Determining T2 relaxation time and stroke onset relationship in ischaemic stroke within apparent diffusion coefficient-defined lesions. A user-independent method for quantifying the impact of stroke in the human brain

Abstract

Background and objective:

In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions.

Methods:

Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients ( $n = 38$ ) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods.

Results:

ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively.

Conclusions:

Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.

Keywords

T2 relaxation time diffusion MRI stroke onset time acute ischaemic stroke

Get full access to this article

View all access options for this article.

References

Busch

Kruger

Allegrini

P.R.

Kerskens

C.M.

Gyngell

M.L.

Hoehn-Berlage

and Hossmann

K.A.

, Reperfusion after thrombolytic therapy of embolic stroke in the rat: Magnetic resonance and biochemical imaging, J Cereb Blood Flow Metab. 18 (1998), 407–418. doi:10.1097/00004647-199804000-00009.

Busza

A.L.

Allen

K.L.

King

M.D.

van Bruggen

Williams

S.R.

and Gadian

D.G.

, Diffusion-weighted imaging studies of cerebral ischemia in gerbils. Potential relevance to energy failure, Stroke. 23 (1992), 1602–1612. doi:10.1161/01.STR.23.11.1602.

Calamante

Lythgoe

M.F.

Pell

G.S.

Thomas

D.L.

King

M.D.

Busza

A.L.

Sotak

C.H.

Williams

S.R.

Ordidge

R.J.

and Gadian

D.G.

, Early changes in water diffusion, perfusion, T1, and T2 during focal cerebral ischemia in the rat studied at 8.5 T, Magn Reson Med. 41 (1999), 479–485. doi:10.1002/(SICI)1522-2594(199903)41:3<479::AID-MRM9>3.0.CO;2-2.

DeLong

E.R.

DeLong

D.M.

and Clarke-Pearson

D.L.

, Comparing the areas under two or more correlated receiver operating characteristic curves: A nonparametric approach, Biometrics. 44 (1988), 837–845. doi:10.2307/2531595.

Hossmann

K.A.

, Viability thresholds and the penumbra of focal ischemia, Ann Neurol. 36 (1994), 557–565. doi:10.1002/ana.410360404.

Jenkinson

and Smith

, A global optimisation method for robust affine registration of brain images, Med Image Anal. 5 (2001), 143–156. doi:10.1016/S1361-8415(01)00036-6.

Jokivarsi

K.T.

Hiltunen

Grohn

Tuunanen

Grohn

O.H.

and Kauppinen

R.A.

, Estimation of the onset time of cerebral ischemia using T1rho and T2 MRI in rats, Stroke. 41 (2010), 2335–2340. doi:10.1161/STROKEAHA.110.587394.

Kato

Kogure

Ohtomo

Izumiyama

Tobita

Matsui

Yamamoto

Kohno

Ikebe

and Watanabe

, Characterization of experimental ischemic brain edema utilizing proton nuclear magnetic resonance imaging, J Cereb Blood Flow Metab. 6 (1986), 212–221. doi:10.1038/jcbfm.1986.34.

Kauppinen

R.A.

, Multiparametric magnetic resonance imaging of acute experimental brain ischaemia, Prog NMR Spectr. 80 (2014), 12–25. doi:10.1016/j.pnmrs.2014.05.002.

10.

Kettunen

M.I.

Grohn

O.H.

Silvennoinen

M.J.

Penttonen

and Kauppinen

R.A.

, Quantitative assessment of the balance between oxygen delivery and consumption in the rat brain after transient ischemia with T2 -BOLD magnetic resonance imaging, J Cereb Blood Flow Metab. 22 (2002), 262–270. doi:10.1097/00004647-200203000-00003.

11.

Knight

M.J.

Dillon

Jarutyte

and Kauppinen

R.A.

, Magnetic resonance relaxation anisotropy: Physical principles and uses in microstructure imaging, Biophys J. 112 (2017), 1517–1528. doi:10.1016/j.bpj.2017.02.026.

12.

Knight

M.J.

McCann

Tsivos

Dillon

Coulthard

and Kauppinen

, Quantitative T2 mapping of white matter: Applications for ageing and cognitive decline, Phys Med Biology. 61 (2016), 5587–5605. doi:10.1088/0031-9155/61/15/5587.

13.

Knight

M.J.

McGarry

B.L.

Rogers

H.J.

Jokivarsi

K.T.

Grohn

O.H.

and Kauppinen

R.A.

, A spatiotemporal theory for MRI T2 relaxation time and apparent diffusion coefficient in the brain during acute ischaemia: Application and validation in a rat acute stroke model, J Cereb Blood Flow Metab. 36 (2015), 1232–1243. doi:10.1177/0271678X15608394.

14.

Knight

M.J.

Wood

Coulthard

and Kauppinen

R.A.

, Anisotropy of spin-echo T2 relaxation by magnetic resonance imaging in the human brain in vivo, Biomed Spectr Imag. 4 (2015), 299–310. doi:10.3233/BSI-150114.

15.

Longa

E.Z.

Weinstein

P.R.

Carlson

and Cummins

, Reversible middle cerebral artery occlusion without craniectomy in rats, Stroke. 20 (1989), 84–91. doi:10.1161/01.STR.20.1.84.

16.

McGarry

B.L.

Rogers

H.J.

Knight

M.J.

Jokivarsi

K.T.

Sierra

Grohn

O.H.

and Kauppinen

R.A.

, Stroke onset time estimation from multispectral quantitative magnetic resonance imaging in a rat model of focal permanent cerebral ischemia, Int J Stroke. 11 (2016), 677–682. doi:10.1177/1747493016641124.

17.

Minnerup

Broocks

Kalkoffen

Langner

Knauth

Psychogios

M.N.

Wersching

Teuber

Heindel

Eckert

Wiendl

Schramm

Fiehler

and Kemmling

, Computed tomography-based quantification of lesion water uptake identifies patients within 4.5 hours of stroke onset: A multicenter observational study, Ann Neurol. 80 (2016), 924–934. doi:10.1002/ana.24818.

18.

Norton

T.J.T.

Pereyra

Knight

M.J.

McGarry

B.M.

Jokivarsi

K.T.

Grohn

O.H.J.

and Kauppinen

R.A.

, Stroke onset time determination using MRI relaxation times without non-ischaemic reference in a rat stroke model, Biomed Spectrosc Imaging. 6 (2017), 25–35. doi:10.3233/BSI-160155.

19.

Rimmele

D.L.

and Thomalla

, Wake-up stroke: Clinical characteristics, imaging findings, and treatment option – an update, Front Neurol. 5 (2014).

20.

Saver

J.L.

Goyal

van der Lugt

Menon

B.K.

Majoie

C.B.

Dippel

D.W.

Campbell

B.C.

Nogueira

R.G.

Demchuk

A.M.

Tomasello

Cardona

Devlin

T.G.

Frei

D.F.

du Mesnil de Rochemont

Berkhemer

O.A.

Jovin

T.G.

Siddiqui

A.H.

van Zwam

W.H.

Davis

S.M.

Castano

Sapkota

B.L.

Fransen

P.S.

Molina

van Oostenbrugge

R.J.

Chamorro

Lingsma

Silver

F.L.

Donnan

G.A.

Shuaib

Brown

Stouch

Mitchell

P.J.

Davalos

Roos

Y.B.

Hill

M.D.

and Collaborators

, Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: A meta-analysis, JAMA. 316 (2016), 1279–1288. doi:10.1001/jama.2016.13647.

21.

Siemonsen

Mouridsen

Holst

Ries

Finsterbusch

Thomalla

Ostergaard

and Fiehler

, Quantitative T2 values predict time from symptom onset in acute stroke patients, Stroke. 40 (2009), 1612–1616. doi:10.1161/STROKEAHA.108.542548.

22.

Thomalla

Boutitie

Fiebach

J.B.

Simonsen

C.Z.

Nighoghossian

Pedraza

Lemmens

Roy

Muir

K.W.

Ebinger

Ford

Cheng

Galinovic

Cho

T.H.

Puig

Thijs

Endres

Fiehler

and Gerloff

, Stroke with unknown time of symptom onset: Baseline clinical and magnetic resonance imaging data of the first thousand patients in WAKE-UP (efficacy and safety of MRI-based thrombolysis in wake-up stroke: A randomized, doubleblind, placebo-controlled trial), Stroke. 48 (2017), 770–773. doi:10.1161/STROKEAHA.116.015233.

23.

Thomalla

Boutitie

Fiebach

J.B.

Simonsen

C.Z.

Pedraza

Lemmens

Nighoghossian

Roy

Muir

K.W.

Ebinger

Ford

Cheng

Galinovic

Cho

T.H.

Puig

Thijs

Endres

Fiehler

and Gerloff

, Clinical characteristics of unknown symptom onset stroke patients with and without diffusion-weighted imaging and fluid-attenuated inversion recovery mismatch, Int J Stroke. 11 (2017), 134–147.

24.

Thomalla

Cheng

Ebinger

Hao

Tourdias

Kim

J.S.

Breuer

Singer

O.C.

Warach

Christensen

Treszl

Forkert

N.D.

Galinovic

Rosenkranz

Engelhorn

Köhrmann

Endres

Kang

D.W.

Dousset

Sorensen

A.G.

Liebeskind

D.S.

Fiebach

J.B.

Fiehler

and Gerloff

, DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4.5 h of symptom onset (PRE-FLAIR): A multicentre observational study, Lancet Neurol. 10 (2011), 978–986. doi:10.1016/S1474-4422(11)70192-2.

25.

Thomalla

Rossbach

Rosenkranz

Siemonsen

Krützelmann

Fiehler

and Gerloff

, Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less, Ann Neurol. 65 (2009), 724–732. doi:10.1002/ana.21651.

26.

Thomalla

Simonsen

C.Z.

Boutitie

Andersen

Berthezene

Cheng

Cheripelli

Cho

T.H.

Fazekas

Fiehler

Ford

Galinovic

Gellissen

Golsari

Gregori

Gunther

Guibernau

Hausler

K.G.

Hennerici

Kemmling

Marstrand

Modrau

Neeb

Perez de la Ossa

Puig

Ringleb

Roy

Scheel

Schonewille

Serena

Sunaert

Villringer

Wouters

Thijs

Ebinger

Endres

Fiebach

J.B.

Lemmens

Muir

K.W.

Nighoghossian

Pedraza

Gerloff

, for the WAKE-UP Investigators, MRI-guided thrombolysis for stroke with unknown time of onset, N Engl J Med. 379 (2018), 611–622. doi:10.1056/NEJMoa1804355.

27.

Tofts

, Quantitative MRI of the Brain: Measuring Changes Caused by Disease, John Wiley& Sons, Ltd., Chichester, England, 2004. doi:10.1002/0470869526.

28.

Wouters

Dupont

Norrving

Laage

Thomalla

Albers

G.W.

Thijs

and Lemmens

, Prediction of stroke onset is improved by relative fluid-attenuated inversion recovery and perfusion imaging compared to the visual diffusion-weighted imaging/fluid-attenuated inversion recovery mismatch, Stroke. 47 (2016), 2559–2564. doi:10.1161/STROKEAHA.116.013903.

29.

Zhang

Brady

and Smith

, Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm, IEEE Trans Med Imaging. 20 (2001), 45–57. doi:10.1109/42.906424.