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EVALUATION OF HUMAN STROKE BYMR IMAGING

Ph.D Thesis by

Sverre Rosenbaum

Faculty of Medicine, University of Copenhagen, Denmark

and

Danish Research Center of Magnetic Resonance, Hvidovre Hospital

August 2000

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Preface

This Ph.D. project was carried out at the Danish Research Center of Magnetic Resonance,

Hvidovre Hospital, in cooperation with Division of Stroke, Medical Center, Hvidovre Hospital,

during my employment as a research assistent (1995-1999). It has been a unique opportunity for

me to acquire insight in the exciting fields of human stroke and Magnetic Resonance Imaging.

I wish to express gratitude to my three supervisors, Professor Olaf B. Paulson, Dr. Henrik B.W.

Larsson and Dr. Palle Petersen. Also I want to thank Professor Ole Henriksen for initiating the

project.

The project would not have been possible without the support of many people. Especially I want

to thank Egill Rostrup who developed the programs for post-processesing and with whom I have

had many inspiring discusions on the interpretation of the perfusion studies. Also special thanks

to Jacob Rrbech Marstrand for help with the recruitment of patients in the later part of the

study and for inspiring discussions. I wish to thank Helle Simonsen for assistance with the MRI

examinations, also at late nights, and for help with preparation of the illustrations for this thesis.

Thanks to Lars Hanson for his thorough readings of the manuscript, to Katja Krabbe helping

with evaluating the data for chapter 4, to Peter Born who helped with the lay-out of the thesis

and to Pia Olsen for assistance with the MRI examinations. Also thanks to the secretaries Lisa

Simonsen, Lotte Hansen, Marianne Rnn for all kinds of help and to the Department of Clinical

Physiology and Nuclear Medicine Bispebjerg Hospital for SPECT images used in figure 30 and

figure 40.

However, most I want to thank August, Sofie and Anne, for being patient with me never being at

home. Also thanks to my mother for taking care of August and Sofie when Anne and I were at

work.

Furthermore, I wish to thank Apotekerfonden af 1991and H:S forskningspulje for their financial

support.

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This thesis is written as a monograph although it incorporates a submitted paper

Tissue Patterns Characterized with Perfusion- and Diffusion Weighted MRI in Acute Stroke,

by Rosenbaum S., Rostrup E., Larsson H.B.W., Petersen P., corresponding to chapter 6.

The work also resulted in an abstract

Tissue Patterns Characterized with Perfusion- and Diffusion Weighted MRI in Acute Stroke,

by Rosenbaum S., Rostrup E., Larsson H.B.W., Petersen P., Proceedings of the International

Society for Magnetic Resonance in Medicine 7thScientific Meeting and Exhibition, Philidelphia,

846 (1999).

And a published paper

MR-visible Water in Acute Stroke Gideon P., Rosenbaum S., Sperling B., Petersen P. published

in Magnetic Resonance Imaging , vol.17: no2, pp 301-304 (1999)

Sverre Rosenbaum

Copenhagen, August 2000

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Figures and Tables

Figure 1. The large arteries of the brain

Figure 2. Influence of collaterality

Figure 3. Thresholds of ischemia

Figure 4. Collateral flow and the Penumbra

Figure 5. Diffusion-Gaussian distribution

Figure 6. Diffusion detected in magnetic resonance

Figure 7. The Pulses Gradient Spin Echo experiment

Figure 8. Diffusion coefficient

Figure 9. Motion effects on net phase and the echo signal

Figure 10. Motion compensation by phase correction

Figure 11. Echo planar Imaging

Figure 12. Diffusion - signal attenuation

Figure 13. Tortuosity

Figure 14. Diffusion anisotropy

Figure 15. Vessel size and susceptibility effects

Figure 16. Contrast agent bolus tracking

Figure 17. Time-of-flight

Figure 18. MR angiography, Time-of-flight

Figure 19. Stages in hemorrhages

Figure 20. A case of acute hemorrhages

Figure 21. The sensitivity of EPI

Figure 22. Incidences of Hemorrhagic infarcts (HI) and BBB leakage

Figure 23. Hemorrhagic infarct - T2*W and T1W images

Figure 24. Hemorrhagic transformation and leaky BBB

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Figure 25. Incidences and temporal course

Figure 26. Ischemia cytotoxic edema decrease of ADC

Figure 27. ADC and signal on T2WI - time course during ischemia

Figure 28. MR Measures With Tissue Signature, Attribution and Their Significance

Figure 29. Human ischemic stroke

Figure 30. Perfusion thresholds of ADC changes

Figure 31. PWI>DWI mismatch Stroke in progression. Enlargement at follow up

Figure 32. Reperfusion

Figure 33. PWI>DWI mismatch corresponding to stenosis on left ICA/MCA

Figure 34. A patient suffering from and infarct in the left MCA

Figure 35. Dynamic susceptibility contrast MRI

Figure 36. Compensatory Vasodilation

Figure 37. Luxury Perfusion

Figure 38. Collateral and Ichemic patterns

Figure 39. Reperfusion with normalization of PWI

Figure 40. Incomplete Infarct

Table I MRI Findings in Acute Cerebral Ischemia

Table II The stages of Hemorrhages

Table III Patient data and examinations

Table IV Hemorrhagic infarctions (HI)-numbers of examinations

Table V Blood brain barrier-leakage - number of examinations

Table VI Patient data. Time for MR-examinations

Table VII Acute MR-findings

Table VIII MR-findings in the chronic phase

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Abbreviations

ACA Anterior Cerebral Artery

ADC Apparent Diffusion Coefficient

AICA Anterior Inferior Cerebellar Artery

AMPA Alpha-amino-3-hydroxy-55-methyl-4-isoxazole Propionic Acid

AUC Area under Curve

ATP Adenosine Triphosphate

BBB Blood Brain Barrier

BI Barthel Index

CBV Cerebral Blood Volume

CMRGl Cerebral Metabolic Rate Glucose

CMRO2 Cerebral Metabolic Rate Oxygen

CPP Cerebral Perfusion Pressure

CSF Cerebro-Spinal Fluid

CT Computer Assisted Tomography

CNR Contrast to Noise

DSC-MRI Dynamic Susceptibility Contrast Magnetic Resonance Imaging

DTPA Dithylen-Triamin-Penta-Acetiacid

DTPA-BMA DTPA-Bismethylamide

DW Diffusion Weighted

DWI Diffusion Weighted MR Imaging

DWI Diffusion Weighted Imaging

ECASS European Cooperative Acute Stroke Study

EEG Electric Encephalogram

EP Echo Planar

EPI Echo Planar Imaging

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EAA Excitatory Amino Acids

FLAIR Fluid Attenuate Inversion Recovery

FLASH Fast Low Angle Shot

FOV Field Of View

Gd Gadolinium

HASTE Half-Fourier Single-shot Turbo spin-Echo

HI Hemorrhagic Infarction

HMPAO 99mTc-hexa-methyl-propylene-amine-oxime

HT Hemorrhagic Transformation

ICA International Carotid Artery

ICH Intracerebral Hemorrhage

IEPI Interleaved Echo Planar Imaging

IIH Intra Infarct Hemorrhage

ITT Intention to Treat

LP Luxury Perfusion

MCA Middle Cerebral Artery

MIP Maximal Intensity Projection

MRI Magnetic Resonance Imaging

MTT Mean Transit Time

NAA N-Acetyl Aspartate

NIH National Institute of Health

NINDS National Institute of Neurological Disorders and Stroke rt-PA Stroke

Study Group

NMDA N-Methyl-D-Aspartate

OEF Oxygen Extraction Fraction

PCA Posterior Cerebral Artery

PD Proton Density

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PDW Proton Density Weighted

PET Positron Emission Tomography

PICA Posterior Anterior Cerebellar Artery

PWI Perfusion Weighted Imaging

rCBF regional Cerebral Blood Flow

rCBV regional Cerebral Blood Volume

RF Radio Frequency

RIND Reversible Ischemic Neurologic Deficit

RS Ranking Score

rt-PA recombinant Plasminogen Activator

SCA Superior Cerebellar Artery

SD Spreading Depression

SNR Signal to Noise

SPECT Single Photon Emission Tomography

T1W T1-Weighted

T1WI T1-Weighted Imaging

T2*W T2*-Weighted

T2*WI T2*-Weighted Imaging

T2W T2-Weighted

T2WI T2-Weighted Imaging

TE Echo Time

TIA Transient Ischemic Attack

TOF Time of Flight

TP Target Population

TR Repetition Time

TTP Time To Peak

WM White Matter

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Summary in Danish

Ph.d. projektet er gennemfrt i perioden 1995-1999, under min ansttelse som klinisk assistent

p Dansk Videncenter for Magnetisk Resonans, Hvidovre Hospital.

Gennem de sidste 10 r er der sket vsentlige fremskridt indenfor Magnetisk Resonans

billeddannelse (MRI), som har gjort det muligt at visualisere tidlige forandringer hos patienter

efter iskmisk slagtilflde. Iskmisk hjernevv kan visualiseres med de nye MR teknikker:

diffusionsvgtet MR billeddannelse (DWI) og perfusionssvgtet MR billeddannelse (PWI).

