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1.  Neuropathology in the Adult Changes in Thought Study: A Review 
The neuropathology underlying dementia syndromes in older populations is complex. The contributions of Alzheimer’s and Lewy body pathology are well appreciated. Recent studies with brain autopsies have highlighted the high prevalence of vascular disease as an independent, but often co-morbid contributor to dementia. The Adult Changes in Thought Study is a community-based, longitudinal study of brain aging and cognitive decline which has recently confirmed cerebral microinfarcts as a strong correlate of cognitive impairment and dementia. This study examines correlations between clinical characteristics including extensive, longitudinal medication histories, and longitudinal cognitive testing against structural and biochemical features of disease. Keywords: Aging, community-based, microinfarct, longitudinal, neuropathology.
doi:10.3233/JAD-2009-1180
PMCID: PMC4008877  PMID: 19661627
Aging; community-based; microinfarct; longitudinal; neuropathology
2.  Validation sampling can reduce bias in healthcare database studies: an illustration using influenza vaccination effectiveness 
Journal of clinical epidemiology  2013;66(8 0):S110-S121.
Objective
Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased due to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias.
Study Design and Setting
We applied two such methods, imputation and reweighting, to Group Health administrative data (full sample) supplemented by more detailed confounder data from the Adult Changes in Thought study (validation sample). We used influenza vaccination effectiveness (with an unexposed comparator group) as an example and evaluated each method’s ability to reduce bias using the control time period prior to influenza circulation.
Results
Both methods reduced, but did not completely eliminate, the bias compared with traditional effectiveness estimates that do not utilize the validation sample confounders.
Conclusion
Although these results support the use of validation sampling methods to improve the accuracy of comparative effectiveness findings from healthcare database studies, they also illustrate that the success of such methods depends on many factors, including the ability to measure important confounders in a representative and large enough validation sample, the comparability of the full sample and validation sample, and the accuracy with which data can be imputed or reweighted using the additional validation sample information.
doi:10.1016/j.jclinepi.2013.01.015
PMCID: PMC3911878  PMID: 23849144
aged; bias (epidemiologic); comparative effectiveness research; confounding factors (epidemiology); influenza vaccines; propensity score
3.  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
4.  Neuropathologic correlates of cognition in a population-based sample 
Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer’s disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (μVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2=0.31, p< 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2= 0.23, p< 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical μVBI, executive function with subcortical μVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and μVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults.
doi:10.3233/JAD-130281
PMCID: PMC3737376  PMID: 23666176
Alzheimer’s disease; brain; cerebrovascular disorders; cognition; dementia; Lewy bodies; pathologic processes
5.  Relationship Between Longitudinal Measures of Renal Function and Onset of Dementia Among a Community Cohort of Older Adults 
Background
Prior studies have described a higher incidence of dementia or worsening cognitive function in patients with lower levels of kidney function at a single point in time.
Objectives
To evaluate the association between dynamic measures of renal function ascertained over time with onset of dementia.
Design
prospective community cohort study.
Setting and Participants
2,968 adults aged 65 and older followed for the development of dementia over a median of 6.0 years (interquartile range 3.1–10.1 years).
Measurements
Time varying measures of renal function were constructed based on a total of 49,340 serum creatinine measurements and included: the average level of estimated glomerular filtration rate (eGFR), eGFR trajectory and variability in eGFR around this trajectory over 5-year exposure windows. The association between these three eGFR exposure measures and risk of dementia was estimated using a Cox regression model adjusted for other patient characteristics. In sensitivity analyses, we also adjusted for time-varying measures of urine protein by dipstick.
Results
Patients with lower levels of eGFR had a higher incidence of dementia but this did not reach statistical significance in adjusted analyses (omnibus p value=0.14). There were trends toward a higher adjusted incidence of dementia in patients with positive eGFR trajectories (omnibus p value=0.07) and greater variability in eGFR (omnibus p value=0.04) over time. The results of sensitivity analyses, including those in which we included time-varying measures of proteinuria, were consistent with those of the primary analysis.
