Neuropsychiatric Symptoms and Alzheimer Disease Biomarkers Independently Predict Progression to Incident Cognitive Impairment.

OBJECTIVES: To investigate the effect of neuropsychiatric symptoms and depression symptoms, respectively, and Alzheimer disease (AD) biomarkers (cerebrospinal fluid [CSF] or Positron Emission Tomography [PET] imaging) on the progression to incident cognitive impairment among cognitively normal older adults. DESIGN: Prospective, observation, longitudinal study. SETTING: Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine. PARTICIPANTS: Older adults aged 65 and above who participated in AD longitudinal studies (n = 286). MEASUREMENTS: CSF and PET biomarkers, Clinical Dementia Rating (CDR), Geriatric Depression Scale (GDS), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Participants had an average follow-up of eight years, and 31 progressed from CDR 0 to CDR >0. After adjusting for sex, age, and education in the Cox proportional hazards survival models, neuropsychiatric symptoms as a time-dependent covariate was statistically significant in the three CSF (Aß42/Aß40, t-Tau/Aß42, p-Tau/Aß42) PET imaging models (HR = 1.33-1.50). The biomarkers were also significant as main effects (HR = 2.00-4.04). Change in depression symptoms was not significant in any models. The interactions between biomarkers and neuropsychiatric symptoms and depression were not statistically significant. CONCLUSIONS: Changes in neuropsychiatric symptoms increase the risk of progression to cognitive impairment among healthy, cognitively normal adults, independent of AD biomarkers. Routine assessment of neuropsychiatric symptoms could provide valuable clinical information about cognitive functioning and preclinical disease state.

Everyday Driving and Plasma Biomarkers in Alzheimer's Disease: Leveraging Artificial Intelligence to Expand Our Diagnostic Toolkit.

BACKGROUND: Driving behavior as a digital marker and recent developments in blood-based biomarkers show promise as a widespread solution for the early identification of Alzheimer's disease (AD). OBJECTIVE: This study used artificial intelligence methods to evaluate the association between naturalistic driving behavior and blood-based biomarkers of AD. METHODS: We employed an artificial neural network (ANN) to examine the relationship between everyday driving behavior and plasma biomarker of AD. The primary outcome was plasma Aß42/Aß40, where Aß42/Aß40 < 0.1013 was used to define amyloid positivity. Two ANN models were trained and tested for predicting the outcome. The first model architecture only includes driving variables as input, whereas the second architecture includes the combination of age, APOE ɛ4 status, and driving variables. RESULTS: All 142 participants (mean [SD] age 73.9 [5.2] years; 76 [53.5%] men; 80 participants [56.3% ] with amyloid positivity based on plasma Aß42/Aß40) were cognitively normal. The six driving features, included in the ANN models, were the number of trips during rush hour, the median and standard deviation of jerk, the number of hard braking incidents and night trips, and the standard deviation of speed. The F1 score of the model with driving variables alone was 0.75 [0.023] for predicting plasma Aß42/Aß40. Incorporating age and APOE ɛ4 carrier status improved the diagnostic performance of the model to 0.80 [>0.051]. CONCLUSION: Blood-based AD biomarkers offer a novel opportunity to establish the efficacy of naturalistic driving as an accessible digital marker for AD pathology in driving research.

Strategic adaptation to dual-task in verbal working memory: Potential routes for theory integration.

How working memory supports dual-task performance is the focus of a long-standing debate. Most previous research on this topic has focused on participant performance data. In three experiments, we investigated whether changes in participant-reported strategies across single- and dual-task conditions might help resolve this debate by offering new insights that lead to fruitful integration of theories rather than perpetuating debate by attempting to identify which theory best fits the data. Results indicated that articulatory suppression was associated with reduced reports of the use of rehearsal and clustering strategies but to an increase of the reported use of a visual strategy. Elaboration and clustering strategies were reported less for memory under dual task compared with single task. Under both dual task and articulatory suppression, more participants reported attempting to remember fewer memory items than were presented (memory reduction strategy). For arithmetic verification, articulatory suppression and dual task resulted in a reduction in reports of a counting strategy and an increase in reports of a retrieval strategy for arithmetic knowledge. It is argued that experimenters should not assume that participants perform the same task in the same way under different experimental conditions and that carefulty investigation of how participants change their strategies in response to changes in experimental conditions has considerable potential for resolving theoretical challenges. It is argued further that this approach points toward the value of attempting to integrate rather than proliferate theories of working memory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Adverse driving behaviors increase over time as a function of preclinical Alzheimer's disease biomarkers.