Studier af dyr og mennesker har indiceret at iskmisk vv, som kan undg udvikling til egentligt

infarkt hvis thrombolyse eller nervecelleskyttende behandling etableres i tide, kan pvises med

DWI og PWI. Specielt har en kombination af DWI og PWI vist sig interessant til pvisning af

vv som potentielt kan reddes.

Implementering af hurtige T2*-vgtede ekkoplanare billedoptagelser (EPI) har muliggjort tidlig

detektion af bldninger, indenfor de frste timer efter symptomdebut.

Der er med disse fremskridt kommet fokus p, om MRI kan bruges til rationelt at stratifisere

patienter med akut slagtilflde til behandling med trombolyse og/eller neuroprotektiv behandling

udfra en viden om vvets metaboliske status samt til udelukkelse af bldning.

Afhandlingen er udformet som en monografi. Den teoretiske baggund for de anvendte MR

teknikker og deres applikationer og fund p iskmiske dyremodeller og patienter med slagtilflde

gennemgs. I afhandlingen indgr desuden tre studier samt fire kausistikker:

T2*vgtet EPI synes lovende med henblik p at detektere bldninger i den akutte fase og som

prsernteret i en kausistik mere sensitive end andre MR-teknikker. Imidlertid er sammenlignende

studier af sensitiviteten af CT versus MR ndvendige, som illustreret i en kausistik, hvor en akut

bldning ikke blev detekteret.

Med ialt 92 undersgelser over 6 mneder af 43 patienter med iskmisk slagtilflde blev det

undersgt om T2* vgtet EPI havde strre flsomhed i forhold til konventionel T1 vgtet MR

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billeddannelse., med henblik p at detektere bldninger som opstr sekundrt i det afficerede

vv efter et iskmisk slagtilflde, skaldt hmoragisk infarkt (HI). Udviklingen af HI er ogs

forsgt belyst i forhold til om blodhjerne barrieren er defekt eller ej. Pvisning af HI er vsentlig

ved etablering af trombolysebehandling - til vurdering af bldningsrisiko. Det blev fundet at T2*

vgtet EPI er langt drligere end konventionel T1 vgtet MR billeddanelse til at detektere HI.

Dette fund skyldes formentlig at oxygeneringen ved HI formentlig er hjere end ved

rumopfyldende bldninger.. Det blev ikke fundet, at en defekt blodhjerne barriere var associeret

til forekomsten af HI. Dog var forekomsten af HI associeret til defekt blodhjerne barriere hvis

HI blev pvist p bde T2* EPI og T1 vgtet MR billeddannelse. Denne patientgruppe blev

tolket som havende specielt stor bldningsrisiko ved etablering af trombolyse eller

blodfortyndende behandling.

Ni patienter med iskmisk slagtilflde blev undersgt serielt med DWI og PWI indenfor 24

timer til den kronsike fase 2 mneder efter symtomdebut, hvor slutinfarktvolumenet blev

bestemt.. Formlet var at undersge om der med DWI og PWI i den akutte fase kunne

identificeres viabelt vv. Der blev identificeret fire typer: vv:

To af disse blev tolket som identificerende viabelt vv i de skaldte mismatch omrder mellem

DWI og PWI. En vvstype indikerede spontan reperfusion. Endelig blev en type tolket som

iskmisk uden viabelt vv.

Identificering af disse typer i den akutte fase blev fundet vrdifuld med henblik p stratifisering

af patienter til trombolytisk og /eller neuroprotektiv behandling.

Det blev det foreslet at kombinationen af DWI og PWI ville kunne bruges til at stratifisere

patienterne med henblik p forskellige mekanismer ved "stroke in progression".

Slutinfarktstrrelsen mlt p T2 vgtede billeder br tage hjde for et varierende vandindhold,

som illustreret i en kausistik. Vandindholdet er maximalt een uge efter debut, som bestemt i et

studie.

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Summary in English

The Ph.d project was carried out between 1995-1999 during my employment as a research

assistant at the Danish Research Center for Magnetic Resonance, Hvidovre Denmark.

During the last 10 years, major advances have been made in Magnetic Resonance Imaging (MRI)

which have made it possible to visualize early changes in patients suffering from ischemic stroke.

Ischemic brain tissue can be visualized by new MR techniques: diffusion weighted MR imaging

(DWI) and perfusion weighted MR imaging (PWI). Studies of animals and humans have

indicated that ischemic tissue, that will survive if thrombolysis or neuroprotection is established

in time, can be depicted by DWI and PWI. The combination of DWI and PWI have shown

promising identifying ischemic areas potentially salvageable.

Implementation of fast T2* weighted echo planar imaging (EPI) has made it possible to detect

hemorrhages, within the first hours after onset of symptoms.

These advances have turned attention to the possible use of MRI for rational statification of

patients with stroke to thrombolytic or neuroprotective treament, from a knowledge of the

metabolic status and from the exclusion of hemorrhages.

The thesis is formed as a monography. The theoretical background to the applied MR techniques

and their applications and findings in animal and human studies on ischemic stroke are reviewed.

The thesis also consists of three studies and four case studies:

T2* weighted EPI seems promising detecting acute hemorrhages and it is more sensitive than

other MR techniques as demonstrated in a case study. However, further studies are needed to

compare the sensitivity to that of CT exemplified by a case of false negative detection of acute

hemorrhage.

In 43 patients suffering from ischemic stroke being examined 92 times during 6 months, it was

examined if T2* EPI was more sensitiv compared to T1 weigted imaging detecting secondary

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bleedings, hemorrhagic infarcts (HI). It was also examined if occurrence of HI was associated to

leakage of the the blod brain barrier. Detection of HI is important prior to thrombolytic therapy

estimating the risk of inducing hemorrhages. It was found that T2* EPI detected HI with very

low sensitivity compared to conventional T1 weighted MRI. It was hypothesized that this was

caused by a higher oxygenation state than in space-occupying haemorrhages. It was not found

that leakage of the blod brain barrier was associated to development of HI. However HI and

leakage of the blood barin barrier was associated if HI was identified on both T2* EPI and T1

weighted imaging. This group of patients was hypothesized to have an increased risk of bleeding

after thrombolysis or anticoagulant treatment.

Nine patients suffering from ischemic stroke were examined serially by DWI and PWI from

within 24 hours to the chronic phase at 2 months after onset of symptoms, where the final infarct

was measured.. The purpose was to investigate if DWI and PWI could be used to identify

potentially salvageable ischemic tissue. Four tissue patterns were identified.

Two of these patterns were interpreted as identifying viable tissue. One pattern indicated

reperfusion. Finally one pattern was interpreted as identifying ischemic tissue without any

potential for tissue salvation.

The identification of these four patterns was found valuable stratifying acute stroke patients to

thrombolytic or neuroprotective treatment.

It was suggested that the combination of DWI and PWI can be used to stratify the patients

regarding different mechanisms related to stroke in progression.

The final infarct as measured on T2 weighted images should be interpreted with consideration of

the water content, as illustrated in a case study. The water content is at its peak within the first

week after onset of symptoms as measured in a study.

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Introduction

During the past ten years advances in neuroimaging and magnetic resonance imaging (MRI) have

made it possible to image the brain during the period of ischemic evolution. Evolving ischemic

lesions can now be imaged with new MRI techniques including diffusion-weighted imaging

(DWI) (decreased diffusion is a marker of cellular injury in ischemia) and perfusion weighted

imaging (PWI) (for assessment of the perfusion in the tissue). Simultaneously with the advances

in MRI technology, there has been an increased clinical need for imaging of evolving focal

cerebral ischemia due to the developments in acute stroke therapy. The first therapy for acute

stroke, thrombolysis, has been approved in the USA since 1996. Imaging of stroke should be

used prior to thrombolysis to exclude hemorrhages and to stratify patients according to the risks

of the therapy and to guide treatment. Before the advances in MRI, only anatomical modalities

i.e. Computer Tomography (CT) or T2 and T1 weighted magnetic resonance imaging, were used.

However, these modalities do not reliably depict the evolving ischemic lesions within the first 24

hours. Functional imaging techniques such as positron emission tomography (PET) and single

photon emission computer tomography (SPECT) have drawbacks: PET is restricted to a few

centers and is logistically demanding. SPECT is more available but is insufficient for detecting

hemorrhages. MR imaging is clinically available and the new DWI and PWI techniques seem

promising for evaluating acute human stroke, for acquiring knowledge on the pathophysiological

state in acute human ischemic stroke, and for guiding pre-thrombolytic assessment. Most

recently, also detection of primary hyperacute intracerebral hemorrhages by T2* weighted echo

planar MRI (EPI) has become possible.

The aim of this study is to provide answers to the following questions:

Can MRI by echo planar imaging (EPI) improve the detection of intracerebral hemorrhages?

Can EPI improve detection of secondary bleedings, i.e. hemorrhagic transformations compared

to conventional MRI techniques?

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Is it possible from EPI, T1 weighted imaging and evaluation of the blood brain barrier by post

contrast T1 weighted imaging to provide information on pathophysiological aspects of

hemorrhagic transformation regarding the risk induced by thrombolysis or anticoagulant therapy?

