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Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions.In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Understanding the properties and variability of the ionosphere is vital for understanding the atmosphere of Mars. The presence and property of waves provide insight into the plasma and magnetic environment. We conducted a search for 5 - 16 Hz signals below 400 km in magnetic field data from Mars Global Surveyor (MGS), the Mars Atmosphere and Volatile Evolution (MAVEN), and Interior Exploration using Seismic Investigations, Geodesy, and Heat Transport (InSight) missions. We discuss an analysis of 54 identified MAVEN events using multiple instruments and present a case study event. Nearly half the wave events occur near the cusps of strong crustal magnetic fields (CMFs). The stronger regions have fewer events and may be a result of stronger CMFs preventing draped field lines from reaching lower altitudes. A majority of the observed magnetic waves occur on the nightside, are associated with greater fluxes of electrons traveling downward along the local magnetic field compared to those traveling upward, and correspond to increases in thermal plasma density. These aspects indicate electron precipitation was present during these wave events. We conclude that these waves are observed under magnetic field conditions favorable for the penetration of electrons and waves into the lower ionosphere, but that the electron precipitation cannot solely account for the waves or plasma changes.We then discuss our null results regarding Schumann resonances, which are electromagnetic signals generated by lightning that, if they exist on Mars, are expected to propagate at 7-14 Hz. Future studies specifically looking for Schumann resonances will require higher sensitivity instruments and would benefit from additional missions that reach into the ionosphere of Mars. Finally, we comment on the inconsistency between identifying MGS events purely via by-eye analysis versus using quantitative methods for guidance.

Since September 2014, NASA's Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft has been measuring the in-situ ionospheric constituents of Mars. Recently, MAVEN detected the presence of large-scale plasma depletions (at least ten-fold) within the Martian ionosphere, also known as Plasma Depletion Events (PDEs). Geometrically, the Martian PDEs appear to be bubble-like plasma structures. Although the origin and formation of PDEs are not entirely understood, they are known to occur primarily on the nightside and in regions with stronger crustal magnetic fields.In this study, we analyze the variation of magnetic field magnitude and direction and electric field power (2–100 Hz) associated with PDEs. We show that, in most cases, the magnetic fields do not considerably change within the plasma-depleted region. Conversely, the low-frequency electric field wave power is enhanced by up to two orders of magnitude at the peak depletion. Both ions and electrons within PDEs are highly magnetized. We present possible formation mechanisms of PDEs supported by recent findings.

Accelerated electron populations observed in the nightside ionosphere of Mars are investigated using measurements obtained by MAVEN’s Solar Wind Electron Analyzer. The measurements are of particular interest as they extend to altitudes as low as 130 km and to regions characterized by strong crustal magnetic fields, allowing us to investigate the evolution of the electron distributions in the complex crustal fields and determine the rate by which the accelerated populations precipitate into the Martian upper atmosphere.The majority of the observed accelerated electrons are trapped in the crustal fields, bouncing between mirror points, presumably drifting across magnetic field lines, but without instantaneous access to the collisional atmosphere. The average energy flux of these electrons is significant when compared to that of the much more common ‘unaccelerated’ sheath electrons. Considering that the Martian crustal magnetic fields do not provide a closed path for drifting particles, the trapped electrons are bound to exit the crustal fields and either precipitate into the atmosphere or escape. Currently, we estimate that, despite their low detection rate (< 1%), the accelerated electrons account for about 10% of the total energy that is deposited into the nightside ionosphere by electron precipitation. Further, the peak energy of the accelerated electrons is generally found in the range of tens to hundreds of eV, consistent with the energy range previously suggested for the generation of discrete aurora emissions observed on Mars.

