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1.  Association of Functional Impairments and Co-Morbid Conditions with Driving Performance among Cognitively Normal Older Adults 
PLoS ONE  2016;11(12):e0167751.
Objectives
To examine the relationship between key functional impairments, co-morbid conditions and driving performance in a sample of cognitively normal older adults.
Design
Prospective observational study
Setting
The Knight Alzheimer’s Disease Research Center, Washington University at St. Louis
Participants
Individuals with normal cognition, 64.9 to 88.2 years old (N = 129), with a valid driver’s license, who were currently driving at least once per week, and who had participated in longitudinal studies at the Knight Alzheimer’s Disease Research Center
Measurements
Static visual acuity, contrast sensitivity, physical frailty measures, motor skills, total medical conditions, and the modified Washington University Road Test.
Results
When controlling for age, race, gender, APOE, and education the total number of medical conditions was unassociated with both road test scores (pass vs. marginal + fail) and the total driver error count. There were marginal associations of our measure of physical frailty (p = 0.06) and contrast sensitivity score (p = 0.06) with total driving error count.
Conclusion
Future research that focuses on older adults and driving should consider adopting measures of physical frailty and contrast sensitivity, especially in samples that may have a propensity for disease impacting visual and/or physical function (e.g. osteoarthritis, Parkinson’s, eye disorders, advanced age >80 years, etc.).
doi:10.1371/journal.pone.0167751
PMCID: PMC5179007  PMID: 28005921
2.  Cerebrospinal Fluid Biomarkers and Reserve Variables as Predictors of Future “Non-Cognitive” Outcomes of Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2016;52(3):1055-1064.
Background
The influence of reserve variables and Alzheimer’s disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on “non-cognitive” outcomes, including functional abilities and mood.
Objective
We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior.
Methods
Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants.
Results
Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers.
Conclusions
The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD.
doi:10.3233/JAD-150478
PMCID: PMC5031142  PMID: 27104893
Alzheimer’s disease; biomarkers; cognitive reserve; dementia
3.  Creating a driving profile for older adults using GPS devices and naturalistic driving methodology 
F1000Research  2016;5:2376.
Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. Our objective was to describe the process and associated challenges in adapting an existing, commercial, off-the-shelf (COTS), in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers.
Design: The Azuga G2 Tracking Device TM was installed in each participant’s vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven. 
Setting: The Knight Alzheimer’s Disease Research Center at Washington University School of Medicine.
Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance.  Participants were aged 65+ years and had normal cognition.
Measurements:  Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations.  Temporal components included number of trips taken during different times of the day.  Behavioral components included number of hard braking, speeding and sudden acceleration events.
Methods:  Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS. 
Results: Primary locations were confirmed to be 100% accurate when compared to known addresses.  Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns.  Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night.  Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period.
Conclusions: Compared to cameras and highly instrumented vehicle in other naturalistic studies, the compact COTS device was quickly installed and transmitted high volumes of data. Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions.
doi:10.12688/f1000research.9608.2
PMCID: PMC5133689  PMID: 27990264
naturalistic driving; global positioning data acquisition systems; geographic information system; in-vehicle technology; older adults; Alzheimer’s disease
4.  Neuropsychological Markers of Cognitive Decline in Persons With Alzheimer Disease Neuropathology 
To evaluate cognitive performance among persons who did and did not develop clinical Alzheimer disease (AD) but had AD neuropathology at autopsy, we examined neuropsychological performance in cognitively normal (Clinical Dementia Rating [CDR] = 0) participants who returned for at least one follow-up and died within 2 years of their last assessment. Non-progressors remained at CDR = 0 until death; progressors developed symptomatic AD during life (CDR > 0). Cognitive performance at baseline was compared between progressors and non-progressors on a global cognitive composite and 4 domain-specific composites (episodic memory, language, attention/working memory, and executive function). Models adjusted for age, education, sex, and non-AD neuropathology. Progressors (n = 173) had worse performance than non-progressors (n = 141) in nearly all cognitive domains. Progressors scored lower on composites of global cognition (p < 0.001), executive function (p = 0.0006), language (p < 0.0001), and episodic memory (p = 0.0006), but not on attention/working memory (p = 0.91). These data indicate that individuals with underlying AD neuropathology who are clinically normal but who later develop symptomatic AD have worse performance in a wide range of domains vs. individuals with underlying AD neuropathology who are clinically normal but do not become symptomatic during life. Therefore, subtle cognitive decline at baseline may indicate an increased risk of progression to symptomatic AD.
doi:10.1097/NEN.0000000000000254
PMCID: PMC4610245  PMID: 26469250
Alzheimer disease; Braak staging; Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) plaque; Clinical diagnosis; Memory; Mild cognitive impairment; Neuropathology
6.  Creating a driving profile for older adults using GPS devices and naturalistic driving methodology 
F1000Research  2016;5:2376.
