Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

Short-Term Neural and Glial Response to Mild Traumatic Brain Injury in the Hippocampus.

Traumatic brain injury (TBI) is an established risk factor for developing neurodegenerative disease. However, how TBI leads from acute injury to chronic neurodegeneration is limited to post-mortem models. There is a lack of connections between in vitro and in vivo TBI models that can relate injury forces to both macroscale tissue damage and brain function at the cellular level. Needle-induced cavitation (NIC) is a technique that can produce small cavitation bubbles in soft tissues, which allows us to relate small strains and strain rates in living tissue to ensuing acute cell death, tissue damage, and tissue remodeling. Here, we applied NIC to mouse brain slices to create a new model of TBI with high spatial and temporal resolution. We specifically targeted the hippocampus, which is a brain region critical for learning and memory and an area in which injury causes cognitive pathologies in humans and rodent models. By combining NIC with patch-clamp electrophysiology, we demonstrate that NIC in the Cornu Ammonis (CA)3 region of the hippocampus dynamically alters synaptic release onto CA1 pyramidal neurons in a cannabinoid 1 receptor (CB1R)-dependent manner. Further, we show that NIC induces an increase in extracellular matrix protein GFAP associated with neural repair that is mitigated by CB1R antagonism. Together, these data lay the groundwork for advanced approaches in understanding how TBI impacts neural function at the cellular level, and the development of treatments that promote neural repair in response to brain injury.

Reported Incidence of Infections Caused by Pathogens Transmitted Commonly Through Food: Impact of Increased Use of Culture-Independent Diagnostic Tests - Foodborne Diseases Active Surveillance Network, 1996-2023.

Reducing foodborne disease incidence is a public health priority. This report summarizes preliminary 2023 Foodborne Diseases Active Surveillance Network (FoodNet) data and highlights efforts to increase the representativeness of FoodNet. During 2023, incidences of domestically acquired campylobacteriosis, Shiga toxin-producing Escherichia coli infection, yersiniosis, vibriosis, and cyclosporiasis increased, whereas those of listeriosis, salmonellosis, and shigellosis remained stable compared with incidences during 2016-2018, the baseline used for tracking progress towards federal disease reduction goals. During 2023, the incidence and percentage of infections diagnosed by culture-independent diagnostic tests (CIDTs) reported to FoodNet continued to increase, and the percentage of cases that yielded an isolate decreased, affecting observed trends in incidence. Because CIDTs allow for diagnosis of infections that previously would have gone undetected, lack of progress toward disease reduction goals might reflect changing diagnostic practices rather than an actual increase in incidence. Continued surveillance is needed to monitor the impact of changing diagnostic practices on disease trends, and targeted prevention efforts are needed to meet disease reduction goals. During 2023, FoodNet expanded its catchment area for the first time since 2004. This expansion improved the representativeness of the FoodNet catchment area, the ability of FoodNet to monitor trends in disease incidence, and the generalizability of FoodNet data.

Association of Caregiving Receipt With Mental Health Utilization in a National Cohort of Older Adults.

OBJECTIVE: There exist significant age disparities in mental health (MH) utilization, such that older adults, including older veterans, are much less likely to use MH services. In-home caregivers represent a novel, yet understudied, pathway to increase appropriate utilization. We sought to examine the association between receiving caregiving assistance and MH utilization and test moderation effects of cognitive status and depression severity in a sample of older veterans. METHODS: Cross-sectional, mixed effects logistic regression with moderation analyses was used with a unique data resource combining survey data from the 2000-2012 U.S. Health and Retirement Study with Veterans Affairs (VA) healthcare administrative records. The analytic sample included N=1,957 Community-dwelling veterans (mean age 68.2 [9.7]), primarily male (96.5%) and non-Hispanic white (77.0%). Measures included MH utilization extracted from VA records or self-report; CESD-8 for depressive symptoms; and the Langa-Weir cognitive status classification using the modified TICS. RESULTS: After accounting for demographics, spousal caregiver availability, health factors, and socioeconomic status, caregiving receipt was associated with two-fold odds of MH utilization, compared to receiving no assistance (8,839 person-year observations; OR = 2.02; 95% CI 1.54-2.65) and remained similar following VA policy changes to enhance MH access. Exploratory analyses revealed that categories of cognition and depressive symptoms may moderate the association. CONCLUSION: Receipt of any in-home caregiving is associated with increased likelihood of MH use by older adults. Caregivers may represent an underutilized resource to reduce age-related mental health access disparities.

