The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial.

BACKGROUND: Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. METHODS/DESIGN: In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. DISCUSSION: The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. TRIAL REGISTRATION: Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. PROTOCOL VERSION: This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Principal components analysis of agitation outcomes in Alzheimer's disease.

BACKGROUND: We developed a composite measure of agitation as a secondary outcome of change over time in the Citalopram for Agitation in Alzheimer's disease study (CitAD). CitAD demonstrated a positive effect of citalopram on agitation on the Neurobehavioral Rating Scale agitation subscale (NBRS-A). CitAD included additional agitation measures such as the Cohen-Mansfield Agitation Inventory and the Neuropsychiatric Inventory. METHODS: We performed principal components analyses on change in individual item of these scales for the same, original CitAD subjects. RESULTS: The first principal component accounted for 12.6% of the observed variance and was composed of items that appear to reflect agitation. The effect size for citalopram calculated using this component was 0.53 (95% CI 0.22-0.83) versus 0.32 for the NBRS-A (95% CI 0.01-0.62). CONCLUSIONS: Results suggest that a composite measure of change in agitation might be more sensitive than change in a single primary agitation measure.

Sedation mediates part of Citalopram's effect on agitation in Alzheimer's disease.

BACKGROUND: We found a benefit of citalopram for agitation in the Citalopram for Agitation in Alzheimer's Disease study (CitAD), and wondered if this was mediated by a sedative effect. CitAD was a randomized, placebo-controlled, double-blind, parallel group trial conducted at 8 academic centers in the United States and Canada from August 2009 to January 2013. One hundred sixty-two participants with probable Alzheimer's disease (AD) and clinically significant agitation were analyzed in this study. Participants received a psychosocial intervention and were randomized to receive either citalopram or placebo (approximately half assigned to each group). Participants were rated on the Neurobehavioral Rating Scale Agitation subscale and measures of sedation (i.e., fatigue and somnolence). METHODS: Using the MacArthur Foundation procedures for documenting a mediator effect, we performed a secondary analysis examining whether sedation mediates the effect of treatment on agitation outcome. RESULTS: We found a statistically significant mediating effect of sedation on agitation outcomes, but the magnitude of the effect was small, only explaining 11% of the variance in agitation, with a significant, but modest effect size of 0.16 (95% CI: 0.08 to 0.22). CONCLUSIONS: The benefit of citalopram was partly due to sedation but largely due to other mechanisms of action.

Donepezil treatment in ethnically diverse patients with Alzheimer disease.

OBJECTIVE: To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. RESULTS: The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION: Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Higher landing accuracy in expert pilots is associated with lower activity in the caudate nucleus.

The most common lethal accidents in General Aviation are caused by improperly executed landing approaches in which a pilot descends below the minimum safe altitude without proper visual references. To understand how expertise might reduce such erroneous decision-making, we examined relevant neural processes in pilots performing a simulated landing approach inside a functional MRI scanner. Pilots (aged 20-66) were asked to "fly" a series of simulated "cockpit view" instrument landing scenarios in an MRI scanner. The scenarios were either high risk (heavy fog-legally unsafe to land) or low risk (medium fog-legally safe to land). Pilots with one of two levels of expertise participated: Moderate Expertise (Instrument Flight Rules pilots, n = 8) or High Expertise (Certified Instrument Flight Instructors or Air-Transport Pilots, n = 12). High Expertise pilots were more accurate than Moderate Expertise pilots in making a "land" versus "do not land" decision (CFII: d' = 3.62 ± 2.52; IFR: d' = 0.98 ± 1.04; p<.01). Brain activity in bilateral caudate nucleus was examined for main effects of expertise during a "land" versus "do not land" decision with the no-decision control condition modeled as baseline. In making landing decisions, High Expertise pilots showed lower activation in the bilateral caudate nucleus (0.97 ± 0.80) compared to Moderate Expertise pilots (1.91 ± 1.16) (p<.05). These findings provide evidence for increased "neural efficiency" in High Expertise pilots relative to Moderate Expertise pilots. During an instrument approach the pilot is engaged in detailed examination of flight instruments while monitoring certain visual references for making landing decisions. The caudate nucleus regulates saccade eye control of gaze, the brain area where the "expertise" effect was observed. These data provide evidence that performing "real world" aviation tasks in an fMRI provide objective data regarding the relative expertise of pilots and brain regions involved in it.

APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years.

Atrophy of the hippocampus and surrounding temporal regions occurs in Alzheimer's disease (AD). APOE ε4, the major genetic risk factor for late-onset AD, has been associated with smaller volume in these regions before amyloidosis can be detected by AD biomarkers. To examine APOE ε4 effects in relation to aging, we performed a longitudinal magnetic resonance imaging study involving cognitively normal adults (25 APOE ε4 carriers and 31 ε3 homozygotes), initially aged 51-75 years. We used growth curve analyses, which can provide information about APOE ε4-related differences initially and later in life. Hippocampal volume was the primary outcome; nearby medial temporal regions were secondary outcomes. Brain-derived neurotrophic factor, val66met was a secondary covariate. APOE ε4 carriers had significantly smaller initial hippocampal volumes than ε3 homozygotes. Rate of hippocampal atrophy was not greater in the APOE ε4 group, although age-related atrophy was detected in the overall sample. The findings add to the growing evidence that effects of APOE ε4 on hippocampal size begin early in life, underscoring the importance of early interventions to increase reserve.

Pilot expertise and hippocampal size: associations with longitudinal flight simulator performance.

BACKGROUND: Previous research suggests that the size of the hippocampus can vary in response to intensive training (e.g., during the acquisition of expert knowledge). However, the role of the hippocampus in maintenance of skilled performance is not well understood. The Stanford/Veterans Affairs Aviation MRI Study offers a unique opportunity to observe the interaction of brain structure and multiple levels of expertise on longitudinal flight simulator performance. METHODS: The current study examined the relationship between hippocampal volume and three levels of aviation expertise, defined by pilot proficiency ratings issued by the U.S. Federal Aviation Administration (11). At 3 annual time points, 60 pilots who varied in their level of aviation expertise (ages ranging from 45 to 69 yr) were tested. RESULTS: At baseline, higher expertise was associated with better flight simulator performance, but not with hippocampal volume. Longitudinally, there was an Expertise x Hippocampal volume interaction, in the direction that a larger hippocampus was associated with better performance at higher levels of expertise. DISCUSSION: These results are consistent with the notion that expertise in a cognitively demanding domain involves the interplay of acquired knowledge ('mental schemas') and basic hippocampal-dependent processes.

Influences of APOE ε4 and expertise on performance of older pilots.

Little is known about how APOE ε4-related differences in cognitive performance translate to real-life performance, where training and experience may help to sustain performance. We investigated the influences of APOE ε4 status, expertise (FAA pilot proficiency ratings), and their interaction on longitudinal flight simulator performance. Over a 2-year period, 139 pilots aged 42-69 years were tested annually. APOE ε4 carriers had lower memory performance than noncarriers (p = .019). APOE interacted with Expertise (p = .036), such that the beneficial influence of expertise (p = .013) on longitudinal flight simulator performance was more pronounced for ε4 carriers. Results suggest that relevant training and activity may help sustain middle-aged and older adults' real-world performance, especially among APOE ε4 carriers.

Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE ɛ4 allele.

