Sleep, Perivascular Spaces, and Cognition in Alzheimer's Disease and Parkinson's Disease

Cognitive dysfunction, particularly involving memory and executive function, is a core component of neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease. Two factors that are likely related to and may contribute to these cognitive deficits are sleep changes and enlarged perivascular spaces, which are an indicator of cerebral small vessel disease. In addition to being related to cognition, they may also be interconnected, further exacerbating their impact on cognition. This dissertation lays out our current knowledge on these topics and explores the association of these factors with cognition. In this dissertation, I investigated the relationship that perivascular space volumes and sleep (i.e., sleep duration or sleep quality) have with cognitive performance and cognitive status category in Alzheimer’s disease and Parkinson’s disease. Study 1 included individuals with Alzheimer’s-related mild cognitive impairment (MCI) or dementia. Among the individuals with Alzheimer’s disease, longer sleep durations were related to lower memory and executive function performance, and larger white matter perivascular space volumes exacerbated the relationship between longer sleep durations and memory after accounting for relevant covariates. Study 2 included individuals with Parkinson’s disease with intact cognition, MCI, or dementia. Analyses revealed an interaction in which individuals with Parkinson’s disease with smaller white matter perivascular space volumes and better sleep quality exhibited better executive function performance after accounting for relevant covariates. There was also a significant negative correlation between sleep quality and white matter perivascular spaces, and this correlation stayed relatively consistent when covariates were individually included in the model. Finally, analyses across cognitive status groupings revealed that individuals with Parkinson’s disease with MCI exhibited significantly larger white matter perivascular space volumes relative to those with intact cognition, but no other group differences were observed. These results indicate that cognition has a complex relationship with perivascular spaces and/or sleep in Alzheimer’s disease and Parkinson’s disease and that some indicators of sleep and perivascular space volume may be related to cognitive abilities in these populations

Sleep, Perivascular Spaces, and Cognition in Alzheimer's Disease and Parkinson's Disease

Cognitive dysfunction, particularly involving memory and executive function, is a core component of neurodegenerative conditions, such as Alzheimers disease and Parkinsons disease. Two factors that are likely related to and may contribute to these cognitive deficits are sleep changes and enlarged perivascular spaces, which are an indicator of cerebral small vessel disease. In addition to being related to cognition, they may also be interconnected, further exacerbating their impact on cognition. This dissertation lays out our current knowledge on these topics and explores the association of these factors with cognition. In this dissertation, I investigated the relationship that perivascular space volumes and sleep (i.e., sleep duration or sleep quality) have with cognitive performance and cognitive status category in Alzheimers disease and Parkinsons disease. Study 1 included individuals with Alzheimers-related mild cognitive impairment (MCI) or dementia. Among the individuals with Alzheimers disease, longer sleep durations were related to lower memory and executive function performance, and larger white matter perivascular space volumes exacerbated the relationship between longer sleep durations and memory after accounting for relevant covariates. Study 2 included individuals with Parkinsons disease with intact cognition, MCI, or dementia. Analyses revealed an interaction in which individuals with Parkinsons disease with smaller white matter perivascular space volumes and better sleep quality exhibited better executive function performance after accounting for relevant covariates. There was also a significant negative correlation between sleep quality and white matter perivascular spaces, and this correlation stayed relatively consistent when covariates were individually included in the model. Finally, analyses across cognitive status groupings revealed that individuals with Parkinsons disease with MCI exhibited significantly larger white matter perivascular space volumes relative to those with intact cognition, but no other group differences were observed. These results indicate that cognition has a complex relationship with perivascular spaces and/or sleep in Alzheimers disease and Parkinsons disease and that some indicators of sleep and perivascular space volume may be related to cognitive abilities in these populations

Analysis of the inhibitory activity and mode of action of novel antimicrobial organic nanoparticles

