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Abstract Coccolithophores are marine calcifying phytoplankton important to the carbon cycle and a model organism for studying diversity. Here, we present CASCADE (Coccolithophore Abundance, Size, Carbon And Distribution Estimates), a new global dataset for 139 extant coccolithophore taxonomic units. CASCADE includes a trait database (size and cellular organic and inorganic carbon contents) and taxonomic-unit-specific global spatiotemporal distributions (Latitude/Longitude/Depth/Month/Year) of coccolithophore abundance and organic and inorganic carbon stocks. CASCADE covers all ocean basins over the upper 275 meters, spans the years 1964-2019 and includes 33,119 gridded taxonomic-unit-specific abundance observations. Within CASCADE, we characterise the underlying uncertainties due to measurement errors by propagating error estimates between the different studies. This error propagation pipeline is statistically robust and could be applied to other plankton groups. CASCADE can contribute to (observational or modelling) studies that focus on coccolithophore distribution and diversity and the impacts of anthropogenic pressures on historical populations. Additionally, our new taxonomic-unit-specific cellular carbon content estimates provide essential conversions to quantify the role of coccolithophores on ecosystem functioning and global biogeochemistry.

Abstract Calcification and biomass production by planktonic marine organisms influences the global carbon cycle and fuels marine ecosystems. The major calcifying plankton group coccolithophores are highly diverse, comprising ca. 250–300 extant species. However, coccolithophore size (a key functional trait) and degree of calcification are poorly quantified, as most of our understanding of this group comes from a small number of species. We generated a novel reference dataset of coccolithophore morphological traits, including cell-specific data for coccosphere and cell size, coccolith size, number of coccoliths per cell, and cellular calcite content. This dataset includes observations from 1074 individual cells and represents 61 species from 25 genera spanning equatorial to temperate coccolithophore populations that were sampled during the Atlantic Meridional Transect (AMT) 14 cruise in 2004. This unique dataset can be used to explore relationships between morphological traits (cell size and cell calcite) and environmental conditions, investigate species-specific and community contributions to pelagic carbonate production, export and plankton biomass, and inform and validate coccolithophore representation in marine ecosystem and biogeochemical models.

Abstract L1CAM-positive extracellular vesicles (L1EV) are an emerging biomarker that may better reflect ongoing neuronal damage than other blood-based biomarkers. The physiological roles and regulation of L1EVs and their small RNA cargoes following stroke is unknown. We sought to characterize L1EV small RNAs following stroke and assess L1EV RNA signatures for diagnosing stroke using weighted gene co-expression network analysis and random forest (RF) machine learning algorithms. Interestingly, small RNA sequencing of plasma L1EVs from patients with stroke and control patients (n = 28) identified micro(mi)RNAs known to be enriched in the brain. Weighted gene co-expression network analysis (WGCNA) revealed small RNA transcript modules correlated to diagnosis, initial NIH stroke scale, and age. L1EV RNA signatures associated with the diagnosis of AIS were derived from WGCNA and RF classification. These small RNA signatures demonstrated a high degree of accuracy in the diagnosis of AIS with an area under the curve (AUC) of the signatures ranging from 0.833 to 0.932. Further work is necessary to understand the role of small RNA L1EV cargoes in the response to brain injury, however, this study supports the utility of L1EV small RNA signatures as a biomarker of stroke.

IntroductionImmune dysfunction is important in aging and neurodegeneration; lacking clinically available tools limits research translation. We tested associations of cerebral spinal fluid (CSF) monocyte-to-lymphocyte ratio (MLR)-innate immune activation surrogate-with cognition in an aging and dementia cohort, hypothesizing that elevated MLR is associated with poorer executive functioning.MethodsCSF MLR was calculated in well-characterized, genotyped participants enrolled in studies of aging and dementia at University of California, San Francisco Memory and Aging Center (n = 199, mean age 57.5 years, SD 11.9). Linear models tested associations with episodic memory and executive function (verbal fluency, speeded set-shifting).ResultsAging was associated with higher CSF monocyte, lower lymphocyte counts, and higher MLRs (p

A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP  80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.

Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.