Background/Objectives: Road tests and driving simulators are most commonly used in research studies and clinical evaluations of older drivers. We adapted an existing, commercial, off-the-shelf, in-vehicle device for naturalistic, longitudinal research to better understand daily driving behavior in older drivers.
Design: The Azuga G2 Tracking Device TM was installed in each participant’s vehicle, and we collected data over 5 months (speed, latitude/longitude) every 30-seconds when the vehicle was driven. 
Setting: The Knight Alzheimer’s Disease Research Center at Washington University School of Medicine.
Participants: Five individuals enrolled in a larger, longitudinal study assessing preclinical Alzheimer disease and driving performance.  Participants were aged 65+ years and had normal cognition.
Measurements:  Spatial components included Primary Location(s), Driving Areas, Mean Centers and Unique Destinations.  Temporal components included number of trips taken during different times of the day.  Behavioral components included number of hard braking, speeding and sudden acceleration events.
Methods:  Individual 30-second observations, each comprising one breadcrumb, and trip-level data were collected and analyzed in R and ArcGIS. 
Results: Primary locations were confirmed to be 100% accurate when compared to known addresses.  Based on the locations of the breadcrumbs, we were able to successfully identify frequently visited locations and general travel patterns.  Based on the reported time from the breadcrumbs, we could assess number of trips driven in daylight vs. night.  Data on additional events while driving allowed us to compute the number of adverse driving alerts over the course of the 5-month period.
Conclusions: This pilot study indicated that Driving Profiles for older adults can be created and compared month-to-month or year-to-year, allowing researchers to identify changes in driving patterns that are unavailable in controlled conditions.
doi:10.12688/f1000research.9608.1
PMCID: PMC5133689  PMID: 27990264
naturalistic driving; global positioning data acquisition systems; geographic information system; in-vehicle technology; older adults; Alzheimer’s disease
7.  Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research 
F1000Research  2016;5:1716.
Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer’s disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD. 
Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval.
Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation.
Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction.  However, these devices require strict protocols and controlled testing for adoption into research paradigms.  After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD.  Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.
doi:10.12688/f1000research.9150.2
PMCID: PMC5063038  PMID: 27785360
naturalistic driving; interval testing; geographic information system; global positioning systems; in-vehicle technology
8.  Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research 
F1000Research  2016;5:1716.
Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer’s disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD. 
Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval.
Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation.
Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction.  However, these devices require strict protocols and controlled testing for adoption into research paradigms.  After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD.  Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.
doi:10.12688/f1000research.9150.1
PMCID: PMC5063038  PMID: 27785360
naturalistic driving; interval testing; geographic information system; global positioning systems; in-vehicle technology
9.  Increased Susceptibility to Oxidative Death of Lymphocytes from Alzheimer Patients Correlates with Dementia Severity 
Current Alzheimer research  2014;11(9):892-898.
We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer’s disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer’s disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity. Peripheral lymphocytes from 23 AD patients, classified using the Clinical Dementia Rating (CDR) into severe dementia (CDR 3, n=10) and mild-to-moderate dementia (CDR 1–2, n=13), and 15 healthy controls (HC) (CDR 0), were exposed to H2O2 for 20 hours. Lymphocyte death was determined by flow cytometry and propidium iodide staining. The greatest susceptibility to H2O2-induced death was observed for lymphocytes from severe dementia patients, whereas those with mild-to-moderate dementia exhibited intermediate values, compared to healthy controls. A significant increase in the apoptosis/necrosis ratio was found in AD patients. Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibition significantly protected from H2O2-induced death of lymphocytes, whereby a lower degree of protection was observed in severe AD patients. Moreover, inhibition of PARP-1 abolished the differences in apoptosis/necrosis ratios observed between the three groups of patients. These results support the notion that AD is a systemic disorder, whereby enhanced susceptibility to H2O2-induced death in peripheral lymphocytes correlates with dementia severity and enhanced death in AD patients is attributable to a PARP-dependent increase in the apoptosis/necrosis ratio.
