A dynamic microsimulation model for epidemics.

A large evidence base demonstrates that the outcomes of COVID-19 and national and local interventions are not distributed equally across different communities. The need to inform policies and mitigation measures aimed at reducing the spread of COVID-19 highlights the need to understand the complex links between our daily activities and COVID-19 transmission that reflect the characteristics of British society. As a result of a partnership between academic and private sector researchers, we introduce a novel data driven modelling framework together with a computationally efficient approach to running complex simulation models of this type. We demonstrate the power and spatial flexibility of the framework to assess the effects of different interventions in a case study where the effects of the first UK national lockdown are estimated for the county of Devon. Here we find that an earlier lockdown is estimated to result in a lower peak in COVID-19 cases and 47% fewer infections overall during the initial COVID-19 outbreak. The framework we outline here will be crucial in gaining a greater understanding of the effects of policy interventions in different areas and within different populations.

Neural Correlates of Hand-Object Congruency Effects during Action Planning.

Selecting hand actions to manipulate an object is affected both by perceptual factors and by action goals. Affordances may contribute to "stimulus-response" congruency effects driven by habitual actions to an object. In previous studies, we have demonstrated an influence of the congruency between hand and object orientations on response times when reaching to turn an object, such as a cup. In this study, we investigated how the representation of hand postures triggered by planning to turn a cup was influenced by this congruency effect, in an fMRI scanning environment. Healthy participants were asked to reach and turn a real cup that was placed in front of them either in an upright orientation or upside-down. They were instructed to use a hand orientation that was either congruent or incongruent with the cup orientation. As expected, the motor responses were faster when the hand and cup orientations were congruent. There was increased activity in a network of brain regions involving object-directed actions during action planning, which included bilateral primary and extrastriate visual, medial, and superior temporal areas, as well as superior parietal, primary motor, and premotor areas in the left hemisphere. Specific activation of the dorsal premotor cortex was associated with hand-object orientation congruency during planning and prior to any action taking place. Activity in that area and its connectivity with the lateral occipito-temporal cortex increased when planning incongruent (goal-directed) actions. The increased activity in premotor areas in trials where the orientation of the hand was incongruent to that of the object suggests a role in eliciting competing representations specified by hand postures in lateral occipito-temporal cortex.

Baseline cognition is the best predictor of 4-year cognitive change in cognitively intact older adults.

BACKGROUND: We examined in cognitively intact older adults the relative weight of cognitive, genetic, structural and amyloid brain imaging variables for predicting cognitive change over a 4-year time course. METHODS: One hundred-eighty community-recruited cognitively intact older adults (mean age 68 years, range 52-80 years, 81 women) belonging to the Flemish Prevent Alzheimer's Disease Cohort KU Leuven (F-PACK) longitudinal observational cohort underwent a baseline evaluation consisting of detailed cognitive assessment, structural MRI and 18F-flutemetamol PET. At inclusion, subjects were stratified based on Apolipoprotein E (APOE) ε4 and Brain-Derived Neurotrophic Factor (BDNF) val66met polymorphism according to a factorial design. At inclusion, 15% were amyloid-PET positive (Centiloid >23.4). All subjects underwent 2-yearly follow-up of cognitive performance for a 4-year time period. Baseline cognitive scores were analysed using factor analysis. The slope of cognitive change over time was modelled using latent growth curve analysis. Using correlation analysis, hierarchical regression and mediation analysis, we examined the effect of demographic (age, sex, education) and genetic variables, baseline cognition, MRI volumetric (both voxelwise and region-based) as well as amyloid imaging measures on the longitudinal slope of cognitive change. RESULTS: A base model of age and sex explained 18.5% of variance in episodic memory decline. This increased to 41.6% by adding baseline episodic memory scores. Adding amyloid load or volumetric measures explained only a negligible additional amount of variance (increase to 42.2%). A mediation analysis indicated that the effect of age on episodic memory scores was partly direct and partly mediated via hippocampal volume. Amyloid load did not play a significant role as mediator between age, hippocampal volume and episodic memory decline. CONCLUSION: In cognitively intact older adults, the strongest baseline predictor of subsequent episodic memory decline was the baseline episodic memory score. When this score was included, only very limited explanatory power was added by brain volume or amyloid load measures. The data warn against classifications that are purely biomarker-based and highlight the value of baseline cognitive performance levels in predictive models.