Apolipoprotein (APOE) ɛ4-related differences in memory performance have been detected before age 65. The hippocampus and the surrounding medial temporal lobe (MTL) structures are the first site affected by Alzheimer's disease (AD) and the MTL is the seat of episodic memory, including visuo-spatial memory. While reports of APOE ɛ4-related differences in these brain structures are not consistent in either cross-sectional or longitudinal structural and functional magnetic resonance imaging (fMRI) studies, there is increasing evidence that brain activity at baseline (defined as activity during fixation or rest) may differ in APOE ɛ4 carriers compared to non-carriers. In this fMRI study, cognitively normal APOE ɛ4 carriers and non-carriers engaged in a perspective-dependent spatial learning task (Shelton & Gabrieli, 2002) previously shown to activate MTL structures in older participants (Borghesani et al., 2008). A low-level, visually engaging dot-control task was used for comparison, in addition to fixation. APOE ɛ4 carriers showed less activation than non-carriers in the hippocampus proper during encoding. Specifically, when spatial encoding was contrasted against the dot-control task, encoding-related activation was significantly lower in carriers than non-carriers. By contrast, no ɛ4-related differences in the hippocampus were found when spatial encoding was compared with fixation. Lower activation, however, was not global since encoding-related activation in early visual cortex (left lingual gyrus) was not different between APOE ɛ4 carriers and non-carriers. The present data document APOE ɛ4-related differences in the hippocampus proper during encoding and underscore the role of low-level control contrasts for complex encoding tasks. These results have implications for fMRI studies that investigate the default-mode network (DMN) in middle-aged to older APOE ɛ4 carriers to help evaluate AD risk in this otherwise cognitively normal population.

Initial cognitive performance predicts longitudinal aviator performance.

OBJECTIVES: The goal of the study was to improve prediction of longitudinal flight simulator performance by studying cognitive factors that may moderate the influence of chronological age. METHOD: We examined age-related change in aviation performance in aircraft pilots in relation to baseline cognitive ability measures and aviation expertise. Participants were aircraft pilots (N = 276) aged 40-77.9. Flight simulator performance and cognition were tested yearly; there were an average of 4.3 (± 2.7; range 1-13) data points per participant. Each participant was classified into one of the three levels of aviation expertise based on Federal Aviation Administration pilot proficiency ratings: least, moderate, or high expertise. RESULTS: Addition of measures of cognitive processing speed and executive function to a model of age-related change in aviation performance significantly improved the model. Processing speed and executive function performance interacted such that the slowest rate of decline in flight simulator performance was found in aviators with the highest scores on tests of these abilities. Expertise was beneficial to pilots across the age range studied; however, expertise did not show evidence of reducing the effect of age. DISCUSSION: These data suggest that longitudinal performance on an important real-world activity can be predicted by initial assessment of relevant cognitive abilities.

Nicotine deprivation and pilot performance during simulated flight.

OBJECTIVES: Most airlines enforce no-smoking policies, potentially causing flight performance decrements in pilots who are smokers. We tested the hypotheses that nicotine withdrawal affects aircraft pilot performance within 12 h of smoking cessation and that chewing nicotine gum leads to significant relief of these withdrawal effects. METHODS: There were 29 pilots, regular smokers, who were tested in a Frasca 141 flight simulator on two 13-h test days, each including three 75-min flights (0 hr, 6 hr, 12 hr) in a randomized, controlled trial. On the first day (baseline), all pilots smoked one cigarette per hour. On the second day, pilots were randomly assigned to one of four groups: (1) nicotine cigarettes; (2) nicotine gum; (3) placebo gum; (4) no cigarettes/no gum. Flight Summary Scores (FSS) were compared between groups with repeated measures ANOVAs. RESULTS: No statistically significant differences in overall simulator flight performance were revealed between pilots who smoked cigarettes and pilots who were not allowed to smoke cigarettes or chew nicotine gum, but there was a trend for pilots who were not allowed to smoke to perform worse. However, pilots who chewed placebo gum performed significantly worse during the 6-h (FSS = -0.03) as well as during the 12-h flight (FSS = -0.08) than pilots who chewed nicotine gum (FSS = 0.15 / 0.30, respectively). CONCLUSIONS: Results suggest that nicotine withdrawal effects can impair aircraft pilot performance within 12 h of smoking cessation and that during smoking abstinence chewing one stick of 4-mg nicotine gum per hour may lead to significantly better overall flight performance compared to chewing placebo gum.

Age and expertise effects in aviation decision making and flight control in a flight simulator.