PMCID: PMC4378649  PMID: 25274115
Alzheimer; apoptosis; dementia; necrosis; PARP-dependent cell death; peripheral lymphocytes
10.  Interrater Reliability of the Record of Driving Errors (RODE) 
The American Journal of Occupational Therapy  2015;69(2):6902350020p1-6902350020p6.
Researchers examined the RODE's interrater reliability using 2 occupational therapy driving rehabilitation specialists working with 24 older adults diagnosed with dementia.
The Record of Driving Errors (RODE) is a novel standardized tool designed to quantitatively document the specific types of driving errors that occur during a standardized performance-based road test. The purpose of this study was to determine interrater reliability between two occupational therapy driver rehabilitation specialists who quantitatively scored specific driving errors using the RODE in a sample of older adults diagnosed with dementia (n = 24). Intraclass correlation coefficients of major driving error and intervention categories indicated almost perfect agreement between raters. Using raters with adequate training and similar professional backgrounds, it is possible to have good interrater reliability using the RODE on a standardized road test.
doi:10.5014/ajot.2015.013128
PMCID: PMC4406108  PMID: 26122691
automobile driving; dementia; occupational therapy; reproducibility of results; task performance and analysis
11.  “Noncognitive” symptoms of early Alzheimer disease 
Neurology  2015;84(6):617-622.
Objectives:
To observe the natural time course of noncognitive symptoms before the onset of symptomatic Alzheimer disease dementia.
Methods:
Using the National Alzheimer's Coordinating Center Uniform Data Set from September 2005 to March 2013, data from cognitively normal individuals who were aged 50 years or older at first visit and had subsequent follow-up were analyzed. Survival analyses were used to examine the development of particular symptoms relative to each other on the Neuropsychiatric Inventory Questionnaire (NPI-Q), Functional Activities Questionnaire, and Geriatric Depression Scale, and to compare the development of individual symptoms for persons who did and did not receive a Clinical Dementia Rating (CDR) >0 (indicating abnormal cognition) during the follow-up period.
Results:
The order of symptom occurrence on the NPI-Q was similar for participants who remained at CDR 0 and for those who received a CDR >0 over the follow-up period, although the time to most NPI-Q symptoms was faster for participants who received a CDR >0 (p < 0.001). With the exception of memory, Geriatric Depression Scale symptoms reported by both CDR groups were similar.
Conclusions:
We found a significantly earlier presence of positive symptoms on the NPI-Q in cognitively normal patients who subsequently developed CDR >0. Among participants with no depression symptoms at baseline, results suggest that depressive symptoms may increase with aging regardless of incipient dementia. Such findings begin to delineate the noncognitive course of Alzheimer disease dementia in the preclinical stages. Future research must further elucidate the correlation between noncognitive changes and distinct dementia subtypes.
doi:10.1212/WNL.0000000000001238
PMCID: PMC4335988  PMID: 25589671
12.  Pathological Correlates of White Matter Hyperintensities on MRI 
Background/Aims
We investigated the histopathological correlates of White matter hyperintensities (WMHs) in participants with Alzheimer's disease (AD), cerebrovascular disease, and aged controls.
Methods
We reviewed 57 participants who had both neuroimaging and neuropathology. In addition to AD pathology, cortical microinfarcts, lacunes, and cerebral hemorrhages were assessed. Small vessel disease included arteriolosclerosis and cerebral amyloid angiopathy. Postmortem brain tissue corresponding to regions of WMHs were investigated in 14 participants; variables included: demyelination of the deep and periventricular WM, atrophy of the ventricular ependyma, and thickness of blood vessels. Partial Spearman rank test and linear regression analysis, adjusted for age at the clinical evaluation and the duration to death, were performed.
Results
The severity of arteriosclerosis was correlated with the MRI-estimated volume of periventricular hyperintensity (PVH). Deep white matter hyperintensity (DWMH) volume was correlated with the presence of cortical microinfarcts and cerebral hemorrhages. The severity of the breakdown of the ventricular lining was correlated with PVHs and DWMHs correlated with the severity of deep WM demyelination. The diameter of small blood vessels was not associated with WMHs.
