[Show abstract][Hide abstract] ABSTRACT: The citalopram for Alzheimer's disease trial evaluated citalopram for the management for agitation in Alzheimer's disease patients. Sparse data was available from this elderly patient population. A nonlinear mixed effects population pharmacokinetic modeling approach was used to describe the pharmacokinetics of R- and S-citalopram and their primary metabolite (desmethylcitalopram). A structural model with 4 compartments (one compartment/compound) with linear oral absorption and elimination described the data adequately. Overall, the model showed that clearance of the R-enantiomer was slower than the clearance of the S-enantiomer. Without accounting for any patient-specific covariates, the population estimate of the metabolic clearance of citalopram was 8.6 (R-citalopram) and 14 L/h (S-citalopram). The population estimate of the clearance of desmethylcitalopram was 23.8 (R-Dcit) and 38.5 L/h (S-Dcit). Several patient-specific covariates were found to have a significant effect on the pharmacokinetics of R,S-citalopram and desmethylcitalopram. A significant difference in the metabolic clearance of R-citalopram between males and females (13 vs 9.05 L/h) was identified in this analysis. Both R- and S-citalopram metabolic clearance decreased with age. Additionally, consistent with literature reports S-citalopram metabolic clearance increased with increasing body weight and was significantly influenced by CYPC19 genotype, with a difference of 5.8 L/h between extensive/rapid and intermediate/poor metabolizers. R,S-desmethylcitalopram clearance increased with increasing body weight. This model may allow for the opportunity to delineate the effect of R- and S-citalopram on pharmacodynamics outcomes related to the management of agitation in Alzheimer's disease.
Journal of Pharmacokinetics and Pharmacodynamics 11/2015; DOI:10.1007/s10928-015-9457-6 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).
In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
International Psychogeriatrics 08/2015; DOI:10.1017/S1041610215001106 · 1.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Understanding the possible effects of the number of practice sessions (practice) and time between practice sessions (interval) among middle-aged and older adults in real-world tasks has important implications for skill maintenance. Prior training and cognitive ability may impact practice and interval effects on real-world tasks. In this study, we took advantage of existing practice data from 5 simulated flights among 263 middle-aged and older pilots with varying levels of flight expertise (defined by U.S. Federal Aviation Administration proficiency ratings). We developed a new Simultaneous Time Effects on Practice (STEP) model: (a) to model the simultaneous effects of practice and interval on performance of the 5 flights, and (b) to examine the effects of selected covariates (i.e., age, flight expertise, and 3 composite measures of cognitive ability). The STEP model demonstrated consistent positive practice effects, negative interval effects, and predicted covariate effects. Age negatively moderated the beneficial effects of practice. Additionally, cognitive processing speed and intraindividual variability (IIV) in processing speed moderated the benefits of practice and/or the negative influence of interval for particular flight performance measures. Expertise did not interact with practice or interval. Results indicated that practice and interval effects occur in simulated flight tasks. However, processing speed and IIV may influence these effects, even among high-functioning adults. Results have implications for the design and assessment of training interventions targeted at middle-aged and older adults for complex real-world tasks. (PsycINFO Database Record
(c) 2015 APA, all rights reserved).
Psychology and Aging 08/2015; 30(3). DOI:10.1037/pag0000043 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: With the influx of veterans entering older adulthood, it is increasingly important to understand risk factors for cognitive decline. Posttraumatic stress disorder (PTSD) and the metabolic syndrome (MetS) are highly prevalent in older veterans. Although both increase risk for cognitive decline and often co-occur, it is unclear how they may interact to negatively impact cognition. The aim of this cross-sectional study was to investigate associations among PTSD, MetS, and cognitive function in older veterans. We hypothesized that co-occurring PTSD and MetS would be associated with worse cognitive performance than seen in either illness alone.
Participants completed cognitive testing to assess processing speed, verbal memory, and executive function. Data from 204 male veterans aged 55-89 were analyzed with the use of hierarchical multiple regression models.
Veterans with MetS demonstrated poorer performance on tasks of executive function (response inhibition and cognitive set shifting) and immediate verbal memory regardless of PTSD status. There was an interaction between MetS and PTSD on delayed verbal memory, suggesting that the negative impact of MetS on verbal memory was only significant for veterans not classified as having PTSD.
This is the first study to examine the impact of comorbid PTSD and MetS on cognition. The results suggest that MetS is associated with poorer verbal learning and executive functioning independent of PTSD. We discuss the necessity of monitoring cerebrovascular risk factors and providing early behavioral and/or pharmaceutical interventions to lessen the risk of cognitive decline in older age.
Published by Oxford University Press on behalf of the Gerontological Society of America 2015.
