Cognitive impairment in Parkinson’s disease: Impact and identification of comorbid disease mechanisms

Cognitive impairment is a common and debilitating feature of Parkinson's disease (PD). While it is primarily caused by cerebral propagation of α-synuclein protein, evidence of comorbid diseases is frequently found in autopsy samples. This includes tau and amyloid-β pathologies – the hallmarks of Alzheimer's disease (AD) – and cerebrovascular damage. Comorbid diseases may influence cognition in PD over and above the effects of α-synuclein alone, and this influence may interfere with the results of clinical trials of next-generation medical treatments that target α-synuclein. The primary aims of this thesis were to define the extent and the effects of comorbid disease mechanisms in PD, and to identify viable clinical strategies for detecting coexistent disorders in vivo. Methods included a systematic review of autopsy studies; a factor analysis of the Montreal Cognitive Assessment (MoCA); a regression analysis of two genes; and a cross-sectional neuropsychological study of 45 patients. The systematic review found significant tau pathology in around one-third of PD patients at death. Significant amyloid-β pathology affected over half, and conferred a worse prognosis. Other pathologies (e.g. cerebrovascular disease) were less common, and did not contribute to dementia in PD. The factor analysis showed that the MoCA has limited value for distinguishing cognitive profiles in PD, suggesting that it should be used only for screening. The genetic project found that variation in the APOE gene influenced cognitive decline in early PD; the effect varied between men and women. Variation in MAPT did not affect cognitive decline. Finally, the neuropsychological study found that over half of cognitively impaired PD patients could be clinically diagnosed with a coexistent cognitive disorder, with AD being the most common. Collectively, the results of this thesis show that comorbid diseases, particularly AD, are common in PD, and these contribute to the cognitive phenotype. Consequently, a clinical assessment incorporating selected neuropsychological tests can be used to identify comorbid diseases in PD patients. It is important to consider the potentially confounding impact of multimorbidity in the design and analysis of clinical trials that aim to modulate neurodegeneration in PD by targeting α-synuclein

On the Impact of Antenna Topologies for Massive MIMO Systems

Approximate expressions for the spatial correlation of cylindrical and uniform rectangular arrays (URA) are derived using measured distributions of angles of departure (AOD) for both the azimuth and zenith domains. We examine massive multiple-input-multiple-output (MIMO) convergence properties of the correlated channels by considering a number of convergence metrics. The per-user matched filter (MF) signal-to-interference-plus-noise ratio (SINR) performance and convergence rate, to respective limiting values, of the two antenna topologies is also explored.Comment: 6 pages, 6 figure

On the Convergence of Massive MIMO Systems

In this paper we examine convergence properties of massive MIMO systems with the aim of determining the number of antennas required for massive MIMO gains. We consider three characteristics of a channel matrix and study their asymptotic behaviour. Furthermore, we derive ZF SNR and MF SINR for a scenario of unequal receive powers. In our results we include the effects of spatial correlation. We show that the rate of convergence of channel metrics is much slower than that of the ZF/MF precoder properties.Comment: 6 pages, 6 figures, ICC 201

Patterns of glacio‐isostatic adjustment in mainland Scotland: new data from western central Scotland, proximal to the zone of maximum rebound

The results of geomorphological mapping and survey of Lateglacial and Holocene displaced shorelines in the Clyde estuary and around Loch Lomond, western central Scotland are described. On the basis of morphology, sedimentology, altitude and radiocarbon dating, four discrete shorelines are identified and are correlated with previously identified Scottish displaced shorelines. The shoreline formerly referred to as the Main Postglacial Shoreline is renamed the Menteith Shoreline. This body of data, combined with data on displaced shorelines for Scotland as a whole has been analysed using Gaussian quadratic trend surface analysis in order to determine the centre of glacio‐isostatic displacement for each shoreline. These Gaussian models of palaeo‐relative sea‐level suggest that the zone of greatest displacement lay NNW of Loch Lomond in the Lateglacial then moved SSE to the region of Loch Lomond during the Holocene and the Clyde in the Late Holocene. The factors responsible for the movement of the zone of greatest uplift are discussed, including temporal variations in the ice‐sheet thickness, variations in water load in the adjacent sea‐lochs and neotectonic processes. Comparison is made with glacial isostatic adjustment (GIA) models. A sensitivity analysis has been carried out on the use of Gaussian trend surface analysis glacio‐isostatic modelling and this is included in the research evaluation, and reported in full in the Supporting Information files, along with the raw data used throughout this study

Delivery of Interventions for Multiple Lifestyle Factors in Primary Healthcare Settings:A Narrative Review Addressing Strategies for Effective Implementation

