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1.  Web-enabled Conversational Interactions as a Means to Improve Cognitive Functions: Results of a 6-Week Randomized Controlled Trial 
Increasing social interaction could be a promising intervention for improving cognitive function. We examined the feasibility of a randomized controlled trial to assess whether conversation-based cognitive stimulation, through personal computers, webcams, and a user-friendly interactive Internet interface had high adherence and a positive effect on cognitive functions among older adults without dementia.
Daily 30 minute face-to-face communications were conducted over a 6-week trial period in the intervention group. The control group had only a weekly telephone interview. Cognitive status of normal and MCI subjects was operationally defined as Global Clinical Dementia Rating (CDR) = 0 and 0.5, respectively. Age, sex, education, Mini-Mental State Exam and CDR score were balancing factors in randomization. Subjects were recruited using mass-mailing invitations. Pre-post differences in cognitive test scores and loneliness scores were compared between control and intervention groups using linear regression models.
Eighty-three subjects participated (intervention: n=41, control: n=42). Their mean (std) age was 80.5 (6.8) years. Adherence to the protocol was high; there was no dropout and mean % of days completed out of the targeted trial days among the intervention group was 89% (range: 77%–100%). Among the cognitively intact participants, the intervention group improved more than the control group on a semantic fluency test (p=0.003) at the post-trial assessment and a phonemic fluency test (p=0.004) at the 18th week assessments. Among those with MCI, a trend (p=0.04) of improved psychomotor speed was observed in the intervention group.
Daily conversations via user-friendly Internet communication programs demonstrated high adherence. Among cognitively intact, the intervention group showed greater improvement in tests of language-based executive functions. Increasing daily social contacts through communication technologies could offer cost-effective home-based preventions. Further studies with a longer duration of follow-up are required to examine whether the intervention slows cognitive declines and delays the onset of dementia.
PMCID: PMC4507295  PMID: 26203461
Social Engagement; Conversational Interaction; Internet; Communication Technology; Oregon Center for Aging and Technology (ORCATECH); Randomized controlled clinical trial (RCT); prevention study; Mild Cognitive Impairment (MCI)
2.  Memory Complaints in Older Adults: Prognostic Value and Stability in Reporting over Time 
SAGE open medicine  2015;3:10.1177/2050312115574796.
The purpose of this longitudinal study was to examine the prognostic value of subjective memory complaints in 156 cognitively intact community-dwelling older adults with a mean age of 83 years.
Participants were assessed for subjective memory complaints, cognitive performance, functional status, and mood at annual evaluations with a mean follow-up of 4.5 years.
Subjective memory complaint at entry (n=24) was not associated with impaired memory performance and did not predict memory decline or progression to incipient dementia. Memory complaints were inconsistent across examinations for 62% of participants who reported memory problems.
Memory complaints by older adults are inconsistent over time. Memory complaint’s value as a research criterion for selecting people at risk for dementia is weak among community dwelling older adults. Age, length of follow-up, and other population characteristics may affect the implication of self-reported memory problems.
PMCID: PMC4459758  PMID: 26064522
subjective memory complaints; memory complaint; mild cognitive impairment; Alzheimer’s disease; preclinical dementia; cognitive aging; dementia
3.  A simple method to rule out dementia with temporal orientation 
To explore the performance of a test of temporal orientation (TTO) comprising four items derived from the Mini-Mental State Examination over 4 years.
Responses were obtained from two large cohorts participating in longitudinal studies of aging in the United States (352 normal elderly, 98 persons with very mild probable or possible Alzheimer’s disease). Sensitivity, specificity, and predictive value (positive, PV+, negative, PV−) of the TTO were estimated for each of four annual visits.
When four correct answers were treated as “oriented to time” and 0 to 3 correct answers were treated as “not oriented to time,” sensitivity (to the presence of AD) ranged from 46.0% to 69.2% and PV+ ranged from 32.1% to 49.5%. Specificity (for normal cognition) decreased from 93.2% at the first visit to 81.3% at the fourth visit; TTO performed most reliably in terms of PV−, the probability of normal cognitive function given orientation to time (TTO = 4), which ranged from 92.8% to 95.4%.
