Fully Automated MRI-based Analysis of the Locus Coeruleus in Aging and Alzheimer's Disease Dementia using ELSI-Net.

INTRODUCTION: The Locus Coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's Disease (AD). Magnetic Resonance Imaging based LC features have shown potential to assess LC integrity in vivo. METHODS: We present a Deep Learning based LC segmentation and feature extraction method: ELSI-Net and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology. RESULTS: ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found. DISCUSSION: Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Nets general applicability.

Evaluating phasic transcutaneous vagus nerve stimulation (taVNS) with pupil dilation: the importance of stimulation intensity and sensory perception.

The efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive method to modulate physiological markers of noradrenergic activity of the Locus Coeruleus (LC), such as pupil dilation, is increasingly more discussed. However, taVNS studies show high heterogeneity of stimulation effects. Therefore, a taVNS setup was established here to test different frequencies (10 Hz and 25 Hz) and intensities (3 mA and 5 mA) during phasic stimulation (3 s) with time-synchronous recording of pupil dilation in younger adults. Specifically, phasic real taVNS and higher intensity led to increased pupil dilation, which is consistent with phasic invasive VNS studies in animals. The results also suggest that the influence of intensity on pupil dilation may be stronger than that of frequency. However, there was an attenuation of taVNS-induced pupil dilation when differences in perception of sensations were considered. Specifically, pupil dilation during phasic stimulation increased with perceived stimulation intensity. The extent to which the effect of taVNS induces pupil dilation and the involvement of sensory perception in the stimulation process are discussed here and require more extensive research. Additionally, it is crucial to strive for comparable stimulation sensations during systematic parameter testing in order to investigate possible effects of phasic taVNS on pupil dilation in more detail.

Functional locus coeruleus imaging to investigate an ageing noradrenergic system.

The locus coeruleus (LC), our main source of norepinephrine (NE) in the brain, declines with age and is a potential epicentre of protein pathologies in neurodegenerative diseases (ND). In vivo measurements of LC integrity and function are potentially important biomarkers for healthy ageing and early ND onset. In the present study, high-resolution functional MRI (fMRI), a reversal reinforcement learning task, and dedicated post-processing approaches were used to visualise age differences in LC function (N = 50). Increased LC responses were observed during emotionally and task-related salient events, with subsequent accelerations and decelerations in reaction times, respectively, indicating context-specific adaptive engagement of the LC. Moreover, older adults exhibited increased LC activation compared to younger adults, indicating possible compensatory overactivation of a structurally declining LC in ageing. Our study shows that assessment of LC function is a promising biomarker of cognitive aging.

Audio tagging of avian dawn chorus recordings in California, Oregon and Washington.

Background: Declines in biodiversity and ecosystem health due to climate change are raising urgent concerns. In response, large-scale multispecies monitoring programmes are being implemented that increasingly adopt sensor-based approaches such as acoustic recording. These approaches rely heavily on ecological data science. However, developing reliable algorithms for processing sensor-based data relies heavily on labelled datasets of sufficient quality and quantity. We present a dataset of 1,575 dawn chorus soundscape recordings, 141 being fully annotated (n = 32,994 annotations) with avian, mammalian and amphibian vocalisations. The remaining recordings were included to facilitate novel research applications. These recordings are paired with 48 site-level climatic, forest structure and topographic covariates. This dataset provides a valuable resource to researchers developing acoustic classification algorithms or studying biodiversity and wildlife behaviour and its relationship to environmental gradients. The dawn chorus recordings were collected as part of a long-term Northern Spotted Owl monitoring program; this demonstrates the complementary value of harnessing existing monitoring efforts to strengthen biodiversity sampling. New information: This dataset of dawn chorus soundscape recordings is one of the few open-access acoustic datasets annotated with non-biotic and both interspecific (across species) and intraspecific (within species) bird, mammal and amphibian sonotypes and the first that is paired with climatic, forest structure and topographical covariates extracted at recorder locations. This makes it a valuable resource for researchers studying the dawn chorus and its relationship to the environment.

Different inflammatory signatures based on CSF biomarkers relate to preserved or diminished brain structure and cognition.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) and both positive and negative associations of individual inflammation-related markers with brain structure and cognitive function have been described. We aimed to identify inflammatory signatures of CSF immune-related markers that relate to changes of brain structure and cognition across the clinical spectrum ranging from normal aging to AD. A panel of 16 inflammatory markers, Aß42/40 and p-tau181 were measured in CSF at baseline in the DZNE DELCODE cohort (n = 295); a longitudinal observational study focusing on at-risk stages of AD. Volumetric maps of gray and white matter (GM/WM; n = 261) and white matter hyperintensities (WMHs, n = 249) were derived from baseline MRIs. Cognitive decline (n = 204) and the rate of change in GM volume was measured in subjects with at least 3 visits (n = 175). A principal component analysis on the CSF markers revealed four inflammatory components (PCs). Of these, the first component PC1 (highly loading on sTyro3, sAXL, sTREM2, YKL-40, and C1q) was associated with older age and higher p-tau levels, but with less pathological Aß when controlling for p-tau. PC2 (highly loading on CRP, IL-18, complement factor F/H and C4) was related to male gender, higher body mass index and greater vascular risk. PC1 levels, adjusted for AD markers, were related to higher GM and WM volumes, less WMHs, better baseline memory, and to slower atrophy rates in AD-related areas and less cognitive decline. In contrast, PC2 related to less GM and WM volumes and worse memory at baseline. Similar inflammatory signatures and associations were identified in the independent F.ACE cohort. Our data suggest that there are beneficial and detrimental signatures of inflammatory CSF biomarkers. While higher levels of TAM receptors (sTyro/sAXL) or sTREM2 might reflect a protective glia response to degeneration related to phagocytic clearance, other markers might rather reflect proinflammatory states that have detrimental impact on brain integrity.

Interactive effects of locus coeruleus structure and catecholamine synthesis capacity on cognitive function.

Background: The locus coeruleus (LC) produces catecholamines (norepinephrine and dopamine) and is implicated in a broad range of cognitive functions including attention and executive function. Recent advancements in magnetic resonance imaging (MRI) approaches allow for the visualization and quantification of LC structure. Human research focused on the LC has since exploded given the LC's role in cognition and relevance to current models of psychopathology and neurodegenerative disease. However, it is unclear to what extent LC structure reflects underlying catecholamine function, and how LC structure and neurochemical function are collectively associated with cognitive performance. Methods: A partial least squares correlation (PLSC) analysis was applied to 19 participants' LC structural MRI measures and catecholamine synthesis capacity measures assessed using [18F]Fluoro-m-tyrosine ([18F]FMT) positron emission tomography (PET). Results: We found no direct association between LC-MRI and LC-[18F]FMT measures for rostral, middle, or caudal portions of the LC. We found significant associations between LC neuroimaging measures and neuropsychological performance that were driven by rostral and middle portions of the LC, which is in line with LC cortical projection patterns. Specifically, associations with executive function and processing speed arose from contributions of both LC structure and interactions between LC structure and catecholamine synthesis capacity. Conclusion: These findings leave open the possibility that LC MRI and PET measures contribute unique information and suggest that their conjoint use may increase sensitivity to brain-behavior associations in small samples.

Artificial intelligence for diagnostic and prognostic neuroimaging in dementia: A systematic review.

INTRODUCTION: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. METHODS: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. RESULTS: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. DISCUSSION: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. HIGHLIGHTS: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias.

Age-related differences in the functional topography of the locus coeruleus and their implications for cognitive and affective functions.

The locus coeruleus (LC) is an important noradrenergic nucleus that has recently attracted a lot of attention because of its emerging role in cognitive and psychiatric disorders. Although previous histological studies have shown that the LC has heterogeneous connections and cellular features, no studies have yet assessed its functional topography in vivo, how this heterogeneity changes over aging, and whether it is associated with cognition and mood. Here, we employ a gradient-based approach to characterize the functional heterogeneity in the organization of the LC over aging using 3T resting-state fMRI in a population-based cohort aged from 18 to 88 years of age (Cambridge Centre for Ageing and Neuroscience cohort, n=618). We show that the LC exhibits a rostro-caudal functional gradient along its longitudinal axis, which was replicated in an independent dataset (Human Connectome Project [HCP] 7T dataset, n=184). Although the main rostro-caudal direction of this gradient was consistent across age groups, its spatial features varied with increasing age, emotional memory, and emotion regulation. More specifically, a loss of rostral-like connectivity, more clustered functional topography, and greater asymmetry between right and left LC gradients was associated with higher age and worse behavioral performance. Furthermore, participants with higher-than-normal Hospital Anxiety and Depression Scale (HADS) ratings exhibited alterations in the gradient as well, which manifested in greater asymmetry. These results provide an in vivo account of how the functional topography of the LC changes over aging, and imply that spatial features of this organization are relevant markers of LC-related behavioral measures and psychopathology.

