Investigating molecular pathology in Parkinson's disease in vivo using PET imaging

The overarching aim of this thesis was to investigate four molecular markers of pathology in Parkinson’s disease (PD), namely phosphodiesterase 4 (PDE4), synaptic vesicle protein 2A (SV2A), sigma 1 receptor (1R) and mitochondrial complex 1 (MC1), using molecular positron emission tomography (PET) imaging with [11C]Rolipram for PDE4, [11C]UCB-J for SV2A, [11C]SA-4503 for 1R and [18F]BCPP-EF for MC1. A secondary aim was to investigate the relationship between changes in these molecular markers in vivo with clinical markers of Parkinson’s disease burden. The main hypothesis was that PDE4, SV2A, 1R and MC1 could be altered in PD patients with relevance to clinical measures of disease burden. Study 1 (Chapter 3) investigates the expression of the intracellular enzyme PDE4, using [11C]Rolipram PET, and its relevance to cognitive impairment and excessive daytime sleepiness (EDS), in 12 levodopa-treated PD patients. This work showed reductions in [11C]Rolipram volume of distribution (VT) in PD compared to healthy controls (n=12) in the caudate, thalamus, prefrontal and temporal thalamic nuclei, hypothalamus, posterior dorsolateral frontal cortex, medial frontal cortex and supplementary motor area. In PD, worse performance in spatial working memory correlated with lower [11C]Rolipram VT in the posterior dorsolateral frontal cortex, medial frontal cortex, supplementary motor area, precentral gyrus, caudate, and prefrontal thalamic nuclei. PD patients with EDS showed increased [11C]Rolipram VT in the caudate, hypothalamus, hippocampus and limbic striatum compared to patients without EDS. Furthermore, higher Epworth sleepiness scale scores correlated with increased [11C]Rolipram VT in the caudate, hypothalamus, hippocampus and limbic subdivisions of the striatum. The findings demonstrate loss of PDE4 expression in the striato-thalamo-cortical circuit, which is associated with deficits of spatial working memory in PD; and translate into humans preclinical data indicating that increased PDE4 could be associated with EDS in PD. Study 2 (Chapter 4) investigates cross-sectional and longitudinal changes in synaptic integrity, using [11C]UCB-J for SV2A, in drug-naïve PD patients. At baseline, [11C]UCB-J VT was reduced in the caudate, putamen, thalamus, brainstem, dorsal raphe, as well as across cortical regions in PD (n=11) compared with healthy controls (n=16). [11C]UCB-J VT was reduced in the locus coeruleus and substantia nigra but not reaching statistical significance. Lower brainstem [11C]UCB-J VT correlated with the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) Part-III and MDS-UPDRS total scores. No significant longitudinal changes were identified in seven PD patients, at a mean follow-up of 11±1.3 months, compared with baseline. The findings represent the first in vivo evidence of SV2A loss in drug-naïve PD, suggesting that loss of synaptic integrity likely occurs early in disease pathophysiology and has relevance to symptomatology. Studies in larger cohorts, with longer follow-up, will determine the validity of [11C]UCB-J PET as a marker to track disease progression. Study 3 (Chapter 5) investigates cross-sectional and longitudinal molecular pathology of the endoplasmic reticulum and mitochondria, using [11C]SA-4503 for 1R and [18F]BCPP-EF for MC1, respectively, in drug-naïve PD patients. This work showed non-significant lower levels of 1R and MC1, with the greatest effect size in the caudate and dorsal raphe, respectively, in PD (n=12) compared to healthy controls (n=16). Longitudinal analyses in nine PD patients, at a mean follow-up period of 11±1.3 months, showed the highest annualised increases of 1R in the caudate and MC1 in the putamen, but not reaching statistical significance. The results did not reach statistical significance in this cohort, possibly due to small sample size, early disease stage and short follow-up period. MC1 and 1R pathology warrants further in vivo investigations in PD. Exploratory analysis showed preliminary indications for the concurrent and colocalised loss of SV2A, 1R and MC1 in the caudate and brainstem regions in drug-naïve PD. These findings suggest the potential pathophysiological interplay between mitochondrial, endoplasmic reticulum and synaptic pathology in PD. Overall, the findings of this thesis indicate the presence of PDE4 and SV2A pathology, detected using molecular PET imaging, in PD patients. This work highlights the clinical relevance of PDE4 pathology to cognitive and sleep symptomatology, and SV2A pathology to the severity of motor symptoms and PD clinical burden. Future work is required to delineate changes in 1R and MC1 in PD and their relevance to symptomatology. Taken together, the findings from the studies constituting this thesis add to the evolving literature aiming to characterise the pathophysiology of PD