Given the stability and strength of the predictive negative value of a dichotomized TTO over time, a TTO could contribute to monitoring normal cognitive functioning in longitudinal studies in which cognitive status is not the primary focus. Prospective validation of the TTO is warranted.
PMCID: PMC4420176  PMID: 19595914
Aged; Orientation; Dementia; Longitudinal; Epidemiologic methods
4.  A Multicenter, Placebo-controlled Trial of Melatonin for Sleep Disturbance in Alzheimer’s Disease 
Sleep  2003;26(7):893-901.
To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer’s disease.
A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer’s Disease Cooperative Study. Subjects with Alzheimer’s disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.
Private homes and long-term care facilities.
157 individuals were recruited by 36 Alzheimer’s disease research centers. Subjects with a diagnosis of Alzheimer’s disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.
Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.
No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.
Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer’s disease.
PMCID: PMC4418658  PMID: 14655926
5.  A Systematic Review of Clinician and Staff Views on the Acceptability of Incorporating Remote Monitoring Technology into Primary Care 
Telemedicine Journal and e-Health  2014;20(5):428-438.
Objective: Remote monitoring technology (RMT) may enhance healthcare quality and reduce costs. RMT adoption depends on perceptions of the end-user (e.g., patients, caregivers, healthcare providers). We conducted a systematic review exploring the acceptability and feasibility of RMT use in routine adult patient care, from the perspectives of primary care clinicians, administrators, and clinic staff. Materials and Methods: We searched the databases of Medline, IEEE Xplore, and Compendex for original articles published from January 1996 through February 2013. We manually screened bibliographies of pertinent studies and consulted experts to identify English-language studies meeting our inclusion criteria. Results: Of 939 citations identified, 15 studies reported in 16 publications met inclusion criteria. Studies were heterogeneous by country, type of RMT used, patient and provider characteristics, and method of implementation and evaluation. Clinicians, staff, and administrators generally held positive views about RMTs. Concerns emerged regarding clinical relevance of RMT data, changing clinical roles and patterns of care (e.g., reduced quality of care from fewer patient visits, overtreatment), insufficient staffing or time to monitor and discuss RMT data, data incompatibility with a clinic's electronic health record (EHR), and unclear legal liability regarding response protocols. Conclusions: This small body of heterogeneous literature suggests that for RMTs to be adopted in primary care, researchers and developers must ensure clinical relevance, support adequate infrastructure, streamline data transmission into EHR systems, attend to changing care patterns and professional roles, and clarify response protocols. There is a critical need to engage end-users in the development and implementation of RMT.
PMCID: PMC4011427  PMID: 24731239
home health monitoring; e-health; telehealth
6.  Social activity decreases risk of placement in a long-term care facility for a prospective sample of community-dwelling older adults 
The purpose of this study was to determine the role of modifiable factors in the risk of long-term care placement. Using data from a cohort of community-residing older adults (n = 189), we conducted a secondary analysis of the contribution of social activity, sleep disturbances, and depressive symptoms to the risk of placement. Analyses controlled for cognitive and functional impairment, age, and medical conditions. Within 5 years, 20% of participants were placed in a long-term care facility. Each unit increase in social activity was associated with a 24% decrease in the risk of placement (odds ratio [OR] = 0.763, p = 0.001, 95% confidence interval [CI] [0.65, 0.89]). Cognitive impairment (OR = 3.05, p =.017, 95% CI [1.23, 7.59]), medical conditions (OR = 1.22, p=.039, 95% CI [1.01, 1.47]), and age (OR = 1.101, p =.030, 95% CI [1.01, 1.20]) were also significant individual predictors of placement. Although many of the strongest risk factors for placement are not modifiable, older adults who engage in more social activity outside the home may be able to delay transition from independent living.