Can the combination of DWI and PWI in acute human stroke identify ischemic tissue at risk of

infarction?

In Chapter 1, the background of human stroke is given. At the start of the project, the MRI

techniques for DWI and PWI as used in the project, were not available, and a considerable

amount of time was used establishing these techniques at the Danish Research Center of

Magnetic Resonance. These techniques are introduced in Chapter 2. Detection of hemorrhages

by MRI is reviewed in Chapter 3, and three cases of acute primary intracerebral hemorrhages

evaluated using EPI are presented. In Chapter 4, data is presented on detection of hemorrhagic

transformation by EPI in comparison to T1 weighted imaging. Data on the integrity of the blood

brain barrier in the context of hemorrhagic transformation is presented. In Chapter 5, the

literature on DWI and PWI in animal ischemic models and in humans are reviewed. Three case

studies on perfusion thresholds in DWI, on stroke in progression and on edema, respectively,

are presented. In Chapter 6, serial data on acute ischemic stroke on patients using DWI and PWI

are presented.

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Chapter 1. Background

1.1. Epidemiology of Stroke

In Denmark, there are 10.000 new cases of stroke per year (1). Approximately20% of these

patients die within the first month (2). In the aging population, stroke is the leading cause of

disability and cognitive impairment and is one of the major causes of disability in people between

20-50. The number of fatal strokes has decreased in the last 50 years without any change in the

incidence of stroke, thereby increasing the number of persons with disability from stroke. The

incidence of stroke increases with age and with an increasing population of elderly people. In the

future, the number of persons with disability due to stroke will increase (3), i.e. stroke is a major

and important contributor to human suffering and it is an economic burden for the society.

Therefore, effective therapies in the acute phase and intensive rehabilitation are areas of

increasing importance. Development in different imaging modalities such as Computer

Tomography (CT), Single Photon Emission Computer Tomography (SPECT), Positron

Emission Tomography (PET) and Magnetic Resonance (MR) have improved diagnostic

possibilities giving more differentiated knowledge of which patients should receive acute medical

therapy such as thrombolytic or neuroprotective therapy.

1.2. Pathogenesis of Stroke

1.2.1. Classification

Stroke may result from localized cerebral ischemia, intracerebral hemorrhage (ICH),

subarachnoid hemorrhage or venous sinus thrombosis. If the stroke etiology is ischemia, it may

be caused by embolism or by thrombosis. The incidences differ between studies (4), (5). In one

autopsy series of 179 cases (4) the following incidences were found: Ischemic stroke 63%,

thrombotic infarcts 12%, embolic infarcts 32% (51% of the ischemic strokes), lacunes 18.5%,

ICH 15.5%, subarachnoid hemorrhages 4.5%, intermediate 9.5% and others 8%.

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From a clinical point of view, the temporal course of the localized stroke after cerebral ischemia

can be classified in different subtypes: 1. Transient Ischemic Attack (TIA) is disturbances of

localized neurologic function reversible within 24 hours. 2. Reversible Ischemic Neurologic

Deficit (RIND) is completely reversible within a few days up to a week. 3. Progressive ischemia,

neurological deficits increase in severity and extent within the first 48 hours from onset of

symptoms. 4. Completed infarction with stable neurological deficits lasting longer than 2-3 weeks

(6). ICH is characterized by demarcated bleedings from arteriolar eruptions with mass effect and

eventually blood breakthrough to the ventricles. ICH is the most serious stroke incidence with

the highest mortality rate (7). ICH clinically mimics the time course of progressive ischemia or

completed infarction and therefore should be confirmed by CT or Magnetic Resonance Imaging

(MRI).

1.2.2. Arteries of the brain

The internal carotid artery (ICA) splits into the anterior cerebral artery (ACA) and the middle

cerebral artery (MCA) (figure 1). The middle part of the frontal and parietal lobes are supplied

from ACA. The lateral part of the frontal, parietal and temporal lobes are supplied from MCA.

From the first part of the MCA, penetrating end-arteries supply the corpus striatum and part of

the internal capsule (the lenticostriate arteries).

The two vertebral arteries continue in the basilar artery that split into the two posterior cerebral

arteries (PCA). The PCAs supply the medial part of the temporal lobe and the whole occipital

lobe. They also supply the thalamus and the mesencephalon. The basilar artery supplies the

ventral part of the medulla, pons and mesencephalon. The dorsal part of the medulla, the pons,

the mesencephalon and the cerebellum is supplied by the cerebellar branches: The superior

cerebellar artery (SCA) and the anterior inferior cerebellar artery (AICA) both branches from the

basilar artery and the posterior inferior cerebellar artery (PICA), a branch from the vertebral

arteries.

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Figure 1. The large arteries of the brain(adapted from(6))

1.2.3. Anastomoses and collaterals

To understand the etiology of ischemic stroke, knowledge of the collateral blood supply is

essential. Collaterals form systems of physiological anastomoses constituting a safeguard to the

cerebral blood supply. Important anastomoses are formed between the external carotid and the

internal carotid siphon due to the facial-, angular- and especially the ophthalmic arteries.

Collaterals also exist between the vertebral artery and the external carotid, the external occipital

artery, the thyro-cervical trunk, leptomeningeal branches and in some individuals via the

pharyngeal artery. The vertebral and carotid supply areas are connected through the two posterior

communicant arteries connecting PCA with ICA. The PCAs and ICAs are connected to the

ACAs by the anastomosing Circle of Willis. Meningeal collaterals exist inter-hemispherically

between the ACAs and MCAs and intra-hemispherically between the supply areas of MCA, PCA

and ACA territories known as watershed or border zone areas. The direct penetrating end-

arteries of MCA and ACA are poorly collateralized, i.e. occlusion always leads to infarction.

Ophthalmic artery

ACA

MCAICA

PCA

Basilar artery

Vertebral artery

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1.2.4. Arterial anatomy and infarct types

The degree and extent of the infarct zone is defined by the lesion site and the presence and state

of the collaterals. This is essential if the lesions are related to small non-collateralized penetrating

arteries (microangiopathies) or to large cerebral arteries (macroangiopathies) or both. Infarcts

may lie in the supply area of an artery (territorial infarcts) or in the border region between the

supply zones of different arteries (extraterritorial infarction). Macroangiopathies cause impaired

hemodynamics due to decreased cerebral perfusion pressure (CPP) through embolism or local

thrombosis. Hemodynamically produced infarcts are seen as low-flow infarcts in the

distribution area of the non-collateralized part of the MCA (the lenticostriate arteries) or as

border zone infarcts in the supply areas of the large vessels in the parasagittal border zones and

parieto-occipital border zones (extraterritorial infarcts). Territorial infarcts, caused by embolism

or thrombotic occlusion, develop in the supply territory of large superficial arteries and are often

wedge-shaped and limited to the supply territory of the artery. If the collaterals supply the

marginal zones sufficiently, only a central infarct will develop. Occlusion of the lenticostriate end-

arteries is a subgroup of territorial infarcts (lacunar infarct), (figure 2). Microangiopathies are

caused by local thrombosis in the small non-collateralized, penetrating end-arteries, e.g.

lenticostriate arteries, known as lacunar infarcts (8).

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Figure 2. Influence of collaterality

Fromleft to right: Adequatecollaterality with no infarction. Collaterally proximal branch occlusion; theadditional

thrombosis leads to a lacunar infarct. Occlusion of a non-collaterally branch leadingto territorial infarct (adapted

from(6))

1.2.5. Occlusion mechanisms

The various vascular territories affected in cerebral infarcts correlate to different etiologies (6).

A. ICA occlusions are most commonly caused by thrombosis in an arteriosclerotic vessel, often

in the carotid bifurcation. However, clinical symptoms are not obligatory and are dependent

on the circulation in the circle of Willis, the retrograde flow of the ophthalmic artery and the

flow in the meningeal collaterals.

B. MCA occlusions are supposed to be caused by emboli. When the MCA is occluded proximal

to the origin of the deep lenticulostriate end-arteries, the infarction will involve the

lenticostriate artery supply area and part of the cortical and the subcortical region of the

territory of MCA, depending of the collateral blood supply. If the occlusion is in the distal

part of the MCA, the infarct will only involve the cortical region and the underlying white

matter. The volume of infarcted cortex and underlying white matter will depend on the

sufficiency of the cortical meningeal collaterals (8)

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C. Infarction in the supply area of the ACA, supposed to be caused by embolic occlusion, is 20

to 30 times less frequent than infarcts in the MCA territory. Infarction in the supply area of

the ACA involves cortical and/or subcortical tissue and is most frequently caused by an

embolus. The mechanisms determining the infarct topography are similar in the ACA and

MCA territories with deep end-arteries and superficial branches connected to meningeal

anastomoses.

D. The deep penetrating end-arteries of MCA and PCA can be occluded individually leading to

lacunar infarcts. These occlusions are due to local lipohyalinosis induced by hypertension or

thrombosis caused by arteriosclerosis. Because these arteries are end-arteries with no

collateral blood supply, occlusion will inevitable lead to infarction.