Conclusion
Among a community cohort of older adults followed for a median of 6 years, we did not find strong associations between measures of kidney disease severity and progression and incident dementia.
doi:10.1111/j.1532-5415.2012.04238.x
PMCID: PMC3531894  PMID: 23231548
dementia; renal function; eGFR; variability; trajectory
6.  Insulin and Sex Interactions in Older Adults with Mild Cognitive Impairment 
Alzheimer’s disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ε4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype.
doi:10.3233/JAD-2012-120202
PMCID: PMC3798013  PMID: 22571978
Age-related memory disorders; aging; Alzheimer’s disease; cognition; dementia; hyperinsulinemia; insulin; vascular
7.  Impact on Seniors of the Patient-Centered Medical Home: Evidence From a Pilot Study 
The Gerontologist  2012;52(5):703-711.
Purpose: To assess the impact on health care cost and quality among seniors of a patient-centered medical home (PCMH) pilot at Group Health Cooperative, an integrated health care system in Washington State. Design and Methods: A prospective before-and-after evaluation of the experience of seniors receiving primary care services at 1 pilot clinic compared with seniors enrolled at the remaining 19 primary care clinics owned and operated by Group Health. Analyses of secondary data on quality and cost were conducted for 1,947 seniors in the PCMH clinic and 39,396 seniors in the 19 control clinics. Patient experience with care was based on survey data collected from 487 seniors in the PCMH clinic and of 668 in 2 specific control clinics that were selected for their similarities in organization and patient composition to the pilot clinic.Results: After adjusting for baseline, seniors in the PCMH clinic reported higher ratings than controls on 3 of 7 patient experience scales. Seniors in the PCMH clinic had significantly greater quality outcomes over time, but this difference was not significant relative to control. PCMH patients used more e-mail, phone, and specialist visits but fewer emergency services and inpatient admissions for ambulatory care sensitive conditions. At 1 and 2 years, the PCMH and control clinics did not differ significantly in overall costs. Implications: A PCMH redesign can be associated with improvements in patient experience and quality without increasing overall cost.
doi:10.1093/geront/gnr158
PMCID: PMC3605940  PMID: 22421916
PCMH; Medicare; Geriatric health care
8.  Prospects for delaying the rising tide of worldwide, late-life dementias 
International psychogeriatrics / IPA  2010;22(8):1196-1202.
Worldwide, lifespan is lengthening. Concomitantly, late-life dementias are increasingly common, challenging both personal and public health internationally. After age 65, rates of dementia tend to double every five years in developed countries and every seven in developing ones. The late-life dementias, particularly Alzheimer’s disease, have profound effects on aging individuals and their caregivers. Multidisciplinary research has explored the potential for various approaches to prevent or delay the onset of late-life dementias. Outlining that research, including our team’s Adult Changes in Thought and Kame studies, this review concludes that delaying these dementias’ onset appears feasible, although absolute prevention may not be. Today the most promising methods appear to include controlling vascular risk factors like hypertension and engaging in physical exercise—and possibly mental exercise—on and off the job. If people can delay the onset of dementias, they can lead more fulfilling lives for longer—spending less time suffering from dementia and letting their families spend less time coping with the disease. It is possible that trends toward more knowledge-based societies, where cognitive health is so vital, may increasingly exert evolutionary pressure favoring larger and healthier brains—and a “compression of cognitive morbidity”—well into old age. Public health’s great triumph, increased lifespan, should give more of the world’s people the reward of many years of dementia-free life—rather than the personal difficulties and public health burdens of many years of functional impairment, dependency, and suffering with dementia some interventions may delay the onset of Alzheimer’s disease and other dementias.
doi:10.1017/S1041610210001080
PMCID: PMC3164829  PMID: 20594386
Alzheimer’s disease; prevention; lifestyle risk factors; aging; exercise; demographics; evolution
9.  Risk for late-life re-injury, dementia and death among individuals with traumatic brain injury: a population-based study 
Objectives
To determine the association of self-reported traumatic brain injury (TBI) with loss of consciousness (LOC) with late-life re-injury, dementia diagnosis and mortality.
Design
Ongoing longitudinal population-based prospective cohort study.
Setting
Seattle-area integrated health system.
