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1.  Comparison of cerebral blood flow and structural penumbras in relation to white matter hyperintensities: A multi-modal magnetic resonance imaging study 
Normal-appearing white matter (NAWM) surrounding WMHs is associated with decreased structural integrity and perfusion, increased risk of WMH growth, and is referred to as the WMH penumbra. Studies comparing structural and cerebral blood flow (CBF) penumbras within the same individuals are lacking, however, and would facilitate our understanding of mechanisms resulting in WM damage. This study aimed to compare both CBF and structural WMH penumbras in non-demented aging. Eighty-two elderly volunteers underwent 3T-MRI including fluid attenuated inversion recovery (FLAIR), pulsed arterial spin labeling and diffusion tensor imaging (DTI). A NAWM layer mask was generated for periventricular and deep WMHs. Mean CBF, DTI-fractional anisotropy (DTI-FA), DTI-mean diffusivity (DTI-MD) and FLAIR intensity for WMHs and its corresponding NAWM layer masks were computed and compared against its mean within total brain NAWM using mixed effects models. For both periventricular and deep WMHs, DTI-FA, DTI-MD and FLAIR intensity changes extended 2-9 mm surrounding WMHs (p ≤ 0.05), while CBF changes extended 13-14 mm (p ≤ 0.05). The CBF penumbra is more extensive than structural penumbras in relation to WMHs and includes WM tissue both with and without microstructural changes. Findings implicate CBF as a potential target for the prevention of both micro and macro structural WM damage.
doi:10.1177/0271678X16651268
PMCID: PMC5010096  PMID: 27270266
Arterial spin labeling; cerebral blood flow; diffusion tensor imaging; vascular cognitive impairment; magnetic resonance imaging; aging
2.  Computer mouse movement patterns: A potential marker of mild cognitive impairment 
Introduction
Subtle changes in cognitively demanding activities occur in MCI but are difficult to assess with conventional methods. In an exploratory study, we examined whether patterns of computer mouse movements obtained from routine home computer use discriminated between older adults with and without MCI.
Methods
Participants were 42 cognitively intact and 20 older adults with MCI enrolled in a longitudinal study of in-home monitoring technologies. Mouse pointer movement variables were computed during one week of routine home computer use using algorithms that identified and characterized mouse movements within each computer use session.
Results
MCI was associated with making significantly fewer total mouse moves (p<.01), and making mouse movements that were more variable, less efficient, and with longer pauses between movements (p<.05). Mouse movement measures were significantly associated with several cognitive domains (p’s<.01–.05).
Discussion
Remotely monitored computer mouse movement patterns are a potential early marker of real-world cognitive changes in MCI.
doi:10.1016/j.dadm.2015.09.006
PMCID: PMC4748737  PMID: 26878035
everyday functioning; cognitive assessment; technology; ecological validity; instrumental activities of daily living (IADLs); aging; computer use; early detection of cognitive decline; mild cognitive impairment; functional assessment; remote monitoring
3.  Clustering Home Activity Distributions for Automatic Detection of Mild Cognitive Impairment in Older Adults1 
The public health implications of growing numbers of older adults at risk for dementia places pressure on identifying dementia at its earliest stages so as to develop proactive management plans. The prodromal dementia phase commonly identified as mild cognitive impairment is an important target for this early detection of impending dementia amenable to treatment. In this paper, we propose a method for home-based automatic detection of mild cognitive impairment in older adults through continuous monitoring via unobtrusive sensing technologies. Our method is composed of two main stages: a training stage and a test stage. For training, room activity distributions are estimated for each subject using a time frame of ω weeks, and then affinity propagation is employed to cluster the activity distributions and to extract exemplars to represent the different emerging clusters. For testing, room activity distributions belonging to a test subject with unknown cognitive status are compared to the extracted exemplars and get assigned the labels of the exemplars that result in the smallest normalized Kullbak–Leibler divergence. The labels of the activity distributions are then used to determine the cognitive status of the test subject. Using the sensor and clinical data pertaining to 85 homes with single occupants, we were able to automatically detect mild cognitive impairment in older adults with an F0.5 score of 0.856. Also, we were able to detect the non-amnestic sub-type of mild cognitive impairment in older adults with an F0.5 score of 0.958.
