Axonal damage and astrocytosis are biological correlates of grey matter network integrity loss: a cohort study in autosomal dominant Alzheimer disease.

Brain development and maturation leads to grey matter networks that can be measured using magnetic resonance imaging. Network integrity is an indicator of information processing capacity which declines in neurodegenerative disorders such as Alzheimer disease (AD). The biological mechanisms causing this loss of network integrity remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and network integrity in mutation carriers (N=219) and noncarriers (N=136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Aß, Tau, synaptic (SNAP-25, neurogranin) and neuronal calcium-sensor protein (VILIP-1) preceded grey matter network disruptions by several years, while inflammation related (YKL-40) and axonal injury (NfL) abnormalities co-occurred and correlated with network integrity. This suggests that axonal loss and inflammation play a role in structural grey matter network changes. Key points: Abnormal levels of fluid markers for neuronal damage and inflammatory processes in CSF are associated with grey matter network disruptions.The strongest association was with NfL, suggesting that axonal loss may contribute to disrupted network organization as observed in AD.Tracking biomarker trajectories over the disease course, changes in CSF biomarkers generally precede changes in brain networks by several years.

Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer's disease.

Alzheimer's disease (AD) is increasingly prevalent worldwide, and disease-modifying treatments may soon be at hand; hence, now, more than ever, there is a need to develop techniques that allow earlier and more secure diagnosis. Current biomarker-based guidelines for AD diagnosis, which have replaced the historical symptom-based guidelines, rely heavily on neuroimaging and cerebrospinal fluid (CSF) sampling. While these have greatly improved the diagnostic accuracy of AD pathophysiology, they are less practical for application in primary care, population-based and epidemiological settings, or where resources are limited. In contrast, blood is a more accessible and cost-effective source of biomarkers in AD. In this review paper, using the recently proposed amyloid, tau and neurodegeneration [AT(N)] criteria as a framework towards a biological definition of AD, we discuss recent advances in biofluid-based biomarkers, with a particular emphasis on those with potential to be translated into blood-based biomarkers. We provide an overview of the research conducted both in CSF and in blood to draw conclusions on biomarkers that show promise. Given the evidence collated in this review, plasma neurofilament light chain (N) and phosphorylated tau (p-tau; T) show particular potential for translation into clinical practice. However, p-tau requires more comparisons to be conducted between its various epitopes before conclusions can be made as to which one most robustly differentiates AD from non-AD dementias. Plasma amyloid beta (A) would prove invaluable as an early screening modality, but it requires very precise tests and robust pre-analytical protocols.

Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Enriched environment exposure accelerates rodent driving skills.

Although rarely used, long-term behavioral training protocols provide opportunities to shape complex skills in rodent laboratory investigations that incorporate cognitive, motor, visuospatial and temporal functions to achieve desired goals. In the current study, following preliminary research establishing that rats could be taught to drive a rodent operated vehicle (ROV) in a forward direction, as well as steer in more complex navigational patterns, male rats housed in an enriched environment were exposed to the rodent driving regime. Compared to standard-housed rats, enriched-housed rats demonstrated more robust learning in driving performance and their interest in the ROV persisted through extinction trials. Dehydroepiandrosterone/corticosterone (DHEA/CORT) metabolite ratios in fecal samples increased in accordance with training in all animals, suggesting that driving training, regardless of housing group, enhanced markers of emotional resilience. These results confirm the importance of enriched environments in preparing animals to engage in complex behavioral tasks. Further, behavioral models that include trained motor skills enable researchers to assess subtle alterations in motivation and behavioral response patterns that are relevant for translational research related to neurodegenerative disease and psychiatric illness.

C-Reactive Protein Levels and the Risk of Incident Cardiovascular and Cerebrovascular Events in Patients with Obstructive Sleep Apnea.

