Background: Rare genetic mutations cause familial early-onset stroke disorders, known as “Mendelian strokes”. The broader relevance of rare mutations in unrelated young stroke patients is uncertain. We hypothesize that rare mutations in known and novel genes are important risk factors for stroke. Methods: Exome sequencing was used to characterize rare disruptive protein-altering mutations in 185 young cases and 185 matched controls from INTERSTROKE, a large and globally representative stroke study. The major objectives were: 1) to precisely define the role of known Mendelian stroke genes and 2) to discover novel gene and pathway associations. Results: A focused assessment of known Mendelian stroke genes revealed a significant contribution from NOTCH3, the causal gene for Cerebral Autosomal Dominant Arteriopathies with Subcortical Infarcts and Leucoencephalopathies (CADASIL). CADASIL mutations were identified in six cases and no controls (P=0.03). The clinical presentation of CADASIL mutation carriers deviated from known symptomatology, consisting of small-vessel ischemic strokes (SVIS) accompanied by secondary features including migraine and depression. A novel role for non-CADASIL NOTCH3 mutations in ICH was also elucidated (OR=2.86; 95% CI, 1.13 to 7.93, P=0.02). Such mutations were present in 22% of ICH cases and 8% of matching controls. An agnostic evaluation of all genes did not reveal any genome-wide significant associations. However, NOTCH3 was among the top ICH genes out of 13,706 tested, and many others were also biologically relevant, notably, AARS2 and NBEAL2. A protective association was identified for the renin angiotensin system (P=8.1x10-4), whereas type II diabetes mellitus was associated with increased risk (P=1.9x10-2). Conclusion: Rare mutations influence risk of early-onset stroke. CADASIL mutations play an important role in unrelated stroke patients. Beyond CADASIL, a novel role was uncovered for other NOTCH3 mutations as common and significant risk factors for ICH. Novel biologically relevant genes and pathways may also affect stroke susceptibility. / Thesis / Master of Science in Medical Sciences (MSMS)

Bakgrund: Stroke är ett sjukdomstillstånd som skadar hjärnvävnaden. Tillståndet innebär stora konsekvenser för de drabbade. De patienter som drabbats av stroke känner oftast skam och förtvivlan med en förlorad livsglädje som resultat. Idag upptar sjukdomsgruppen flest antal vårdplatser på sjukhusen runtom i Sverige. Med ökad kunskap i omhändertagande i kombination med stöttning för patienten efter insjuknandet, kan känslan av förlorad livskvalitet minskas markant. Syftet: Syfte med denna studie var att belysa patienters erfarenheter av att drabbas av stroke. Metod: En litteraturbaserad studie där 12 kvalitativa artiklar har analyserats. Resultat: Ur analysen av datamaterialet framträdde tre kategorier: Tappat kontrollen över sin kropp, Hamnar i beroendeställning och Återfå ett liv som självständig med åtta underkategorier. Slutsats: Studien bidrar med kunskap om patienters erfarenheter efter att ha drabbats av en stroke. Det kan vara omtumlande känslor att bearbeta för dessa patienter. Behovet av stöd är nödvändigt för att patienterna ska finna livskvalité. Motivation, hopp och uppmuntran stärker patientens självförtroende och leder till ett ökat välbefinnande. Genom en ökad förståelse för patientens upplevelser efter insjuknandet kan sjuksköterskan främja patientens hälsa och välbefinnande.

The study evaluated whether the activity of the indoleamine 2,3 dioxygenase (IDO) enzyme is increased post-stroke and contributes to the development of post-stroke depression (PSD) via tryptophan (TRP) depletion and neurotoxic kynurenine (KYN) metabolite production. The activity of IDO was measured using the KYN/TRP ratio. Participants were assessed for depression severity using the Center for Epidemiological Studies Depression Scale (CES-D). Blood TRP, KYN, large neutral amino acids and cytokines were measured and compared. Fifty-four (mean age=69.9±15.2, male=52.7%, mean NIHSS=7.3±4.6) patients within 28.9±40.3 days of stroke were separated into two groups: non-depressed (n=38, CES-D=6.1±4.9) and those with significant depressive symptoms (n=16, CES-D=26.8±10.8). Higher mean KYN/TRP ratios were demonstrated in stroke patients with depressive symptoms (non-depressed=69.3±36.9 vs. depressive symptoms=78.3±42.0, F3,50=4.61, p=0.006) after controlling for LNAA (p=0.026) and hypertension (p=0.039). As the KYN/TRP ratio reflects decreased TRP and increased neurotoxic KYN metabolites, both mechanisms may play an etiological role in PSD.

The study evaluated whether the activity of the indoleamine 2,3 dioxygenase (IDO) enzyme is increased post-stroke and contributes to the development of post-stroke depression (PSD) via tryptophan (TRP) depletion and neurotoxic kynurenine (KYN) metabolite production. The activity of IDO was measured using the KYN/TRP ratio. Participants were assessed for depression severity using the Center for Epidemiological Studies Depression Scale (CES-D). Blood TRP, KYN, large neutral amino acids and cytokines were measured and compared. Fifty-four (mean age=69.9±15.2, male=52.7%, mean NIHSS=7.3±4.6) patients within 28.9±40.3 days of stroke were separated into two groups: non-depressed (n=38, CES-D=6.1±4.9) and those with significant depressive symptoms (n=16, CES-D=26.8±10.8). Higher mean KYN/TRP ratios were demonstrated in stroke patients with depressive symptoms (non-depressed=69.3±36.9 vs. depressive symptoms=78.3±42.0, F3,50=4.61, p=0.006) after controlling for LNAA (p=0.026) and hypertension (p=0.039). As the KYN/TRP ratio reflects decreased TRP and increased neurotoxic KYN metabolites, both mechanisms may play an etiological role in PSD.

Stroke är den näst vanligaste orsaken till funktionsnedsättning och död i världen. Vid en stroke kan livet förändras plötsligt och medför ofta en stor omställning för individen. Syftet med litteraturstudien var att undersöka patienters upplevelse av att ha drabbats av en stroke, upplevelse av tiden på sjukhus i direkt anslutning till stroke. Litteraturstudien genererade elva vetenskapliga artiklar och vars resultat resulterade i fyra teman: Den oförutsägbara kroppen, Förlusten av identitet, I vårdarens händer och Viljan och hoppet om livet. Patienters upplevelser visar att god omvårdnad är anpassad utefter varje individ. Att drabbas av en stroke upplevdes som att mista sin självständighet, genom förlust av förmågor som medförde att patienter blev beroende av andra. Att bli beroende upplevdes som en svår situation och det skapade en känsla av att förlora sin kropp och identitet, då förmågor som tagits för givet var förlorade. Upplevelserna och behoven var individuella och bör utgå från varje enskild person. Genom att ta reda på hur patienter upplever att drabbas av en stroke kan det bidra till en ökad förståelse för enskilde individen och dess behov, vilket resulterar i en bättre omvårdnadskvalitet. / Stroke is worldwide the second common cause to disabilities and death. At a stroke life can sudden change and is often a great conversion for the individual. The purpose with this literature review was to investigate patients experiences of suffering a stroke, in directly connection to hospitalization. The literature review generated in eleven scientific articles that resulted in four themes: The unpredictable body, Loss of identity, In the hands of the caregiver and The will and hope of life. Patients´ experiences show that they consider the care as good when the care is custom along each individual. Suffering a stroke was experienced as a loss of independency, thru loss of abilities that resulted in that patients became dependent of others. To become dependent of others was experienced as difficult and it created a feeling of losing its body and identity, when abilities that were taken for granted was lost. The experiences and the needs from individuals should arise from each person. By investigating how patients experience the suffering of a stroke it could contribute to an increased understanding for the individual and its needs, which results in a better quality of nursing.

ABSTRACT   Aim: The aim of this retrospective study was to identify which indications prompted an MRI examination using the protocol ”Brain screening/Stroke” and whether the screening revealed recent infarcts and their localisation.   Method: The data, which was subtracted from RIS (Röntgeninformationssystem), covered all consultation responses from stroke-rounds performed during 2015 at Akademiska Hospital in Uppsala (UAS).  A total of 235 patients underwent an MRI-examination using the protocol ”Brain screening/Stroke”. Of this total population, 9 patients with a suspected or confirmed tumour were excluded. The information was collected at UAS during the period 11-22 April, 2016.   Results: No indications were reported from the material collected. Hence, the method was insufficient to give an answer to the question at hand. In the final selection of 226 patients, no stroke could be detected in 42 % of the cases, 23 % had recent infarcts, 21 % had both recent and old infarcts and 14 % had only old infarcts. By gender the results were as follows: Of the total population, 85 patients were female. In 48% of these cases no stroke was detected, 21 % had recent infarcts, 20 % had old infarcts and 11 % had both recent and old infarcts. The remaining 142 patients were male. In 38% of these no stroke was detected, in 27% of the cases both an old an a recent stroke were detected , in 24% of the cases a recent stroke was detected and 11% had only old infarcts. Looking again at the total population, the consultation responses mentioned only recent infarcts and where these were located. The majority of the recent infarcts detected, 23 % were located in the Lobes of the brain, followed by 16% in the Cortex of the brain, 16% in the Brainstem,  13% in the Cerebellum, 10 % were locaded in ”Other parts of the brain”, 8 % were in the Talamus, 7 % were in White matter and the final 6 % in the Basala ganglia. The total number of recent infarcts detected was 189. Conclusion: The main question for this study was to see if it was possible to discover acute infarcts, using diffusion weighted MRI, and the localisation of those discovered. The method chosen worked well, but to get a better overview, more studies should be done, examining infarcts in greater detail. This knowledge may, in turn, be used as a basis for stroke diagnosis. It might also be of interest to complete this study, with a more in-depth analysis of the connection between different kinds of infarcts and the patient’s gender and age.

Stroke is the third leading cause of death in the developed world and is the leading neurological cause of disability with a massive impact on personal life and society. Large artery atherosclerosis is one of the main causes of ischaemic stroke. However, in several aspects of this condition there is still a significant amount of uncertainty about its prevalence, appropriate investigation and possible treatment. Reliable data on epidemiology are therefore necessary to provide clinicians and researchers with crucial information to guide diagnostic and therapeutic management as well as further research. With this thesis I aimed to provide useful information about the prevalence of large artery disease in certain groups of patients, and to contribute to investigation- and managementstrategies using data from a large population based study, the Oxford Vascular Study (OXVASC). OXVASC is a prospective, population-based incidence study of vascular disease in Oxfordshire, UK, which started in 2002 and is ongoing. The study population comprises all 91,106 individuals registered with nine general practices and uses multiple methods of case ascertainment to identify all patients with vascular events. Firstly, I have shown that the prevalence of ≥50% vertebral or basilar artery stenosis in posterior circulation TIA or minor stroke is more than twice as high as the prevalence of ≥50% carotid stenosis in patients with carotid territory events, and is associated with a very high early risk of stroke of 22% and TIA of 46%. Furthermore, severe vertebral and/or basilar artery stenosis is associated with multiple TIAs at first presentation. Secondly, I have shown that early risk of stroke was higher after posterior circulation TIA, with a 1-year risk of 16%, than after carotid territory TIA, with a 1-year risk of 9%. In addition, I was able to show for the first time, that the ABCD2 score was predictive of early stroke not only in patients with carotid circulation TIA but also in patients with vertebrobasilar TIA. Thirdly, in a pilot feasibility study about arterial spin labelling magnetic resonance imaging in patients with large artery disease in the vertebrobasilar circulation I have shown that patients with severe large artery disease have significantly impaired occipital brain perfusion. My results suggest that this new technique might be a useful tool to identify suitable patients for interventional treatment of vertebrobasilar large artery disease. Fourthly, I was able to show that the risk of ipsilateral stroke and TIA in patients with an asymptomatic carotid stenosis is very low with contemporary best medical treatment alone, suggesting that routine carotid endarterectomy for asymptomatic carotid stenosis might not longer be feasible. Finally, I have clarified that lower rates of intervention for moderate to severe symptomatic carotid stenosis in women than in men can be explained by sex-differences in the populationbased incidence of carotid large artery disease and not due to under-investigation or reluctance amongst women to undergo investigation or treatment.

Bakgrund: Att drabbas av stroke i unga år innebär en stor livsförändring. Försämrad livskvalitét, nedsatt välbefinnande och påverkade relationer är några konsekvenser av att insjukna. Många får dessutom bestående funktionsnedsättningar som påverkar vardagen, såväl i hemmet som på arbetet. En stroke innebär ett trauma som är svårt att hantera för de drabbade individerna, sjukdomen ses som något som bara drabbar äldre. Tidigare studier visar att professionellt stöd till unga individer som drabbas av stroke är begränsat. Syfte: Syftet med studien var att beskriva unga kvinnors upplevelser av livet efter att ha drabbats av stroke. Metod: Analysmetoden som användes var en kvalitativ innebördsanalys av narrativa texter från sex bloggar, skrivna på svenska av kvinnor i åldrarna 26-45 år, bosatta i Sverige. Resultat: Unga kvinnor som drabbats av stroke upplevde att livet efter insjuknandet bestod av ett ständigt sökande efter mening och sammanhang. De fick genomleva mycket oförståelse och kände skuld och skam över att inte längre passa in. Kvinnorna upplevde brist på professionellt stöd och fick därmed stödja sig på sina anhöriga. Slutsats: Unga kvinnor som drabbats av stroke är i behov av stöd och rehabilitering. Omvårdnaden behöver bli mer person- och familjecentrerad för att minska lidande hos kvinnor som lever med konsekvenserna av stroke. / Background: Suffering a stroke at a young age is life-changing. Reduced quality of life and well-being, and impact on relationships are some of the consequences following the disease. Some people get permanent disabilities that affects everyday life, both at home and at work. A stroke often means a trauma that is hard to handle for the individuals, and the disease is seen as something that only affects older people. Previous studies show that professional support to young individuals suffering a stroke is limited. Aim: The aim of this study was to describe young women's experiences of life after having suffered a stroke. Method: This study was made with a qualitative meaning analysis of narrative texts from six blogs, written in Swedish by women, age 26-45, living in Sweden. Results: Young women experienced life following a stroke as a constant search for meaning and coherence. They had lived through a lot of misunderstandings and they felt guilty and ashamed because they no longer fit in. The women experienced lack of professional support and therefore had to rely on their relatives for support. Conclusion: Young women who have suffered a stroke are in need of support and rehabilitation. Nursing care needs to be more person- and family centered to minimize suffering in women living with the consequences of stroke.