Conclusion
WMHs are consistent with small vessel disease and increased tissue water content. We found no association between WMHs and thickness of small blood vessels.
doi:10.1159/000366411
PMCID: PMC4312498  PMID: 25401390
small vessel disease; dementia; neuropathology; leukoaraiosis
13.  Attitudes of Research Participants and the General Public Regarding Disclosure of Alzheimer Disease Research Results 
JAMA neurology  2015;72(12):1484-1490.
IMPORTANCE
Results of Alzheimer disease (AD) research assessments typically are not disclosed to participants. Recent research has suggested interest in disclosure, but, to our knowledge, few studies have accounted for awareness of potential benefits and limitations of disclosure.
OBJECTIVE
To determine the attitudes of cognitively normal research participants and members of the general public regarding disclosure of AD research results.
DESIGN, SETTING, AND PARTICIPANTS
Participants in a longitudinal aging study (Alzheimer Disease Research Center [ADRC]) were given preintervention and postintervention surveys about disclosure attitudes. In a general public sample (The American Panel Survey), participants responded to a similar survey about disclosure attitudes.
INTERVENTIONS
Participants in the ADRC sample were randomly assigned to a group (n = 119) that read an education intervention about the usefulness of AD biomarkers or to a placebo group (n = 100) that read as its intervention general information about the ADRC. Participants in the general public sample read a brief vignette describing participation in a longitudinal AD study.
MAIN OUTCOME AND MEASURE
Interest in disclosure of AD research results.
RESULTS
Cognitively normal ADRC participants (n = 219) were 60.7% (n = 133) female, 83.6% (n = 183) of white race, and reported a mean of 15.91 years of education. Twenty-nine individuals refused participation. The American Panel Survey participants (n = 1418) indicated they did not have AD and were 50.5% (n = 716) female, 76.7% (n = 1087) of white race, and reported a mean of 13.85 years of education. Overall, 77.6% of eligible participants (1583 of 2041) completed the survey in July 2014. Interest in disclosure was high among the ADRC participants (55.1% [119 of 216] were “extremely interested”). Viewing the education intervention predicted lower interest in disclosure (odds ratio, 2.01; 95% CI, 1.15–3.53; P = .02). High subjective risk of AD, a family history of AD, and minimal attendance at research meetings were associated with high interest after the intervention. In the general public, interest was lower overall (12.5% [174 of 1389] were “extremely interested”), but the subset of participants most likely to join an AD research study reported higher interest (43.5% [40 of 92] were extremely interested).
CONCLUSIONS AND RELEVANCE
Experience with AD appears to increase interest in disclosure of AD research results. Learning about potential limitations of disclosure somewhat tempered interest. These findings should inform the development of disclosure policies for asymptomatic individuals in AD studies.
doi:10.1001/jamaneurol.2015.2875
PMCID: PMC4694568  PMID: 26501506
14.  Mild Physical Impairment Predicts Future Diagnosis of Dementia of the Alzheimer Type 
Journal of the American Geriatrics Society  2013;61(7):10.1111/jgs.12255.
OBJECTIVES
To determine whether mildly impaired physical function (based on performance-based assessment) is associated with the development of dementia of the Alzheimer type (DAT) in cognitively normal older adults.
DESIGN
Longitudinal, observational study with yearly assessments of physical and cognitive function. Mean follow-up was 5 years.
SETTING
Knight Alzheimer’s Disease Research Center at Washington University, St. Louis, Missouri.
PARTICIPANTS
Four hundred thirty-five cognitively normal adults, age 60 years or older participating in longitudinal studies of aging.
MEASUREMENTS
Survival analyses were used to examine whether scores on the 9-item Physical Performance Test (PPT) predicted time to DAT diagnosis. Cox proportional hazards models were used to examine associations between the PPT total scores and time to cognitive impairment and DAT; as well as the association of time to these events while adjusting for, and simultaneously testing the effects of age, gender, education, and presence of at least one apolipoprotein (APOE) ε4 allele.