The thermal electron temperature, Te, is an important quantity in planetary ionospheres because many photochemical reaction rates depend on it. Te thus plays a role in driving ion composition, structure and dynamics. In addition, enhancements in Te with altitude have been shown to drive ambi-polar electric fields that can energize cold planetary ions and lead to ion escape to space.The Mars Atmosphere and Volatile EvolutioN (MAVEN) mission acquires Te profiles on each orbit and as a result, a comprehensive data set exists that spans the full range of Mars local times, latitudes and solar zenith angles, allowing us to determine which physical processes control the Te profile shapes and temperature values. We focus on the “transition region,” where Te values can rapidly increase from small values (1000 K), over a relatively narrow altitude range. The suite of plasma instruments carried by MAVEN allows us to investigate the role of, for example, electron-neutral collisions, ion temperature, wave heating, etc. This study focuses on the effect of electron-neutral collisions on the location and width of the Te transition region. We utilize observations of the neutral atmosphere made by MAVEN’s Neutral Gas and Ion Mass Spectrometer (NGIMS) instrument to calculate electron–neutral collision frequencies, which are compared to measured Te profiles. The calculated collision frequencies provide insight on when collisional processes dominate (over transport and electromagnetic waves, for example), and allow us to identify trends between driving processes and the shape and location of the Te transition region. Understanding the physical processes that control the form of Te profiles will inform us of the mechanisms key to structuring the current day Mars ionosphere. Such understanding will also provide key insight needed for studies of ionospheric escape to space and long-term evolution of the Martian atmosphere.

The health care delivery system in the United States, structured to provide single-disease care, presents unique challenges for patients with complex physical and psychiatric comorbidities. Patients in these populations are often referred to multiple specialty clinics, encounter little continuity of care or collaboration among their providers, incur high health care costs, and experience poor treatment outcomes. Given these barriers, questions remain about the extent to which siloed and fragmented care, as opposed to the complex nature of the illnesses themselves, contribute to poor outcomes. If given the opportunity to receive well-integrated, consistent, and personalized care, can patients with historically difficult-to-treat comorbid medical and mental illnesses make progress? This article describes an innovative model of care called functional rehabilitation that is designed to address existing barriers in treatment. The functional rehabilitation program seeks to disrupt the escalating effects of interacting comorbidities by offering highly collaborative treatment from a small team of clinicians, personalized interventions using a shared decision-making framework, multipronged treatment options, colocation in a large hospital system, and significant 1:1 time with patients. The article includes a case example with longitudinal outcome data that illustrates how progress can be made with appropriate programmatic supports. Future research should examine the cost-effectiveness of this model of care.

Background and ObjectivesThis prospective study sought to determine the association of modifiable/nonmodifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) risk score with hippocampal volume (HV) loss and episodic memory (EM) decline in cognitively normal (CN) older adults classified as brain β-amyloid (Aβ) negative (Aβ−) or positive (Aβ+).MethodsAustralian Imaging, Biomarkers and Lifestyle study participants (age 58–91 years) who completed ≥2 neuropsychological assessments and a brain Aβ PET scan (n = 592) were included in this study. We computed the CAIDE risk score (age, sex, APOE ε4 status, education, hypertension, body mass index [BMI], hypercholesterolemia, physical inactivity) and a modifiable CAIDE risk score (CAIDE-MR; education, hypertension, BMI, hypercholesterolemia, physical inactivity) for each participant. Aβ+ was classified using Centiloid >25. Linear mixed models assessed interactions between each CAIDE score, Aβ group, and time on HV loss and EM decline. Age, sex, and APOE ε4 were included as separate predictors in CAIDE-MR models to assess differential associations. Exploratory analyses examined relationships between individual modifiable risk factors and outcomes in Aβ− cognitively normal (CN) adults.ResultsWe observed a significant Aβ group × CAIDE × time interaction on HV loss (β [SE] = –0.04 [0.01]; p < 0.000) but not EM decline (β [SE] = –2.33 [9.96]; p = 0.98). Decomposition revealed a significant CAIDE × time interaction in Aβ+ participants only. When modifiable/nonmodifiable CAIDE components were considered separately, we observed a significant Aβ group × CAIDE-MR × time interaction on EM decline only (β [SE] = 3.03 [1.18]; p = 0.01). A significant CAIDE-MR score × time interaction was observed in Aβ− participants only. Significant interactions between APOE ε4 and age × time on HV loss and EM decline were observed in both groups. Exploratory analyses in Aβ− CN participants revealed a significant interaction between BMI × time on EM decline (β [SE] = –3.30 [1.43]; p = 0.02).DiscussionThese results are consistent with studies showing that increasing age and APOE ε4 are associated with increased rates of HV loss and EM decline. In Aβ− CN adults, lower prevalence of modifiable cardiovascular risk factors was associated with less HV loss and EM decline over ∼10 years, suggesting interventions to reduce modifiable cardiovascular risk factors could be beneficial in this group.

Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine ( n = 13), and age- and sex-matched controls ( n = 59). Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman’s r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia ( r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight ( r = −0.305, 95% confidence interval: [−0.504, −0.076]). Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

Though ion escape to space is an important mechanism for atmospheric loss on Mars, the processes that accelerate ions to escape velocity have not been identifed and quantified. The lowest altitude where suprathermal planetary ions appear is an important source region for ion escape, where electromagnetic forces and waves begin to energize ions to escape velocity. We have conducted a statistical study of O2+ distribution functions measured by Mars Volatile EvolutioN SupraThermal And Thermal Ion Composition (MAVEN-STATIC) in order to identify this source region for Martian ion escape. We have fit Maxwellians to each measured O2+ distribution function in order to identify distributions containing a suprathermal component. Suprathermal ions appear just above the exobase region at all solar zenith angles, but Maxwellian ion distributions persist to higher altitudes near the terminator than on the dayside or the nightside. We also investigated the effects of crustal magnetism, finding that crustal fields protect planetary plasma from energization on the dayside and enhance energization on the nightside.

The thermal electron temperature, Te, is an important quantity in planetary ionospheres because many photochemical reaction rates depend on it. Te thus plays a role in driving ion composition, structure and dynamics. In addition, enhancements in Te with altitude have been shown to drive ambi-polar electric fields that can energize cold planetary ions and lead to ion escape to space. The Mars Atmosphere and Volatile EvolutioN (MAVEN) mission acquires Te profiles on each orbit and as a result, a comprehensive data set exists that spans the full range of Mars local times, latitudes and solar zenith angles. We will determine which physical processes control the Te profile shapes and temperature values. In particular, we will focus on the “transition region” where Te values can rapidly increase from small values (1000 K), over a relatively narrow altitude range. The suite of plasma instruments carried by MAVEN allows us to investigate the role of, for example, electron-neutral collisions, ion temperature, wave heating, etc. Understanding the physical processes that control the form of Te profiles will inform us of the mechanisms key to structuring the current day Mars ionosphere. Such understanding will also provide key insight needed for studies of ionospheric escape to space and long term evolution of the Mars atmosphere.

At Mars, the solar wind is usually decelerated and heated at the bow shock, then diverted around the planet by the induced magnetosphere. Recently, however, Crismani et. al. (2019) presented MAVEN (Mars Atmosphere and Volatile EvolutioN) observations of an interesting event, where near-pristine solar wind was observed in the collisional atmosphere below 200 km. We searched through seven years of MAVEN SWIA (Solar Wind Ion Analyzer) observations to determine how often these types of events occur. We found at least 15 orbits during which near-pristine solar wind was observed below 200 km. In this presentation, we will discuss the occurrence rate of the events and characterize the planetary and solar wind conditions under which they are observed. Finally, we will discuss the implications of solar wind having direct access to the collisional atmosphere, which may include localized (1) ionization that alters the structure of the ionosphere, (2) heating of the thermosphere, (3) energization of ions to escape speeds, and (4) patchy proton aurora. Reference: Crismani, M. M. J., Deighan, J., Schneider, N. M., Plane, J. M. C., Withers, P., Halekas, J., et al. (2019). Localized ionization hypothesis for transient ionospheric layers. Journal of Geophysical Research: Space Physics, 124, 4870–4880. https://doi.org/ 10.1029/2018JA026251