PMCID: PMC4040300  PMID: 24444452
social activity; nursing home placement; long-term care
7.  Sleep Habits in Mild Cognitive Impairment 
We explored the relationship between sleep disturbances and mild cognitive impairment (MCI) in community-dwelling seniors. Recent evidence suggests that sleep habits are differentially compromised in different subtypes of MCI, but the relationship between sleep disruption and MCI remains poorly understood. We gathered daily objective measures of sleep disturbance from 45 seniors, including 16 with MCI (mean age 86.9 ± 4.3 years), over a six month period. We also collected self-report measures of sleep disturbance. Although there were no differences between groups in any of our self-report measures, we found that amnestic MCI (aMCI) volunteers had less disturbed sleep than both non-amnestic MCI (naMCI) and cognitively intact volunteers, as measured objectively by movement in bed at night (F2,1078=4.30, p=0.05), wake after sleep onset (F2,1078=41.6, p<0.001), and times up at night (F2,1078=26.7, p<0.001). The groups did not differ in total sleep time. In addition, the aMCI group had less day-to-day variability in these measures than the intact and naMCI volunteers. In general, the naMCI volunteers showed a level of disturbed sleep that was intermediate to that of aMCI and intact volunteers. These differences in sleep disruption between aMCI and naMCI may be related to differences in the pathology underlying these MCI subtypes.
PMCID: PMC3990656  PMID: 24145694
MCI (Mild Cognitive Impairment); Assessment of cognitive disorders/dementia; Sleep Habits; Cohort studies
8.  Symptoms of sleep disturbance in persons with Alzheimer’s disease and normal elderly 
Journal of sleep research  2005;14(2):177-185.
We retrospectively analyzed sleep time and sleep disturbance symptoms in 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer’s disease (AD). Our primary objective was to determine differences in subjective sleep disturbance between these samples. Secondary objectives were to determine if subjects with time in bed (TIB) ≤6 h per night reported more sleep disturbance and whether sleep complaints were associated with more severe cognitive and/or functional impairment. The prevalence of ‘sleep problems’ (a single item) was significantly lower in NDE (18.3%) than AD (27.6%), and the proportions of each cohort reporting TIB ≤6 h per night were very low (NDE: 6.0%; AD: 3.5%) and not significantly different. Less TIB was correlated with better cognitive function for AD (P < 0.01), and cognition and function were significantly worse for AD subjects with estimates of >6 h of TIB compared with those with estimates of ≤6 h (P < 0.05). Greater sleep disturbance was correlated with greater functional impairment in both cohorts; but only in AD did greater estimated TIB also correlate with greater functional impairment (all P < 0.05). In general, estimated TIB was not associated with mood in either cohort; however, in both cohorts depression was significantly associated with sleep disturbance symptoms and was significantly worse in those who reported having ‘sleep problems’. There was no association between subjective perception of ‘sleep problems’, the number and frequency of sleep disturbance symptoms, and estimated TIB in either group.
PMCID: PMC4371732  PMID: 15910515
alzheimer’s disease; healthy elderly; measurement; sleep; sleep disturbance
9.  Characterizing sleep problems in persons with Alzheimer’s disease and normal elderly 
Journal of sleep research  2006;15(1):97-103.
We retrospectively analyzed sleep disturbance symptoms and estimated time in bed from the intake interviews of 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer’s disease (AD). Our primary objective was to identify what symptoms might underlie an individual’s perception of ‘sleep problems’ and to determine if these were consistent within, and across, our two cohorts. We stratified each cohort according to whether or not they (or their caregiver) indicated that they had a ‘sleep problem’, and compared the frequency and endorsement rates of each of 21 sleep disturbance symptoms across those who did or did not endorse ‘sleep problem’. For less than half of the symptoms in persons with AD, and a quarter of those in NDE, endorsement rates were significantly different depending on whether the reporter (or their sleep partner) did or did not report a sleep problem. Differences in mean frequency ratings between individuals reporting sleep problems relative to those not reporting were observed on 10 symptoms in both cohorts; six of these were the same symptom for both cohorts. When persons with subjective sleep problems in the AD and NDE cohorts were compared, only four of 21 symptoms were endorsed in one and not the other; two symptoms were significantly more frequent in one cohort than the other. Thus, within cohorts, the differences between persons with and without ‘sleep problems’ were relatively pronounced while the main differences in specific sleep-related symptoms between AD and NDE were not. Observed between-cohort differences appear to be driven by who is reporting, and the high prevalence of daytime sleeping in AD. Within-cohort differences reflect a clear distinction between persons with and without sleep problems, regardless of the reporter.
