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Background Dysphagia, frailty and negative patient outcomes are interlinked1. Changes in communication may result from the ageing process, chronic conditions, and/or neurologic conditions presenting in later years2. However, unlike other cohorts, including stroke, frail older patients are not routinely screened for swallowing/communication difficulties in acute settings. We investigated the proportion of Speech and Language Therapy (SLT) referrals generated for older patients attending our Emergency Department (ED) following use of a swallowing/communication screening tool and their association with Clinical Frailty Scale (CFS) scores. Methods A retrospective analysis of data collected over a four week period was completed. Older patients presenting to ED were screened by the interdisciplinary gerontological ED team using a screening tool, including a locally developed swallow/communication screen. Statistical analyses were performed using STATA Version 12. Results Of 176 patients screened (mean age 81.8 years, SD 5.9 years), median CFS score was 5 (IQR 3-6). Thirty-seven percent (66/176) of patients were referred for SLT assessment following initial screen. SLT referrals were more commonly required in patients with a CFS score of ≥4 (46.2% vs. 19.3%, P=0.001) and likelihood of requiring SLT referral increased with greater CFS score (P Conclusion Results suggest that screening for swallowing and communication difficulties in older patients yields a high level of SLT referrals, with a higher frequency of SLT referrals observed with increasing frailty scores. Further research is required to determine the optimum swallowing/communication screening tool in the acute setting. Future research will focus on evaluating outcomes of SLT assessments completed and determining the prevalence of swallowing and/or communication difficulties in this cohort.

Background The physical phenotype of frailty shows significant overlap with sarcopenia, and sarcopenia phenotype is associated with malnutrition. Integrating screening of these interrelated conditions, could help identify those most vulnerable in the Emergency Department (ED) setting. Methods Patients ≥75 were screened in the Emergency department (ED) by an interdisciplinary Gerontological ED team using a standardised assessment tool, incorporating the Clinical Frailty Scale (CFS) and the mini-nutritional assessment short form (MNA-SF). Patients at risk of malnutrition ( MNA-SF Results In a convenience sample of patients referred to dietetics following initial screen in ED, 57% were female (25/44) and the mean age was 83 years (range 75-94). Eighty-eight percent (39/44) were at risk of malnutrition/malnourished and 25% (11/44) were diagnosed with malnutrition (MNA-SF score 0-7). Seventy-three percent (32/44) scored ≥4 on the CFS. Fifty-two percent of all patients (23/44) had a Sarc-F ≥ 4, suggestive of sarcopenia, while 45% (20/44) had a probable diagnosis of sarcopenia and 39% (17/44) met diagnostic criteria for sarcopenia. Risk of malnutrition was more commonly observed in those patients with a CFS score ≥4 (94% vs. 75%), as was risk of sarcopenia (81% vs. 17%). Fifty percent (22/44) of all patients screened positive for suspicion of both frailty and sarcopenia (frailty score≥4 and Sarc-F score≥4). Patients with a probable diagnosis of sarcopenia and concomitant frailty had more ED attendances, falls and longer lengths of stay. Conclusion Frailty, malnutrition and sarcopenia are frequently observed in older patients in the acute setting. The integration of screening measures for malnutrition, frailty and sarcopenia in clinical practice can facilitate the identification of patients for multi-component targeted interventions.

Background Delirium is a medical emergency and is associated with increased risk of mortality, in-hospital complications, length of stay and institutionalisation. Delirium screening is recommended for patients at risk on admission. Despite this, delirium screening is frequently not undertaken in the acute setting leading to undiagnosed delirium and sub-optimal clinical care. We aim to investigate the prevalence of delirium in patients aged ≥75 years attending the Emergency Department (ED) of a tertiary referral centre. Methods Patients aged ≥75yrs presenting to the ED between 08.30 and 18.30, Monday- Friday were assessed by an interdisplinary gerontological service using a standardised assessment tool including the 4AT to screen for delirium. Data was collected and analysed via Excel. Results Of 163 patients screened over a 4 week period 47.9% (78/163) were male with a mean age of 81.8 years (SD 2.7). Twenty three percent (34/148) scored ≥4 indicating a possible delirium. Patients with delirium were older (85 yrs vs. 80 yrs, P Conclusion Routine screening of patients in the acute setting detected a high rate of delirium at a level which is consistent with previous studies. Patients with delirium were older, more frequently frail and at risk of malnutrition. Our results support the evidence for routine screening for delirium in the acute setting.