doi:10.3233/AIS-160385
PMCID: PMC5016038  PMID: 27617044
Mild Cognitive Impairment; Generalized Linear Models; Room Activity Distributions; Unobtrusive Sensing Technologies; Clustering
4.  Comparison of cerebral blood flow and structural penumbras in relation to white matter hyperintensities: A multi-modal magnetic resonance imaging study 
Normal-appearing white matter (NAWM) surrounding WMHs is associated with decreased structural integrity and perfusion, increased risk of WMH growth, and is referred to as the WMH penumbra. Studies comparing structural and cerebral blood flow (CBF) penumbras within the same individuals are lacking, however, and would facilitate our understanding of mechanisms resulting in WM damage. This study aimed to compare both CBF and structural WMH penumbras in non-demented aging. Eighty-two elderly volunteers underwent 3T-MRI including fluid attenuated inversion recovery (FLAIR), pulsed arterial spin labeling and diffusion tensor imaging (DTI). A NAWM layer mask was generated for periventricular and deep WMHs. Mean CBF, DTI-fractional anisotropy (DTI-FA), DTI-mean diffusivity (DTI-MD) and FLAIR intensity for WMHs and its corresponding NAWM layer masks were computed and compared against its mean within total brain NAWM using mixed effects models. For both periventricular and deep WMHs, DTI-FA, DTI-MD and FLAIR intensity changes extended 2-9 mm surrounding WMHs (p ≤ 0.05), while CBF changes extended 13-14 mm (p ≤ 0.05). The CBF penumbra is more extensive than structural penumbras in relation to WMHs and includes WM tissue both with and without microstructural changes. Findings implicate CBF as a potential target for the prevention of both micro and macro structural WM damage.
doi:10.1177/0271678X16651268
PMCID: PMC5010096  PMID: 27270266
Arterial spin labeling; cerebral blood flow; diffusion tensor imaging; vascular cognitive impairment; magnetic resonance imaging; aging
5.  Less daily computer use is related to smaller hippocampal volumes in cognitively intact elderly 
Background
Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown.
Objective
The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI.
Methods
Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one month period surrounding the MRI. Spearman’s rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH) and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel based morphometry analysis identified relationships between regional GM density and DCU.
Results
Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes.
Conclusions
Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer’s pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.
doi:10.3233/JAD-160079
PMCID: PMC4866889  PMID: 26967228
Alzheimer’s Disease; Cognitive aging; Assessment of cognitive disorders/dementia; MRI; volumetric MRI
6.  ICC-dementia (International Centenarian Consortium - dementia): an international consortium to determine the prevalence and incidence of dementia in centenarians across diverse ethnoracial and sociocultural groups 
BMC Neurology  2016;16:52.
Background
Considerable variability exists in international prevalence and incidence estimates of dementia. The accuracy of estimates of dementia in the oldest-old and the controversial question of whether dementia incidence and prevalence decline at very old age will be crucial for better understanding the dynamics between survival to extreme old age and the occurrence and risk for various types of dementia and comorbidities. International Centenarian Consortium – Dementia (ICC-Dementia) seeks to harmonise centenarian and near-centenarian studies internationally to describe the cognitive and functional profiles of exceptionally old individuals, and ascertain the trajectories of decline and thereby the age-standardised prevalence and incidence of dementia in this population. The primary goal of the ICC-Dementia is to establish a large and thorough heterogeneous sample that has the power to answer epidemiological questions that small, separate studies cannot. A secondary aim is to examine cohort-specific effects and differential survivorship into very old age. We hope to lay the foundation for further investigation into risk and protective factors for dementia and healthy exceptional brain ageing in centenarians across diverse ethnoracial and sociocultural groups.
Methods
Studies focusing on individuals aged ≥95 years (approximately the oldest 1 percentile for men, oldest 5th percentile for women), with a minimum sample of 80 individuals, including assessment of cognition and functional status, are invited to participate. There are currently seventeen member or potential member studies from Asia, Europe, the Americas, and Oceania. Initial attempts at harmonising key variables are in progress.
