Plasma concentrations of anti-inflammatory cytokine TGF-ß are associated with hippocampal structure related to explicit memory performance in older adults.

Human cognitive abilities, and particularly hippocampus-dependent memory performance typically decline with increasing age. Immunosenescence, the age-related disintegration of the immune system, is increasingly coming into the focus of research as a considerable factor contributing to cognitive decline. In the present study, we investigated potential associations between plasma levels of pro- and anti-inflammatory cytokines and learning and memory performance as well as hippocampal anatomy in young and older adults. Plasma concentrations of the inflammation marker CRP as well as the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine TGF-ß1 were measured in 142 healthy adults (57 young, 24.47 ± 4.48 years; 85 older, 63.66 ± 7.32 years) who performed tests of explicit memory (Verbal Learning and Memory Test, VLMT; Wechsler Memory Scale, Logical Memory, WMS) with an additional delayed recall test after 24 h. Hippocampal volumetry and hippocampal subfield segmentation were performed using FreeSurfer, based on T1-weighted and high-resolution T2-weighted MR images. When investigating the relationship between memory performance, hippocampal structure, and plasma cytokine levels, we found that TGF-ß1 concentrations were positively correlated with the volumes of the hippocampal CA4-dentate gyrus region in older adults. These volumes were in turn positively associated with better performance in the WMS, particularly in the delayed memory test. Our results support the notion that endogenous anti-inflammatory mechanisms may act as protective factors in neurocognitive aging.

The relationship between resting-state amplitude fluctuations and memory-related deactivations of the default mode network in young and older adults.

The default mode network (DMN) typically exhibits deactivations during demanding tasks compared to periods of relative rest. In functional magnetic resonance imaging (fMRI) studies of episodic memory encoding, increased activity in DMN regions even predicts later forgetting in young healthy adults. This association is attenuated in older adults and, in some instances, increased DMN activity even predicts remembering rather than forgetting. It is yet unclear whether this phenomenon is due to a compensatory mechanism, such as self-referential or schema-dependent encoding, or whether it reflects overall reduced DMN activity modulation in older age. We approached this question by systematically comparing DMN activity during successful encoding and tonic, task-independent, DMN activity at rest in a sample of 106 young (18-35 years) and 111 older (60-80 years) healthy participants. Using voxel-wise multimodal analyses, we assessed the age-dependent relationship between DMN resting-state amplitude (mean percent amplitude of fluctuation, mPerAF) and DMN fMRI signals related to successful memory encoding, as well as their modulation by age-related hippocampal volume loss, while controlling for regional grey matter volume. Older adults showed lower resting-state DMN amplitudes and lower task-related deactivations. However, a negative relationship between resting-state mPerAF and subsequent memory effect within the precuneus was observed only in young, but not older adults. Hippocampal volumes showed no relationship with the DMN subsequent memory effect or mPerAF. Lastly, older adults with higher mPerAF in the DMN at rest tend to show higher memory performance, pointing towards the importance of a maintained ability to modulate DMN activity in old age.

Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging.

Memory-related functional magnetic resonance imaging (fMRI) activations show age-related differences across multiple brain regions that can be captured in summary statistics like single-value scores. Recently, we described two single-value scores reflecting deviations from prototypical whole-brain fMRI activity of young adults during novelty processing and successful encoding. Here, we investigate the brain-behavior associations of these scores with age-related neurocognitive changes in 153 healthy middle-aged and older adults. All scores were associated with episodic recall performance. The memory network scores, but not the novelty network scores, additionally correlated with medial temporal gray matter and other neuropsychological measures including flexibility. Our results thus suggest that novelty-network-based fMRI scores show high brain-behavior associations with episodic memory and that encoding-network-based fMRI scores additionally capture individual differences in other aging-related functions. More generally, our results suggest that single-value scores of memory-related fMRI provide a comprehensive measure of individual differences in network dysfunction that may contribute to age-related cognitive decline.

Structural and Functional MRI Data Differentially Predict Chronological Age and Behavioral Memory Performance.