Exposure of Polycyclic Aromatic Hydrocarbons (PAHs) and Crude Oil to Atlantic Haddock (Melanogrammus aeglefinus): A Unique Snapshot of the Mercapturic Acid Pathway.

Fish exposed to xenobiotics like petroleum-derived polycyclic aromatic hydrocarbons (PAHs) will immediately initiate detoxification systems through effective biotransformation reactions. Yet, there is a discrepancy between recognized metabolic pathways and the actual metabolites detected in fish following PAH exposure like oil pollution. To deepen our understanding of PAH detoxification, we conducted experiments exposing Atlantic haddock (Melanogrammus aeglefinus) to individual PAHs or complex oil mixtures. Bile extracts, analyzed by using an ion mobility quadrupole time-of-flight mass spectrometer, revealed novel metabolites associated with the mercapturic acid pathway. A dominant spectral feature recognized as PAH thiols set the basis for a screening strategy targeting (i) glutathione-, (ii) cysteinylglycine-, (iii) cysteine-, and (iv) mercapturic acid S-conjugates. Based on controlled single-exposure experiments, we constructed an interactive library of 33 metabolites originating from 8 PAHs (anthracene, phenanthrene, 1-methylphenanthrene, 1,4-dimethylphenanthrene, chrysene, benz[a]anthracene, benzo[a]pyrene, and dibenz[a,h]anthracene). By incorporation of the library in the analysis of samples from crude oil exposed fish, PAHs conjugated with glutathione and cysteinylglycine were uncovered. This qualitative study offers an exclusive glimpse into the rarely acknowledged mercapturic acid detoxification pathway in fish. Furthermore, this furnishes evidence that this metabolic pathway also succeeds for PAHs in complex pollution sources, a notable discovery not previously reported.

Longitudinal normative standards for cognitive tests and composites using harmonized data from two Wisconsin AD-risk-enriched cohorts.

INTRODUCTION: Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. METHODS: Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. RESULTS: Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. DISCUSSION: This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. HIGHLIGHTS: Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.

Chronic social and psychological stress impact select neuropathologies in the PS19 mouse model of tauopathy.

OBJECTIVE: Despite advances toward understanding the etiology of Alzheimer's disease (AD), it remains unclear which aspects of this disease are affected by environmental factors. Chronic life stress increases risk for aging-related diseases including AD. The impact of stress on tauopathies remains understudied. We examined the effects of stress elicited by social (chronic subordination stress, CSS) or psychological/physical (chronic restraint stress, CRS) factors - on the PS19 mouse model of tauopathy. METHODS: Male PS19 mice (average age 6.3 months) were randomized to receive CSS, CRS, or to remain as singly-housed controls. Behavioral tests were used to assess anxiety-like behaviors and cognitive functions. Immunofluorescence staining and western blotting analysis were used to measure levels of astrogliosis, microgliosis and tau burden. Immunohistochemistry was used to assess glucocorticoid receptor expression. RESULTS: PS19 mice exhibit neuroinflammation (GFAP, t-tests; p = 0.0297; Iba1, t-tests; p = 0.006) and tau hyperphosphorylation (t-test, p = 0.0446) in the hippocampus, reduced anxiety (post hoc, p = 0.046), and cognitive deficits, when compared to wild type mice. Surprisingly, CRS reduced hippocampal levels of both total tau and phospho-tauS404 (t-test, p = 0.0116), and attenuated some aspects of both astrogliosis and microgliosis in PS19 mice (t-tests, p = 0.068 to p = 0.0003); however, this was not associated with significant changes in neurodegeneration or cognitive function. Anxiety-like behaviors were increased by CRS (post hoc, p = 0.046). Conversely, CSS impaired spatial learning in Barnes Maze without impacting tau phosphorylation or neurodegeneration and having a minimal impact on gliosis. CONCLUSIONS: Our results demonstrate that social or psychological stress can differentially impact anxiety-like behavior, select cognitive functions, and some aspects of tau-dependent pathology in PS19 male mice, providing entry points for the development of experimental approaches designed to slow AD progression.