E. Occlusions in the vertebrobasilar arteries can be classified according to their locations. The

distal part of the basilar artery is the most frequent position often caused by an embolus.

Conclusions of the middle part of the basilar artery, in the transition region from the basilar

to the vertebral arteries, and large occlusions involving both arteries, are more often due to a

thrombus in the arteriosclerotic vessel. Cerebellum can be involved in brainstem infarctions.

Isolated cerebellar infarctions are caused by emboli in PICA in 50 % of the cases. Isolated

occlusions of SCA are often embolic while occlusions of AICA are thrombotic (9).

1.2.6. Reperfusion

The original pathological observations that proximal to the infarcts arterial occlusions were

missing, have been confirmed in studies showing spontaneous recanalization in serial

angiographies (9). The observed reperfusion rate depends on the time from onset of symptoms

to the first angiography and on the time between angiographies. The rate of spontaneous

reperfusion in the acute period relevant for induced thrombolysis appears to be less than 20%

(10). Spontaneous and induced thrombolysis is more effective to occlusions caused by an

embolus rather than a thrombus, because of the organization of the thrombus(8). This is not true

if the embolus is well organized as seen in rheumatic heart disease (8). It has been shown that

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reperfusion is associated with better clinical outcome and smaller size of the infarction (11),(12).

Partial reperfusion or embolus migration is known to occur in human stroke. If a proximal MCA

occlusion migrates distally in the supply territory, a cortical area rescued from infarction by

meningeal collateral blood supply collaterals can become infarcted when the migrated occlusion

is situated distal to the collateral anastomoses (figure 2). Reperfusion often leads to luxury

perfusion as discovered by Lassen (13) in 1966. Luxury perfusion (LP) is characterized by

decreased oxygen extraction fraction (OEF) by definition. LP explains the reddish venous blood

following neurosurgery on cerebral arteries and the fast flow seen on conventional angiography

following reperfusion. LP is often accompanied with hyperperfusion, then classified as absolute

LP. In relative LP, perfusion is normal or even decreased. LP is ideally investigated with PET, by

which OEF and perfusion can be measured.

1.2.7. Hemorrhagic transformation

Hemorrhagic transformation (HT) occurs in an ischemic infarct with bleeding in the necrotizing

cerebral tissue. The definition of HT includes development of petechial hemorrhagic infarction

(HI) and secondary intra-infarct hematoma (IIH). In HI, bleeding is petechial with blood

interspersed with intact brain elements. This is a result from increased permeability of the

capillary bed, caused by disruptions of endothelial junctions, which is known as diapedesis. In

IIH, brain parenchyma is destroyed. IIH is probably caused by vascular rupture dependent on the

intensity and duration of ischemia, thus explaining the predilection of IIH in the lenticostriate

artery supply area (14). The latter is difficult to differentiate from primary ICH (14). In

pathological studies of ischemic stroke, the frequency of HT has been found to be about 30%

(14;15). It is of prognostic importance if HT is of petechial type or is an IIH, with severe clinical

disability associated with IIH, not demonstrated in HI (16).

It has been thought that HT is caused by embolus fragmentation and reperfusion followed by

bleeding from ischemic damaged capillaries or arterioles (4). HT, however, occurs in spite of a

permanent occlusion. In that case, blood is supplied via a collateral leptomeningeal vessel (17). It

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has been hypothesized that reperfusion is neither necessary nor sufficient to cause HT, since the

incidence of HT is low in the human trials of thrombolysis with early recanalization (18). It was

suggested that early reperfusion actually prevents HT (18).

HT is most often seen within the two first weeks after debut of symptoms and is positively

correlated to the rate of reperfusion, collateral perfusion and infarct size.HT may be associated

with high blood pressure in the acute phase, age and anticoagulant therapy. Chronic arterial

hypertension does not seem to increase the incidence of HT (14;17).

HT due to IIH is the most feared complication of thrombolytic therapy in humans. The

important topic of identification and prediction of HT will be reviewed and discussed in relation

to MRI in section 3.2.8. and data will be presented in Chapter 4.

1.3. Pathophysiology of Ischemic Stroke

It has been known for several decades that brain tissue can remain viable during ischemia and

that functional deficits and cell death are not equivalent (19). This chapter reviews the

hemodynamics and cellular and biochemical events in focal cerebral ischemia.

1.3.1. Perfusion metabolism - coupling and uncoupling

Under physiological conditions, a coupling exist between the demand for oxygen and glucose by

the cells and the regional cerebral perfusion (rCBF) (20;21). During cerebral ischemia, the supply

of blood and therefore the supply of oxygen and glucose are decreased and energy demands may

not be met. The uncoupling process of rCBF and metabolism has been examined by PET in

several animal and human studies (22). The thresholds of rCBF and metabolism in ischemia are

reviewed in the following.

1.3.2. Thresholds of Ischemia

Ischemia of the brain is characterized by a series of thresholds. Each decrease of the rCBF relates

to essential pathological events (figure 3):

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Normal Cerebral Blood Flow

The normal range of CBF (45-55 ml/100g/minute) is maintained by the cerebrovascular

autoregulation: The pre-capillary resistance vessels dilate thereby increasing the cerebral blood

volume (CBV) in response to a decrease in the cerebral perfusion pressure (CPP). This is seen

distal to an obstructive embolus or thrombus.

Oligemia

Beyond the limit of maximal dilation a further decrease of CPP will decrease rCBF and the

oxygen extraction fraction (OEF) will increase to maintain normal cerebral metabolic rate of

oxygen CMRO2 this stage is called oligemia with rCBF in the range of 35-45 ml/100g/minute

(23;24).

Mild Ischemia

If rCBF is further reduced and compensation is no longer possible since the OEF is maximal,

CMRO2will decrease. rCBF in the range of 20-35 ml/100g/minute is called mild ischemia. The

neurons posses electrical activity at this stage, and tissue lactate is increased due to anaerobic

glycolysis. The effects of lactate are complex and still uncertain. It has been thought that lactic

acid in severe ischemia is responsible for necrosis of the ischemic tissue (25) but in mild ischemia

on the contrary can protect ischemic brain tissue against harmful effects of Ca ++-influx (26).

Lactate is supposed to be taken up by glia-cells from the extracellular space leading to a cellular

(cytotoxic) edema (27). The adenosine triphosphate (ATP) concentration is in the normal

range. The energy source is thereby sustained although a decrease of tissue phosphocreatin and

an increase of inorganic phosphate reflect an impaired energy capacity. This makes brain areas of

mild ischemia vulnerable to energy consuming events such as electrical DC charges (spreading

depressions), from the ischemic core (28). There is some evidence from animal models that

energy metabolism deteriorates although the mild ischemia is stable. This indicates that the rCBF

threshold for energy failure at which ATP concentrations are decreased increases with time in

mildly ischemic tissue (29).

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ModerateIschemia ElectricFailure

At rCBF between 10-20ml/100g/minute OEF, is elevated and CMRO2 is further decreased. If

CMRO2is below 1.4 ml/100g/minute, the tissue will become infarcted. Above this threshold, the

tissue outcome is uncertain, which is consistent with the concept of the penumbra (reviewed in

section 1.3.3) (22). In animal models, the electric encephalogram (EEG) is becoming isoelectric

corresponding to a cessation of neuronal electric activity and appearance of neurological deficits.

If rCBF is restored before energy failure occurs, the functional failure will reverse (30). The

energy source is sustained since the ATP content is in the normal range. The mechanism

underlying this potentially reversible functional failure is not fully understood, but it may reflect a

compromised neurotransmitter system (31). Associated with the threshold of moderate ischemia

and reversible functional electric failure, is extracellular release of the excitatory amino acids

(EAA) (glutamate and aspartate). Release of EAA induces intracellular Ca++ influx in channels

associated to the glutamate receptor N-methyl-D-aspartate (NMDA). If the intracellular energy

reserves are sufficient, this Ca++increase will be buffered and no damage will occur. However, if

energy consuming events such as spreading depression occur, the limit of the energy reserve

may be exceeded leading to a decrease of ATP i.e. energy failure and to harmful effects of

Ca++on the neurones (28).

SevereIschemia

If rCBF is less than 10-12 ml/100g/minutes, the tissue will become infarcted and CMRO2 and

OEF will decrease. This severe ischemia leads to increased extracellular K

+

and intracellular Ca

++

caused by failure of ATP dependent membrane pumps, (Na+-/K+-, Ca++- pumps). Normally,

these systems maintain the electrochemical gradients. Increased extracellular K+ can lead to

irreversible cellular injury by

1. Energy dependent depolarization spreading depression of neurons, leading to a further

increase of intracellular Ca++(28).

2. Stimulation of Na+/K+-ATPase of the endothelial cells of the vessels indirectly leading to

cytotoxic edema due to impaired Na+/K+ATPase level in the cellular membranes (32).

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3. Vasoconstriction impairing rCBF further (33).

Increased intracellular Ca++at the threshold of severe ischemia can not be buffered due to energy

depletion and therefore numerous events with irreversible damage on the membranes,

mitochondria and enzymes take place leading to cell necrosis (34).

