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.

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.

The complex relationship between depression and progression to incident cognitive impairment across race and ethnicity.

INTRODUCTION: We examined baseline differences in depression and antidepressant use among cognitively normal older adults in five ethnoracial groups and assessed whether depression predicted a faster progression to incident cognitive impairment across groups. METHODS: Data from the National Alzheimer's Coordinating Center (n = 8168) were used to examine differences between non-Hispanic Whites (nHW), African Americans (AA), Hispanics, Asians, and American Indian and Alaskan Natives in cross-sectional and longitudinal models. RESULTS: AA had a lower risk of depression compared to nHW at baseline. No statistical interactions were noted between ethnoracial groups and depression. However, depression independently predicted a faster progression to incident cognitive impairment. Hispanics and Asian participants had a higher hazard for progression compared to nHW. DISCUSSION: Previously established risk factors between depression and dementia were not found among AA and nHW participants. The relationship between depression and ethnoracial groups is complex and suggests differential effects on progression from cognitive normality to impairment.

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.

A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity.

Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-gamma. In humans, blood CD56(dim) NK cells specialize in the lysis of cell targets. In the lymph nodes, CD56(bright) NK cells secrete IFN-gamma cooperating with dendritic cells and T cells in the generation of adaptive responses. Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer's patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23. In vitro, NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate and express a variety of mitogenic and anti-apoptotic molecules. NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.

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.

Cohort profile: The Scottish SHARE Mental Health (SHARE-MH) cohort - linkable survey, genetic and routinely collected data for mental health research.

PURPOSE: The SHARE Mental Health (SHARE-MH) cohort was established to address the paucity of clinical and genetic data available for mental health research. The cohort brings together detailed mental health questionnaire responses, routinely collected electronic health data and genetic data to provide researchers with an unprecedented linkable dataset. This combination of data sources allows researchers to track mental health longitudinally, across multiple settings. It will be of interest to researchers investigating the genetic and environmental determinants of mental health, the experiences of those interacting with healthcare services, and the overlap between self-reported and clinically derived mental health outcomes. PARTICIPANTS: The cohort consists of individuals sampled from the Scottish Health Research Register (SHARE). To register for SHARE, individuals had to be over the age of 16 years and living in Scotland. Cohort participants were recruited by email and invited to take part in an online mental health survey. When signing up for SHARE, participants also provided written consent to the use of their electronic health records and genetic data-derived from spare blood samples-for research purposes. FINDINGS TO DATE: From 5 February 2021 to 27 November 2021, 9829 individuals completed a survey of various mental health topics, capturing information on symptoms, diagnoses, impact and treatment. Survey responses have been made linkable to electronic health records and genetic data using a single patient identifier. Linked data have been used to describe the cohort in terms of their demographics, self-reported mental health, inpatient and outpatient hospitalisations and dispensed prescriptions. FUTURE PLANS: The cohort will be improved through linkage to a broader variety of routinely collected data and to increasing amounts of genetic data obtained through blood sample diversion. We see the SHARE-MH cohort being used to drive forward novel areas of mental health research and to contribute to global efforts in psychiatric genetics.

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).

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.

Medication and Road Test Performance Among Cognitively Healthy Older Adults.

