PhysiologyPhysiologyhttp://hdl.handle.net/2262/382024-03-19T10:35:49Z2024-03-19T10:35:49ZThe Impact and Influence of Sports Related Concussion and Cardiovascular Risk Factors on Brain and Heart Health across an Ageing PopulationJoyce, Oisín Cormac Jameshttp://hdl.handle.net/2262/1041682023-11-20T18:03:23Z2023-01-01T00:00:00ZThe Impact and Influence of Sports Related Concussion and Cardiovascular Risk Factors on Brain and Heart Health across an Ageing Population
Joyce, Oisín Cormac James
This study focused on the relationship between perceptual performance, brain health, and cardiovascular (CV) profiles in both recreational athletes and non-athletes, bridging the gap between sensory integration, cognitive function, and physical well-being. The study's primary aim was to explore brain health in young and middle-aged recreational athletes in diverse contact and non-contact sports via a neuropsychological measure of multisensory integration (MSI) known as the Sound-Induced Flash Illusion (SIFI) task. This task may be of use as an objective diagnostic test of sports-related concussion, thus history of concussion in all subjects was recorded. Additionally, the impact of exercise on SIFI performance and the test's reliability and overall level of agreement were examined since, if the test is to be of diagnostic use in a sports setting, performance must be resistant to exercise and the test must be robust and reliable across multiple testing sessions. Finally, the link between older community-level athletes' CV health profile and cognition in midlife was investigated alongside a systematic review of the literature investigating the influence of midlife CV risk factors on cognition across multiple domains.
Our results show that healthy young adults (aged 18-30) with or without a history of concussion showed comparable perceptual accuracy in the SIFI task across illusory conditions. While females exhibited greater susceptibility to the illusion, factors like sex and concussion history did not account for perceptual performance variance. Contact sports participants demonstrated heightened MSI, possibly due to training in open skill sports, but overall sporting cohort did not significantly affect perceptual differences. A follow-up study confirmed sex-based and sports-specific disparities in perceptual performance with open skill sport participants excelling in larger temporal asynchrony conditions, and a subgroup exhibiting a nuanced learning effect linked to cumulative SIFI exposure. The influence of moderate and high-intensity exercise on SIFI performance was negligible, supporting the hypothesis that the test may be of use in sport settings. Remarkably, the SIFI displayed strong reliability across multiple testing sessions, further supporting its utility in concussion diagnosis and prognosis.
A series of systematic reviews highlighted the complex relationship between midlife CV risk factors (hypertension, diabetes, cholesterol) and cognitive function, underscoring the need for targeted interventions at particular life stages in order to protect brain health in older age. Findings varied across different cognitive domains; notably, impairments in memory, executive function, and global cognition were correlated with poorer CV health. Longitudinal studies predominantly affirmed an adverse link between midlife CV risk factors, specifically hypertension and type 2 diabetes (T2DM), and cognitive decline in later life. In contrast, the relationship with cholesterol was less clear, with some studies indicating positive associations while others identified negative links with cholesterol, high-density lipoproteins, low density lipoproteins, and triglycerides.
A study of SIFI performance, markers of CV health and history of concussion in middle-aged subjects with a history of recreational sporting activity revealed sex differences in BMI and health measures, with sporting engagement influencing blood pressure (BP) and mental health outcomes. A notable distinction emerged in sports participation; females engaged exclusively in non-contact sports, whereas males participated in both sporting types. Lifetime sporting involvement showed a positive correlation with systolic BP and depression, but conversely showed a negative correlation with overall physical activity and mental health metrics. Markedly, no significant correlation emerged between cognitive functioning and sports experience. Sex differences in global cognition were not significant, although females displayed an average score below the clinical cut-off, suggesting a potential increased risk of mild cognitive impairment. Susceptibility patterns to SIFI illusory conditions among older community athletes at midlife resembled those in our study of younger subjects, revealing high, moderate, and low performers. While sex did not significantly predict perceptual accuracy, males exhibited reduced susceptibility to the SIFI. Intriguingly, those who had participated in non-contact sports consistently outperformed contact sports across all SOA conditions, and despite differing outcomes from those in young participants, no significant distinctions emerged between open skill and closed skill sports.
