Functional-biochemical relationships in the posterior cingulate cortex, and their application to the genetic risk of Alzheimer’s disease

A major challenge in Alzheimer’s disease (AD) research is to improve understanding of the earliest brain changes associated with AD, in order to develop treatments to combat this disease. One strategy potentially able to inform this need is the study of brain regions associated with AD in young adults at genetic risk of AD. A key region of increasing interest to AD researchers is the posterior cingulate cortex (PCC). Despite being implicated in AD pathogenesis, its function is not well understood. Neuroimaging studies in young adults who carry the strongest genetic risk factor for AD, the Apolipoprotein (APOE) E4 allele, have detected glucose metabolism, activity and functional connectivity alterations in the PCC. A better understanding of PCC function would aid interpretation of these changes, to improve insight into AD pathogenesis. This thesis applied functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) to study PCC activity correlates with brain metabolites in vivo (Chapters 3 and 4), prior to investigating whether these metabolites might be altered in APOE-E4 carriers aged 18-25 years (Chapter 5). Chapters 3 and 4 detected a category-sensitive fMRI response and fMRI-MRS relationship for the scene condition of a perception task and a working memory task, specifically a positive correlation between PCC activity and the metabolite N-acetyl- aspartate (tNAA), a marker of neuronal integrity associated with neuronal mitochondrial metabolism. The scene conditions of these paradigms previously elicited an altered pattern of PCC activity in young APOE-E4 carriers. Chapter 5 therefore compared PCC tNAA and other MRS metabolites between young APOE-E4 carriers and non-carriers. No MRS differences, however, were evident between APOE groups. These findings contribute to our understanding of the biochemistry underpinning PCC activity, but suggest that an alteration in such a pathway may not be linked with the activity alterations detected in young APOE-E4 carriers

Shared neural processes support semantic control and action understanding

Executive-semantic control and action understanding appear to recruit overlapping brain regions but existing evidence from neuroimaging meta-analyses and neuropsychology lacks spatial precision; we therefore manipulated difficulty and feature type (visual vs. action) in a single fMRI study. Harder judgements recruited an executive-semantic network encompassing medial and inferior frontal regions (including LIFG) and posterior temporal cortex (including pMTG). These regions partially overlapped with brain areas involved in action but not visual judgements. In LIFG, the peak responses to action and difficulty were spatially identical across participants, while these responses were overlapping yet spatially distinct in posterior temporal cortex. We propose that the co-activation of LIFG and pMTG allows the flexible retrieval of semantic information, appropriate to the current context; this might be necessary both for semantic control and understanding actions. Feature selection in difficult trials also recruited ventral occipital-temporal areas, not implicated in action understanding

Shared neural processes support semantic control and action understanding

Executive-semantic control and action understanding appear to recruit overlapping brain regions but existing evidence from neuroimaging meta-analyses and neuropsychology lacks spatial precision; we therefore manipulated difficulty and feature type (visual vs. action) in a single fMRI study. Harder judgements recruited an executive-semantic network encompassing medial and inferior frontal regions (including LIFG) and posterior temporal cortex (including pMTG). These regions partially overlapped with brain areas involved in action but not visual judgements. In LIFG, the peak responses to action and difficulty were spatially identical across participants, while these responses were overlapping yet spatially distinct in posterior temporal cortex. We propose that the co-activation of LIFG and pMTG allows the flexible retrieval of semantic information, appropriate to the current context; this might be necessary both for semantic control and understanding actions. Feature selection in difficult trials also recruited ventral occipital-temporal areas, not implicated in action understanding

Evidence against altered excitatory/inhibitory balance in the posteromedial cortex of young adult APOE E4 carriers: a resting state 1H-MRS study

A strategy to gain insight into early changes that may predispose people to Alzheimer's disease (AD) is to study the brains of younger cognitively healthy people that are at increased genetic risk of AD. The Apolipoprotein (APOE) E4 allele is the strongest genetic risk factor for AD, and several neuroimaging studies comparing APOE E4 carriers with non-carriers at age ∼20–30 years have detected hyperactivity (or reduced deactivation) in posteromedial cortex (PMC), a key hub of the default network (DN), which has a high susceptibility to early amyloid deposition in AD. Transgenic mouse models suggest such early network activity alterations may result from altered excitatory/inhibitory (E/I) balance, but this is yet to be examined in humans. Here we test the hypothesis that PMC fMRI hyperactivity could be underpinned by altered levels of excitatory (glutamate) and/or inhibitory (GABA) neurotransmitters in this brain region. Forty-seven participants (20 APOE E4 carriers and 27 non-carriers) aged 18–25 years underwent resting-state proton magnetic resonance spectroscopy (1H-MRS), a non-invasive neuroimaging technique to measure glutamate and GABA in vivo. Metabolites were measured in a PMC voxel of interest and in a comparison voxel in the occipital cortex (OCC). There was no difference in either glutamate or GABA between the E4 carriers and non-carriers in either MRS voxel, or in the ratio of glutamate to GABA, a measure of E/I balance. Default Bayesian t-tests revealed evidence in support of this null finding. Our findings suggest that PMC hyperactivity in APOE E4 carriers is unlikely to be associated with, or possibly may precede, alterations in local resting-state PMC neurotransmitters, thus informing our understanding of the spatio-temporal sequence of early network alterations underlying APOE E4 related AD risk

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: A multimodal fMRI and 1H-MRS study

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease and disease risk, the underlying neurochemical modulators of PCu/PCC's task‐evoked activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether interindividual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting‐state 1H‐MRS. Forty healthy young adult participants completed an fMRI perceptual odd‐one‐out task for scenes, objects and faces. 1H‐MRS metabolites N‐acetyl‐aspartate (tNAA), glutamate (Glx) and γ‐amino‐butyric acid (GABA+) were quantified via PRESS and MEGA‐PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (vs. faces and objects and also vs. baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A voxel‐wise regression analysis restricted to the PCu/PCC 1H‐MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene‐related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on interindividual differences in the task‐driven activity of a key brain hub

Association of travel time, patient characteristics, and hospital quality with patient mobility for breast cancer surgery: A national population-based study

BACKGROUND: This national study investigated hospital quality and patient factors associated with treatment location for breast cancer surgery. METHODS: By using linked administrative data sets from the English National Health Service, the authors identified all women diagnosed between January 2, 2016, and December 31, 2018, who underwent breast-conserving surgery (BCS) or a mastectomy with or without immediate breast reconstruction. The extent to which patients bypassed their nearest hospital was investigated using a geographic information system (ArcGIS). Conditional logistic regressions were used to estimate the impact of travel time, hospital quality, and patient characteristics. RESULTS: 22,622 Of 69,153 patients undergoing BCS, 22,622 (32.7%) bypassed their nearest hospital; and, of 23,536 patients undergoing mastectomy, 7179 (30.5%) bypassed their nearest hospital. Women who were younger, without comorbidities, or from rural areas were more likely to travel to more distant hospitals (p < .05). Patients undergoing BCS (odds ratio [OR], 1.85; 95% confidence interval [CI], 1.36-2.50) or mastectomy (OR, 1.52; 95% CI, 1.14-2.02) were more likely to be treated at specialist breast reconstruction centers despite not undergoing the procedure. Patients receiving mastectomy and immediate breast reconstruction were more likely to travel to hospitals employing surgeons who had a media reputation (OR, 2.41; 95% CI, 1.28-4.52). Patients undergoing BCS were less likely to travel to hospitals with shorter surgical waiting times (OR, 0.65; 95% CI, 0.46-0.92). The authors did not observe a significant impact for research activity, hospital quality rating, breast re-excision rates, or the status as a multidisciplinary cancer center. CONCLUSIONS: Patient choice policies may drive inequalities in the health care system without improving patient outcomes

Curious connections: white matter pathways supporting individual differences in epistemic and perceptual curiosity

Across the lifespan, curiosity motivates us to learn, yet curiosity varies strikingly between individuals. Such individual differences have been shown for two distinct dimensions of curiosity: epistemic curiosity (EC), the desire to acquire knowledge about facts, and perceptual curiosity (PC), the desire for sensory information. It is not known, however, whether both dimensions of curiosity depend on different brain networks and whether inter-individual differences in curiosity depend on variation in anatomical connectivity within these networks. Here, we investigated the neuroanatomical connections underpinning individual variation in trait curiosity. Fifty-one female participants underwent a two-shell diffusion MRI sequence and completed questionnaires measuring EC and PC. Using deterministic spherical deconvolution tractography we extracted microstructural metrics (fractional anisotropy (FA) and mean diffusivity (MD)) from two key white matter tracts: the fornix (implicated in novelty processing, exploration, information seeking and episodic memory) and the inferior longitudinal fasciculus (ILF) (implicated in semantic learning and memory). In line with our predictions, we found that EC – but not PC – correlated with ILF microstructure. Fornix microstructure, in contrast, correlated with both EC and PC with posterior hippocampal fornix fibres - associated with posterior hippocampal network connectivity - linked to PC specifically. These findings suggest that differences in distinct dimensions of curiosity map systematically onto specific white matter tracts underlying well characterized brain networks. Furthermore, the results pave the way to study the anatomical substrates of inter-individual differences in dimensions of trait curiosity that motivate the learning of distinct forms of knowledge and skills

A cross-sectional investigation of the importance of park features for promoting regular physical activity in parks

Introduction: Parks in the US and Australia are generally underutilised, and park visitors typically engage in low levels of physical activity (PA). Better understanding park features that may encourage visitors to be active is important. This study examined the perceived importance of park features for encouraging park-based PA and examined differences by sex, age, parental-status and participation in PA. Methods: Cross-sectional surveys were completed by local residents (n = 2775) living near two parks (2013/2015). Demographic variables, park visitation and leisure-time PA were self-reported, respondents rated the importance of 20 park features for encouraging park-based PA in the next fortnight. Chi-square tests of independence examined differences in importance of park features for PA among sub-groups of local residents (sex, age, parental-status, PA). Results: Park features ranked most important for park-based PA were: well maintained (96.2%), feel safe (95.4%), relaxing atmosphere (91.2%), easy to get to (91.7%), and shady trees (90.3%). All subgroups ranked ‘well maintained’ as most important. Conclusions: Natural and built environment features of parks are important for promoting adults’ park-based PA, and should be considered in park (re)design

The effects of corn gluten feed and corn dried distillers grains as a replacement for soybean meal on Boer type goat diets

No information regarding the use of corn dried distillers grains (DDGS) or corn gluten feed (CGF) is available in the 2007 Nutrient Requirements of Small Ruminants (NRC, 2007) This has caused a lack of knowledge about improving the nutritional requirements of the growing goat industry. The objective of this study was to evaluate the ability for CGF and DDGS to economically replace soybean meal (SBM) in Boer-type goat diets without affecting growth performance. This 35 d study included 75 Boer-type goats (26.9 ±0.2 kg) at approximately 70 d of age. Goats and treatments were randomly assigned to pens. There were 25 pens with 3 goats per pen and pen was the experimental unit. There were 5 isocaloric and isonitrogenous treatments for the study: 1) SBM; 2) 100% DDGS/0% CGF; 3) 66% DDGS/33% CGF; 4) 33% DDGS/66% CGF; 5) 0% DDGS/100% CGF. Goats and feeders were weighed weekly to calculate ADG, ADFI, and F:G. The data was analyzed using the GLIMMIX procedure of SAS (Cary, NC, V.4.4). There were no detected differences between treatments according to final BW, ADG, and F:G (P>0.05). Feeding goats a diet consisting of SBM increased (P=0.0008) feed costs/goat by approximately $0.04/kg of feed. This caused feed costs for goats being fed corn co-products to be lower than the feed costs for goats being fed SBM. Feeding a diet of corn co-product also increased (P=0.038) ADFI of the goats by approximately 0.045 kg/d, though there was no detected (P=0.444) difference in ADG. In conclusion, this study supports the use of CGF or DDGS as an economic replacement for SBM in Boer type goat diets