PURPOSE: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease (CVD) but it is unclear who are at greatest risk. We determined whether the inflammatory marker, C-reactive protein (CRP), could be a useful prognostic biomarker. METHODS: Adult patients referred for polysomnography (PSG) with OSA were studied. Serum CRP levels were measured using ELISA the morning after PSG. Validated CV events within 4 years of PSG were ascertained by linking to provincial research datasets. RESULTS: 155 patients with OSA (AHI ≥ 5/h) had CRP measured. Median age was 53 and median AHI was 21/h. 10 patients (7.1%) suffered at least one event, but rates varied substantially by CRP (0/35 patients in the lowest quartile, and 7/39 in the highest CRP quartile). In the unadjusted analysis, patients in the highest CRP quartile (≥ 2.38 mg/L) were significantly more likely to suffer an event (odds ratio = 9.72 (95% CI 2.43-38.84), p = 0.001). CRP continued to be a significant predictor after controlling for multiple confounders. OSA severity and desaturation were not significantly associated with prospective events. CONCLUSIONS: In this small preliminary study, OSA patients with an elevated CRP were significantly more likely to suffer a CVD event in the 4 years after PSG. Although these findings need to be confirmed in larger prospective cohorts, CRP may be useful in risk stratifying OSA patients to guide therapy or to identify patients that might be most appropriate for clinical trials of CVD prevention.

Land-Atmosphere Responses to a Total Solar Eclipse in Three Ecosystems With Contrasting Structure and Physiology.

Mid-Missouri experienced up to 2 min 40 s of totality at around solar noon during the total eclipse of 2017. We conducted the Mid-Missouri Eclipse Meteorology Experiment to examine land-atmosphere interactions during the eclipse. Here, research examining the eclipse responses in three contrasting ecosystems (forest, prairie, and soybeans) is described. There was variable cloudiness around first and fourth contacts (i.e., the start and end of partial solar obscuration) at the forest and prairie; however, solar irradiance (K ↓) signals during the eclipse were relatively clean. Unfortunately, the eclipse forcing at the soybean field was contaminated by convective activity, which decreased K ↓ beginning about an hour before first contact and exposed the field to cold outflow ~30 min before second contact. Turbulence was suppressed during the eclipse at all sites; however, there was also an amplified signal at the soybean field during the passage of a gust front. The standard deviations of the horizontal and vertical wind velocities and friction velocities decreased by ~75% at the forest (aerodynamically rough), and ~60% at the prairie (aerodynamically smooth). The eddy fluxes of energy were highly coherent with the solar forcing with the latent and sensible heat fluxes approaching 0 W/m2 and changing in direction, respectively. For the prairie site, we estimated a canopy-scale time constant for the surface conductance light response of 10 min. Although the eclipse imparted large forcings on surface energy balances, the air temperature response was relatively muted (1.5-2.5 °C decrease) due to the absence of topographic effects and the relatively moist land and atmosphere.

Early-childhood social reticence predicts SCR-BOLD coupling during fear extinction recall in preadolescent youth.

Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.

Frontal alpha asymmetry moderates the relations between behavioral inhibition and social-effect ERN.

Behavioral inhibition (BI) is an early temperamental precursor of anxiety disorders, characterized by withdrawal from novel situations. Some but not all young children with BI go on to display anxiety disorders. Neural correlates, such as frontal alpha asymmetry or event-related negativity (ERN), could moderate the relations between early BI and later anxiety. The goal of this longitudinal study was to test frontal alpha asymmetry as a potential moderator of the relation between BI and later anxiety, and of the relation between BI and the social-effect ERN. 100 children were assessed for BI at ages 2 and 3, and we collected EEG during resting state and the social Flanker task at age 12. Frontal alpha asymmetry did not correlate with BI or anxiety, nor did it moderate the relation between early BI and later anxiety. However, frontal alpha asymmetry did moderate the relation between BI and the social-effect ERN. This suggests that, in adolescents who previously manifested BI, a pattern of resting EEG associated with avoidance predicts hypersensitivity to errors in a social context.

Time-frequency approaches to investigating changes in feedback processing during childhood and adolescence.