Results included in this thesis have broad implications for athletes, coaches, healthcare professionals, policymakers, and the general public. As well as providing evidence to support the potential use of a simple but robust test of MSI in the diagnosis of concussion and monitoring of recovery, it also adds to our knowledge of the influence of CV wellbeing on brain health and function in middle age and later life. Future research should investigate the physiological mechanisms underlying the age-, sex-, disease- and exercise-related influences on cognitive function that we have observed and work towards development of tailored interventions to promote healthy aging for athletes and non-athletes alike. Ultimately, this research advances our understanding of the intricate relationships between cognitive function, brain health, and cardiovascular well-being, urging proactive measures to ensure the well-being of both athletes and the wider population.
APPROVED
2023-01-01T00:00:00ZIdentifying the therapeutic potential of novel compounds in the treatment of Glioblastoma MultiformeKeenan, Emilyhttp://hdl.handle.net/2262/1029932023-06-28T17:02:29Z2023-01-01T00:00:00ZIdentifying the therapeutic potential of novel compounds in the treatment of Glioblastoma Multiforme
Keenan, Emily
Glioblastoma multiforme (GBM) is the most common and aggressive brain cancer in adults with a dismal 5-year survival rate of <5%. Despite advanced diagnostic and multimodal treatments including surgery, followed by radiotherapy and chemotherapy (CRT), treatment resistance is a major clinical challenge and the survival rates for GBM are not improving. Therefore, innovative therapeutic approaches are urgently needed for GBM patients. (E)-2-(2-(Pyrazin-2-yl)vinyl)phenol, Pyrazinib (P3) a small molecule pyrazine compound has shown significant therapeutic potential as a radiosensitiser in oesophageal cancer and here we assess its therapeutic potential in GBM. (E)-2-(2-quinolin-2-yl-vinyl)-benzene-1,4-diol HCl, 1,4 dihydroxy quininib (Q8), an antagonist of the cysteinyl leukotriene receptor-1 has shown potential as novel anti-angiogenic in colorectal cancer models and here we assess its therapeutic utility in GBM. Natural killer (NK) cells are potent anti-tumour immune cells and are gaining momentum as cell-based immunotherapies. This study investigates Pyrazinib (P3), 1,4 dihydroxy quininib (Q8) and a P3 prodrug called P3 Phosphate for their potential to sensitise GBM tumours to current standard-of-care chemotherapy and for their utility in combination with NK cell therapies.
APPROVED
2023-01-01T00:00:00ZAntipsychotics Prevent Psychosine Induced Toxicity in Glial Cells.Sharma, Kapilhttp://hdl.handle.net/2262/1021872023-02-24T18:02:13Z2023-01-01T00:00:00ZAntipsychotics Prevent Psychosine Induced Toxicity in Glial Cells.