INTRODUCTION: We investigated the relationship between preclinical Alzheimer's disease (AD) biomarkers and adverse driving behaviors in a longitudinal analysis of naturalistic driving data. METHODS: Naturalistic driving data collected using in-vehicle dataloggers from 137 community-dwelling older adults (65+) were used to model driving behavior over time. Cerebrospinal fluid (CSF) biomarkers were used to identify individuals with preclinical AD. Additionally, hippocampal volume and cognitive biomarkers for AD were investigated in exploratory analyses. RESULTS: CSF biomarkers predicted the longitudinal trajectory of the incidence of adverse driving behavior. Abnormal amyloid beta (Aß42 /Aß40 ) ratio was associated with an increase in adverse driving behaviors over time compared to ratios in the normal/lower range. DISCUSSION: Preclinical AD is associated with increased adverse driving behavior over time that cannot be explained by cognitive changes. Driving behavior as a functional, neurobehavioral marker may serve as an early detection for decline in preclinical AD. Screening may also help prolong safe driving as older drivers age.

Neuropsychological Correlates of Changes in Driving Behavior Among Clinically Healthy Older Adults.

OBJECTIVES: To determine the extent to which cognitive domain scores moderate change in driving behavior in cognitively healthy older adults using naturalistic (Global Positioning System-based) driving outcomes and to compare against self-reported outcomes using an established driving questionnaire. METHODS: We analyzed longitudinal naturalistic driving behavior from a sample (N = 161, 45% female, mean age = 74.7 years, mean education = 16.5 years) of cognitively healthy, nondemented older adults. Composite driving variables were formed that indexed "driving space" and "driving performance." All participants completed a baseline comprehensive cognitive assessment that measured multiple domains as well as an annual self-reported driving outcomes questionnaire. RESULTS: Across an average of 24 months of naturalistic driving, our results showed that attentional control, broadly defined as the ability to focus on relevant aspects of the environment and ignore distracting or competing information as measured behaviorally with tasks such as the Stroop color naming test, moderated change in driving space scores over time. Specifically, individuals with lower attentional control scores drove fewer trips per month, drove less at night, visited fewer unique locations, and drove in smaller spaces than those with higher attentional control scores. No cognitive domain predicted driving performance such as hard braking or sudden acceleration. DISCUSSION: Attentional control is a key moderator of change over time in driving space but not driving performance in older adults. We speculate on mechanisms that may relate attentional control ability to modifications of driving behaviors.

Driving, Social Distancing, Protective, and Coping Behaviors of Older Adults Before and During COVID-19.

A thorough understanding of individual characteristics of older adults during the COVID-19 pandemic is critical for managing the ongoing pandemic course and planning for the future pandemics. Here, we explore the impact of the COVID-19 pandemic on driving, social distancing, protective, and coping behaviors of older adults. This study reports data on participants aged above 65 whose driving behaviors are being monitored using Global Positioning System (GPS) devices. Participants completed a COVID-19 survey in May 2020. We found that older adults decreased their number of days driving, number of trips per day, as well as average driving speed, and had fewer speeding incidents following COVID-19 onset. We also show that female and African American older adults engaged in more positive coping and cleaning behaviors, and had greater decreases in the number of days driving during the pandemic. The findings highlight the importance of considering older adults' individual characteristics for an equitable response to the COVID-19 pandemic.

Naturalistic driving measures of route selection associate with resting state networks in older adults.

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities.

Adverse driving behaviors are associated with sleep apnea severity and age in cognitively normal older adults at risk for Alzheimer's disease.

Alzheimer's disease (AD) pathology accumulates for decades before the onset of cognitive decline. Cognitively normal individuals with biomarker evidence of AD brain pathology (i.e. biomarker + or preclinical AD) can be differentiated from individuals without AD brain pathology based on naturalistic driving data, such as hard acceleration or braking and speeding, measured using in-vehicle dataloggers. Older adults are at increased risk of injury and death from motor vehicle crashes and driving cessation is also linked to negative health outcomes. Identifying potentially modifiable risk factors that increase driving risk may prolong safe driving in old age. Sleep apnea is associated with adverse driving behaviors across the age span. In this study, we hypothesized that high-risk driving behaviors would be associated with increased sleep apnea severity and AD pathology. We found that higher sleep apnea severity measured by a home sleep apnea test was associated with a higher incidence of adverse driving behaviors even after controlling for multiple confounders (ß = 0.24 ±â€…0.09, p < 0.01). This association was independent of AD biomarker positivity (i.e. increased t-tau/Aß 42 ratio). Increasing age was associated with a higher likelihood of high-risk driving behaviors in individuals with AD brain pathology (ß = 0.12 ±â€…0.04, p < 0.01), but a lower likelihood in individuals without AD brain pathology (ß = -0.06 ±â€…0.03, p < 0.05). These findings suggest that adverse driving behaviors linked to a higher rate of traffic crashes in older adults are associated with sleep apnea severity and AD pathology even in cognitively unimpaired individuals. Further studies are needed to determine if treatment of sleep apnea decreases high-risk driving behaviors and therefore motor vehicle crashes.