INTRODUCTION: Age (due to declines in cognitive abilities necessary for navigation) and level of aviation expertise are two factors that may affect aviation performance and decision making under adverse weather conditions. We examined the roles of age, expertise, and their relationship on aviation decision making and flight control performance during a flight simulator task. METHODS: Seventy-two IFR-rated general aviators, aged 19-79 yr, made multiple approach, holding pattern entry, and landing decisions while navigating under Instrument Flight Rules weather conditions. Over three trials in which the fog level varied, subjects decided whether or not to land the aircraft. They also completed two holding pattern entries. Subjects' flight control during approaches and holding patterns was measured. RESULTS: Older pilots (41+ yr) were more likely than younger pilots to land when visibility was inadequate (older pilots' mean false alarm rate: 0.44 vs 0.25). They also showed less precise flight control for components of the approach, performing 0.16 SD below mean approach scores. Expertise attenuated an age-related decline in flight control during holding patterns: older IFR/CFI performed 0.73 SD below mean score; younger IFR/CFI, younger CFII/ATP, older CFII/ATP: 0.32, 0.26, 0.03 SD above mean score. Additionally, pilots with faster processing speed (by median split) had a higher mean landing decision false alarm rate (0.42 vs 0.28), yet performed 0.14 SD above the mean approach control score. CONCLUSIONS: Results have implications regarding specialized training for older pilots and for understanding processes involved in older adults' real world decision making and performance.

The impact of brain size on pilot performance varies with aviation training and years of education.

Previous studies have consistently reported age-related changes in cognitive abilities and brain structure. Previous studies also suggest compensatory roles for specialized training, skill, and years of education in the age-related decline of cognitive function. The Stanford/VA Aviation Study examines the influence of specialized training and skill level (expertise) on age-related changes in cognition and brain structure. This preliminary report examines the effect of aviation expertise, years of education, age, and brain size on flight simulator performance in pilots aged 45-68 years. Fifty-one pilots were studied with structural magnetic resonance imaging, flight simulator, and processing speed tasks. There were significant main effects of age (p < .01) and expertise (p < .01), but not of whole brain size (p > .1) or education (p > .1), on flight simulator performance. However, even though age and brain size were correlated (r = -0.41), age differences in flight simulator performance were not explained by brain size. Both aviation expertise and education were involved in an interaction with brain size in predicting flight simulator performance (p < .05). These results point to the importance of examining measures of expertise and their interactions to assess age-related cognitive changes.

Apolipoprotein E epsilon4 influences on episodic recall and brain structures in aging pilots.

The apolipoprotein (APOE) epsilon4 allele is associated with cognitive deficits and hippocampal atrophy in nondemented middle-aged and older adults. It is not known to what extent this genetic risk factor for Alzheimer's disease (AD) impacts performance in late middle-aged and older workers in cognitively demanding occupations. This cross-sectional analysis examines brain-cognitive-genetic relationships in actively flying general aviation pilots, half of whom are APOE epsilon4 carriers. Fifty pilots were studied with structural MRI and memory tasks. Average visual paired associate memory recall performance was lower in APOE epsilon4 carriers than non-carriers. Memory performance correlated positively with hippocampal volume, but no structural differences were found in hippocampal or frontal volumes with respect to APOE epsilon4 allele. These results were evident in healthy professionals without any presenting memory problems and without selection for a family history of AD. These findings point to basic memory testing as a sensitive tool for detecting APOE epsilon4-related influences on memory in aging workers.

[Adaptation and convergent validity of a telephone-based Mini-Mental State Examination]. / Adaptación y validez convergente de una versión telefónica del Mini-Mental State Examination.

BACKGROUND AND OBJECTIVE: To adapt to Spanish and to determine the convergent validity of a Telephone Mini-Mental State Examination (t-MMSE) in order to assess the cognitive functions in Alzheimer's disease (AD) patients. PATIENTS AND METHOD: Prospective and observational study of a clinical sample consisting of patients with dementia from a memory clinic. Consecutive sampling of participants was used and convergent validity of the t-MMSE and MMSE scores was determined using several statistics measures. Patients were randomly assigned depending on the administration of the in-person/telephone test (MMSE and t-MMSE) or telephone/in-person (t-MMSE and MMSE) test within a 1- to 7-day interval. The effect of the confusion variables (age, gender, years of education, dementia severity, presence or absence of hearing impairment and administration order) on the concordance between the in-person and telephone MMSE versions was analysed. RESULTS: After translating and retranslating the t-MMSE, of 141 participants, 77.47% subjects completed the protocol of the study. For the total score, the statistics for the convergent validity suggested a high consistency, independently of the order of test administration (intraclass correlation coefficient = 0.87, Spearman's rho = 0.77); for the all subscores, it suggested moderate and good correlations. The difference between subscores did not range more than 1 point in any case. Confusion variables did not affect the variability of the performance scores between t-MMSE and MMSE. CONCLUSIONS: The t-MMSE can be used as a good tool to estimate the MMSE score of patients with dementia.

Adaptación y validez convergente de una versión telefónica del Mini-Mental State Examination / Adaptation and convergent validity of a telephone-based Mini-Mental State Examination

Fundamento y objetivo: Adaptar al castellano y determinar la validez convergente de una versión telefónica del Mini-Mental State Examination (t-MMSE) para valorar las funciones cognoscitivas de los pacientes con demencia. Pacientes y método: Estudio observacional y prospectivo de pacientes con demencia seleccionados mediante muestreo consecutivo de las consultas ambulatorias de una unidad hospitalaria. Se evaluó la validez convergente de las puntuaciones del t-MMSE respecto a las puntuaciones del MMSE mediante diversos indicadores. Los participantes fueron aleatorizados a la aplicación de los tests, en el intervalo de 1 semana, presencial-telefónica (MMSE y t-MMSE) y telefónica- presencial (t-MMSE y MMSE). Se analizó el efecto de variables de confusión (edad, sexo, escolaridad, gravedad de la demencia, déficit auditivo y orden de aplicación) en el grado de concordancia entre el t-MMSE y el MMSE. Resultados: Tras el proceso de traducción directa e inversa del t-MMSE, fue posible aplicar el protocolo de estudio al 77,47% de los candidatos a participar (n=141). Para la puntuación total, los indicadores de validez convergente fueron elevados independientemente del orden de aplicación (coeficiente de correlación intraclase = 0,87; rho de Spearman = 0,77). Los indicadores de validez de las subpuntuaciones presentaron valores entre moderados y buenos. Las diferencias entre las subpuntuaciones no fueron superiores a 1 punto en ningún caso. No se observó ningún efecto de las variables de confusión en la variación de las puntuaciones entre el t-MMSE y el MMSE. Conclusiones: El t-MMSE puede ser utilizado de forma válida para estimar la puntuación del MMSE en pacientes con demencia

Background and objective: To adapt to Spanish and to determine the convergent validity of a Telephone Mini-Mental State Examination (t-MMSE) in order to assess the cognitive functions in Alzheimer's disease (AD) patients. Patients and method: Prospective and observational study of a clinical sample consisting of patients with dementia from a memory clinic. Consecutive sampling of participants was used and convergent validity of the t-MMSE and MMSE scores was determined using several statistics measures. Patients were randomly assigned depending on the administration of the in-person/telephone test (MMSE and t-MMSE) or telephone/in-person (t-MMSE and MMSE) test within a 1- to 7-day interval. The effect of the confusion variables (age, gender, years of education, dementia severity, presence or absence of hearing impairment and administration order) on the concordance between the in-person and telephone MMSE versions was analysed. Results: After translating and retranslating the t-MMSE, of 141 participants, 77.47% subjects completed the protocol of the study. For the total score, the statistics for the convergent validity suggested a high consistency, independently of the order of test administration (intraclass correlation coefficient = 0.87, Spearman's rho = 0.77); for the all subscores, it suggested moderate and good correlations. The difference between subscores did not range more than 1 point in any case. Confusion variables did not affect the variability of the performance scores between t-MMSE and MMSE. Conclusions: The t-MMSE can be used as a good tool to estimate the MMSE score of patients with dementia

Donepezil treatment and Alzheimer disease: can the results of randomized clinical trials be applied to Alzheimer disease patients in clinical practice?

OBJECTIVE: To determine if results from randomized clinical trials of donepezil in Alzheimer disease (AD) patients can be applied to AD patients in clinical practice by comparing the findings from a Nordic one-year randomized AD donepezil trial with data from a one-year prospective, observational study of AD patients. METHODS: AD patients from a consortium of California sites were systematically followed for at least one year. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. RESULTS: The 148 California patients treated with donepezil had a one-year decline of 1.3 (3.5 SD) points on the Mini-Mental State Exam compared to a decline of 3.3 (4.4 SD) in the 158 AD patients who received no anti-Alzheimer drugs. The Mini-Mental State Exam decline in Nordic sample was approximately 0.25 points for the 91 patients receiving donepezil and approximately 2.2 for the 98 placebo patients. The overall effect sizes were estimated at about 0.49 in both studies. The California data were further analyzed using propensity methods; after taking into account differences that could bias prescribing decisions, benefits associated with taking donepezil remained. CONCLUSION: A comparison of a randomized clinical trial of donepezil in AD patients and this observational study indicates that if appropriate methodological and statistical precautions are undertaken, then results from randomized clinical trials can be predictive with AD patients in clinical practice. This California study supports the modest effectiveness of donepezil in AD patients having clinical characteristics similar to those of the Nordic study.

Pilot age and expertise predict flight simulator performance: a 3-year longitudinal study.

BACKGROUND: Expert knowledge may compensate for age-related declines in basic cognitive and sensory-motor abilities in some skill domains. We investigated the influence of age and aviation expertise (indexed by Federal Aviation Administration pilot ratings) on longitudinal flight simulator performance. METHODS: Over a 3-year period, 118 general aviation pilots aged 40 to 69 years were tested annually, in which their flight performance was scored in terms of 1) executing air-traffic controller communications; 2) traffic avoidance; 3) scanning cockpit instruments; 4) executing an approach to landing; and 5) a flight summary score. RESULTS: More expert pilots had better flight summary scores at baseline and showed less decline over time. Secondary analyses revealed that expertise effects were most evident in the accuracy of executing aviation communications, the measure on which performance declined most sharply over time. Regarding age, even though older pilots initially performed worse than younger pilots, over time older pilots showed less decline in flight summary scores than younger pilots. Secondary analyses revealed that the oldest pilots did well over time because their traffic avoidance performance improved more vs younger pilots. CONCLUSIONS: These longitudinal findings support previous cross-sectional studies in aviation as well as non-aviation domains, which demonstrated the advantageous effect of prior experience and specialized expertise on older adults' skilled cognitive performances.

Strategies to reduce site differences in multisite studies: a case study of Alzheimer disease progression.

OBJECTIVES: The objectives of this study were to evaluate the magnitude and sources of site differences in a multisite study of rates of cognitive decline among patients with Alzheimer disease and to seek strategies to reduce the magnitude of site differences in this and future such studies. METHODS: A total of 3,280 participants from 15 different sites was analyzed. For each participant, the average rate of change in the Mini-Mental State Examination (MMSE) was calculated. Participants who declined at least three MMSE points per year were classified "rapid decliners." Site differences in sociodemographic distributions and the percentage of rapid decliners were examined, and a signal detection approach was used to identify the main correlates of rapid decline. RESULTS: The percentage of rapid decliners for the 15 sites initially varied from 8%-40%. Two of the correlates of rapid decline were largely the result of different sampling protocols, namely baseline MMSE and elapsed time between the first and last MMSE. By selecting only those participants at each site with a baseline MMSE between 15 and 23, and limiting the follow-up time to a period of 11-24 months, the authors created greater homogeneity in the protocols across sites and reduced site variability of rapid decliners from 27%-50%. CONCLUSION: Results of single-site studies are often nonreproducible, and multisite studies that follow different protocols and do not take site differences into account may be misleading. This study indicates the importance of site differences and how relatively simple efforts to impose common sampling, measurement, and design criteria can reduce, if not totally remove, site differences.