Quantity and type of peer-reviewed evidence for popular free medical apps: Cross-sectional review.

INTRODUCTION: - Mobile apps are being increasingly used as a tool to deliver clinical care. Evidence of efficacy for such apps varies, and appropriate levels of evidence may depend on the app's intended use. The UK's National Institute for Health and Care Excellence (NICE) recently developed an evidence standards framework, aiming to explicitly set out the required standards of evidence for different categories of digital health technologies. To determine current compliance with the evidence standards framework, the current study quantified the amount and type of peer-reviewed evidence associated with a cross-section of popular medical apps. METHODS: - Apps were identified by selecting the top 100 free medical apps in the Apple App Store and all free apps in the NHS Apps Library. Each app was assigned to one of the four tiers (1, 2, 3a, 3b) in the NICE evidence standards framework. For each app, we conducted searches in Ovid-MEDLINE, Web of Science, Google Scholar, and via manufacturer websites to identify any published articles that assessed the app. This allowed us to determine our primary outcome, whether apps in tiers 3a/3b were more likely than apps in tier 1/2 to be associated with academic peer-reviewed evidence. RESULTS: - We reviewed 125 apps in total (Apple App Store (n = 72), NHS Apps Library (n = 45), both (n = 8), of which 54 were categorized into the higher evidence standards framework tiers, 3a/3b. After screening, we extracted 105 relevant articles which were associated with 25 of the apps. Only 6 articles, pertaining to 3 apps, were reports of randomised controlled trials. Apps in tiers 3a/3b were more likely to be associated with articles than apps in lower tiers (χ2 = 5.54, p = .01). The percentage of tier 3a/3b apps with associated articles was similar for both the NHS Apps Library (10/28) and Apple App store (7/24), (χ2 = 0.042, p = .84). DISCUSSION: - Apps that were in higher tiers 3a and 3b, indicating higher clinical risk, were more likely to have an associated article than those in lower categories. However, even in these tiers, supporting peer-reviewed evidence was missing in the majority of instances. In our sample, Apps from the NHS Apps Library were more no more likely to have supporting evidence than popular Apple App Store apps. This is of concern, given that NHS approval may influence uptake of app usage.

Medical Mobile App Classification Using the National Institute for Health and Care Excellence Evidence Standards Framework for Digital Health Technologies: Interrater Reliability Study.

BACKGROUND: Clinical governance of medical mobile apps is challenging, and there is currently no standard method for assessing the quality of such apps. In 2018, the National Institute for Health and Care Excellence (NICE) developed a framework for assessing the required level of evidence for digital health technologies (DHTs), as determined by their clinical function. The framework can potentially be used to assess mobile apps, which are a subset of DHTs. To be used reliably in this context, the framework must allow unambiguous classification of an app's clinical function. OBJECTIVE: The objective of this study was to determine whether mobile health apps could be reliably classified using the NICE evidence standards framework for DHTs. METHODS: We manually extracted app titles, screenshots, and content descriptions for all apps listed on the National Health Service (NHS) Apps Library website on July 12, 2019; none of the apps were downloaded. Using this information, 2 mobile health (mHealth) researchers independently classified each app to one of the 4 functional tiers (ie, 1, 2, 3a, and 3b) described in the NICE digital technologies evaluation framework. Coders also answered contextual questions from the framework to identify whether apps were deemed to be higher risk. Agreement between coders was assessed using Cohen κ statistic. RESULTS: In total, we assessed 76 apps from the NHS Apps Library. There was classification agreement for 42 apps. Of these, 0 apps were unanimously classified into Tier 1; 24, into Tier 2; 15, into Tier 3a; and 3, into Tier 3b. There was disagreement between coders in 34/76 cases (45%); interrater agreement was poor (Cohen κ=0.32, 95% CI 0.16-0.47). Further investigation of disagreements highlighted 5 main explanatory themes: apps that did not correspond to any tier, apps that corresponded to multiple tiers, ambiguous tier descriptions, ambiguous app descriptions, and coder error. CONCLUSIONS: The current iteration of the NICE evidence standards framework for DHTs did not allow mHealth researchers to consistently and unambiguously classify digital health mobile apps listed on the NHS app library according to their functional tier.

The NASSS-CAT Tools for Understanding, Guiding, Monitoring, and Researching Technology Implementation Projects in Health and Social Care: Protocol for an Evaluation Study in Real-World Settings.

