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.

Fluorescent 4-amino-1,8-naphthalimide Tröger's bases (TBNaps) possessing (orthogonal) 'α-amino acids', esters and di-peptides and their solvent dependent photophysical properties.

The synthesis of fifteen luminescent bis-naphthalimide based Tröger's bases (TBNaps) derived from 4-amino-1,8-naphthalimide (4-Amino-Nap) precursors is described; these scaffolds possess α-amino acids, esters or di-peptides conjugated at the imide site and show minor fluorescence in aqueous solution while being highly emissive in organic solvents. The investigation shows that these TBNaps possessing ICT excited state properties are capable of generating either positive or negative solvatochromic effects in response to changes in polarity and/or the hydrogen bonding capabilities of the medium.

Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents.

The development of functional 1,8-naphthalimide derivatives as DNA targeting, anticancer and cellular imaging agents is a fast growing area and has resulted in several such derivatives entering into clinical trials. This review gives an overview of the many discoveries and the progression of the use of 1,8-naphthalimides as such agents and their applications to date; focusing mainly on mono-, bis-naphthalimide based structures, and their various derivatives (e.g. amines, polyamine conjugates, heterocyclic, oligonucleotide and peptide based, and those based on metal complexes). Their cytotoxicity, mode of action and cell-selectivity are discussed and compared. The rich photophysical properties of the naphthalimides (which are highly dependent on the nature and the substitution pattern of the aryl ring) make them prime candidates as probes as the changes in spectroscopic properties such as absorption, dichroism, and fluorescence can all be used to monitor their binding to biomolecules. This also makes them useful species for monitoring their uptake and location within cells without the use of co-staining. The photochemical properties of the compounds have also been exploited, for example, for photocleavage of nucleic acids and for the destruction of tumour cells.

Predicting Driving Cessation Among Cognitively Normal Older Drivers: The Role of Alzheimer Disease Biomarkers and Clinical Assessments.

BACKGROUND AND OBJECTIVES: With the aging US population and increasing incidence of Alzheimer disease (AD), understanding factors contributing to driving cessation among older adults is crucial for clinicians. Driving is integral for maintaining independence and functional mobility, but the risk factors for driving cessation, particularly in the context of normal aging and preclinical AD, are not well understood. We studied a well-characterized community cohort to examine factors associated with driving cessation. METHODS: This prospective, longitudinal observation study enrolled participants from the Knight Alzheimer Disease Research Center and The DRIVES Project. Participants were enrolled if they were aged 65 years or older, drove weekly, and were cognitively normal (Clinical Dementia Rating [CDR] = 0) at baseline. Participants underwent annual clinical, neurologic, and neuropsychological assessments, including ß-amyloid PET imaging and CSF (Aß42, total tau [t-Tau], and phosphorylated tau [p-Tau]) collection every 2-3 years. The primary outcome was time from baseline visit to driving cessation, accounting for death as a competing risk. The cumulative incidence function of driving cessation was estimated for each biomarker. The Fine and Gray subdistribution hazard model was used to examine the association between time to driving cessation and biomarkers adjusting for clinical and demographic covariates. RESULTS: Among the 283 participants included in this study, there was a mean follow-up of 5.62 years. Driving cessation (8%) was associated with older age, female sex, progression to symptomatic AD (CDR ≥0.5), and poorer performance on a preclinical Alzheimer cognitive composite (PACC) score. Aß PET imaging did not independently predict driving cessation, whereas CSF biomarkers, specifically t-Tau/Aß42 (hazard ratio [HR] 2.82, 95% CI 1.23-6.44, p = 0.014) and p-Tau/Aß42 (HR 2.91, 95% CI 1.28-6.59, p = 0.012) ratios, were independent predictors in the simple model adjusting for age, education, and sex. However, in the full model, progression to cognitive impairment based on the CDR and PACC score across each model was associated with a higher risk of driving cessation, whereas AD biomarkers were not statistically significant. DISCUSSION: Female sex, CDR progression, and neuropsychological measures of cognitive functioning obtained in the clinic were strongly associated with future driving cessation. The results emphasize the need for early planning and conversations about driving retirement in the context of cognitive decline and the immense value of clinical measures in determining functional outcomes.

Recruiting a prospective community cohort to study Alzheimer's disease and structural and social determinants of health among adults racialized as Black: The ARCHES cohort.

INTRODUCTION: This ongoing, prospective study examines the effectiveness of methods used to successfully recruit and retain 238 Black older adults in a longitudinal, observational Alzheimer's disease (AD) study. METHODS: Recruitment strategies included traditional media, established research registries, speaking engagements, community events, and snowball sampling. Participants were asked to complete an annual office testing session, blood-based biomarker collection, optional one-time magnetic resonance imaging (MRI) scan, and community workshop. RESULTS: Within the first 22 months of active recruitment, 629 individuals expressed interest in participating, and 238 enrolled in the ongoing study. Of the recruitment methods used, snowball sampling, community events, and speaking engagements were the most effective. DISCUSSION: The systemic underrepresentation of Black participants in AD research impacts the ability to generalize research findings and determine the effectiveness and safety of disease-modifying treatments. Research to slow, stop, or prevent AD remains a top priority but requires diversity in sample representation. Highlights: Provide flexible appointments in the evening or weekends, offering transportation assistance, and allowing participants to complete study visits at alternative locations, such as senior centers or community centers.Continuously monitor and analyze recruitment data to identify trends, challenges, and opportunities for improvement.Implement targeted strategies to recruit participants who are underrepresented based on sex, gender, or education to increase representation.Diversify the research team to include members who reflect the racial and cultural backgrounds of the target population, to enhance trust and rapport with prospective participants.

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.

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.

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.

[Formula: see text] The role of family burden on informant discrepancies between parents and youths with protracted recovery from mild traumatic brain injury.

Previous literature shows that family burden can lead to symptom-report discrepancies between parents and children. The present study sought to extend this research by investigating the influence of family burden factors, including socioeconomic status (SES) and family stress on informant discrepancies between parents and youths with mild traumatic brain injury (mTBI). Participants were clinically referred youths with mTBI ages 8-17, consecutively seen in a hospital-based neuropsychology concussion clinic (N = 81; females = 54.3%). Parents and children completed the Behavioral Assessment for Children System (BASC) and the Postconcussive Symptom Scale (PCSS). Parents rated changes in family stress related to the mTBI (categorized as "no change," "minor change," or "major change") and provided information to calculate SES. Results revealed that family stress but not SES influenced parent-child report discrepancies for the BASC Internalizing Symptoms Index (F = 8.72(2, 79), p <.000), and that the discrepancies were independent of postconcussive symptom severity. Clinical implications of these findings are discussed.

The Importance of Advancing Research on Aging and Driving.

Between 2009 and 2018, the number of older adults (i [...].