Participants
4225 dementia-free individuals age 65 and older were randomly selected and enrolled between 1994 and 2010. Participants were seen every 2 years, with mean (range) follow-up of 7.4 (0–16) years. 606 (14%) participants reported a lifetime history of TBI with LOC at enrolment. 3466 participants provided information regarding lifetime history of TBI and completed at least one follow-up visit.
Main outcome measures
Self-reported TBI with LOC after study entry, incident all-cause dementia and Alzheimer’s disease (AD), and all-cause mortality.
Results
There were 25 567 person-years of follow-up. History of TBI with LOC reported at study enrolment was associated with increased risk for TBI with LOC during follow-up, with adjusted HRs ranging from 2.54 (95% CI 1.42 to 4.52) for those reporting first injury before age 25 to 3.79 (95% CI 1.89 to 7.61) for those with first injury after age 55. History of TBI with LOC was not associated with elevated risk for developing dementia or AD. There was no association between baseline history of TBI with LOC and mortality, though TBI with LOC since the previous study visit (‘recent TBI’) was associated with increased mortality (HR 2.12, 95% CI 1.62 to 2.78).
Conclusions
Individuals aged 65 or older who reported a history of TBI with LOC at any time in their lives were at elevated risk of subsequent re-injury. Recent TBI with LOC sustained in older adulthood was associated with increased risk for mortality. Findings support the need for close clinical monitoring of older adults who sustain a TBI with LOC.
doi:10.1136/jnnp-2012-303938
PMCID: PMC3752841  PMID: 23172868
10.  A “virtually minimal” visuo-haptic training of attention in severe traumatic brain injury 
Background
Although common during the early stages of recovery from severe traumatic brain injury (TBI), attention deficits have been scarcely investigated. Encouraging evidence suggests beneficial effects of attention training in more chronic and higher functioning patients. Interactive technology may provide new opportunities for rehabilitation in inpatients who are earlier in their recovery.
Methods
We designed a “virtually minimal” approach using robot-rendered haptics in a virtual environment to train severely injured inpatients in the early stages of recovery to sustain attention to a visuo-motor task. 21 inpatients with severe TBI completed repetitive reaching toward targets that were both seen and felt. Patients were tested over two consecutive days, experiencing 3 conditions (no haptic feedback, a break-through force, and haptic nudge) in 12 successive, 4-minute blocks.
Results
The interactive visuo-haptic environments were well-tolerated and engaging. Patients typically remained attentive to the task. However, patients exhibited attention loss both before (prolonged initiation) and during (pauses during motion) a movement. Compared to no haptic feedback, patients benefited from haptic nudge cues but not break-through forces. As training progressed, patients increased the number of targets acquired and spontaneously improved from one day to the next.
Conclusions
Interactive visuo-haptic environments could be beneficial for attention training for severe TBI patients in the early stages of recovery and warrants further and more prolonged clinical testing.
doi:10.1186/1743-0003-10-92
PMCID: PMC3750632  PMID: 23938101
Virtual reality; Robotics; Attention; Rehabilitation; TBI
12.  Novel antibody capture assay for paraffin-embedded tissue detects wide-ranging amyloid beta and paired helical filament–tau accumulation in cognitively normal older adults 
Quantifying antigens in formalin-fixed tissue is challenging and limits investigation in population-based studies of brain aging. To address this major limitation, we have developed a new technique that we call “Histelide”: immunohistochemistry (HIST-) and ELISA (-EL-) performed on a glass slide (-IDE). We validated Histelide in sections of prefrontal cortex from 20 selected cases: 12 subjects with clinically and neuropathologically diagnosed Alzheimer’s disease (AD), either autosomal dominant or late-onset forms, and 8 clinical and neuropathologic Controls. AD cases had significantly increased amyloid beta (Aβ) peptide and paired helical filament– (PHF-) tau per area of neocortex that was proteinase K-sensitive, and significantly decreased amount of synaptophysin. We next investigated prefrontal cortex from 81 consecutive cases of high cognitive performers from the Adult Changes in Thought (ACT) study, a population-based study of brain aging and incident dementia. As expected, latent AD was common in this group; however, our results quantified widely individually-varying levels of Aβ peptides and PHF-tau among these high cognitive performers. This novel approach obtains quantitative data from population-based studies, and our initial studies with high cognitive performers provide important quantitative insights into latent AD that should help guide expectations from neuroimaging and prevention studies.
doi:10.1111/j.1750-3639.2011.00542.x
PMCID: PMC3295908  PMID: 21999410
13.  Adult Changes in Thought Study: Dementia is an Individually Varying Convergent Syndrome with Prevalent Clinically Silent Diseases that may be Modified by Some Commonly Used Therapeutics 
Current Alzheimer research  2012;9(6):718-723.
