Project

Stroke is the third leading cause of death in Sweden. Stroke is the leading cause of physical disability in adults. Many things affect the outcome of a stroke and, therefore, Karolinska Institutet researchers in Mission: Fight Stroke designed the world’s broadest research effort for dramatically improved treatment of acute stroke.The project is managed and conducted by Karolinska Institutet’s leading researchers in the field of stroke. Learn more about research team.

Investments in research will be done in five areas
• Find Stroke
• Open the Vessel
• Save the Brain
• Protect the Brain
• Secure the Future

Find Stroke means to quickly call 112 and that the emergency personnel faster and safer understand that someone is having or had a stroke. Open the Vessel involves research to develop diagnostics, refine tools and methods so that clots can be removed without risk of inflicting damage. Save the Brain does research to minimize the damage by finding the optimal balance between body temperature, blood sugar levels and blood pressure. Protect the Brain accounts for new treatments and drugs to protect the brain against damage of the blood-brain barrier. Secure the Futureinclude research and new knowledge of the atherosclerosis that are dangerous and can cause stroke. It also includes research on neurogenesis after stroke.

Aim
• Halve the number who die from stroke
• Double the number of survivors who manage without help

Learn more about each area in the left menu.

Find Stroke

Background
Every year approximately 30,000 patients suffer a stroke in Sweden. Today, there is efficient, evidence based treatment for ischemic stroke in patients arriving early after onset of stroke symptoms. Too few patients arrive to hospital in time for treatment. For many stroke patients, the first part of the chain of care is the telephone call to 112. Earlier studies related to calls to 112 revealed that the emergency operator can have difficulties in interpreting the information the person seeking help provides during the conversation. This places great demands on the communication between the parties. A tool (FAST-Face, Arm, Speech-Test) was implemented in the Emergency Medical Service (EMS) to enhance the identification but the effect of the tool is still unknown.

Aim
To improve the sensitivity and specificity of the instrument for early identification of stroke by 112 and ambulance staff.

Method
We will further investigate the sensitivity of the FAST test, and the component of the FAST test that optimally identifies the stroke patient at earliest possible time point. In an earlier study it was shown that less than half of the patients identified as stroke from the EMS were diagnosed as a stroke or TIA at the hospital. We need to study to what extent the FAST test was used, the validity of the three components of the test (asymmetry of the face, lowering of and arm and the ability to complete a sentence), and of the dispatcher’s or ambulance staff’s own clinical suspicion, to more accurately define if and how the test will work and if further tools are needed. We also need to further investigate patient registers, monitor calls and patient files to clarify how many patients were not detected, and how these could be identified in the future. Another part of this program is to study in detail a selected number of recorded conversations between the caller to 112 and the emergency medicine dispatchers, to identify components during the talk that raises the operator’s suspicion that this the call is about stroke.

Maaret Castrén
Professor of Emergency, Chief

Open the Vessel – clinical part (in Swedish)

Bakgrund
Om en blodpropp stänger av ett blodkärl i hjärnan kan detta få omedelbara effekter inom det område av centrala nervsystemet som kärlet försörjer. Neurologiska funktioner som styrs från det utsatta området drabbas och förlamningar, talsvårigheter och synfältsinskränkningar kan uppstå. Orsaken är att blodflödet inom området minskat i sådan grad att nervcellerna slutat att fungera. Energiberoende processer har upphört på grund av att allt syre som finns i blodet utnyttjats. Under en begränsad tid överlever cellerna, men under trycket av ökande mjölksyrabildning och kollapsande membranfunktioner börjar cellerna att dö och en hjärninfarkt uppkommer. Hur lång tid som förlöper mellan att cellerna upphör att fungera och att de dör beror på hur väl andra blodkärl, så kallade kollateraler, kan kompensera bortfallet blodflöde. Andra faktorer inverkar också, t.ex. blodtrycket, hemoglobinhalten i blodet, kroppstemperaturen och blodsockerhalten.

En ändamålsmässig åtgärd som kan vidtas i denna situation är att öppna det avstängda blodkärlet. De celler som fortfarande lever kan då återuppta sin funktion och celldödsprocessen upphör.

