New Diagnosis and Acute Changes - Center For Hjerneskade · 2020. 3. 28. · Concussion Conference Copenhagen, Denmark 45min Diagnosis and Acute Changes. Credit where credit deserved!

Concussion Pathophysiology 1:

Christopher C. Giza, M.D.Pediatric Neurology and Neurosurgery

Nov 8th, 2018

Copenhagen

Concussion Conference

Copenhagen, Denmark

45min

Diagnosis and Acute Changes

Credit where credit deserved!

Basic Science Faculty

David Hovda, Ph.D.

Fernando Gomez-Pinilla, Ph.D.

Tiffany Greco, Ph.D.

Neil Harris, Ph.D.

Dejan Markovic, Ph.D.

Raman Sankar, M.D., Ph.D.

Medical Students

Stephanie Pham

Kwame Firempong

Lilian Yousefi

Lab Managers

Yan Cai, M.S.

Sima Ghavim

Residents/Fellows

Dorothy Harris, M.D., Ph.D.

Beth Nakae, M.D.

Rafael Romeu-Mejia, M.D.

Tara Sharma, M.D.

Aliyah Snyder, Ph.D.

Clinical Faculty

Robert Asarnow, Ph.D.

Michelle Kraske, Ph.D.

Adam Darby, M.D.

Josh Goldman, M.D.

Josh Kamins, M.D.

Jason Lerner, M.D.

Andy Madikians, M.D.

Joyce Matsumoto, M.D.

David McArthur, Ph.D., M.P.H.

Doug Polster, Ph.D.

Raj Rajaraman, M.D.

www.uclahealth.org/brainsport

[email protected]

Twitter: @griz1

Admin Assistants

Janet Kor

Nikol Ledesma

Post-docs

Emily Dennis, Ph.D.

Annie Hoffman, Ph.D.

Saman Sargolzaei, Ph.D.

Funded by: NIH NS27544, NCAA, Dept of Defense,

Stan & Patti Silver, UCLA BIRC, UCLA Steve Tisch

BrainSPORT, Richie Fund, UCLA Easton Clinic for

Brain Health, Avanir, Neural Analytics

Advisor: MLS, NBA, USSoccer; Consultant: Neural

Analytics, NFL-NCP, NHLPA, LA Lakers

Research Assistants

Mania Alexandrian

Michael Amick

Anne Brown

Yena Kim

Chris Sheridan

Program Management

Constance Johnson

Philip Rosenbaum

Associate Directors,

BrainSPORT

Talin Babikian, Ph.D.

Meeryo Choe, M.D.

Joshua Goldman, M.D.

Mayumi Prins, Ph.D.

Graduate Student

Alexandra Tanner

Student

Holly Kular

Occupational Therapist

Madison Harris, O.T.D.