The Adult Changes in Thought (ACT) study is a longitudinal population-based prospective cohort study of brain aging and incident dementia in the Seattle metropolitan area. Observational studies using autopsies from ACT indicate that dementia is a convergent syndrome that commonly derives from Alzheimer’s disease (AD), microvascular brain injury (μVBI), and Lewy body disease (LBD), and that these diseases have prevalent subclinical forms that also are commonly co-morbid. The existence of subclinical diseases highlights potential opportunities to intervene before the development of clinically apparent impairments. Our observations suggest that some such interventions already may exist to suppress processes of AD (statin therapy) or μVBI (treatment of hypertension). Reduced burden of LBD is associated with cigarette smoking; although smoking is not recommended as an intervention, these exposure data may provide clues to alternative neuroprotective mechanisms. Self reported anti-oxidant supplementation was without apparent effect in this cohort on indices of AD, μVBI, or LBD. Continued observational studies of brain aging will provide further insight into the convergent complexity of the dementia syndrome and its subclinical forms as well as highlight potential interventions that will require validation in clinical trials.
PMCID: PMC3409333  PMID: 22471861
14.  Informed Consent in Genome-Scale Research: What Do Prospective Participants Think? 
AJOB primary research  2012;3(3):3-11.
Background
To promote effective genome-scale research, genomic and clinical data for large population samples must be collected, stored, and shared.
Methods
We conducted focus groups with 45 members of a Seattle-based integrated healthcare delivery system to learn about their views and expectations for informed consent in genome-scale studies.
Results
Participants viewed information about study purpose, aims, and how and by whom study data could be used to be at least as important as information about risks and possible harms. They generally supported a tiered consent approach for specific issues, including research purpose, data sharing, and access to individual research results. Participants expressed a continuum of opinions with respect to the acceptability of broad consent, ranging from completely acceptable to completely unacceptable. Older participants were more likely to view the consent process in relational – rather than contractual – terms, compared with younger participants. The majority of participants endorsed seeking study subjects’ permission regarding material changes in study purpose and data sharing.
Conclusions
Although this study sample was limited in terms of racial and socioeconomic diversity, our results suggest a strong positive interest in genomic research on the part of at least some prospective participants and indicate a need for increased public engagement, as well as strategies for ongoing communication with study participants.
doi:10.1080/21507716.2012.662575
PMCID: PMC3593675  PMID: 23493836
Informed consent; participant views; genomic research; biobank; research ethics
15.  Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans 
Importance
Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment.
Objective
To identify genetic loci associated with late-onset Alzheimer disease in African Americans.
Design, Setting, and Participants
The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance–weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci.
Main Outcomes and Measures
Presence of Alzheimer disease according to standardized criteria.
Results
Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10–9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8
Conclusions and Relevance
In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
doi:10.1001/jama.2013.2973
PMCID: PMC3667653  PMID: 23571587
ABSTRACT
Improving health literacy is one key to buoying our nation’s troubled health care system. As system-level health literacy improvement strategies take the stage among national priorities for health care, the patient-centered medical home (PCMH) model of care emerges as a compelling avenue for their widespread implementation. With a shared focus on effective communication and team-based care organized around patient needs, health literacy principles and the PCMH are well aligned. However, their synergy has received little attention, even as PCMH demonstration projects and health literacy interventions spring up nationwide. While many health literacy interventions are limited by their focus on a single point along the continuum of care, creating a “room” for health literacy within the PCMH may finally provide a multi-dimensional, system-level approach to tackling the full range of health literacy challenges. Increasing uptake coupled with federal support and financial incentives further boosts the model’s potential for advancing health literacy. On the journey toward a revitalized health care system, integrating health literacy into the PCMH presents a promising opportunity that deserves consideration.
doi:10.1007/s11606-011-1964-6
PMCID: PMC3326113  PMID: 22215273
communication; health literacy; patient-centered care; medical home
Context
The identification of genetic variants associated with common disease is accelerating rapidly. “Multiplex tests” that give individuals feedback on large panels of genetic variants have proliferated. Availability of these test results may prompt consumers to use more healthcare services.
