Biology subjects

Mackay, C. E.

Publications and source records attributed to Mackay, C. E..

7 recordsLinked to original sources

bioRxiv2023

Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging

LRRK2 mutations are the most common cause of dominantly inherited Parkinsons disease (PD). Here, we conducted PET imaging in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride. We interrogate presynaptic integrity and postsynaptic dopamine receptor availability, and compared these to non-transgenic rats. LRRK2 mutant rats displayed similar [18F]FDOPA uptake to non-transgenic animals, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, exhibiting regionally selective binding increase in the dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to the dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit observed in this genotype. These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, detecting upregulation of D2 receptors that parallels observations in early human sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.

neuroscience↗

bioRxiv2023

A comprehensive analysis of APOE genotype effects on human brain structure in the UK Biobank

Alzheimers disease (AD) risk is increased in carriers of the apolipoprotein E (APOE) {varepsilon}4 allele and decreased in {varepsilon}2 allele carriers compared with the {varepsilon}3{varepsilon}3 genotype. The aim of this study was to determine whether: APOE genotype affects brain grey (GM) or white matter (WM) structure; and if differences exist, the age when they become apparent and whether there are differential effects by sex. We used cross-sectional magnetic resonance imaging data from ~43,000 (28,494 after pre-processing) white British cognitively healthy participants (7,446 APOE {varepsilon}4 carriers) aged 45-80 years from the UK Biobank cohort and investigated image-derived phenotypes (IDPs). We observed no statistically significant effects of APOE genotype on GM structure volumes or median T2* in subcortical structures, a measure related to iron content. Volume of white matter hyperintensities differed significantly between APOE genotype groups with higher volumes in APOE {varepsilon}4{varepsilon}4 (effect size 0.14 standard deviations [SD]) and {varepsilon}3{varepsilon}4 carriers (effect size 0.04 SD) but no differences in {varepsilon}2 carriers compared with {varepsilon}3{varepsilon}3 carriers. WM integrity measures in the dorsal (mean diffusivity [MD]) and ventral cingulum (MD and intracellular volume fraction), posterior thalamic radiation (MD and isotropic volume fraction) and sagittal stratum (MD) indicated lower integrity in APOE {varepsilon}4{varepsilon}4 carriers (effect sizes around 0.2-0.3 SD) and {varepsilon}3{varepsilon}4 (effect sizes around 0.05 SD) carriers but no differences in {varepsilon}2 carriers compared with the APOE {varepsilon}3{varepsilon}3 genotype. Effects did not differ between men and women. APOE {varepsilon}4 homozygotes appeared to have lower WM integrity specifically at older ages with a potentially steeper decline of WM integrity from the age of 60 that corresponds to around 5 years greater "brain age". APOE genotype affects various white matters measures, which might be indicative of preclinical AD processes. This hypothesis can be assessed in future when clinical outcomes become available.

neuroscience↗

bioRxiv2021

A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation

Polycystin-1 (PC-1, PKD1), a receptor-like protein expressed by the Pkd1 gene, is present in a wide variety of cell types, but its cellular location, signaling mechanisms and physiological functions are poorly understood. Here, by studying tamoxifen-inducible, endothelial cell (EC)-specific Pkd1 knockout (Pkd1 ecKO) mice, we show that flow activates PC-1-mediated, Ca2+-dependent cation currents in ECs. EC-specific PC-1 knockout attenuates flow-mediated arterial hyperpolarization and vasodilation. PC-1-dependent vasodilation occurs over the entire functional shear stress range and primarily via the activation of nitric oxide synthase (NOS), with a smaller contribution from small-conductance Ca2+-activated K+ (SK) channels. EC-specific PC-1 knockout increases systemic blood pressure without altering kidney anatomy. PC-1 coimmunoprecipitates with polycystin-2 (PC-2, PKD2), a TRP polycystin channel, and clusters of both proteins locate in nanoscale proximity in the EC plasma membrane. Knockout of either PC-1 or PC-2 (Pkd2 ecKO mice) abolishes surface clusters of both PC-1 and PC-2 in ECs. Single knockout of PC-1 or PC-2 or double knockout of PC-1 and PC-2 (Pkd1/Pkd2 ecKO mice) similarly attenuates flow-mediated vasodilation. Flow stimulates non-selective cation currents in ECs that are similarly inhibited by either PC-1 or PC-2 knockout or by interference peptides corresponding to the C-terminus coiled-coil domains present in PC-1 or PC-2. In summary, we show that PC-1 regulates arterial contractility and demonstrate that this occurs through the formation of an interdependent signaling complex with PC-2 in endothelial cells. Flow stimulates PC-1/PC-2 clusters in the EC plasma membrane, leading to Ca2+ influx, NOS and SK channel activation, vasodilation and a reduction in blood pressure.