http://www.uclahealth.org/brainsport

Outline1. The Acute Neurometabolic Cascade

2. Clinical Correlates of Acute Pathophysiology

3. Seeing is Believing: Neuroimaging Biomarkers

4. Detecting is Believing: Fluid Biomarkers

5. Summary

Threshold for Concussion

Katayama Y, et al., J Neurosurg 1990

Impacts below a

threshold did not

initiate the

neurometabolic

cascade

Neurometabolic Cascade:Potassium & Glutamate Flux

K+

K+

K+

K+

K+

Katayama , et.al., J Neurosurg 1990

Glu

tam

ate

Ionic flux

Glutamate

Release

Ionic flux

Ionic flux

Neurometabolic Cascade:Hyperglycolysis & Energy Crisis

Pump

Energy

Crisis

Mito

K+

ADPatp

K+

K+

Ionic flux

Glu

tam

ate

Katayama , et.al., J Neurosurg 1990

For review, Giza & Hovda, Neurosurg 2014

Barkhoudarian et al, PMR Clin NA 2016

Blood flow

Glucose

Neurometabolic Cascade:Acute Axonal Injury

Axonal injury

Ca2+

Ionic flux

Glu

tam

ate

Synaptic

dysfunction

Giza & Hovda, Neurosurg 2014


Blood flow

Axonal degeneration

Neurometabolic Cascade:Calcium & mitochondria

Pump

Energy

Crisis

Mito

K+

ADPatp

K+ Ionic flux

Cytoskeletal

Change ±

Cell Death

Ca2+

Ionic flux

Glu

tam

ate

Synaptic

dysfunction



Blood flow

Neurometabolic Cascade Following

Traumatic Brain Injury

1 2 3 4 5 6 7-10

days

500

400

300

200

0

50

100

% o

f norm

al

Potassium

Glutamate

Glucose

Cerebral Blood Flow

Calcium


Pathophysiology of TBI

Axonal injury

Pump

Energy

Crisis

Mito

K+

ADPatp

K+

K+

K+

K+Ionic flux

Cell Death

Protease

activation

Ca2+

Ionic flux

Glu

tam

ate

Synaptic

dysfunction



Inflammation

Blood flow





5. Summary

Pathophysiology meets Dysfunction

Axonal injury /

Inflammation

Pump

Energy

Crisis

Mito

K+

ADPatp

K+

K+

K+

K+Ionic flux

Cell Death

Protease

activation

Ca2+

Ionic flux

Glu

tam

ate

Synaptic

dysfunction

Adapted from Giza & Hovda, Neurosurg 2014

Blood flow

Migraine?

Migraine?

Slowed

learning &

plasticity?

Impaired cognition

and processing?

Vulnerability?

Inactivation?

Vulner-

ability?

Vulner-

ability?

Vulnerability: Metabolic Crisis?

Athletes with delayed removal from play after

concussion take longer to recover.

Eblin et al., Pediatrics 2016

Asken et al. J Athl Training 2016

Asken et al. AJSM 2018

Metabolism

Memory Metabolism

Memory

Metabolism

Memory

Metabolism

Memory

Prins ML, et al., J Neurotrauma 2013

Vulnerability: Energy Crisis & Repeat mTBI

2nd TBI occurs DURING metabolic crisis

Single Impact

3 Metabolic studies1

day1 day2 day3 day4 day5 day6 day7 day8

3

1 31

2nd TBI occurs AFTER metabolic crisis

3

1

Glu

co

se

me

tab

olis

m

2nd concussion during

metabolic crisis worsens

metabolism & cognition

Vulnerability: Energy Crisis & Repeat mTBI

Vagnozzi, et al., Neurosurgery, 2008

Vagnozzi, et al., Brain 2010

Single

concussion

Double

concussion Human MRS data support the

concept of metabolic vulnerability

after concussion

Migraine: Ionic Flux & mTBI

Kors EE, et al., Ann Neurol 2001

Black = coma

Stripes = ataxia, migraine

½ black = migraine only

= mTBI

induced comaFerrari MD, et al., Lancet

Neurol 2015

TBI & migraine share common physiology

with ionic flux playing a prominent role

Slowed Learning & Cognition:Glutamate-NMDAR dysfunction

PID1Sham FPI FPI

PID2Sham FPI

PID4Sham FPI

PID7Sham

Hippocampus: Ipsilateral NR2A

-60

-40

-20

0

20

40

1 2 3 4 5 6 7

Post-injury day

% o

f S

ha

m

*

Giza, Santa Maria & Hovda, J. Neurotrauma 2006

NR2A protein (IQ gene) is selectively

reduced after developmental TBI.

**

ANOVA, Overall effect of injury, p<0.05

*

N-methyl-D-aspartate (NMDA)

Receptor = IQ Gene?????