Figure 3. Thresholds of ischemia (adapted from(35))

1.3.3. The Ischemic Penumbra

In focal ischemia, a rCBF reduction is rarely totally absent distal to the occlusion. Due to

collateral supply, rCBF ranges from normal to severely reduced (figure 4).

Regions between the rCBF thresholds for electric and ionic failure are characterized by reversible

functional failure if perfusion is restored in time. If not, initially viable tissues will deteriorate into

infarction. These regions of electrical failure with reversible functional failure are called the

ischemic penumbra (figure 4) (36). Another more recent definition is given: The penumbra is a

region of constrained blood flow with preserved energy metabolism, which contrasts the

SEVERE

100 50

80 40

60 30

40 20

20 10

I

S

C

H

E

M

I

A

MODERATE

MILD

OLIGEMIA

NORMAL

RANGE

CBF

ml/100g/minute%

Maintained by autoregulation;

higher CBF in gray matter

Increased O2extraction

may maintain normal CMRO2

? Glycolysis? Protein synthesis

Threshold of electrical failure

The Penumbra

Threshold of ionic failure

Anoxic depolarization

(ECF K+& ECF Ca++)

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ischemic core, being salvageable (37). A broader definition of the penumbra refers to the

ischemic tissue being salvageable by appropriate therapy (38). The latter definition is the one

adapted in the study presented in Chapter 6, where the potential of PWI and DWI predicting

salvageable tissue is investigated. The concept of the penumbra is essential for identifying the

potential of acute therapeutic intervention. The definition and pathophysiology of stroke and the

duration from onset of symptoms to treatment in human acute stroke are factors of investigation

and discussion (39). The existence of the ischemic penumbra has been documented by various

methods both in animal models of ischemia (36) and in human ischemic stroke, the latter by

different imaging modalities as reviewed in section 1.5-1.8. The rCBF range for the penumbra is

known to be around 10-20ml/100g/min in animal studies (36). The mechanisms by which the

ischemic penumbra deteriorates into infarct are not known. Studies have shown that the

penumbra deteriorates into infarction during stable low rCBF and that the rCBF threshold for

energy failure (ATP depletion) increases with time (40). This indicates that reduced rCBF is not

the only cause of infarct evolution in the penumbra. Other mechanisms in stable hypoperfused

tissues could be: a) exposure to the tissue of toxic plasma constituents due to early leakage of the

blood brain barrier, b) spreading depressions and c) interference of residual aerobic

metabolism by Ca++and lactate (41).

Little is known about the anatomic extent, biochemical features and time course in the human

ischemic penumbra, although studies with imaging modalities such as SPECT, PET and

functional MRI recently have shed some light on the natural history of human ischemic

penumbra as discussed in section 1.5-1.8 and 5.2.

Figure 4. Collateral flow and the Penumbra(adapted from (35))

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1.4. Medical Therapies for Ischemic Stroke

1.4.1. Thrombolytic Therapy

Efforts to treat acute stroke with thrombolysis are based on the observation that 80-90% of early

ischemic stroke is associated with thrombotic or embolic occlusion of a supplying artery (42).

Also the introduction of the ischemic penumbra has encouraged the prospect of a therapeutic

window for reperfusion therapy. Thrombolysis in acute ischemic stroke has been investigated in

several clinical trials using human recombinant plasminogen activator (rt-PA) (43;44) (45).

In the European Cooperative Acute Stroke study (ECASS), patients were randomized for rt-PA

or placebo within six hours from debut of symptoms. CT imaging exclusion criteria were early

infarct signs: hypointensity in one third of the supply area of the MCA, effacement of the sulci

due to edema or hemorrhage. Two groups of patients were chosen for evaluation. The Intention

to treat (ITT) group contained all patients included, whereas the target population (TP)

contained only patients in whom the protocol had not been broken. The most frequent cause of

breaking the protocol was inclusion of patients with early infarct signs on CT scan. In the TP, a

clinical effect of the treatment was seen. In the ITT group no clinical effect was seen. The

number of hemorrhages was significantly higher in both ITT and TP. Significantly higher

mortality occurred in the ITT population. The conclusion was that thrombolytic therapy was

effective in a selected population of patients, but because this selection was difficult using CT,

the treatment could not be recommended (43).

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group

(NINDS) examined the effect of rt-PA in stroke patients within three hours from debut of

symptoms. Patients with ICH on a CT scan were excluded. No significant effects were seen after

24 hours, but after three months, a significantly better outcome was seen in the rt-PA treated

group. A significantly higher incidence of symptomatic IIH was seen in the treated group but this

was out-weighted by the beneficial effects of treatment. It was concluded that, despite the higher

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incidence of symptomatic hemorrhages, rt-PA treatment given within three hours is effective. In

1996, rt-PA was accepted by the Food and Drug Administration in the USA for treatment of

ischemic stroke within three hours (44).

ECASS II was designed with a lower dose of rt-PA compared to ECASS (similar to NINDS),

strict blood-pressure control matching the NINDS criteria, and more strict application of the CT

exclusion criteria. Patients with symptoms within 6 hours were randomized in the study. The

incidence of IIH was increased in the treated group. The study did not confirm a statistical

benefit of rt-PA within 6 hours from onset of symptoms although it was stated that thrombolysis

using rt-PA in selected patients within 3 hours might improve the clinical outcome (45). Whether

thrombolysis should be given within 3 hours is still a matter of controversy (46).

1.4.2. Neuroprotective Therapy

The knowledge of pathophysiological events during ischemia and reperfusion have led to the

development of numerous drugs for neuroprotection in human ischemic stroke (41)

Substances hindering the damaging effects of excitatory amino acid release during ischemia

(such as glutamate) by 1) inhibition of glutamate synthesis, 2) blockade of glutamate release

and 3) postsynaptic receptor blockade (N-methyl-D-aspartate (NMDA)- and alpha-amino-3-

hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors) hindering the damaging

associated with Ca++influx. This group of compounds antagonizing the effect of EEAs is by

far the largest.

In addition to hindering effects from excitatory amino acids, an increasing number of methods

for neuroprotection in ischemia have been considered. Calcium channel antagonists, free radical

scavengers, hypothermia, hyperpolarizing cells by the inhibitory neurotransmitter GABA-

agonists, serotonin agonists, neurotrophic growth factors, anti-adhesion molecules, nitric oxide

inhibitors and agents interfering with apoptosis (47). None of these neuroprotective

pharmaceuticals although having convincing effects in animal models, have shown clinical effects

in trials or have had severe side effects leading to cessation of initiated trials. Several authors have

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1.6. CT in Acute Stroke

CT has been the method of choice in diagnostic evaluation of cerebrovascular diseases since its

introduction in the 1970s. CT image reconstruction relies on digital decoding of absorbed x-rays

measured in a slice. Images of the entire brain can be obtained in a few minutes. Due to artifacts

caused by contrast in the region of the part petrosa ossis temporalis, it is associated with major

difficulty to use CT for evaluation of infarcts in the brain stem (52).

CT images most often do not show the affected artery supply area or give information about the

degree of collateral blood supply. The localization or extent of the involved area or spontaneous

reperfusion can therefore not be determined using CT. Acute ischemic lesions are usually visible

after 24 hours. In 20% they are even visible as blurred, low intensity areas within the first eight

hours.CT identifies ischemic lesions, as hypointensities, 3mm in diameter at least in regions

above the part petrosa ossis temporalis. Hypointensity seen on CT is caused by an increased

water content, i.e., cytotoxic or vasogenic edema (53).

Special attention has been paid to the correlation of clinical outcome and early CT findings

within the first six hours, in thrombolytic trials. These findings are (54)

Effacement of sulci due to swelling from edema.

Loss of border between gray and white matter.

Relative blurring of especially the lentiform nucleus.

Findings on CT obtained before thrombolytic therapy have indicated

Early hypointensities indicate irreversible damage.

Hypointensity in more than one third of the supply area of the middle cerebral artery MCA

indicates a high risk of developing secondary hemorrhage leading to disability and death.

In the ECASS (43) these early findings were used as exclusion criteria, but were difficult to use;

i.e. they were the most frequent reason for breaking the protocol (thrombolysis started in patients

with early infarct signs). Some studies have questioned the role of early infarct signs for

predicting infarction. In a study of CT and PET, no direct correlation was found between CT

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signs and critically hypoperfused tissues (55). Although early infarct signs correlated with poor

outcome, some patients with early signs had good spontaneous outcome. Also some patients

with early findings did not develop infarcts. Incidence of HT after treatment by thrombolytic

therapy in the ECASS could, however, be predicted CT by early infarct signs" using (56).

However, CT is still much more widely available than MR and has been superior for detecting

hyperacute ICH within the first 6 hours, which is of paramount importance when stratifying

patients for thrombolytic therapies. CT is therefore still the method of choice for diagnosing

patients with stroke, although recent developments in MRI are very promising for detecting

hyperacute ICH as reviewed in section 3.2.3. (57;58).