The escalating burden of lifestyle-related diseases stands as a critical global public health challenge, contributing substantially to the prevalence of chronic conditions and a large portion of premature mortality. Despite this, concise evidence-based lifestyle interventions targeting physical inactivity, nutrition, alcohol and smoking continue to be underutilised. Although good evidence exists for addressing the four lifestyle-related risk factors independently, rarely do these present in isolation. Evidence is lacking regarding how to integrate interventions targeting multiple risk factors. Consequently, this paper aims to provide an overview of the evidence for delivering multiple interventions in primary healthcare settings. Different lifestyle factors are inter-related, with decisions around ordering of the delivery of multiple lifestyle interventions an important consideration. There is evidence supporting the effectiveness of addressing some lifestyle factors simultaneously (e.g., physical activity and nutrition), although smoking cessation may be delivered best in a sequential approach. While the World Health Organisation highlights four key lifestyle factors (nutrition, physical activity, alcohol and smoking), incorporating additional elements such as sleep, mental well-being and social connectedness offers a holistic framework for promoting well-being. Despite the presentation of multiple behaviour risk factors being commonplace in healthcare settings, the evidence (outlined in the paper) for how best to deliver interventions to address this is limited, with further research and subsequent clinical guidance required. In order to address the barriers to delivering lifestyle interventions in primary care, innovation will be required. The use of non-medical personnel, social prescribers and health coaches has the potential to alleviate time constraints, whilst mounting evidence exists for group consultations for addressing lifestyle-related non-communicable diseases (NCDs). If the challenges to implementation can be addressed, and if healthcare systems can adapt for the promotion of healthy lifestyles, the impact of NCDs can be mitigated.</p

Amplification of a radially-polarised beam in an Yb:YAG thin slab

Amplification of an axially-symmetric, doughnut-shaped radially-polarised beam at 1030nm in a diode-bar-pumped double-pass thin Yb:YAG slab amplifier architecture without degradation in polarisation purity is demonstrated. Preliminary experiments yielded a small-signal gain of 9dB for 50W of incident pump power while maintaining the polarisation purity of the seed beam

Genetic analysis of radiation resistance in Haloferax volcanii

Archaea,considered as the third domain of life alongside bacteria and eukaryotes, represent a highly diverse group of organisms. Attention to archaeal DNA repair pathways has been considerable for a long time and many archaeal species inhabit extreme environmental niches where there is a higher rate of genomic insult. It is therefore thought that such archaea possess efficient and robust novel DNA repair pathways, allowing survival in such conditions. Such extreme conditions can also be found beyond Earth, such as on the surface of Mars and investigation into DNA repair in the archaea represents a pivotal stepping stone to understanding how organisms adapt to “Martian” conditions. In the work presented here, the gene encoding a XerCD-like integrase, found within the integrated prophage on the main chromosome of Haloferax volcanii was isolated from a genomic library and overexpression leads to increased resistance to genotoxic stress imposed by ultraviolet light and mitomycin C. Deletion of this gene does not impact the growth rate or sensitivity to DNA damaging agents, likely due to the presence of an additional eleven homologs within the genome. Deletion of the entire prophage region does not delete all XerCD homologs, yet shows an even larger increase in cell survival after UV and MMC treatment. Genetic analysis suggests that XerCD may interact, directly or indirectly, with UvrC as overexpression of XerCD somewhat mitigates the UV sensitivity seen in a UvrC deleted strain. The defect is not fully complemented, so further study is required. Previous data has shown that various XerCD-like integrases are upregulated in the presence of MMC. Real-time PCR carried out here indicates that phage induction may occur when cells are treated with DNA damaging agents, which may contribute to the cell death seen, and therefore strains deleted for the integrated prophage may be more beneficial to use for DNA damaging assays due to increased cellular survival. Replication Protein A transcripts are upregulated in response to MMC, aiding in interstrand crosslink repair. The interplay between XerCD-like integrases, that usually function in DNA replication, and DNA repair warrants further study

Dual NHC/photoredox catalytic synthesis of 1,4-diketones using an MR-TADF photocatalyst (DiKTa)

The authors thank AstraZeneca and the University of St Andrews for funding (Case studentship to C.P.).The use of the recently reported organic multi-resonant thermally activated delayed fluorescence (MR-TADF) photocatalyst DiKTa allows for the modular synthesis of 1,4-diketones under mild and metal-free conditions. The reaction proceeds via a three-component relay process in the presence of an N-heterocyclic carbene (NHC) organocatalyst.Publisher PDFPeer reviewe