The Gerontologist 07/2015; DOI:10.1093/geront/gnv040 · 3.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Naming or word-finding tasks are a mainstay of the typical neuropsychological evaluation, particularly with older adults. However, many older adults have significant visual impairment and there are currently no such word-finding tasks developed for use with older visually impaired populations. This study presents a verbal, non-visual measure of word-finding for use in the evaluation of older adults with possible dysnomia. Stimuli were chosen based on their frequency of usage in everyday spoken language. A 60-item scale was created and given to 131 older Veterans. Rasch analyses were conducted and differential item functioning assessed to eliminate poorly-performing items. The final 55-item scale had a coefficient alpha of 0.84 and correlated with the Neuropsychological Assessment Battery Naming test, r=0.84, p<.01, Delis-Kaplan Executive Function System (D-KEFS) Category Fluency, r=0.45, p<.01, and the D-KEFS Letter Fluency, r=0.40, p<.01. ROC analyses found the measure to have sensitivity of 79% and specificity of 85% for detecting dysnomia. Patients with dysnomia performed worse on the measure than patients with intact word-finding, t(84)=8.2, p<.001. Patients with no cognitive impairment performed significantly better than patients with mild cognitive impairment, who performed significantly better than patients with dementia. This new measure shows promise in the neuropsychological evaluation of word-finding ability in older adults with or without visual impairment. Future directions include the development of a shorter version and the generation of additional normative data. (JINS, 2015, 21, 1-10).
Journal of the International Neuropsychological Society 03/2015; 21(03):1-10. DOI:10.1017/S1355617715000120 · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A significant proportion of military personnel deployed in support of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) were exposed to war-zone events potentially associated with traumatic brain injury (TBI), depression (DEP) and posttraumatic stress disorder (PTSD). The co-occurrence of TBI, PTSD and DEP in returning Veterans and the symptom overlap between the three disorders has recently increased both research and clinical interest. The purpose of this study was to test the hypothesis that white matter abnormalities are present and are further impacted by depression. We studied ten prominent white matter tracts. Specifically, the uncinate fasciculus (UF), which is a key fronto-temporal tract involved in mood regulation, and the cingulum a tract that connects to the hippocampus and is involved in memory integration. Both the UF and Cingulum tracts are part of the limbic system, involved in emotion processing, attention and memory, and have been previously implicated in clinical depression. We performed diffusion tensor imaging (DTI) on 25 patients with a combination of PTSD, TBI and DEP and 20 patients with PTSD and TBI but without DEP. Participants were matched on key variables including age, gender distribution and education. Our results provide evidence of microstructural changes of white matter in the Cingulum and UF. Fractional anisotropy (FA) was lower in Veterans with DEP compared to those without. These findings complement those observed in previous work on depression and support the hypothesis that the disruption of cortical–subcortical circuits may be involved in the etiology of depression. Notably, this is the first study to demonstrate the robustness of white matter abnormalities in DEP even in the presence of co-occurring PTSD and TBI.
[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 11/2014; 9(11):e112607. DOI:10.1371/journal.pone.0112607 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
Previous work has demonstrated the relatively high prevalence of risk factors for cognitive impairment, such as sleep disordered breathing (SDB) and obesity, in Vietnam War era veterans with post-traumatic stress disorder (PTSD). No data are currently available on the longitudinal stability of SDB as a risk factor for cognitive decline in that population, which this study now reports.
Sample consisted of 48 veterans of the Vietnam War with PTSD who completed longitudinal sleep assessments over a 3-year period. The primary outcome measure, the Apnea-Hypopnea Index (AHI) indicator, was determined during standard overnight polysomnography. Body mass index (BMI) was calculated using standard measurements. Measures of cognitive function tapped auditory verbal memory as measured by the Rey Auditory Verbal Learning Test and executive functioning as measured by the Color-Word Interference Test of the Delis–Kaplan Executive Function System battery. Statistical analyses included mixed effects modeling.
In this sample, AHI increased significantly by 2.19 points per year (β=2.19; P<0.005). AHI worsened over the 3-year period, increasing from a mean of 18.7±15.7 to 24.7±17.4 points. Neither BMI nor cognition showed significant change over the 3-year period.
SDB worsened in a group of veterans of the Vietnam War with PTSD over a 3-year period. The worsening of SDB over time suggests the need for appropriate countermeasures in populations at risk for progression of the condition.
Nature and Science of Sleep 10/2014; 6:123-7. DOI:10.2147/NSS.S65034
[Show abstract][Hide abstract] ABSTRACT: Objective
To compare the outcome of donepezil treatment in ethnically diverse Alzheimer Disease (AD) patients to ethnically diverse AD patients who did not receive donepezil. Design: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least one 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 one year decline of 2.30 points (3.9 SD) on the 30-point MMSE compared with a 1.70 point (4.2 SD) 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: California ethnically diverse AD patients in this study apparently did not benefit from one 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.
American Journal of Geriatric Psychiatry 09/2014; 23(4). DOI:10.1016/j.jagp.2014.09.007 · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group. Methods: CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1:1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began. Results: Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase >= 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death. Conclusion: Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation.
PLoS ONE 07/2014; 9(6):e98426. DOI:10.1371/journal.pone.0098426 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Well-known risk factors for cognitive impairment are also associated with obesity. Research has highlighted genetic risk factors for obesity, yet the relationship of those risk factors with cognitive impairment is unknown. The objective of this study was to determine the associations between cognition, hypertension, diabetes, sleep-disordered breathing, and obesity. Genetic risk factors of obesity were also examined.
The sample consisted of 369 nondemented individuals aged 50 years or older from four community cohorts. Primary outcome measures included auditory verbal memory, as measured by the Rey Auditory Verbal Learning Test, and executive functioning, as measured by the Color–Word Interference Test of the Delis–Kaplan Executive Function System battery. Apnea–hypopnea index indicators were determined during standard overnight polysomnography. Statistical analyses included Pearson correlations and linear regressions.
Poor executive function and auditory verbal memory were linked to cardiovascular risk factors, but not directly to obesity. Genetic factors appeared to have a small but measureable association to obesity.
A direct linkage between obesity and poor executive function and auditory verbal memory is difficult to discern, possibly because nonobese individuals may show cognitive impairment due to insulin resistance and the “metabolic syndrome”.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 05/2014; 7:145-51. DOI:10.2147/DMSO.S60294
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.
[Show abstract][Hide abstract] ABSTRACT: Agitation is common, persistent, and associated with adverse consequences for patients with Alzheimer disease. Pharmacological treatment options, including antipsychotics are not satisfactory.
The primary objective was to evaluate the efficacy of citalopram for agitation in patients with Alzheimer disease. Key secondary objectives examined effects of citalopram on function, caregiver distress, safety, cognitive safety, and tolerability.
The Citalopram for Agitation in Alzheimer Disease Study (CitAD) was a randomized, placebo-controlled, double-blind, parallel group trial that enrolled 186 patients with probable Alzheimer disease and clinically significant agitation from 8 academic centers in the United States and Canada from August 2009 to January 2013.
Participants (n = 186) were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks. Dosage began at 10 mg per day with planned titration to 30 mg per day over 3 weeks based on response and tolerability.
Primary outcome measures were based on scores from the 18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) and the modified Alzheimer Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC). Other outcomes were based on scores from the Cohen-Mansfield Agitation Inventory (CMAI) and the Neuropsychiatric Inventory (NPI), ability to complete activities of daily living (ADLs), caregiver distress, cognitive safety (based on scores from the 30-point Mini Mental State Examination [MMSE]), and adverse events.
Participants who received citalopram showed significant improvement compared with those who received placebo on both primary outcome measures. The NBRS-A estimated treatment difference at week 9 (citalopram minus placebo) was -0.93 (95% CI, -1.80 to -0.06), P = .04. Results from the mADCS-CGIC showed 40% of citalopram participants having moderate or marked improvement from baseline compared with 26% of placebo recipients, with estimated treatment effect (odds ratio [OR] of being at or better than a given CGIC category) of 2.13 (95% CI, 1.23-3.69), P = .01. Participants who received citalopram showed significant improvement on the CMAI, total NPI, and caregiver distress scores but not on the NPI agitation subscale, ADLs, or in less use of rescue lorazepam. Worsening of cognition (-1.05 points; 95% CI, -1.97 to -0.13; P = .03) and QT interval prolongation (18.1 ms; 95% CI, 6.1-30.1; P = .01) were seen in the citalopram group.
Among patients with probable Alzheimer disease and agitation who were receiving psychosocial intervention, the addition of citalopram compared with placebo significantly reduced agitation and caregiver distress; however, cognitive and cardiac adverse effects of citalopram may limit its practical application at the dosage of 30 mg per day.
clinicaltrials.gov Identifier: NCT00898807.
JAMA The Journal of the American Medical Association 02/2014; 311(7):682-91. DOI:10.1001/jama.2014.93 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Nocturia (nocturnal awakenings associated with urination) is so common a nocturnal behavior that its association with poor sleep is often overlooked. This study examined nocturia and its potential role in poor sleep by examining reported nightly awakenings and associated bathroom trips.
Sleep diaries were kept by 119 adults with poor sleep for intervals up to 14 days. Diaries collected data on nightly number of awakenings and nightly number of bathroom trips. The proportion of nocturnal awakenings accompanied by voiding for each night was calculated and averaged within each individual. Demographics and various health conditions were examined in relation to this measure.
Nocturia was defined when at least two-thirds of all awakenings were associated with nocturnal voiding. Absence of nocturia was defined when less than one-third of awakenings were associated with voiding. Remaining cases were defined as having possible nocturia. Estimates of nocturia derived from prestudy screening were related to nocturia as defined by sleep diaries. Neither gender nor sleep apnea was associated with nocturia. Unadjusted analyses indicated that individuals with nocturia were more likely to have arthritis and attribute their nighttime awakenings to urge to void than individuals without nocturia.
Nocturia is an exceedingly common phenomenon and may be associated with multiple morbidities. RESULTS are discussed in terms of causality and whether the perceived urge to void precedes or follows nocturnal awakening. Correlates of nocturia have important implications, because they can inform interventions that target brain (e.g., cognitive-behavioral treatments for insomnia, sedative/hypnotic medications) versus bladder (e.g., bladder control exercises, medications affecting urine production or urgency).
Health Psychology 11/2013; 33(11). DOI:10.1037/a0034401 · 3.59 Impact Factor