Developments in CT include very fast acquisition using spiral techniques. CT therefore offers the

possibility of functional studies of the blood circulation using 133Xe as a tracer (59) although a bad

signal-to-noise ratio (SNR) and high sensitivity to patient movements hampers the clinical

assessment.Also, acquisition of CT images during a bolus injection of a contrast agent, has made

it possible to visualize the extra- and intracranial blood supplying vessels (60).

1.7. SPECT in Acute Stroke

Fast rotating multi detector systems have made the assessment of rCBF by SPECT possible. The

spatial resolution is reduced compared to PET and MRI. The tracers used for SPECT are

commercially available and instrumental and logistic demands are reduced compared to PET.

SPECT is more appropriate for clinical studies and clinical practice and has been applied to

human ischemic stroke studies and thrombolytic trials (61;62). SPECT is used for rCBF

measurements and receptor studies, of which only rCBF measurements in stroke studies will be

dealt with in this thesis. 133Xe is an ideal free diffusible tracer used in SPECT for absolute

quantification of the rCBF. The spatial resolution is low and requires a dedicated tomograph, why

only few studies of stroke patients have been performed. 99mTc-hexa-methyl-propylene-amine-

oxime (HMPAO) is a non-diffusible perfusion tracer. It is taken up and is fixed in brain tissue

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having a high first-pass extraction fraction with a distribution proportional to rCBF in normal

brain, although not quantifiable. The affected supplying artery can be determined visualizing

rCBF by SPECT (63). SPECT rCBF measurements are also valuable for answering the question

of spontaneous reperfusion resulting in normal or increased perfusion. In the patients treated

with thrombolysis, reperfusion can be documented by serial SPECT measurements (64),

increasing knowledge of which occlusions are sensitive to thrombolysis. SPECT has been applied

in clinical trials of thrombolytic therapy within three to six hours using HMPAO as tracer (61;62).

In two studies, the perfusion reduction determined by HMPAO-SPECT prior to thrombolysis

was used to estimate the risk of hemorrhagic transformation (62). In several studies, the rCBF

ratio between the infarcted and the healthy hemisphere has been calculated showing correlation

to the clinical course and tissue survival (61;65). Also in one recent study of intra-arterial

thrombolysis, a rCBF-index threshold was identified for predicting infarction or recovery (66). It

seems therefore possible to estimate if there is a penumbra and if thrombolysis can be considered

safe using SPECT with HMPAO as a tracer (68). However, one serious drawback of SPECT is

the inability to detect hemorrhages.

1.8. PET in Acute Stroke

With PET it is possible to obtain quantitative maps of rCBF, CBV, CMRO2 and glucose

metabolism in the brain (CMRGl): The patophysiological findings in normal and ischemic brain

tissue were reviewed in section 1.3. The rCBF and CMRO2allow calculation of the OEF. It is

possible to measure the pH in the brain tissue and to investigate numerous specific receptors in

the brain.

1.8.1. Findings of rCBF and metabolism in acute ischemic stroke with PET

Marchal et al. (67), (68) examined 30 patient with acute MCA stroke by PET and compared acute

findings of rCBF and CMRO2 to clinical outcome at 2 months. They identified three patterns of

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PET changes within 5 to 18 hours from onset of symptoms, into which each patient could be

classified:Pattern 1: Profoundly decreased rCBF and CMRO2suggesting beginning of necrosis.

All patients in this group had poor outcome.Pattern 2: Moderately to markedly reduced rCBF,

normal to little decreased CMRO2 and increased OEF. This pattern reflects ongoing ischemia

with still limited necrosis. The clinical outcome could not be predicted from pattern 2 ranging

from death to recovery. Pattern 3: Hyperperfusion, Luxury Perfusion, with normal or slightly

depressed CMRO2, reflecting early spontaneous reperfusion with only limited damage. All

patients in this group had a good clinical outcome. In conclusion: Pattern 1 and 3 were predictive

for clinical outcome. None of the two patterns can be used for thrombolytic therapy trials

because no positive effect would be obtained due to irreversible damage with increased risk of

HT in pattern 1 and spontaneous reperfusion in pattern 3. Effects from neuroprotection aimed

at avoiding reperfusion injury could be expected in the patients with pattern 3.The unpredictable

outcome of pattern 2 indicates that the ischemic tissue in this group only sometimes progressed

to infarction in agreement with the concept of the penumbra. This group of patients may

benefit in therapeutic trials. The fact that this pattern was observed up to 18 hours after debut

indicates that the time window of three to six hours should be reconsidered and be

individualized.

PET is considered to be the imaging technique that most significantly has increased the

knowledge of the pathophysiology of acute human stroke (22). PET being available in few

centers only, is complex to perform and has no clinically relevance as a pre-thrombolytic imaging

modality.

In summary, CT has proven clinically useful, especially for excluding patients with ICH. A

drawback is the missing information of the metabolism in the ischemic tissue. SPECT is a

potentially clinically available technique, but it provides information on rCBF only. PET is the

superior supplier of pathophysiological information in ischemic tissue. MRI and especially the

newer MRI-modalities, DWI and PWI, are promising for characterizing ischemic tissue and

recently also for detecting acute ICH. MR is the only mentioned imaging technique not relying on

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ionizing radiation. MR scanners have become widely available for clinical use in the last decade.

The new possibilities of MRI will be reviewed in chapter 3 and 5. But first the fundamentals of

MR and especially DWI and PWI will be reviewed.

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to the external field represents a more favorable, i.e. lower energy state resulting in a tiny net

magnetization in an ensemble of spinning nuclei. The distribution between low and high, energy

states depends on the strength of B0, and the temperature. The distribution is given by the

Boltzmann equation:

where n)and n+are numbers of nuclei in the two different states, kis the Boltzmann constant, )E

is the energy difference and Tthe temperature.

The magnetic moment of the nuclei will precess around the axis of theB0at a frequency given

by the Larmor equation:

where (is the gyro magnetic ratio characteristic of the nucleus under consideration.

Transitions between the low and the high energy states occur when RF energy at the frequency of

the precessing magnetic moment (the Larmor frequency) is applied to the ensemble of nuclei

(aligned alongB0). This transistion between spin-up and spin-down, occurs when the resonance

condition is fulfilled, referring to and the frequency of the applied RF pulse being identical.

This is the reason for the magnetic resonance.

)( TkEnn /exp/ =+ [ ]1.2

0B= [ ]2.2

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2.1.2. T1and T2 relaxation

When a RF pulse is applied at the Larmor frequency, the nuclei absorb energy and will thereby be

excited to a higher energy state where the net-magnetization is no longer parallel to the external

magnetic field B0. When the RF excitation stops, the nuclei will return to a lower energy state

dissipating the excess energy to the surroundings the so-called spin lattice relaxation

characterized by the time constant T1. After the nuclei are excited by RF radiation at the Larmor

frequency, they will all precess at the same frequency and at the same phase with the Larmor

frequency. In a homogeneous magnetic field, the transverse part of the net-magnetization will

decrease with time due to interactions between the magnetic moments. This process called

transversal relaxation, is also referred to as the spin-spin relaxation characterized by a time

constant T2. In practice the magnetic field is inhomogeneous due to hardware constraints and

local variation in the magnetic susceptibility. This causes the nuclei to precess at slightly different

frequencies. The resulting phase incoherence leads to a decrease of the transversal magnetization.

The time constant for signal loss caused by magnetic field inhomogenity and spin-spin interaction

is called apparent T2 or T2* relaxation. T2 and T2* relaxation differ due to different

environments in tissues and are therefore important factors influencing the contrast in MR

imaging as described in section 2.2.

2.1.3. Magnetic Resonance Imaging

MR images can be obtained by applying external magnetic field gradients in addition to the

homogeneous field B0. As seen by inspecting the Larmor equation, this will cause the magnetic

moments of the nuclei to precess at slightly different frequencies depending on position in space.

2D MR images can be acquired when magnetic field gradients are applied in two directions, the

phase-encoding and the frequency-encoding gradients. The slice thickness is adjusted by

matching a magnetic field gradient to the bandwidth of the slice-selective RF pulse. The concept

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of k-space is a convenient mathematical tool describing the acquisition of MR images: In a

conventional MR experiment e.g. 256 data points are sampled in the time domain covering one

line in of k-space the frequency encoding direction. The following lines, e.g. a total of 256, are

acquired by increasing the phase encoding gradient stepwise. The set of 256x256 data points in k-

space are then transformed to the frequency domain by a 2D Fourier transformation resulting in

a 256x256 point image.

2.2. Anatomical MRI Image Contrast

The contrasts of tissues in MRI are primarily due to differences in proton spin densities (PD),

longitudinal relaxation times (T1) and transverse relaxation times (T2). The PD contribution to

the MR signal varies up to 30% whereas T1 and T2 in the brain varies up to more than 100%

between gray and white matter compared to cerebrospinal fluid CSF (73). In pathologies these

changes of PD, T1 and T2 in tissues may be even greater. Tissue contrast derived from

differences in T1 relaxation is dependent on the strength of the applied field. T2 and PD

contrasts are less influenced by the field strength (73). Contrasts in conventional MR images are

based on combinations of PD and T1- and T2 relaxation. Changes of image contrasts can be

obtained by modifying the timing parameters TE and TR. TE is the echo time (the time between

the RF excitation and the refocusing of the spins) and TR is the repetition time of the MR

imaging sequence (time between two excitations of the same ensemble of spins).

