Many current drugs for stroke act by targeting circulating molecules, yet these have not been exhaustively evaluated for therapeutic potential. A central challenge is that while many molecules correlate with stroke risk, only a subset cause stroke. To disentangle causality from association, a statistical genetics framework called “Mendelian Randomization” can be used by integrating genetic, biomarker, and phenotypic information. In Study 1, we screened 653 circulating proteins using this technique and found evidence supporting causal roles for seven proteins, two of which (SCARA5 and TNFSF12) were not previously implicated in stroke pathogenesis. We also characterized potential side-effects of targeting these molecules for stroke prevention and did not identify any adverse effects for SCARA5. The remaining two studies focused on investigating the role of an emerging marker of mitochondrial activity, leukocyte mitochondrial DNA copy number (mtDNA-CN). Mitochondria have long been known to play a protective role in stroke recovery; however, a mitochondrial basis for stroke protection has not been extensively studied in humans. In Study 2, we first sought to better understand the genetic basis of mtDNA-CN in a series of genetic association studies involving 395,781 UK residents. We identified 71 loci which represents a 40% increase in our knowledge. In Study 3, epidemiological analyses of 3,498 acute stroke demonstrated that low mtDNA-CN was associated with higher risk of subsequent mortality and worse functional outcome 1-month after stroke. Furthermore, Mendelian Randomization analyses corroborated a causative relationship for the first time, implying that interventions that increase mtDNA-CN levels in stroke patients may represent a novel strategy for mitigating post-stroke complications. Ultimately, this work uncovered several novel therapeutic leads for preventing stroke onset and ameliorating its progression. Future investigations are necessary to better understand the underlying biological mechanisms connecting these molecules to stroke and to further interrogate their validity as potential drug targets. / Thesis / Doctor of Philosophy (PhD) / Current stroke medications work by targeting circulating molecules. Our aim was to discover new drug candidates by combining genetic and circulating biomarker data using a technique called “Mendelian Randomization”. In Study 1, we screened 653 circulating proteins and found evidence supporting causal roles for two novel candidates, SCARA5 and TNFSF12. Prior experimental studies suggest an important role for mitochondria in stroke recovery. Accordingly, in Study 2, we characterized the genetic basis of an emerging biomarker, mitochondrial DNA copy number (mtDNA-CN). Analyses of 395,781 participants revealed 71 associated genetic regions, representing a 40% increase in our knowledge. In Study 3, we measured mtDNA-CN in 3,498 acute patients and observed that lower levels predicted elevated risk of worse post-stroke functional outcomes. Furthermore, Mendelian Randomization analysis suggested a likely causal relationship. Overall, this work uncovered several novel therapeutic leads for preventing stroke onset and progression that warrant further investigation to verify therapeutic utility.

Introducción: Los eventos cerebro vasculares son una de las principales causas de mortalidad a nivel mundial y la actual pandemia por la COVID-19 ha producido un gran impacto en la atención de estos pacientes. El objetivo es describir las características de los pacientes con evento cerebro vascular en pacientes hospitalizados con COVID-19 en un hospital peruano de referencia. El Estudio. Estudio retrospectivo, se incluyó a pacientes mayores de 18 años hospitalizados con el diagnostico de COVID-19 y evento cerebro vascular. Hallazgos. Se incluyeron 26 pacientes con ECV y COVID-19, la edad promedio fue 69.8 años y la mediana del tiempo de admisión fue 24 horas. La mortalidad fue elevada (42.3%) y estuvo asociada a la edad y al compromiso respiratorio por COVID-19. La mayoría de sobrevivientes obtuvieron un pobre resultado funcional. Conclusión. Es necesaria la mejora en los procesos de atención para así realizar un diagnóstico precoz y un tratamiento oportuno.

Thesis (M.A.)--Boston University

Cerebrovascular burden (CVB) is a significant factor among the aging population. Age-related cognitive decline is an important social and economic issue, and understanding the mechanisms has clinical implications, both in selecting potential therapies and in choosing specific modifiers for their evaluation. In summary, past work suggests that high CVB is one source of variance in neurovascular functioning among older adults. High CVB and associated brain-changes have been identified as causes of age-related changes and it may be that high CVB is a correlate of age-related changes in sleep quality. The primary hypothesis to be tested is that cerebrovascular burden measured using an index variable reflecting blood pressure, resting heart rate, and blood oxygen saturation, will predict subjective sleep quality in a sample of adults over age 70. Sleep quality was measured using the Pittsburgh Sleep Quality Index. A sample of 8 dementia-free, community dwelling participants over the age of 70 completed the study. Though individual cerebrovascular risk factors (blood pressure, resting heart rate) had moderate but non-significant correlations with sleep quality, only the CVB index variable significantly related (1-tailed) to sleep quality. Findings support the hypothesized relationship. Future research should seek to replicate these findings with a larger sample, and to identify mechanisms by which this relationship may function.

Stroke, or cerebrovascular accident (CVA), is a prominent cause of long term disability in the United States. It has been evidenced that the outcome of a CVA patient differs as a function of the cerebral hemisphere that is damaged by the stroke, especially in terms of emotional changes. The Right Hemisphere Model of Emotion posits that the right hemisphere is specialized for processing emotional content, regardless of valence. In contrast, the Bi-Hemispheric Model of Emotion posits that each hemisphere has its own emotional specialization. The current experiment tested the competing predictions of the two theoretical perspectives in a mixed sample of left cerebrovascular accident (LCVA) patients and right cerebrovascular accident (RCVA) patients using a Dichotic Listening task and the Affective Auditory Verbal Learning Test (AAVLT). Heart Rate (HR) and Pulse Oxygen Saturation (SpO2) were also recorded as sympathetic measures. It was expected that the predictions of the Bi-Hemispheric Model would be supported. A series of mixed design ANOVAs were used to analyze the data. Results revealed that both groups may have exhibited decreased auditory detection abilities in the ear contralateral to CVA location. Additionally, CVA patients recalled significantly more positive words, than negative or neutral words, and exhibited a significant learning curve. LCVA patients exhibited a recency effect, while RCVA patients exhibited a heightened primacy effect. Findings from HR and SPO2 measures suggested a parasympathetic response to neutral information as well as an impaired sympathetic response to negative information in RCVA patients. Taken together these results lend partial support to the hypotheses drawn from the Bi-Hemispheric Model of Emotion, as evidenced by the diametrically opposite effects in these groups, which appears to reflect opposing cerebral processes. / Ph. D.

Thesis (MPhil (Interdisciplinary Health Sciences. Speech-Language and Hearing Therapy. Centre for Rehabilitation Studies))--University of Stellenbosch, 2007. / Current emphasis for rehabilitation in South Africa remains on individual intervention within the move towards primary health care. Primary health care is the strategy that has been adopted by the South African department of health to bring access and equity in health care services. Even so, the burden of providing effective rehabilitative services with limited resources requires innovative strategies, such as the use of therapeutic groups, to address certain aspects of rehabilitation. These strategies must be proven effective. There is a paucity of literature detailing the uses of group therapy in physical rehabilitation, and particularly the use of interdisciplinary group work in stroke rehabilitation. Furthermore, evidence shows that stroke survivors feel ill equipped to return to their communities despite rehabilitation. Stroke is a major cause of death and disability in South Africa, and is a condition shown to benefit from rehabilitation. These factors led to the selection of the Bishop Lavis Rehabilitation Centre stroke group as the setting for this study, which aims to describe the range of experiences relating to attendance or non-attendance of those referred to this programme. This descriptive study, employing quantitative means (to describe the demographic details of the participants) and qualitative means (to describe the experiences of participants), was conducted with twenty participants. Data was collected by means of an administered questionnaire. Following that, a focus group discussion involving six participants was used to gather in-depth information. Quantitative data was analysed with the assistance of a statistician, utilising the computer program, Statistica. The Chi-Squared, Kruskal-Wallis and ANOVA tests were used, with p>0.05 showing statistical significance. Qualitative data was thematically analysed, whereby data was categorised by means of an inductive approach. The study population consisted of 20 participants, with an average age of 59 years, of whom 15 were female and five male. The stroke group provided meaning to participants on two levels. On a psychosocial level, the phenomena of universality (identifying with others in a similar position), development of socialising techniques, imparting information and cohesiveness emerged strongly. On the level of meaning related to stroke recovery, improvement in ability to execute activities of daily living, mobility and strength were most frequently mentioned. Transportation issues were most commonly mentioned as factors negatively influencing attendance. Staff attitude and activities of the programme were most often cited as positive factors. Given the positive response of study participants, and the programme’s ability to sustain intervention with limited resources, it was concluded that this programme has a valid place within stroke rehabilitation in Bishop Lavis. Recommendations in terms of the group programme included investigating methods of providing transportation, providing childcare facilities and expanding the content of educational sessions. Further recommendations were to maintain the positive attitude of staff and the current activities of the programme. Frequency of group outings should also be increased and compensatory strategies for inclement weather must be explored.

Introdução e Objetivos: A craniectomia descompressiva com duroplastia (CDD) reduz a mortalidade e melhora o prognóstico funcional em doentes com acidente vascular encefálico isquêmico (AVEi) hemisférico e proporciona a redução da pressão intracraniana. Entretanto, pouco se sabe sobre sua repercussão na hemodinâmica cerebral. O objetivo do presente trabalho é o de avaliar com a tomografia computadorizada com estudo de perfusão (TCP) as alterações hemodinâmicas nos doentes com AVEi após a CDD e identificar possíveis marcadores prognósticos substitutos. Métodos: Foram avaliados 27 doentes com AVEi com indicação de CDD. Os parâmetros hemodinâmicos da TCP estudados no período pré-operatório e em até 24h após a cirurgia foram: duração média de trânsito (DMT), volume sanguíneo encefálico (VSE) e fluxo sanguíneo encefálico (FSE). O desfecho primário utilizado foi a melhora ou a ausência de melhora hemodinâmica. Os desfechos secundários foram a escala de Rankin modificada em seis meses, dicotomizada como favorável (0-3) ou desfavorável (4-6); casos fatais em um mês e em seis meses. Resultados: 18 (70,3%) doentes eram do sexo feminino e 12 (44,4%) tinham idade superior a 55 anos. Houve melhora da DMT (queda de 8,74 para 8,24, p=0,01) e tendência a melhora do FSE (aumento de 22,37 para 25,26, p=0,06) após a CDD. Não houve diferença estatística em relação ao VSC (aumento de 2,14 para 2,26, p=0,33). A idade superior a 55 anos foi o preditor independente de prognóstico desfavorável (p=0,03) e a DMT pré-operatória, foi preditora hemodinâmica para mortalidade em seis meses (8,20 vs 9,23, p=0,04). Conclusões: A craniectomia descompressiva com expansão dural determinou melhora hemodinâmica na maioria dos doentes com AVEi hemisférico. A DTM préoperatória é um bom marcador substituto para a possibilidade de óbito em seis meses / Background and Objectives: Decompressive craniectomy (DC) reduces the mortality and improves the functional outcome in patients with malignant cerebral infarction (MCI). This procedure causes a decrease of the intracranial pressure, however, little is known about its impact in brain hemodynamics. Therefore, our goal is to study through CT perfusion the hemodynamics changes that may occur in patients with MCI after the DC. Methods: 27 patients with MCI treated with DC were studied. The CT perfusion hemodynamic parameters - the mean transit time (MTT), the cerebral blood volume (CBV) and cerebral blood flow (CBF) - were evaluated preoperatively and within the first 24 hours after the DC. The primary outcome measure was improvement or lack of improvement in cerebral hemodynamics. Secondary outcomes were the modified Rankin scale in 6 months, classified as favorable (0-3) and unfavorable (4-6); and, fatal cases at 1 month and 6 months. Results: 18 (70.3%) patients were female and 12 (44.4%) were older than 55 years. There was improvement of MTT (decrease from 8.74 to 8.24, p = 0.01) and a trend towards improvement of the CBF (increase from 22.37 to 25.26, p = 0.06) after DC. There was no statistical difference in the CBV before and after DC (increase from 2.14 to 2.26, p = 0.33). Patients over 55 years had poorer prognosis (p=0.03) and preoperative MTT was an independent hemodynamic predictor of mortality at 6 months (8.20 vs 9.23, p=0.04). Conclusions: DC improved cerebral hemodynamics in most patients with malignant ischemic stroke. Preoperative MTT seems to be a good marker for case fatality in 6 months

Racial differences in the distribution of cerebrovascular occlusive disease are well documented. Extracranial stenosis is more common in Caucasian while intracranial stenosis is more common in Asian, Hispanic and African-American. The prevalence of asymptomatic intracranial stenosis in middle age and elderly general population in China was about 7%. The frequency of intracranial atherosclerosis among patients with stroke and TIA is 40 to 50% in Chinese populations. Concurrent extracranial and intracranial stenoses is common in Asian, the incidence range from 10 to 39% in patients with stroke. The current population of China is 1.3 billion and it was estimated that 30% of the population will be aged 60 and above by 2050 in China. The incidence of stroke in China is 215 per 100000 which is one of the highest among the world and this burden is expected to escalate in the coming decades. However, studies of concurrent stenoses among Chinese are scarce. The aim of this precis is to present my studies that were conducted mainly among Chinese stroke patients on this particular field. The scope of the studies covers the following 4 areas: (1) Identification of Long-term prognosis of patients with concurrent stenoses; (2) Long-term prognosis of patients with concurrent stenoses and ischemic heart disease; (3) Lesion pattern and stroke mechanisms in concurrent stenoses; and (4) genetic polymorphisms of ischemic stroke patients with concurrent stenoses. The background, objectives, subjects, methods, results, and conclusions of these studies will be presented in this precis. / Man, Bik Ling. / Adviser: Lawrence K.S. Wong. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (M.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 144-184). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.

