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1.  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
2.  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
3.  Exploration of 100 commonly used drugs and supplements on cognition in older adults 
Background
There are conflicting reports and a lack of evidence-based data regarding effects of medications on cognition in cognitively normal older adults. We explored whether use of 100 common medications taken by older adults is associated with longitudinal cognitive performance.
Methods
A longitudinal observational cohort was used with analysis of data collected September 2005 through May 2011 and maintained in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. Participants were aged 50 years or older and cognitively normal (N=4414). Composite scores were constructed from 10 psychometric tests. Scores for each participant reflecting change in the psychometric composite score from the baseline clinical assessment to the next assessment were calculated. General linear models were used to test whether the mean composite change score differed for participants who reported starting, stopping, continuing, or not taking each of the 100 most frequently-used medications in the NACC sample.
Results
The average time between assessments was 1.2 years (SD=0.42). Nine medications showed a difference (p<0.05) across the four participant groups in mean psychometric change scores from the first to the second assessment. Medications associated with improved psychometric performance were: naproxen, calcium-vitamin D, ferrous sulfate, potassium chloride, flax, and sertraline. Medications associated with declining psychometric performance were: bupropion, oxybutynin, and furosemide.
Conclusions
Reported use of common medications is associated with cognitive performance in older adults, but studies are needed to investigate the mechanisms underlying these effects.
doi:10.1016/j.jalz.2012.12.002
PMCID: PMC3823812  PMID: 23954027
cognition; medications; psychometric tests; National Alzheimer’s Coordinating Center
4.  Preclinical Alzheimer disease and risk of falls 
Neurology  2013;81(5):437-443.
Objective:
We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau.
Methods:
We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors.
Results:
The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall.
Conclusions:
Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.
doi:10.1212/WNL.0b013e31829d8599
PMCID: PMC3776538  PMID: 23803314
5.  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
6.  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
7.  Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology 
Neurology  2013;80(23):2121-2129.
Objectives:
We sought to identify demographic and clinical features that were associated with expression of symptoms in the presence of Alzheimer disease (AD) neuropathologic changes.
Methods:
We studied 82 asymptomatic (Clinical Dementia Rating global score = 0) and 824 symptomatic subjects (Clinical Dementia Rating score >0) with low to high AD neuropathologic changes at autopsy who were assessed at 1 of 34 National Institute on Aging–funded Alzheimer’s Disease Centers. All subjects underwent a clinical examination within 1 year of death. Logistic regression was used to evaluate factors associated with the odds of being asymptomatic vs symptomatic.
Results:
Asymptomatic subjects tended to have low neurofibrillary tangle scores but a wide range of neuritic plaque frequencies. There were, however, a few asymptomatic subjects with very high tangle and neuritic plaque burden, as well as symptomatic subjects with few changes. In the multivariable model, asymptomatic subjects were older (odds ratio [OR] = 1.04; 95% confidence interval [CI] = 1.01–1.07), had lower clinical Hachinski Ischemic Score (OR = 0.82; 95% CI = 0.69–0.97), were less likely to have an APOE ε4 allele (OR = 0.36; 95% CI = 0.16–0.83), and had lower neurofibrillary tangle score (OR = 0.28; 95% CI = 0.17–0.45) compared with symptomatic subjects.
Conclusions:
Dissociating clinical symptoms from pathologic findings better allows for investigation of preclinical AD. Our results suggest that although the severity of the pathology, particularly neurofibrillary tangles, has a large role in determining the extent of symptoms, other factors, including age, APOE status, and comorbidities such as cerebrovascular disease also explain differences in clinical presentation.
doi:10.1212/WNL.0b013e318295d7a1
PMCID: PMC3716351  PMID: 23645594
8.  Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later 
Neurology  2013;80(19):1784-1791.
Objectives:
We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.
Methods:
Longitudinal data from Knight Alzheimer's Disease Research Center participants (N = 201) followed for a mean of 3.70 years (SD = 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. “Expanded” models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.
Results:
Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p > 0.074), nor did we find differences between the expanded biomarker models (p > 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p < 0.005).
