Chasing Biomarkers in Post-concussion Syndrome

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

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.

Study Overview

• Status: Completed
• Conditions: Post Concussive Symptoms
• Intervention / Treatment: Behavioral: Enhanced usual care; Behavioral: Early intervention programme

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Patients with severe post-concussive symptoms:

Inclusion Criteria:

1. Concussion caused by a head trauma based on the diagnostic criteria recommended by the World Health Organization (WHO) Task Force
2. Age between 18 and 30 years
3. Able to understand, speak and read Danish.
4. A score of 20 or more on the Rivermead Post Concussion Symptoms Questionnaire (RPQ).

Exclusion Criteria:

1. Objective neurological findings indicating neurological disease or brain damage.
2. Previous concussion leading to persistent post-concussional symptoms within the last two years.
3. Severe misuse of alcohol, prescription drugs and / or illegal drugs.
4. Severe psychiatric, neurological,or other medical disease that would impede participation in the intervention
5. 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:

1. Age between 18-30 years
2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Enhanced Usual Care; 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; For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).
Experimental: Enhanced Usual Care + Early intervention programme; 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: Enhanced usual care; For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).; Behavioral: Early intervention programme; For more information, please go to the original registration of the RCT-study (NCT02337101) or the published article (PMID: 31891145).

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Fonden til Lægevidenskabens Fremme; Sygekassernes Helsefond; Region MidtJylland Denmark; Direktør Emil C. Hertz og Hustru Inger Hertz Fond; Helga Og Peter Kornings Fond
• Investigators: Principal Investigator: Peter Preben Eggertsen, MD, Hammel Neurorehabilitation Centre and University Research Clinic and Research Unit for Molecular Medicine (Aarhus University)

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2015
• Primary Completion (Actual): July 1, 2023
• Study Completion (Actual): July 1, 2023

Study Registration Dates

• First Submitted: March 1, 2023
• First Submitted That Met QC Criteria: April 11, 2023
• First Posted (Actual): April 14, 2023

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Concussion; Head Injuries, Closed; Wounds, Nonpenetrating; Post-Concussion Syndrome
• Other Study ID Numbers: Biomarkers in GAIN 1.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No