Sedan senare delen av 1990-talet har det varit känt att behandling med vävnadsplaminogenaktivator, tissue plasminogen activator (tPA), kan lösa upp blodproppar i hjärnan och ge omedelbar symtomlindring. Läkemedlet, alteplase, ges som ett dropp under en timme och har godkänts av europeiska läkemedelsmyndigheten. Ursprungligen bestämdes att behandlingen skulle ges inom 3 timmar efter insjuknandet till patienter under 80 års ålder. Senare forskning, där SITS givit avgörande bidrag, har visat att tidsfönstret kan utökas till 4.5 timmar och att även patienter över 80 års ålder har fördel av behandlingen. Det finns ett stort behov av fortsatt forskning om trombolys för att öka behandlingens effekt och säkerhet.

Erfarenheten av trombolys har visat att effekten av behandling av patienter med mycket allvarliga symtom vid insjuknandet oftast inte är fullt tillfredsställande. Även om trombolys medför förbättring kvarstår ofta ett betydande funktionsbortfall. Intresset för behandling där man avlägsnar blodproppen mekaniskt, trombektomi, har därför ökat snabbt och erfarenheterna hittills har varit övervägande goda. Många fallstudier med spektakulära resultat finns publicerade och överensstämmer med vår egen kliniska erfarenhet. Studier och register har visat på förbättringar jämfört med tidigare erfarenheter. På grund av avsaknaden av kontrollerade studier är behandlingen inte allmänt vedertagen och effekt och säkerhet är ofullständigt utforskade. Behovet av forskning inom detta område kan inte underskattas, eftersom metoden har förutsättningar att bli en helt central behandlingsform för de allvarligast drabbade patienterna.

Målsättning
Projektet syftar till att evidensbasera trombektomibehandling vid stroke och ge underlag för ändring av kliniska riktlinjer. I målsättningen ingår också att förbättra effekten och säkerheten av trombolysbehandling.

Arbetssätt
En internationell multicenterstudie av trombektomi som tillägg till trombolys kommer att genomföras med SITS-databasen som plattform. Utförliga data om patienter som behandlas med trombektomi på grund av en större blodpropp i hjärnan kommer att dokumenteras i databasen. Patienterna har initialt behandlats med trombolys enligt gällande riktlinjer och därefter har man gått vidare med trombektomi. SITS-databasen väljer sedan, enligt ett förutbestämt regelverk, ut en kontrollpatient med överensstämmande bakgrundsdata, för vilken man givit enbart trombolysbehandling. På detta sätt byggs två jämförbara grupper upp, en med trombolys + trombektomibehandlng, en med enbart trombolysbehandling. Frågeställningen är om patienterna med kombinationsbehandlingen har en bättre funktionsstatus efter tre månader utan att behandlingsrisken ökar.

Förutom denna studie kommer forskning avseende bland annat blödningsrisk vid trombolys, förbättrat urval av patienter för trombolys, och samband mellan tid till behandling och behandlingsresultat att utföras.

Nils Wahlgren
Professor i Neurologi, Överläkare

 

Open the Vessel – experimentel part

Background
Imaging technology is of great importance for the new diagnostic- and treatment options for acute stroke. When a patient is admitted with acute stroke symptoms, a series of imaging tests are performed to determine what type of stroke that occurred, where in the vascular tree a possible blood clot is located and if there is brain tissue that can be saved with by clot-dissolving therapy or mechanical clot removal. Furthermore, with the aid of X-ray techniques, one can navigate inside the vessels with thin plastic tubes, called microcatheters, to perform mechanical clot removal, but also to selectively inject substances or cells to a brain region affected by stroke. X-ray and magnetic resonance imaging techniques have great potential in these respects and this part of the UBS project aims to in an experimental setting develop and refine imaging techniques for both diagnosis and treatment.

Aim
The project has access to a state of the art laboratory for development and evaluation of both magnetic resonance-, computerized tomography- and microcatheter-techniques. Thus, with the help of experimental models, we can refine the diagnostic methods underlying the choice of treatment for acute stroke. We can develop the optimal method for mechanical clot removal in different situations and we can also develop new microcatheter-based techniques for e.g. cell therapy in stroke.