Nanoparticles are difficult to define specifically hut usually encompass engineered particles ranging in size from 1 to 1000 nm. The physical and chemical properties. of nanoparticles can vary significantly from those of their bulk counterparts largely due to their large surface area to volume ratios. Approximately 40% antimicrobial agents emerging from development programs exhibit low solubility. This results in inadequate bioavailability, pharmacokinetics and stability. The use of appropriate nano-carriers has been shown to improve the efficacy of antimicrobial agents with the' explanation that the biodistribution of the antimicrobial follows that of the carrier rather than being dependent on the physiochemical properties of the compound itself. Therefore characteristics such as solubility and bioavailability can be enhanced. Here, a range of poorly water-soluble antifungal agents, biocides and an antibiotic were processed using a novel emulsion-evaporation technique to produce organic nanoparticles. These preparations were characterised on the basis of size and zeta potential and tested for inhibitory activity against relevant microorganisms including: C. albicans, E. coli, S. aureus and MRSA. Nanoparticle formulated antimicrobials were usually more inhibitory than the equivalent eo-solvent dissolved antimicrobials or water dissolved salt equivalents where available. However, efficacy was dependent on nanoparticle composition. Optimisation of nanoparticle dichlorophen inhibitory activity was attempted using a generic polymer and surfactant screen. The results were subsequently utilised in a computer modelling design approach. Due to formulation problems, predictive optimisation was not possible. However, nanoparticles of dichlorophen were usually most inhibitory when increased loading ratios of sodium dodecyl sulphate and hydroxy propyl methyl cellulose and reduced loading ratios of dichlorophen and gelatin were used in the preparation. No correlations between particle size, zeta potential and inhibitory activity were identified. No correlation between the inhibitory activities of blank nanoparticles and active equivalents were identified. A detailed series of controls prepared for one formulation usually produced low MIC values. However, the nanoparticle formulation exhibited the greatest efficacy. This suggested that enhanced activity due to nanoparticle formulation of the antimicrobial was not simply attributed to a synergistic effect between the different materials. The molecular response of S. aureus SH1000 to nanoparticle-formulated ciprofloxacin was investigated using RNA-Seq. All 5 investigated treatments induced differential gene expression. Moreover, comparative analysis between nanoparticle formulated and DMSO dissolved ciprofloxacin treated S. aureus SH1000 revealed the differential expression of 61 transcripts. No significant differential expression in DNA repair and replication targets was observed. This suggested that ciprofloxacin may not be more bioavailable to S. aureus SH1000 and therefore enhanced efficacy is not attributed to increased bioavailability. However, genes involved in stress response and cell division were shown to be up regulated in response to nanoparticle delivery. The results also revealed that 39 transcripts were differentially expressed due to nanoparticle exposure alone and these included stress response, cell division and virulence-associated genes. The identified differentially expressed transcripts are unlikely to account for the enhanced efficacy associated with nanoparticle delivery. Nanoparticles represent a novel approach to the delivery of hydrophobic anti microbials in aqueous dispersions. The advantageous features of nanoparticles are discussed throughout this thesis. The study used a variety of approaches with the aim of elucidating the mechanisms underpinning the observed enhancement in antimicrobial activity. The improved efficacy observed could not be correlated with any physical characteristics of the particles used. The transcriptional profiling results suggested that the improved antimicrobial activity observed was not associated with differential molecular targeting, and challenges current concepts that link enhanced efficacy with increased bioavailability

Long-Acting Injectable Statins-Is It Time for a Paradigm Shift?

In recent years, advances in pharmaceutical processing technologies have resulted in development of medicines that provide therapeutic pharmacokinetic exposure for a period ranging from weeks to months following a single parenteral administration. Benefits for adherence, dose and patient satisfaction have been witnessed across a range of indications from contraception to schizophrenia, with a range of long-acting medicines also in development for infectious diseases such as HIV. Existing drugs that have successfully been formulated as long-acting injectable formulations have long pharmacokinetic half-lives, low target plasma exposures, and low aqueous solubility. Of the statins that are clinically used currently, atorvastatin, rosuvastatin, and pitavastatin may have compatibility with this approach. The case for development of long-acting injectable statins is set out within this manuscript for this important class of life-saving drugs. An overview of some of the potential development and implementation challenges is also presented

Are practical recommendations practiced? A national multi-centre cross-sectional study on frequency of visual field testing in glaucoma