ObjectiveThere are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia.MethodsWe studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.ResultsHigher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = -0.33, p = .002; Cohort 2: β = -0.36, p = .03) and parietal ROIs (Cohort 1: β = -0.31, p = .01; Cohort 2: β = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = -0.38, p = .01; Cohort 2: β = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.ConclusionsPlasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Abstract Conservation funding is currently limited; cost‐effective conservation solutions are essential. We suggest that the thousands of field stations worldwide can play key roles at the frontline of biodiversity conservation and have high intrinsic value. We assessed field stations’ conservation return on investment and explored the impact of COVID‐19. We surveyed leaders of field stations across tropical regions that host primate research; 157 field stations in 56 countries responded. Respondents reported improved habitat quality and reduced hunting rates at over 80% of field stations and lower operational costs per km2 than protected areas, yet half of those surveyed have less funding now than in 2019. Spatial analyses support field station presence as reducing deforestation. These “earth observatories” provide a high return on investment; we advocate for increased support of field station programs and for governments to support their vital conservation efforts by investing accordingly.

White matter pathologies are critically involved in the etiology of vascular cognitive impairment-dementia (VCID), Alzheimer's disease (AD), and Alzheimer's disease and related diseases (ADRD), and therefore need to be considered a treatable target ( Roseborough A, Hachinski V, Whitehead S. White matter degeneration - a treatable target? Roseborough et al. JAMA Neurol [Internet]. 2020 Apr 27;77(7):793-4, [1] . To help address this often-missed area of research, several workshops have been sponsored by the Leo and Anne Albert Charitable Trust since 2015, resulting in the incorporation of "The Albert Research Institute for White Matter and Cognition" in 2020. The first annual "Institute" meeting was held virtually on March 3-4, 2021. The Institute provides a forum and workspace for communication and support of the advancement of white matter science and research to better understand the evolution and prevention of dementia. It serves as a platform for young investigator development, to introduce new data and debate biology mechanisms and new ideas, and to encourage and support new research collaborations and directions to clarify how white matter changes, with other genetic and health risk factors, contribute to cognitive impairment. Similar to previous Albert Trust-sponsored workshops (Barone et al. in J Transl Med 14:1-14, [2]; Sorond et al. in GeroScience 42:81-96, [3]), established expert investigators were identified and invited to present. Opportunities to attend and present were also extended by invitation to talented research fellows and younger scientists. Also, updates on institute-funded research collaborations were provided and discussed. The summary that follows is a synopsis of topics and discussion covered in the workshop.

The Alzheimer's Association International Conference held its sixth Satellite Symposium in Sydney, Australia in 2019, highlighting the leadership of Australian researchers in advancing the understanding of and treatment developments for Alzheimer's disease (AD) and other dementias. This leadership includes the Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing (AIBL), which has fueled the identification and development of many biomarkers and novel therapeutics. Two multimodal lifestyle intervention studies have been launched in Australia; and Australian researchers have played leadership roles in other global studies in diverse populations. Australian researchers have also played an instrumental role in efforts to understand mechanisms underlying vascular contributions to cognitive impairment and dementia; and through the Women's Healthy Aging Project have elucidated hormonal and other factors that contribute to the increased risk of AD in women. Alleviating the behavioral and psychological symptoms of dementia has also been a strong research and clinical focus in Australia.

IntroductionDevelopment of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize cerebral arteriolar walls in vivo. Retinal arterioles offer a window into the cerebral circulation.MethodsIntensity-based retinal arteriolar visualization in optical coherence tomography (I-bRAVO) was applied to evaluate mean wall thickness (MWT) and wall-to-lumen ratio (WLR) in 250 subjects with sporadic and genetic cerebral small vessel disease (CSVD), non-vascular neurodegenerative diseases (NVND), and healthy controls (HC) in association with imaging and cognitive markers.ResultsMWT and WLR were higher in CSVD, associated with severity of vascular white matter lesions, and correlated with magnetic resonance imaging-based intracranial arteriolosclerosis score. WLR correlated with gray and white matter volume and differentiated asymptomatic sporadic CSVD from HC (area under the curve = 0.82).DiscussionI-bRAVO is a rapid, non-invasive tool. MWT and WLR were associated with imaging markers of CSVD and could contribute to early identification of sporadic CSVD.

Brain health means optimal physiological brain function across the normal life-course. It encompasses not only healthy brain aging but also brain diseases, their diagnosis and treatment. In all these areas, molecular science has advanced our understanding.This multi-disciplinary review combines viewpoints from laboratory science, clinical medicine and the bioscience industry. First, we review the advances that molecular science has brought to brain health in the past twenty years. These include therapeutic antibodies for CNS diseases (multiple sclerosis, Alzheimer disease) and the dramatic introduction of RNA-targeted therapeutics. Second, we highlight areas where greater molecular understanding is needed. Salient examples are the relation of brain structure to cognitive symptoms, and molecular biomarkers for diagnosis, target discovery and testing of interventions. Finally, we speculate on aspects of molecular science that are likely to advance brain health in the next twenty years. These include: cell senescence and chronobiology; gene editing (notably, CRISPR) and RNA targeting (RNA interference, miRNA manipulation); brain-immune interactions; novel drug targets (AQP4, HIF1, Toll-like receptors); and novel chemistry to make new drugs (molecular machines, quantum molecular modelling and “click” chemistry). Early testing of the relationships between molecular pathways and clinical manifestations will drive much-needed breakthroughs in neurology and psychiatry.

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.

IntroductionCognitive composite scores offer a means of precisely measuring executive functioning (EF).MethodsWe developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models.ResultsFinal model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

IntroductionApolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries.MethodsWe collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations.ResultsOur analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature.DiscussionThese results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.

IntroductionWe investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD).MethodsPlasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults.ResultsPrinciple component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age.DisucssionPlasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

Small cerebral vascular disease (SCeVD) demonstrated by white matter hyperintensity (WMH) on MRI contributes to the development of dementia in Alzheimer's disease (AD), but it has not been possible to correlate onset, severity, or protein components of SCeVD with characteristics of WMH in living patients. Plasma endothelial-derived exosomes (EDEs) were enriched by two-step immunoabsorption from four groups of participants with no clinical evidence of cerebrovascular disease: cognitively normal (CN) without WMH (CN without SCeVD, n = 20), CN with SCeVD (n = 22), preclinical AD (pAD) + mild cognitive impairment (MCI) without SCeVD (pAD/MCI without SCeVD, n = 22), and pAD/MCI with SCeVD (n = 16) for ELISA quantification of cargo proteins. Exosome marker CD81-normalized EDE levels of the cerebrovascular-selective biomarkers large neutral amino acid transporter 1 (LAT-1), glucose transporter type 1 (Glut-1), and permeability-glycoprotein (p-GP, ABCB1) were similarly significantly higher in the CN with SCeVD and pAD/MCI with SCeVD groups than their corresponding control groups without SCeVD. CD81-normalized EDE levels of Aβ40 and Aβ42 were significantly higher in the pAD/MCI with SCeVD group but not in the CN with SCeVD group relative to controls without SCeVD. Levels of normal cellular prion protein (PrPc), a receptor for amyloid peptides, and phospho-181T-tau were higher in both CN and pAD/MCI with SCeVD groups than in the corresponding controls. High EDE levels of Aβ40, Aβ42, and phospho-181T-tau in patients with WMH suggesting SCeVD appear at the pre-clinical or MCI stage of AD and therapeutic lowering of neurotoxic peptide levels may delay progression of AD angiopathy.

Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell-autonomous in nature, including nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane-associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome-based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC-derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC-derived exosome-based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC-exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation.

BackgroundMeasuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer's disease (AD).ObjectiveTo examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum.MethodsWe studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity.ResultsIn both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP.ConclusionThe relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

The present-day marine nitrogen (N) cycle is strongly regulated by biology. Deficiencies in the availability of fixed and readily bioavailable nitrogen relative to phosphate (P) in the surface ocean are largely corrected by the activity of diazotrophs. This feedback system, termed the "nitrostat," is thought to have provided close regulation of fixed-N speciation and inventory relative to P since the Proterozoic. In contrast, during intervals of intense deoxygenation such as Cretaceous ocean anoxic event (OAE) 2, a few regional sedimentary δ15N records hint at the existence of a different mode of marine N cycling in which ammonium plays a major role in regulating export production. However, the global-scale dynamics during this time remain unknown. Here, using an Earth System model and taking the example of OAE 2, we provide insights into the global marine nitrogen cycle under severe ocean deoxygenation. Specifically, we find that the ocean can exhibit fundamental transitions in the species of nitrogen dominating the fixed-N inventory--from nitrate (NO3 -) to ammonium (NH4 +)--and that as this transition occurs, the inventory can partially collapse relative to P due to progressive spatial decoupling between the loci of NH4 + oxidation, NO3 - reduction, and nitrogen fixation. This finding is relatively independent of the specific state of ocean circulation and is consistent with nitrogen isotope and redox proxy data. The substantive reduction in the ocean fixed-N inventory at an intermediate state of deoxygenation may represent a biogeochemical vulnerability with potential implications for past and future (warmer) oceans.

IntroductionLevels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).MethodsParticipants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs.ResultsADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS.DiscussionADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.

Abstract The H-02 constructed wetland was designed to remove metals (primarily copper and zinc) to treat building process water and storm water runoff from multiple sources associated with the Tritium Facility at the DOE-Savannah River Site, Aiken, SC. The concentration of Cu and Zn in the sediments has increased over the lifetime of the wetland and is a concern. A bioremediation option was investigated at the laboratory scale utilizing a newly isolated bacterium of the copper metabolizing genus Cupriavidus isolated from Tim’s Branch Creek, a second-order stream that eventually serves as a tributary to the Savannah River, contaminated with uranium and other metals including copper, nickel, and mercury. Cupriavidus basilensis SRS is a rod-shaped, gram-negative bacterium which has been shown to have predatory tendencies. The isolate displayed resistance to the antibiotics ofloxacin, tetracycline, ciprofloxacin, select fungi, as well as Cu2+ and Zn2+. Subsequent ribosomal sequencing demonstrated a 100% confidence for placement in the genus Cupriavidus and a 99.014% match to the C. basilensis type strain. When H-02 wetland samples were inoculated with Cupriavidus basilensis SRS samples showed significant (p

Abstract Alzheimer's disease and related dementias (ADRD) remain a major health‐care challenge with few licensed medications. Repurposing existing drugs may afford prevention and treatment. Phosphodiesterase‐5 (PDE5) is widely expressed in vascular myocytes, neurons, and glia. Potent, selective, Food and Drug Administration–approved PDE5 inhibitors are already in clinical use (sildenafil, vardenafil, tadalafil) as vasodilators in erectile dysfunction and pulmonary arterial hypertension. Animal data indicate cognitive benefits of PDE5 inhibitors. In humans, real‐world patient data suggest that sildenafil and vardenafil are associated with reduced dementia risk. While a recent clinical trial of acute tadalafil on cerebral blood flow was neutral, there may be chronic actions of PDE5 inhibition on cerebrovascular or synaptic function. We provide a perspective on the potential utility of PDE5 inhibitors for ADRD. We conclude that further prospective clinical trials with PDE5 inhibitors are warranted. The choice of drug will depend on brain penetration, tolerability in older people, half‐life, and off‐target effects. HIGHLIGHTS Potent phosphodiesterase‐5 (PDE5) inhibitors are in clinical use as vasodilators. In animals PDE5 inhibitors enhance synaptic function and cognitive ability. In humans the PDE5 inhibitor sildenafil is associated with reduced risk of Alzheimer's disease. Licensed PDE5 inhibitors have potential for repurposing in dementia. Prospective clinical trials of PDE5 inhibitors are warranted.

Cerebral perfusion declines across the lifespan and is altered in the early stages of several age-related neuropathologies. Little is known, however, about the longitudinal evolution of perfusion in healthy older adults, particularly when perfusion is quantified using magnetic resonance imaging with arterial spin labeling (ASL). The objective was to characterize longitudinal perfusion in typically aging adults and elucidate associations with cognition and brain structure. Adults who were functionally intact at baseline (n = 161, ages 47-89) underwent ASL imaging to quantify whole-brain gray matter perfusion; a subset (n = 136) had repeated imaging (average follow-up: 2.3 years). Neuropsychological testing at each visit was summarized into executive function, memory, and processing speed composites. Global gray matter volume, white matter microstructure (mean diffusivity), and white matter hyperintensities were also quantified. We assessed baseline associations among perfusion, cognition, and brain structure using linear regression, and longitudinal relationships using linear mixed effects models. Greater baseline perfusion, particularly in the left dorsolateral prefrontal cortex and right thalamus, was associated with better executive functions. Greater whole-brain perfusion loss was associated with worsening brain structure and declining processing speed. This study helps validate noninvasive MRI-based perfusion imaging and underscores the importance of cerebral blood flow in cognitive aging.