Discussion
General challenges facing large, international consortia like ICC-Dementia include timely and effective communication among member studies, ethical and practical issues relating to human subject studies and data sharing, and the challenges related to data harmonisation. A specific challenge for ICC-Dementia relates to the concept and definition of’abnormal’ in this exceptional group of individuals who are rarely free of physical, sensory and/or cognitive impairments.
doi:10.1186/s12883-016-0569-4
PMCID: PMC4839126  PMID: 27098177
Centenarians; Dementia; International; Prevalence; Incidence; Risk factors
7.  The impact of sleep on neuropsychological performance in cognitively intact older adults using a novel in-home sensor based sleep assessment approach 
The Clinical neuropsychologist  2015;29(1):53-66.
The relationship between recent episodes of poor sleep and cognitive testing performance in healthy cognitively intact older adults is not well understood. In this exploratory study, we examined the impact of recent sleep disturbance, sleep duration, and sleep variability on cognitive performance in 63 cognitively intact older adults using a novel unobtrusive in-home sensor based sleep assessment methodology. Specifically, we examined the impact of sleep the night prior, the week prior, and the month prior to a neuropsychological evaluation on cognitive performance. Results showed that mildly disturbed sleep the week prior and month prior to cognitive testing was associated with reduced working memory on cognitive evaluation. One night of mild sleep disturbance was not associated with decreased cognitive performance the next day. Sleep duration was unrelated to cognition. In-home, unobtrusive sensor monitoring technologies provide a novel method for objective, long-term, and continuous assessment of sleep behavior and other everyday activities that might contribute to decreased or variable cognitive performance in healthy older adults.
doi:10.1080/13854046.2015.1005139
PMCID: PMC4348222  PMID: 25642948
Healthy Aging; Sleep; Cognition; In-home monitoring; Smart environment technology
8.  The EADC-ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity 
Background
An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance.
Methods
Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web-platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T.
Results
The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001).
Conclusions
The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
doi:10.1016/j.jalz.2014.05.1756
PMCID: PMC4422168  PMID: 25267715
Hippocampal volumetry; Magnetic resonance; Alzheimer's disease; Biomarkers; Diagnostic criteria; Enrichment; Clinical trials; Validation; Harmonized protocol; Standard operating procedures; Manual segmentation
9.  Targeted Lipidomics of Fontal Cortex and Plasma Diacylglycerols (DAG) in Mild Cognitive Impairment (MCI) and Alzheimer’s Disease: Validation of DAG Accumulation Early in the Pathophysiology of Alzheimer’s Disease 
Previous studies have demonstrated augmented levels of diacylglycerols (DAG) in the frontal cortex and plasma of Alzheimer’s disease (AD) patients. We extended these findings from non-targeted liopidomics studies to design a lipidomics platform to interrogate DAGs and monoacylglycerols (MAG) in the frontal cortex and plasma of MCI subjects. Control subjects included both aged normal controls and controls with normal cognition, but AD pathology at autopsy, individuals termed non-demented AD neuropathology (NDAN). DAGs with saturated, unsaturated, and polyunsaturated fatty acid substituents were found to be elevated in MCI frontal cortex and plasma. Tandem mass spectrometry of the DAGs did not reveal any differences in the distributions of the fatty acid substitutions between MCI and control subjects. While triacylglycerols were not altered in MCI subjects there were increases in monoacylglycerol levels both in the frontal cortex and plasma. In toto, increased levels of DAGs and MAGs appear to occur early in AD pathophysiology and require both further validation in a larger patient cohort and elucidation of the lipidomics alteration(s) that lead to the accumulation of DAGs in MCI subjects.
doi:10.3233/JAD-150336
PMCID: PMC4713833  PMID: 26402017
diacylglycerols; monoacylglycerols; Alzheimer’s disease; Mild Cognitive Impairment
10.  Social Markers of Mild Cognitive Impairment: Proportion of Word Counts in Free Conversational Speech 
Current Alzheimer research  2015;12(6):513-519.