Background Older admitted patients are at risk of deconditioning related to immobility. “Fit to Sit” is a simple change in the Emergency Department (ED) culture and attitude, promoting independence, maximizing well-being and improving health outcomes. We aim to describe the prevalence of patients deemed “Fit to Sit” who were in hospital gowns and lying on trolleys in our ED prior to the commencement of the “Fit to Sit” pilot. Methods An observational study was conducted prospectively, over five working days, to determine the proportion of patients present who were dressed and sitting out on a chair, opposed to wearing pyjamas (PJs) and lying on a trolley. Nursing staff familiar with each patient were asked whether or not the patient was fit to sit out in a chair. Statistical analysis was conducted with Microsoft Excel using the chi squared test to calculate differences between the two groups. Results Data was collected on 147 patients, median age 66 years (IQR 47-74). 82% were on a trolley and 18% in a chair. 33% were in their clothes, the remaining 67% were in PJs or hospital gowns. 45% of those deemed “Fit to Sit” were on a trolley. Patients 65 and older were more likely to be wearing PJs (p= 0.03), but not more likely to be on a trolley (p= 0.23). Patients in ED for greater than 12 hours were also more likely to be in PJs (p= 0.001) and on a trolley (p= 0.057). Conclusion Our study suggests that a significant proportion of ED patients are lying on trolleys despite being deemed to be “Fit to Sit”. Introduction of an ED “Fit to Sit” programme may alleviate deconditioning and promote patient independence.

Background and purpose The prevalence of chronic kidney disease (estimated glomerular filtration rate (eGFR) 2 for ≥3 months, chronic kidney disease (CKD)) in ischemic stroke and transient ischemic attack (TIA) is unknown, as estimates have been based on single-point estimates of renal function. Studies investigating the effect of renal dysfunction (eGFR 2, renal dysfunction) on post-stroke outcomes are limited to hospitalized cohorts and have provided conflicting results. Methods We investigated rates, determinants and outcomes of renal dysfunction in ischemic stroke and TIA in the North Dublin Population Stroke Study. We also investigate the persistence of renal dysfunction in 90-day survivors to determine the prevalence of CKD. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using Kaplan–Meier survival curves and Cox proportional hazards modeling. Results In 547 patients (ischemic stroke in 76.4%, TIA in 23.6%), the mean eGFR at presentation was 63.7 mL/min/1.73 m2 (SD 22.1). Renal dysfunction was observed in 44.6% (244/547). Among 90-day survivors, 31.2% (139/446) met criteria for CKD. After adjusting for age and stroke severity, eGFR 2 (hazard ratio 2.53, p = 0.01) independently predicted 28-day fatality but not at two years. Poor post-stroke functional outcome (Modified Rankin Scale 3–5) at two years was more common in those with renal dysfunction (52.5% vs. 20.6%, p Conclusion Renal dysfunction and CKD are common in ischemic stroke and TIA. Renal dysfunction is associated with considerable post-stroke morbidity and mortality. Further studies are needed to investigate if modifiable mechanisms underlie these associations.

Background Few studies have directly compared stroke recurrence rates after stroke and transient ischemic attack, and the risk factors underlying early recurrence are poorly understood. We aimed to investigate risk factors for recurrent stroke after first stroke and transient ischemic attack in a population-based study. Methods The North Dublin Population Stroke Study applied multiple overlapping hot and cold pursuit methods, to ascertain hospital- and community-treated stroke and transient ischemic attack patients over a 12-month period. Inclusion criteria were: (1) Stroke-physician confirmed transient ischemic attack/ischemic stroke; (2) first-stroke/transient ischemic attack event within the ascertainment period. Patients were prospectively followed at 72 h, 7, 28 and 90 days. Results A total of 584 patients met eligibility criteria (172 transient ischemic attack, 412 stroke). More transient ischemic attack than stroke patients presented to medical attention with recurrent stroke (8.24% vs. 0.24%, p = 0.0002). Recurrent stroke was more common after transient ischemic attack than index stroke at each time-interval (at 72 h, 4.07% vs. 1.23%, p = 0.03; at 90 days, 13.45% vs. 5.72%, p = 0.002). Stroke recurrence at 90 days was also associated with delay seeking medical attention after the index event (OR 3.2, p = 0.001), delayed anti-platelet (OR 2.8, p = 0.001) and statin (OR 2.4, p = 0.009) treatment, carotid stenosis/occlusion (OR 2.4, p = 0.008). On multivariable analysis, transient ischemic attack as index event (adjusted OR 2.3, p = 0.02), delayed statin treatment (OR 2.5, p = 0.02), and carotid stenosis/occlusion (OR 2.4, p = 0.02) were independent predictors of 90-day recurrent stroke. Conclusion A combination of pathophysiological and behavioral factors was associated with early stroke recurrence risk. Improved public awareness to reduce delays to self-referral for transient ischemic attack symptoms is needed.

