Habitual intake of fat and sugar is associated with poorer memory and greater impulsivity in humans.

The vicious cycle model of obesity suggests that repeated habitual intake of a diet high in fat and sugar (HFS) results in impairment in hippocampal function which in turn increases impulsive behaviours, making it harder to resist unhealthy diet choices. Evidence from studies with rodents consistently show switching to a HFS diet impairs performance on hippocampally-sensitive memory tasks. The limited literature in humans also suggest impaired memory and increased impulsivity related to higher habitual HFS intake. However, these changes in memory and impulsivity have been looked at independently. To investigate how these effects are inter-related, three experiments were conducted where relative HFS intake was related to measures of memory and impulsivity. In Experiment 1 (90 female participants), HFS was associated with higher scores on the Everyday Memory Questionnaire-revised (EMQ), and higher scores on the total, Attention (BISatt) and Motor (BISmot) sub-scales of the Barratt Impulsiveness Scale (BIS11). Experiment 2 (84 women and 35 men), replicated the association between HFS and EMQ, and also found HFS related to poorer performance on the hippocampally-sensitive 4 mountain (4MT) memory task. The association between HFS intake and the BISatt replicated, but there were no significant associations with other BIS11 measures or delay-discounting for monetary rewards. Experiment 3 (199 women and 87 men) replicated the associations between DFS and 4MT and EMQ, and also found an association with overall recall, but not response inhibition, from a Remembering Causes Forgetting task: HFS was also significantly associated with BIS total, BISatt and BISmot. In all three studies these associations remained when potential confounds (BMI, age, gender, hunger state, restrained and disinhibited eating) were controlled for. Mediation analysis found that the effect of HFS on memory at least part mediated the relationship between HFS and impulsivity in Experiments 1 and 3, but not 2. Overall these data provide some support for the vicious cycle model, but also suggest that trait impulsivity may be a risk factor for poor dietary choice.

A non-targeted metabolomics approach to quantifying differences in root storage between fast- and slow-growing plants.

Life history theory posits that slower-growing species should invest proportionally more resources to storage, structural (e.g. stems) or defence traits than fast-growing species. Previously, we showed that the slower-growing monocarpic plants had lower mortality rates and higher bolting probabilities after two defoliation events. Here, we consider a mechanistic explanation, that the slower-growing species invested relatively more resources to storage. We compared the relative levels of root storage compounds between eight monocarpic species using metabolomic profiling, and characterized plant growth using a size-corrected estimate of relative growth rate (RGR). Growth rate was negatively correlated with the proportional allocation of root metabolites identified as sucrose, raffinose and stachyose and with amino acids known for their roles in nitrogen storage, particularly proline and arginine. The total amount and concentration of energy-corrected carbohydrates were also negatively correlated with RGR. Our results show for the first time that slower-growing species invest proportionally more of their total root metabolites in carbon- and nitrogen-storage compounds. We conclude that the increased investment in these reserves is an important resource allocation strategy underlying the growth-survival trade-off in plants.

Plant growth rates and seed size: a re-evaluation.

Small-seeded plant species are often reported to have high relative growth rate or RGR. However, because RGR declines as plants grow larger, small-seeded species could achieve higher RGR simply by virtue of their small size. In contrast, size-standardized growth rate or SGR factors out these size effects. Differences in SGR can thus only be due to differences in morphology, allocation, or physiology. We used nonlinear regression to calculate SGR for comparison with RGR for 10 groups of species spanning a wide range of life forms. We found that RGR was negatively correlated with seed mass in nearly all groups, but the relationship between SGR and seed mass was highly variable. We conclude that small-seeded species only sometimes possess additional adaptations for rapid growth over and above their general size advantage.

A comparison of time to event analysis methods, using weight status and breast cancer as a case study.

Survival analysis with cohort study data has been traditionally performed using Cox proportional hazards models. Random survival forests (RSFs), a machine learning method, now present an alternative method. Using the UK Women's Cohort Study (n = 34,493) we evaluate two methods: a Cox model and an RSF, to investigate the association between Body Mass Index and time to breast cancer incidence. Robustness of the models were assessed by cross validation and bootstraping. Histograms of bootstrap coefficients are reported. C-Indices and Integrated Brier Scores are reported for all models. In post-menopausal women, the Cox model Hazard Ratios (HR) for Overweight (OW) and Obese (O) were 1.25 (1.04, 1.51) and 1.28 (0.98, 1.68) respectively and the RSF Odds Ratios (OR) with partial dependence on menopause for OW and O were 1.34 (1.31, 1.70) and 1.45 (1.42, 1.48). HR are non-significant results. Only the RSF appears confident about the effect of weight status on time to event. Bootstrapping demonstrated Cox model coefficients can vary significantly, weakening interpretation potential. An RSF was used to produce partial dependence plots (PDPs) showing OW and O weight status increase the probability of breast cancer incidence in post-menopausal women. All models have relatively low C-Index and high Integrated Brier Score. The RSF overfits the data. In our study, RSF can identify complex non-proportional hazard type patterns in the data, and allow more complicated relationships to be investigated using PDPs, but it overfits limiting extrapolation of results to new instances. Moreover, it is less easily interpreted than Cox models. The value of survival analysis remains paramount and therefore machine learning techniques like RSF should be considered as another method for analysis.

