Chasing Biomarkers in Post-concussion Syndrome

Study Overview
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Brief Summary
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The goal of this study was to investigate the biomarkers, neurofilament light chain, inflammatory markers, calcitonin-gene-related peptide, and metabolites from the kynurenine pathway in patients with severe post-concussive symptoms. The main question it aimed to answer was: Are the biomarker concentrations significantly changed in patients with severe post-concussive symptoms compared to healthy individuals? Do the biomarker concentrations change at follow-up? Participants were recruited from a recently published randomized controlled trial (Clinicaltrials.gov no. NCT02337101 / PMID: 31891145 ). The biomarker concentrations were compared to a healthy control group recruited from the Blood Bank at Aarhus University Hospital in 2022.

Detailed Description
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In the previously published RCT-study (PMID: 31891145), 86 participants with severe post-concussive symptoms provided blood samples at baseline (4 months after the concussion). Severe post-concussive symptoms were defined as having a Rivermead Post Concussion Questionnaire >20. Around 7 months later, a follow-up blood sample was obtained from 54 participants. These blood samples were used to investigate blood biomarkers for the condition.

Official Title
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Neurofilament Light Chain, Inflammatory Markers, Calcitonin Gene-related Peptide, and Kynurenine Metabolites in Patients With Severe Post-concussive Symptoms

Conditions
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Post Concussive Symptoms

Intervention / Treatment
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* Behavioral: Early intervention programme
* Behavioral: Enhanced usual care


Participation Criteria
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Eligibility Criteria
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Patients with severe post-concussive symptoms: Inclusion Criteria: Concussion caused by a head trauma based on the diagnostic criteria recommended by the World Health Organization (WHO) Task Force Age between 18 and 30 years Able to understand, speak and read Danish. A score of 20 or more on the Rivermead Post Concussion Symptoms Questionnaire (RPQ). Exclusion Criteria: Objective neurological findings indicating neurological disease or brain damage. Previous concussion leading to persistent post-concussional symptoms within the last two years. Severe misuse of alcohol, prescription drugs and / or illegal drugs. Severe psychiatric, neurological,or other medical disease that would impede participation in the intervention Inability to speak and read Danish Healthy control group (recruited from December 2021 - March 2022): - Individuals from the Blood Bank at Aarhus University Hospital in Denmark. Inclusion criteria were: Age between 18-30 years Equal distribution between the genders (60 men and 60 women). This number was based on a power analysis using published data from neurofilament light chain.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Enhanced Usual Care<br>For more details on the intervention, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145). Enhanced Usual Care (EUC) All patients had a brief clinical psychiatric and neurological assessment in order to determine eligibility, and they were provided with information and advice about typical post-concussional symptoms, the typical recovery process and the use of pain medication. | Behavioral: Enhanced usual care<br>* For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).<br>|
| Experimental: Enhanced Usual Care + Early intervention programme<br>For more details on the intervention, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145). Behavioral: EUC + Early intervention programme All patients had a brief clinical psychiatric and neurological assessment in order to determine eligibility, and were provided with information and advice about typical post-concussional symptoms, the typical recovery process and the use of pain medication. The early intervention programme was interdisciplinary and was provided by an occupational therapist and a physiotherapist under supervision of a neuropsychologist. It was based on psychoeducation and principles from Cognitive Behavioral Therapy and Graded Exercise Therapy and targeted to patients' individual goals. Patients received 8 weekly treatment sessions (3 group based and 5 individual sessions). The intervention started approximately 4 months after the concussion. | Behavioral: Early intervention programme<br>* For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).<br>Behavioral: Enhanced usual care<br>* For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurofilament light chain at baseline (primary outcome) | The investigators hypothesized: The concentration of neurofilament light chain (ng/L) is significantly increased at baseline in patients compared to the healthy control group. | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Neurofilament light chain at follow-up (primary outcome) | The investigators hypothesized: 1)The neurofilament light chain concentration (ng/L) normalizes (decreases) at follow-up compared to the baseline concentration in patients. | The follow-up blood sample was taken up to 12 months after baseline (7 months median) after the baseline blood sample. | 
| Self-reported post-concussion symptoms score (primary outcome) | The symptom score was measured at both baseline and follow-up using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) which is a self-reported questionnaire. The Rivermead Post-Concussion Symptoms Questionnaire contains 16 items which is rated from 0 (not experienced) to 4 (a severe problem). The total score thus ranges on a scale between 0-64. | The baseline symptom score (RPQ) was obtained from the patients up to 7 months after the concussion (4 months median), and the follow-up score was obtained up to 16 months (10.5 median) after the concussion | 
| Calcitonin-gene related peptide at baseline (CGRP) | The investigators hypothesized: The concentration of calcitonin gene-related peptide (pg/mL) is decreased compared to the healthy control group at baseline | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Calcitonin-gene related peptide at follow-up (CGRP) | The investigators hypothesized: The CGRP concentrations (pg/mL) will normalize (increase) at follow-up compared to baseline. | The follow-up blood sample was taken up to 12 months after baseline (7 months median) after the baseline blood sample. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quinolinic acid at baseline | The investigators hypothesized that: The concentration of the neurotoxic metabolite, quinolinic acid (measured in nM), is increased in patients compared to healthy controls | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Quinolinic acid at follow-up | The investigators hypothesized: The quinolinic acid concentration (nM) normalizes (decreases) at follow-up compared to the baseline concentration. | The follow-up blood sample was taken up to 12 months after baseline (7 months median) after the baseline blood sample. | 
| Neuroprotective index at baseline | The investigators hypothesized: The ratio between the neuroprotective metabolite kynurenic acid (KYNA) and the neurotoxic metabolite quinolinic acid (KynA/QUIN) is lower than the ratio in healthy individuals at baseline. A higher ratio means a better outcome. | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Neuroprotective index at follow-up | The investigators hypothesized: The ratio between the neuroprotective metabolite kynurenic acid (KYNA) and the neurotoxic metabolite quinolinic acid (QUIN) normalizes (increases) at follow-up compared to baseline. A higher ratio thus means a better outcome. | The follow-up blood sample was taken up to 12 months after baseline (7 months median) after the baseline blood sample. | 
| Inflammatory markers at baseline | The investigators hypothesized that: Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) (both pg/mL) are increased in patients compared to healthy controls. | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Inflammatory markers at baseline | The investigators hypothesized: Basic fibroblast growth factor (Basic FGF), Eotaxin, interferon gamma (IFN-y), interleukin 1 beta (IL-1B), interleukin 8 (IL-8), interleukin 9 (IL-9), interleukin 17 (IL17), Interferon gamma-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and Macrophage Inflammatory Protein beta (MIP-1b) (all pg/mL) are significantly increased in patients compared to controls (hypothesis is based on a recent study (PMID: 32326805) | The baseline blood sample was taken up to 7 months after the concussion (4 months median). | 
| Inflammatory markers at follow-up | TNF-α and IL-6 (both pg/mL) decreases at follow-up compared to the baseline value in patients. | The follow-up blood sample was taken up to 12 months after baseline (7 months median) after the baseline blood sample. |