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Figure.  Timeline for Neurofilament Light Chain, Glial Fibrillary Acidic Protein, Total Tau, and Aβ42/Aβ40 Ratio Response
Timeline for Neurofilament Light Chain, Glial Fibrillary Acidic Protein, Total Tau, and Aβ42/Aβ40 Ratio Response

A, Neurofilament light chain protein showed a 33% increase on day 1 and a 50% increase 1 week after return from a long-duration mission compared with preflight measurements. This may represent an axonal injury. B, Glial fibrillary acidic protein showed an increase of 20% and 27% for the same comparisons in time, pointing to a concurrent and sustained astrocytic response. C, Total tau protein as a surrogate for the neuronal tissue showed nonsignificant elevation for the first week postflight with a significant drop of more than 50% below baseline levels 3 weeks after return to Earth. D, Amyloid β (Aβ)40 and Aβ42 increased significantly postflight (Table) with the stronger relative elevation in Aβ40. Therefore, the course for the ratio of the 2 amyloid proteins, Aβ42/Aβ40, showed a decreasing trajectory after return to Earth from a long-duration mission. This kind of downward trajectory is often viewed as unfavorable with respect to long-term brain health in the general population. The solid line represents the mean group response, while dashed lines show the individual’s parameter course. Error bars give the standard error of mean for each time point. Actual percentage change from preflight baseline indicated for the greatest deviation for the respective parameter.

Table.  Summary Statistics of the Blood-Based Brain Biomarkers at Different Times
Summary Statistics of the Blood-Based Brain Biomarkers at Different Times
1.
Lee  AG, Mader  TH, Gibson  CR, Tarver  W.  Space flight-associated neuro-ocular syndrome.   JAMA Ophthalmol. 2017;135(9):992-994. doi:10.1001/jamaophthalmol.2017.2396PubMedGoogle ScholarCrossref
2.
Van Ombergen  A, Jillings  S, Jeurissen  B,  et al.  Brain tissue-volume changes in cosmonauts.   N Engl J Med. 2018;379(17):1678-1680. doi:10.1056/NEJMc1809011PubMedGoogle ScholarCrossref
3.
Ashton  NJ, Hye  A, Rajkumar  AP,  et al.  An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.   Nat Rev Neurol. 2020;16(5):265-284. doi:10.1038/s41582-020-0348-0PubMedGoogle ScholarCrossref
4.
Thornton  WE, Hoffler  GW, Rummel  JA. Anthropometric changes and fluid shifts. Paper presented at: Skylab Life Science Symposium; November 1, 1974; Houston, Texas.
5.
Lakin  WD, Stevens  SA, Penar  PL.  Modeling intracranial pressures in microgravity: the influence of the blood-brain barrier.   Aviat Space Environ Med. 2007;78(10):932-936. doi:10.3357/ASEM.2060.2007PubMedGoogle ScholarCrossref
6.
Leach  CS, Altchuler  SI, Cintron-Trevino  NM.  The endocrine and metabolic responses to space flight.   Med Sci Sports Exerc. 1983;15(5):432-440. doi:10.1249/00005768-198315050-00016PubMedGoogle ScholarCrossref
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    1 Comment for this article
    EXPAND ALL
    Clinical significance may suffice
    Sandro Tsang, PhD | People's Open Access Education Initiative
    The blood samples were collected from five male cosmonauts. The letter did not specify which correlation measure was applied. If Pearson correlation coefficient was applied, then the sample size was too small to obtain reliable results. The results showed a significant association of NfL, GFAP, and Aβ40 levels with each other across the participants and times by the widely adapted P<0.05 threshold. However, only the association between Aβ40 and Aβ42 was shown to be strong, as its correlation (r = 0.885, P < .001) surpassed the widely adapted minimum acceptable explained variance (r^2=0.783>0.5). I am looking forward to learning more about the clinical significance of the findings.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    October 11, 2021

    Changes in Blood Biomarkers of Brain Injury and Degeneration Following Long-Duration Spaceflight

    Author Affiliations
    • 1Institute for Neuroradiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
    • 2Department of Anesthesiology, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
    • 3Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
    • 4Institute of Biomedical Problems of the Russian Academy of Sciences (SSC RF-IBMP RAS), Moscow, Russia
    JAMA Neurol. 2021;78(12):1525-1527. doi:10.1001/jamaneurol.2021.3589

    Long-duration spaceflight has a widespread effect on human physiology. The past decade first revealed eyeball alterations, and then neuroimaging studies hinted at potentially detrimental effects on the brain.1,2 Expansion of cerebrospinal fluid spaces occurs at the cost of the gray and white matter compartment. A neurobiological integrity assessment of the brain’s tissues after prolonged exposure to microgravity has never been conducted, to our knowledge. Therefore, we investigated the longitudinal course of blood-based biomarkers representing the brain parenchyma in long-duration spaceflight.