Lab-scale anaerobic treatment of organic waste streams : an Australian experience

Lab-scale anaerobic treatment of organic waste streams : an Australian experienc

Scoping report on the use of inner urban parks to provide respite care for carers of a child with a disability

Scoping report on the use of inner urban parks to provide respite care for carers of a child with a disabilit

The impact of note-taking and justice-vengeance motives on juror decision-making in a criminal murder trial

This study examined the effects of note-taking and justice-vengeance motives on juror decision making in a criminal trial. The study predicted that (1) jurors who took notes would render more appropriate decisions and recall more evidentiary content, (2) jurors high in vengeance would sentence the defendant more harshly and recall less probative information, and (3) note-taking would interact with justice and vengeance motives and impact upon sentencing and the recall of information. The sample of 149 jury eligible participants recruited from the Central Queensland community were assigned to one of two conditions (note-taking or non note-taking). All participants viewed the same murder trial and subsequently, rendered a verdict and sentencing decision, as well as recalled the trial facts. Lastly, they completed the Justice-Vengeance scale (Ho, ForsterLee, ForsterLee, & Crofts, 2002). Results of the study indicated that (1) jurors who took notes recalled more probative information than their non note-taking counterparts, (2) jurors high in vengeance sentenced the defendant more harshly and recalled fewer case-related facts, and (3) note-taking offset the vengeance motive for punishment, suggesting that note-taking would be a useful memory aid for vengeance-oriented jurors. The implications of these findings are discussed, as well as recommendations for future research in the field of juror decision-making

Alcohol-related harms and street service care in entertainment districts

Alcohol-related harms and street service care in entertainment district

Faecal immunochemical test (FIT) to triage patients with abdominal symptoms for suspected colorectal cancer in primary care: review of international use and guidelines

Background Recently, faecal immunochemical tests (FITs) have been introduced for investigation of primary care patients with low-risk symptoms of colorectal cancer (CRC), but recommendations vary across the world. This systematic review of clinical practice guidelines aimed to determine how FITs are used in symptomatic primary care patients and the underpinning evidence for these guidelines. Methods MEDLINE, Embase and TRIP databases were systematically searched, from 1 November 2008 to 1 November 2018 for guidelines on the assessment of patients with symptoms suggestive of CRC. Known guideline databases, websites and references of related literature were searched. The following questions were addressed: (i) which countries use FIT for symptomatic primary care patients; (ii) in which populations is FIT used; (iii) what is the cut-off level used for haemoglobin in the faeces (FIT) and (iv) on what evidence are FIT recommendations based. Results The search yielded 2433 publications; 25 covered initial diagnostic assessment of patients with symptoms of CRC in 15 countries (Asia, n = 1; Europe, n = 13; Oceania, n = 4; North America, n = 5; and South America, n = 2). In three countries (Australia, Spain and the UK), FIT was recommended for patients with abdominal symptoms, unexplained weight loss, change in bowel habit or anaemia despite a low level of evidence in the symptomatic primary care patient population. Conclusions Few countries recommend FITs in symptomatic patients in primary care either because of limited evidence or because symptomatic patients are directly referred to secondary care without triage. These results demonstrate a clear need for research on FIT in the symptomatic primary care population

Impaired connectivity within neuromodulatory networks in multiple sclerosis and clinical implications

There is mounting evidence regarding the role of impairment in neuromodulatory networks for neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. However, the role of neuromodulatory networks in multiple sclerosis (MS) has not been assessed. We applied resting-state functional connectivity and graph theory to investigate the changes in the functional connectivity within neuromodulatory networks including the serotonergic, noradrenergic, cholinergic, and dopaminergic systems in MS. Twenty-nine MS patients and twenty-four age- and gender-matched healthy controls performed clinical and cognitive assessments including the expanded disability status score, symbol digit modalities test, and Hamilton Depression rating scale. We demonstrated a diffuse reorganization of network topography (P < 0.01) in serotonergic, cholinergic, noradrenergic, and dopaminergic networks in patients with MS. Serotonergic, noradrenergic, and cholinergic network functional connectivity derangement was associated with disease duration, EDSS, and depressive symptoms (P < 0.01). Derangements in serotonergic, noradrenergic, cholinergic, and dopaminergic network impairment were associated with cognitive abilities (P < 0.01). Our results indicate that functional connectivity changes within neuromodulatory networks might be a useful tool in predicting disability burden over time, and could serve as a surrogate endpoint to assess efficacy for symptomatic treatments