Background
Detecting early signs of Alzheimer’s disease (AD) and mild cognitive impairment (MCI) during the pre-symptomatic phase is becoming increasingly important for cost-effective clinical trials and also for deriving maximum benefit from currently available treatment strategies. However, distinguishing early signs of MCI from normal cognitive aging is difficult. Biomarkers have been extensively examined as early indicators of the pathological process for AD, but assessing these biomarkers is expensive and challenging to apply widely among pre-symptomatic community dwelling older adults. Here we propose assessment of social markers, which could provide an alternative or complementary and ecologically valid strategy for identifying the pre-symptomatic phase leading to MCI and AD
Methods
The data came from a larger randomized controlled clinical trial (RCT), where we examined whether daily conversational interactions using remote video telecommunications software could improve cognitive functions of older adult participants. We assessed the proportion of words generated by participants out of total words produced by both participants and staff interviewers using transcribed conversations during the intervention trial as an indicator of how two people (participants and interviewers) interact with each other in one-on-one conversations. We examined whether the proportion differed between those with intact cognition and MCI, using first, generalized estimating equations with the proportion as outcome, and second, logistic regression models with cognitive status as outcome in order to estimate the area under ROC curve (ROC AUC).
Results
Compared to those with normal cognitive function, MCI participants generated a greater proportion of words out of the total number of words during the timed conversation sessions (p=0.01). This difference remained after controlling for participant age, gender, interviewer and time of assessment (p=0.03). The logistic regression models showed the ROC AUC of identifying MCI (vs. normals) was 0.71 (95% Confidence Interval: 0.54 – 0.89) when average proportion of word counts spoken by subjects was included univariately into the model.
Conclusions
An ecologically valid social marker such as the proportion of spoken words produced during spontaneous conversations may be sensitive to transitions from normal cognition to MCI.
PMCID: PMC4526336  PMID: 26027814
11.  At the interface of sensory and motor dysfunctions and Alzheimer’s Disease 
Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer’s disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled “Sensory and Motor Dysfunctions in Aging and Alzheimer’s Disease”. The scientific sessions of the workshop focused on age-related and neuropathological changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the CNS are affected by Alzheimer pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.
doi:10.1016/j.jalz.2014.04.514
PMCID: PMC4287457  PMID: 25022540
12.  Biomarker Progressions Explain Higher Variability in Stage-Specific Cognitive Decline than Baseline Values in Alzheimer Disease 
Background
It is unknown which commonly employed Alzheimer disease biomarker values-baseline or progression-best predict longitudinal cognitive decline.
Methods
526 subjects from the Alzheimer’s Disease Neuroimaging Initiative. ADNI composite memory (ADNI-Mem) and executive (ADNI-Exe) scores were the primary outcomes. Individual-specific slope of the longitudinal trajectory of each biomarker was first estimated. These estimates and observed baseline biomarker values were used as predictors of cognitive declines. Variability in cognitive declines explained by baseline biomarker values were compared with variability explained by biomarker progression values.
Results
About 40% of variability in memory and executive function declines was explained by ventricular volume progression among MCI. 84% of memory and 65% of executive function declines were explained by FDG-PET score progression and ventricular volume progression, respectively, among AD.
Conclusions
Biomarker progressions explained higher variability in cognitive decline than biomarker baseline values. This has important implications for clinical trials targeted to modify AD biomarkers.
doi:10.1016/j.jalz.2014.04.513
PMCID: PMC4253728  PMID: 25022534
ADNI; Cognitive declines; Biomarker; Biomarker progressions; ADNI-Mem; ADNI-Exe; MCI; FDG-PET; MRI volume
13.  Computer mouse movement patterns: A potential marker of mild cognitive impairment 
Introduction
Subtle changes in cognitively demanding activities occur in mild cognitive impairment (MCI) but are difficult to assess with conventional methods. In an exploratory study, we examined whether patterns of computer mouse movements obtained from routine home computer use discriminated between older adults with and without MCI.
Methods
Participants were 42 cognitively intact and 20 older adults with MCI enrolled in a longitudinal study of in-home monitoring technologies. Mouse pointer movement variables were computed during one week of routine home computer use using algorithms that identified and characterized mouse movements within each computer use session.
Results
MCI was associated with making significantly fewer total mouse moves (P < .01) and making mouse movements that were more variable, less efficient, and with longer pauses between movements (P < .05). Mouse movement measures were significantly associated with several cognitive domains (P values <.01–.05).
Discussion
Remotely monitored computer mouse movement patterns are a potential early marker of real-world cognitive changes in MCI.
doi:10.1016/j.dadm.2015.09.006
PMCID: PMC4748737  PMID: 26878035
Everyday functioning; Cognitive assessment; Technology; Ecological validity; Instrumental activities of daily living; Aging; Computer use; Early detection of cognitive decline; Mild cognitive impairment; Functional assessment; Remote monitoring
14.  Time Out-of-Home and Cognitive, Physical, and Emotional Wellbeing of Older Adults: A Longitudinal Mixed Effects Model 
PLoS ONE  2015;10(10):e0139643.