PMCID: PMC4372193  PMID: 16490008
Alzheimer’s disease; healthy elderly; sleep disturbance; measurement
10.  Aging and cytomegalovirus (CMV) infection differentially and jointly affect distinct circulating T cell subsets in humans1 
The impact of intrinsic aging upon human peripheral blood T-cell subsets remains incompletely quantified and understood. This impact must be distinguished from the influence of latent persistent microorganisms, particularly cytomegalovirus (CMV), which has been associated with age-related changes in the T cell pool. In a cross-sectional cohort of 152 CMV-negative individuals, aged 21–101 years, we found that aging correlated strictly to an absolute loss of naïve CD8, but not CD4, T cells, but, contrary to many reports, did not lead to an increase in memory T cell numbers. The loss of naïve CD8 T cells was not altered by CMV in 239 subjects (range 21–96 years) but the decline in CD4+ naïve cells showed significance in CMV+ individuals. These individuals also exhibited an absolute increase in the effector/effector memory CD4+ and CD8+ cells with age. That increase was seen mainly, if not exclusively, in older subjects with elevated anti-CMV Ab titers, suggesting that efficacy of viral control over time may determine the magnitude of CMV impact upon T cell memory, and perhaps upon immune defense. These findings provide important new insights into the age-related changes in the peripheral blood pool of older adults, demonstrating that aging and CMV exert both distinct and joint influence upon blood T cell homeostasis in humans.
PMCID: PMC3989163  PMID: 24501199
Aging; T cell; homeostasis; CMV
11.  Measuring In-Home Walking Speed using Wall-Mounted RF Transceiver Arrays 
In this paper we present a new method for passively measuring walking speed using a small array of radio transceivers positioned on the walls of a hallway within a home. As a person walks between a radio transmitter and a receiver, the received signal strength (RSS) detected by the receiver changes in a repeatable pattern that may be used to estimate walking speed without the need for the person to wear any monitoring device. The transceivers are arranged as an array of 4 with a known distance between the array elements. Walking past the first pair of transceivers will cause a peak followed by a second peak when the person passes the second pair of transceivers. The time difference between these peaks is used to estimate walking speed directly. We further show that it is possible to estimate the walking speed by correlating the shape of the signal using a single pair of transceivers positioned across from each other in a hallway or doorframe. RMSE performance was less than 15 cm/s using a 2-element array, and less than 8 cm/s using a 4-element array relative to a gait mat used for ground truth.
PMCID: PMC4288466  PMID: 25570108
12.  Inferring Social Nature of Conversations from Words: Experiments on a Corpus of Everyday Telephone Conversations 
Computer speech & language  2013;28(1):10.1016/j.csl.2013.06.003.
Language is being increasingly harnessed to not only create natural human-machine interfaces but also to infer social behaviors and interactions. In the same vein, we investigate a novel spoken language task, of inferring social relationships in two-party conversations: whether the two parties are related as family, strangers or are involved in business transactions. For our study, we created a corpus of all incoming and outgoing calls from a few homes over the span of a year. On this unique naturalistic corpus of everyday telephone conversations, which is unlike Switchboard or any other public domain corpora, we demonstrate that standard natural language processing techniques can achieve accuracies of about 88%, 82%, 74% and 80% in differentiating business from personal calls, family from non-family calls, familiar from unfamiliar calls and family from other personal calls respectively. Through a series of experiments with our classifiers, we characterize the properties of telephone conversations and find: (a) that 30 words of openings (beginnings) are sufficient to predict business from personal calls, which could potentially be exploited in designing context sensitive interfaces in smart phones; (b) our corpus-based analysis does not support Schegloff and Sack’s manual analysis of exemplars in which they conclude that pre-closings differ significantly between business and personal calls – closing fared no better than a random segment; and (c) the distribution of different types of calls are stable over durations as short as 1–2 months. In summary, our results show that social relationships can be inferred automatically in two-party conversations with sufficient accuracy to support practical applications.
PMCID: PMC3810970  PMID: 24187435
conversation telephone speech; social networks; social relationships
13.  Unobtrusive measurement of daily computer use to detect mild cognitive impairment 
Mild disturbances of higher order activities of daily living are present in people diagnosed with mild cognitive impairment (MCI). These deficits may be difficult to detect among those still living independently. Unobtrusive continuous assessment of a complex activity such as home computer use may detect mild functional changes and identify MCI. We sought to determine whether long-term changes in remotely monitored computer use differ in persons with MCI in comparison to cognitively intact volunteers.
Participants enrolled in a longitudinal cohort study of unobtrusive in-home technologies to detect cognitive and motor decline in independently living seniors were assessed for computer usage (number of days with use, mean daily usage and coefficient of variation of use) measured by remotely monitoring computer session start and end times.
Over 230,000 computer sessions from 113 computer users (mean age, 85; 38 with MCI) were acquired during a mean of 36 months. In mixed effects models there was no difference in computer usage at baseline between MCI and intact participants controlling for age, sex, education, race and computer experience. However, over time, between MCI and intact participants, there was a significant decrease in number of days with use (p=0.01), mean daily usage (~1% greater decrease/month; p=0.009) and an increase in day-to-day use variability (p=0.002).
Computer use change can be unobtrusively monitored and indicate individuals with MCI. With 79% of those 55–64 years old now online, this may be an ecologically valid and efficient approach to track subtle clinically meaningful change with aging.
PMCID: PMC3872486  PMID: 23688576
Mild Cognitive Impairment; Assessment of cognitive disorders/dementia; Cohort studies; Activities of daily living; Computer use
14.  Pervasive Computing Technologies to Continuously Assess Alzheimer’s Disease Progression and Intervention Efficacy 
Traditionally, assessment of functional and cognitive status of individuals with dementia occurs in brief clinic visits during which time clinicians extract a snapshot of recent changes in individuals’ health. Conventionally, this is done using various clinical assessment tools applied at the point of care and relies on patients’ and caregivers’ ability to accurately recall daily activity and trends in personal health. These practices suffer from the infrequency and generally short durations of visits. Since 2004, researchers at the Oregon Center for Aging and Technology (ORCATECH) at the Oregon Health and Science University have been working on developing technologies to transform this model. ORCATECH researchers have developed a system of continuous in-home monitoring using pervasive computing technologies that make it possible to more accurately track activities and behaviors and measure relevant intra-individual changes. We have installed a system of strategically placed sensors in over 480 homes and have been collecting data for up to 8 years. Using this continuous in-home monitoring system, ORCATECH researchers have collected data on multiple behaviors such as gait and mobility, sleep and activity patterns, medication adherence, and computer use. Patterns of intra-individual variation detected in each of these areas are used to predict outcomes such as low mood, loneliness, and cognitive function. These methods have the potential to improve the quality of patient health data and in turn patient care especially related to cognitive decline. Furthermore, the continuous real-world nature of the data may improve the efficiency and ecological validity of clinical intervention studies.
PMCID: PMC4462097  PMID: 26113819
in-home monitoring; technologies; smart home; sleep; gait; dementia; medication adherence; aging in place
15.  MobileRF: A Robust Device-Free Tracking System Based On a Hybrid Neural Network HMM Classifier 
We present a device-free indoor tracking system that uses received signal strength (RSS) from radio frequency (RF) transceivers to estimate the location of a person. While many RSS-based tracking systems use a body-worn device or tag, this approach requires no such tag. The approach is based on the key principle that RF signals between wall-mounted transceivers reflect and absorb differently depending on a person’s movement within their home. A hierarchical neural network hidden Markov model (NN-HMM) classifier estimates both movement patterns and stand vs. walk conditions to perform tracking accurately. The algorithm and features used are specifically robust to changes in RSS mean shifts in the environment over time allowing for greater than 90% region level classification accuracy over an extended testing period. In addition to tracking, the system also estimates the number of people in different regions. It is currently being developed to support independent living and long-term monitoring of seniors.
PMCID: PMC4275659  PMID: 25544964
Indoor localization; indoor tracking; device-free passive localization; tag-free tracking; machine learning; neural network; health care; mobility
16.  Characteristics associated with willingness to participate in a randomized controlled behavioral clinical trial using home-based personal computers and a webcam 
Trials  2014;15:508.
Trials aimed at preventing cognitive decline through cognitive stimulation among those with normal cognition or mild cognitive impairment are of significant importance in delaying the onset of dementia and reducing dementia prevalence. One challenge in these prevention trials is sample recruitment bias. Those willing to volunteer for these trials could be socially active, in relatively good health, and have high educational levels and cognitive function. These participants’ characteristics could reduce the generalizability of study results and, more importantly, mask trial effects. We developed a randomized controlled trial to examine whether conversation-based cognitive stimulation delivered through personal computers, a webcam and the internet would have a positive effect on cognitive function among older adults with normal cognition or mild cognitive impairment. To examine the selectivity of samples, we conducted a mass mail-in survey distribution among community-dwelling older adults, assessing factors associated with a willingness to participate in the trial.
Two thousand mail-in surveys were distributed to retirement communities in order to collect data on demographics, the nature and frequency of social activities, personal computer use and additional health-related variables, and interest in the prevention study. We also asked for their contact information if they were interested in being contacted as potential participants in the trial.
Of 1,102 surveys returned (55.1% response rate), 983 surveys had complete data for all the variables of interest. Among them, 309 showed interest in the study and provided their contact information (operationally defined as the committed with interest group), 74 provided contact information without interest in the study (committed without interest group), 66 showed interest, but provided no contact information (interest only group), and 534 showed no interest and provided no contact information (no interest group). Compared with the no interest group, the committed with interest group were more likely to be personal computer users (odds ratio (OR) = 2.78), physically active (OR = 1.03) and had higher levels of loneliness (OR = 1.16).
Increasing potential participants’ familiarity with a personal computer and the internet before trial recruitment could increase participation rates and improve the generalizability of future studies of this type.
Trial registration
The trial was registered on 29 March 2012 at (ID number NCT01571427).
PMCID: PMC4307639  PMID: 25539637
Sample recruitment selection bias; Volunteer bias; Behavioral randomized controlled trial; PC; Internet; Webcam; Conversation-based social interaction; Cognitive function; Mild cognitive impairment
17.  Longitudinal relaxographic imaging of white matter hyperintensities in the elderly 
Incidental white matter hyperintensities (WMHs) are common findings on T2-weighted magnetic resonance images of the aged brain and have been associated with cognitive decline. While a variety of pathogenic mechanisms have been proposed, the origin of WMHs and the extent to which lesions in the deep and periventricular white matter reflect distinct etiologies remains unclear. Our aim was to quantify the fractional blood volume (vb) of small WMHs in vivo using a novel magnetic resonance imaging (MRI) approach and examine the contribution of blood–brain barrier disturbances to WMH formation in the deep and periventricular white matter.
Twenty-three elderly volunteers (aged 59–82 years) underwent 7 Tesla relaxographic imaging and fluid-attenuated inversion recovery (FLAIR) MRI. Maps of longitudinal relaxation rate constant (R1) were prepared before contrast reagent (CR) injection and throughout CR washout. Voxelwise estimates of vb were determined by fitting temporal changes in R1 values to a two-site model that incorporates the effects of transendothelial water exchange. Average vb values in deep and periventricular WMHs were determined after semi-automated segmentation of FLAIR images. Ventricular permeability was estimated from the change in CSF R1 values during CR washout.
In the absence of CR, the total water fraction in both deep and periventricular WMHs was increased compared to normal appearing white matter (NAWM). The vb of deep WMHs was 1.8 ± 0.6 mL/100 g and was significantly reduced compared to NAWM (2.4 ± 0.8 mL/100 g). In contrast, the vb of periventricular WMHs was unchanged compared to NAWM, decreased with ventricular volume and showed a positive association with ventricular permeability.
Hyperintensities in the deep WM appear to be driven by vascular compromise, while those in the periventricular WM are most likely the result of a compromised ependyma in which the small vessels remain relatively intact. These findings support varying contributions of blood–brain barrier and brain-CSF interface disturbances in the pathophysiology of deep and periventricular WMHs in the aged human brain.
PMCID: PMC4209516  PMID: 25379172
Aging; Blood–brain barrier; Blood volume; Relaxographic imaging; Periventricular; White matter hyperintensity; 7T
18.  Developing Dementia Prevention Trials: Baseline Report of the Home-Based Assessment Study 
This report describes the baseline experience of the multi-center, Home Based Assessment (HBA) study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Non-demented individuals ≥ 75 years old were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: 1) mail-in questionnaire/live telephone interviews (MIP); 2) automated telephone with interactive voice recognition (IVR); and 3) internet-based computer Kiosk (KIO). Brief versions of cognitive and non-cognitive outcomes, were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. “Efficiency” measures assessed the time from screening to baseline, and staff time required for each methodology. 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms and 581 completed baseline. Drop out, time from screening to baseline and total staff time were highest among those assigned to KIO. However efficiency measures were driven by non-recurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among HBA instruments collected via different technologies will be compared to established outcomes over this 4 year study.
PMCID: PMC3943465  PMID: 23151596
Alzheimer’s disease; clinical trials; in-home assessment; prevention studies
19.  Neuropathologic basis of white matter hyperintensity accumulation with advanced age 
Neurology  2013;81(11):977-983.
To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation.
Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1.
Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003).
Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.
PMCID: PMC3888199  PMID: 23935177
20.  Assessment of cognition in mild cognitive impairment: A comparative study 
The demand for rapidly administered, sensitive, and reliable cognitive assessments that are specifically designed for identifying individuals in the earliest stages of cognitive decline (and to measure subtle change over time) has escalated as the emphasis in Alzheimer’s disease clinical research has shifted from clinical diagnosis and treatment toward the goal of developing presymptomatic neuroprotective therapies. To meet these changing clinical requirements, cognitive measures or tailored batteries of tests must be validated and determined to be fit-for-use for the discrimination between cognitively healthy individuals and persons who are experiencing very subtle cognitive changes that likely signal the emergence of early mild cognitive impairment. We sought to collect and review data systematically from a wide variety of (mostly computer-administered) cognitive measures, all of which are currently marketed or distributed with the claims that these instruments are sensitive and reliable for the early identification of disease or, if untested for this purpose, are promising tools based on other variables. The survey responses for 16 measures/batteries are presented in brief in this review; full survey responses and summary tables are archived and publicly available on the Campaign to Prevent Alzheimer’s Disease by 2020 Web site ( A decision tree diagram highlighting critical decision points for selecting measures to meet varying clinical trials requirements has also been provided. Ultimately, the survey questionnaire, framework, and decision guidelines provided in this review should remain as useful aids for the evaluation of any new or updated sets of instruments in the years to come.
PMCID: PMC4042858  PMID: 21575877
Cognition; Neuropsychological assessment; Alzheimer’s disease; Mild cognitive impairment; Clinical trials
21.  Associations Between Observed In-Home Behaviors and Self-Reported Low Mood in Community-Dwelling Older Adults 
Using novel monitoring technologies, we sought to ascertain the association between self-report of low mood and unobtrusively measured behaviors (walking speed, time out of residence, frequency of room transitions, and computer use) in community-dwelling older adults.