Objective
To examine whether offers of multiplex genetic testing increases healthcare utilization among healthy patients aged 25–40.
Participants
1,599 continuously insured adults aged 25–40 were surveyed and offered a multiplex genetic susceptibility test (MGST) for eight common health conditions.
Main Outcome Measure
Healthcare utilization from automated records was compared in 12 month pre- and post-test periods among persons who completed a baseline survey only (68.7%), those who visited a study Web site but opted not to test (17.8%), and those who chose the MGST (13.6%).
Results
In the pre-test period, persons choosing genetic testing used an average of 1.02 physician visits per quarter compared to 0.93 and 0.82 for the other groups (p<0.05). There were no statistically significant differences by group in the pre-test use of any common medical tests or procedures associated with four common health conditions. When changes in physician and medical test/procedure use in the post-test period were compared among groups, no statistically significant differences were observed for any utilization category.
Conclusions
Persons offered and completing multiplex genetic susceptibility testing used more physician visits prior to testing, but testing was not associated with subsequent changes in use. This study supports that multiplex genetic testing offers can be provided directly to patients in such a way that use of health services are not inappropriately increased.
doi:10.1038/gim.2012.52
PMCID: PMC3424345  PMID: 22595941
genetic susceptibility; delivery of health care; genetic testing; genetic counseling
Archives of neurology  2012;69(10):1270-1279.
Objective
To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).
Design
Conditional logistic regression models and survival analysis.
Setting
Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.
Participants
Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.
Main Outcome Measures
Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.
Results
In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P<.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.
Conclusions
APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.
doi:10.1001/archneurol.2012.2052
PMCID: PMC3579659  PMID: 22869155
The Permanente Journal  2005;9(4):33-35.
The NIH Roadmap is a major effort to reshape the US health research enterprise to accelerate medical discovery and to do so in such a way that actually hastens population health improvement through research. The Roadmap's ultimate goal resonates with the HMO Research Network, a consortium of integrated health care systems that uses its collective scientific capabilities to integrate research, practice, and policy for the improvement of health and health care among diverse populations. (See page 6 for abstracts from the HMO Research Network annual conference.) As such, the HMO Research Network was ideally suited to propose a new consortium project as a part of the NIH Roadmap, the Coordinated Clinical Studies Network (CCSN). The CCSN was funded in 2004 to create a path-breaking research facility that leverages several distinctive features of the HMO Research Network: the multidisciplinary scientific capabilities of its researchers; the ability to rapidly move clinical research findings into care delivery; its large, diverse patient populations; and a commitment to placing its findings in the public domain. Among the goals of the CCSN are to augment the capacity and infrastructure for conducting research, and to use considerable investments in health informatics to improve the scope and efficiency of research data collection. The NIH Roadmap is a revolutionary step toward a new paradigm for research and responds to both a compelling social need and rapid technological advances in biomedicine. The CCSN's participation in the Roadmap Initiative is a unique opportunity for researchers, clinicians, and our patients.
PMCID: PMC3396093  PMID: 22811643
Health Services Research  2003;38(3):919-922.
doi:10.1111/1475-6773.00153
PMCID: PMC1360915
Electronic medical records (EMRS) allow for real time access to blood pressure information on a population basis and improved identification and treatment of individuals with hypertension. Despite the potential uses of the data available from EMRs relatively little research has examined the reliability of this data. To address this gap, we examined the reliability of blood pressure taken at primary care visits and recorded in an electronic medical record with those taken at a research study visit at which standard protocols were used to measure blood pressure among all adults as well as by gender and age. Systolic blood pressure (BP) averaged 3.7 (17.3) points and diastolic BP was 2.8 (10.6) points lower in the EMR than in the study visit across age and gender groups with all differences statistically significant. For this cohort of patients with a diagnosis of hypertension there was moderate correlation between BP measurements taken in clinic and at research. However BP control for individuals, as defined by a BP of less the 140 mm Hg systolic and 90 mm Hg diastolic, differed by almost 25%. Known variability of BP and clinic procedures for measuring and recording BP may account for these differences.