Background
Time out-of-home has been linked with numerous health outcomes, including cognitive decline, poor physical ability and low emotional state. Comprehensive characterization of this important health metric would potentially enable objective monitoring of key health outcomes. The objective of this study is to determine the relationship between time out-of-home and cognitive status, physical ability and emotional state.
Methods and Findings
Participants included 85 independent older adults, age 65–96 years (M = 86.36; SD = 6.79) who lived alone, from the Intelligent Systems for Assessing Aging Changes (ISAAC) and the ORCATECH Life Laboratory cohorts. Factors hypothesized to affect time out-of-home were assessed on three different temporal levels: yearly (cognitive status, loneliness, clinical walking speed), weekly (pain and mood) or daily (time out-of-home, in-home walking speed, weather, and season). Subject characteristics including age, race, and gender were assessed at baseline. Total daily time out-of-home in hours was assessed objectively and unobtrusively for up to one year using an in-home activity sensor platform. A longitudinal tobit mixed effects regression model was used to relate daily time out-of-home to cognitive status, physical ability and emotional state. More hours spend outside the home was associated with better cognitive function as assessed using the Clinical Dementia Rating (CDR) Scale, where higher scores indicate lower cognitive function (βCDR = -1.69, p<0.001). More hours outside the home was also associated with superior physical ability (βPain = -0.123, p<0.001) and improved emotional state (βLonely = -0.046, p<0.001; βLow mood = -0.520, p<0.001). Weather, season, and weekday also affected the daily time out-of-home.
Conclusions
These results suggest that objective longitudinal monitoring of time out-of-home may enable unobtrusive assessment of cognitive, physical and emotional state. In addition, these results indicate that the factors affecting out-of-home behavior are complex, with factors such as living environment, weather and season significantly affecting time out-of-home. Studies investigating the relationship between time out-of-home and health outcomes may be optimized by taking into account the environment and life factors presented here.
doi:10.1371/journal.pone.0139643
PMCID: PMC4593630  PMID: 26437228
15.  Use of High-Frequency In-Home Monitoring Data May Reduce Sample Sizes Needed in Clinical Trials 
PLoS ONE  2015;10(9):e0138095.
Background
Trials in Alzheimer’s disease are increasingly focusing on prevention in asymptomatic individuals. This poses a challenge in examining treatment effects since currently available approaches are often unable to detect cognitive and functional changes among asymptomatic individuals. Resultant small effect sizes require large sample sizes using biomarkers or secondary measures for randomized controlled trials (RCTs). Better assessment approaches and outcomes capable of capturing subtle changes during asymptomatic disease stages are needed.
Objective
We aimed to develop a new approach to track changes in functional outcomes by using individual-specific distributions (as opposed to group-norms) of unobtrusive continuously monitored in-home data. Our objective was to compare sample sizes required to achieve sufficient power to detect prevention trial effects in trajectories of outcomes in two scenarios: (1) annually assessed neuropsychological test scores (a conventional approach), and (2) the likelihood of having subject-specific low performance thresholds, both modeled as a function of time.
Methods
One hundred nineteen cognitively intact subjects were enrolled and followed over 3 years in the Intelligent Systems for Assessing Aging Change (ISAAC) study. Using the difference in empirically identified time slopes between those who remained cognitively intact during follow-up (normal control, NC) and those who transitioned to mild cognitive impairment (MCI), we estimated comparative sample sizes required to achieve up to 80% statistical power over a range of effect sizes for detecting reductions in the difference in time slopes between NC and MCI incidence before transition.
Results
Sample size estimates indicated approximately 2000 subjects with a follow-up duration of 4 years would be needed to achieve a 30% effect size when the outcome is an annually assessed memory test score. When the outcome is likelihood of low walking speed defined using the individual-specific distributions of walking speed collected at baseline, 262 subjects are required. Similarly for computer use, 26 subjects are required.
Conclusions
Individual-specific thresholds of low functional performance based on high-frequency in-home monitoring data distinguish trajectories of MCI from NC and could substantially reduce sample sizes needed in dementia prevention RCTs.
doi:10.1371/journal.pone.0138095
PMCID: PMC4574479  PMID: 26379170
16.  Unobtrusive in-home detection of time spent out-of-home with applications to loneliness and physical activity 
Loneliness is a common condition in elderly associated with severe health consequences including increased mortality, decreased cognitive function, and poor quality of life. Identifying and assisting lonely individuals is therefore increasingly important—especially in the home setting—as the very nature of loneliness often makes it difficult to detect by traditional methods. One critical component in assessing loneliness unobtrusively is to measure time spent out-of-home, as loneliness often presents with decreased physical activity, decreased motor functioning, and a decline in activities of daily living, all of which may cause decreases in the amount of time spent outside the home. Using passive and unobtrusive in-home sensing technologies, we have developed a methodology for detecting time spent out-of-home based on logistic regression. Our approach was both sensitive (0.939) and specific (0.975) in detecting time out-of-home across over 41,000 epochs of data collected from 4 subjects monitored for at least 30 days each in their own homes. In addition to linking time spent out-of-home to loneliness (r=−0.44, p=0.011) as measured by the UCLA Loneliness Index, we demonstrate its usefulness in other applications such as uncovering general behavioral patterns of elderly and exploring the link between time spent out-of-home and physical activity (r=0.415, p=0.031), as measured by the Berkman Social Disengagement Index.
doi:10.1109/JBHI.2013.2294276
PMCID: PMC4159765  PMID: 25192570
Smart homes; loneliness; outings; logistic regression; physical activity
17.  Web-enabled Conversational Interactions as a Means to Improve Cognitive Functions: Results of a 6-Week Randomized Controlled Trial 
INTRODUCTION
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.
METHODS
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.
RESULTS
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.
DISCUSSION
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.
doi:10.1016/j.trci.2015.01.001
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)
18.  Memory Complaints in Older Adults: Prognostic Value and Stability in Reporting over Time 
SAGE open medicine  2015;3:10.1177/2050312115574796.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1177/2050312115574796
PMCID: PMC4459758  PMID: 26064522
subjective memory complaints; memory complaint; mild cognitive impairment; Alzheimer’s disease; preclinical dementia; cognitive aging; dementia
19.  A simple method to rule out dementia with temporal orientation 
Objective
To explore the performance of a test of temporal orientation (TTO) comprising four items derived from the Mini-Mental State Examination over 4 years.
Methods
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.
Results
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%.
Conclusion
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.
doi:10.1016/j.jalz.2006.10.005
PMCID: PMC4420176  PMID: 19595914
Aged; Orientation; Dementia; Longitudinal; Epidemiologic methods
20.  A Multicenter, Placebo-controlled Trial of Melatonin for Sleep Disturbance in Alzheimer’s Disease 
Sleep  2003;26(7):893-901.
Objectives
To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer’s disease.
Design
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.
Setting
Private homes and long-term care facilities.
Participants
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.
Measurements
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.
Results
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.
Conclusions
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
21.  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.
Abstract
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.
doi:10.1089/tmj.2013.0166
PMCID: PMC4011427  PMID: 24731239
home health monitoring; e-health; telehealth
22.  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.
doi:10.3928/19404921-20140110-02
PMCID: PMC4040300  PMID: 24444452
social activity; nursing home placement; long-term care
23.  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.
doi:10.1097/WAD.0000000000000010
PMCID: PMC3990656  PMID: 24145694
MCI (Mild Cognitive Impairment); Assessment of cognitive disorders/dementia; Sleep Habits; Cohort studies
24.  Symptoms of sleep disturbance in persons with Alzheimer’s disease and normal elderly 
Journal of sleep research  2005;14(2):177-185.
SUMMARY
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.
doi:10.1111/j.1365-2869.2005.00445.x
PMCID: PMC4371732  PMID: 15910515
alzheimer’s disease; healthy elderly; measurement; sleep; sleep disturbance
25.  Characterizing sleep problems in persons with Alzheimer’s disease and normal elderly 
Journal of sleep research  2006;15(1):97-103.
SUMMARY
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.
doi:10.1111/j.1365-2869.2006.00499.x
PMCID: PMC4372193  PMID: 16490008
Alzheimer’s disease; healthy elderly; sleep disturbance; measurement

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