Longitudinal Changes in Anger, Anxiety, and Fatigue Are Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease.

Alzheimer's disease (AD) studies in cognitively normal (CN) older adults age≥65 suggest depression is associated with molecular biomarkers (imaging and cerebrospinal fluid [CSF]). This study used linear mixed models (covariance pattern model) to assess whether baseline CSF biomarkers (Aß42/Aß40, t-Tau/Aß42, p-Tau/Aß42) predicted changes in non-depressed mood states in CN older adults (N = 248), with an average of three follow-up years. Participants with higher levels of CSF biomarkers developed more anger, anxiety, and fatigue over time compared to those with more normal levels. Non-depressed mood states in preclinical AD may be a prodrome for neuropsychiatric symptoms in symptomatic AD.

Cognitive and brain reserve predict decline in adverse driving behaviors among cognitively normal older adults.

Daily driving is a multi-faceted, real-world, behavioral measure of cognitive functioning requiring multiple cognitive domains working synergistically to complete this instrumental activity of daily living. As the global population of older adult continues to grow, motor vehicle crashes become more frequent among this demographic. Cognitive reserve (CR) is the brain's adaptability or functional robustness despite damage, while brain reserve (BR) refers the structural, neuroanatomical resources. This study examined whether CR and BR predicted changes in adverse driving behaviors in cognitively normal older adults. Cognitively normal older adults (Clinical Dementia Rating 0) were enrolled from longitudinal studies at the Knight Alzheimer's Disease Research Center at Washington University. Participants (n = 186) were ≥65 years of age, required to have Magnetic Resonance Imaging (MRI) data, neuropsychological testing data, and at least one full year of naturalistic driving data prior to the beginning of COVID-19 lockdown in the United States (March 2020) as measured by Driving Real World In-vehicle Evaluation System (DRIVES). Findings suggest numerous changes in driving behaviors over time were predicted by increased hippocampal and whole brain atrophy, as well as lower CR scores as proxied by the Wide Range Achievement Test 4. These changes indicate that those with lower BR and CR are more likely to reduce their driving exposure and limit trips as they age and may be more likely to avoid highways where speeding and aggressive maneuvers frequently occur.

Exploring the influence of temporal factors on age differences in working memory dual task costs.

Working memory is defined by many as the system that allows us to simultaneously store information over brief time periods while engaging in other information processing activities. In a previous study (Rhodes, Jaroslawska et al. (2019) Journal of Experimental Psychology: General, 148, 1204-1227.) we found that retention of serially presented letters was disrupted by the introduction of an arithmetic processing task during a 10 second delay period. Importantly, the magnitude of this dual task disruption increased with age from 18 to 81. The demands of each task were adjusted prior to dual task so that age differences did not reflect baseline differences in single task performance. Motivated by these findings, theories of working memory, and additional analyses of processing reaction times from this previous experiment, we report two experiments, using the same tasks and adjustment procedure, attempting to modulate the magnitude of age differences in dual task effects via manipulations focused on time for encoding to-be-remembered material. Providing a delay prior to processing activities, to facilitate switching between the two tasks, did not modulate age differences. Neither did separating the to-be-remembered material temporally, to allow for the creation of more distinct representations. These findings provide two replications of our initial finding and suggest that age differences in working memory dual tasking are not due to limitations in the speed of encoding. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

What affects the magnitude of age-related dual-task costs in working memory? The role of stimulus domain and access to semantic representations.

Although there is evidence that the effect of including a concurrent processing demand on the storage of information in working memory is disproportionately larger for older than younger adults, not all studies show this age-related impairment, and the critical factors responsible for any such impairment remain elusive. Here we assess whether domain overlap between storage and processing activities, and access to semantic representations, are important determinants of performance in a sample of younger and older adults (N = 119). We developed four versions of a processing task by manipulating the type of stimuli involved (either verbal or non-verbal) and the decision that participants had to make about the stimuli presented on the screen. Participants either had to perform a spatial judgement, in deciding whether the verbal or non-verbal item was presented above or below the centre of the screen, or a semantic judgement, in deciding whether the stimulus refers to something living or not living. The memory task was serial-ordered recall of visually presented letters. The study revealed a large increase in age-related memory differences when concurrent processing was required. These differences were smaller when storage and processing activities both used verbal materials. Dual-task effects on processing were also disproportionate for older adults. Age differences in processing performance appeared larger for tasks requiring spatial decisions rather than semantic decisions. We discuss these findings in relation to three competing frameworks of working memory and the extant literature on cognitive ageing.