    Methods

    Blood samples were taken from cosmonauts prior to and after missions (mean duration, 169 days) on the International Space Station from 2016 to 2020. Baseline data acquisition occurred 20 days before launch. Postflight sampling occurred on 1 day, 1 week, and 21 to 25 days after landing. Single-molecule array (Simoa) immunoassay quantification of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau, and 2 amyloid-β (Aβ) proteins (Aβ40 and Aβ42) including hemoglobin as a control protein was performed (eMethods in the Supplement). Data on race and ethnicity were not collected. The protocol was evaluated by the Russian Ethical Board (Biomedicine Ethics Committee) at the Institute of Biomedical Problems, Moscow, and the ESA Medical Board as well as the Russian Space Agency. The local Ethical Committee of Ludwig-Maximilians University Munich, in Munich, Germany, also approved the protocol. All individuals gave written informed consent.

    Statistical evaluation of the data set was performed using SPSS statistical software, version 26 (IBM). We performed nonparametric testing of the repeated measurements against baseline values with the paired Wilcoxon signed-rank test. A Spearman-Rho correlation analysis between the biomarkers with each other and with mission time (days from preflight baseline) was also conducted. All tests were 2-sided. A value of P < .05 was considered statistically significant.

    Results

    Five male cosmonauts (mean [SEM] age, 49.2 [2.7] years) were included. NfL was significantly elevated compared with preflight levels directly postflight, 1 week, and 3 weeks after return to Earth (Table). The longitudinal course of hemoglobin as a systemic control protein for the blood-based analysis did not show any significant change or even trend over the same time course using the identical statistical approach in this cohort. For each point, mean (SEM) values of hemoglobin (g/dL; to convert to grams per liter, multiply by 10) are as follows: postflight: 15.7 (0.6); 1 day after landing: 14.2 (0.5); 1 week after landing: 15.5 (1.2); and 21 to 25 days after landing: 14.1 (0.5). GFAP showed an increase at the end of the first week postflight and beyond (mean [SEM] preflight, 169 [43] pg/mL vs 1 week after landing, 215 [31] pg/mL; P < .08 and vs 21 to 25 days after landing, 205 [34] pg/mL; P < .08). Total tau showed a nonsignificant elevation throughout the course of the first week, followed by a significant drop below baseline 3 weeks after return (mean [SEM] preflight, 0.46 [0.06] pg/mL vs 21 to 25 days after return, 0.22 [0.06] pg/mL; P < .04). Aβ40 was significantly increased throughout the follow-up period (mean [SEM] preflight, 101 [17] pg/mL vs 1 day after landing, 156 [16] pg/mL; P < .04; vs 1 week after landing, 183 [18] pg/mL; P < .04; and vs 21 to 25 days after landing, 167 [20] pg/mL; P < .04), while levels of Aβ42 showed a similar but less pronounced increase (mean [SEM] preflight, 5.63 [0.7] pg/mL vs 1 day after landing, 8.43 [1.21] pg/mL; P < .08; vs 1 week after landing, 9.63 [1.4] pg/mL; P < .04; and vs 21 to 25 days after landing, 8.60 [1.4] pg/mL; P < .08) (Figure).

    Correlation analyses showed a significant association of NfL, GFAP, and Aβ40 levels with each other across the participants and times. GFAP was correlated with NfL (r = 0.423, P = .04). GFAP was correlated with Aβ40 (r = 0.499, P = .03), and NfL was correlated with Aβ40 (r = 0.451, P = .046). Aβ40 and Aβ42 were correlated with each other (r = 0.885, P < .001). Each amyloid protein was also significantly correlated with the number of days from mission start (Aβ40: r = 0.697, P < .001; Aβ42: r = 0.672, P < .001).