Age-related cognitive decline is a public health problem but highly diverse and difficult to predict. We captured nonoverlapping cognitive phenotypes in high-functioning adults and identified baseline factors differentiating trajectories. Three hundred fourteen functionally normal adults (M = 69 y) completed 2+ visits. Participants with sample-based longitudinal slopes in memory or processing speed less than -1 SD were classified as "declining" on that measure; 29 and 50 individuals had slopes less than -1 SD on processing speed or memory, respectively; 2.5% met criteria for both, who were excluded. At baseline, speed decliners demonstrated greater age, inflammation, and cognitive complaints compared with speed-stable adults; memory decliners were more likely to be male and had lower depressive symptoms, gray matter volumes, and white matter hyperintensities compared with memory-stable adults. Baseline speed, TNFα, and cognitive complaints accurately classified 96.3% of future speed decliners; baseline memory, sex, precuneal volume, and white matter hyperintensities accurately classified 88.5% of future memory decliners. There are discrete cognitive aging phenotypes reflecting nonoverlapping vulnerabilities in high-functioning adults. Early markers can predict cognition even within the "normal" spectrum and underscore therapeutic targets.

Frontotemporal dementia refers to a group of progressive neurodegenerative syndromes usually caused by the accumulation of pathological tau or TDP-43 proteins. The effects of these proteins in the brain are complex, and each can present with several different clinical syndromes. Clinical efficacy trials of drugs targeting these proteins must use endpoints that are meaningful to all participants despite the variability in symptoms across patients. There are many candidate clinical measures, including neuropsychological scores and functional measures. Brain imaging is another potentially attractive outcome that can be precisely quantified and provides evidence of disease modification. Most imaging studies in frontotemporal dementia have been cross-sectional, and few have compared longitudinal changes in cortical volume with changes in other measures such as perfusion and white matter integrity. The current study characterized longitudinal changes in 161 patients with three frontotemporal dementia syndromes: behavioural variant frontotemporal dementia (n = 77) and the semantic (n = 45) and non-fluent (n = 39) variants of primary progressive aphasia. Visits included comprehensive neuropsychological and functional assessment, structural MRI (3 T), diffusion tensor imaging, and arterial spin labelled perfusion imaging. The goal was to identify measures that are appropriate as clinical trial outcomes for each group, as well as those that might be appropriate for trials that would include more than one of these groups. Linear mixed effects models were used to estimate changes in each measure, and to examine the correlation between imaging and clinical changes. Sample sizes were estimated based on the observed effects for theoretical clinical trials using bootstrapping techniques to provide 95% confidence intervals for these estimates. Declines in functional and neuropsychological measures, as well as frontal and temporal cortical volumes and white matter microstructure were detected in all groups. Imaging changes were statistically significantly correlated with, and explained a substantial portion of variance in, the change in most clinical measures. Perfusion and diffusion tensor imaging accounted for variation in clinical decline beyond volume alone. Sample size estimates for atrophy and diffusion imaging were comparable to clinical measures. Corpus callosal fractional anisotropy led to the lowest sample size estimates for all three syndromes. These findings provide further guidance on selection of trial endpoints for studies in frontotemporal dementia and support the use of neuroimaging, particularly structural and diffusion weighted imaging, as biomarkers. Diffusion and perfusion imaging appear to offer additional utility for explaining clinical change beyond the variance explained by volume alone, arguing for considering multimodal imaging in treatment trials.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR

Despite the important role of planktonic foraminifera in regulating the ocean carbonate production and their unrivalled value in reconstructing paleoenvironments, our knowledge on their ecology is limited. A variety of observational techniques such as plankton tows, sediment traps and experiments have contributed to our understanding of foraminifera ecology. But, fundamental questions around costs and benefits of calcification and the effect of nutrients, temperature and ecosystem structure on these organisms remain unanswered. To tackle these questions, we take a novel mechanistic approach to study planktonic foraminifera ecology based on trait theory. We develop a zero-dimensional (0-D) trait-based model to account for the biomass of prolocular (20 m) and adult (160 m) stages of non-spinose foraminifera species and investigate their potential interactions with phytoplankton and other zooplankton under different temperature and nutrient regimes. Building on the costs and benefits of calcification, we model two ecosystem structures to explore the effect of resource competition and temperature on planktonic foraminifera biomass. By constraining the model results with ocean biomass estimations of planktonic foraminifera, we estimate that the energetic cost of calcification could be about 10 50% and 10 40% for prolocular and adult stages respectively. Our result suggest that the shell provides protection against processes other than predation (e.g. pathogen invasion). We propose that the low standing biomass of planktonic foraminifera plays a key role in their survival from predation, along with their shell protection. Our model suggests a shift from temperature as a main regulator of foraminifera biomass in the early developmental stage to resource competition for adult biomass.