Processing feedback from the environment is an essential function during development to adapt behavior in advantageous ways. One measure of feedback processing, the feedback negativity (FN), is an ERP observed following the presentation of feedback. Findings detailing developmental changes in the FN have been mixed, possibly due to limitations in traditional ERP measurement methods. Recent work shows that both theta and delta frequency activity contribute to the FN; utilizing time-frequency methods to measure change in power and phase in these frequency bands may provide more accurate representation of feedback processing development in childhood and adolescence. We employ time-frequency power and intertrial phase synchrony measures, in addition to conventional time-domain ERP methods, to examine the development of feedback processing in the theta (4-7 Hz) and delta (.1-3 Hz) bands throughout adolescence. A sample of 54 female participants (8-17 years old) completed a gambling task while EEG was recorded. As expected, time-domain ERP amplitudes showed no association with age. In contrast, significant effects were observed for the time-frequency measures, with theta power decreasing with age and delta power increasing with age. For intertrial phase synchrony, delta synchrony increased with age, while age-related changes in theta synchrony differed for gains and losses. Collectively, these findings highlight the importance of considering time-frequency dynamics when exploring how the processing of feedback develops through late childhood and adolescence. In particular, the role of delta band activity and theta synchrony appear central to understanding age-related changes in the neural response to feedback.

Ubiquitous parasites drive a 33% increase in methane yield from livestock.

Of anthropogenic methane emissions, 40% can be attributed to agriculture, the majority of which are from enteric fermentation in livestock. With international commitments to tackle drivers of climate change, there is a need to lower global methane emissions from livestock production. Gastrointestinal helminths (parasitic worms) are globally ubiquitous and represent one of the most pervasive challenges to the health and productivity of grazing livestock. These parasites influence a number of factors affecting methane emissions including feed efficiency, nutrient use, and production traits. However, their effects on methane emissions are unknown. This is to our knowledge the first study that empirically demonstrates disease-driven increases in methane (CH4) yield in livestock (grams of CH4 per kg of dry matter intake). We do this by measuring methane emissions (in respiration chambers), dry matter intake, and production parameters for parasitised and parasite-free lambs. This study shows that parasite infections in lambs can lead to a 33% increase in methane yield (g CH4/kg DMI). This knowledge will facilitate more accurate calculations of the true environmental costs of parasitism in livestock, and reveals the potential benefits of mitigating emission through controlling parasite burdens.

A 6-month open-label extension study of the safety and efficacy of subcutaneous belimumab in patients with systemic lupus erythematosus.

Objective To evaluate the safety, tolerability and efficacy of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE) beyond 1 year. Methods This was a 24-week, open-label extension following a 52-week, double-blind, placebo-controlled trial of belimumab SC. Patients who completed the double-blind phase were eligible to enter the open-label phase. All patients received weekly belimumab 200 mg SC plus standard SLE therapy. Outcome measures included safety and efficacy (SLE Response Index (SRI) and SLE Flare Index (SFI) rates), and changes in biomarker and B cell levels. Results Of 677 patients who completed the 52-week, double-blind phase, 662 entered the open-label phase; 206 had previously received placebo and 456 had previously received belimumab. Despite differences in total belimumab exposure (24 weeks in the placebo-to-belimumab group versus 76 weeks in the belimumab group), the proportions of patients experiencing more than one adverse event (AE) or a serious AE in the open-label phase were similar between groups (placebo-to-belimumab: 51.5 and 6.8%; belimumab: 48.2 and 5.5%, respectively). Most AEs were mild/moderate in severity. Efficacy was maintained through the extension phase. An SRI response was achieved by 16.1% of patients in the placebo-to-belimumab group and 76.3% patients in the belimumab group. Furthermore, 1.0% of patients in the placebo-to-belimumab group and 2.6% of patients in the belimumab group experienced a severe SFI flare. Conclusion Belimumab SC was well tolerated and efficacy was maintained during the extension phase of this study. The safety profile of belimumab SC is consistent with that of previous experience with belimumab. Trial registration ClinicalTrials.gov identifier: NCT01484496.

Biomarker and Clinical Trial Design Support for Disease-Modifying Therapies: Report of a Survey of the EU/US: Alzheimer's Disease Task Force.

BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer's disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs. DESIGN/SETTING/PARTICIANTS: A survey of members of the EU/US Alzheimer's Disease Task Force was conducted. Ninety-three members (87%) responded. The details were analyzed to understand what clinical trial design and biomarker data support disease modification. MEASUREMENTS/RESULTS/CONCLUSIONS: Task Force members favored the parallel group design compared to delayed start or staggered withdrawal clinical trial designs to support disease modification. Amyloid biomarkers were regarded as providing mild support for disease modification while tau biomarkers were regarded as providing moderate support. Combinations of biomarkers, particularly combinations of tau and neurodegeneration, were regarded as providing moderate to marked support for disease modification and combinations of all three classes of biomarkers were regarded by a majority as providing marked support for disease modification. Task Force members considered that evidence derived from clinical trials and biomarkers supports clinical meaningfulness of an intervention, and when combined with a single clinical trial outcome, nearly all regarded the clinical trial design or biomarker evidence as supportive of disease modification. A minority considered biomarker evidence by itself as indicative of disease modification in prevention trials. Levels of evidence (A,B,C) were constructed based on these observations. CONCLUSION: The survey indicates the view of knowledgeable stakeholders regarding evidence derived from clinical trial design and biomarkers in support of disease modification. Results of this survey can assist in designing clinical trials of DMTs.

Efficacy and Safety of Subcutaneous Belimumab in Anti-Double-Stranded DNA-Positive, Hypocomplementemic Patients With Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the efficacy and safety of belimumab, a human immunoglobulin monoclonal antibody against B lymphocyte stimulator, in a subset of patients with systemic lupus erythematosus (SLE) who were hypocomplementemic (C3 <90 mg/dl and/or C4 <10 mg/dl) and anti-double-stranded DNA (anti-dsDNA) positive (≥30 IU/ml) at baseline. METHODS: In this phase III, double-blind, placebo-controlled study (BEL112341; ClinicalTrials.gov identifier: NCT01484496), patients with moderate to severe SLE (Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI] score ≥8) were randomized (2:1) to receive weekly subcutaneous (SC) belimumab 200 mg or placebo, plus standard SLE therapy, for 52 weeks. The primary end point was SLE Responder Index 4 (SRI-4) response rate at week 52. Secondary end points were time to severe flare and reduction in corticosteroid dose (weeks 40-52). Safety was assessed throughout. RESULTS: Of the 836 patients in the intent-to-treat (ITT) population, 356 were hypocomplementemic and anti-dsDNA positive at baseline (108 in the placebo group and 248 in the SC belimumab 200 mg group). Compared with placebo, the belimumab group contained more SRI-4 responders (47.2% versus 64.6%; P = 0.0014), had a lower incidence of severe flare according to the SELENA-SLEDAI flare index (31.5% versus 14.1%), and had a greater percentage of patients who reduced corticosteroid dosage by ≥25% to ≤7.5 mg/day during weeks 40-52 (11.4% versus 20.7%; P = 0.0844). Adverse events (AEs) were similar between treatment groups. CONCLUSION: Our findings indicate that in hypocomplementemic, anti-dsDNA-positive SLE patients, weekly SC belimumab 200 mg significantly improves SRI-4 response, decreases severe flare incidence, and reduces corticosteroid use versus placebo; a trend toward greater benefit compared with the overall ITT population was observed. AEs were consistent with the known safety profile of belimumab.

EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials.

At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.

Defining Disease Modifying Therapy for Alzheimer's Disease.

BACKGROUND: Disease-modifying therapies (DMTs) are urgently needed to treat the growing number of individuals with Alzheimer's disease (AD) or at immanent risk for AD. A definition of DMT is required to facilitate the process of DMT drug development. PROCESS: This is a review of the state of the science with regard to definition and development of DMTs. RESULTS: A DMT is as an intervention that produces an enduring change in the clinical progression of AD by interfering in the underlying pathophysiological mechanisms of the disease process that lead to cell death. Demonstration of DMT efficacy is garnered through clinical trial designs and biomarkers. Evidence of disease modification in the drug development process is based on trial designs such as staggered start and delayed withdrawal showing an enduring effect on disease course or on combined clinical outcomes and correlated biomarker evidence of an effect on the underlying pathophysiological processes of the disease. Analytic approaches such as showing change in slope of cognitive decline, increasing drug-placebo difference over time, and delay of disease milestones are not conclusive by themselves but support the presence of a disease modifying effect. Neuroprotection is a related concept whose demonstration depends on substantiating disease modification. No single type of evidence in itself is sufficient to prove disease modification - consistency, robustness, and variety of sources of data will all contribute to convincing stakeholders that an agent is a DMT. CONCLUSION: DMT is defined by its enduring effect on processes leading to cell death. A variety of types of data can be used to support the hypothesis that disease modification has occurred.