Abstract
Objectives
The purpose of this study was to evaluate levels and kinetics of cerebrospinal fluid (CSF) markers of inflammation and brain injury in patients with Lyme neuroborreliosis (LNB).
Methods
Adult patients with clinically suspected LNB were enrolled, in a prospective clinical study in the South East of Sweden. Patients were classified according to the European Federation of Neurological Societies’ guidelines. Definite cases of LNB were re-examined one month later including a repeat CSF investigation. Routine laboratory parameters were investigated along with CSF levels of neurodegenerative markers glial fibrillary acidic protein (GFAp), total tau (t-tau) and neurofilament light protein (NFL), as well as neuroinflammatory markers soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL-40 and CXCL13. Non-LNB served as controls. An additional comparison group consisted of spinal anesthesia subjects (SAS) without known central nervous system conditions.
Results
CSF levels of sTREM2 and CXCL13 were elevated in definite LNB patients at diagnosis compared with non-LNB patients (p<0.001) and SAS (p≤0.01). In addition, CSF levels of sTREM2, YKL-40 and CXCL13 rapidly declined in at follow-up after antibiotic treatment. In contrast, CSF levels of GFAp and t-tau did not differ across LNB groups, and did not change after treatment.
Conclusions
Although in a limited number of LNB patients, the results indicate a predominance of microglial and neuroinflammatory involvement rather than parenchymal CNS injury in CSF at diagnosis of LNB with a prompt decline after antibiotic treatment. The findings provide pathogenetic insights and may be of value in differential diagnosis of CSF findings.
Funding source: Futurum - the Academy of Health and Welfare, Region Jönköping County
Funding source: AD Strategic Fund and the Alzheimer’s Association
Award Identifier / Grant number: #ADSF-21
Award Identifier / Grant number: #ADSF-21-831376-C
Award Identifier / Grant number: #ADSF-21-831381-C
Funding source: Svenska Läkaresällskapet
Funding source: Olav Thon Foundation
Funding source: Hjärnfonden
Award Identifier / Grant number: #FO2017-0243
Award Identifier / Grant number: #FO2019-0228
Funding source: Forskningsrådet i sydöstra Sverige
Funding source: Alzheimer's Association 2021 Zenith Award
Award Identifier / Grant number: ZEN-21-848495
Funding source: European Union Joint Program for Neurodegenerative Disorders
Award Identifier / Grant number: JPND2019-466-236
Funding source: H2020 European Research Council
Award Identifier / Grant number: #681712
Funding source: Alzheimer Drug Discovery Foundation (ADDF), USA
Award Identifier / Grant number: #201809-2016862
Award Identifier / Grant number: #RDAPB-201809-2016615
Funding source: UK Dementia Research Institute at UCL
Funding source: Swedish State Support for Clinical Research
Award Identifier / Grant number: #ALFGBG-715986
Award Identifier / Grant number: #ALFGBG-720931
Award Identifier / Grant number: #RÖ-936276
Funding source: European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement
Award Identifier / Grant number: No 860197 (MIRIADE)
Funding source: National Institute of Health (NIH), USA
Award Identifier / Grant number: #1R01AG068398-01
Funding source: Familjen Erling-Perssons Stiftelse
Funding source: Swedish Alzheimer Foundation
Award Identifier / Grant number: #AF-742881
Funding source: Vetenskapsrådet
Award Identifier / Grant number: #2017-00915
Award Identifier / Grant number: #2018-02532
Award Identifier / Grant number: #2018-02776
Funding source: Stiftelsen för Gamla Tjänarinnor, Sweden
Award Identifier / Grant number: #FO2019-0228
Acknowledgments
We thank all involved patients and healthcare and laboratory staff for valuable assistance.
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Research funding: This study was conducted with support from the Swedish Society of Medicine, the Medical Research Council of South East Sweden (FORSS) and Futurum – the Academy of Health and Welfare, Region Jönköping County. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495). JE is supported by the Swedish Research Council (2018-02776), the Medical Inflammation and Infection Centre (MIIC), and ALF grants Region Östergötland (RÖ-936276).
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Author contribution: IT had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: IT, HZ, KB, JE, AJH. Acquisition of data: IT, PG, JS, HZ, KB, JE, PF, AJH. Analysis and interpretation of data: IT, PG, JS. Laboratory analyses: HZ, KB. Drafting of the manuscript: IT, PG, JS. Critical revision of the manuscript for important intellectual content: IT, PG, JS, HZ, KB, JE, PF, AJH. Statistical analysis: IT. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: IT has served at advisory board for Pfizer Inc. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx and Red Abbey Labs, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. JE has given lectures, unrelated to the present work, in symposia sponsored by Merck, Biogen och Abbvie. JS has given lectures and participated in advisory boards in collaboration with Merck and Biogen. PG and PF report no conflicts of interest. AJH has a collaborative research agreement with Abbott Laboratories, Chicago, IL and Reagena Ltd, Toivala, Finland.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: Written consent was obtained from all participants before study inclusion. The study conforms with World Medical Association Declaration of Helsinki and was approved by the Regional Ethical Review Board in Linköping, Sweden (Dnr M106-04, 2011/65-32, 2015/192-32, 2018/388-32, 2019-02449).
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