concussions and biomarkers · overview • concussions – background – recognition – recovery...

Concussions and Biomarkers

Stephanie F. Alessi-LaRosa, MD, MPHAssociate Director of HHC Sports Neurology Program

March 20, 2020

Disclosures

• No relevant financial or nonfinancial relationships exist

3/20/2020Concussions and Biomarkers 2

Overview

• Concussions– Background– Recognition– Recovery

• Biomarkers– Imaging– Fluid– Limitations– Future directions

33/20/2020Concussions and Biomarkers

Concussion Definition


• A transient, complex pathophysiologic response to biomechanical forces imparted to the brain, resulting in onset of neurologic symptoms that predominantly reflect a functional disturbance, rather than a gross structural injury.

– Distinction of sports-related concussion: implicit assumption that the athlete will purposely be returning to contact risk (vs. MVA-related etc)


• Brain in the skull with CSF like an egg in a glass with water – if shaken, the brain can strike the skull

• Axons run in groups from brain to brainstem to cord like string cheese –rotational or whiplash injuries can stretch/shear them

“Network” Injury



INJU

RY

TIME


• Possible: In a list, concussion is not most likely– Common mimickers: dehydration, viral

illness, migraines, hyperthermia

• Probable: In a list, concussion is most likely

• Definite: Concussion is only explanation

Treat as Concussed

Situational Treatment


• Based on:– Mechanism – Not every hit to the head is a concussion

– Symptom course – first 24-48 hours•Ex: Headache resolved in 12 hrs and no further symptoms

•Ex: Headache with migraine features, sleep issues, persistent nausea/change in appetite, dizziness –lasting longer than 24 hours

Mechanisms



NFL~ 1,800

COLLEGE FOOTBALL~ 73,660

HIGH SCHOOL FOOTBALL~ 1,100,000

YOUTH FOOTBALL ~ 2,800,000

YOUTH SOCCER ~ 3,000,000YOUTH ICE HOCKEY >500,000

Research being done here

Most of the players here


– Mental status•How did you get injured?•What was last play?•What is the current score?•Which team did you play last game?

– Pupil exam– VOMS testing*– Coordination/balance testing

•Finger-to-nose•Tandem gait forward and reverse•Single leg stance + squat


• Smooth pursuits• Saccades:

– Horizontal– Vertical

• Convergence• VOR

– Horizontal– Vertical

• Visual motion sensitivity test


•The brain likes:


• As a principle, use the fewest prescription medications and maximize lifestyle changes– Use lowest effective dose possible


• Avoid Avoidance!– Activity/light/sound etc.

•Leads to prolonged recovery/difficulty when reintroduced

– Ex: Wearing sunglasses indoors– Ex: No physical activity for a week

After first 48 hours, can always do something!


• After initial injury is healed, symptoms persist for other reasons

• NOT a “long concussion” but is a separate, complex disorder

• Requires a different approach:

DEPRESSION/ANXIETY

SLEEP DISTURBANCE

HEADACHES

MEMORY CHANGES

CONCENTRATION ISSUES

Traumatic Brain injury and biomarkers

• TBIs are heterogeneous conditions• Unable to manage different patients with the identical treatment• Biomarkers may help identify subsets for specific treatment and

prognosis• A more objective tool for assessing presence/severity of

concussion


Biomarkers• Imaging

– fMRI– MR Spectroscopy– DTI

• Serum/plasma– GFAP plasma– Tau plasma

• Saliva• CSF• EEG/qEEG• Urine

– NMR Spectroscopy - prognosis


Imaging

• First neuroimaging and then treatment based on these results personalized approach

• 76 studies reviewed: Moderate risk of bias from lack of generalizability and inclusion of limited age ranges/male athletes/small sample sizes

• What is DTI?

• DTI: decreased mean diffusivity and/or increased fractional anisotropy in WM w/i 6 mos post injury


Functional MRI (fMRI)

• What is fMRI?

• If typical MRI shows structural white matter integrity, fMRI would show success of treatment from transcranial brain stimulation

• Variable results. Looked at working memory +/- activity in task-related networks. Activity outside of core regions with tasks after concussion.


MR Spectroscopy – dopamine transporters

• What is MR spectroscopy?

• May predict patients who would benefit from cognitive-enhancing therapy

• relative decreased NAA in WM acutely and subsequent recovery – also studies with chronically decreased NAA


Urine NMR spectroscopy

• What is NMR spectroscopy?

• Experimental • Within 72 hours of injury identified 5 different metabolites

altered compared to pre-concussion.


• What is EEG/qEEG?

• At rest or during tasks – electrographic changes compared to baseline– qEEG: severity of injury


GFAP

• What is GFAP?

• Detect TBI early on with MRI positive findings (not mild TBI/concussion)

• Diagnostic not prognostic


Tau

• What is tau?

• Acute and chronic TBI• Diagnostic and prognostic


Salivary cortisol


Fluid biomarkers

• Serum/plasma: AMPAR, S100 calcium binding protein, tau, GFAP, NSE

• CSF: decreased amyloid-beta-42 and increased neurofilamentlight – athletes with PCS (sx >1 year)

• Moderate to high bias risk: limited external validity and poor generalizability males/age/sport/sample size small, no controls

• More helpful in understanding pathophysiology of concussion in humans than actually useful clinically.


Other related areas of research

• Genetics in TBI – predicting risk of injury, prolonged recovery, long-term brain health problems from repetitive head impacts in athletes.

• Can alter outcome by:– Modulating force of neurotrauma and injury extent– Repair mechanisms trajectory of recovery and outcome– Preinjury traits – cognitive reserve etc– Genetic vulnerability to mood disorders and neurotrauma


Take-Home Points

• Biomarkers require further research to determine ultimate utility in the clinical setting



Thank You!

Stephanie F. Alessi-LaRosa, MD, MPHAssociate Director of HHC Sports Neurology Program

Website: hartfordhealthcare.org/sportsneuroOffice number: (860) 524-4330

Questions? Comments?

@SAlessiLaRosa

http://hartfordhealthcare.org/sportsneuro


• Eckner, JT, YK Oh, et al. Effect of neck muscle strength and anticipatory cervical muscle activation on the kinematic response of the head to impulsive loads. Am J Sports Med 42(3):566-576, 2014.

• Thomas D, et al. Benefits of strict rest after acute concussion: A Randomized Control Trial. Pediatrics 135(2) 213-226, 2016.

• Harmon, K, et al. American Medical Society for Sports Medicine Position Statement: Concussion in Sport. Clinical Journal of Sport Medicine 23(1) 1-8, 2013.

• Mucha et al. A Brief Vestibular/Ocular Motor Screening (VOMS) Assessment to Evaluate Concussions: Preliminary Findings. American Journal of Sports Medicine 42(10), 2014.

• Leddy J et al. Early Subthreshold Aerobic Exercise for Sport-Related Concussion A Randomized Control Trial. Feb 2019.

• Feng, J. Traumatic brain injury in 2019: databases, biomarkers, and stratified treatment. Lancet Neurology (19) 7-9. Jan 2020.

• Papa, L. Potential Blood-Based Biomarkers for Concussion. Sports Med Arthrosc. 2016; 24(3):108-115.• Asken, B. Concussion Biomarkers: Deviating From the Garden Path. JAMA Neurol. 2019;76(5):515-516.• McCrea, M. et al. Role of advanced neuroimaging, fluid biomarkers and genetic testing in the

assessment of sport-related concussion: a systematic review. Br J Sports Med. 51 (12), 919-929, 2017.• Paxman, E. Et al. Metabolomic biomarkers of concussion. Br J Sports Med. 51(11), 2017.

concussions and biomarkers · overview • concussions – background – recognition – recovery...

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