physiology↗

bioRxiv2021

Individual variation in brain microstructural-cognition relationships in aging

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52{+/-} 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 {+/-}4.9 years) and late-life (mean age = 67.7 {+/-}4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 {+/-}4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions that are both positively and negatively associated with cortical structure.

neuroscience↗

bioRxiv2020

Integrating large-scale neuroimaging research datasets: harmonisation of white matter hyperintensity measurements across Whitehall and UK Biobank datasets

Large scale neuroimaging datasets present the possibility of providing normative distributions for a wide variety of neuroimaging markers, which would vastly improve the clinical utility of these measures. However, a major challenge is our current poor ability to integrate measures across different large-scale datasets, due to inconsistencies in imaging and non-imaging measures across the different protocols and populations. Here we explore the harmonisation of white matter hyperintensity (WMH) measures across two major studies of healthy elderly populations, the Whitehall II imaging sub-study and the UK Biobank. We identify pre-processing strategies that maximise the consistency across datasets and utilise multivariate regression to characterise sample differences contributing to study-level differences in WMH variations. We also present a parser to harmonise WMH-relevant non-imaging variables across the two datasets. We show that we can provide highly calibrated WMH measures from these datasets with: (1) the inclusion of a number of specific standardised processing steps; and (2) appropriate modelling of sample differences through the alignment of demographic, cognitive and physiological variables. These results open up a wide range of applications for the study of WMHs and other neuroimaging markers across extensive databases of clinical data. HIGHLIGHTSO_LIWe harmonised measures of WMHs across two studies on healthy ageing C_LIO_LISpecific pre-processing strategies can increase comparability across studies C_LIO_LIModelling of biological differences is crucial to provide calibrated measures C_LI

neuroscience↗

bioRxiv2019

Hippocampal volume across age: Nomograms derived from over 19,700 people in UK Biobank

Measurement of hippocampal volume has proven useful to diagnose and track progression in several brain disorders, most notably in Alzheimers disease (AD). For example, an objective evaluation of a patients hippocampal volume status may provide important information that can assist diagnosis or risk stratification of AD. However, clinicians and researchers require access to age-related normative percentiles to reliably categorise a patients hippocampal volume as being pathologically small. Here we analysed effects of age, sex, and hemisphere on the hippocampus and neighbouring temporal lobe volumes, in 19,793 generally healthy participants in the UK Biobank. A key finding of the current study is a significant acceleration in the rate of hippocampal volume loss in middle age, more pronounced in females than in males. In this report, we provide normative values for hippocampal and total grey matter volume as a function of age for reference in clinical and research settings. These normative values may be used in combination with our online, automated percentile estimation tool to provide a rapid, objective evaluation of an individuals hippocampal volume status. The data provide a large-scale normative database to facilitate easy age-adjusted determination of where an individual hippocampal and temporal lobe volume lies within the normal distribution.

neuroscience↗

bioRxiv2018

Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure

Systemic blood pressure is determined, in part, by arterial smooth muscle cells (myocytes). Several Transient Receptor Potential (TRP) channels are proposed to be expressed in arterial myocytes, but it is unclear if these proteins control physiological blood pressure and contribute to hypertension in vivo. We generated the first inducible, smooth muscle-specific knockout for a TRP channel, namely for PKD2 (TRPP1), to investigate arterial myocyte and blood pressure regulation by this protein. Using this model, we show that intravascular pressure and 1-receptors activate PKD2 channels in arterial myocytes of different systemic organs. PKD2 channel activation in arterial myocytes leads to an inward Na+ current, membrane depolarization and vasoconstriction. Inducible, smooth muscle cell-specific PKD2 knockout lowers both physiological blood pressure and hypertension and prevents pathological arterial remodeling during hypertension. In summary, we show for the first time that arterial myocyte PKD2 channels control systemic blood pressure and targeting reduces high blood pressure.

neuroscience↗