    Discussion

    The increases in NfL and GFAP argue for an axonal disintegration process (NfL) along with astrocytic activation (GFAP) during the postflight course of a long-duration mission.3 The increases of both Aβ proteins over the entire postflight phase potentially depict an accumulative association of the cephalad fluid shift with the interstitial tissue. The findings could reflect coherent reparatory processes of intracranial pressure associations from cephalad fluid shift with the brain with subsequent restoration of the blood-brain barrier integrity.4 We speculate the elevation of amyloid proteins back on Earth to represent a washout phase after months of hindered protein waste clearance since albumin has been shown to remain stable or even decrease.5,6 The effective half-life of the parameters in our study (GFAP, 24 to 48 hours; NfL, 1 to 3 weeks; Aβ40, 2 to 4 hours) argues for ongoing reparatory processes postflight. The 3-way association between NfL, GFAP, and Aβ40 illustrates the broadness of the brain tissue response. Our observed changes of blood-based biomarkers indicate brain injury as a previously unknown risk for humans in long-duration spaceflight. Further longitudinal studies in larger samples are needed to characterize the association of long-duration space flight with neurological health.

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    Article Information

    Corresponding Author: Peter zu Eulenburg, MD, PhD, Institute for Neuroradiology, University Hospital, Ludwig-Maximilians-University Munich, 81377 Munich, Germany (peter.zu.eulenburg@med.uni-muenchen.de).

    Accepted for Publication: June 25, 2021.

    Published Online: October 11, 2021. doi:10.1001/jamaneurol.2021.3589

    Author Contributions: Drs zu Eulenburg and Ashton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs zu Eulenburg and Buchheim contributed equally as co–first authors; Drs Zetterberg and Choukér contributed equally as co–senior authors.

    Concept and design: zu Eulenburg, Buchheim, Vassilieva, Zetterberg, Choukér.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: zu Eulenburg, Ashton, Zetterberg.

    Critical revision of the manuscript for important intellectual content: zu Eulenburg, Buchheim, Vassilieva, Blennow, Zetterberg, Choukér.

    Statistical analysis: zu Eulenburg, Ashton.

    Obtained funding: Blennow, Choukér.

    Administrative, technical, or material support: Buchheim, Ashton, Zetterberg, Choukér.

    Supervision: zu Eulenburg, Vassilieva, Choukér.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This work was supported by the German Space Agency (DLR) on behalf of the Federal Ministry of Economics and Technology/Energy (grants 50WB2027 to Dr zu Eulenburg and grants 50WB0919, 50WB1319, and 50WB1622 to Dr Choukér), the ESA (ELIPS 3 and 4 and SciSpaceE programs) and the Roscosmos Program of Fundamental Research (theme 65.1) of the Institute for Biomedical Problems in Moscow, Russia.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank all operators, scientists, and administrators at Roscosmos (the Russian Space Agency), the Institute for Biomedical Problems (IBMP) and TsNIIMash in Russia at DLR (the German Space Agency), at the European Space Agency, and the members of the laboratory of translational research who made this project possible. In honor and memory of the former cosmonaut, vice director of the IBMP and IMMUNO co–principal investigator Boris Morukov, MD, PhD (Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia), who passed away during the course of the project.

    References
    1.
    Lee  AG, Mader  TH, Gibson  CR, Tarver  W.  Space flight-associated neuro-ocular syndrome.   JAMA Ophthalmol. 2017;135(9):992-994. doi:10.1001/jamaophthalmol.2017.2396PubMedGoogle ScholarCrossref
    2.
    Van Ombergen  A, Jillings  S, Jeurissen  B,  et al.  Brain tissue-volume changes in cosmonauts.   N Engl J Med. 2018;379(17):1678-1680. doi:10.1056/NEJMc1809011PubMedGoogle ScholarCrossref
    3.
    Ashton  NJ, Hye  A, Rajkumar  AP,  et al.  An update on blood-based biomarkers for non-Alzheimer neurodegenerative disorders.   Nat Rev Neurol. 2020;16(5):265-284. doi:10.1038/s41582-020-0348-0PubMedGoogle ScholarCrossref
    4.
    Thornton  WE, Hoffler  GW, Rummel  JA. Anthropometric changes and fluid shifts. Paper presented at: Skylab Life Science Symposium; November 1, 1974; Houston, Texas.
    5.
    Lakin  WD, Stevens  SA, Penar  PL.  Modeling intracranial pressures in microgravity: the influence of the blood-brain barrier.   Aviat Space Environ Med. 2007;78(10):932-936. doi:10.3357/ASEM.2060.2007PubMedGoogle ScholarCrossref
    6.
    Leach  CS, Altchuler  SI, Cintron-Trevino  NM.  The endocrine and metabolic responses to space flight.   Med Sci Sports Exerc. 1983;15(5):432-440. doi:10.1249/00005768-198315050-00016PubMedGoogle ScholarCrossref
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