Self-monitoring of blood pressure in pregnancy: a mixed methods evaluation of a national roll-out in the context of a pandemic

Objective: To evaluate how English maternity units implemented self-monitoring of blood pressure (SMBP) in pregnancy in response to the COVID-19 pandemic. Design: Mixed methods including surveys, anonymised patient data and in-depth interviews with women. Setting: Maternity units across England. Participants: 45 maternity units completed a survey about the implementation of SMBP (supported by the provision of guidance and blood pressure monitors) during the pandemic, 166 women completed a survey about their experiences of SMBP, and 23 women took part in in-depth interviews. Clinical data from 627 women undertaking SMBP were available from 13 maternity units. Results: SMBP was predominantly used to provide additional BP monitoring for hypertensive or high-risk pregnant women. Overall maternity units and women were positive about its use in terms of reducing the need for additional face-to-face contacts and giving women more control and insight into their own BP. However, there were challenges in setting up SMBP services rapidly and embedding them within existing care pathways, particularly around interpreting readings and managing the provision of monitors. Conclusions: A considerable proportion of maternity units in England commenced a SMBP service for hypertensive or high-risk women from March 2020. There is a need for further research into appropriate care pathways, including guidance around white coat or masked hypertension and the use of SMBP postnatally.</p

Rapid implementation of blood pressure self-monitoring in pregnancy at a UK NHS Trust during the COVID-19 pandemic: a quality improvement evaluation

Background This service evaluation describes the rapid implementation of self-monitoring of blood pressure (SMBP) into maternity care at a tertiary referral centre during the COVID-19 pandemic. It summarises findings, identifies knowledge gaps and provides recommendations for further research and practice. Intervention Pregnant and postpartum women monitored their blood pressure (BP) at home, with instructions on actions to take if their BP exceeded pre-determined thresholds. Some also conducted proteinuria self-testing. Data collection and analysis Maternity records, app data and staff feedback were used in interim evaluations to assess process effectiveness and guide adjustments, employing a Plan-Do-Study-Act and root cause analysis approach. Results Between March 2020 and August 2021, a total of 605 women agreed to self-monitor their BP, including 10 women with limited English. 491 registered for telemonitoring (81.2%). 21 (3.5%) took part in urine self-testing. Engagement was high and increased over time with no safety issues. Biggest concerns related to monitor supply and postnatal monitoring. In December 2020, SMBP was integrated into the standard maternity care pathway. Conclusions This project demonstrated successful integration of SMBP into maternity care. Early stakeholder engagement and clear guidance were crucial and community midwifery support essential. Supplying BP monitors throughout pregnancy and post partum could improve the service and fully digitised maternity records would aid data collection. More research is needed on SMBP in the postnatal period and among non-English speakers. These findings support efforts to implement app-supported self-monitoring and guide future research.</p

Cross-sectional diagnostic accuracy study of self-testing for proteinuria during hypertensive pregnancies: The UDIP study

Objective: To determine the accuracy of self-testing for proteinuria during pregnancy. Design: Diagnostic accuracy study. Setting: Antenatal clinics, maternity assessment units and inpatient wards at three hospital sites. Population or Sample: 345 pregnant women. Methods: Pregnant women self-tested in-clinic for urinary protein using visually read dipsticks with samples then sent for laboratory estimation of the spot protein-creatinine ratio (PCR) (primary reference test). Secondary index tests included testing by antenatal healthcare professionals and an automated colorimetric reader. Main outcome measures: Sensitivity, specificity, negative predictive value, positive predictive value and likelihood ratios were calculated for self-testing (primary index test) along with healthcare professional and colorimetric testing compared to the primary reference test (PCR). Results: 335/345 (97%) had sufficient data to be included in the analysis. Self-testing had a sensitivity of 0.71 (95% confidence interval [CI] 0.62–0.79) and a specificity of 0.89 (95% CI 0.84–0.92) compared to PCR. Sensitivity and specificity of testing by healthcare professionals and the colorimetric reader were similar: sensitivity 0.73 (95% CI 0.64–0.80) and 0.78 (95% CI 0.69–0.85), respectively; specificity 0.88 (95% CI 0.82–0.92) and 0.83 (95% CI 0.78–0.88), respectively. Conclusion: Pregnant women can visually read a dipstick for urinary protein with similar accuracy to antenatal healthcare professionals. Automated colorimetric testing was not significantly different, in contrast to some previous studies. Self-testing has the potential to form part of a self-monitoring regime in pregnancy.</p