2.3. Diffusion Weighted Imaging

Diffusion is a physical process important in many physiological functions. Transport of

metabolites such as oxygen and glucose from the capillaries through a liquid medium to the cells

relies on diffusion. Diffusive motion arises from intrinsic energy in the molecules leading to

random molecular motions. Diffusion is the flux of molecules along the concentration gradient,

as described by Ficks' law, which states that the flux is proportional to the concentration gradient.

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The constant of proportionality is called the diffusion coefficient (74). With no concentration

gradient the molecules are still diffusing but no net transport occurs. Traditionally, diffusion is

measured by the introduction of a tracer in the medium. The concentration of the tracer is

monitored using chemical or radio- tracer techniques. Use of a tracer gives a spatial resolution of

millimeters. Methods such as infra red spectroscopy or Rayleigh scattering allows a spatial

resolution of micrometers. These techniques, however, are invasive and may therefore perturb

the system studied. MR is the only non-invasive method that provides information of diffusive

motions in the range of micrometers (74).

In 1950 Hahn (75) discovered that the MR signal was influenced by diffusion. Carr and Purcell in

1954 (76) demonstrated that the diffusion effects on the MR signal are reduced when applying

multiple spin echoes in the MR experiment. In 1965 Stejskal and Tanner (77) introduced the

pulsed gradient spin echo method (PGSE), which improved MR diffusion measurements. The

methods have been extended to DWI and through the last fifteen years DWI has proven to be a

valuable tool for in vivostudies. In 1984 DWI was used for detecting ischemic lesions (78) and

today changes in water diffusion measured by DWI is established as a sensitive early indication of

ischemia as first proved for cats in 1990 (79), (80). By measuring the diffusion asymmetry

(anisotropy) DWI provides visualization of white matter tracts (81).

2.4. Diffusion measurements based on Magnetic Resonance

Molecular diffusion is random motions of molecules caused by thermal energy. The random walk

of a molecule leads to a net displacement increasing with time. Looking at an ensemble of

molecules initially located at a particular position, the spatial distribution for homogeneous,

unrestricted diffusion will be Gaussian, with a mean displacement of zero, because the probability

of displacements in every direction is the same (figure 5).

The expected value of the squared distance of displacements in three dimensions is proportional

to the time taccording to the Einstein equation:

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Dis termed the diffusion constant, and characterizes the mobility of molecules within a medium.

This means that the expected diffusion distance |r| increases with the square root of t.

The sensitivity of the MR signal to diffusion results from phase variations when the spins are

diffusing in an inhomogeneous magnetic field. A gradient pulse gives the spins a position

dependent labelling. The refocusing of the echo in the MR experiment will be incomplete due to

diffusion of the spins along the field gradient and the MR signal will be attenuated (figure 6). The

signal attenuation S/Sofor homogenous diffusion has an exponential dependence:

where bis a factor depending only on the magnetic field gradients and their timing, as given in

formula [2.9].

Figure 5. Diffusion - Gaussian distribution(adapted from(74))

)exp(/ 0 bDSS =

[ ]4.2

Dtr 62 = [ ]3.2

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where

The PGSE experiment offered several advantages to previous MR diffusion measurements: The

diffusion measurement time is known exactly and controllable in the PGSE experiment as ()!/3)

which gives the possibility of studying time dependent diffusion, which is valuable in biological

systems (83). Also, because the diffusion encoding gradients are turned off during data collection,

the diffusion encoding gradients can be increased along with the diffusion sensitivity without

inducing an increased acquisition bandwidth i.e. increased noise.

Finally with large amplitude Gand short duration, , of the pulsed gradients the residual B0field

inhomogenities will be negligible thereby allowing measurements of very low diffusion

coefficients (74).

Figure 7. The Pulsed Gradient Spin Echo experiment

[ ]7.2( ) )3/exp(/ 2220 DGSS =

[ ]8.2( )Db = exp

[ ]9.2( )3/222 = Gb

90 180 Echo

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Figure 8. Diffusion coefficient

2.4.3. Temperature effects

The diffusion coefficientDdepends on the temperature T. Within the physiological range (T=

32-42 C) the correlation of D and T is linear with an estimated 2.4% change in Dfor a 1%

change in the temperature (85).

2.4.4. Motion artifacts

Diffusion sensitive pulse sequences are highly sensitive to microscopic and macroscopic motions

from other sources than diffusion leading to severe artifacts in diffusion weighted in vivostudies.

Cardiac pulsation in the brain tissue and CSF, micro-circulation, breathing motions, head

translations and rotations with displacement in the order of micrometers all induce image

artifacts. Using phase contrast MR imaging, it has been shown that during the cardiac cycle, brain

tissue is displaced by 0.5 mm (86),(87). Cardiac gating should be used for acquiring DWI to

0 200 400 600 800 1000

b s/mm2

lnS

-D

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compensate for movements induced by the cardiac cycle. The phase shifts due to motion results

in ghosting artifacts and leads to signal attenuation and therefore misinterpretation of the

calculated diffusion coefficients. Phase shifts are pronounced when diffusion gradients with large

amplitudes are applied in a MR sequence. However, the average phase shift due to diffusion is

zero (intravoxel phase incoherence) (figure 9 top). For linear bulk motion (coherent translation in

a given spatial direction) a phase shift develops depending on the applied gradient strength and

the velocity of the spins. No changes in the signal amplitude happen, (figure 9 middle). Finally,

nonlinear motions (e.g. rotations and incoherent motions) lead to both phase shifts and signal

loss in every acquisition (figure 9 bottom) (88). Three approaches have been applied in reducing

motion artifacts: bipolar diffusion gradients, navigation in spin-echo sequences and high speed

imaging as now discussed:

Figure 9. Motion effects on net phase and the echo signal(adapted from(88))

Diffusion

Linear motion

Nonlinearmotion

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2.4.5. Bipolar motion compensating gradients

Linear bulk motion e.g. flow effects are dependent on the velocity of the spins and on the used

gradients and can be cancelled out by adding bipolar motion compensating gradients in the

diffusion weighted pulse sequence. Such gradients should be placed on each side of the 180RF-

pulse and should have identical Gt area. As an unfortunate side effect, the use of bipolar

gradients in diffusion weighted MR experiments with a fixed TE will reduce the effective

diffusion time and sensitivity compared to the unipolar diffusion weighting sequence (89).

2.4.6. Navigation

Different navigator echo techniques have been suggested for correction of linear velocity

motion in spin echo sequences (90) (91). These techniques use an additional echo acquired before

or after each spatially encoded echo. Any phase variation in the navigator echoes will be due to

motions along the gradient applied during navigator echo acquisition. Line-wise back rotation in

k-space can be performed using the individual navigator echoes. This retrospective modification

compensates for linear velocity of the head (figure 10). More advances techniques have been

developed, compensating for more complex motion patterns (92).

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diffusion coefficient is calculated as the slope when plotting the natural logarithm of the signal

attenuation versus the b values as expressed in formula [2.8] and illustrated in figure 8. The signal

attenuation depends on the diffusion distance obtained in the experiment. When the critical

diffusion distance for restriction has been reached, the signal attenuation will tend to level off as a

function of the b-factor as will the diffusion coefficient as shown in figure 12.

However, it has been shown that the measured diffusion coefficient in brain white matter is

independent of diffusion times longer than 20 ms (97). Several other studies indicate that there is

no effective hindrance to water exchange between the extra-and intracellular compartments (83),

(98).

This implies that restriction can not be the major mechanism explaining the acquisition-

dependence of the apparent diffusion coefficient measured in vivo.

Figure 12. Diffusion - signal attenuation isotropic(full line) in vivo (dotted line)

2.6.3. Hindered Diffusion tortuosity

Another mechanism to explain the concept of ADC is that of tortuosity introduced in studies

with external tracers and non-MR techniques (99). The observed molecule has to travel a longer

path because of obstacles such as axons and macromolecules, i.e. molecules have to diffuse

0 200 400 600 800 1000

0

-1

ln S

b

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water very fast in about 20-50ms (97). In DWI experiments, the diffusion time is essential for

determining which of two models describes diffusion signal attenuation. If the diffusion time is

short relative to the exchange time between the extra- and intracellular compartments, the

exchange should be considered slow. The expression for the diffusion attenuation then becomes

bi-exponential:

In most diffusion MR experiments the diffusion time is longer than the water exchange time and

the system observed is then a fast exchange system. The diffusion attenuation becomes a mono-

exponential function (83):

wherefinand fexis the intracellular and extracellular volume fraction respectively.

2.6.5. Apparent restriction

Moonen et al. (97) has showed that at diffusion times longer than 20 ms, the diffusion coefficient

does not change as a function of diffusion time because water exchange is relatively fast and

appears unrestricted. In this case, the diffusion coefficient should be considered as a fast

exchange system and is an average of intra- and extracellular diffusion coefficients. From studies

of Norris et al. (95), (98) it appears that when diffusion times are set very short (< 2ms) the signal

attenuation is bi-exponential signifying slow exchange between the two compartments as in

formula [2.13]. When diffusion time is intermediary, the diffusion seems restricted as determined

by the exchange rates between the intra- and extracellular compartments. This is known as

apparent restriction. The transitions between the different stages are shown in figure 14.

