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Objective: The objective was to compare a standardized road test to naturalistic driving by older people who may have cognitive impairment to define improvements that could potentially enhance the validity of road testing in this population.Background: Road testing has been widely adapted as a tool to assess driving competence of older people who may be at risk for unsafe driving because of dementia; however, the validity of this approach has not been rigorously evaluated.Method: For 2 weeks, 80 older drivers (38 healthy elders and 42 with cognitive impairment) who passed a standardized road test were video recorded in their own vehicles. Using a standardized rating scale, 4 hr of video was rated by a driving instructor. The authors examine weighting of individual road test items to form global impressions and to compare road test and naturalistic driving using factor analyses of these two assessments.Results: The road test score was unidimensional, reflecting a major factor related to awareness of signage and traffic behavior. Naturalistic driving reflected two factors related to lane keeping as well as traffic behavior.Conclusion: Maintenance of proper lane is an important dimension of driving safety that appears to be relatively underemphasized during the highly supervised procedures of the standardized road test.Application: Road testing in this population could be improved by standardized designs that emphasize lane keeping and that include self-directed driving. Additional information should be sought from observers in the community as well as crash evidence when advising older drivers who may be cognitively impaired. [ABSTRACT FROM AUTHOR]

Although automobiles remain the transportation of choice for many older adults, late-life cognitive impairment and dementia often impair the ability to drive safely. However, there is no commonly used method of assessing dementia severity in relation to driving, no consensus on the assessment of older drivers with cognitive impairment, and no gold standard for determining driving fitness. Yet clinicians are called on by patients, their families, other health professionals, and often their state's Department of Motor Vehicles to assess their patients' fitness to drive and to make recommendations about driving privileges. This article describes the challenges of driving with cognitive impairment for both the patient and caregiver, summarizes the literature on dementia and driving, discusses evidence-based assessment of fitness to drive, and addresses important ethical and legal issues. It also describes the role of physician assessment, referral for neuropsychological testing, screening for functional ability, tools to assess dementia severity, driving evaluation clinics, and Department of Motor Vehicles referrals that may assist with evaluation. Lastly, it discusses mobility counseling (eg, exploration of transportation alternatives), because health professionals need to address this important issue for older adults who lose the ability to drive. The application of a comprehensive, interdisciplinary approach to the older driver with cognitive impairment will have the best opportunity to enhance patients' social connectedness and quality of life while meeting their psychological and medical needs and maintaining personal and public safety. [ABSTRACT FROM AUTHOR]

Patients with mild cognitive impairment and mild to moderate Alzheimer's disease can provide information about their quality of life. This study determined whether aggregating patient and informant quality-of-life reports on the Cornell-Brown Scale for Quality of Life in Dementia can provide a broader perspective on the quality of life relative to patient or informant reports separately. Aggregated Cornell-Brown Scale for Quality of Life in Dementia scores were hypothesized to correlate more strongly with both patient and informant perspectives of patient's memory, function, and neuropsychiatric symptoms than the unaggregated measures. Results indicated that aggregated Cornell-Brown Scale for Quality of Life in Dementia scores reflected a blend of patient and informant perspectives on patient function. This study contributes to a growing line of research that recommends integrating patient and informant perspectives to achieve the most complete assessment of quality of life. [ABSTRACT FROM AUTHOR]

This study follows previous work to determine the effect of patient insight and cognitive impairment on the reliability and validity of self-reported quality of life (QOL) from patients diagnosed with Alzheimer's disease (AD) and mild cognitive impairment (MCI). AD and MCI patients (N = 68) and their caregivers participated. Patients with impaired insight provided QOL ratings that were less reliable than those provided by patients with better insight. Patient-caregiver agreement for. QOL reports was used as an index of validity. Neither better insight nor lesser cognitive impairment suggested better agreement. Thus, even when patient insight is intact, patient reports are unlikely to agree with caregiver reports. Patient and caregiver reports about patient QOL may represent 2 unique, yet potentially valid, perspectives. [ABSTRACT FROM AUTHOR]

The objective of this study was to define the technical and clinical variables which affect the sensitivity of single photon emission computed tomography (SPECT) for the diagnosis of Alzheimer's disease (AD). This was a retrospective analysis of 250 consecutive SPECT studies performed for the diagnostic evaluation of degenerative dementia or memory disorder. The sensitivity of bilateral temporoparietal perfusion defects for probable AD cases was not affected by age, education, or technical factors such as the interpreting radiologist, type of radionuclide, and use of a ring detector system. Sensitivity increased with severity of dementia and duration of disease. Sensitivity also increased with male gender due to a higher prevalence of unilateral defects in women with probable AD. This gender effect was absent if unilateral temporoparietal defects were considered diagnostic of AD. Due to the high prevalence of AD, the most common outcome of SPECT in this series was to confirm the clinical diagnosis of AD; however, SPECT may be of greatest value for ruling in a diagnosis of AD in questionable or early dementia cases. For this purpose, the maximum yield of positive diagnosis came from examination of those who had dementia symptoms greater than one year and those who were male. [ABSTRACT FROM AUTHOR]

Background: Clinical and epidemiological research has been done regarding the potential therapeutic benefit of estrogen in outpatients with and without dementia; however, the effects of estrogen therapy on cognition in elderly nursing home patients have not been previously examined.Methods: This retrospective cohort study compared 191 women estrogen users with 663 women nonestrogen users, matched according to age, nursing home facility, year of assessment, and baseline level of cognitive function. The outcome was decline in cognition, measured by the Cognitive Performance Scale, over a minimum follow-up period of 6 months.Results: No significant difference was found in the rate of cognitive decline among estrogen users and nonusers.Conclusions: Estrogen therapy administered to nursing home residents is not associated with a reduction in cognitive decline. This study lends further support to recent controlled clinical trials that found no benefit for estrogen treatment on cognition in outpatients with dementia. [ABSTRACT FROM AUTHOR]

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer's disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Aging Association.)

Objectives: Nursing home (NH) administrator perceptions regarding the utility of Alzheimer's disease (AD) disease-modifying medications in NHs are important because many short and long-stay residents have mild AD. This study examined the interest of directors of nursing (DoNs) in using new AD disease-modifying treatments, changes in attitudes based on differences in costs to the NH, and characteristics (DoN and NH) associated with such changes., Design: This is a cross-sectional study., Setting and Participants: This study is based on a 2022 nationally representative survey of 340 NH DoNs, which was drawn from a stratified random sample of US NHs with ≥30 beds and with a 26.6% response rate., Methods: We conducted a descriptive analysis to assess the awareness of new AD disease-modifying treatments and the support for their use. We applied logistic regression models to explore the associations between the interest of the DoN in using these new AD treatments and various characteristics., Results: Most (86%) DoNs stated that they would at least sometimes support the usage of a new disease-modifying medication if there were no NH costs. This percentage was lower if the NH costs per resident were $2000 per year (51.3%) and $20,000 per year (14%). NHs with moderate shares of dual-eligible residents were more sensitive to cost., Conclusions and Implications: Our findings indicated that the interest of DoNs in using disease-modifying treatments for dementia varies widely according to the cost to the NHs. The uptake of new AD medications in the NH setting should be monitored, and targeted efforts may be needed to mitigate inequities in access for less-resourced NHs., Competing Interests: Disclosure S.L., A.R., and M.A. received funding from the National Institute on Aging. B.R.O. received consulting fees from Seelos Therapeutics and participated on Data Safety Monitoring Boards of Lexeo Therapeutics and Institute for Molecular Medicine. K.L.L. received funding from the National Institute on Aging and consulting fees from Exponent on projects unrelated to this manuscript. J.T. received funding from the National Institute on Aging and consulting fees from CVS Health Corporation., (Copyright © 2024 Post-Acute and Long-Term Care Medical Association. Published by Elsevier Inc. All rights reserved.)

Background: Concerns persist regarding the cognitive safety of achieving very low levels of low-density lipoprotein (LDL) cholesterol. Although short-term studies are reassuring, the long-term cognitive effects of sustained exposure to very low LDL cholesterol levels through combined proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition and statin therapy remain unknown., Methods: This prospective study enrolled a subset of adults with atherosclerotic cardiovascular disease who had completed a neurocognitive substudy (EBBINGHAUS) of a placebo-controlled randomized trial of evolocumab (FOURIER) and were eligible for a long-term open-label extension. The objective of this current study was to assess the long-term effect of evolocumab on cognitive function. Cognitive function was assessed annually, and the primary end point was change from baseline in executive function within each group, measured using the spatial working memory strategy index score (range, 4-28), with lower scores indicating better performance., Results: A total of 473 patients out of the 1974 patients in the parent EBBINGHAUS study were enrolled and additionally followed for a median of 5.1 years (maximum follow-up since original random assignment 7.2 years). The median age was 62 years; 70% were male, and 91% were White. At 12 weeks into the open-label extension period, median LDL cholesterol across the overall population was 35 mg/dl (interquartile range, 21-55 mg/dl). Treatment with evolocumab was not associated with a change in executive function during the open-label extension in either patients who were originally randomly assigned to and continued evolocumab (mean±standard deviation of 0.1±2.8, P=0.49) or patients originally randomly assigned to placebo who then started on evolocumab (-0.1±2.5, P=0.64). At the final study visit, executive function scores were similar between randomly assigned groups (17.5±3.7 and 17.3±3.7, respectively)., Conclusions: Exposure to very low levels of LDL cholesterol, achieved via PCSK9 inhibition and statin therapy, was not associated with cognitive impairment through long-term follow-up. Further studies are needed to assess the generalizability to adults at higher risk of dementia.

Importance: Although older adults may use potentially driver-impairing (PDI) medications that can produce psychomotor impairment, little is known about changes to PDI medication use among older adults from the time before to the time after a motor vehicle crash (MVC)., Objective: To quantify use of and changes in PDI medications among older adults before and after an MVC., Design, Setting, and Participants: This cohort study used linked Medicare claims and police-reported MVC data on 154 096 person-crashes among 121 846 older drivers. Eligible persons were drivers aged 66 years or older, involved in a police-reported MVC in New Jersey from May 1, 2007, through December 31, 2017, and with continuous enrollment in Medicare fee-for-service Parts A and B for at least 12 months and Part D for at least 120 days prior to the MVC. Data were analyzed from January 2022 to May 2024., Main Outcomes and Measures: Use of benzodiazepines, nonbenzodiazepine hypnotics, opioid analgesics, and other PDI medications in the 120 days before and 120 days after the MVC. Because each person could contribute multiple MVCs during the study period if they met eligibility criteria, the unit of analysis was the number of person-crashes. The proportion of person-crashes after which PDI medications were started, discontinued, or continued was quantified as well., Results: Among 154 096 eligible person-crashes, the mean (SD) age of the drivers was 75.2 (6.7) years at the time of the MVC. Of 121 846 unique persons, 51.6% were women. In 80.0% of the person-crashes, drivers used 1 or more PDI medications before the crash, and in 81.0% of the person-crashes, drivers used 1 or more PDI medications after the crash. Use of benzodiazepines (8.1% before the crash and 8.8% after the crash), nonbenzodiazepine hypnotics (5.9% before the crash and 6.0% after the crash), and opioid analgesics (15.4% before the crash and 17.5% after the crash) was slightly higher after the MVC. After the MVC, drivers in 2.1% of person-crashes started benzodiazepines and 1.4% stopped benzodiazepines, drivers in 1.2% of person-crashes started nonbenzodiazepine hypnotics and 1.2% stopped nonbenzodiazepine hypnotics, and drivers in 8.4% of person-crashes started opioid analgesics and 6.3% stopped opioid analgesics., Conclusions and Relevance: This cohort study suggests that most older drivers involved in MVCs did not use fewer PDI medications after crashes than before crashes. Qualitative research of perceived risks vs benefits of PDI medications is necessary to understand the reasons why MVCs do not appear to motivate clinicians to deprescribe PDI medications as a strategy to avert potential harms, including additional MVCs.

In 30 states, licensing agencies can restrict the distance from home that "medically-at-risk" drivers are permitted to drive. However, where older drivers crash relative to their home or how distance to crash varies by medical condition is unknown. Using geocoded crash locations and residential addresses linked to Medicare claims, we describe how the relationship between distance from home to crash varies by driver characteristics. We find that a majority of crashes occur within a few miles from home with little variation across driver demographics or medical conditions. Thus, distance restrictions may not reduce crash rates among older adults, and the tradeoff between safety and mobility warrants consideration.

Background: Administrative healthcare databases, such as Medicare, are increasingly used to identify groups at risk of a crash. However, they only contain information on crash-related injuries, not all crashes. If the driver characteristics associated with crash and crash-related injury differ, conflating the two may result in ineffective or imprecise policy interventions., Methods: We linked 10 years (2008-2017) of Medicare claims to New Jersey police crash reports to compare the demographics, clinical diagnoses, and prescription drug dispensings for crash-involved drivers ≥ 68 years with a police-reported crash to those with a claim for a crash-related injury. We calculated standardized mean differences to compare characteristics between groups., Results: Crash-involved drivers with a Medicare claim for an injury were more likely than those with a police-reported crash to be female (62.4% vs. 51.8%, standardized mean difference [SMD] = 0.30), had more clinical diagnoses including Alzheimer's disease and related dementias (13.0% vs. 9.2%, SMD = 0.20) and rheumatoid arthritis/osteoarthritis (69.5% vs 61.4%, SMD = 0.20), and a higher rate of dispensing for opioids (33.8% vs 27.6%, SMD = 0.18) and antiepileptics (12.9% vs 9.6%, SMD = 0.14) prior to the crash. Despite documented inconsistencies in coding practices, findings were robust when restricted to claims indicating the injured party was the driver or was left unspecified., Conclusions: To identify effective mechanisms for reducing morbidity and mortality from crashes, researchers should consider augmenting administrative datasets with information from police crash reports, and vice versa. When those data are not available, we caution researchers and policymakers against the tendency to conflate crash and crash-related injury when interpreting their findings., (© 2024. The Author(s).)

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Antidementia medication can provide symptomatic improvements in patients with Alzheimer's disease, but there is a lack of consensus guidance on when to start and stop treatment in the nursing home setting., Methods: We describe utilization patterns of cholinesterase inhibitors (ChEI) and memantine for 3,50,197 newly admitted NH residents with dementia between 2011 and 2018., Results: Overall, pre-admission use of antidementia medications declined from 2011 to 2018 (ChEIs: 44.5% to 36.9%; memantine: 27.4% to 23.2%). Older age, use of a feeding tube, and greater functional dependency were associated with lower odds of ChEI initiation. Coronary artery disease, parenteral nutrition, severe aggressive behaviors, severe cognitive impairment, and high functional dependency were associated with discontinuation of ChEIs. Comparison of clinical factors related to anti-dementia drug treatment changes from pre to post NH admission in 2011 and 2018 revealed a change toward lower likelihood of initiation of treatment among residents with more functional dependency and those with indicators of more complex illness as well as a change toward higher likelihood of discontinuation in residents having 2 or more hospital stays., Conclusions: These prescribing trends highlight the need for additional research on the effects of initiating and discontinuing antidementia medications in the NH to provide clear guidance for clinicians when making treatment decisions for individual residents., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Large research cohorts show robust associations between neuropsychological tests and Alzheimer's disease (AD) biomarkers, but studies in clinical settings are limited. The increasing availability of AD biomarkers to the practicing clinician makes it important to understand the relationship between comprehensive clinical neuropsychological assessment and biomarker status. This study examined concordance between practicing clinical neuropsychologists' diagnostic impressions and AD biomarker status in patients seen at an outpatient medical center, with a secondary aim of defining the characteristics of discordant cases., Method: Participants ( N = 79) seen for clinical neuropsychological assessment who subsequently underwent lumbar puncture or amyloid positron emission tomography imaging were identified via retrospective chart review. Concordance between clinical neuropsychological diagnosis (non-AD, indeterminate, possible/probable AD) and AD biomarker status (negative, indeterminate, positive) was determined. Individual test score data were used to examine between-group differences based on amyloid status., Results: AD biomarker positive and negative patients did not differ on individual neuropsychological tests after correcting for multiple comparisons, though the small number of AD biomarker indeterminate individuals performed better than biomarker positive patients. However, there was 76.7% concordance between neuropsychologists' diagnostic impressions and AD biomarker status (88% sensitivity and 55% specificity of neuropsychological assessment in detecting AD biomarker status). AD biomarker negative patients diagnosed as possible/probable AD (discordant) versus non-AD (concordant) had significantly lower Neuropsychological Assessment Battery Story Delayed Recall, higher Wechsler Adult Intelligence Scale-Fourth Edition Coding, and higher Trail-Making A (i.e., an amnestic memory profile)., Conclusions: Comprehensive neuropsychological assessment showed modest concordance with AD biomarker status in patients seen in an outpatient medical center for routine clinical care. Low specificity for the clinical diagnosis of AD could be explained by the multiplicity of etiologies that cause memory impairment (i.e., TAR DNA-binding protein 43, suspected non-AD pathology). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background: Medications are one of the most easily modifiable risk factors for motor vehicle crashes (MVCs) among older adults, yet limited information exists on how the use of potentially driver-impairing (PDI) medications changes following an MVC. Therefore, we examined the number and types of PDI medication classes dispensed before and after an MVC., Methods: This observational study included Medicare fee-for-service beneficiaries aged ≥67 years who were involved in a police-reported MVC in New Jersey as a driver between 2008 and 2017. Analyses were conducted at the "person-crash" level because participants could be involved in more than one MVC. We examined the use of 36 PDI medication classes in the 120 days before and 120 days after MVC. We described the number and prevalence of PDI medication classes in the pre-MVC and post-MVC periods as well as the most common PDI medication classes started and stopped following the MVC., Results: Among 124,954 person-crashes, the mean (SD) age was 76.0 (6.5) years, 51.3% were female, and 83.9% were non-Hispanic White. The median (Q 1 , Q 3 ) number of PDI medication classes was 2 (1, 4) in both the pre-MVC and post-MVC periods. Overall, 20.3% had a net increase, 15.9% had a net decrease, and 63.8% had no net change in the number of PDI medication classes after MVC. Opioids, antihistamines, and thiazide diuretics were the top PDI medication classes stopped following MVC, at incidences of 6.2%, 2.1%, and 1.7%, respectively. The top medication classes started were opioids (8.3%), skeletal muscle relaxants (2.2%), and benzodiazepines (2.1%)., Conclusions: A majority of crash-involved older adults were exposed to multiple PDI medications before and after MVC. A greater proportion of person-crashes were associated with an increased rather than decreased number of PDI medications. The reasons why clinicians refrain from stopping PDI medications following an MVC remain to be elucidated., (© 2023 The American Geriatrics Society.)

Background: Elevated amyloid-β (Aβ) on positron emission tomography (PET) scan is used to aid diagnosis of Alzheimer's disease (AD), but many prior studies have focused on patients with a typical AD phenotype such as amnestic mild cognitive impairment (MCI). Little is known about whether elevated Aβ on PET scan predicts rate of cognitive and functional decline among those with MCI or dementia that is clinically less typical of early AD, thus leading to etiologic uncertainty., Objective: We aimed to investigate whether elevated Aβ on PET scan predicts cognitive and functional decline over an 18-month period in those with MCI or dementia of uncertain etiology., Methods: In 1,028 individuals with MCI or dementia of uncertain etiology, we evaluated the association between elevated Aβ on PET scan and change on a telephone cognitive status measure administered to the participant and change in everyday function as reported by their care partner., Results: Individuals with either MCI or dementia and elevated Aβ (66.6% of the sample) showed greater cognitive decline compared to those without elevated Aβ on PET scan, whose cognition was relatively stable over 18 months. Those with either MCI or dementia and elevated Aβ were also reported to have greater functional decline compared to those without elevated Aβ, even though the latter group showed significant care partner-reported functional decline over time., Conclusions: Elevated Aβ on PET scan can be helpful in predicting rates of both cognitive and functional decline, even among cognitively impaired individuals with atypical presentations of AD.

Objective: Little is known about who is involved and what factors influence changes in antidementia medications for older adults living in nursing homes. The study sought to describe factors associated with initiation and discontinuation of antidementia medications in nursing home residents with dementia., Design: National survey of nursing homes with ≥30 beds; homes with dementia units were oversampled., Settings and Participants: Nursing home administrators [eg, Directors of Nursing (DoNs)]., Methods: In 2022, 1293 homes were surveyed (response rate: 26.6%, n = 340). Weighted analyses provided nationally representative results corrected for nonresponse (n = 14,455)., Results: DoNs reported that people always/almost always involved in antidementia medication decisions included nursing home prescriber (84.4%), nursing staff (33.2%), family (23.4%), resident (13.8%), community primary care provider (12.1%), and dementia specialist (5.8%). DoNs reported that antidementia medications were much more likely to be initiated if residents (55.8%) and family members (53.2%) wanted antidementia medications, a dementia specialist was involved (51.9%), resident had aggressive behaviors (44.8%), resisted care (31.6%), or had severe physical/cognitive impairment (22.3%). DoNs reported that antidementia medications were much more likely to be discontinued with dementia specialist involvement (46.5%), progression to severe impairment (39.2%), hospice involvement (31.5%), <6 months' prognosis (28.5%), emergence of aggressive behaviors (25.2%), or resisting care (19.0%) and much less likely to be discontinued if residents (30.2%) and family (27.3%) were reluctant to discontinue. One in 6 homes reported that residents had no immediate family/caregivers usually or almost always/always., Conclusions and Implications: DoNs report that family/caregivers and dementia specialists have significant influence on antidementia medication decisions in nursing homes, but many residents lack their involvement. Real-world evidence on the risks and benefits of antidementia medications in nursing homes is needed to inform clinical guidance about appropriate use of antidementia medications in nursing homes., Competing Interests: Disclosure Dr Lapane is a consultant to Exponent on an NIH-funded nursing home initiative (Long Term Care Data Collaborative). Her work as a consultant was not related to this study. The other authors declare no conflicts of interest., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer's disease., Competing Interests: The FOURIER and EBBINGHAUS trials were supported by Amgen. No funds were provided for writing this manuscript. This does not alter our adherence to PLOS ONE policies on data sharing and materials. Dr. Giugliano reports research grant support through Brigham and Women’s Hospital from Amgen, Anthos, and Daiichi Sankyo; honoraria for continuing medical education lectures from Amgen, Daiichi Sankyo, Dr Reddy’s Laboratories, Menarini, Merck, Pfizer, SAJA, and Servier; honoraria for consulting from Amarin, Amgen; AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, Esperion, GlaxoSmithKline, Janssen, Merck, and Pfizer. Dr Sabatine reports honoraria for consulting from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda. Prof. Mach was a member of the Steering Committee of the FOURIER trial and of the Executive Committee of the EBBINGHAUS trial. Dr. Ott reports honoraria for consulting from Amgen, Biogen, and Corium and research grant support from Biogen, Eli Lilly, and AbbVie. Drs Giugliano, Sabatine, Ms Guo are members of the TIMI Study Group, which has also received research grant support through Brigham and Women’s Hospital from Abbott, Anthos, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Daiichi Sankyo, Eisai, Intarcia, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Roche, and Zora Biosciences. This does not alter our adherence to PLOS ONE policies on data sharing and materials.

Background: Research on Alzheimer disease and related dementias is increasingly focused on preventative strategies to target modifiable risk factors (eg, exercise, diet, cognitive stimulation) to reduce risk of cognitive decline, though it remains difficult for adults to adopt and maintain these behaviors on their own., Methods/participants: In this survey study, we examined knowledge about modifiable risk factors for dementia, engagement in healthy lifestyle behaviors, and associated barriers/facilitators in an Alzheimer disease prevention registry of at-risk, cognitively normal adults (n=135: 77% female; 96% Caucasian and non-Hispanic; mean age=66.1; 79% with family history of dementia; 46% with subjective memory decline)., Results: Participants reported high levels of engagement in exercise (mean 3.4 d/wk), a healthy diet (60% with a healthy/balanced diet), and cognitive stimulation (52% engaging in cognitive stimulation 3 to 7 d/wk), and most (56% to 57%) reported moderate to high knowledge about dementia and modifiable risk factors. Family history of dementia was associated with greater knowledge of risk factors for dementia (P=0.017), but not with knowledge of lifestyle recommendations to reduce risk (P=0.85). Most participants (63%) reported a preference for walking/running over other types of aerobic exercise. On average, participants reported that they would be willing to increase healthy lifestyle behaviors to achieve "moderate" risk reduction for dementia (∼21% to 23%, on a scale from 0% to 40%, reflecting mildly to substantially reduced risk)., Conclusion: Results broaden our understanding of current habits and willingness to engage in healthy lifestyle behaviors, which may inform individualized lifestyle interventions and/or design of prevention trials, particularly among at-risk adults with subjective or mild cognitive concerns, who may be especially motivated and able to engage in lifestyle interventions, to optimize brain health and reduce risk of cognitive decline., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Yoga is a potentially low risk intervention for cognitive impairment that combines mental and physical practice and includes instruction on breathing, stress reduction, and mindfulness meditation. Previous research documents that yoga can target modifiable risk factors for mild cognitive impairment (MCI) progression. The authors describe a randomized feasibility trial of yoga for individuals with MCI. Methods: Participants were 37 individuals with amnestic MCI who were randomly assigned to receive 12 weeks of twice-weekly yoga intervention (YI) or healthy living education (HLE) classes. Acceptability and feasibility were assessed by tracking adverse events, class attendance, and participant satisfaction. Participants completed neuropsychological and mood measures as well as measures of potential intervention mechanisms at baseline and immediately postintervention. Results: Participants in both conditions reported high levels of satisfaction and reasonable class attendance rates. Home practice rates were low. There were no adverse events deemed related to the YI. Results showed a medium effect size in favor of the YI in visuospatial skills. The yoga group also showed a large effect size indicating decline in perceived stress compared with the HLE group, whereas HLE resulted in greater reductions in depressive symptoms after the intervention (large effect size). Conclusions: Study findings indicated that the YI was safe, modestly feasible, and acceptable to older adults with MCI. The authors found preliminary evidence that yoga may improve visuospatial functioning in individuals with MCI. Results support stress reduction as a possible mechanism for the YI. Future studies should address a YI in a larger sample and include strategies to enhance engagement and home practice.

A non-invasive and sensitive blood test has long been a goal for early stage disease diagnosis and treatment for Alzheimer's disease (AD) and other proteinopathy diseases. We previously reported that preeclampsia (PE), a severe pregnancy complication, is another proteinopathy disorder with impaired autophagy. We hypothesized that induced autophagy deficiency would promote accumulation of pathologic protein aggregates. Here, we describe a novel, sensitive assay that detects serum protein aggregates from patients with PE (n = 33 early onset and 33 late onset) and gestational age-matched controls (n = 77) as well as AD in both dementia and prodromal mild cognitive impairment (MCI, n = 24) stages with age-matched controls (n = 19). The assay employs exposure of genetically engineered, autophagy-deficient human trophoblasts (ADTs) to serum from patients. The aggregated protein complexes and their individual components, including transthyretin, amyloid β-42, α-synuclein, and phosphorylated tau231, can be detected and quantified by co-staining with ProteoStat, a rotor dye with affinity to aggregated proteins, and respective antibodies. Detection of protein aggregates in ADTs was not dependent on transcriptional upregulation of these biomarkers. The ROC curve analysis validated the robustness of the assay for its specificity and sensitivity (PE; AUC: 1, CI: 0.949-1.00; AD; AUC: 0.986, CI: 0.832-1.00). In conclusion, we have developed a novel, noninvasive diagnostic and predictive assay for AD, MCI and PE., (© 2021. The Author(s).)

Background: Anticholinergic/sedative drug use, measured by the Drug Burden Index (DBI), has been linked to cognitive impairment in older adults. Subjective cognitive decline (SCD) may be among the first symptoms patients with Alzheimer's disease (AD) experience. We examined whether DBI values are associated with SCD in older adults at risk of AD. We hypothesized that increased DBI would be associated with greater SCD at older ages., Method: Two-hundred-six community-dwelling, English-speaking adults (age = 65 ± 9 years) at risk of AD (42% apolipoprotein ε4 carriers; 78% with AD family history) were administered a single question to ascertain SCD: "Do you feel like your memory is becoming worse?" Response options were "No"; "Yes, but this does not worry me"; and "Yes, this worries me." DBI values were derived from self-reported medication regimens using older adult dosing recommendations. Adjusting for relevant covariates (comorbidities and polypharmacy), we examined independent effects of age and DBI on SCD, as well as the moderating effect of age on the DBI-SCD association at mean ± 1 SD of age., Results: Both SCD and anticholinergic/sedative drug burden were prevalent. Greater drug burden was predictive of SCD severity, but age alone was not. A significant DBI*Age interaction emerged with greater drug burden corresponding to more severe SCD among individuals age 65 and older., Conclusion: Anticholinergic/sedative drug exposure was associated with greater SCD in adults 65 and older at risk for AD. Longitudinal research is needed to understand if this relationship is a pre-clinical marker of neurodegenerative disease and predictive of future cognitive decline., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The standard in vivo diagnostic imaging technique for cerebral amyloid angiopathy (CAA) is costly and thereby of limited utility for point-of-care diagnosis and monitoring of treatment efficacy. Recent recognition that retinal changes may reflect cerebral changes in neurodegenerative disease provides an ideal opportunity for development of accessible and cost-effective biomarkers for point-of-care use in the detection and monitoring of CAA. In this pilot study, we examined structural and angiographic retinal changes in CAA patients relative to a control group, and compared retinal and cerebral pathology in a group of CAA patients., Methods: We used spectral domain optical coherence tomography (SD-OCT) to image the retina and compared retinal microbleeds to both cerebral microbleeds and white matter hyperintensities (WMH) in CAA patients, as seen on MRI. We compared retinal angiographic changes, along with structural retinal neuronal layer changes in CAA patients and cognitively normal older adults, and examined the relationship between retinal and cerebral microbleeds and cognition in CAA patients., Results: We found a trend level correlation between retinal and cerebral microbleeds in CAA patients. Moreover, we found a significant correlation between retinal microbleeds and episodic memory performance in CAA patients. There were no significant group differences between CAA patients and cognitively normal older adults on retinal angiographic or structural measurements., Conclusion: Retinal microbleeds may reflect degree of cerebral microbleed burden in CAA. This picture was complicated by systolic hypertension in the CAA group, which is a confounding factor for the interpretation of these data. Our results stimulate motivation for pursuit of a more comprehensive prospective study to determine the feasibility of retinal biomarkers in CAA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: This clinical trial aimed to determine whether in-car video feedback about unsafe driving events (UDE) to cognitively impaired older drivers and family members leads to a reduction in such driving behaviors., Methods: We randomized 51 cognitively impaired older drivers to receive either (1) a weekly progress report with recommendations and access to their videos, or (2) video monitoring alone without feedback over 3 months., Results: UDE frequency/1000 miles was reduced by 12% in feedback (rate ratio [RR] = 0.88, 95% confidence interval [CI] = .58-1.34), while remaining constant with only monitoring (RR = 1.01, 95% CI = .68-1.51). UDE severity/1000 miles was reduced by 37% in feedback (RR = 0.63, 95% CI = .31-1.27), but increased by 40% in monitoring (RR = 1.40, 95% CI = .68-2.90). Cognitive impairment moderated intervention effects ( P  = .03) on UDE frequency., Discussion: Results suggest the potential to improve driving safety among mild cognitively impaired older drivers using a behavior modification approach aimed at problem behaviors detected in their natural driving environment., Competing Interests: None of the authors have any conflicts of interest to disclose related to this research or the manuscript., (© 2021 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Introduction: The goal of this study was to pilot a referral-based cognitive screening and genetic testing program for Alzheimer's disease (AD) risk assessment in a primary care setting., Methods: Primary care providers (PCPs; N  = 6) referred patients ( N  = 94; M  = 63 years) to the Rhode Island Alzheimer's Disease Prevention Registry for apolipoprotein E (APOE) genotyping and cognitive screening. PCPs disclosed test results to patients and counseled them about risk factor modification., Results: Compared to the Registry as a whole, participants were younger, more likely to be non-White, and had lower cognitive screening scores. Mild cognitive impairment participants correctly reported a higher perceived risk of developing AD. Patients who recalled being counseled about modifiable risk factors were more likely to report positive health behavior changes., Discussion: A referral-based program for cognitive and genetic AD risk assessment in a primary care setting is feasible, acceptable to patients, and yielded a more demographically diverse sample than an AD prevention registry., Competing Interests: The authors have no conflicts of interest to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer's disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood., Objective: We utilized Alzheimer's Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD., Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis)., Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ42 (all < p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent., Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

Cognitive impairment is a significant risk factor for hazardous driving among older drivers with Alzheimer's dementia, but little is known about how the driving behavior of mildly symptomatic compares with those in the preclinical, asymptomatic phase of Alzheimer's disease (AD). This study utilized two in-car technologies to characterize driving behavior in symptomatic and preclinical AD. The goals of this pilot study were to (1) describe unsafe driving behaviors in individuals with symptomatic early AD using G-force triggered video capture and (2) compare the driving habits of these symptomatic AD drivers to two groups of cognitively normal drivers, those with and those without evidence of cerebral amyloidosis (CN/A+ and CN/A-) using a global positioning system (GPS) datalogger. Thirty-three drivers (aged 60+ years) were studied over 3 months. G-force triggered video events captured instances of near-misses/collisions, traffic violations, risky driver conduct, and driving fundamentals. GPS data were sampled every 30 s and all instances of speeding, hard braking, and sudden acceleration were recorded. For the early AD participants, video capture identified driving unbelted, late response, driving too fast for conditions, traffic violations, poor judgment, and not scanning intersections as the most frequently occurring safety errors. When evaluating driving using the GPS datalogger, hard breaking events occurred most frequently on a per trip basis across all three groups. The CN/A+ group had the lowest event rate across all three event types with lower instances of speeding. Slower psychomotor speed (Trail Making Part A) was associated with fewer speeding events, more hard acceleration events, and more overall events. GPS tracked instances of speeding were correlated with total number of video-captured near-collisions/collisions and driving fundamentals. Results demonstrate the utility of electronic monitoring to identify potentially unsafe driving events in symptomatic and preclinical AD. Results suggest that drivers with preclinical AD may compensate for early, subtle cognitive changes by driving more slowly and cautiously than healthy older drivers or those with cognitive impairment. Self-regulatory changes in driving behavior appear to occur in the preclinical phase of AD, but safety concerns may not arise until symptoms of cognitive impairment emerge and the ability to self-monitor declines., (Copyright © 2020 Davis, Babulal, Papandonatos, Burke, Rosnick, Ott and Roe.)

Objective: Accessing semantic representations of real-world objects requires integration of multimodal perceptual features that are represented across relevant neocortical areas. Early Alzheimer's disease (AD) neuropathology, including neurofibrillary tangles in the perirhinal cortex as well as disrupted cortico-cortical connectivity, would be expected to disrupt the integration of object features. This integration deficit may underlie AD patients' semantic memory deficits and would be predicted to be more prominent for living objects, which tend to be more defined by sensory features compared with nonliving objects., Method: Two experiments were conducted to assess feature integration in cognitively healthy older adults and patients with amnestic mild cognitive impairment (MCI). In both experiments, pictures of real-world objects were presented in congruent or incongruent colors. Participants were instructed to make a speeded color congruency judgment (Experiment 1) or name the presented surface color (Experiment 2)., Results: Across experiments, MCI patients showed a selective integration deficit for living, but not nonliving, objects across both experimental paradigms that was consistent with a deterioration in semantic structural representations rather than a deficit in controlled semantic retrieval. Planned secondary analyses with a subset of patients (Experiment 1) for whom PET imaging was available indicated that the degree of impairment was associated with the magnitude of cortical amyloid burden., Conclusions: These findings suggest that early AD pathology leads to impaired integration of distributed semantic object representations. The development of integration tasks as sensitive markers of early AD pathology may lead to more effective diagnostic tools for early detection and intervention. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Purpose: Visually impaired people may be allowed to drive if they wear bioptic telescopes. Bioptic driving safety is debatable, especially given that the telescopes are seldom used by most bioptic drivers. This preliminary study examined bioptic safety based on critical events that occurred in naturalistic daily driving., Methods: Daily driving activities were recorded using in-car video recorders in 20 bioptic drivers (median age 55, visual acuity, 20/60-160) and 19 control subjects (median age 74) for two to eight weeks. In a secondary analysis, these subjects were compared with 44 cognitively impaired drivers with normal vision (median age 75)., Results: In 292 hours of driving by bioptic drivers and 169 hours by control drivers, seven bioptic drivers and three control drivers had eight and four near-collisions, respectively. Near-collision survival times were not significantly different between the two groups (hazard ratio [HR] = 1.93, P = 0.591) according to Cox hazards regression. Even without compensation for bioptic drivers' longer driving exposure, their odds ratio (OR) was not statistically significant (OR = 2.88, P = 0.18). When including cognitively impaired drivers with normal vision, cognition was a significant predictor of near collisions (HR = 3.86, P = 0.036), but vision loss was not (HR = 0.47, P = 0.317)., Conclusions: This preliminary study failed to find any evidence suggesting that bioptic drivers were more prone to near-collision than healthy drivers. Vision might be a less-significant factor than cognition., Translational Relevance: Given that bioptic drivers use the telescope for less than 2% of the driving time, this study suggests that driving safety might not be substantially affected even when visual acuity is in the low vision range., Competing Interests: Disclosure: M. Moharrer, None; S. Wang, None; B.E. Dougherty, None; W. Cybis, None; B.R. Ott, None; J.D. Davis, None; G. Luo, None, (Copyright 2020 The Authors.)

Background: The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk)., Objectives: The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey., Methods: FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks., Results: A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57)., Conclusions: The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Abnormal beta-amyloid (Aβ) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval., Methods: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam., Results: Significant differences in both cognitive performance and in Aβ neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period., Conclusions: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Objective: Previous studies in young adults have demonstrated strong functional links between phasic alerting and exogenous orienting. The present study examined changes in the dynamic interaction between these attentional networks in healthy aging and in amnestic mild cognitive impairment., Method: Healthy young adults, healthy older adults, and patients with amnestic mild cognitive impairment (MCI) were asked to identify as quickly as possible the color of a target stimulus that appeared within one of 2 peripheral boxes. Orienting was manipulated by a brief flashing of the same (valid cue) or opposite (invalid cue) box in which the target subsequently appeared. Alerting was manipulated by presenting an auditory white noise burst simultaneously with the visual orienting cue on half of the trials., Results: All 3 groups displayed significant alerting and orienting effects but differed in the nature of the interaction between alerting and orienting. As expected, young adults displayed increased orienting under high alerting conditions through a selective enhancement of validly cued targets. While older adults displayed a greater effect of alerting on orienting compared to young adults, MCI patients did not display a significant interaction between attentional networks., Conclusions: Results provide support for the presence of increased compensatory interactions between attentional networks in healthy aging that may be no longer effective with the emergence of clinical symptoms in MCI. The demonstration of qualitatively distinct effects of healthy aging and MCI suggests that behavioral tests of attentional network interactions may serve as cognitive markers in individuals at increased risk for developing AD. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Background: Controlled naturalistic driving for examining impacts of cognitive impairment on driving safety is rare., Objective: Evaluating the safety among drivers with mild cognitive impairment based on near collision incidents using naturalistic driving, and investigating its correlation with cognitive measures., Methods: Frequency of near collisions of 44 cognitively impaired [Age = 75.1(±6.7), MMSE = 25.5(±2.5)] and 19 control group drivers [Age = 72.5(±7.8), MMSE = 29.3(±0.8)] were obtained from two weeks of recorded driving. Survival time free of predicted collision based on a previously established near-collision to collision estimate ratio of 11 : 1, for 140 hours of driving exposure was calculated. Participants were also tested using Mini-Mental Status Examination (MMSE), Trail A, and Trail B. Spearman correlation and Cox survival analysis were conducted., Results: Near collision frequency per driving hour was correlated with MMSE ( r  = -0.258, p  = 0.041). Survival analyses showed that cognitively impaired drivers might be prone to higher probability of having collision ( p  = 0.056) with a hazard ratio of 5.78 ( p  = 0.092). When all participants were combined, there was a significant difference ( p  < 0.017) in all the three cognitive measures between drivers with and without predicted collision, which were not significant within patient or control group alone ( p  > 0.186). Cox regression analysis showed MMSE as the only significant factor ( p  < 0.025) for survival time of predicted collision, but not age, gender, or driving experience., Conclusion: The association between driving critical events and cognitive measures suggests that some drivers with mild cognitive impairment might have an elevated driving collision risk compared to control drivers. Standard clinical cognitive measures may be reasonable predictors., Competing Interests: The authors declare no conflict of interest., (© 2020 – IOS Press and the authors. All rights reserved.)

A clinical consequence of symptomatic Alzheimer's disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with ( n = 10) and without ( n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

Background: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer's disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown., Objective: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD., Method: We prospectively followed cognitively normal drivers (aged 65 + years) with (n = 10) and without preclinical AD (n = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant's vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded., Results: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1-5 miles., Conclusion: Changes in driving occur even during the preclinical stage of AD.

Background: Brain insulin resistance is a well-recognized abnormality in Alzheimer's disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity., Objective: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related., Methods: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and 21 controls using a multiplex ELISA platform., Results: In MCI/AD, both the CSF and serum samples had significantly elevated mean levels of C-peptide and an incretin, and reduced expression of Visfatin, whereas only CSF showed significant reductions in insulin and leptin and only serum had increased glucagon, PAI-1, and ghrelin. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different., Conclusion: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors.

Lane changes are important behaviors to study in driving research. Automated detection of lane-change events is required to address the need for data reduction of a vast amount of naturalistic driving videos. This paper presents a method to deal with weak lane-marker patterns as small as a couple of pixels wide. The proposed method is novel in its approach to detecting lane-change events by accumulating lane-marker candidates over time. Since the proposed method tracks lane markers in temporal domain, it is robust to low resolution and many different kinds of interferences. The proposed technique was tested using 490 h of naturalistic driving videos collected from 63 drivers. The lane-change events in a 10-h video set were first manually coded and compared with the outcome of the automated method. The method's sensitivity was 94.8% and the data reduction rate was 93.6%. The automated procedure was further evaluated using the remaining 480-h driving videos. The data reduction rate was 97.4%. All 4971 detected events were manually reviewed and classified as either true or false lane-change events. Bootstrapping showed that the false discovery rate from the larger data set was not significantly different from that of the 10-h manually coded data set. This study demonstrated that the temporal processing of lane markers is an effcient strategy for detecting lane-change events involving weak lane-marker patterns in naturalistic driving.

Background: The pathophysiology underlying altered blood-cerebrospinal fluid barrier (BCSFB) function in Alzheimer's disease (AD) is unknown but may relate to endothelial cell activation and cytokine mediated inflammation. Methods: Cerebrospinal fluid (CSF) and peripheral blood were concurrently collected from cognitively healthy controls ( N = 21) and patients with mild cognitive impairment (MCI) ( N = 8) or AD ( N = 11). The paired serum and CSF samples were assayed for a panel of cytokines, chemokines, and related trophic factors using multiplex ELISAs. Dominance analysis models were conducted to determine the relative importance of the inflammatory factors in relationship to BCSFB permeability, as measured by CSF/serum ratios for urea, creatinine, and albumin. Results: BCSFB disruption to urea, a small molecule distributed by passive diffusion, had a full model coefficient of determination ( r 2 ) = 0.35, and large standardized dominance weights (>0.1) for monocyte chemoattractant protein-1, interleukin (IL)-15, IL-1rα, and IL-2 in serum. BCSFB disruption to creatinine, a larger molecule governed by active transport, had a full model r 2 = 0.78, and large standardized dominance weights for monocyte inhibitor protein-1b in CSF and tumor necrosis factor-α in serum. BCSFB disruption to albumin, a much larger molecule, had a full model r 2 = 0.62, and large standardized dominance weights for IL-17a, interferon-gamma, IL-2, and VEGF in CSF, as well IL-4 in serum. Conclusions: Inflammatory proteins have been widely documented in the AD brain. The results of the current study suggest that changes in BCSFB function resulting in altered permeability and transport are related to expression of specific inflammatory proteins, and that the shifting distribution of these proteins from serum to CSF in AD and MCI is correlated with more severe perturbations in BCSFB function.

Competing Interests: Conflicts of Interest/Disclosures Dr. Roe reports no disclosures. Dr. Babulal reports no disclosures. Ms. Stout reports no disclosures. Dr. Ott reports that neither he nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Ott has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies: Janssen, Eli Lilly/Avid, Merck, AbbVie, Biogen, and TauRx. Dr. Ott has served as a consultant for Accera and Amgen. He also receives research support from Long Term Care Group. Dr. Williams reports no disclosures. Dr. Benzinger reports that neither she nor her family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Benzinger is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company, Biogen, and Janssen. She receives research support from Eli Lilly/Avid Radiopharmaceuticals, including provision of the PET tracer florbetapir used in this study, and precursor for the tracer flortaucipir, used in this study and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276 and UF01AG032438. Dr. Fagan is on the scientific advisory boards of IBL International, Roche Diagnostics and AbbVie and is a consultant for Biogen, Araclon/Grifols and DiamiR. Dr. Fagan reports no conflicts of interest. Dr. Holtzman receives funding from C2N Diagnostics SAB, Genentech SAB, and Proclara SAB. He is a consultant for AbbVie and Glaxosmithkline. His lab receives grants from the NIH, the JPB Foundation, Cure Alzheimer’s Fund, the Tau Consortium, Eli Lilly, and C2N Diagnostics. Dr. Holtzman reports no conflicts of interest. Dr. Ances reports no disclosures.

Analyzing naturalistic driving behavior recorded with in-car cameras is an ecologically valid method for measuring driving errors, but it is time intensive and not easily applied on a large scale. This study validated a semi-automated, computerized method using archival naturalistic driving data collected for drivers with mild Alzheimer's disease (AD; n = 44) and age-matched healthy controls (HC; n = 16). The computerized method flagged driving situations where safety concerns are most likely to occur (i.e., rapid stops, lane deviations, turns, and intersections). These driving epochs were manually reviewed and rated for error type and severity, if present. Ratings were made with a standardized scoring system adapted from DriveCam ® . The top eight error types were applied as features to train a logistic model tree classifier to predict diagnostic group. The sensitivity and specificity were compared among the event-based method, on-road test, and composite ratings of two weeks of recorded driving. The logistic model derived from the event-based method had the best overall accuracy (91.7%) and sensitivity (97.7%) and high specificity (75.0%) compared to the other methods. Review of driving situations where risk is highest appears to be a sensitive data reduction method for detecting cognitive impairment associated driving behaviors and may be a more cost-effective method for analyzing large volumes of naturalistic data., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.