How Do Scientific Views Change? Notes From an Extended Adversarial Collaboration.

There are few examples of an extended adversarial collaboration, in which investigators committed to different theoretical views collaborate to test opposing predictions. Whereas previous adversarial collaborations have produced single research articles, here, we share our experience in programmatic, extended adversarial collaboration involving three laboratories in different countries with different theoretical views regarding working memory, the limited information retained in mind, serving ongoing thought and action. We have focused on short-term memory retention of items (letters) during a distracting task (arithmetic), and effects of aging on these tasks. Over several years, we have conducted and published joint research with preregistered predictions, methods, and analysis plans, with replication of each study across two laboratories concurrently. We argue that, although an adversarial collaboration will not usually induce senior researchers to abandon favored theoretical views and adopt opposing views, it will necessitate varieties of their views that are more similar to one another, in that they must account for a growing, common corpus of evidence. This approach promotes understanding of others' views and presents to the field research findings accepted as valid by researchers with opposing interpretations. We illustrate this process with our own research experiences and make recommendations applicable to diverse scientific areas.

Storage and processing in working memory: Assessing dual-task performance and task prioritization across the adult lifespan.

There is a theoretical disagreement in the working memory literature, with some proposing that the storage and processing of information rely on distinct parts of the cognitive system and others who posit that they rely, to some extent, on a shared attentional capacity. This debate is mirrored in the literature on working memory and aging, where there have been mixed findings on the ability of older adults to perform simultaneous storage and processing tasks. We assess the overlap between storage and processing and how this changes with age using a procedure in which both tasks have been carefully adjusted to produce comparable levels of single-task performance across a sample (N = 164) of participants aged 18-81. By manipulating incentives to perform one task over the other, this procedure was also capable of disentangling concurrence costs (single- vs. dual-task performance) from prioritization costs (relative payoffs for storage vs. processing performance) in a theoretically meaningful manner. The study revealed a large general cost to serial letter recall performance associated with concurrent performance of an arithmetic verification processing task, a concurrence cost that increased with age. For the processing task, there was no such general concurrence cost. Rather, there was a prioritization effect in dual-task performance for both tasks, irrespective of age, in which performance levels depended on the relative emphasis assigned to memory versus processing. This prioritization effect was large, albeit with a large residual in performance. The findings place important constraints on both working memory theory and our understanding of how working memory changes across the adult lifespan. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Dual-task costs in working memory: An adversarial collaboration.

[Correction Notice: An Erratum for this article was reported in Vol 45(9) of Journal of Experimental Psychology: Learning, Memory, and Cognition (see record 2019-48991-001). In the article, the copyright attribution was incorrectly listed and should have published under the Creative Commons CC-BY license. The correct copyright is "© 2018 The Author(s)." All versions of this article have been corrected.] Theories of working memory often disagree on the relationships between processing and storage, particularly on how heavily they rely on an attention-based limited resource. Some posit separation and specialization of resources resulting in minimal interference to memory when completing an ongoing processing task, while others argue for a greater overlap in the resources involved in concurrent tasks. Here, we present four experiments that investigated the presence or absence of dual-task costs for memory and processing. The experiments were carried in an adversarial collaboration in which researchers from three opposing theories collaboratively designed a set of experiments and provided differential predictions in line with each of their models. Participants performed delayed recall of aurally and visually presented letters and an arithmetic verification task either as single tasks or with the arithmetic verification task between presentation and recall of letter sequences. Single- and dual-task conditions were completed with and without concurrent articulatory suppression. A consistent pattern of dual-task and suppression costs was observed for memory, with smaller or null effects on processing. The observed data did not fit perfectly with any one framework, with each model having partial success in predicting data patterns. Implications for each of the models are discussed, with an aim for future research to investigate whether some combination of the models and their assumptions can provide a more comprehensive interpretation of the pattern of effects observed here and in relevant previous studies associated with each theoretical framework. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Resource-sharing in multiple-component working memory.