Bakgrund: Fatigue (hjärntrötthet) är ett tillstånd som kan uppkomma till följd av exempelvis en stroke och förklaras som en extrem trötthet som inte går att vila bort. Detta är ett tillstånd som många gånger kan upplevas som ett problem efter en stroke. Syfte: Att belysa hur det är att leva med fatigue till följd av stroke. Metod: En litteraturstudie bestående av nio vetenskapliga artiklar med kvalitativ ansats genomfördes för att besvara syftet. Artiklarna kvalitetsgranskades och en innehållsanalys av artiklarnas resultat utfördes. Resultat: Post-stroke fatigue kunde upplevas påfrestande och inverkade negativt på livet. Sömn och vila tog upp mycket tid och nya rutiner krävdes för att orka med det vardagliga livet. Det blev svårare att upprätthålla samma sociala liv som tidigare. Informationen som gavs till patienterna upplevdes som bristfällig och vårdpersonalen kunde uppfattas okunniga om fatigue till följd av stroke. De personer som hade en ökad kunskap om fatigue kunde lättare hantera och anpassa sig till situationen. Slutsats: Att arbeta personcentrerat kan underlätta för att upptäcka vårdbehovet av fatigue. För att upptäcka vårdbehovet kan en större kunskap hos sjuksköterskorna behövas än vad patienterna upplever att de har. Kunskapen om post-stroke fatigue kan utökas genom att implementera det i sjuksköterskeutbildningen.

Stroke is the third leading cause of mortality in the United States, and so far, no clinical interventions have been shown completely effective in stroke treatment. Stroke may result in hypoxia, glutamate release and oxidative stress. One approach for protecting neurons from excitotoxic damage in stroke is to attenuate receptor activity with specific antagonists. Disulfiram requires bio-activation to S-methyl N, N-diethylthiolcarbamate sulfoxide (DETC-MeSO). In vivo, DETC-MeSO is further oxidized to the sulfone which is carbamoylated forming Carbamathione, a glutathione adducts. Carbamathione proved to be useful as a pharmacological agent in the treatment of cocaine dependence with the advantage that it lacks ALDH2 inhibitory activity. Carbamathione is a partial NMDA glutamate antagonist. The purpose of this dissertation study is to evaluate the neuroprotective effects of Carbamathione drug on PC-12 cell line and to understand the protective mechanisms underlying in three stroke-related models: excessive glutamate, hypoxia/reoxygenation and bilateral carotid artery occlusion (BCAO). Carbamathione was administered 14 mg/kg subcutaneously for 4 days with the first injection occurring 30 min after occlusion in the mouse BCAO stroke model. Mice were subjected to the locomotor test, and the brain was analyzed for infarct size. Heat shock proteins, key proteins involved in apoptosis and endoplasmic reticulum (ER) stress, were analyzed by immunoblotting. Carbamathione reduced both cell death following hypoxia/reoxygenation and brain infarct size. It improved performance on the locomotor test. The level of pro-apoptotic proteins declined, and anti-apoptotic, P-AKT and HSP27 protein expressions were markedly increased. We found that Carbamathione suppresses the up- regulation of Caspase-12, Caspase-3 and significantly declined ER stress protein markers GRP 78, ATF4, XBP-1, and CHOP. Carbamathione can down- regulate ATF 4 and XBP1 expression, indicating that Carbamathione inhibits the ER stress induced by hypoxia/reoxygenation through suppressing PERK and IRE1 pathways. Carbamathione elicits neuroprotection through the preservation of ER resulting in reduction of apoptosis by increase of anti-apoptotic proteins and decrease of pro-apoptotic proteins. Carbamathione can suppress the activation of both PERK and IRE1 pathways in PC-12 cell cultures and has no inhibitory effect on ATF6 pathway. These findings provide promising and rational strategies for stroke therapy. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection