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This study investigated the hypothesis that severity of depressive symptoms following acute ischemic stroke is associated with degree of tissue infarction and severity of white matter changes (WMCs). It employed a novel quantitative region-based approach considering both infarction and WMCs. Of 54 ischemic stroke patients recruited, 50 (72.3 ± 12.8 years, 52.0% male) had useable CT scans. The typical patient was recruited within 3 weeks of their stroke (19.7 ± 31.0 days), exhibited minor cognitive impairment (MMSE score 25.8 ± 4.6), and had mild to moderate stroke severity (NIHSS score 6.5 ± 5.4). 28.0% of patients screened positive for clinical depression with a CES-D score ≥16. While neither degree of infarction nor severity of WMCs (ARWMC score) in the 12 brain regions correlated with depressive symptoms (CES-D score), stroke severity was a significant predictor of depressive symptoms. This stressor, related to physical disability, was a predominant predictor over lesion characteristics.

This study investigated the hypothesis that severity of depressive symptoms following acute ischemic stroke is associated with degree of tissue infarction and severity of white matter changes (WMCs). It employed a novel quantitative region-based approach considering both infarction and WMCs. Of 54 ischemic stroke patients recruited, 50 (72.3 ± 12.8 years, 52.0% male) had useable CT scans. The typical patient was recruited within 3 weeks of their stroke (19.7 ± 31.0 days), exhibited minor cognitive impairment (MMSE score 25.8 ± 4.6), and had mild to moderate stroke severity (NIHSS score 6.5 ± 5.4). 28.0% of patients screened positive for clinical depression with a CES-D score ≥16. While neither degree of infarction nor severity of WMCs (ARWMC score) in the 12 brain regions correlated with depressive symptoms (CES-D score), stroke severity was a significant predictor of depressive symptoms. This stressor, related to physical disability, was a predominant predictor over lesion characteristics.

The ability to walk and negotiate stairs is an important predictor of independent ambulation. The superposition of mobility impairments to the effects of natural aging in persons with stroke render the completion of many daily activities unsafe, thus limiting individuals’ independence within their communities. Currently however, no means exist for the monitoring of mobility levels during daily living in survivors after the completion of rehabilitation programs. The application of inertial sensors for stroke survivors could provide a basis for the study of gait outside of traditional laboratory settings. The main objective of this thesis was to evaluate the performance of inertial sensors in measuring gait of hemiparetic stroke survivors through the completion of three studies. The first study explored the use of inertial measurement units (IMUs) for the measurement of lower limb joint kinematics during stair ascent and descent in both stroke survivors and healthy older adults. Results suggested that IMUs were suitable for the measurement of lower limb range of motion in both healthy and post-stroke subjects during stair ambulation. The second study evaluated the measurement of step length and spatial symmetry during overground walking using IMUs. A systematic error resulting in the underestimation of step lengths calculated using IMUs compared with those measured using video analysis was found, however results suggested that IMUs were suitable for the assessment of spatial symmetry between affected and less-affected limbs in stroke survivors. The final study evaluated the automatic classification of gait activities using inertial sensor data. Findings revealed that the use of a classifier composed of frequency-features extracted from IMU accelerometer and gyroscope data from both the affected and less-affected limbs most accurately identified gait activities from post stroke gait data. This thesis provides a first attempt at applying IMUs to the study of gait post-stroke. Future work may extend the findings of these studies to provide a better understanding to rehabilitation professionals of the demands of everyday life for stroke survivors. / Thesis (Master, Mechanical and Materials Engineering) -- Queen's University, 2013-08-29 12:42:05.505

The majority of stroke survivors return to living in the community; however, muscle weakness and cardiovascular deconditioning can restrict mobility, limit community access and independence, particularly when challenging activities like stair negotiation are involved. A “step-by-step” (SBS) strategy (both feet per step) may be adopted in lieu of a “step-over-step” (SOS) method (one foot per step) to increase stability and off-load the paretic limb though the physical demands of the two methods are unknown. The main objective of this thesis was to investigate the strength and energy demands of the two stair-stepping strategies in chronic stroke compared to healthy adults. The first study identified the relative strength and aerobic demands of both strategies. The results showed that the stroke group produced similar peak joint moments compared to controls, despite their slower cadence suggesting that the stroke group exerts comparable ‘effort’ to move more slowly. The SBS method was associated with lower strength costs (relative to individuals’ maximum strength output) than SOS, however aerobic cost was significantly higher. The second study identified the mechanical energy expenditures (MEEs) and transfers related to both strategies. The MEEs were found to be lower when the SBS strategy was used. Though expenditures were similar between groups, the stroke group had higher expenditures associated with the work of the less affected knee extensors (lead limb) during ascent and descent and controls exhibited higher expenditures for the plantarflexors during ascent. The reduced output of the trail (affected) limb plantarflexors likely resulted in the increased workload of the knee extensors. Overall, the aerobic cost per step was higher in stroke, particularly during descent, suggesting that in addition to reducing cadence, persons with stroke may be co-contracting to increase stabilization during descent, thus increasing oxygen demands. This thesis provides novel information on the physical demands associated with two methods of stair negotiation demonstrating that the SBS strategy might be better suited to persons with chronic stroke by minimizing the strength demands on the paretic side, but the benefit comes at an elevated aerobic cost. This information is valuable to rehabilitation professionals engaged in retraining mobility to facilitate community reintegration. / Thesis (Master, Rehabilitation Science) -- Queen's University, 2013-09-30 13:42:08.209

Ischaemic stroke is responsible for substantial death and disability and creates a huge financial burden for healthcare budgets worldwide. At present there are few effective treatments for acute stroke and these are urgently required. Increased understanding of the ischaemic cascade has generated interest in neuroprotection for focal cerebral ischaemia. However, treatment effects observed in of over 500 interventions in animal models have yet to be translated to the clinic. Systematic review and meta-analysis allows unbiased identification of all relevant data for a given intervention, gives a clearer view of its true efficacy and the limitations to its therapeutic potential. Understanding the reasons for this bench-to-bedside failure and providing quantitative explanations may help to address these discrepancies. Random effects weighted mean difference meta-analysis of six interventions (tirilazad, tPA, NXY-059, Hypothermia, Piracetam and IL1-RA) reported study quality to be consistently low. In some instances, potential sources of bias were associated with overestimations of efficacy. Likewise, clinical trials have tested interventions in conditions where efficacy was not observed in animals. Cumulative meta-analysis suggests that for tPA the estimate of efficacy is stable after the inclusion of data from 1500 animals; hypothermia and FK506 are the only other interventions to have been tested in at least 1500 animals. Meta-regression suggests biological rather methodical factors are better predictors of outcome; a major limitation of these data is the impact of publication bias, and this work suggests effect sizes from met-analyses are inflated by about 31% because 16% of studies remain unpublished. The systematic review and meta-analysis of hypothermia was used to plan experiments investigating the possible impact of pethidine, a drug used to prevent shivering. This in vivo experiment, in which potential sources of bias were minimised, suggests that pethidine does not influence the observed efficacy of hypothermia in an animal model of ischaemic stroke. This thesis reports that animal studies of ischaemic stroke are often not conducted with sufficient rigour. Both minimising potential sources of bias in individual experiments and using meta-analysis to summarise data from a number of experiments may be helpful in improving the translation of neuroprotective efficacy in ischaemic stroke.

Many blood markers have been associated with stroke. I set out to determine whether blood markers can be applied to: (i) improve the accuracy of the clinical diagnosis of stroke or TIA, and/or (ii) improve the prediction of poor outcome in patients who are still symptomatic at the time of admission with stroke or TIA. I systematically reviewed the existing literature on the diagnostic performance of a range of blood markers measured soon after stroke onset, to inform the choice of markers for my subsequent prospective studies in this thesis. Many studies had deficiencies in their design, which may have explained the apparently – and perhaps spuriously - impressive diagnostic performance of several markers. In the light of these data I was able to improve the design of my own studies and suggest how future studies of diagnostic markers could be improved. In order to define an appropriate comparator test for assessing the diagnostic accuracy of blood markers, I first examined the performance of emergency room nurses and doctors. I assessed the accuracy of their diagnosis of TIA or stroke (‘acute cerebrovascular disease’) in patients presenting with symptoms of suspected stroke, and compared them with a number of stroke diagnostic scales. In the 405 patients recruited to the study, the sensitivity of emergency department staff was 77% and specificity 58%. Each stroke diagnostic scale had a slightly better sensitivity, though worse specificity, than an emergency department clinician. I decided to use the diagnosis by an emergency department clinician of ‘probable or definite acute cerebrovascular disease’ as the best clinical performance reference standard. In blood taken from the same cohort of 405 patients, accredited research laboratories measured markers of inflammation, thrombosis, thrombolysis, cardiac strain and cerebral damage. Tissue plasminogen activator and loge N-terminal pro brain natriuretic peptide were associated positively with a diagnosis of acute cerebrovascular disease, though each marker did not add diagnostic value to the diagnosis of an emergency department doctor or nurse. I systematically reviewed the literature examining the association between the levels of blood markers with poor outcome (i.e. death or dependency) after stroke. I found that although almost all markers studied had a positive association with poor outcome, there were methodological problems with many studies, chiefly small sample size, publication bias or within study reporting biases, and lack of adjustment for important confounders such as age or stroke severity. With data from the Edinburgh Stroke Study, I examined the association between circulating markers of the inflammatory response (white cell count, interleukin-6, Creactive protein and fibrinogen) and poor outcome after stroke. After adjustment for age, whether the patient lived alone, was independent of activities of daily living, was orientated, able to lift both arms and able to walk, I found that higher levels of interleukin-6, white cell count and glucose were associated with poor outcome. The relevant test of a biological marker is not its predictive ability alone, but whether, when added to a validated predictive model based on clinical variables, it improves the prediction of outcome. No individual marker improved the prediction of poor outcome when added to a validated prognostic model based on clinical variables alone. From my cohort of 405 patients with suspected stroke 285 patients had a confirmed diagnosis. Follow up of these 285 patients with confirmed acute cerebrovascular disease showed that, after adjustment for neurological impairment and age, only interleukin-6 and N-terminal pro brain natriuretic peptide were significantly associated with death or disability at 3 months. Neither marker improved the predictions of a model to predict poor outcome based on clinical variables alone. To examine the relationship between circulating markers of the inflammatory response and recurrent stroke, myocardial infarction, and vascular death (‘recurrent vascular events’), again I used data from the Edinburgh Stroke Study. After adjustment for clinical predictors (age, prior MI, stroke, or TIA and AF) I found that higher levels of interleukin-6, C-reactive protein and fibrinogen remained significantly associated with an increased risk of recurrent vascular events. However, the relationship with deaths from all causes was somewhat stronger for each marker, perhaps suggesting that higher marker levels were associated with debility rather than vascular events per se. In conclusion, I found no marker measured could improve on the diagnostic accuracy of an emergency department clinician for acute cerebrovascular disease, nor improve the prediction of poor outcome by a prognostic model based upon clinical variables. The work of this thesis does not support the routine use of blood markers as an aid to the diagnosis of, or the prediction of outcome of, acute stroke.