Human cognitive abilities decline with increasing chronological age, with decreased explicit memory performance being most strongly affected. However, some older adults show "successful aging," that is, relatively preserved cognitive ability in old age. One explanation for this could be higher brain-structural integrity in these individuals. Alternatively, the brain might recruit existing resources more efficiently or employ compensatory cognitive strategies. Here, we approached this question by testing multiple candidate variables from structural and functional neuroimaging for their ability to predict chronological age and memory performance, respectively. Prediction was performed using support vector machine (SVM) classification and regression across and within two samples of young (N = 106) and older (N = 153) adults. The candidate variables were (1) behavioral response frequencies in an episodic memory test; (2) recently described functional magnetic resonance imaging (fMRI) scores reflecting preservation of functional memory networks; (3) whole-brain fMRI contrasts for novelty processing and subsequent memory; (4) resting-state fMRI maps quantifying voxel-wise signal fluctuation; and (5) gray matter volume estimated from structural MRIs. While age group could be reliably decoded from all variables, chronological age within young and older subjects was best predicted from gray matter volume. In contrast, memory performance was best predicted from task-based fMRI contrasts and particularly single-value fMRI scores, whereas gray matter volume has no predictive power with respect to memory performance in healthy adults. Our results suggest that superior memory performance in healthy older adults is better explained by efficient recruitment of memory networks rather than by preserved brain structure.

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging.

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803-814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age-group-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.

Bayesian model selection favors parametric over categorical fMRI subsequent memory models in young and older adults.

Subsequent memory paradigms allow to identify neural correlates of successful encoding by separating brain responses as a function of memory performance during later retrieval. In functional magnetic resonance imaging (fMRI), the paradigm typically elicits activations of medial temporal lobe, prefrontal and parietal cortical structures in young, healthy participants. This categorical approach is, however, limited by insufficient memory performance in older and particularly memory-impaired individuals. A parametric modulation of encoding-related activations with memory confidence could overcome this limitation. Here, we applied cross-validated Bayesian model selection (cvBMS) for first-level fMRI models to a visual subsequent memory paradigm in young (18-35 years) and older (51-80 years) adults. Nested cvBMS revealed that parametric models, especially with non-linear transformations of memory confidence ratings, outperformed categorical models in explaining the fMRI signal variance during encoding. We thereby provide a framework for improving the modeling of encoding-related activations and for applying subsequent memory paradigms to memory-impaired individuals.

Neurocan genome-wide psychiatric risk variant affects explicit memory performance and hippocampal function in healthy humans.

Alterations of the brain extracellular matrix (ECM) can perturb the structure and function of brain networks like the hippocampus, a key region in human memory that is commonly affected in psychiatric disorders. Here, we investigated the potential effects of a genome-wide psychiatric risk variant in the NCAN gene encoding the ECM proteoglycan neurocan (rs1064395) on memory performance, hippocampal function and cortical morphology in young, healthy volunteers. We assessed verbal memory performance in two cohorts (N = 572, 302) and found reduced recall performance in risk allele (A) carriers across both cohorts. In 117 participants, we performed functional magnetic resonance imaging using a novelty-encoding task with visual scenes. Risk allele carriers showed higher false alarm rates during recognition, accompanied by inefficiently increased left hippocampal activation. To assess effects of rs1064395 on brain morphology, we performed voxel-based morphometry in 420 participants from four independent cohorts and found lower grey matter density in the ventrolateral and rostral prefrontal cortex of risk allele carriers. In silico eQTL analysis revealed that rs1064395 SNP is linked not only to increased prefrontal expression of the NCAN gene itself, but also of the neighbouring HAPLN4 gene, suggesting a more complex effect of the SNP on ECM composition. Our results suggest that the NCAN rs1064395 A allele is associated with lower hippocampus-dependent memory function, variation of prefrontal cortex structure and ECM composition. Considering the well-documented hippocampal and prefrontal dysfunction in bipolar disorder and schizophrenia, our results may reflect an intermediate phenotype by which NCAN rs1064395 contributes to disease risk.

Role of Oral Rabies Vaccines in the Elimination of Dog-Mediated Human Rabies Deaths.

Domestic dogs are responsible for nearly all the ¼59,000 global human rabies deaths that occur annually. Numerous control measures have been successful at eliminating dog-mediated human rabies deaths in upper-income countries, including dog population management, parenteral dog vaccination programs, access to human rabies vaccines, and education programs for bite prevention and wound treatment. Implementing these techniques in resource-poor settings can be challenging; perhaps the greatest challenge is maintaining adequate herd immunity in free-roaming dog populations. Oral rabies vaccines have been a cornerstone in rabies virus elimination from wildlife populations; however, oral vaccines have never been effectively used to control dog-mediated rabies. Here, we convey the perspectives of the World Organisation for Animal Health Rabies Reference Laboratory Directors, the World Organisation for Animal Health expert committee on dog rabies control, and World Health Organization regarding the role of oral vaccines for dogs. We also issue recommendations for overcoming hesitations to expedited field use of appropriate oral vaccines.