Frontal lobe atrophy (FLA) is associated with late-life depression and cognitive impairment, although the pathogenesis of FLA in stroke is unclear. In an aim to ascertain whether FLA is affected by WMLs, we analyzed the MRIs of 471 Chinese ischemic stroke patients. Lobar atrophy was defined by a widely-used visual rating scale. WML severity was rated using the Fazekas scale. There was no correlation between PVH and DWMH and temporal and parietal atrophy. The results of this study suggest that FLA in ischemic stroke may be associated with SVD. / Poststroke depression (PSD) is the most common form of poststroke psychiatric morbidity. Small subcortical infarcts (SSIs) can result from small vessel disease (SVD) and large artery disease (LAD). No study has yet explored PSD in different etiological types of SSIs. To address this gap, 127 patients with SSIs resulting from LAD or SVD were examined. PSD was evaluated with the Geriatric Depression Scale (GDS) three months after stroke. The LAD group had a significantly higher frequency of PSD, and LAD was found to be a significant independent risk factor for PSD. This study suggests that cerebral blood perfusion may play an important role in PSD. / Post-stroke emotional lability (PSEL) is a distressing and embarrassing complaint among stroke survivors. Lesions located in various cortical and subcortical areas are thought to be involved in the pathophysiology of PSEL.The clinical significance of microbleeds (MBs) in the development of psychiatric conditions following stroke is unknown. We carried out a study to examine the association between PSEL and MBs in 519 Chinese patients with acute ischemic stroke admitted consecutively. PSEL was evaluated three months after the index stroke, and the number and location of MBs were evaluated with MRI. According to Kim's criteria, 74 (14.3%) of the patients had PSEL. Our results suggest that MBs in the thalamus may play a role in the development of PSEL. The importance of MBs in PSEL and other psychiatric conditions in stroke survivors warrants further investigation. / The first study reported in this thesis involved 328 Chinese ischemic stroke patients who were administered a series of neuropsychological tests covering seven domains three months after stroke. Two hundred and fifty-six of these patients were followed-up for one year. Volumetry of the infarcts, WMLs, and hippocampus atrophy on magnetic resonance imaging (MRI) was conducted. The prevalence of cognitive impairment was 54.9% at baseline and 52.4% at the one-year follow-up, although most of the patients (85.5%) remained cognitively stable. The evolution of cognitive impairment no dementia (CIND) at the one-year follow-up was bidirectional, with 11.2% progressing to dementia and 21.0% reverting to cognitive intact. WMLs volume rather than hippocampal volume was a significant predictor of cognitive impairment, cognitive decline, and delayed dementia. WMLs also had an independent effect on executive function, attention, visual memory, visuoconstruction, and visuomotor speed. / This thesis investigates the clinical and imaging characterization of cognitive impairment and psychiatric morbidity in Chinese stroke patients. The conclusions of the studies reported herein can be summarized as follows. (1) The prevalence of cognitive impairment is high among Chinese poststroke patients, but most remain cognitively stable at one year after stroke; WMLs rather than hippocampal atrophy predict cognitive impairment, longitudinal cognitive decline, and delayed dementia; (2) DLPFC atrophy is correlated with poor verbal fluency in elderly women with stroke, but not in their male counterparts; (3) LAD may be associated with PSD in patients with small subcortical infarcts; (4) MBs in the thalamus are associated with PSEL; (5) frontal lobe infarction and diabetes may be risk factors of insomnia symptoms in stroke patients; and (6) FLA in ischemic stroke may be associated with SVD. (Abstract shortened by UMI.) / Chen, Yangkun. / Adviser: Wai Kwong Tang. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 217-238). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Seat belts save lives; however, unintentional injuries are still the leading cause of death for those between 1 and 44 years in the United States. Seat belts also cause injuries during motor vehicle crashes (MVCs) and obesity changes how seat belts fit. The purpose of this retrospective causal inference quantitative study was to reduce the knowledge gap in scholarly research on seat belt fit in relation to blunt cerebrovascular injuries (BCVI) during MVCs and seat belt compliance. The theoretical framework used was based on H.W. Heinrich's domino theory. The research questions focused on the following dependent variables: BCVI, compliance, and seat belt fit; and independent variables: the size of the individual and seat belt fit. Secondary and primary data were used and analyzed using Spearman's Rank-Order Correlation. The results yielded no relationship between seat belt fit and BCVI in the secondary data (n = 97). In the primary data (n = 138), there was significance found between seatbelt fit and a) seat belt use, and b) BMI. The study contributed to positive social change by enhancing the awareness of the knowledge deficit regarding seat belt fit, and BCVIs sustained during MVCs, and that comfort was influenced by seat belt fit and had a role in compliance. Seat belts were not used by 5.3% and 9.5% or used incorrectly by 3.2% and 2.9% of the people in the primary data and secondary data sets. This knowledge may contribute to a) future seat belt testing to ensure it is done in such a manner that seat belts fit everyone; b) new seat belt laws to ensure that they are consistent across all states, and c) medical care focusing on seat belt fit as a mechanism of injury (blunt) to ensure screenings are done with the appropriate diagnostic tools.