RESULTS
During the follow-up period, 81 participants developed DAT. Compared to those who remained cognitively normal, participants diagnosed with DAT were older (81 vs 74.2 years; p=.001) and had worse performance on the PPT (25.5 vs 28.1; p=.009). Time to DAT diagnosis was associated with total scores on the PPT (hazard ratio [HR] =.89, 95% CI=.86–.93, p<.001) such that time to a DAT diagnosis was slower for participants with higher physical performance scores. In the adjusted analysis, the PPT scores significantly predicted time to a DAT diagnosis (HR =.94, 95% CI=.89–.99, p<.022).
CONCLUSION
The presence of mild physical impairment in cognitively normal older adults is associated with subsequent development of DAT. Although the physical impairment may be sufficiently mild that it is recognized only with performance-based assessments, its presence may predate clinically detectable cognitive decline.
doi:10.1111/jgs.12255
PMCID: PMC3809089  PMID: 23647233
Dementia of Alzheimer type; physical performance; predictors; frailty
15.  Progression of Alzheimer disease as measured by Clinical Dementia Rating sum of boxes scores 
Background
This study examined rates of dementia progression as ascertained by the Clinical Dementia Rating sum of boxes (CDR-SB) for symptomatic Alzheimer disease (sAD) and assessed participant characteristics as predictors of CDR-SB progression.
Methods
Participants (n = 792) were enrolled in longitudinal studies at an Alzheimer’s Disease Research Center, received a diagnosis of sAD with a global CDR of 0.5 (n = 466) or 1 (n = 326), and had at least one follow-up assessment. Progression in CDR-SB over time as a function of baseline global CDR was examined.
Results
A longitudinal increase (p<.0001) in CDR-SB was observed. The annual rate of change in CDR-SB scores was 1.43 (SE=.05) in the CDR 0.5 sample and 1.91 (SE=.07) in the CDR 1 sample. For participants followed from the beginning of the CDR stage, time to progression to a higher global CDR was longer for individuals who were CDR 0.5 (3.75 years; 95% CI 3.18-4.33) than those who were CDR 1 at baseline (2.98 years; 95%CI 2.75-3.22). In the total CDR 0.5 sample, the significant predictors of progression to the next global CDR stage (p<.01) were age at first sAD diagnosis and apolipoprotein E4 genotype.
Conclusions
The study findings are relevant to sAD clinical trial design and accurate, reliable ascertainment of the effect of disease-modifying treatments.
doi:10.1016/j.jalz.2012.01.005
PMCID: PMC3660405  PMID: 22858530
Alzheimer disease; assessment of dementia; Clinical Dementia Rating; Clinical Dementia Rating sum of boxes; cohort studies
16.  Neuropsychological changes in asymptomatic persons with Alzheimer disease neuropathology 
Neurology  2014;83(5):434-440.
Objective:
To determine whether asymptomatic persons with Alzheimer disease (AD) neuropathologic change differ in the trajectory of their cognitive performance compared to asymptomatic persons without AD neuropathologic change.
Methods:
Longitudinal performance on standard neuropsychological tests was examined in participants who died within 2 years of their last cognitive assessment and who were never diagnosed with mild cognitive impairment or dementia (Clinical Dementia Rating global score of 0 at all assessments). Using cognitive and neuropathologic data collected between 2005 and 2013 from the 34 National Institute on Aging–sponsored Alzheimer's Disease Centers, cognitive trajectories were compared for persons with and without evidence of AD neuropathologic change. We evaluated rates of decline in 4 domains (episodic memory, language, attention/working memory, executive function). The significance of the differences (β) in rates of decline was tested using linear regression, adjusting for age, education, sex, and other neuropathologic lesions.
Results:
Participants who had low to high levels of AD neuropathologic change (n = 131) showed a greater rate of decline on the attention/working memory domain score (β = −0.11; 95% confidence interval = −0.19, −0.02; p = 0.02) when compared to 80 participants who died without evidence of AD neuropathologic change.
Conclusions:
Clinically normal individuals who come to autopsy with AD neuropathologic change exhibit subtle evidence of declining cognitive trajectories for attention/working memory.
doi:10.1212/WNL.0000000000000650
PMCID: PMC4132573  PMID: 24951474
17.  Clinical Features of Alzheimer Disease With and Without Lewy Bodies 
JAMA neurology  2015;72(7):789-796.
IMPORTANCE
Lewy bodies are a frequent coexisting pathology in late-onset Alzheimer disease (AD). Previous studies have examined the contribution of Lewy bodies to the clinical phenotype of late-onset AD with variable findings.