Rabies post-exposure prophylaxis: A systematic review on abridged vaccination schedules and the effect of changing administration routes during a single course.

Rabies is a fatal zoonotic disease preventable through timely and adequate post-exposure prophylaxis (PEP) to potentially exposed persons i.e. wound washing and antisepsis, a series of intradermal (ID) or intramuscular (IM) rabies vaccinations, and rabies immunoglobulin in WHO category III exposures. The 2010 WHO position on rabies vaccines recommended PEP schedules requiring up to 5 clinic visits over the course of approximately one month. Abridged schedules with less doses have potential to save costs, increase patient compliance, and thereby improve equitable access to life-saving PEP for at-risk populations. We systematically reviewed new evidence since that considered for the 2010 position paper to evaluate (i) the immunogenicity and effectiveness of PEP schedules of reduced dose and duration; (ii) new evidence on effective PEP protocols for special populations; and (iii) the effect of changing routes of administration (ID or IM) during a single course of PEP. Our search identified a total of 14 relevant studies. The identified studies supported a reduction in dose or duration of rabies PEP schedules. The 1-week, 2-site ID PEP schedule was found to be most advantageous, as it was safe, immunogenic, supported by clinical outcome data and involved the least direct costs (i.e. cost of vaccine) compared to other schedules. To supplement this evidence, as yet unpublished additional data were reviewed to support the strength of the recommendations. Evidence suggests that changes in the rabies vaccine product and/or the route of administration during PEP is possible. Few studies have evaluated PEP schedules in persons with suspect or confirmed rabies exposures. Gaps exist in understanding the safety and immunogenicity of novel PEP schedules in special populations such as infants and immunocompromised individuals. Available data indicate that administering rabies vaccines during pregnancy is safe and effective.

An overview of the immunogenicity and effectiveness of current human rabies vaccines administered by intradermal route.

Pre- as well as post-exposure prophylaxis plays an important role in controlling the number of deaths associated with human rabies. Rabies vaccines, classically injected intramuscularly, are now also administered by intradermal (ID) route. Vaccines to be administered by the ID route should meet the same quality, safety and efficacy specifications as vaccines for intramuscular (IM) use. The aim of this paper is to provide information based on publicly available data regarding the ID use of rabies vaccines and to identify potential needs for further analysis of the potency, immunogenicity and effectiveness of rabies vaccines administered by this route. A first literature search, focused on the immunogenicity of rabies vaccines given by ID route, identified 338 publications in the period 1997-2018, 40 of which were included in our analyses. A second search investigating the effectiveness of ID vaccination resulted in 371 hits for the period 2007-2018, of which 13 suitable publications were retained. The immunogenicity of current rabies vaccines was analyzed in 3 ways: proportion of subjects reaching the antibody threshold of 0.5 IU/ml after ID vaccination, relationship between potency and immunogenicity of the vaccine given intradermally, and comparison of antibody responses after IM or ID vaccination. Overall, vaccines administered intradermally were found immunogenic. Post-exposure prophylaxis by ID route appeared at least as immunogenic as by IM regimens. By contrast, ID pre-exposure prophylaxis trended towards lower antibody titers than IM vaccination, but the observation was not associated with any clinical relevance. Vaccine effectiveness was assessed by investigating survival after exposure. Data from more than 30,000 patients who sought rabies post-exposure prophylaxis did not indicate that current vaccines administered by ID route lack efficacy. These results support current recommendations for ID vaccination against rabies. However, published data on ID performance were associated with significant weaknesses that future research should better address.

Descriptive assessment of rabies post-exposure prophylaxis procurement, distribution, monitoring, and reporting in four Asian countries: Bangladesh, Bhutan, Cambodia, and Sri Lanka, 2017-2018.

BACKGROUND: There are approximately 35,000 human deaths from rabies in Asia annually. Rabies can be prevented through timely post-exposure prophylaxis (PEP) consisting of wound washing, rabies vaccine, and in some cases, rabies immunoglobulin (RIG). However, access to rabies PEP often remains limited to urban areas and is cost-prohibitive. There is little information on procurement, distribution, monitoring, and reporting of rabies PEP. METHODS: We interviewed key informants in the public sector from various levels in Bangladesh, Bhutan, Cambodia, and Sri Lanka between March 2017 and May 2018 using a descriptive assessment tool to obtain information on procurement, distribution, monitoring, and reporting of rabies PEP. These four countries in Asia were chosen to showcase a range of rabies PEP systems. National rabies focal points were interviewed in each country and focal points helped identify additional key informants at lower levels. RESULTS: A total of 22 key informants were interviewed at various levels (central level to health facility level) including national rabies focal points in each country. Each country has a unique system for managing rabies PEP procurement, distribution, monitoring, and reporting. There are varying levels of PEP access for those with potential rabies exposures. Rabies PEP is available in select health facilities throughout the country in Bangladesh, Bhutan, and Sri Lanka. In Cambodia, rabies PEP is limited to two urban centers. The availability of RIG in all four countries is limited. In these four countries, most aspects of the rabies PEP distribution system operate independently of systems for other vaccines. However, in Bhutan, rabies PEP and Expanded Programme on Immunization (EPI) vaccines share cold chain space in some locations at the lowest level. All countries have a monitoring system in place, but there is limited reporting of data, particularly to the central level. CONCLUSION: Systems to procure, deliver, monitor, and report on rabies PEP are variable across countries. Sharing information on practices more widely among countries can help programs to increase access to this life-saving treatment.