Sharma, Kapil
Glial cells are implicated in the neuropathophysiology of schizophrenia and other neuropsychiatric disorders. Also, the role of altered myelin in the onset and development of schizophrenia and changes in myelin due to antipsychotics remains unclear. There is growing interest in the effects of antipsychotics on glial cells, to explore the ways these drugs may act via non-neuronal mechanisms. To investigate if antipsychotic drugs modulate glial cell dysfunction, human astrocytes were treated with the toxin psychosine, with or without antipsychotics (chapter 3). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and LDH (Lactate Dehydrogenase) assays showed that psychosine decreased cell viability and induced cell toxicity in human astrocytes. This was returned to almost control levels by antipsychotics. Immunocytochemical analysis showed that psychosine impaired astrocyte morphology which was reversed significantly by antipsychotics. Selective D2 and 5HT2A receptor antagonists were found to attenuate psychosine-induced decrease in cell viability, toxic effects, and reductions in astrocyte processes with advantage of dopamine over serotonin antagonism (Results, chapter 3). The effects of the antipsychotics, haloperidol and clozapine, on levels of myelin using mouse organotypic cerebellar slices treated with the demyelinating agent psychosine was also investigated (Chapter 4). Psychosine induced a concentration-dependent loss of myelin. Importantly, both haloperidol and clozapine, reduced this psychosine-induced loss. Similarly, these drugs attenuated psychosine-induced loss of astrocyte markers. Psychosine also induced a decrease in nonphosphorylated neurofilament levels, which were restored by both haloperidol and clozapine, indicating neuroprotective and neurorestorative processes (Results, chapter 4). Having shown that antipsychotics prevented psychosine toxicity to human astrocytes in-vitro and ameliorated psychosine induced demyelination in mouse organotypic cerebellar slice cultures ex-vivo. Another study aimed to examine if these findings would translate into improved survival, mobility, and behavioural metrics in an in-vivo model of psychosine toxicity i.e., the twitcher mouse model of Krabbe Disease (Chapter 5). The antipsychotic haloperidol increased survival, improved mobility, and positively influenced behaviours in twitcher mice (Results, chapter 5). Overall, this work suggests that antipsychotics may regulate astrocyte cell damage and exert a protective effect on oligodendrocytes. Also, this suggests that antipsychotics or agents with similar pharmacology, namely D2/5HT2A receptor antagonists, may be a potential novel treatment for KD, a leukodystrophy that leads to the accumulation of the toxin psychosine.
APPROVED
2023-01-01T00:00:00ZLow-volume HIIT and MICT speed VO2 kinetics during high-intensity "work-to-work" cycling with a similar time-course in type 2 diabetesGildea, NoritaEgana, Mikelhttp://hdl.handle.net/2262/1018872022-12-16T18:01:55Z2022-01-01T00:00:00ZLow-volume HIIT and MICT speed VO2 kinetics during high-intensity "work-to-work" cycling with a similar time-course in type 2 diabetes
Gildea, Norita; Egana, Mikel
We assessed the rates of adjustment in oxygen uptake (V̇o2) and muscle deoxygenation [i.e., deoxygenated hemoglobin and myoglobin, (HHb + Mb)] during the on-transition to high-intensity cycling initiated from an elevated baseline (work-to-work, w-to-w) before training and at weeks 3, 6, 9, and 12 of low-volume high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) in type 2 diabetes (T2D). Participants were randomly assigned to MICT (n = 11, 50 min of moderate-intensity cycling), HIIT (n = 8, 10 × 1 min of high-intensity cycling separated by 1 min of light cycling) or nonexercising control (n = 9) groups. Exercising groups trained three times per week. Participants completed two w-to-w transitions at each time point consisting of sequential step increments to moderate- and high-intensity work-rates. [HHb + Mb] kinetics were measured by near-infrared spectroscopy at the vastus lateralis muscle. The pretraining time constant of the primary phase of V̇o2 (V̇o2 τp) and the amplitude of the V̇o2 slow component (V̇o2 As) of the high-intensity w-to-w bout decreased (P < 0.05) by a similar magnitude at week 3 of training in both MICT (from 56 ± 9 to 43 ± 6 s, and from 0.17 ± 0.07 to 0.09 ± 0.05 L/min, respectively) and HIIT (from 56 ± 8 to 42 ± 6 s, and from 0.18 ± 0.05 to 0.09 ± 0.08 L/min, respectively) with no further changes thereafter. No changes were reported in controls. The parameter estimates of Δ[HHb + Mb] remained unchanged in all groups. MICT and HIIT elicited comparable improvements in V̇o2 kinetics without changes in muscle deoxygenation kinetics during high-intensity exercise initiated from an elevated baseline in T2D despite training volume and time commitment being ∼50% lower in the HIIT group.
NEW & NOTEWORTHY Three weeks of high-intensity interval training and moderate-intensity continuous training decreased the time constant of the primary phase of oxygen uptake (V̇o2) and amplitude of the V̇o2 slow component during a high-intensity exercise initiated from an elevated baseline, a protocol that mimics the abrupt metabolic transitions akin to those in daily life, in type 2 diabetes. These V̇o2 kinetics improvements were maintained until the end of the 12-wk intervention without changes in muscle deoxygenation kinetics.
PUBLISHED
2022-01-01T00:00:00Z