BACKGROUND: Projects to implement health care and social care innovations involving technologies are typically ambitious and complex. Many projects fail. Greenhalgh et al's nonadoption, abandonment, scale-up, spread, and sustainability (NASSS) framework was developed to analyze the varied outcomes of such projects. OBJECTIVE: We sought to extend the NASSS framework to produce practical tools for understanding, guiding, monitoring, and researching technology projects in health care or social care settings. METHODS: Building on NASSS and a complexity assessment tool (CAT), the NASSS-CAT tools were developed (in various formats) in seven co-design workshops involving 50 stakeholders (industry executives, technical designers, policymakers, managers, clinicians, and patients). Using action research, they were and are being tested prospectively on a sample of case studies selected for variety in conditions, technologies, settings, scope and scale, policy context, and project goals. RESULTS: The co-design process resulted in four tools, available as free downloads. NASSS-CAT SHORT is a taster to introduce the instrument and gauge interest. NASSS-CAT LONG is intended to support reflection, due diligence, and preliminary planning. It maps complexity through stakeholder discussion across six domains, using free-text open questions (designed to generate a rich narrative and surface uncertainties and interdependencies) and a closed-question checklist; this version includes an action planning section. NASSS-CAT PROJECT is a 35-item instrument for monitoring how subjective complexity in a technology implementation project changes over time. NASSS-CAT INTERVIEW is a set of prompts for conducting semistructured research or evaluation interviews. Preliminary data from empirical case studies suggest that the NASSS-CAT tools can potentially identify, but cannot always help reconcile, contradictions and conflicts that block projects' progress. CONCLUSIONS: The NASSS-CAT tools are a useful addition to existing implementation tools and frameworks. Further support of the implementation projects is ongoing. We are currently producing digital versions of the tools, and plan (subject to further funding) to establish an online community of practice for people interested in using and improving the tools, and hold workshops for building cross-project collaborations. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16861.

Multivariate analysis reveals anatomical correlates of naming errors in primary progressive aphasia.

Primary progressive aphasia (PPA) is an overarching term for a heterogeneous group of neurodegenerative diseases which affect language processing. Impaired picture naming has been linked to atrophy of the anterior temporal lobe in the semantic variant of PPA. Although atrophy of the anterior temporal lobe proposedly impairs picture naming by undermining access to semantic knowledge, picture naming also entails object recognition and lexical retrieval. Using multivariate analysis, we investigated whether cortical atrophy relates to different types of naming errors generated during picture naming in 43 PPA patients (13 semantic, 9 logopenic, 11 nonfluent, and 10 mixed variant). Omissions were associated with atrophy of the anterior temporal lobes. Semantic errors, for example, mistaking a rhinoceros for a hippopotamus, were associated with atrophy of the left mid and posterior fusiform cortex and the posterior middle and inferior temporal gyrus. Semantic errors and atrophy in these regions occurred in each PPA subtype, without major between-subtype differences. We propose that pathological changes to neural mechanisms associated with semantic errors occur across the PPA spectrum.

Beyond negative valence: 2-week administration of a serotonergic antidepressant enhances both reward and effort learning signals.

To make good decisions, humans need to learn about and integrate different sources of appetitive and aversive information. While serotonin has been linked to value-based decision-making, its role in learning is less clear, with acute manipulations often producing inconsistent results. Here, we show that when the effects of a selective serotonin reuptake inhibitor (SSRI, citalopram) are studied over longer timescales, learning is robustly improved. We measured brain activity with functional magnetic resonance imaging (fMRI) in volunteers as they performed a concurrent appetitive (money) and aversive (effort) learning task. We found that 2 weeks of citalopram enhanced reward and effort learning signals in a widespread network of brain regions, including ventromedial prefrontal and anterior cingulate cortex. At a behavioral level, this was accompanied by more robust reward learning. This suggests that serotonin can modulate the ability to learn via a mechanism that is independent of stimulus valence. Such effects may partly underlie SSRIs' impact in treating psychological illnesses. Our results highlight both a specific function in learning for serotonin and the importance of studying its role across longer timescales.

Excitation and inhibition in anterior cingulate predict use of past experiences.