Method
This part of the UBS project aims to optimize imaging-based diagnosis and treatment of stroke. Imaging techniques have during the last 5 years had a very important role for the new concepts of treating stroke but the technology’s potential is far from exploited. From the studies in this part of the project, we want to be able to offer the patients individualized treatment based on diagnostic criteria and also to provide new therapies in the acute- and subacute phase of stroke.

Staffan Holmin
Associate Professor of Clinical Neuroscience, Neuroradiolog

 

Save the Brain – blood pressure and blood sugar

Background
Scientific studies have clearly shown a relationship between high blood pressure, high blood sugar and elevated body temperature and the risk of suffering a stroke. One or more of these risk factors may also pose an increased risk of death, more severe paralysis, and bleeding complications. Surprisingly, newly developed results show that there may be reason to be much more active when it comes to treating these risk factors, to reduce the damaging effects of stroke, than current guidelines recommend. We therefore now will further and in great detail identify the importance of these risk factors, both individually and in combination, and above all elucidate how an active treatment of them affects the course of disease in stroke.

Aim
Sub-goal of these studies is to identify in detail the importance of the risk factors high blood pressure, high blood sugar and elevated body temperature, partly individually and partly in combination, and above all clarify how an active treatment of them affect the course of disease in stroke. Since these risk factors have already been shown to affect disease progression in stroke more than unfavourably, our well-founded belief that these studies will lead to better treatment strategies resulting in reduced mortality and loss of function (e.g. paralysis) in stroke patients.

Method
We will employ a broad approach in these studies and plan both ongoing registry studies (in the so-called SITS registry), clinical patient research with ways to actively treat high blood pressure, high blood glucose and elevated body temperature, similar studies in animal models to identify mechanisms of damage and treatment gains, and cell and molecular biological studies to identify future drug targets against stroke.

Nils Wahlgren
Professor of Neurology, Chief

Åke Sjöholm
Professor of Experimental Endocrinology, Chief

 

Skydda hjärnan – kliniska delen (in Swedish)

Bakgrund
Blödning och svullnad, ödem, är vanliga komplikationer till hjärninfarkt oavsett om trombolysbehandling givits eller inte. Trombolysbehandling kan göra blödningarna allvarligare och förvandla ett mindre allvarligt blödningsinslag till en större expansiv hjärnblödning. Forskning inom Ulf Erikssons grupp har nu visat att en tillväxtfaktor, PDGF-CC, kan aktiveras av vävnadsplasminogenaktivator som används som behandling för trombolys. Aktiverat PDGF-CC kan i sin tur aktivera en receptor i kärlväggen, PDGF-α, som öppnar barriären mellan blodkärl och hjärna och släpper igenom blodkroppar och vätska. Forskningen har också visat att imatinib, ett läkemedel som används mot vissa former av blodcancer, kan blockera denna effekt. Experimentella studier av stroke på försöksmodeller har visat att imatinib kan minska blödning och ödem i samband med hjärninfarkt. Syftet med den kliniska delen av projektet är att pröva säkerheten med denna behandling hos strokepatienter och studera tecken på effekt i form av minskad frekvens blödningar och mindre utbredning av ödem.

Målsättning
Målsättningen med denna studie är att bedöma om det föreligger säkerhetsproblem vid behandling med imatinib vid stroke. En ytterligare målsättning är att avgöra om det finns tecken i form av minskat ödemförekomst och blödningsfrekvens som kan tala för att imatinib har den skyddande effekt som man noterat i försöksmodeller. Om studien visar att behandlingen är säker, planeras en utvidgning till en större studie via SITS-registret.

Arbetssätt
En klinisk prövning har inletts för att utvärdera säkerheten och effekten av imatinib vid akut stroke. Patienter som har minst måttligt allvarliga stroke och behandlas med trombolys enligt gällande riktlinjer kan tillfrågas om deltagande i studien. Vid medgivande avgörs genom randomisering (lottning) om patienten får behandling med imatinib eller ingen behandling utöver trombolys. Behandlingen ges under 5 dygn. I ett inledande skede används en dos av 400 mg dagligen, därefter ökas dosen i två steg till 800 mg. En oberoende säkerhetskommitté avgör utifrån tillgängliga data om det finns några säkerhetsmässiga hinder att öka dosen för varje steg. Resultatet bedöms enligt förekomst av allvarliga eller intolerabla biverkningar (obehag) samt förekomst av ödem och blödning.

Nils Wahlgren
Professor i Neurologi, Överläkare

 

Protect the Brain – experimentel part

Background
Already within a few minutes following the occlusion of a blood vessel by a thrombus, injuries to the brain can be observed. These injuries are caused by the lack of a normal supply of oxygen and nutrients. Simultaneously, an injury develops in the blood vessels surrounding the occluded area. In brain, the innermost layer of the blood vessels, the endothelium, forms a tight barrier, the so-called blood-brain barrier. This barrier function in the endothelium separates the blood and its constituents from the brain. The underlying reason for this is that blood contains substances that are incompatible with normal functions of the brain. Following a stroke, the blood-brain barrier becomes compromised and blood plasma constituents start to leak into the brain tissue, and in extreme case even red blood cells can leak from the blood vessels. The reason underlying the loss of normal blood-brain function in stroke has remained unknown. Together with American collaborators, we have now showed in animal studies that an endogenous protein, a growth factor called PDGF-CC, has a major role in this process. We have also shown that inhibiting the normal action of PDGF-CC in stroke, and thereby preventing the loss of normal blood-brain function, we can limit the stroke-induced injuries to the brain otherwise seen.

Aim
Our aim is to increase our knowledge, and provide us with new tools to regulate blood-brain barrier function in stroke, and thereby protect the brain from stroke-related injuries. We are already now clinically testing a drug that prevents blood-brain barrier dysfunction in stroke patients within the framework of the Fighting Stroke Project.

Method
We will continue to study the molecular mechanisms that control the integrity of the blood-brain barrier and how the growth factor PDGF-CC can compromise blood-brain barrier function in stroke. These studies will give us an increased understanding of the molecular events that underlies normal blood-brain barrier function in health and disease.

Ulf Eriksson
Professor of Vascular Biochemistry

 

Secure the Future – regeneration

Background

The symptoms after a stroke are caused by the damage to or loss of neurons. It was long believed that neurons could not be generated in the adult brain, but it is now well established that some neurons are generated from stem cells in the adult brain. Studies in experimental animals have established that stroke increases the generation of new neurons, which may contribute to the replacement of some lost neurons and some recovery. It is, however, not known whether new neurons are generated in response to stroke in humans, and we aim to establish whether that is the case.

Aim
The long term goal is to develop strategies to promote the replacement of neurons in patients after stroke.

Method
We measure the age of neurons in the adult human brain by measuring the level of 14C in DNA. 14C was generated at high levels by nuclear bomb tests during the Cold War, and the levels in the atmosphere have gradually decreased since the early 1960s. By measuring the level of 14C we can establish the age of cells and assess whether new neurons have been generated after stroke.

Jonas Frisén
Professor of Stem Cell Research

 

Secure the Future – experimentel part

Background
Release of blood clots and tissue material from unstable atherosclerotic plaques in the blood vessels of the neck is a major cause of stroke. Prevention of stroke is therefore obtained by surgery and removal of the unstable lesion in the blood vessel. Today, there are no clinical methods available for the identification of unstable atherosclerotic plaques.

Aim
The aim of this project is to identify central mechanisms and critical molecules in the biology of atherosclerosis that are involved in plaque instability, plaque rupture and stroke. The identification of such factors may be used in the development of future methods through diagnostic blood tests and diagnostic imaging that can identify patients with dangerous atherosclerotic plaques in the blood vessels and thereby be used for the prevention of stroke.

Method
The project is based on the examination of blood and plaques retrieved from patients undergoing surgery for unstable and stable atherosclerosis in the carotid artery at the Department of Vascular Surgery, Karolinska University Hospital, Stockholm. Patient material is investigated using high-technology methodology for analysis of structure as well as expression of genes and proteins in collaboration with Mathias Uhlén and Jacob Odeberg and the HPR project at the Royal School of Technology. New target molecules for plaque instability will thereafter be tested in animal models for the development of new diagnostic imaging methods

Ulf Hedin
Professor of Experimental Vascular Surgery