OBJECTIVE
To determine whether the presence of Lewy body pathology influences the clinical phenotype and progression of symptoms in longitudinally assessed participants with AD.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective clinical and pathological cohort study of 531 deceased participants who met the neuropathologic criteria for intermediate or high likelihood of AD according to the National Institute on Aging–Ronald Reagan Institute guidelines for the neuropathologic diagnosis of AD. All participants had a clinical assessment within 2 years of death. The data were obtained from 34 AD centers maintained by the National Alzheimer Coordinating Center and spanned from September 12, 2005, to April 30, 2013.
EXPOSURES
Standardized neuropathologic assessment and then brain autopsy after death.
MAIN OUTCOMES AND MEASURES
Clinical and neuropsychiatric test scores.
RESULTS
The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). After adjusting for age, sex, education, frequency of plaques (neuritic and diffuse), and tangle stage, we found that participants who had AD with Lewy bodies had a statistically significantly higher mean (SD) Neuropsychiatric Inventory Questionnaire score (6.59 [1.44] [95% CI, 3.75–9.42] vs 5.49 [1.39] [95% CI, 2.76–8.23]; P = .04) and a statistically significantly higher mean (SD) Unified Parkinson Disease Rating Scale motor score (0.81 [0.18] [95% CI, 0.45–1.17] vs 0.54 [0.18] [95% CI, 0.19–0.88]; P < .001) than did participants who had AD without Lewy bodies.
CONCLUSIONS AND RELEVANCE
Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.
doi:10.1001/jamaneurol.2015.0606
PMCID: PMC4501861  PMID: 25985321
18.  Relationships between late-life hypertension, blood pressure, and Alzheimer's disease 
Relationships between late-life hypertension and AD remain less clear. Both cross-sectional and longitudinal methods were used to examine whether systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), mean arterial pressure (MAP), and self-reported hypertension (S-HTN) in late life were associated with having and developing AD. In the cross-sectional examination were 1,768 individuals with AD and 818 nondemented individual, and AD was not significantly associated with S-HTN or any of blood pressure measures (S-HTN: p=0.236; SBP: p=0.095; DBP: p=0.429; PP: p=0.145; MAP: p=0.162). In the longitudinal examination, 594 nondemented individuals, 171 with and 423 without self-reported hypertension at entry, were included. DBP was significantly related to the development of AD (p=0.030), but not S-HTN (p=0.251), SBP (p=0.294) PP (p=0.919), and MAP (p=0.060). The association underscores the necessity of further investigation to outline the detailed mechanisms and biological relevance, if any, of late-life DBP to later AD.
doi:10.1177/1533317511421779
PMCID: PMC3312309  PMID: 21921085
hypertension; systolic blood pressure; diastolic blood pressure; pulse pressure; mean arterial pressure; Alzheimer's disease
19.  Cerebrospinal Fluid Biomarkers, Education, Brain Volume and Future Cognition 
Archives of neurology  2011;68(9):1145-1151.
Objective
To evaluate the combination of cerebrospinal fluid biomarkers of Aβ42, tau, and phosphorylated tau (ptau181) with education and normalized whole brain volume (nWBV) to predict incident cognitive impairment and test the cognitive/brain reserve hypothesis.
Design
Longitudinal cohort study.
Setting
Charles F. and Joanne Knight Alzheimer’s Disease Research Center of Washington University, St. Louis, Missouri.
Participants
Convenience sample of 197 participants aged 50 years and above, with normal cognition (Clinical Dementia Rating [CDR] of 0) at baseline, followed for a mean of 3.3 years.
Main outcome measure
Time to cognitive impairment (CDR ≥ 0.5).
Results
Three-factor interactions between the baseline biomarker values, education, and nWBV were found for Cox proportional hazards models testing tau (p=.03) and ptau (p=.008). Among those with lower tau values, nWBV (hazard ratio [HR]=.54, 95% confidence interval [CI]=.31–.91; p=.02), but not education, was related to time to cognitive impairment. For participants with higher tau values, education interacted with nWBV to predict incident impairment (p=.01). For individuals with lower ptau values, there was no effect of education or nWBV. Education interacted with nWBV to predict incident cognitive impairment among those with higher ptau values (p=.02). In models testing Aβ42, larger nWBV was associated with a slower time to cognitive impairment (HR=.84, 95%CI=.71–.99, p=.0348), but there was no effect of Aβ42 or education.
Conclusions
Among individuals with higher levels of CSF tau and ptau, but normal cognition at baseline, time to incident cognitive impairment is moderated by education and brain volume as predicted by the cognitive/brain reserve hypothesis.
doi:10.1001/archneurol.2011.192
PMCID: PMC3203689  PMID: 21911695
20.  The effects of white matter hyperintensities and amyloid deposition on Alzheimer dementia 
NeuroImage : Clinical  2015;8:246-252.
Background and purpose
Elevated levels of amyloid deposition as well as white matter damage are thought to be risk factors for Alzheimer Disease (AD). Here we examined whether qualitative ratings of white matter damage predicted cognitive impairment beyond measures of amyloid.
Materials and methods
The study examined 397 cognitively normal, 51 very mildly demented, and 11 mildly demented individuals aged 42–90 (mean 68.5). Participants obtained a T2-weighted scan as well as a positron emission tomography scan using 11[C] Pittsburgh Compound B. Periventricular white matter hyperintensities (PVWMHs) and deep white matter hyperintensities (DWMHs) were measured on each T2 scan using the Fazekas rating scale. The effects of amyloid deposition and white matter damage were assessed using logistic regressions.
Results
Levels of amyloid deposition (ps < 0.01), as well as ratings of PVWMH (p < 0.01) and DWMH (p < 0.05) discriminated between cognitively normal and demented individuals.
Conclusions
The amount of amyloid deposition and white matter damage independently predicts cognitive impairment. This suggests a diagnostic utility of qualitative white matter scales in addition to measuring amyloid levels.
Highlights
•White matter damage was quantified using the Fazekas rating scale.•Measures of amyloid were measured using positron emission tomography.•There was a greater severity of damage in demented individuals.•White matter damage significantly predicted dementia after controlling for amyloid.•There is a clinical utility to using the Fazekas scale in addition to amyloid levels.
doi:10.1016/j.nicl.2015.04.017
PMCID: PMC4474174  PMID: 26106548
Alzheimer's; White matter; Amyloid; Biomarkers; Vascular; Myelin
21.  The effect of APOE ε4 allele on cholinesterase inhibitors in patients with Alzheimer’s disease: Evaluation of the feasibility of resting state functional connectivity magnetic resonance imaging 
This work is to determine whether apolipoprotein E (APOE) genotype modulates the effect of cholinesterase inhibitor (ChEI) treatment on resting state functional connectivity magnetic resonance imaging (rs-fcMRI) in patients with Alzheimer’s disease (AD). We retrospectively studied very mild and mild AD participants who were treated (N=25) or untreated (N=19) with ChEIs with respect to rs-fcMRI measure of 5 resting state networks (RSNs): default mode, dorsal attention (DAN), control (CON), salience (SAL), and sensory-motor. For each network, a composite score was computed as the mean of Pearson’s correlations between pairwise time courses extracted from areas comprising this network. The composite scores were analyzed as a function of ChEI treatment and APOE ε4 allele. Across all participants, significant interactions between ChEI treatment and APOE ε4 allele were observed for all 5 RSNs. Within APOE ε4 carriers, significantly greater composite scores were observed in the DAN, CON and SAL for treated compared to untreated participants. Within APOE ε4 non-carriers, treated and untreated participants did not have significantly different composite scores for all RSNs. These data suggest that APOE genotype affects the response to ChEI using rs-fcMRI. Rs-fcMRI may be useful for assessing the therapeutic effect of medications in AD clinical trials.
doi:10.1097/WAD.0b013e318299d096
PMCID: PMC4024181  PMID: 24830360
Alzheimer’s disease (AD); functional magnetic resonance imaging (fMRI); Cholinesterase inhibitor; Apolipoprotein E (APOE); resting state functional connectivity
22.  Education and Reported Onset of Symptoms among Individuals with Alzheimer’s Disease 
Archives of neurology  2008;65(1):108-111.
Objective
To examine whether reported age at onset (AAO) of dementia symptoms among participants with Alzheimer’s disease (AD) is later for those with fewer years of education and, if so, to see if it is attributed to delayed detection of symptoms.
Design
Case series.
Setting
National Alzheimer’s Coordinating Center Minimum Data Set (N=21,880 participants) and Washington University Alzheimer’s Disease Research Center (N=1,449 participants).