Background and Purpose— Few recent studies have investigated the rates and predictors of early and late stroke recurrence using prospective population–based methodology. We investigated recurrent stroke at 2 years in the North Dublin Population Stroke Study (NDPSS). Methods— Patients were ascertained from December 2005 to 2006 from overlapping community and hospital sources using hot and cold pursuit. Stroke recurrence, survival, and functional outcome were ascertained at 72 hours, 7 days, 28 days, 90 days, 1 year, and 2 years. Results— Of 567 patients, cumulative 2-year stroke recurrence rate was 10.8% and case fatality was 38.6%. Recurrence subtype was associated with initial stroke subtype ( P P =0.005) and prior stroke (adjusted hazard ratio, 2.92; P =0.01) were independent predictors of 2-year recurrence in 28-day survivors. Conclusions— Despite rigorous ascertainment, recurrent stroke rates were lower in current study than in earlier studies. Our data suggest that large sample sizes may be needed for future secondary prevention trials in patients treated with modern preventive medications.

Background and Purpose— Demographic trends in atrial fibrillation (AF) incidence may yield a substantial rise in the societal burden of AF-related stroke (AF-stroke). Accurate population-wide outcome data are essential to inform health service planning to improve AF-stroke prevention, and provision of rehabilitation, nursing home, and community supports for AF-stroke survivors. Methods— We investigated rates and determinants of 5-year fatality, stroke recurrence, functional outcomes, and prescribing of secondary prevention medications in AF-stroke in the North Dublin Population Stroke Study. Ascertainment included hot and cold pursuit using multiple overlapping sources. Survival analysis was performed using lifetables and Kaplan–Meier survival curves, and Cox proportional hazard modeling was performed to identify predictors of death and recurrent stroke. Results— Five hundred sixty-eight patients with new stroke were identified, including 177 (31.2%) AF-stroke. At 5 years, 39.2% (confidence interval, 31.5–46.8) of ischemic AF-stroke patients were alive. Congestive heart failure, hypertension, age 2 DS 2 -VASc) score (hazard ratio [HR], 1.34; P 2 score (HR 1.42, P =0.004), National Institute of Health Stroke Scale (HR, 1.09; P P =0.003) were independently associated with 5-year fatality, whereas warfarin (HR, 0.40; P =0.001) and statin use after index stroke (HR, 0.52; P =0.005) were associated with improved survival. The 5-year recurrence rate after ischemic AF-stroke was 21.5% (confidence interval, 14.5–31.3). Trends toward greater risk of recurrence were observed for persistent AF (HR, 3.09; P =0.07) and CHA 2 DS 2 -VASc score (HR, 1.34; P =0.07). Nursing home care was needed for 25.9% of patients. Conclusions— AF-stroke is associated with considerable long-term morbidity, fatality, stroke recurrence, and nursing home requirement. Adequately resourced national AF strategies to improve AF detection and prevention are needed.