)exp()exp( exexinin bDSbDSS += [ ]11.2

( )( )exexinin DfDfbSS += exp0 [ ]12.2

C

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If the media observed is isotropic then Dxx=Dyy=Dzz and the diffusion coefficient can be

expressed as a scalarand the off-diagonal elements in the tensor are zero. If one of the axis in the

reference coordinate system used, is chosen parallel to the axons the diffusion tensor D is

described only by the principal diffusivities (Dxx, Dyy, Dzz), with all off-diagonal components of

the matrix being zero. In practice, the diffusion measurements are made in a laboratory reference

frame with axis along the applied diffusion gradients. These are not necessarily aligned to the

principal axis of the diffusion tensor and the D,of the laboratory reference, frame is related to

the diagonal Dby a rotation matrix. The matrix Dis symmetric,Dzx=Dxz,Dyx=Dxy,Dzy=Dyz, so

Dcan be calculated by applying only six different diffusion encoding directions instead of nine.

In recent years, the diffusion tensor has been shown to be measurable in vivoby diffusion tensor

imaging (101). A number of properties of the diffusion tensor are independent of the reference

frame and the rotation of the acquired tensor. If the purpose is to measure the average diffusion

coefficient without effects from orientation within the magnet, the most commonly the rotation

in-variant, is the diffusion trace, that is the sum of the diagonal components of the acquired D,

the directional mean of the diffusion coefficient. For imaging purposes in vivo, diffusion encoding

in only three directions are needed instead of the six needed to determine the entire tensor (102).

2.6.8. Values of ADC

In normal brain tissue, approximately 20% of the brain water is distributed in the extracellular

space and 80% in the intracellular space. The intracellular diffusion coefficient is lower than in

the extracellular space due to intracellular barriers as organelles, membranes and macromolecules.

In one study, van Zijl et al. (103) measured the diffusion coefficient in cell cultures and

determined the intra- and extracellular diffusion coefficients to Din= 1.43 x 10-4mm2/sec and

Dex =3.25 x 10-3 mm2/sec, respectively. Assuming free water exchange Benveniste (104)

proposed a model to calculate the macroscopic ADC in vivo. For use in formula [2.12], the value

(0.8 xDintracellular+ 0.2 xDextracellular) is 0.8 x 10-3mm2/sec. In the rat brain, the ADC is somewhat

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The most commonly used of these techniques is (1a): contrast agent bolus tracking also known as

dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). DSC-MRI was applied

in our studies and will be further described.

2.7.1. Contrast agents

Opposite to radioactive tracers, MR contrast agents are considered safe. Their effect is due to

paramagnetic properties causing shortening in T1 and T2 relaxation (further described below).

MR contrast agents containing gadolinium-chelates are approved for use in humans. Gadolinium

is a lanthanide metal being paramagnetic property due to seven unpaired electrons. Due to

toxicity gadolinium is chelated to different compounds: Gadolinium-DTPA (Dithylen-Triamin-

Penta-Acetiacid) is known as gadopentate and sold as Magnevist (Schering), DTPA-BMA

(DTPA-bismethylamide) known as gadodiamide and sold as Omniscan.

2.7.2. Vascular effects

The effect of MR contrast agents on T1 relaxation is caused by so-called dipole-dipole

interactions i.e. on direct interaction of protons in the water molecules with the dipole moment

of the unpaired electrons of the paramagnetic contrast agent. Gadolinium-compounds in the

brain are intravascular when the blood brain barrier is intact. T1 shortening produces signal

enhancement in the blood volume, that contributes about 5% of the total brain volume.

Susceptibility is a measure of the ability of a compound to become magnetized when subject to a

magnetic field thus increasing or decreasing the applied external magnetic field.

The intravascular paramagnetic contrast agents cause susceptibility changes and increase the local

external magnetic field. A magnetic field gradient between the lumen of the vessel and the

surrounding tissue is induced (figure15), thereby increasing the T2* relaxation rate and dephasing.

This effect on T2* relaxation extends beyond the blood vessel, thus generating relative large and

distant signal changes. The method is therefore more suitable for MRI perfusion measurements,

than the dipole-dipole effect changing T1 relaxation in the vessel only (106), (107). The signal

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Figure 15. Vessel size and susceptibility effects

Fromleft to right: small vessel, intermediatevessel, largevessel

2.7.3. Contrast agent bolus tracking

When tracking a bolus injection of paramagnetic contrast agent by fast imaging, the MRI signal

will drop transiently, due to the susceptibility effect when the gadolinium-compound passes

through the detecting plane (figure16). The bolus of 0.1-0.2mmol/kg is injected via the

antecubital vein (3-5ml/sec), using a power injector. With the availability of EPI, it has become

possible in the last five years to obtain the passage with high temporal (1-2 seconds) and high

spatial resolution (~1mm) by multislice imaging (6-11slices). 10-40 frames of baseline images

should be acquired before the bolus is injected increasing SNR ratio when calculating )R2*(see

formula [2.20]) (111). The TE should be long (60-75 ms) increasing the susceptibility sensitivity

(111).

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h(t),thefrequency distribution function, describing the distribution of transit times through the

VOI following an ideal instantaneous bolus.

R(t),theresidueimpulseresponsefunction i.e., the fraction of the bolus still present in the VOI at

time tfollowing a ideal instantaneous bolus.R(t)and h(t)arerelated by:

[2.16], represents the accumulated fraction of the bolus that has left the VOI. Formula [2.15]

state that after a instantaneous bolus,R(t)is the fraction of the bolus in the VOI at time - t.

AIF, thearterial input function,Ca(t), the concentration of contrast agent in the supplying vessel

to the VOI.

From these definitions Cvoi(t)is calculated as:

where

- CBFvoiis the perfusion in VOI,

-is the density of the tissue,

- kh is correcting for differences in hemotocrit in capillaries and large vessels.

=t

dhtH0

)()(

[ ] ( )tHdhtRt

== 1)(1)( 0 [ ]15.2

[ ]16.2

tRtCaCBFvoiktCvoi h ))()((/)( = [ ]17.2

dtRCaCBFvoikt

h )()(/0

= [ ]18.2

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Formula [2.17] states that Cvoi can be expressed as a convolution of the residue impulse

response function, R(t), and the arterial input function, Ca(t). To calculate CBFvoi, the arterial

input function Ca(t) and the Cvoi(t) therefore must be deconvolved determining the residue

response function R(t)and CBFvoi. Deconvolution is theoretically demanding with inherent

uncertainties in the estimated R(t),because the signal time curve in the artery and the tissue is

almost identical when using intravascular tracers. However, attempts of calculating the rCBF

have shown good agreement with values from PET measurements (114), (115). An accurate

estimate of the arterial input function is necessary but can be difficult to obtain due to partial

volume effects and bad SNR in EPI. Also it is assumed in the model that the bolus curve in the

VOI is not dispersed or delayed compared to the AIF, which is certainly not valid in ischemic

regions (116).

The CBVis expressed as:

Relative CBV can be estimated without knowledge of theAIF, assuming the same AIF to all

parts of the tissue. This approach has therefore often been applied in human studies.

For intravascular tracers used in DSC-MRI, the time concentration curve obtained in the VOI,

also depend on the vascular architecture. The first moment of the tissue concentration curve

differs from the true MTT (117). Calculating CBF by the central volume theorem [2.14], with

MTT calculated as the first moment of the tissue curve, is therefore wrong.

2.7.5. Concentration dependency

The concentration in the VOI Cvoiused in the calculation of the hemodynamics is related to the

change in T2*relaxation:

= dttCa

dttCvoik

CBV

h

)(

)(

Cvoik*R2*2T

1==

[ ]19.2

[ ]20.2

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kis the relaxivity constant.

Assuming the linear relationship [2.20] between the concentration of the gadolinium-compound,

Cvoi, and the change inR2*.)R2*is determined from the baseline signal S0, and SVOI(t),the

signal in the VOI at time t (118), (107), (119). TEis the chosen echo time:

[2.21], is valid for both the tissue and arterial input function, (however kmay differ).

2.7.6. Perfusion parameter maps

With the technical and practical difficulty of absolute quantification of perfusion using DSC-

MRI, various parameters derived from the )R2*time curve can been calculated. The time toR2*

peak, (TTP), the bolus arrival time (BAT), the peak height, the area under the )R2*curve (AUC)

(which is related the CBV) and the first moment of theR2*time curve used as an approximation

for the MTT. The interpretation, except for AUC = CBV is not straightforward because there is

no simple relation between these parameters and the rCBF. Also the parameters should be

normalized, because they vary depending on the vascular architecture, cardiac output, injection

rate and dose. In ischemia, the normal contralateral side will often be used for normalization of

the different parametric maps.

The effects of re-circulation can be eliminated either by considering only the first part of the

signal-time curve or by fitting the curve to