Results
Reported AAO of dementia symptoms is slightly earlier for participants with more education. Participants with fewer years of education show greater clinical severity of AD at first assessment.
Conclusion
Symptoms of AD are recognized later among those with less education.
doi:10.1001/archneurol.2007.11
PMCID: PMC2830808  PMID: 18195147
23.  Alzheimer’s and Cognitive Reserve 
Archives of neurology  2008;65(11):1467-1471.
Objective
To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid.
Design, Setting, and Participants
Uptake of N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroybenzothiazole, or [11C]PIB for “Pittsburgh Compound-B,” was measured for participants assessed between August 15, 2003 and January 8, 2008 at the Washington University Alzheimer’s Disease Research Center and diagnosed either as nondemented (N=161) or with dementia of the Alzheimer type (N=37). Multiple regression was used to determine whether [11C]PIB uptake interacted with level of educational attainment to predict cognitive function.
Main Outcome Measures
Scores on the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Mini-Mental State Exam (MMSE), and Short Blessed Test (SBT), and individual measures from a psychometric battery.
Results
[11C]PIB uptake interacted with years of education in predicting scores on the CDR-SB (p=.003), the MMSE (p<.001), the SBT (p=.03) and a measure of verbal abstract reasoning and conceptualization (p=.02), such that performance on these measures increased with increasing education for participants with elevated PIB uptake. Education was unrelated to global cognitive functioning scores among those with lower PIB uptake.
Conclusions
These results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathology and cognition.
doi:10.1001/archneur.65.11.1467
PMCID: PMC2752218  PMID: 19001165
24.  Interaction of Neuritic Plaques and Education Predicts Dementia 
In exploring the cognitive reserve hypothesis in persons with substantial Alzheimer disease neuropathology, we aimed to determine the extent to which educational attainment and densities of diffuse plaques, neuritic plaques, and neurofibrillary tangles predict dementia. Participants were 1563 individuals aged 65 years or above who were assessed for dementia within 1 year of death. Generalized linear mixed models were used to examine whether education and density ratings of diffuse plaques and neuritic plaques, and neurofibrillary tangle stage were associated with a dementia diagnosis. Education interacted with densities of neuritic plaques to predict dementia. Tangle density independently predicted dementia, but did not interact with education. Diffuse plaque density was unrelated to dementia when adjusted for densities of neuritic plaques and tangles. Among individuals with Alzheimer disease neuropathology, educational attainment, as a surrogate of cognitive reserve, modifies the influence of neuritic, but not diffuse, plaque neuropathology on the expression of dementia.
doi:10.1097/WAD.0b013e3181610fff
PMCID: PMC2770714  PMID: 18525294
Alzheimer disease; cognitive reserve; education; neuropathology
25.  CSF biomarkers of Alzheimer disease 
Neurology  2013;81(23):2028-2031.
Objectives:
To test whether CSF Alzheimer disease biomarkers (β-amyloid 42 [Aβ42], tau, phosphorylated tau at threonine 181 [ptau181], tau/Aβ42, and ptau181/Aβ42) predict future decline in noncognitive outcomes among individuals cognitively normal at baseline.
Methods:
Longitudinal data from participants (N = 430) who donated CSF within 1 year of a clinical assessment indicating normal cognition and were aged 50 years or older were analyzed. Mixed linear models were used to test whether baseline biomarker values predicted future decline in function (instrumental activities of daily living), weight, behavior, and mood. Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination scores were also examined.
Results:
Abnormal levels of each biomarker were related to greater impairment with time in behavior (p < 0.035) and mood (p < 0.012) symptoms, and more difficulties with independent activities of daily living (p < 0.012). However, biomarker levels were unrelated to weight change with time (p > 0.115). As expected, abnormal biomarker values also predicted more rapidly changing Mini-Mental State Examination (p < 0.041) and Clinical Dementia Rating Sum of Boxes (p < 0.001) scores compared with normal values.
Conclusions:
CSF biomarkers among cognitively normal individuals are associated with future decline in some, but not all, noncognitive Alzheimer disease symptoms studied. Additional work is needed to determine the extent to which these findings generalize to other samples.
doi:10.1212/01.wnl.0000436940.78152.05
PMCID: PMC3854826  PMID: 24212387

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