Digital Approaches to Music-Making for People With Dementia in Response to the COVID-19 Pandemic: Current Practice and Recommendations.

Before COVID-19, dementia singing groups and choirs flourished, providing activity, cognitive stimulation, and social support for thousands of people with dementia in the UK. Interactive music provides one of the most effective psychosocial interventions for people with dementia; it can allay agitation and promote wellbeing. Since COVID-19 has halted the delivery of in-person musical activities, it is important for the welfare of people with dementia and their carers to investigate what alternatives to live music making exist, how these alternatives are delivered and how their accessibility can be expanded. This community case study examines recent practice in online music-making in response to COVID-19 restrictions for people with dementia and their supporters, focusing on a UK context. It documents current opportunities for digital music making, and assesses the barriers and facilitators to their delivery and accessibility. Online searches of video streaming sites and social media documented what music activities were available. Expert practitioners and providers collaborated on this study and supplied input about the sessions they had been delivering, the technological challenges and solutions they had found, and the responses of the participants. Recommendations for best practice were developed and refined in consultation with these collaborators. Over 50 examples of online music activities were identified. In addition to the challenges of digital inclusion and accessibility for some older people, delivering live music online has unique challenges due to audio latency and sound quality. It is necessary to adapt the session to the technology's limitations rather than expect to overcome these challenges. The recommendations highlight the importance of accessibility, digital safety and wellbeing of participants. They also suggest ways to optimize the quality of their musical experience. The pandemic has prompted innovative approaches to deliver activities and interventions in a digital format, and people with dementia and their carers have adapted rapidly. While online music is meeting a clear current need for social connection and cognitive stimulation, it also offers some advantages which remain relevant after COVID-19 restrictions are relaxed. The recommendations of this study are intended to be useful to musicians, dementia care practitioners, and researchers during the pandemic and beyond.

Overview of advances in educational and social supports for young persons with NCL disorders.

Vision loss, dementia, and motor and speech declines all impact the educational experience of individuals with Batten disease and can adversely impact effective learning. There are as yet limited data to support evidence-based approaches to meeting the educational needs of affected individuals. This paper provides an overview of recent work to evaluate and address educational issues with a life-long perspective relevant to individuals with juvenile-onset neuronal ceroid lipofuscinosis (JNCL) and the professionals that provide them with educational support. In particular, several main activities of the recently completed 'JNCL and Education' project are summarised, including a survey of parents, educational professionals and social/health workers, development of a formative assessment tool to identify and respond to an individual student's strengths and needs in the learning environment, and proposed strategies for prolonging literacy and language skills. A key concept that should be emphasised in the educational plan for students with JNCL is that of 'proactive' and 'hastened' learning, that is, providing an early emphasis on adaptive skills that will be required in the later stages of disease progression when new learning will be more difficult to achieve. An additional key concept is participation in real-life activities to maintain skills and quality of life, particularly in the later stages of disease progression.

The costs and benefits of fast living.

Growth rates play a fundamental role in many areas of biology (Q. Rev. Biol., 67, 1992, 283; Life History Invariants. Some Explorations of Symmetry in Evolutionary Biology, 1993; Philos. Trans. R. Soc. Lond. B Biol. Sci., 351, 1996, 1341; Plant Strategies, Vegetation Processes, and Ecosystem Properties, 2002; Trends Ecol. Evol., 18, 2003, 471; Q. Rev. Biol., 78, 2003, 23; J. Ecol., 95, 2007, 926.) but the cost and benefits of different growth rates are notoriously difficult to quantify (Q. Rev. Biol., 72, 1997, 149; Funct. Ecol., 17, 2003, 328). This is because (1) growth rate typically declines with size and yet the most widely used growth measure - relative growth rate or RGR (conventionally measured as the log of the ratio of successive sizes divided by the time interval) - is not size-corrected and so confounds growth and size, (2) organisms have access to different amounts of resource and (3) it is essential to allow for the long-term benefits of larger size. Here we experimentally demonstrate delayed costs and benefits of rapid growth in seven plant species using a novel method to calculate size-corrected RGR. In control treatments, fast-growing plants benefited from increased reproduction the following year; however, fast-growing plants subjected to an experimental stress treatment (defoliation) showed strongly reduced survival and reproduction the following year. Importantly, when growth was estimated using the classical RGR measure, no costs or benefits were found. These results support the idea that life-history trade-offs have a dominant role in life-history and ecological theory and that the widespread failure to detect them is partly due to methodological shortcomings.

Responses to executive demand in young adulthood differ by APOE genotype.

Despite evidence of a relationship between Apolipoprotein E (APOE) ε4+ and later-life cognitive decline, the lifespan effects of carrying an ε4+ allele on cognitive ageing are not well understood. Evidence of ε4+ advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE ε4+ cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision-making, prospective memory, and sustained attention tasks. Participants aged 18-25 years (21 ε4+, 63 ε33) also completed a measure of subjective effort. Under low executive demand, ε4+ made fewer verbal fluency word repeats compared to ε33 carriers. Under high executive demand, ε4+ showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, ε4+ appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to ε33 carriers, including speed-accuracy trade-offs.

Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume.

OBJECTIVE: To investigate the influence of microglial activation in the early stages of Alzheimer's disease trajectory, we assessed the relationship between microglial activation and gray matter volume and hippocampal volume in patients with mild cognitive impairment (MCI). METHODS: In this study, 55 participants (37 with early stages of MCI and 18 controls) underwent [11C]PBR28 PET, a marker of microglial activation; volumetric MRI to evaluate gray matter and hippocampal volumes as well as clinical and neuropsychometric evaluation. [11C]PBR28 VT (volume of distribution) was calculated using arterial input function and Logan graphical analysis. Gray matter volume and hippocampal volumes were calculated from MRI for each participant. Statistical parametric mapping software was used to perform voxel-wise correlations and biological parametric mapping analysis. Amyloid status was assessed using [18F]flutemetamol PET. RESULTS: Higher [11C]PBR28 VT in different cortical areas correlated with higher gray matter volume in both amyloid-positive and -negative MCI. In addition, higher hippocampal volume correlated with higher cortical [11C]PBR28 Logan VT. CONCLUSIONS: In this in vivo study, we have demonstrated that microglial activation quantified using [11C]PBR28 PET was associated with higher gray matter volume and higher hippocampal volume in patients with MCI. This might suggest that microglial activation may not always be associated with neuronal damage, and indeed it may have a beneficial effect in the early stages of the Alzheimer trajectory. While further longitudinal studies are necessary, these findings have significant implications on therapeutic strategies targeting microglial activation.

Does Microglial Activation Influence Hippocampal Volume and Neuronal Function in Alzheimer's Disease and Parkinson's Disease Dementia?

BACKGROUND: The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) is still unclear. OBJECTIVES: Here we investigated whether microglial activation measured by [11C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements. METHODS: We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11C](R)PK11195, [18F]FDG, and volumetric MRI scanning. RESULTS: SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD. CONCLUSIONS: These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases.

C4 photosynthesis boosts growth by altering physiology, allocation and size.

C4 photosynthesis is a complex set of leaf anatomical and biochemical adaptations that have evolved more than 60 times to boost carbon uptake compared with the ancestral C3 photosynthetic type(1-3). Although C4 photosynthesis has the potential to drive faster growth rates(4,5), experiments directly comparing C3 and C4 plants have not shown consistent effects(1,6,7). This is problematic because differential growth is a crucial element of ecological theory(8,9) explaining C4 savannah responses to global change(10,11), and research to increase C3 crop productivity by introducing C4 photosynthesis(12). Here, we resolve this long-standing issue by comparing growth across 382 grass species, accounting for ecological diversity and evolutionary history. C4 photosynthesis causes a 19-88% daily growth enhancement. Unexpectedly, during the critical seedling establishment stage, this enhancement is driven largely by a high ratio of leaf area to mass, rather than fast growth per unit leaf area. C4 leaves have less dense tissues, allowing more leaves to be produced for the same carbon cost. Consequently, C4 plants invest more in roots than C3 species. Our data demonstrate a general suite of functional trait divergences between C3 and C4 species, which simultaneously drive faster growth and greater investment in water and nutrient acquisition, with important ecological and agronomic implications.

Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein.

Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide (18F-GE180) is a recently developed third-generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18F-GE180 PET in (older) healthy controls. METHODS: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min 18F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. RESULTS: 18F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (VT) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain 18F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a VT highly consistent with VT in the kinetic model, which could be used for voxelwise analysis. CONCLUSION: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand 18F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low VT, the methodology presented here forms the basis for quantification for future PET studies using 18F-GE180 in different pathologies.