Mars is an unmagnetized planet meaning that it has no internally generated global dipole magnetic field; the solar wind interaction with Mars is thus highly dependent on upstream conditions that include the orientation of the Interplanetary Magnetic Field (IMF). This interaction controls the transfer of energy and momentum from the solar wind into the magnetosphere, ionosphere and atmosphere, driving structure and dynamics within each. The Mars-solar wind interaction has been studied in detail for “nominal” Parker Spiral IMF conditions, but few studies exist that investigate the interaction under less typical “radial IMF” conditions. We utilize in-situ measurements made by NASAs Mars Atmosphere and Volatile EvolutioN (MAVEN) mission during radial IMF conditions at Mars to identify several prominent features that arise during this interaction:Highly disturbed magnetic and plasma conditions exist over the nose of the planet, which are reminiscent of foreshock like conditions and indicative of radial IMF. Solar wind protons and alphas are observed to penetrate directly into the dayside ionosphere down to MAVEN periapsis altitudes (~230 km). The magnetic pileup region (or magnetic barrier) forms deep within the dayside ionosphere, directly exposing significant heavy planetary ion densities above to the solar wind flow. Planetary ions above the magnetic barrier are mass loaded by the solar wind flow, characterized by signatures consistent with VxB acceleration under near radial IMF conditions. Thermal ion distributions in the ionosphere are observed to possess significant suprathermal energetic tails, suggesting that additional energization mechanisms are present that heat the cold ion core. Electron and ion temperatures are 2-10 times higher than average values that occur under more typical IMF conditions. Significant erosion of the dayside upper ionosphere occurs and appears to drive substantial ion escape to space.

Discrete aurorae have been observed at Mars by multiple spacecraft, including Mars Express, Mars Atmosphere and Volatile EvolutioN (MAVEN), and most recently the United Arab Emirates’ Hope spacecraft. Meanwhile, there have been studies on the source particle responsible for producing these detectable aurorae, that is accelerated electrons or hotter solar wind electrons (termed “auroral electrons"). By utilizing empirical criteria to select auroral electrons established by Xu et al. [2022], we conduct statistical analyses of the impact of upstream drivers on the occurrence rate and electron fluxes of auroral electrons. We find the occurrence rate is well organized and increases with upstream dynamic pressure and weakly depends on the interplanetary magnetic field strength. Meanwhile, the integrated auroral electron flux is somewhat insensitive to the upstream drivers. In the meantime, the auroral emission is not the sole effect of electrons impacting the collisional atmosphere. Auroral electrons are expected to cause significant ionization and enhance the plasma density locally. In this study, we also quantify the ionospheric impact of auroral electron precipitation, specifically the thermal ion (O+, O2+, CO2+) density enhancement, with MAVEN observations and also modeling. Our results show the ion density to increase up to 1-2 orders of magnitude at low altitudes.

BACKGROUND: Comorbid anxiety and depression are common and are associated with greater disease burden than either alone. Our recent efforts have identified an association between gut microbiota dysfunction and severity of anxiety and depression. In this follow-up, we applied Differential Co-Expression Analysis (DiffCoEx) to identify potential gut microbiota biomarker(s) candidates of treatment resistance among psychiatric inpatients. METHODS: In a sample of convenience, 100 psychiatric inpatients provided clinical data at admission and discharge; fecal samples were collected early during the hospitalization. Whole genome shotgun sequencing methods were used to process samples. DiffCoEx was used to identify clusters of microbial features significantly different based on treatment resistance status. Once overlapping features were identified, a knowledge-mining tool was used to review the literature using a list of microbial species/pathways and a select number of medical subject headlines (MeSH) terms relevant for depression, anxiety, and brain-gut-axis dysregulation. Network analysis used overlapping features to identify microbial interactions that could impact treatment resistance. RESULTS: DiffCoEx analyzed 10,403 bacterial features: 43/44 microbial features associated with depression treatment resistance overlapped with 43/114 microbial features associated with anxiety treatment resistance. Network analysis resulted in 8 biological interactions between 16 bacterial species. Clostridium perfringens evidenced the highest connection strength (0.95). Erysipelotrichaceae bacterium 6_1_45 has been most widely examined, is associated with inflammation and dysbiosis, but has not been associated with depression or anxiety. CONCLUSION: DiffCoEx potentially identified gut bacteria biomarker candidates of depression and anxiety treatment-resistance. Future efforts in psychiatric microbiology should examine the mechanistic relationship of identified pro-inflammatory species, potentially contributing to a biomarker-based algorithm for treatment resistance.