Different types: NR2A, NR2B

http://www.time.com/time/magazine/0,9263,1101990913,00.html





5. Summary

Seeing is Believing: Imaging

Axonal injury /

Inflammation

Pump

Energy

Crisis

Mito

K+

ADPatp

K+

K+

K+

K+

Cell Death

Protease

activation

Ca2+

Glu

tam

ate

Synaptic

dysfunction

Blood flow

MRI

fMRI

MRS

MEG

DTI

MEG

PET

MRS

TCD

ASL

fMRI

SWI



McAllister et al., Neurol 1999

Vagnozzi et al.,

Neurosurg 2008

Wilde et al., Neurol 2008

Yuh et al., Ann Neurol 2012

Bergsneider et al., J Neurotrauma 2000

What is a “subconcussion”?

Talavage et al., J Neurotr 2010

Changes in fMRI were

seen in some HS FB

players with no clinical

impairments.

Lipton et al., Radiology 2013

Heading exposure was related to

white matter changes in 3 regions,

and in memory test scores.

Imaging mTBI/Concussion: MRI/SWI

Yuh, et.al. Annals Neurol 2012

≥1 brain contusion or ≥4 hemorrhagic foci on early

MRI were associated with worse 3 month outcome

N=135

Prospective mTBI ED cohort, 3 centers

Time post-injury=12 days

Imaging Early mTBI: Symptoms & DTI

Wilde E, et.al. Neurology, 2008

In adolescents with mTBI, DTI of the CC

performed within 6 days showed

increased FA and decreased diffusivity.

These abnormalities in DTI correlated

well with post-concussion symptoms.

BUT…results from many different

DTI studies have shown a wide

range of results.

McAllister, et al. Neurology, 1999

Imaging: Impaired Activation (fMRI)

Mildly injured individuals

demonstrate abnormal

activation patterns during

a more difficult working

memory task.

Mild TBI patients (GCS 13-15), n=12; controls n=11

Average time of testing was 22.1 ± 10.5 days after TBI.

Loss of consciousness: 1 to 30 min. Post-traumatic amnesia: 15 min to 24 hrs.

% correct

mTBI control

0-back 95.1 96.2

1-back 95.8 95.5

2-back 81.0 89.4

No significant differences

Mild TBIs

Controls

Cerebral Blood Flow (CBF)

Maugans TA et al., Pediatrics, 2011

Meier TB, et al.,

JAMA Neurol 2015

Wang Y et al., J Neurotrauma 2015 epub

Multiple studies show changes in

CBF after concussion.

CBF changes may outlast

symptoms or cognitive impairment.Barlow KM, et al.,

J Neurotrauma 2016

Physiological biomarkers?

Cerebrovascular reactivity (CVR)

Thibeault, et al., Frontiers Neurol 2018

Puls

atilit

yin

dex

(PI)

Bre

ath

-hold

ing

index (

BH

I)

Changes in cerebral blood flow &

measures of cerebrovascular reactivity

are detected after concussion

There is potential for

physiological biomarkers for

diagnosis but also for

recovery

Executive CommitteeHack (DoD), Hainline (NCAA), Koroshetz (NIH)

Administrative

Coordinating Center:

Indiana U School of Medicine

McAllister (coPI)

Advanced Research


Medical College of Wisconsin

McCrea (coPI)

Longitudinal Clinical Study


U of Michigan

Broglio (coPI)

Longitudinal Clinical

Study Core (CSC)

Advanced Research

Core (ARC)

U Nebraska

(BIG10)

Molfese

U Michigan

(BIG10)

Eckner

Washington

(PAC12)

Chrisman

U North Carolina

(ACC)

Guskiewicz &

Mihalik

U Pittsburgh

(ACC)

Kontos & Collins

U Georgia

(SEC)

Schmidt

U Florida

(SEC)

Clugston

U Oklahoma

(BIG12)

Anderson

UCLA

(PAC12)

Giza & DiFiori

Consortium Operating Committee

Anderson, Broglio (co-Chair), Clugston, Duma, Giza, Guskiewicz,

McAllister (co-Chair), McCrea (co-Chair), McGinty, Molfese, Putukian

Senior Scientific

Advisory PanelCrainiceanu, Iverson,

Jordan, Kelly, Marshall,

Saykin, Smith, Talavage,

Wallace

U Wisconsin

(BIG10)