Aim: To estimate current clinical practice for frequency of visual field (VF) monitoring in glaucoma in England. Methods: A cross-sectional review of all patients with chronic open angle glaucoma (COAG) attending specialist glaucoma clinics at six hospitals in England was performed. The number of VF tests undertaken prior to the study date and during the first 2 years since diagnosis were recorded and compared with European Glaucoma Society (EGS) guidelines for newly-diagnosed patients. Clinician-requested monitoring intervals were compared with intervals from the National Institute of Clinical Excellence (NICE) guidelines, and the relationships with disease severity, intraocular pressure (IOP) and glaucoma progression status were reviewed. Results: One-hundred and four patients with COAG were included. 73 patients had at least 2 years of follow-up. Median (IQR) total number of VF tests and in the first 2 years of diagnosis were 4 (2–7) and 2 (2–3), respectively. No patients met EGS guidelines, but 87% of patients had their monitoring intervals requested in accordance with NICE guidelines. These intervals were not related to disease severity or VF stability (Kruskal–Wallis test, p=0.25) but shortened significantly when IOP control was inadequate or when the overall clinical impression was disease progression (p<0.001). Conclusions Most newly-diagnosed COAG patients receive less than three VFs in the first 2 years following diagnosis and an average of 0.7 VF per year over the duration of follow-up

Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV 2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

Background: Ronapreve demonstrated clinical application in post-exposure prophylaxis, mild/moderate disease and in the treatment of seronegative patients with severe COVID19 prior to the emergence of the Omicron variant in late 2021. Numerous reports have described loss of in vitro neutralisation activity of Ronapreve and other monoclonal antibodies for BA.1 Omicron and subsequent sub-lineages of the Omicron variant. With some exceptions, global policy makers have recommended against the use of existing monoclonal antibodies in COVID19. Gaps in knowledge regarding the mechanism of action of monoclonal antibodies are noted, and further preclinical study will help understand positioning of new monoclonal antibodies under development. Objectives: The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication as a paradigm for a monoclonal antibody combination. The study also sought to confirm absence of in vivo activity against BA.1 Omicron (B.1.1.529) relative to the Delta (B.1.617.2) variant. Methods: Virological efficacy of Ronapreve was assessed in K18-hACE2 mice inoculated with either the SARS-CoV-2 Delta or Omicron variants. Viral replication in tissues was quantified using qRT-PCR to measure sub-genomic viral RNA to the E gene (sgE) as a proxy. A histological examination in combination with staining for viral antigen served to determine viral spread and associated damage. Results: Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post infection, for the Delta variant but not the Omicron variant of SARS-CoV-2 at doses 2-fold higher than those shown to be active against previous variants of the virus. It also appeared to block brain infection which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a mild multifocal granulomatous inflammation in which the virus appeared to be confined. A similar tendency was also observed in Omicron infected, Ronapreve-treated animals. Conclusions: The current study provides evidence of an altered tissue response to the SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data also demonstrate that experimental designs that reflect the treatment use case are achievable in animal models for monoclonal antibodies deployed against susceptible variants. Extreme caution should be taken when interpreting prophylactic experimental designs when assessing plausibility of monoclonal antibodies for treatment use cases

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters

Pibrentasvir (PIB) has been demonstrated to block exonuclease activity of the SARS-CoV-2 polymerase, protecting favipiravir (FVP) and remdesivir (RDV) from post-incorporation excision and eliciting antiviral synergy in vitro. The present study investigated the chemoprophylactic efficacy of PIB, FVP, RDV, FVP with PIB, or RDV with PIB dosed intranasally twice a day, using a Syrian golden hamster contact transmission model. Compared to the saline control, viral RNA levels were significantly lower in throat swabs in FVP (day 7), RDV (day 3, 5, 7), and RDV+PIB (day 3, 5) treatment groups. Similarly, findings were evident for nasal turbinate after PIB and RDV treatment, and lungs after PIB, FVP, and FVP+PIB treatment at day 7. Lung viral RNA levels after RDV and RDV+PIB treatment were only detectable in two animals per group, but the overall difference was not statistically significant. In situ examination of the lungs confirmed SARS-CoV-2 infection in all animals, except for one in each of the RDV and RDV+PIB treatment groups, which tested negative in all virus detection approaches. Overall, prevention of transmission was observed in most animals treated with RDV, while other agents reduced the viral load following contact transmission. No benefit of combining FVP or RDV with PIB was observed