Detecting the basis of cognitive

dysfunction in mild TBI:

The role of quantitative MRI

Andrew M. Blamire

Newcastle MR Centre & Institute of Cellular Medicine

Newcastle University

Context - Prognostic Indicators in TBI

• Moderate/severe TBI account for ~10% of all cases

– Prognostic calculators

• CRASH1 - mortality at 14 days

• IMPACT2 - severe disability at 6 months

• Mild TBI : remaining ~90% of all cases

– Prolonged cognitive deficits in 15 - 45% of mild TBI3

– No prognostic calculator

Treatments in mild TBI – limited

(1) Perel P, et al. BMJ. 336(7641):425-9, (2008).

(2) Lingsma HF, et al. Lancet Neurology. 9(5):543-54 (2010).

(3) Thornhill, S., Teasdale, G.M., et al. BMJ. 320, 1631-1635 (2000).

Context - Conventional MRI Disconnection between imaging and clinical assessment

• Out-patients (scanned 4-7 days)

GCS 13

No LoC,

PTA 4 hrs

(M33PG)

GCS 13

No LoC

PTA 12 hrs

(M34GR)

GCS 13

LoC 5 mins

PTA 30 mins

(M16KW)

GCS 14

LoC 2 mins

PTA 12 hours

(M24HM)

GCS 9

LoC 10 mins

PTA 10 days

(H09ET)

GCS 7

LoC 5 mins

PTA 1hr

(H08MM)

Mild TBI Moderate TBI

Context - Conventional MRI Disconnection between imaging and clinical assessment

• Out-patients (scanned 4-7 days)

GCS 13

No LoC,

PTA 4 hrs

(M33PG)

GCS 13

No LoC

PTA 12 hrs

(M34GR)

GCS 13

LoC 5 mins

PTA 30 mins

(M16KW)

GCS 14

LoC 2 mins

PTA 12 hours

(M24HM)

GCS 9

LoC 10 mins

PTA 10 days

(H09ET)

GCS 7

LoC 5 mins

PTA 1hr

(H08MM)

Mild TBI Moderate TBI

Key Questions

1. Can advanced MRI methods identify markers of

acute tissue injury?

2. Do such imaging markers provide a neurobiological

basis for cognitive dysfunction following mild TBI?

3. Do any MRI measures have prognostic value?

Comprehensive imaging battery

Prospective, longitudinal study

mild TBI

Key Questions

1. Can advanced MRI methods identify markers of

acute tissue injury?

2. Do such imaging markers provide a neurobiological

basis for cognitive dysfunction following mild TBI?

3. Do any MRI measures have prognostic value?

Comprehensive imaging battery

Prospective, longitudinal study

mild TBI

Improving Structural Imaging Quantitative T1 Relaxometry

Conventional T1w - qualitative

2.0s 0.5s

Quantitative T1 map 200

400

600

T1 (s)

Pix

els

0.6 0.8 1 0

Evidence of acute cortical injury Regional qT1 Abnormalities

• Brain “parcellated” into 8 regions / hemisphere

– Visible lesions excluded

Significant GM changes in T1 1.100

1.150

1.200

1.250

1.300

1.350

1.400

1.450

1.500

1.550

1.600

Rig

ht

Occ

ipit

al-P

arie

tal G

rey

Mat

ter

T1 (

s)

Control

Mild

Moderate

ANOVA p<<0.001

21/53 outside normal range

Pathophysiology of TBI Diffuse Axonal Injury (DAI)

Compression

Tension

Shearing

Shearing

Disruption of axoplasmic flow

Extrusion of axoplasm & organelles

Microtubule Damage & Disassembly

Axonal bulbs

Tang-Schomer et al, FASEBJ, 24: 1401-1410 (2010)

Assessing Axonal Damage Diffusion Tensor Imaging (DTI)

Fractional

Anisotropy

(FA)

Mean

Diffusivity

(MD)

DTI contrast based on diffusion restriction

Evidence of acute white matter injury TBSS - Groupwise Patients vs Control

53 TBI, 33 Controls, p<0.05, Croall et al, Neurology in press 2014

0 20 40 Z =

MD

Water diffusibility is increased Structural damage

Evidence of acute white matter injury TBSS - Groupwise Patients vs Control

53 TBI, 33 Controls, p<0.05, Croall et al, Neurology in press 2014

Motion is more ordered

Diffusibility is increased along these WM tracts

FA

0 20 40 Z =

Key Questions

1. Can advanced MRI methods identify markers of

acute tissue injury?

2. Do such imaging markers provide a neurobiological

basis for cognitive dysfunction following mild TBI?

3. Do any MRI measures have prognostic value?

Comprehensive imaging battery applied in a

prospective, longitudinal imaging study in mild TBI

Cortical damage & cognitive dysfunction

• Significant correlations between VLF performance and

left hemisphere cortical regions

Relationship between

cortical (GM) T1 and VLF performance score

(Controlled for NART)

1000

1100

1200

1300

1400

1500

1600

0 10 20 30 40 50 60

Le

ft T

em

pe

ro-P

ari

eta

l G

rey

Ma

tte

r T

1(m

s)

VLF Score (Corrected for NART)

R2=0.142, p<0.01

1000

1100

1200

1300

1400

1500

1600

0 10 20 30 40 50 60

Le

ft T

em

pe

ro-P

ari

eta

l G

rey

Ma

tte

r T

1 (

ms

)

VLF Score (Corrected for NART

Controls

WM damage & cognitive dysfunction Regression analysis against Verbal Fluency

• Worse cognitive performance relates to elevated FA

Groupwise

FA Increased

Negative

FA regression to

verbal fluency

0

10

20

30

40

50

60

70

0.30 0.35 0.40 0.45 0.50

Ve

rbal

Flu

en

cy S

core

Fractional Anisotropy

Croall et al, Neurology in press 2014

Key Questions

1. Can advanced MRI methods identify markers of

acute tissue injury?

2. Do such imaging markers provide a neurobiological

basis for cognitive dysfunction following mild TBI?

3. Do any MRI measures have prognostic value?

Comprehensive imaging battery applied in a

prospective, longitudinal imaging study in mild TBI

Relationship to Outcome

• Rivermead Post Concussion Questionnaire • Nausea, Fatigue, Concentration, Depression, Headache, etc

• Assessed as outcome at 12 months (n=37/53)

n=30 n=22 n=15

1180

1200

1220

1240

1260

1280

1300

1320

1340

Control 0 or 1 symptom 2 or more symptoms

p<0.02

p<0.005

Wh

ole

Gre

y M

att

er

T1 (

ms)

AC

UT

E

Chronic RPCQ

Summary

• Acute, diffuse cortical and white matter injury detectable by

quantitative MRI approaches

• Mild TBI behaves differently to moderate/severe TBI

– Axonal compaction (FA) rather than destruction (FA)

• Strong relationship between cortical and WM damage and cognitive

performance

• Index of global cortical damage has prognostic value

Acknowledgements

Sir Jules Thorn Charitable Trust

Funding

MR Physics Jiaboa He

Benjamin Aribisala

Iain Croall

Radiographers Louise Morris

Carol Smith

Tim Hodgson

Tamsin Gaudie

Philips Medical Systems Matthew Clemence

Clinical Team - TBI Chris Cowie

Patrick Mitchell

David Mendelow

Psychology Tom Kelly

David Miller

Josh Wood

Anna Peel