doi:10.1111/j.1751-7176.2011.00528.x
PMCID: PMC3211104  PMID: 22051427
blood pressure; hypertension; electronic medical record; reliability
Context
An increasing number of older adults are being treated for end-stage renal disease (ESRD) with long-term dialysis.
Objectives
To determine how ESRD treatment practices for older adults vary across regions with differing end-of-life intensity of care.
Design, Setting, and Participants
Retrospective observational study using a national ESRD registry to identify a cohort of 41 420 adults (of white or black race), aged 65 years or older, who started long-term dialysis or received a kidney transplant between June 1, 2005, and May 31, 2006. Regional end-of-life intensity of care was defined using an index from the Dartmouth Atlas of Healthcare.
Main Outcome Measures
Incidence of treated ESRD (dialysis or transplant), preparedness for ESRD (under the care of a nephrologist, having a fistula [vs graft or catheter] at time of hemodialysis initiation), and end-of-life care practices.
Results
Among whites, the incidence of ESRD was progressively higher in regions with greater intensity of care and this trend was most pronounced at older ages. Among blacks, a similar relationship was present only at advanced ages (men aged ≥80 years and women aged ≥85 years). Patients living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to be under the care of a nephrologist before the onset of ESRD (62.3% [95% confidence interval {CI}, 61.3%–63.3%] vs 71.1% [95% CI, 69.9%–72.2%], respectively) and less likely to have a fistula (vs graft or catheter) at the time of hemodialysis initiation (11.2% [95% CI, 10.6%–11.8%] vs 16.9% [95% CI, 15.9%–17.8%]). Among patients who died within 2 years of ESRD onset (n=21 190), those living in regions in the highest compared with lowest quintile of end-of-life intensity of care were less likely to have discontinued dialysis before death (22.2% [95% CI, 21.1%–23.4%] vs 44.3% [95% CI, 42.5%–46.1%], respectively), less likely to have received hospice care (20.7% [95% CI, 19.5%–21.9%] vs 33.5% [95% CI, 31.7%–35.4%]), and more likely to have died in the hospital (67.8% [95% CI, 66.5%–69.1%] vs 50.3% [95% CI, 48.5%–52.1%]). These differences persisted in adjusted analyses.
Conclusion
There are pronounced regional differences in treatment practices for ESRD in older adults that are not explained by differences in patient characteristics.
doi:10.1001/jama.2010.924
PMCID: PMC3477643  PMID: 20628131
Annals of neurology  2011;70(3):465-476.
Objective
The cellular and molecular mechanisms underlying MRI-defined white matter (WM) changes associated with age-related cognitive decline remain poorly defined. We tested the hypothesis that WM lesions in older adults, defined by diffusion tensor imaging (DTI), arise in the setting of vascular brain injury (VBI) and are characterized by increased free radical injury and aberrant oligodendrocyte lineage (OL) cell response to injury.
Methods
We undertook a multimodal analysis of prefrontal cortex (PFC) WM from twenty-five autopsies derived from a population-based cohort where VBI and Alzheimer's Disease (AD) frequently coincide. Ex-vivo high field strength DTI measurements of fractional anisotropy (FA), apparent diffusion coefficient (ADC), and axial (D∥) and radial (D⊥) diffusivity were measured at high magnetic field strength (11.7 T) and analyzed relative to quantitative in vivo biomarkers of free radical injury, an OL-specific marker Olig2, and histologic evaluation of hyaluronan (HA), an inhibitor of OL maturation.
Results
Coincident AD and VBI showed significant association with lower FA and a robust relationship between decreasing FA and increasing D⊥. Free radical injury to docosahexaenoate and adrenate in PFC WM was significantly elevated in cases with VBI independent of AD, and were inversely correlated with FA. Similarly, increased density of Olig2-immunoreactive cells in PFC WM was significantly associated with VBI independent of AD and co-localized with regions enriched in HA.