Dorsal anterior cingulate cortex (dACC) mediates updating and maintenance of cognitive models of the world used to drive adaptive reward-guided behavior. We investigated the neurochemical underpinnings of this process. We used magnetic resonance spectroscopy in humans, to measure levels of glutamate and GABA in dACC. We examined their relationship to neural signals in dACC, measured with fMRI, and cognitive task performance. Both inhibitory and excitatory neurotransmitters in dACC were predictive of the strength of neural signals in dACC and behavioral adaptation. Glutamate levels were correlated, first, with stronger neural activity representing information to be learnt about the tasks' costs and benefits and, second, greater use of this information in the guidance of behavior. GABA levels were negatively correlated with the same neural signals and the same indices of behavioral influence. Our results suggest that glutamate and GABA in dACC affect the encoding and use of past experiences to guide behavior.

Cholinergic depletion and basal forebrain volume in primary progressive aphasia.

Primary progressive aphasia (PPA) is a heterogeneous syndrome with various neuropathological causes for which no medical treatment with proven efficacy exists. Basal forebrain (BF) volume loss has been reported in PPA but its relation to cholinergic depletion is still unclear. The primary objective of this study was to investigate whether cholinergic alterations occur in PPA variants and how this relates to BF volume loss. An academic memory clinic based consecutive series of 11 PPA patients (five with the semantic variant (SV), four with the logopenic variant (LV) and two with the nonfluent variant (NFV)) participated in this cross-sectional in vivo PET imaging study together with 10 healthy control subjects. Acetylcholinesterase (AChE) activity was quantitatively measured in the neo- and allocortex using N-[11C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. Whole brain and BF volumes were quantified using voxel-based morphometry on high-resolution magnetic resonance imaging (MRI) scans. In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion.

Predictive decision making driven by multiple time-linked reward representations in the anterior cingulate cortex.

In many natural environments the value of a choice gradually gets better or worse as circumstances change. Discerning such trends makes predicting future choice values possible. We show that humans track such trends by comparing estimates of recent and past reward rates, which they are able to hold simultaneously in the dorsal anterior cingulate cortex (dACC). Comparison of recent and past reward rates with positive and negative decision weights is reflected by opposing dACC signals indexing these quantities. The relative strengths of time-linked reward representations in dACC predict whether subjects persist in their current behaviour or switch to an alternative. Computationally, trend-guided choice can be modelled by using a reinforcement-learning mechanism that computes a longer-term estimate (or expectation) of prediction errors. Using such a model, we find a relative predominance of expected prediction errors in dACC, instantaneous prediction errors in the ventral striatum and choice signals in the ventromedial prefrontal cortex.

Self-Other Mergence in the Frontal Cortex during Cooperation and Competition.

To survive, humans must estimate their own ability and the abilities of others. We found that, although people estimated their abilities on the basis of their own performance in a rational manner, their estimates of themselves were partly merged with the performance of others. Reciprocally, their ability estimates for others also reflected their own, as well as the others', performance. Self-other mergence operated in a context-dependent manner: interacting with high or low performers, respectively, enhanced and diminished own ability estimates in cooperative contexts, but the opposite occurred in competitive contexts. Self-other mergence not only influenced subjective evaluations, it also affected how people subsequently objectively adjusted their performance. Perigenual anterior cingulate cortex tracked one's own performance. Dorsomedial frontal area 9 tracked others' performances, but also integrated contextual and self-related information. Self-other mergence increased with the strength of self and other representations in area 9, suggesting it carries interdependent representations of self and other.

Oxford Lithium Trial (OxLith) of the early affective, cognitive, neural and biochemical effects of lithium carbonate in bipolar disorder: study protocol for a randomised controlled trial.

BACKGROUND: Despite lithium's being the most effective drug for bipolar disorder and in clinical use for decades, we still know very little about its early effects relevant to its mode of action. METHODS/DESIGN: The Oxford Lithium Trial is a double-blind, randomised, placebo-controlled study of 6-week lithium treatment in participants with bipolar disorder and mood instability. Its aim is to identify early clinical, neurocognitive and biological effects. Participants (n = 40) will undergo an intensive battery of multi-modal investigations, including remote monitoring of mood, activity and physiology, as well as cognitive testing, fMRI and magnetoencephalography, together with biochemical and gene expression measurements to assess renal, inflammatory and circadian effects. DISCUSSION: The findings derived from this trial may be of value in predicting subsequent therapeutic response or side effects, not only relevant to the use of lithium but also providing a potential signature to help in more rapid evaluation of novel mood stabilisers. In this respect, OxLith is a step towards the development of a valid experimental medicine model for bipolar disorder. TRIAL REGISTRATION: ISRCTN91624955 . Registered on 22 January 2015.