Working memory research often focuses on measuring the capacity of the system and how it relates to other cognitive abilities. However, research into the structure of working memory is less concerned with an overall capacity measure but rather with the intricacies of underlying components and their contribution to different tasks. A number of models of working memory structure have been proposed, each with different assumptions and predictions, but none of which adequately accounts for the full range of data in the working memory literature. We report 2 experiments that investigated the effects of load manipulations on dual-task verbal temporary memory and spatial processing. Crucially, we manipulated cognitive load around the measured memory span of each individual participant. We report a clear effect of increasing memory load on processing accuracy, but only when memory load is increased above each participant's measured memory span. However, increasing processing load did not affect memory performance. We argue that immediate verbal memory may rely both on a temporary phonological store and on activated traces in long-term memory, with the latter deployed to support memory performance for supraspan lists and when a high memory load is coupled with a processing task. We propose that future research should tailor the load manipulations to the capacities of individual participants and suggest that contrasts between models of working memory may be more apparent than real.

Item response theory analysis of cognitive tests in people with dementia: a systematic review.

BACKGROUND: Performance on psychometric tests is key to diagnosis and monitoring treatment of dementia. Results are often reported as a total score, but there is additional information in individual items of tests which vary in their difficulty and discriminatory value. Item difficulty refers to an ability level at which the probability of responding correctly is 50%. Discrimination is an index of how well an item can differentiate between patients of varying levels of severity. Item response theory (IRT) analysis can use this information to examine and refine measures of cognitive functioning. This systematic review aimed to identify all published literature which had applied IRT to instruments assessing global cognitive function in people with dementia. METHODS: A systematic review was carried out across Medline, Embase, PsychInfo and CINHAL articles. Search terms relating to IRT and dementia were combined to find all IRT analyses of global functioning scales of dementia. RESULTS: Of 384 articles identified four studies met inclusion criteria including a total of 2,920 people with dementia from six centers in two countries. These studies used three cognitive tests (MMSE, ADAS-Cog, BIMCT) and three IRT methods (Item Characteristic Curve analysis, Samejima's graded response model, the 2-Parameter Model). Memory items were most difficult. Naming the date in the MMSE and memory items, specifically word recall, of the ADAS-cog were most discriminatory. CONCLUSIONS: Four published studies were identified which used IRT on global cognitive tests in people with dementia. This technique increased the interpretative power of the cognitive scales, and could be used to provide clinicians with key items from a larger test battery which would have high predictive value. There is need for further studies using IRT in a wider range of tests involving people with dementia of different etiology and severity.

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

Sorting mouse jejunal epithelial cells with CD24 yields a population with characteristics of intestinal stem cells.

Intestinal stem cells (ISCs) have been studied for more than three decades; however, their isolation has remained a challenge. We hypothesized that, just as for stem cells of other tissues, one or more membrane markers would allow positive selection of ISCs by antibody-based sorting. To explore this hypothesis, microarray data of putative ISC fractions generated by side population sorting and laser capture microdissection were subjected to bioinformatic analysis to identify common membrane antigens. The microarray comparison suggested CD24 as a candidate surface marker, and immunohistochemistry showed expression of CD24 in epithelial cells of crypt bases. Flow cytometry of jejunal epithelial preparations revealed a CD24(+) CD45(-) fraction comprising ∼1% of the cells. Analysis with epithelial cell adhesion molecule and CD31 confirmed that the cell preparations were epithelial and without endothelial contamination. Cycling cells identified by prior injection with 5-ethynyl-2'-deoxyuridine were found predominantly in the CD24(lo) subfraction. Transcript analysis by real-time RT-PCR showed this subfraction to be enriched in the ISC markers leucine-rich-repeat-containing G-protein-coupled receptor 5 (40-fold) and Bmi1 (5-fold), but also enriched in lysozyme (10-fold). Flow cytometry with anti-lysozyme antibodies demonstrated that Paneth cells comprise ∼30% of the CD24(lo) subfraction. Additional flow analyses with leucine-rich-repeat-containing G-protein-coupled receptor 5-enhanced green fluorescent protein (EGFP) epithelium demonstrated colocalization of EGFP(hi) and CD24(lo). In contrast, CD24 cells were negative for the quiescent ISC marker doublecortin and CaM kinase-like-1. Culture of CD24(lo) cells in Matrigel generated organoid structures, which included all four epithelial lineages, thus giving functional evidence for the presence of ISCs. We conclude that the CD24(lo) fraction of jejunal epithelium is highly enriched with cycling ISCs. This isolation method should be useful to many investigators in the field to advance both the basic understanding of ISC biology and the therapeutic applications of ISCs.

The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma.

The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFF2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2(+)/MIST1(+) = "hybrid"-SPEM) and established (TFF2(+)/MIST1(-) = SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2(+)/MIST1(-) hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (n > 400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma ( approximately 1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage.