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3.  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.
Objective
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.
Methods
Fourteen randomized controlled trials met inclusion criteria and were reviewed.
Results
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.
Conclusions
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.
doi:10.1007/s11065-013-9230-9
PMCID: PMC3640648  PMID: 23471631
mild cognitive impairment; cognitive rehabilitation therapy; cognitive training; systematic review; neuropsychological; dementia
4.  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.
doi:10.1371/journal.pone.0090256
PMCID: PMC3937357  PMID: 24587302
5.  APOE ε4 Increases Risk for Dementia in Pure Synucleinopathies 
JAMA neurology  2013;70(2):223-228.
Objective
To test for an association between the apolipoprotein E (APOE) ε4 allele and dementias with synucleinopathy.
Design
Genetic case-control association study.
Setting
Academic research.
Patients
Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269).
Main Outcome Measure
The APOE allele frequencies.
Results
The APOE ε4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ42=185.25; P=5.56×10−39), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ε4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4–15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1–19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5–10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7–5.6).
Conclusions
The APOE ε4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ε4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ε4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
doi:10.1001/jamaneurol.2013.600
PMCID: PMC3580799  PMID: 23407718
6.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
doi:10.1212/WNL.0b013e31829d86e8
PMCID: PMC3776529  PMID: 23897875
7.  A Randomized Placebo-Controlled Pilot Trial of Omega-3 Fatty Acids and Alpha Lipoic Acid in Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2014;38(1):10.3233/JAD-130722.
Oxidative stress, inflammation, and increased cholesterol levels are all mechanisms that have been associated with Alzheimer’s disease (AD) pathology. Several epidemiologic studies have reported a decreased risk of AD with fish consumption. This pilot study was designed to evaluate the effects of supplementation with omega-3 fatty acids alone (ω-3) or omega-3 plus alpha lipoic acid (ω-3 +LA) compared to placebo on oxidative stress biomarkers in AD. The primary outcome measure was peripheral F2-isoprostane levels (oxidative stress measure). Secondary outcome measures included performance on: Mini-Mental State Examination (MMSE), Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL), and Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Thirty-nine AD subjects were randomized to one of three groups: 1) placebo, 2) ω-3, or 3) ω-3 + LA for a treatment duration of 12 months. Eighty seven percent (34/39) of the subjects completed the 12-month intervention. There was no difference between groups at 12 months in peripheral F2-isoprostane levels (p = 0.83). The ω-3 +LA and ω-3 were not significantly different than the placebo group in ADAS-cog (p = 0.98, p = 0.86) and in ADL (p = 0.15, p = 0.82). Compared to placebo, the ω-3+LA showed less decline in MMSE (p< 0.01) and IADL (p= 0.01) and the ω-3 group showed less decline in IADL (p < 0.01). The combination of ω-3+LA slowed cognitive and functional decline in AD over 12 months. Because the results were generated from a small sample size, further evaluation of the combination of omega-3 fatty acids plus alpha-lipoic acid as a potential treatment in AD is warranted.
doi:10.3233/JAD-130722
PMCID: PMC3886557  PMID: 24077434
Alpha-lipoic acid; Alzheimer’s disease; clinical trial; omega-3 fatty acids
8.  Hello, Who is Calling?: Can Words Reveal the Social Nature of Conversations? 
This study aims to infer the social nature of conversations from their content automatically. To place this work in context, our motivation stems from the need to understand how social disengagement affects cognitive decline or depression among older adults. For this purpose, we collected a comprehensive and naturalistic corpus comprising of all the incoming and outgoing telephone calls from 10 subjects over the duration of a year. As a first step, we learned a binary classifier to filter out business related conversation, achieving an accuracy of about 85%. This classification task provides a convenient tool to probe the nature of telephone conversations. We evaluated the utility of openings and closing in differentiating personal calls, and find that empirical results on a large corpus do not support the hypotheses by Schegloff and Sacks that personal conversations are marked by unique closing structures. For classifying different types of social relationships such as family vs other, we investigated features related to language use (entropy), hand-crafted dictionary (LIWC) and topics learned using unsupervised latent Dirichlet models (LDA). Our results show that the posteriors over topics from LDA provide consistently higher accuracy (60-81%) compared to LIWC or language use features in distinguishing different types of conversations.
PMCID: PMC3886719  PMID: 24419500
9.  SVM to Detect the Presence of Visitors in a Smart Home Environment 
With the rising age of the population, there is increased need to help elderly maintain their independence. Smart homes, employing passive sensor networks and pervasive computing techniques, enable the unobtrusive assessment of activities and behaviors of the elderly which can be useful for health state assessment and intervention. Due to the multiple health benefits associated with socializing, accurately tracking whether an individual has visitors to their home is one of the more important aspects of elders’ behaviors that could be assessed with smart home technology. With this goal, we have developed a preliminary SVM model to identify periods where untagged visitors are present in the home. Using the dwell time, number of sensor firings, and number of transitions between major living spaces (living room, dining room, kitchen and bathroom) as features in the model, and self report from two subjects as ground truth, we were able to accurately detect the presence of visitors in the home with a sensitivity and specificity of 0.90 and 0.89 for subject 1, and of 0.67 and 0.78 for subject 2, respectively. These preliminary data demonstrate the feasibility of detecting visitors with in-home sensor data, but highlight the need for more advanced modeling techniques so the model performs well for all subjects and all types of visitors.
doi:10.1109/EMBC.2012.6347324
PMCID: PMC3884948  PMID: 23367259
10.  Dementia specialists and early adoption of amyloid imaging 
Objective
To describe the attitudes of U.S. neurologists specializing in dementia toward the use of amyloid imaging in the diagnosis of Alzheimer’s Disease (AD).
Methods
A cross-sectional electronic physician survey of dementia specialists at U.S. medical schools was performed.
Results
The response rate for the survey was 51.9% (135/260). Greater than 83% of respondents plan to use amyloid imaging to evaluate patients for Alzheimer disease. Most respondents intend to use amyloid imaging as an adjunctive diagnostic modality to confirm (77%) or rule-out (73%) a diagnosis of Alzheimer dementia; 24% plan to use amyloid imaging to screen asymptomatic individuals for evidence of cerebral amyloid. Specialists who do not intend to use amyloid imaging (16%) express concern about the cost (73%), the usefulness (55%), and likelihood of patient (55%) and clinician (59%) misinterpretation of findings. The need for patient pre-test counseling was endorsed by a large percentage (92%) of dementia specialists (higher than for genetic testing (82%)).
Conclusions
Dementia specialists, particularly young specialists, are likely to be early adopters of amyloid imaging. Assuming ready availability, this new technology would be used as a confirmatory test in the evaluation of Alzheimer disease, as well as a screening tool for asymptomatic pathology. Specialists recognize the complexity of interpreting amyloid imaging findings and the need for patient counseling before undergoing testing.
doi:10.3233/JAD-2012-121216
PMCID: PMC3640311  PMID: 22976071
Alzheimer’s disease; dementia; amyloid; PET; neuroimaging; biomarker; diagnosis
11.  Reactions to a Remote-Controlled Video-Communication Robot in Seniors' Homes: A Pilot Study of Feasibility and Acceptance 
Telemedicine Journal and e-Health  2012;18(10):755-759.
Abstract
Objective: Remote telepresence provided by tele-operated robotics represents a new means for obtaining important health information, improving older adults' social and daily functioning and providing peace of mind to family members and caregivers who live remotely. In this study we tested the feasibility of use and acceptance of a remotely controlled robot with video-communication capability in independently living, cognitively intact older adults. Materials and Methods: A mobile remotely controlled robot with video-communication ability was placed in the homes of eight seniors. The attitudes and preferences of these volunteers and those of family or friends who communicated with them remotely via the device were assessed through survey instruments. Results: Overall experiences were consistently positive, with the exception of one user who subsequently progressed to a diagnosis of mild cognitive impairment. Responses from our participants indicated that in general they appreciated the potential of this technology to enhance their physical health and well-being, social connectedness, and ability to live independently at home. Remote users, who were friends or adult children of the participants, were more likely to test the mobility features and had several suggestions for additional useful applications. Conclusions: Results from the present study showed that a small sample of independently living, cognitively intact older adults and their remote collaterals responded positively to a remote controlled robot with video-communication capabilities. Research is needed to further explore the feasibility and acceptance of this type of technology with a variety of patients and their care contacts.
doi:10.1089/tmj.2012.0026
PMCID: PMC3523242  PMID: 23082794
robotics; tele-operated; aging; technology; video-communication
12.  GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology 
Neurology  2012;79(19):1944-1950.
Objectives:
Mutations in the GBA gene occur in 7% of patients with Parkinson disease (PD) and are a well-established susceptibility factor for PD, which is characterized by Lewy body disease (LBD) neuropathologic changes (LBDNCs). We sought to determine whether GBA influences risk of dementia with LBDNCs, Alzheimer disease (AD) neuropathologic changes (ADNCs), or both.
Methods:
We screened the entire GBA coding region for mutations in controls and in subjects with dementia and LBDNCs and no or low levels of ADNCs (pure dementia with Lewy bodies [pDLB]), LBDNCs and high-level ADNCs (LBD-AD), and high-level ADNCs but without LBDNCs (AD).
Results:
Among white subjects, pathogenic GBA mutations were identified in 6 of 79 pDLB cases (7.6%), 8 of 222 LBD-AD cases (3.6%), 2 of 243 AD cases (0.8%), and 3 of 381 controls (0.8%). Subjects with pDLB and LBD-AD were more likely to carry mutations than controls (pDLB: odds ratio [OR] = 7.6; 95% confidence interval [CI] = 1.8–31.9; p = 0.006; LBD-AD: OR = 4.6; CI = 1.2–17.6; p = 0.025), but there was no significant difference in frequencies between the AD and control groups (OR = 1.1; CI = 0.2–6.6; p = 0.92). There was a highly significant trend test across groups (χ2(1) = 19.3; p = 1.1 × 10−5), with the likelihood of carrying a GBA mutation increasing in the following direction: control/AD < LBD-AD < pDLB.
Conclusions:
GBA is a susceptibility gene across the LBD spectrum, but not in AD, and appears to convey a higher risk for PD and pDLB than for LBD-AD. PD and pDLB might be more similar to one another in genetic determinants and pathophysiology than either disease is to LBD-AD.
doi:10.1212/WNL.0b013e3182735e9a
PMCID: PMC3484986  PMID: 23035075
13.  Review of selected databases of longitudinal aging studies 
One of the recommendations of the 2010 Leon Thal Symposium, organized to develop strategies to prevent Alzheimer’s disease, was to build a global database of longitudinal aging studies. While several databases of longitudinal aging studies exist, none of these are comprehensive or complete. In this paper we review selected databases of longitudinal aging studies. We make recommendations on future steps to create a comprehensive database. Additionally, we discuss issues related to data harmonization.
doi:10.1016/j.jalz.2011.09.232
PMCID: PMC3483563  PMID: 23102128
14.  Computer related self-efficacy and anxiety in older adults with and without mild cognitive impairment 
Background
This study examines differences in computer related self-efficacy and anxiety in subgroups of older adults, and changes in those measures following exposure to a systematic training program and subsequent computer use.
Methods
Participants were volunteers in the Intelligent Systems for Assessment of Aging Changes Study (ISAAC) carried out by the Oregon Center for Aging and Technology. Participants were administered two questionnaires prior to training and again one year later, related to computer self-efficacy and anxiety. Continuous recording of computer use was also assessed for a subset of participants.
Results
Baseline comparisons by gender, age, education, living arrangement, and computer proficiency, but not cognitive status, yielded significant differences in confidence and anxiety related to specific aspects of computer use. At one-year follow-up, participants reported less anxiety and greater confidence. However, the benefits of training and exposure varied by group and task. Comparisons based on cognitive status showed that the cognitively intact participants benefited more from training and/or experience with computers than did participants with Mild Cognitive Impairment (MCI), who after one year continued to report less confidence and more anxiety regarding certain aspects of computer use.
Conclusion
After one year of consistent computer use, cognitively intact participants in this study reported reduced levels of anxiety and increased self-confidence in their ability to perform specific computer tasks. Participants with MCI at baseline were less likely to demonstrate increased efficacy or confidence than their cognitively intact counterparts.
doi:10.1016/j.jalz.2011.12.008
PMCID: PMC3483565  PMID: 23102124
15.  Trajectory of white matter hyperintensity burden preceding mild cognitive impairment 
Neurology  2012;79(8):741-747.
Objective:
To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly.
Methods:
A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up.
Results:
During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present.
Conclusions:
Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.
doi:10.1212/WNL.0b013e3182661f2b
PMCID: PMC3421153  PMID: 22843262
16.  The ADNI Publication Policy: Commensurate recognition of critical contributors who are not authors 
NeuroImage  2011;59(4):4196-4200.
An efficient approach to certain types of biomedical research requires a scale that precludes involvement of all critical contributors in all aspects of experimental design, execution, and as well as writing of most, if not all, derived works. Guarantors of both the integrity of the data and of its subsequent analyses are required. When separate groups are responsible for each of these activities, each should be readily identifiable both in the primary publication and in all subsequent citations. We describe the publication policy of the Alzheimer Disease Neuroimaging Initiative (ADNI), its origins and its acceptance by the editorial and scientific communities.
doi:10.1016/j.neuroimage.2011.10.085
PMCID: PMC3676932  PMID: 22100665
17.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
Objective:
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
Methods:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
Results:
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
Conclusion:
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
doi:10.1212/WNL.0b013e318253d5b3
PMCID: PMC3345787  PMID: 22491869
18.  Tau Phosphorylation Pathway Genes and Cerebrospinal Fluid Tau Levels in Alzheimer’s Disease 
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
doi:10.1002/ajmg.b.32094
PMCID: PMC3626266  PMID: 22927204
FYN; PPP2R4; MAPT; AD; CSF
19.  Assessment of cognition in early dementia 
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
doi:10.1016/j.jalz.2011.05.001
PMCID: PMC3613863  PMID: 23559893
20.  Willingness of older adults to share data and privacy concerns after exposure to unobtrusive in-home monitoring 
Older adult participants in the Intelligent Systems for Assessment of Aging Changes study (ISAAC) carried out by the Oregon Center for Aging and Technology (ORCATECH) were surveyed regarding their attitudes about unobtrusive home monitoring and computer use at baseline and after one year (n=119). The survey was part of a longitudinal study using in-home sensor technology to detect cognitive changes and other health problems. Our primary objective was to measure willingness to share health or activity data with one’s doctor or family members and concerns about privacy or security of monitoring over one year of study participation. Differences in attitudes of participants with Mild Cognitive Impairment (MCI) compared to those with normal cognition were also examined. A high proportion (over 72%) of participants reported acceptance of in-home and computer monitoring and willingness to have data shared with their doctor or family members. However, a majority (60%) reported concerns related to privacy or security; these concerns increased after one year of participation. Few differences between participants with MCI and those with normal cognition were identified. Findings suggest that involvement in this unobtrusive in-home monitoring study may have raised awareness about the potential privacy risks of technology. Still, results show high acceptance, stable over time, of sharing information from monitoring systems with family members and doctors. Our findings have important implications for the deployment of technologies among older adults in research studies as well as in the general community.
doi:10.4017/gt.2013.11.3.001.00
PMCID: PMC3604979  PMID: 23525351
activity monitoring; technology user receptivity; older adults; mild cognitive impairment
21.  One Walk a Year to 1000 Within a Year: Continuous In-home Unobtrusive Gait Assessment of Older Adults 
Gait & posture  2011;35(2):197-202.
Physical performance measures predict health and function in older populations. Walking speed in particular has consistently predicted morbidity and mortality. However, single brief walking measures may not reflect a person’s typical ability. Using a system that unobtrusively and continuously measures walking activity in a person’s home we examined walking speed metrics and their relation to function. In 76 persons living independently (mean age, 86) we measured every instance of walking past a line of passive infra-red motion sensors placed strategically in their home during a four-week period surrounding their annual clinical evaluation. Walking speeds and the variance in these measures were calculated and compared to conventional measures of gait, motor function and cognition. Median number of walks per day was 18 ± 15. Overall mean walking speed was 61 ± 17 cm/sec. Characteristic fast walking speed was 96 cm/sec. Men walked as frequently and fast as women. Those using a walking aid walked significantly slower and with greater variability. Morning speeds were significantly faster than afternoon/evening speeds. In-home walking speeds were significantly associated with several neuropsychological tests as well as tests of motor performance. Unobtrusive home walking assessments are ecologically valid measures of walking function. They provide previously unattainable metrics (periodicity, variability, range of minimum and maximum speeds) of everyday motor function.
doi:10.1016/j.gaitpost.2011.09.006
PMCID: PMC3278504  PMID: 22047773
Gait; Home-based clinical assessment; Technology
22.  Plasma omega-3 PUFA and white matter mediated executive decline in older adults 
Introduction: Cross-sectional studies have identified long chain omega-3 polyunsaturated fatty acids (eicosapentaenoic acid 20:5n-3 and docosahexaenoic acid 22:6n-3 (O3PUFA) in association with fewer white matter lesions and better executive function in older adults. We hypothesized that O3PUFA are associated with less executive decline over time and that total white matter hyperintensity volume (WMH) mediates this association.
Methods: Eighty-six non-demented older adults were followed over 4 years after measurement of plasma O3PUFA with annual evaluations of cognitive function. A subset of these participants also had brain MRI of total WMH available to conduct a formal mediation analysis of a putative relationship between O3PUFA and cognitive function.
Results: Mean age at baseline was 86, 62% were female and 11% carried the APOE4 allele. Each 100 μg/ml increase in plasma O3PUFA associated with 4 s less change in executive decline per year of aging (p = 0.02, fully adjusted model). O3PUFA was not associated with verbal memory or global cognitive changes. The significance of the association between O3PUFA and better executive function was lost once WMH was added to the regression model.
Conclusion: Executive decline with age appears to be a cognitive domain particularly sensitive to plasma O3PUFA in longitudinal examination. O3PUFA may modulate executive functioning by mechanisms underlying the development of WMH, a biologically plausible hypothesis that warrants further investigation.
doi:10.3389/fnagi.2013.00092
PMCID: PMC3863786  PMID: 24379780
omega-3 fatty acids; white matter hyperintensity; cognitive decline; memory; hypertension
23.  Pilot Study to Show the Feasibility of a Multicenter Trial of Home-based Assessment of People Over 75 Years Old 
This report describes a pilot study to evaluate feasibility of new home-based assessment technologies applicable to clinical trials for prevention of cognitive loss and Alzheimer disease.
Methods
Community-dwelling nondemented individuals ≥ 75 years old were recruited and randomized to 1 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 noncognitive outcomes were adapted to the different methodologies and administered at baseline and 1-month. An Efficiency measure, consisting of direct staff-to-participant time required to complete assessments, was also compared across arms.
Results
Forty-eight out of 60 screened participants were randomized. The dropout rate across arms from randomization through 1-month was different: 33% for KIO, 25% for IVR, and 0% for MIP (Fisher Exact Test P = 0.04). Nearly all participants who completed baseline also completed 1-month assessment (38 out of 39). The 1-way ANOVA across arms for total staff-to-participant direct contact time (ie, training, baseline, and 1-month) was significant: F (2,33) = 4.588; P = 0.017, with lowest overall direct time in minutes for IVR (Mn = 44.4; SD = 21.5), followed by MIP (Mn = 74.9; SD = 29.9), followed by KIO (Mn = 129.4; SD = 117.0).
Conclusions
In this sample of older individuals, a higher dropout rate occurred in those assigned to the high-technology assessment techniques; however, once participants had completed baseline in all 3 arms, they continued participation through 1 month. High-technology home-based assessment methods, which do not require live testers, began to emerge as more time-efficient over the brief time of this pilot, despite initial time-intensive participant training.
doi:10.1097/WAD.0b013e3181d7109f
PMCID: PMC3526375  PMID: 20592583
alzheimer disease; prevention trials; home-based assessment
24.  Measuring motor speed through typing: a surrogate for the finger tapping test 
Behavior research methods  2011;43(4):903-909.
Motor speed is an important indicator and predictor of both cognitive and physical function. One common assessment of motor speed is the finger tapping test (FTT), which is typically administered as part of a neurological or neuropsychological assessment. However, the FTT suffers from several limitations including infrequent in-person administration, the need for a trained assessor and dedicated equipment, and potential short term sensory-motor fatigue. In this article, we propose an alternative method of measuring motor speed, with face validity to the FTT, that addresses these limitations by measuring the interkeystroke interval (IKI) of familiar and repeated login data collected in the home during a subject’s regular computer use. We show significant correlations between the mean tapping speed from the FTT and the median IKIs of the non-dominant (r=0.77) and dominant (r=0.70) hands, respectively, in an elderly cohort of subjects living independently. Finally, we discuss how the proposed method for measuring motor speed fits well into the framework of unobtrusive and continuous in-home assessment.
doi:10.3758/s13428-011-0100-1
PMCID: PMC3151309  PMID: 21494919
Motor speed; Typing; Finger tapping test
25.  Alzheimer Disease Pathology in Cognitively Healthy Elderly:A Genome-wide Study 
Neurobiology of aging  2010;32(12):2113-2122.
Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 344 non-demented subjects with autopsy (201 subjects with low and 143 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided genome-wide significant evidence that variants in the RELNgene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.
doi:10.1016/j.neurobiolaging.2010.01.010
PMCID: PMC2990809  PMID: 20452100

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