UK Dementia Research Institute at UCL, London, WC1E 6BT, UK.
¹⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
²⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Neuropathology, West Wing, Level 1, Oxford, OX3 9DU, UK.
²¹ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
²² Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy, New York, NY, 10029, USA.
²³ Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
²⁴ Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].
²⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
²⁶ Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
²⁷ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
²⁸ NFL Neurological Care Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
²⁹ Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].
³⁰ South Australian Health and Research Medical Institute, Adelaide, 5000, South Australia. [email protected].
³¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
³² Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
³³ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
³⁴ Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].

^# Contributed equally.

PMID: 32094584
PMCID: PMC7484380
DOI: 10.1038/s41380-020-0674-z

Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

Dara L Dickstein et al. Mol Psychiatry. 2021 Oct.

. 2021 Oct;26(10):5940-5954.

doi: 10.1038/s41380-020-0674-z. Epub 2020 Feb 25.

Authors

Affiliations

¹ Department of Pathology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.
² Center for Neuroscience and Regenerative Medicine, Bethesda, MD, 20814, USA.
³ Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA.
⁴ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁵ Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁶ Department of Neurotrauma, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA.
⁷ Department of Rehabilitation and Physical Medicine, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA.
⁸ Department of Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
⁹ Burke Rehabilitation and Research, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA.
¹⁰ Department of Genetics, Rutgers University, Piscataway, NJ, 08854, USA.
¹¹ National Institute of Neurological Disorders and Stroke, NIH Neurological Institute, PO Box 5081, Bethesda, MD, 20824, USA.
¹² Department of Neurology, University of Florida, Gainesville, FL, 32611, USA.
¹³ Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VI, 2903, USA.
¹⁴ VA Northwest Network Mental Illness Research, Education, and Clinical Center, Seattle, WA, 98195, USA.
¹⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA.
¹⁶ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, S-431 80, Mölndal, Sweden.
¹⁷ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.
¹⁸ UK Dementia Research Institute at UCL, London, WC1E 6BT, UK.
¹⁹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
²⁰ Nuffield Department of Clinical Neurosciences, University of Oxford, Neuropathology, West Wing, Level 1, Oxford, OX3 9DU, UK.
²¹ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
²² Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave Levy, New York, NY, 10029, USA.
²³ Department of Geriatrics and Palliative Care, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
²⁴ Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].
²⁵ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
²⁶ Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
²⁷ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
²⁸ NFL Neurological Care Center, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
²⁹ Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].
³⁰ South Australian Health and Research Medical Institute, Adelaide, 5000, South Australia. [email protected].
³¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
³² Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY, 10029, USA. [email protected].
³³ Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected].
³⁴ Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA. [email protected].

^# Contributed equally.

PMID: 32094584
PMCID: PMC7484380
DOI: 10.1038/s41380-020-0674-z

Abstract

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [¹⁸F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [¹⁸F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [¹⁸F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Fig. 1. Hyperphosphorylated tau in hippocampus and anterior cortex of blast-exposed rats.**
Tau phosphorylation was analyzed at 6 weeks a and at 10 months b after blast exposure. Top row, AT270, middle row, total tau (tau), bottom row GAPDH. Graphs indicate p-tau levels expressed as the ratio of p-tau to total tau. Error bars indicate standard deviation (SD) (*p < 0.05, **p < 0.01, ***p < 0.001 vs. controls, unpaired t-tests). n = 5/group except for control at 6 weeks (n = 4). Size markers (kDa) are indicated by arrows next to each panel. p-tau blots were sequentially reprobed for total tau followed by GAPDH.

**Fig. 2. Immunostaining and distribution of p-tau in blast-exposed rat brain.**
a–e increased and somatodendritic redistribution of p-tau in the anterior cingulate cortex and motor cortex of blast-exposed rats 6 weeks following blast exposure. Shown are sections of the anterior cingulate a–e of control a, c and blast-exposed rats b, d, e immunostained with AT270 (green) counterstained with DAPI (blue). Cortical layers are indicated in panel c. Note the general increase of p-tau in all cortical layers in the blast-exposed animals b, d. e Higher power image of the neuron outlined by the white box in panel d showing prominent somatodendritic localization of p-tau. f–k perivascular p-tau in astroglial processes 10 months after blast-exposure. Penetrating cortical vessels from control f–h and blast-exposed rats i–k AT270 (green, f and i) and GFAP (red, g and j). The arrow in panel i indicates p-tau staining. An arrow in panel d indicates p-tau staining that appears to be in an elastic membrane. Arrowheads in panel d indicate other examples of perivascular tau staining. A penetrating cortical vessel that was not stained is indicated by an arrowhead in panel c. Scale bar: 50 μm a, b, 25 μm c, d, 10 μm e. Scale bar for panels f–k: 20 μm.

**Fig. 3. Representative transaxial brain images of [¹⁸F]AV1451 PET of veterans with history of multiple blast exposures.**
Veterans 1 and 2 show cortical ligand retention at the white/gray matter junction, as is characteristic of the distribution of tauopathy in CTE (white arrows). * Indicates areas of non-specific binding and uptake. The top row represents a cognitively healthy control. Insets show higher magnification of foci of [¹⁸F]AV1451 ligand retention.

See this image and copyright information in PMC

Comment in

Brain and blood biomarkers of chronic traumatic encephalopathy.
Lemprière S. Lemprière S. Nat Rev Neurol. 2020 Apr;16(4):186. doi: 10.1038/s41582-020-0340-8. Nat Rev Neurol. 2020. PMID: 32144386 No abstract available.

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Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

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Brain and blood biomarkers of tauopathy and neuronal injury in humans and rats with neurobehavioral syndromes following blast exposure

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Abstract

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