Importance: Older adults are increasingly prescribed medications that have adverse effects. Prior studies have found a higher risk of motor vehicle crashes to be associated with certain medication use. Objective: To determine whether specific medication classes were associated with performance decline as assessed by a standardized road test in a community sample of cognitively healthy older adults, to evaluate additional associations of poor road test performance with comorbid medical conditions and demographic characteristics, and to test the hypothesis that specific medication classes (ie, antidepressants, benzodiazepines, sedatives or hypnotics, anticholinergics, antihistamines, and nonsteroidal anti-inflammatory drugs or acetaminophen) would be associated with an increase in risk of impaired driving performance over time. Design, Setting, and Participants: This was a prospective cohort study of 198 cognitively healthy adults 65 years and older with a valid driver's license who were followed up annually, with rolling enrollment. Data were collected from participants in St Louis, Missouri, and neighboring Illinois who were enrolled in the Knight Alzheimer's Disease Research Center. Data were collected from August 28, 2012, to March 14, 2023, and analyzed from April 1 to 25, 2023. Participants with healthy cognition, defined as a Clinical Dementia Rating score of 0 at baseline and subsequent visits, who had available clinical, neuropsychological, road tests, and self-reported medication data were included. Exposure: Potentially driver-impairing medication use. Main Outcomes and Measures: The primary outcome measure was performance on the Washington University Road Test (pass or marginal/fail). Multivariable Cox proportional hazards models were used to evaluate associations between potentially driver-impairing medication use and road test performance. Results: Of the 198 included adults (mean [SD] baseline age, 72.6 [4.6] years; 87 female [43.9%]), 70 (35%) received a marginal/fail rating on the road test over a mean (SD) follow-up of 5.70 (2.45) years. Any use of antidepressants (adjusted hazard ratio [aHR], 2.68; 95% CI, 1.69-4.71), serotonin and norepinephrine reuptake inhibitors (aHR, 2.68; 95% CI, 1.54-4.64), sedatives or hypnotics (aHR, 2.70; 95% CI, 1.40-5.19), or nonsteroidal anti-inflammatory drugs (aHR, 2.72; 95% CI, 1.31-5.63) was associated with an increase in risk of receiving a marginal/fail rating on the road test compared with control individuals. Conversely, participants taking lipid-lowering agents had a lower risk of receiving a marginal/fail rating compared to control individuals. There were no statistically significant associations found between anticholinergic or antihistamines and poor performance. Conclusions and Relevance: In this prospective cohort study, specific medication classes were associated with an increase in risk of poor road test performance over time. Clinicians should consider this information and counsel patients accordingly when prescribing these medications.

Cortical atrophy and leukoaraiosis, imaging markers of cerebrovascular small vessel disease, are associated with driving behavior changes among cognitively normal older adults.

BACKGROUND: Cerebral small vessel disease (CSVD) as measured by cortical atrophy and white matter hyperintensities [leukoaraiosis], captured via magnetic resonance imaging (MRI) are increasing in prevalence due to the growth of the aging population and an increase in cardiovascular risk factors in the population. CSVD impacts cognitive function and mobility, but it is unclear if it affects complex, functional activities like driving. METHODS: In a cohort of 163 cognitively normal, community-dwelling older adults (age ≥ 65), we compared naturalistic driving behavior with mild/moderate leukoaraiosis, cortical atrophy, or their combined rating in a clinical composite termed, aging-related changes to those without any, over a two-and-a-half-year period. RESULTS: Older drivers with mild or moderate cortical atrophy and aging-related changes (composite) experienced a greater decrease in the number of monthly trips which was due to a decrease in the number of trips made within a one-to-five-mile diameter from their residence. Older drivers with CSVD experience a larger reduction in daily driving behaviors than drivers without CSVD, which may serve as an early neurobehavioral marker for functional decline. CONCLUSIONS: As CSVD markers, leukoaraiosis and cortical atrophy are standard MRI metrics that are widely available and can be used for screening individuals at higher risk for driving safety risk and decline in community mobility.

Skeletal muscle differentiation and fusion are regulated by the BAR-containing Rho-GTPase-activating protein (Rho-GAP), GRAF1.

Although RhoA activity is necessary for promoting myogenic mesenchymal stem cell fates, recent studies in cultured cells suggest that down-regulation of RhoA activity in specified myoblasts is required for subsequent differentiation and myotube formation. However, whether this phenomenon occurs in vivo and which Rho modifiers control these later events remain unclear. We found that expression of the Rho-GTPase-activating protein, GRAF1, was transiently up-regulated during myogenesis, and studies in C2C12 cells revealed that GRAF1 is necessary and sufficient for mediating RhoA down-regulation and inducing muscle differentiation. Moreover, forced expression of GRAF1 in pre-differentiated myoblasts drives robust muscle fusion by a process that requires GTPase-activating protein-dependent actin remodeling and BAR-dependent membrane binding or sculpting. Moreover, morpholino-based knockdown studies in Xenopus laevis determined that GRAF1 expression is critical for muscle development. GRAF1-depleted embryos exhibited elevated RhoA activity and defective myofibrillogenesis that resulted in progressive muscle degeneration, defective motility, and embryonic lethality. Our results are the first to identify a GTPase-activating protein that regulates muscle maturation and to highlight the functional importance of BAR domains in myotube formation.

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.

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.

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.

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.

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.

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.

Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.

Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferator-activated receptor alpha-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial (13)C enrichment of glutamate when (13)C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states.

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.