Conclusions:
Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms.
doi:10.1212/WNL.0b013e3182918ca6
PMCID: PMC3719431  PMID: 23576620
9.  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
10.  Clinicopathologic Study of Alzheimer’s Disease: Alzheimer mimics 
A definite diagnosis of Alzheimer disease (AD) can only be made at autopsy. Even at expert research centers, diagnostic accuracy is relatively low. We conducted this study to examine the accuracy of clinical diagnosis of AD and present a list of clinical and neuropsychological findings that could render the clinical diagnosis difficult. Using the National Alzheimer’s Coordinating Center database, the records of 533 patients who had been diagnosed clinically with AD and later underwent autopsy, were reviewed retrospectively. Since the pathologic results of 119 subjects did not meet the criteria for definite AD, we labeled them as Alzheimer “mimics”. The neuropathological diagnoses of Alzheimer mimics consisted of dementia with Lewy body (n=35, 29%), insufficient AD (n=22, 18%), vascular disease (n=15, 13%), frontotemporal lobar degeneration (n=14, 12%) and hippocampal sclerosis (n=10, 8%). History of pacemaker insertion (10.92% vs. 4.11%, p=0.005), congestive heart failure (13.45% vs. 6.04% p=0.007), hypertension (56.30% vs. 47.83%, p=0.037) and resting tremor (14.29% vs. 10.87%, p=0.170) was more prevalent in Alzheimer mimics. Clinical Dementia Rating score and frequency of Neuropsychiatric Inventory Questionnaire items reflecting delusions, agitation, depression and motor disturbance were more severe in confirmed AD. In addition to Mini-Mental State Examination (16.97±8.29 vs. 12.74±15.26, p<0.001), Logical Memory, Animal Fluency, Boston Naming Test and Digit Span scores showed more severe impairment in confirmed AD. Continuing systematic comparisons of the current criteria for the clinical and pathological dementia diagnoses are essential to clinical practice and research, and may also lead to further improvement of the diagnostic procedure.
doi:10.3233/JAD-121594
PMCID: PMC3725959  PMID: 23481687
Alzheimer’s disease; diagnosis; pathology; dementia with Lewy bodies
11.  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
12.  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
13.  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
14.  Inverse Susceptibility to Oxidative Death of Lymphocytes Obtained From Alzheimer's Patients and Skin Cancer Survivors: Increased Apoptosis in Alzheimer's and Reduced Necrosis in Cancer 
A paucity of cancer in individuals with Alzheimer's disease (AD) and low rates of AD in cancer survivors has been reported in epidemiological studies. Deregulation in opposite directions of biological mechanisms, such as susceptibility to cell death, might be shared in the two disorders. We analyzed lymphocytes from AD and skin cancer patients as well as healthy controls and found significantly increased vulnerability of AD lymphocytes to H2O2-induced apoptotic death and higher resistance to death of skin cancer lymphocytes, due to reduced necrosis, as compared with healthy controls by pairwise comparisons adjusted for age and sex. H2O2-induced death in lymphocytes was caspase independent and significantly reduced by PARP-1 inhibition in all three groups. These differences in the susceptibility to cell death observed for lymphocytes from AD and skin cancer patients may be one of the mechanisms that help explain the inverse correlation detected between these diseases in epidemiological studies.
doi:10.1093/gerona/glr258
PMCID: PMC3437969  PMID: 22367434
Alzheimer; Cancer; Cell death; Apoptosis; Necrosis
15.  Alzheimer’s disease family history impacts resting state functional connectivity 
Annals of neurology  2012;72(4):571-577.
Objective
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
Method
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
Results
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Interpretation
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
doi:10.1002/ana.23643
PMCID: PMC3490438  PMID: 23109152
16.  Role of family history for Alzheimer biomarker abnormalities in the adult children study 
Archives of Neurology  2011;68(10):1313-1319.
Objective
To assess whether family history (FH) of Alzheimer’s disease (AD) alone influences AD biomarker abnormalities.
Design
Adult Children Study (ACS).
Setting
Washington University's Knight Alzheimer's Disease Research Center.
Participants
Cognitively normal middle to older age individuals with and without a FH for AD (n=269).