Preliminary Incidence and Trends of Infections Caused by Pathogens Transmitted Commonly Through Food - Foodborne Diseases Active Surveillance Network, 10 U.S. Sites, 2022.

Each year, infections from major foodborne pathogens are responsible for an estimated 9.4 million illnesses, 56,000 hospitalizations, and 1,350 deaths in the United States (1). To evaluate progress toward prevention of enteric infections in the United States, the Foodborne Diseases Active Surveillance Network (FoodNet) conducts surveillance for laboratory-diagnosed infections caused by eight pathogens transmitted commonly through food at 10 U.S. sites. During 2020-2021, FoodNet detected decreases in many infections that were due to behavioral modifications, public health interventions, and changes in health care-seeking and testing practices during the COVID-19 pandemic. This report presents preliminary estimates of pathogen-specific annual incidences during 2022, compared with average annual incidences during 2016-2018, the reference period for the U.S. Department of Health and Human Services' Healthy People 2030 targets (2). Many pandemic interventions ended by 2022, resulting in a resumption of outbreaks, international travel, and other factors leading to enteric infections. During 2022, annual incidences of illnesses caused by the pathogens Campylobacter, Salmonella, Shigella, and Listeria were similar to average annual incidences during 2016-2018; however, incidences of Shiga toxin-producing Escherichia coli (STEC), Yersinia, Vibrio, and Cyclospora illnesses were higher. Increasing culture-independent diagnostic test (CIDT) usage likely contributed to increased detection by identifying infections that would have remained undetected before widespread CIDT usage. Reducing pathogen contamination during poultry slaughter and processing of leafy greens requires collaboration among food growers and processors, retail stores, restaurants, and regulators.

Anticipated Psychological or Behavioral Reactions to Learning Alzheimer Biomarker Results: Associations With Contextual Factors.

BACKGROUND: As Alzheimer disease (AD) biomarker testing becomes more widely available, adults may opt to learn results. Considering potential reactions to learning biomarker results can guide prebiomarker and postbiomarker testing education and counseling programs. METHODS: Cognitively healthy adults enrolled in observational Alzheimer research responded to a telephone survey about learning AD risk information (n=334; 44% Black or African American; mean age=64.9±7.0). Multiple linear regression models tested if contextual factors predicted anticipated psychological impact (distress, stigma, and cognitive symptoms) or behavior change (planning and risk-reduction). Secondary analyses tested for differences in relationships by racial identity. RESULTS: Internal health locus of control, concern about AD, self-identified sex, education, family dementia history, and belief in AD modifiability predicted anticipated psychological impact. Concern about AD, age, racial identity, belief in AD modifiability, research attitudes, and exposure to brain health-related social norms predicted anticipated behavior change. For Black respondents, there were no sex differences in anticipated distress, whereas there were stronger relationships between health locus of control, brain health social norms, and education on outcomes compared with White respondents. CONCLUSIONS: Results may inform personalized and culturally tailored biomarker testing education and counseling to minimize psychological impacts and increase behavior change related to learning AD risk information.

Co-Exposure of Phenanthrene and the cyp-Inducer 3-Methylchrysene Leads to Altered Biotransformation and Increased Toxicity in Fish Egg and Larvae.

Polycyclic aromatic hydrocarbons (PAHs) have frequently been suspected of governing crude oil toxicity because of similar morphological defects in fish. However, PAH concentrations are often not high enough to explain the observed crude oil toxicity. We hypothesize that one PAH can enhance the metabolism and toxicity of another PAH when administered as a mixture. Early life stage Atlantic haddock (Melanogrammus aeglefinus) were in this study exposed to phenanthrene in the presence and absence of 3-methylchrysene that is known to induce the metabolic enzyme cytochrome P450 1A via cyp1a gene expression. Uptake, metabolism, and multiple toxicity endpoints were then measured in a time-course study up to 3 days post-hatching. Passive dosing provided aqueous concentrations ≈180 µg/L for phenanthrene and ≈0.6 µg/L for 3-methylchrysene, which resulted in tissue concentrations ≈60 µg/g ww for phenanthrene and ≈0.15 µg/g ww for 3-methylchrysene. The low concentration of 3-methylchrysene led to the elevated expression of cyp1a but no toxicity. Levels of phenanthrene metabolites were 5-fold higher, and morphological defects and cardiotoxicity were consistently greater when co-exposed to both compounds relative to phenanthrene alone. This work highlights the metabolic activation of PAH toxicity by a co-occurring PAH, which can lead to excess toxicity, synergistic effects, and the overproportional contribution of PAHs to crude oil toxicity.

Biological Responses of Pacific Herring Embryos to Crude Oil Are Quantifiable at Exposure Levels Below Conventional Limits of Quantitation for PAHs in Water and Tissues.

Pacific herring (Clupea pallasii), a cornerstone of marine food webs, generally spawn on marine macroalgae in shallow nearshore areas that are disproportionately at risk from oil spills. Herring embryos are also highly susceptible to toxicity from chemicals leaching from oil stranded in intertidal and subtidal zones. The water-soluble components of crude oil trigger an adverse outcome pathway that involves disruption of the physiological functions of cardiomyocytes in the embryonic herring heart. In previous studies, impaired ionoregulation (calcium and potassium cycling) in response to specific polycyclic aromatic hydrocarbons (PAHs) corresponds to lethal embryolarval heart failure or subtle chamber malformations at the high and low ends of the PAH exposure range, respectively. Sublethal cardiotoxicity, which involves an abnormal outgrowth (ballooning) of the cardiac ventricular chamber soon after hatching, subsequently compromises juvenile heart structure and function, leading to pathological hypertrophy of the ventricle and reduced individual fitness, measured as cardiorespiratory performance. Previous studies have not established a threshold for these sublethal and delayed-in-time effects, even with total (∑)PAH exposures as low as 29 ng/g of wet weight (tissue dose). Here, we extend these earlier findings showing that (1) cyp1a gene expression provides an oil exposure metric that is more sensitive than typical quantitation of PAHs via GC-MS and (2) heart morphometrics in herring embryos provide a similarly sensitive measure of toxic response. Early life stage injury to herring (impaired heart development) thus occurs below the quantitation limits for PAHs in both water and embryonic tissues as a conventional basis for assessing oil-induced losses to coastal marine ecosystems.

The complete connectome of a learning and memory centre in an insect brain.

Associating stimuli with positive or negative reinforcement is essential for survival, but a complete wiring diagram of a higher-order circuit supporting associative memory has not been previously available. Here we reconstruct one such circuit at synaptic resolution, the Drosophila larval mushroom body. We find that most Kenyon cells integrate random combinations of inputs but that a subset receives stereotyped inputs from single projection neurons. This organization maximizes performance of a model output neuron on a stimulus discrimination task. We also report a novel canonical circuit in each mushroom body compartment with previously unidentified connections: reciprocal Kenyon cell to modulatory neuron connections, modulatory neuron to output neuron connections, and a surprisingly high number of recurrent connections between Kenyon cells. Stereotyped connections found between output neurons could enhance the selection of learned behaviours. The complete circuit map of the mushroom body should guide future functional studies of this learning and memory centre.

Cavitation induced fracture of intact brain tissue.

Nonpenetrating traumatic brain injuries (TBIs) are linked to cavitation. The structural organization of the brain makes it particularly susceptible to tears and fractures from these cavitation events, but limitations in existing characterization methods make it difficult to understand the relationship between fracture and cavitation in this tissue. More broadly, fracture energy is an important, yet often overlooked, mechanical property of all soft tissues. We combined needle-induced cavitation with hydraulic fracture models to induce and quantify fracture in intact brains at precise locations. We report here the first measurements of the fracture energy of intact brain tissue that range from 1.5 to 8.9 J/m2, depending on the location in the brain and the model applied. We observed that fracture consistently occurs along interfaces between regions of brain tissue. These fractures along interfaces allow cavitation-related damage to propagate several millimeters away from the initial injury site. Quantifying the forces necessary to fracture brain and other soft tissues is critical for understanding how impact and blast waves damage tissue in vivo and has implications for the design of protective gear and tissue engineering.

Lifelong chronic psychosocial stress induces a proteomic signature of Alzheimer's disease in wildtype mice.

Late onset, sporadic Alzheimer's disease (AD) accounts for the vast majority of cases. Unlike familial AD, the factors that drive the onset of sporadic AD are poorly understood, although aging and stress play a role. The early onset/severity of neuropathology observed in most genetic mouse models of AD hampers the study of the role of aging and environmental factors; thus alternate strategies are necessary to understand the contributions of these factors to sporadic AD. We demonstrate that mice acquiring a low social status (subordinate) in a lifelong chronic psychosocial stress (CPS) model, accrue widespread proteomic changes in the frontal/temporal cortex during aging. To better understand the significance of these stress-induced changes, we compared the differentially expressed proteins (DEPs) of subordinate mice to those of patients at varying stages of dementia. Sixteen and fifteen DEPs upregulated in subordinate mice were also upregulated in patients with mild cognitive impairment (MCI) and AD, respectively. Six of those upregulated proteins (CPE, ERC2, GRIN2B, SLC6A1, SYN1, WFS1) were shared by subordinate mice and patients with MCI or AD. Finally, comparison with a spatially detailed transcriptomic database revealed that the superior frontal gyrus and hippocampus had the greatest overlap between mice subjected to lifelong CPS and AD patients. Overall, most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship.

Eliminating accidental deviations to minimize generalization error and maximize replicability: Applications in connectomics and genomics.

Replicability, the ability to replicate scientific findings, is a prerequisite for scientific discovery and clinical utility. Troublingly, we are in the midst of a replicability crisis. A key to replicability is that multiple measurements of the same item (e.g., experimental sample or clinical participant) under fixed experimental constraints are relatively similar to one another. Thus, statistics that quantify the relative contributions of accidental deviations-such as measurement error-as compared to systematic deviations-such as individual differences-are critical. We demonstrate that existing replicability statistics, such as intra-class correlation coefficient and fingerprinting, fail to adequately differentiate between accidental and systematic deviations in very simple settings. We therefore propose a novel statistic, discriminability, which quantifies the degree to which an individual's samples are relatively similar to one another, without restricting the data to be univariate, Gaussian, or even Euclidean. Using this statistic, we introduce the possibility of optimizing experimental design via increasing discriminability and prove that optimizing discriminability improves performance bounds in subsequent inference tasks. In extensive simulated and real datasets (focusing on brain imaging and demonstrating on genomics), only optimizing data discriminability improves performance on all subsequent inference tasks for each dataset. We therefore suggest that designing experiments and analyses to optimize discriminability may be a crucial step in solving the replicability crisis, and more generally, mitigating accidental measurement error.

Predictors of Willingness to Enroll in Hypothetical Alzheimer Disease Biomarker Studies that Disclose Personal Results.

INTRODUCTION: We examined factors related to willingness to enroll in hypothetical Alzheimer disease (AD) biomarker studies. METHODS: Using linear regression, we assessed the relationship among enrollment willingness and demographics, family dementia history, research attitudes, concern about AD, experiences of discrimination, and belief in AD risk modifiability. Inductive coding was used to assess qualitative data. RESULTS: In middle-aged and older adult AD research participants (n=334), willingness to enroll in biomarker studies was driven by biomarker collection method, research attitudes, and disclosure of personal results. Predictors of willingness were similar for Black and White participants. Themes associated with increased willingness included a desire to learn biomarker results and support research. DISCUSSION: Research attitudes were an important predictor of biomarker study willingness regardless of race. As seen elsewhere, Black participants were more hesitant to participate in biomarker research. Disclosure of biomarker results/risk can bolster willingness to enroll in biomarker studies, particularly for Black participants.

Cardiology clinic patient attitudes toward and potential personal utility of genetic testing: Findings from a unique multiracial clinical sample.

As more is understood about the hereditary nature of disease risk, the utility of genetic testing within cardiovascular medicine is increasingly being explored. Although testing may afford more personalized risk stratification, there is a paucity of information regarding patient knowledge, attitudes, and beliefs toward genetic testing among cardiology patients. Participants (n = 530) recruited primarily from a cardiology clinic filled out a 41-item written questionnaire assessing knowledge, beliefs, and attitudes toward genetic testing, motivators and detractors for considering genetic testing, and perceived likelihood for behavior change after hypothetical genetic testing risk stratification. Path analysis was used to test the hypothetical models predicting the likelihood of getting a genetic test and making behavior changes following genetic testing. The patient population was late-middle-aged (59.0 ± 14.5 years), majority women (61.5%), and about half reported having a bachelor's degree. 58.1% of participants self-identified as White, 25.7% as African American or Black, 6.8% as Spanish, Latino, or Hispanic, 3.0% as Asian or Pacific Islander, and 0.5% as Native American. Gender (being a woman) and more years of education were related to greater knowledge about genetic testing. Racial identity and years of education were related to beliefs about genetic testing. Beliefs, but not knowledge, were related to more positive attitudes and a higher likelihood of pursuing genetic testing. Positive attitudes were related to greater perceived personal control (PPC). Furthermore, attitudes and PPC were related to higher likelihood of lifestyle change after genetic testing. These results highlight the need to integrate the experiences of racialized communities into education/counseling efforts. Most educational counseling efforts lack a nuanced discussion of social determinants of health or beliefs. In addition to factual information, educational counseling must also address people's beliefs, concerns, and the intersecting experiences and identities, which shape patients' relationships with the evolving landscape of healthcare and personalized medicine.

On a two-truths phenomenon in spectral graph clustering.

Clustering is concerned with coherently grouping observations without any explicit concept of true groupings. Spectral graph clustering-clustering the vertices of a graph based on their spectral embedding-is commonly approached via K-means (or, more generally, Gaussian mixture model) clustering composed with either Laplacian spectral embedding (LSE) or adjacency spectral embedding (ASE). Recent theoretical results provide deeper understanding of the problem and solutions and lead us to a "two-truths" LSE vs. ASE spectral graph clustering phenomenon convincingly illustrated here via a diffusion MRI connectome dataset: The different embedding methods yield different clustering results, with LSE capturing left hemisphere/right hemisphere affinity structure and ASE capturing gray matter/white matter core-periphery structure.

Moving beyond disclosure: Stages of care in preclinical Alzheimer's disease biomarker testing.

Alzheimer's disease (AD) begins with an asymptomatic "preclinical" phase, in which abnormal biomarkers indicate risk for developing cognitive impairment. Biomarker information is increasingly being disclosed in research settings, and is moving toward clinical settings with the development of cheaper and non-invasive testing. Limited research has focused on the safety and psychological effects of disclosing biomarker results to cognitively unimpaired adults. However, less is known about how to ensure equitable access and robust counseling for decision-making before testing, and how to effectively provide long-term follow-up and risk management after testing. Using the framework of Huntington's disease, which is based on extensive experience with disclosing and managing risk for a progressive neurodegenerative condition, this article proposes a conceptual model of pre-disclosure, disclosure, and post-disclosure phases for AD biomarker testing. Addressing research questions in each phase will facilitate the transition of biomarker testing into clinical practice.

Alzheimer's disease biomarkers in Black and non-Hispanic White cohorts: A contextualized review of the evidence.

Black Americans are disproportionately affected by dementia. To expand our understanding of mechanisms of this disparity, we look to Alzheimer's disease (AD) biomarkers. In this review, we summarize current data, comparing the few studies presenting these findings. Further, we contextualize the data using two influential frameworks: the National Institute on Aging-Alzheimer's Association (NIA-AA) Research Framework and NIA's Health Disparities Research Framework. The NIA-AA Research Framework provides a biological definition of AD that can be measured in vivo. However, current cut-points for determining pathological versus non-pathological status were developed using predominantly White cohorts-a serious limitation. The NIA's Health Disparities Research Framework is used to contextualize findings from studies identifying racial differences in biomarker levels, because studying biomakers in isolation cannot explain or reduce inequities. We offer recommendations to expand study beyond initial reports of racial differences. Specifically, life course experiences associated with racialization and commonly used study enrollment practices may better account for observations than exclusively biological explanations.