Brooks

Princeton

(Ivy)

Putukian

Concussion Research Initiative

US Military

Academy

(Independent)

Svoboda & Kelly

US Air Force

Academy

(Mountain West)

McGinty &

Campbell

US Coast Guard

Academy

(New England)

Doria

US Naval

Academy

(Independent)

Pyne & Tsao

Virginia Tech

(ACC)

Duma & Rowson

NCAA-DOD Grand Alliance CARE Consortium

U Delaware

(Colonial)

Buckley &

Kaminski

Humboldt State

(California

Collegiate)

Ortega

Azusa Pacific

(Pacific West)

Hoy

U Rochester

(University)

Bazarian

California

Lutheran

(Southern

California)

Davis

ARC Biospecimen Protocol

Pre-

Season

Acute

Concussion

Sub-Acute Concussion Post-

Concussi

on

Baseline

<6hrs

Post-

Injury

24-48hrs

Post-

Injury

Asymptomatic /

Cleared for

Return to Play

Progression

Unrestricted

Return to

Play

7 days

following

Return to

Play

6 Months

Post-Injury

Neurocognitive

and Behavioral

Testing (CSC)X X X X X X X

Blood

Biomarker &

DNA Collection*X X X X X X

Multi-modal

MRI StudiesX X X X

*Protocol implemented at ARC sites prior to 2015 Spring Football

Concussed

CS Controls

NCS Controls

CARE Enrollment & Accrual

ENROLLED CONCUSSIONS

Proposed Actual Proposed Actual

CSC 25,000 39,610 700 2,869

ARC 1,400 2,273 125 355

TOTAL 26,400 41,883 825 3,224

* Data reported as of June 1, 2018


Nencka et al., Brain Imag Behav 2017





5. Summary

Inflammation

Detecting is Believing: Fluid biomarkers

Cytoskeletal

Change

Axonal injury

Inflammation

Pump

Energy

Crisis

Mito

K+

ADPatp

K+

K+

K+

K+

Cytoskeletal

Change &

Cell Death

Protease

activation

Ca2+

Glu

tam

ate

Synaptic

dysfunction

UCH-L1

CNPase

MBP

MAP2

NSE


NEED Pediatric-

specific Studies

NF-L

Tau

SBDP 150

SBDP 120

MAP2

GluR1

NR2A

NOx

GFAP

In Vitro Neurotrauma Causes

Large Scale Protein Release

50 ms

Pressure controller

Wanner et al.,

2008, 2012

Cell injury controller

Ellis et al., 1995

Levine et al., Glia 2016

Level changes of released proteins

Proteins released into fluids after stretching of astrocytes.

Identified released protein: Aldolase C, ALDOC

Ina Wanner

Serum biomarkers after

mild TBI

Halford et al., JCBFM 2017

GFAP & ALDOC are detected after in vitro astrocyte stretch

injury and in blood after human severe TBI.

ALDOC is detectable in blood after human mild TBI.

Few mild TBI patients have GFAP serum signals, while ALDOC signals

were robust in many of them.

Samples provided by Stefania Mondello, Polyclinic Univ. of Messina, Italy.

Ina Wanner

Biofluid Markers: s100b

Berger, et al, J Neurotrauma 2002

s100b was sensitive (1.0) but not

specific (0.44), but mostly for more

ped severe TBI and not mTBI.

Controls n=16; TBI=45 (mTBI=27)

Geyer, et al, J Neurosurg: Peds 2009

s100b unable to distinguish

comparison between head injury

w no symptoms n=53 & mTBI

n=95

Biofluid Markers

Sorokina et al, Neurosci Behav Physiol 2009

Antibodies to GluR1 & NMDAR-

NR2A elevated vs control in both

mild and severe ped TBI groups

Serum nitrates/nitrites [Nox]

elevated after TBI.