Functional Changes in the Language Network in Response to Increased Amyloid ß Deposition in Cognitively Intact Older Adults.

Word finding symptoms are frequent early in the course of Alzheimer's disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden.

Amyloid imaging in cognitively normal older adults: comparison between (18)F-flutemetamol and (11)C-Pittsburgh compound B.

PURPOSE: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). METHODS: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. RESULTS: Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. CONCLUSION: For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.

Diagnostic value of cerebrospinal fluid Aß ratios in preclinical Alzheimer's disease.

INTRODUCTION: In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aß ratios rather than Aß42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). METHODS: Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aß1-42, Aß1-40, Aß1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. RESULTS: Seven out of 38 subjects (18 %) were positive on amyloid PET. Aß42/ttau, Aß42/Aß40, Aß42/Aß38, and Aß42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aß40 and Aß38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aß42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aß42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). CONCLUSION: For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aß42/ttau rather than using Aß42 in isolation.

The Good, the Bad, and the Irrelevant: Neural Mechanisms of Learning Real and Hypothetical Rewards and Effort.

Natural environments are complex, and a single choice can lead to multiple outcomes. Agents should learn which outcomes are due to their choices and therefore relevant for future decisions and which are stochastic in ways common to all choices and therefore irrelevant for future decisions between options. We designed an experiment in which human participants learned the varying reward and effort magnitudes of two options and repeatedly chose between them. The reward associated with a choice was randomly real or hypothetical (i.e., participants only sometimes received the reward magnitude associated with the chosen option). The real/hypothetical nature of the reward on any one trial was, however, irrelevant for learning the longer-term values of the choices, and participants ought to have only focused on the informational content of the outcome and disregarded whether it was a real or hypothetical reward. However, we found that participants showed an irrational choice bias, preferring choices that had previously led, by chance, to a real reward in the last trial. Amygdala and ventromedial prefrontal activity was related to the way in which participants' choices were biased by real reward receipt. By contrast, activity in dorsal anterior cingulate cortex, frontal operculum/anterior insula, and especially lateral anterior prefrontal cortex was related to the degree to which participants resisted this bias and chose effectively in a manner guided by aspects of outcomes that had real and more sustained relationships with particular choices, suppressing irrelevant reward information for more optimal learning and decision making. SIGNIFICANCE STATEMENT: In complex natural environments, a single choice can lead to multiple outcomes. Human agents should only learn from outcomes that are due to their choices, not from outcomes without such a relationship. We designed an experiment to measure learning about reward and effort magnitudes in an environment in which other features of the outcome were random and had no relationship with choice. We found that, although people could learn about reward magnitudes, they nevertheless were irrationally biased toward repeating certain choices as a function of the presence or absence of random reward features. Activity in different brain regions in the prefrontal cortex either reflected the bias or reflected resistance to the bias.

Reproducibility and robustness of graph measures of the associative-semantic network.

Graph analysis is a promising tool to quantify brain connectivity. However, an essential requirement is that the graph measures are reproducible and robust. We have studied the reproducibility and robustness of various graph measures in group based and in individual binary and weighted networks derived from a task fMRI experiment during explicit associative-semantic processing of words and pictures. The nodes of the network were defined using an independent study and the connectivity was based on the partial correlation of the time series between any pair of nodes. The results showed that in case of binary networks, global graph measures exhibit a good reproducibility and robustness for networks which are not too sparse and these figures of merit depend on the graph measure and on the density of the network. Furthermore, group based binary networks should be derived from groups of sufficient size and the lower the density the more subjects are required to obtain robust values. Local graph measures are very variable in terms of reproducibility and should be interpreted with care. For weighted networks, we found good reproducibility (average test-retest variability <5% and ICC values >0.4) when using subject specific networks and this will allow us to relate network properties to individual subject information.

Polymorphism of brain derived neurotrophic factor influences ß amyloid load in cognitively intact apolipoprotein E ε4 carriers.

Aside from apolipoprotein E (APOE), genetic risk factors for ß amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects ß amyloid burden and the relationship between ß amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of (18)F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of ß amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against ß amyloid-related effects on cognition.