It is the locus coeruleus! Or is it?: a proposition for analyses and reporting standards for structural and functional magnetic resonance imaging of the noradrenergic locus coeruleus.

The noradrenergic locus coeruleus (LC) is one of the protein pathology epicenters in neurodegenerative diseases. In contrast to PET (positron emission tomography), MRI (magnetic resonance imaging) offers the spatial resolution necessary to investigate the 3-4 mm wide and 1.5 cm long LC. However, standard data postprocessing is often too spatially imprecise to allow investigating the structure and function of the LC at the group level. Our analysis pipeline uses a combination of existing toolboxes (SPM12, ANTs, FSL, FreeSurfer), and is tailored towards achieving suitable spatial precision in the brainstem area. Its effectiveness is demonstrated using 2 datasets comprising both younger and older adults. We also suggest quality assessment procedures which allow to quantify the spatial precision obtained. Spatial deviations below 2.5 mm in the LC area are achieved, which is superior to current standard approaches. Relevant for ageing and clinical researchers interested in brainstem imaging, we provide a tool for more reliable analyses of structural and functional LC imaging data which can be also adapted for investigating other nuclei of the brainstem.

Climate-driven variation in dispersal ability predicts responses to forest fragmentation in birds.

Species sensitivity to forest fragmentation varies latitudinally, peaking in the tropics. A prominent explanation for this pattern is that historical landscape disturbance at higher latitudes has removed fragmentation-sensitive species or promoted the evolution of more resilient survivors. However, it is unclear whether this so-called extinction filter is the dominant driver of geographic variation in fragmentation sensitivity, particularly because climatic factors may also cause latitudinal gradients in dispersal ability, a key trait mediating sensitivity to habitat fragmentation. Here we combine field survey data with a morphological proxy for avian dispersal ability (hand-wing index) to assess responses to forest fragmentation in 1,034 bird species worldwide. We find that fragmentation sensitivity is strongly predicted by dispersal limitation and that other factors-latitude, body mass and historical disturbance events-have relatively limited explanatory power after accounting for species differences in dispersal. We also show that variation in dispersal ability is only weakly predicted by historical disturbance and more strongly associated with intra-annual temperature fluctuations (seasonality). Our results suggest that climatic factors play a dominant role in driving global variation in the impacts of forest fragmentation, emphasizing the need for more nuanced environmental policies that take into account local context and associated species traits.

Plant-hummingbird pollination networks exhibit limited rewiring after experimental removal of a locally abundant plant species.

Mutualistic relationships, such as those between plants and pollinators, may be vulnerable to the local extinctions predicted under global environmental change. However, network theory predicts that plant-pollinator networks can withstand species loss if pollinators switch to alternative floral resources (rewiring). Whether rewiring occurs following species loss in natural communities is poorly known because replicated species exclusions are difficult to implement at appropriate spatial scales. We experimentally removed a hummingbird-pollinated plant, Heliconia tortuosa, from within tropical forest fragments to investigate how hummingbirds respond to temporary loss of an abundant resource. Under the rewiring hypothesis, we expected that behavioural flexibility would allow hummingbirds to use alternative resources, leading to decreased ecological specialization and reorganization of the network structure (i.e. pairwise interactions). Alternatively, morphological or behavioural constraints-such as trait-matching or interspecific competition-might limit the extent to which hummingbirds alter their foraging behaviour. We employed a replicated Before-After-Control-Impact experimental design and quantified plant-hummingbird interactions using two parallel sampling methods: pollen collected from individual hummingbirds ('pollen networks', created from >300 pollen samples) and observations of hummingbirds visiting focal plants ('camera networks', created from >19,000 observation hours). To assess the extent of rewiring, we quantified ecological specialization at the individual, species and network levels and examined interaction turnover (i.e. gain/loss of pairwise interactions). H. tortuosa removal caused some reorganization of pairwise interactions but did not prompt large changes in specialization, despite the large magnitude of our manipulation (on average, >100 inflorescences removed in exclusion areas of >1 ha). Although some individual hummingbirds sampled through time showed modest increases in niche breadth following Heliconia removal (relative to birds that did not experience resource loss), these changes were not reflected in species- and network-level specialization metrics. Our results suggest that, at least over short time-scales, animals may not necessarily shift to alternative resources after losing an abundant food resource-even in species thought to be highly opportunistic foragers, such as hummingbirds. Given that rewiring contributes to theoretical predictions of network stability, future studies should investigate why pollinators might not expand their diets after a local resource extinction.

Cerebrospinal fluid and positron-emission tomography biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis.

The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and undergoes substantial neuronal loss in Alzheimer's disease and Parkinson's disease. While a coherent picture of structural decline in post-mortem and in vivo MRI measures seems to emerge, whether this translates into a consistent decline in available noradrenaline levels is unclear. We conducted a meta-analysis of noradrenergic differences in Alzheimer's disease dementia and Parkinson's disease using CSF and PET biomarkers. CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol levels as well as noradrenaline transporters availability, measured with PET, were summarized from 26 articles using a random-effects model meta-analysis. Compared to controls, individuals with Parkinson's disease showed significantly decreased levels of CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol, as well as noradrenaline transporters availability in the hypothalamus. In Alzheimer's disease dementia, 3-methoxy-4-hydroxyphenylglycol but not noradrenaline levels were increased compared to controls. Both CSF and PET biomarkers of noradrenergic dysfunction reveal significant alterations in Parkinson's disease and Alzheimer's disease dementia. However, further studies are required to understand how these biomarkers are associated to the clinical symptoms and pathology.

Fragmentation effects on an endangered species across a gradient from the interior to edge of its range.

Understanding how habitat fragmentation affects individual species is complicated by challenges associated with quantifying species-specific habitat and spatial variability in fragmentation effects within a species' range. We aggregated a 29-year breeding survey data set for the endangered marbled murrelet (Brachyramphus marmoratus) from >42,000 forest sites throughout the Pacific Northwest (Oregon, Washington, and northern California) of the United States. We built a species distribution model (SDM) in which occupied sites were linked with Landsat imagery to quantify murrelet-specific habitat and then used occupancy models to test the hypotheses that fragmentation negatively affects murrelet breeding distribution and that these effects are amplified with distance from the marine foraging habitat toward the edge of the species' nesting range. Murrelet habitat declined in the Pacific Northwest by 20% since 1988, whereas the proportion of habitat comprising edges increased by 17%, indicating increased fragmentation. Furthermore, fragmentation of murrelet habitat at landscape scales (within 2 km of survey stations) negatively affected occupancy of potential breeding sites, and these effects were amplified near the range edge. On the coast, the odds of occupancy decreased by 37% (95% confidence interval [CI] -54 to 12) for each 10% increase in edge habitat (i.e., fragmentation), but at the range edge (88 km inland) these odds decreased by 99% (95% CI 98 to 99). Conversely, odds of murrelet occupancy increased by 31% (95% CI 14 to 52) for each 10% increase in local edge habitat (within 100 m of survey stations). Avoidance of fragmentation at broad scales but use of locally fragmented habitat with reduced quality may help explain the lack of murrelet population recovery. Further, our results emphasize that fragmentation effects can be nuanced, scale dependent, and geographically variable. Awareness of these nuances is critical for developing landscape-level conservation strategies for species experiencing broad-scale habitat loss and fragmentation.

Efectos de la fragmentación sobre las especies en peligro a lo largo de un gradiente desde el interior hasta el borde de su distribución Resumen Es complicado entender el efecto de la fragmentación del hábitat sobre las especies individuales debido a los retos asociados con la cuantificación de hábitats específicos por especie y la variabilidad espacial de los efectos de la fragmentación dentro de la distribución de la especie. Combinamos los datos de un censo reproductivo realizado durante 29 años para el mérgulo jaspeado (Brachyramphus marmoratus) de >42,000 sitios boscosos a lo largo del noroeste del Pacífico (Oregón, Washington, y el norte de California, EE. UU.). Construimos un modelo de distribución de especie (MDE) en el cual los sitios ocupados estuvieron vinculados con imágenes de Landsat para cuantificar el hábitat específico del mérgulo y después usamos los modelos de ocupación para comprobar la hipótesis de que la fragmentación afecta negativamente la distribución reproductiva de la especie y que estos efectos se amplifican con la distancia entre el hábitat de forrajeo marino y el borde de la distribución de anidación de la especie. El hábitat del mérgulo declinó en la zona en un 20% a partir de 1988, mientras que la proporción de hábitat que comprende bordes incrementó en un 17%, lo que indica un aumento en la fragmentación. Además, la fragmentación del hábitat del mérgulo a escala de paisaje (a de 2 km de las estaciones de censo) afectó negativamente a la ocupación de sitios potenciales de reproducción y estos efectos se amplificaron cerca del borde de la distribución. La probabilidad de ocupación disminuyó en un 37% (95% IC -54 a 12) por cada 10% de incremento en el hábitat de borde (es decir, fragmentación) en la costa, pero en el borde de la distribución (88 km tierra adentro), esta probabilidad disminuyó en un 99% (95% IC 98 a 99). De forma contraria, la probabilidad de ocupación incrementó en un 31% (95% IC 14 a 52) por cada 10% de incremento en el hábitat de borde local (a 100 m de las estaciones de censo). La evasión de la fragmentación a gran escala y el uso de hábitats con calidad reducida y fragmentados a nivel local podría explicar la falta de recuperación poblacional del mérgulo. Más allá, nuestros resultados resaltan que los efectos de la fragmentación pueden estar matizados, depender de la escala y tener variación geográfica. Es importante tener conciencia de estos matices para desarrollar estrategias de conservación a nivel paisaje para las especies que experimentan fragmentación y pérdida del hábitat a gran escala.

Bee diversity decreases rapidly with time since harvest in intensively managed conifer forests.

Despite widespread concerns about the anthropogenic drivers of global pollinator declines, little information is available about the impacts of land management practices on wild bees outside of agricultural systems, including in forests managed intensively for wood production. We assessed changes in wild bee communities with time since harvest in 60 intensively managed Douglas-fir (Pseudotsuga menziesii) stands across a gradient in stand ages spanning a typical harvest rotation. We measured bee abundance, species richness, and alpha and beta diversity, as well as habitat characteristics (i.e., floral resources, nesting substrates, understory vegetation, and early seral forest in the surrounding landscape) during the spring and summer of 2018 and 2019. We found that bee abundance and species richness declined rapidly with stand age, decreasing by 61% and 48%, respectively, for every 5 years since timber harvest. Asymptotic estimates of Shannon and Simpson diversity were highest in stands 6-10 years post-harvest and lowest after the forest canopy had closed, ~11 years post-harvest. Bee communities in older stands were nested subsets of bee communities found in younger stands, indicating that changes were due to species loss rather than turnover as the stands aged. Bee abundance-but not species richness-was positively associated with floral resource density, and neither metric was associated with floral richness. The amount of early seral forest in the surrounding landscape seemed to enhance bee species richness in older, closed-canopy stands, but otherwise had little effect. Changes in the relative abundance of bee species did not relate to bee functional characteristics such as sociality, diet breadth, or nesting substrate. Our study demonstrates that Douglas-fir plantations develop diverse communities of wild bees shortly after harvest, but those communities erode rapidly over time as forest canopies close. Therefore, stand-scale management activities that prolong the precanopy closure period and enhance floral resources during the initial stage of stand regeneration will provide the greatest opportunity to enhance bee diversity in landscapes dominated by intensively managed conifer forests.

Priorities for research on neuromodulatory subcortical systems in Alzheimer's disease: Position paper from the NSS PIA of ISTAART.

The neuromodulatory subcortical system (NSS) nuclei are critical hubs for survival, hedonic tone, and homeostasis. Tau-associated NSS degeneration occurs early in Alzheimer's disease (AD) pathogenesis, long before the emergence of pathognomonic memory dysfunction and cortical lesions. Accumulating evidence supports the role of NSS dysfunction and degeneration in the behavioral and neuropsychiatric manifestations featured early in AD. Experimental studies even suggest that AD-associated NSS degeneration drives brain neuroinflammatory status and contributes to disease progression, including the exacerbation of cortical lesions. Given the important pathophysiologic and etiologic roles that involve the NSS in early AD stages, there is an urgent need to expand our understanding of the mechanisms underlying NSS vulnerability and more precisely detail the clinical progression of NSS changes in AD. Here, the NSS Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment highlights knowledge gaps about NSS within AD and provides recommendations for priorities specific to clinical research, biomarker development, modeling, and intervention. HIGHLIGHTS: Neuromodulatory nuclei degenerate in early Alzheimer's disease pathological stages. Alzheimer's pathophysiology is exacerbated by neuromodulatory nuclei degeneration. Neuromodulatory nuclei degeneration drives neuropsychiatric symptoms in dementia. Biomarkers of neuromodulatory integrity would be value-creating for dementia care. Neuromodulatory nuclei present strategic prospects for disease-modifying therapies.

Ocular Biomarkers for Alzheimer Disease Dementia: An Umbrella Review of Systematic Reviews and Meta-analyses.

Importance: Several ocular biomarkers have been proposed for the early detection of Alzheimer disease (AD) and mild cognitive impairment (MCI), particularly fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA). Objective: To perform an umbrella review of systematic reviews to assess the diagnostic accuracy of ocular biomarkers for early diagnosis of Alzheimer disease. Data Sources: MEDLINE, Embase, and PsycINFO were searched from January 2000 to November 2021. The references of included reviews were also searched. Study Selection: Systematic reviews investigating the diagnostic accuracy of ocular biomarkers to detect AD and MCI, in secondary care or memory clinics, against established clinical criteria or clinical judgment. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline checklist was followed and the Risk Of Bias in Systematic reviews tool was used to assess review quality. Main Outcomes and Measures: The prespecified outcome was the accuracy of ocular biomarkers for diagnosing AD and MCI. The area under the curve (AUC) was derived from standardized mean difference. Results: From the 591 titles, 14 systematic reviews were included (median [range] number of studies in each review, 14 [5-126]). Only 4 reviews were at low risk of bias on all Risk of Bias in Systematic Reviews domains. The imaging-derived parameters with the most evidence for detecting AD compared with healthy controls were OCT peripapillary retinal nerve fiber layer thickness (38 studies including 1883 patients with AD and 2510 controls; AUC = 0.70; 95% CI, 0.53-0.79); OCTA foveal avascular zone (5 studies including 177 patients with AD and 371 controls; AUC = 0.73; 95% CI, 0.50-0.89); and saccadic eye movements prosaccade latency (30 studies including 651 patients with AD/MCI and 771 controls; AUC = 0.64; 95% CI, 0.58-0.69). Antisaccade error was investigated in fewer studies (12 studies including 424 patients with AD/MCI and 382 controls) and yielded the best accuracy (AUC = 0.79; 95% CI, 0.70-0.88). Conclusions and Relevance: This umbrella review has highlighted limitations in design and reporting of the existing research on ocular biomarkers for diagnosing AD. Parameters with the best evidence showed poor to moderate diagnostic accuracy in cross-sectional studies. Future longitudinal studies should investigate whether changes in OCT and OCTA measurements over time can yield accurate predictions of AD onset.

Pollinator foraging tactics have divergent consequences for the mating system of a tropical plant.

Resolving the consequences of pollinator foraging behaviour for plant mating systems is a fundamental challenge in evolutionary ecology. Pollinators may adopt particular foraging tactics: complete trapline foraging (repeated movements along a fixed route), sample-and-shift trapline foraging (a variable route that incorporates information from previous experiences) and territorial foraging (stochastic movements within a restricted area). Studies that integrate these pollinator foraging tactics with plant mating systems are generally lacking. We investigate the consequences of particular pollinator foraging tactics for Heliconia tortuosa. We combine parentage and sibship inference analysis with simulation modelling to: estimate mating system parameters; infer the foraging tactic adopted by the pollinators; and quantify the impact of pollinator foraging tactics on mating system parameters. We found high outcrossing rates, ubiquitous multiple paternity and a pronounced departure from near-neighbour mating. We also found that plants repeatedly receive pollen from a series of particular donors. We infer that the pollinators primarily adopt complete trapline foraging and occasionally engage in sample-and-shift trapline foraging. This enhances multiple paternity without a substantial increase in near-neighbour mating. The particular pollinator foraging tactics have divergent consequences for multiple paternity and near-neighbour mating. Thus, pollinator foraging behaviour is an important driver of the ecology and evolution of plant mating systems.

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging.

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [18F]Fluoro-m-tyrosine PET, and tau burden measured with [18F]Flortaucipir PET in cognitively normal older adults (n = 47). ß-amyloid (Aß) status was determined using [11C]Pittsburgh compound B PET (n = 14 Aß positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.