Since the beginning of theorizing about personality disorders (PDs), social factors have figured centrally into models of pathogenesis. The relative emphasis on social factors has changed over the years in response to a growing appreciation of genetic contributions to personality pathology. However, factors such as abuse, neglect, disturbed parental involvement, burden of stress, socio-economic status, and peer victimization continue to receive support from longitudinal studies for their associations with PD development. This chapter reviews theories of PD pathogenesis, details current research on known social factors, and highlights social impairments linked with PDs. A brief review of social cognition research is offered to explain broader functional impairments associated with PDs. Finally, treatment and prevention efforts are highlighted to illustrate that these factors, traditionally researched within the social domain, often have favourable impacts on the course of illness.

Objectives: Individuals with treatment-refractory disorders have high comorbidity. There is little information on whether recovery is possible and how long it might require. We focused on the individual's recovery using a broad measure of psychopathology, regardless of the variety of disorders present.Methods: We recruited 226 adults [mean age 31.0, SD = 10.3; 75.2% female] entering residential treatment for treatment-refractory disorders to delineate their course and outcome. Individuals received periodic Longitudinal Interval Follow-along Evaluation interviews for symptoms and functioning variables for up to 14 years. Periodic psychodynamic and relationship vignette interviews were rated with the Psychodynamic Conflict Rating Scales (PCRS) for a subgroup of 54 subjects. Outcome variables included modeled rates of change, final scores, time to recovery, and time to attaining healthy adaptive functioning, using Kaplan-Meier estimates from time-to-event analyses.Results: Recovery of PCRS Pathological Functioning occurred in 12 (22%) of 54 subjects rated: median time-to-recovery = 11.63 years (CI: 9.64- upper number not calculable). Eight (14.81%) subjects also developed healthy adaptive functioning, with the time-to-attainment for the first quartile at 10.95 years (CI: 7.87 - upper bound not calculable). Recovery from psychopathology was significantly associated with a median percentage recovered in the domains of symptoms (64.29%), functioning (87.50%), and psychodynamic functioning (50%). Although attaining healthy adaptive functioning was less common, it was highly associated with already achieving recovery from dynamic psychopathology, [OR = 57.40, CI 5.80 - 567.83, p = .0001].Conclusions: These results provided convergent validation of recovery in psychodynamic psychopathology. Some recovered individuals also attained healthy adaptive functioning, which took somewhat longer.

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

Objective: Individuals with mental illnesses severe enough to require psychiatric hospitalization often have significant trauma histories, have developed maladaptive attachment styles, and experien...

Background CSF biomarkers are well-established for routine clinical use, yet a paucity of comparative assessment exists regarding CSF extraction methods during lumbar puncture. Here, we compare in detail biomarker profiles in CSF extracted using either gravity drip or aspiration. Methods Biomarkers for β-amyloidopathy (Aβ1–42, Aβ1–40), tauopathy (total tau), or synapse pathology (BACE1, Neurogranin Trunc-p75, α-synuclein) were assessed between gravity or aspiration extraction methods in a sub-population of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study (cognitively normal, N = 36; mild cognitive impairment, N = 8; Alzheimer’s disease, N = 6). Results High biomarker concordance between extraction methods was seen (concordance correlation > 0.85). Passing Bablock regression defined low beta coefficients indicating high scalability. Conclusions Levels of these commonly assessed CSF biomarkers are not influenced by extraction method. Results of this study should be incorporated into new consensus guidelines for CSF collection, storage, and analysis of biomarkers.