Modelling to inform prophylaxis regimens to prevent human rabies.

BACKGROUND: The Strategic Advisory Group of Experts (SAGE) Working Group on rabies vaccines and immunoglobulins was established in 2016 to develop practical and feasible recommendations for prevention of human rabies. To support the SAGE agenda we developed models to compare the relative costs and potential benefits of rabies prevention strategies. METHODS: We examined Post-Exposure Prophylaxis (PEP) regimens, protocols for administration of Rabies Immunoglobulin (RIG) and inclusion of rabies Pre-Exposure Prophylaxis (PrEP) within the Expanded Programme on Immunization (EPI). For different PEP regimens, clinic throughputs and consumables for vaccine administration, we evaluated the cost per patient treated, costs to patients and potential to treat more patients given limited vaccine availability. RESULTS: We found that intradermal (ID) vaccination reduces the volume of vaccine used in all settings, is less costly and has potential to mitigate vaccine shortages. Specifically, the abridged 1-week 2-site ID regimen was the most cost-effective PEP regimen, even in settings with low numbers of bite patients presenting to clinics. We found advantages of administering RIG to the wound(s) only, using considerably less product than when the remaining dose is injected intramuscularly distant to the wound(s). We found that PrEP as part of the EPI programme would be substantially more expensive than use of PEP and dog vaccination in prevention of human rabies. CONCLUSIONS: These modeling insights inform WHO recommendations for use of human rabies vaccines and biologicals. Specifically, the 1-week 2-site ID regimen is recommended as it is less costly and treats many more patients when vaccine is in short supply. If available, RIG should be administered at the wound only. PrEP is highly unlikely to be an efficient use of resources and should therefore only be considered in extreme circumstances, where the incidence of rabies exposures is extremely high.

The Road to Dog Rabies Control and Elimination-What Keeps Us from Moving Faster?

Rabies, a vaccine preventable neglected tropical disease, still claims an estimated 35,000-60,000 human lives annually. The international community, with more than 100 endemic countries, has set a global target of 0 human deaths from dog-transmitted rabies by 2030. While it has been proven in several countries and regions that elimination of rabies as a public health problem is feasible and tools are available, rabies deaths globally have not yet been prevented effectively. While there has been extensive rabies research, specific areas of implementation for control and elimination have not been sufficiently addressed. This article highlights some of the commonest perceived barriers for countries to implementing rabies control and elimination programs and discusses possible solutions for sociopolitical, organizational, technical, and resource-linked requirements, following the pillars of the global framework for the elimination of dog-mediated human rabies adopted at the global rabies meeting in December 2015.

Estimating the global burden of endemic canine rabies.

BACKGROUND: Rabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries. METHODOLOGY/PRINCIPAL FINDINGS: We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%). CONCLUSIONS/SIGNIFICANCE: This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.

Efficiency of risk-based vs . random sampling for the monitoring of tetracycline residues in slaughtered calves in Switzerland.

In all European Union countries, chemical residues are required to be routinely monitored in meat. Good farming and veterinary practice can prevent the contamination of meat with pharmaceutical substances, resulting in a low detection of drug residues through random sampling. An alternative approach is to target-monitor farms suspected of treating their animals with antimicrobials. The objective of this project was to assess, using a stochastic model, the efficiency of these two sampling strategies. The model integrated data on Swiss livestock as well as expert opinion and results from studies conducted in Switzerland. Risk-based sampling showed an increase in detection efficiency of up to 100% depending on the prevalence of contaminated herds. Sensitivity analysis of this model showed the importance of the accuracy of prior assumptions for conducting risk-based sampling. The resources gained by changing from random to risk-based sampling should be transferred to improving the quality of prior information.