Control < mTBI < sevTBI

Concussion blood biomarkers?

Facts: FDA approval for test that

helps predict a positive CT scan

in cases of mild TBI not

diagnostic for concussion!

Biomarkers

• UCH-l1 increased

early after mTBI

• GFAP more

prolonged

increase after

mTBI

No

MM

TB

IM

MT

BI

Papa L, et al., JAMA 2016

“Positive” UCHL1/GFAP indicates higher likelihood of CT+

“Negative” UCHL1/GFAP indicates very high likelihood of CT-

Fluid biomarkers in sport

concussion

• High school athletes

• 32 concussed; 28 contact-controls

• No demographic group differences

• Median time post-injury

• 2 hr

• 22.5 hr

Meier TB, et al., J Neurotrauma 2017

HEAD-to-HEAD study

UCH-L1 & S100B levels 6-

24h post-concussion were

elevated compared to

controls & to preseason

levels

No significant group

differences in GFAP at

these time points

Executive CommitteeHack (DoD), Hainline (NCAA), Koroshetz (NIH)

Administrative


Indiana U School of Medicine

McAllister (coPI)

Advanced Research


Medical College of Wisconsin

McCrea (coPI)

Longitudinal Clinical Study


U of Michigan

Broglio (coPI)

Longitudinal Clinical

Study Core (CSC)

Advanced Research

Core (ARC)

U Nebraska

(BIG10)

Molfese

U Michigan

(BIG10)

Eckner

Washington

(PAC12)

Chrisman

U North Carolina

(ACC)

Guskiewicz &

Mihalik

U Pittsburgh

(ACC)

Kontos & Collins

U Georgia

(SEC)

Schmidt

U Florida

(SEC)

Clugston

U Oklahoma

(BIG12)

Anderson

UCLA

(PAC12)

Giza & DiFiori

Consortium Operating Committee

Anderson, Broglio (co-Chair), Clugston, Duma, Giza, Guskiewicz,

McAllister (co-Chair), McCrea (co-Chair), McGinty, Molfese, Putukian

Senior Scientific

Advisory PanelCrainiceanu, Iverson,

Jordan, Kelly, Marshall,

Saykin, Smith, Talavage,

Wallace

U Wisconsin

(BIG10)

Brooks

Princeton

(Ivy)

Putukian

Concussion Research Initiative

US Military

Academy

(Independent)

Svoboda & Kelly

US Air Force

Academy

(Mountain West)

McGinty &

Campbell

US Coast Guard

Academy

(New England)

Doria

US Naval

Academy

(Independent)

Pyne & Tsao

Virginia Tech

(ACC)

Duma & Rowson

NCAA-DOD Grand Alliance CARE Consortium

U Delaware

(Colonial)

Buckley &

Kaminski

Humboldt State

(California

Collegiate)

Ortega

Azusa Pacific

(Pacific West)

Hoy

U Rochester

(University)

Bazarian

California

Lutheran

(Southern

California)

Davis

Be careful, though…Blood Biomarker Study driven by Outlier Imaging Biomarker Study driven by Outlier

X

X

Statistically significant relationships with biomarkers disappear after

removing outliers in small, underpowered studies.

Posti JP et al. J Neurotrauma

epub 2017

Then this happens…

Sum Up1. Acute concussion pathophysiology drives clinical signs and

symptoms

2. Energy crisis underlies vulnerability

3. Ionic flux underlies migraine & spreading depression

4. Altered glutamate neurotransmission underlies impaired

activation, learning & plasticity

5. Advanced imaging improves our research understanding of

the neurometabolic cascade

6. Fluid biomarkers show promise as potential future clinical

tools

7. Biomarkers may soon serve as objective measures for

diagnosis but also to assist in determining recovery.

Documents

New Diagnosis and Acute Changes - Center For Hjerneskade · 2020. 3. 28. · Concussion Conference Copenhagen, Denmark 45min Diagnosis and Acute Changes. Credit where credit deserved!