We aimed to quantify the risk and predictors of ipsilateral ischemic stroke in patients with symptomatic carotid stenosis awaiting revascularization (carotid endarterectomy [CEA] or carotid artery stenting) by pooling individual patient data from recent prospective studies with high rates of treatment with modern stroke prevention medications.Data were included from 2 prospective hospital-based registries (Umeå, Barcelona) and one prospective population-based study (Dublin). Patients with symptomatic 50%-99% carotid stenosis eligible for carotid revascularization were included and followed for early recurrent ipsilateral stroke or retinal artery occlusion (RAO).Of 607 patients with symptomatic 50%-99% carotid stenosis, 377 met prespecified inclusion criteria. Ipsilateral recurrent ischemic stroke/RAO risk pre-revascularization was 2.7% (1 day), 5.3% (3 days), 11.5% (14 days), and 18.8% (90 days). On bivariate analysis, presentation with a cerebral vs ocular event was associated with higher recurrent stroke risk (log-rank p = 0.04). On multivariable Cox regression, recurrence was associated with older age (adjusted hazard ratio [HR] per 10-year increase 1.5, p = 0.02) with a strong trend for association with cerebral (stroke/TIA) vs ocular symptoms (adjusted HR 2.7, p = 0.06), but not degree of stenosis, smoking, vascular risk factors, or medications.We found high risk of recurrent ipsilateral ischemic events within the 14-day time period currently recommended for CEA. Randomized trials are needed to determine the benefits and safety of urgent vs subacute carotid revascularization within 14 days after symptom onset.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. Although ALS has been extensively studied in post-mortem patient samples and animal models, there are currently no very effective treatments and there is no cure. One reason for the lack of treatment options in ALS may stem from the inaccessibility of living human motor neurons for use in disease research and subsequent therapeutic target validation. Recent developments in the field of stem cell biology can potentially provide access to living human motor neurons from individual ALS patients. It is now possible to derive induced pluripotent stem cells (iPS cells) from the somatic tissues of ALS patients and then to differentiate these iPS cells into motor neurons with the precise genetic makeup of the donor patient (iPS-MNs). Before iPS-MNs can be put to productive use, however, the iPS system as a whole must be validated as a reliable source of motor neurons with characteristics that closely resemble their endogenous or hES-derived counterparts. This thesis will first address a series of issues relating to the validation of iPS cells as a reliable source of motor neurons a then move on to expression profiling studies aimed at identifying a transcriptional signature of ALS in iPS-MNs. I will first describe a collaborative study aimed at determining whether or not iPS cells are as useful as ES cells for the production of motor neurons. By comparing motor neuron differentiation efficiency across a panel of 6 ES lines and 16 iPS lines, we demonstrated that iPS cells are equally capable of producing electrophysiologically active motor neurons as ES cells. Moreover, both ALS and control iPS lines produce motor neurons with equal efficiency, suggesting that iPS cells will be useful in the production of ALS iPS-MNs for disease research. In addition, our results identify some of the variables that contribute to differentiation efficiency, including donor identity and individual iPS/ES line identity. The following section will serve to provide a deeper molecular and electrophysiological understanding of human stem cell-derived motor neurons. I first generated expression profiles from purified hES-MNs to identify potential motor neuron-specific surface markers as well as maturational changes occurring in motor neurons in vitro. Using calcium imaging techniques, I then demonstrated that iPS-MNs behave functionally similarly to ES-MNs and described culture-wide rhythmic depolarizations that are likely influencing multiple properties of iPS-MNs. After characterizing the iPS-MN culture system, I made a first attempt at defining the transcriptional phenotypes of ALS in iPS-MNs. This work relied on the use of a motor neuron-specific lentiviral reporter that I developed to isolate and transcriptionally profile iPS-MNs from two control iPS lines and four ALS iPS lines. I show evidence of significant transcriptional differences between motor neurons isolated from ALS lines and those from control patients. These differences may in the future help to define ALS-specific phenotypes. Lastly, I conducted a meta-analysis comparing transcriptional changes in ALS iPS-MNs to those in existing models of ALS and identified some common stress-related features of ALS in iPS-MNs. In order to form new hypotheses about what sorts of individual patient-specific phenotypes may be present in iPS-MNs, I will then utilize published expression profiles from post-mortem ALS patient motor neurons to identify a previously-overlooked class of genes that exhibit expression levels highly correlated with individual age at ALS onset. This group of 43 onset-correlated genes contains many members with known or hypothesized relationships to neurodegenerative disease. I discuss how onset-correlated genes may function as disease-modifiers or biomarkers and design experiments to investigate these possibilities. Taken together, the work in this thesis will lay the foundations for developing a human iPS-based model of ALS and point toward numerous avenues of future investigation.