Interpretation
DTI-defined PFC WM lesions in older individuals are characterized by free radical injury to myelin and neuro-axonal elements that coincides with pronounced expansion of the pool of OL cells in HA-rich regions.
doi:10.1002/ana.22484
PMCID: PMC3177155  PMID: 21905080
white matter; vascular brain injury; Alzheimer's disease; diffusion tensor imaging; oxidative damage; oligodendroglia
Archives of General Psychiatry  2011;68(9):970-977.
Context
Late-life depression is associated with increased risk of dementia but the temporal relationship between depression and development of dementia remains unclear.
Objectives
To examine the association between risk of dementia and 1) baseline depressive symptoms ; 2) past history of depression, particularly early-life (< 50 years) versus late-life depression; and 3) individual domains of the Center for Epidemiologic Studies Depression Scale (CESD).
Design
A large cohort with initially non-demented participants was followed biennially for up to 15 years for incident dementia. Baseline depressive symptoms were assessed using the 11-item version of CESD (CESD-11), and defined as CESD-11 score ≥ 11. Self-reported history of depression was collected at the baseline interview. Cox proportional hazards regression was used to assess the association between depression and the dementia risk.
Setting
Population-based cohort drawn from members of Group Health Cooperative in Seattle, Washington.
Participants
A cohort of 3,410 participants without dementia aged ≥ 65 years.
Results
Over an average of 7.1 years follow-up, 658 participants (19%) developed dementia. At baseline, 9% of participants had depressive symptoms (CESD-11 ≥ 11) and 21% reported a past history of depression. The adjusted hazard ratio (aHR) for dementia associated with baseline depressive symptoms was 1.71 (95% confidence interval 1.37, 2.13), after adjusting for age-at-entry, gender, education, and wave of enrollment. Compared to participants without depression history, those with late-life depression were at increased dementia risk (aHR =1.46 [1.16, 1.84]), but early-life depression had no association with dementia risk (aHR=1.10 [0.83, 1.47]). Depressed mood (aHR 1.48 [1.25, 1.76]) and perceived performance difficulty (aHR 1.39 [1.15, 1.67]) were independently associated with dementia.
Conclusions
This study confirmed previous observations of an association between late-life depression and increased risk of dementia and provided additional evidence that late-life depression may be an early manifestation of dementia rather than increasing risk for dementia.
doi:10.1001/archgenpsychiatry.2011.86
PMCID: PMC3289582  PMID: 21893662
Objectives
To test the effects of walking, light exposure, and a combination intervention (walking plus light plus sleep education) on the sleep of persons with Alzheimer’s disease (AD).
Design
Randomized, controlled trial with blinded assessors.
Setting
Independent community living.
Participants
132 AD patients and their in-home caregivers.
Interventions
Participants were randomly assigned to one of three active treatments (walking, light, combination treatment) or contact control. Participants received three or six in-home visits.
Measurements
Primary outcomes were patient total wake time based on wrist actigraphy, and caregiver ratings of patient sleep quality on the Sleep Disorders Inventory (SDI). Secondary sleep outcomes included additional actigraphic measurements of patient sleep percent, number of awakenings, and total sleep time.
Results
Patients in walking (p<.05), light (p<.04), and combination treatment (p<.01) had significant improvements in total wake time at post-test (effect size 0.51 – 0.63) compared to control subjects, but no significant improvement on the SDI. Moderate effect size improvements in actigraphic sleep percent were also observed in active treatment subjects. There were no significant differences between active treatment groups, and no group differences for any sleep outcomes at six months. Patients with greater adherence (4+ days/week) to walking and light exposure recommendations had significantly (p<.05) less total wake time and better sleep efficiency at post-test than those with lesser adherence.
Conclusion
Walking, light exposure and the combination are potentially effective treatments for improving sleep in community-dwelling persons with AD, but consistent adherence to treatment recommendations is required.
doi:10.1111/j.1532-5415.2011.03519.x
PMCID: PMC3158242  PMID: 21797835
Sleep; Alzheimer’s disease; walking; light; adherence

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