Longitudinal cohort study of older adults whose homes were outfitted with activity sensors. The participants completed internet-based weekly health questionnaires with questions about mood.
Apartments and homes of older adults living in the Portland, Oregon metropolitan area.
157 adults, average age 84, followed for an average of 3.7 years.
Mood was assessed by self-report each week. Walking speed, time spent out of residence, and room transitions were estimated using data from sensors; computer use was measured by timing actual use. We ascertained the association between global or weekly low mood and the four behavior measures, adjusting for baseline characteristics.
18,960 weekly observations of mood were analyzed; 2.6% involved low mood. Individuals who reported low mood more often showed no average differences in any behavior parameters compared to those who reported low mood less often. During weeks when they reported low mood, participants spent significantly less time out of residence and on the computer, but showed no change in walking speed or room transitions.
Low mood in these community-dwelling older adults involved going out of the house less and using the computer less, but no consistent changes in movements. Technologies to monitor in-home behavior may have potential for research and clinical care.
PMCID: PMC4007277  PMID: 24635020
Psychomotor; mood; sensors; behaviors; monitoring; technologies
24.  Efficacy of cognitive rehabilitation therapies for mild cognitive impairment (MCI) in older adults: Working toward a theoretical model and evidence-based interventions 
Neuropsychology review  2013;23(1):63-80.
To evaluate the efficacy of cognitive rehabilitation therapies (CRTs) for mild cognitive impairment (MCI). Our review revealed a need for evidence-based treatments for MCI and a lack of a theoretical rehabilitation model to guide the development and evaluation of these interventions. We have thus proposed a theoretical rehabilitation model of MCI that yields key intervention targets - cognitive compromise, functional compromise, neuropsychiatric symptoms, and modifiable risk and protective factors known to be associated with MCI and dementia. Our model additionally defines specific cognitive rehabilitation approaches that may directly or indirectly target key outcomes - restorative cognitive training, compensatory cognitive training, lifestyle interventions, and psychotherapeutic techniques.
Fourteen randomized controlled trials met inclusion criteria and were reviewed.
Studies markedly varied in terms of intervention approaches and selected outcome measures and were frequently hampered by design limitations. The bulk of the evidence suggested that CRTs can change targeted behaviors in individuals with MCI and that CRTs are associated with improvements in objective cognitive performance, but the pattern of effects on specific cognitive domains was inconsistent across studies. Other important outcomes (i.e., daily functioning, quality of life, neuropsychiatric symptom severity) were infrequently assessed across studies. Few studies evaluated long-term outcomes or the impact of CRTs on conversion rates from MCI to dementia or normal cognition.
Overall, results from trials are promising but inconclusive. Additional well-designed and adequately powered trials are warranted and required before CRTs for MCI can be considered evidence based.
PMCID: PMC3640648  PMID: 23471631
mild cognitive impairment; cognitive rehabilitation therapy; cognitive training; systematic review; neuropsychological; dementia
25.  Regularity and Predictability of Human Mobility in Personal Space 
PLoS ONE  2014;9(2):e90256.
Fundamental laws governing human mobility have many important applications such as forecasting and controlling epidemics or optimizing transportation systems. These mobility patterns, studied in the context of out of home activity during travel or social interactions with observations recorded from cell phone use or diffusion of money, suggest that in extra-personal space humans follow a high degree of temporal and spatial regularity – most often in the form of time-independent universal scaling laws. Here we show that mobility patterns of older individuals in their home also show a high degree of predictability and regularity, although in a different way than has been reported for out-of-home mobility. Studying a data set of almost 15 million observations from 19 adults spanning up to 5 years of unobtrusive longitudinal home activity monitoring, we find that in-home mobility is not well represented by a universal scaling law, but that significant structure (predictability and regularity) is uncovered when explicitly accounting for contextual data in a model of in-home mobility. These results suggest that human mobility in personal space is highly stereotyped, and that monitoring discontinuities in routine room-level mobility patterns may provide an opportunity to predict individual human health and functional status or detect adverse events and trends.
PMCID: PMC3937357  PMID: 24587302

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