Main Outcome Measures
Clinical and cognitive measures, magnetic resonance imaging (MRI)-based brain volumes, diffusion tensor imaging (DTI)-based white matter microstructure, cerebrospinal fluid (CSF) biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound-B (PIB).
Results
A positive FH for AD was associated with an age-related decrease of CSF Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted CSF Aβ42 was decreased for individuals with APOE4 compared with those without, and the decrease was larger for individuals with a positive FH compared with those without. The variation of CSF tau and PIB mean cortical binding potential (MCBP) increased by age. For individuals younger than 55, an age-related increase in MCBP was associated with APOE4, but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in MCBP. A positive FH was associated with decreased fractional anisotropy from DTI in the genu and splenium of the corpus callosum.
Conclusion
Independent of APOE4, FH is associated with age-related change of several CSF, PIB and DTI biomarkers in cognitively normal middle to older age individuals, suggesting that non-APOE susceptibility genes for AD influence AD biomarkers.
doi:10.1001/archneurol.2011.208
PMCID: PMC3327304  PMID: 21987546
17.  YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer’s Disease 
Biological psychiatry  2010;68(10):903-912.
Background
Disease-modifying therapies for Alzheimer’s disease (AD) would be most beneficial if applied during the ‘preclinical’ stage (pathology present with cognition intact) before significant neuronal loss occurs. Therefore, biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression will be invaluable for patient care and efficient clinical trial design.
Methods
2D–difference gel electrophoresis and liquid chromatography tandem mass spectrometry were used to measure AD-associated changes in cerebrospinal fluid (CSF). Concentrations of CSF YKL-40 were further evaluated by enzyme-linked immunosorbent assay in the discovery cohort (N=47), an independent sample set (N=292) with paired plasma samples (N=237), frontotemporal lobar degeneration (N=9), and progressive supranuclear palsy (PSP, N=6). Human AD brain was studied immunohistochemically to identify potential source(s) of YKL-40.
Results
In the discovery and validation cohorts, mean CSF YKL-40 was higher in very mild and mild AD-type dementia (Clinical Dementia Rating [CDR] 0.5 and 1) vs. controls (CDR 0) and PSP. Importantly, CSF YKL-40/Aβ42 ratio predicted risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) as well as the best CSF biomarkers identified to date, tau/Aβ42 and p-tau181/Aβ42. Mean plasma YKL-40 was higher in CDR 0.5 and 1 vs. CDR 0 groups, and correlated with CSF levels. YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aβ deposition.
Conclusions
These data demonstrate that YKL-40, a putative indicator of neuroinflammation, is elevated in AD, and that, together with Aβ42, has potential prognostic utility as a biomarker for preclinical AD.
doi:10.1016/j.biopsych.2010.08.025
PMCID: PMC3011944  PMID: 21035623
YKL-40; Alzheimer’s disease; biomarkers; cerebrospinal fluid; chitinase-3 like-1; inflammation
18.  Autobiographical Memory Task in Assessing Dementia 
Archives of neurology  2010;67(7):862-866.
Objective
To appraise the relationship of a task assessing memory for recent autobiographical events and those of two commonly used brief memory tasks with the results of a clinical assessment for dementia.
Design, Setting, and Participants
We compared correlations between a task assessing recall of recent autobiographical events and two frequently-used brief clinical memory measures with dementia ratings by clinicians. Participants were enrolled in Washington University Alzheimer’s Disease Research Center studies, were aged 60 years or above, and took part in assessments between May 2002 and August 2005 (N=425).
Main Outcome Measures
Nonparametric, rank-based Spearman correlations, adjusted for age and education, between the Clinical Dementia Rating Sum of Boxes (CDR-SB) and scores on the autobiographical recall query and two clinical memory tasks taken from the Mini-Mental State Exam and the Short Blessed Test.
Results
The autobiographical recall task and each of the other brief clinical measures correlated significantly with the CDR-SB (p<.0001). The autobiographical recall task had a significantly higher correlation (p<.0001) with the CDR-SB than the two commonly-used clinical memory measures.
Conclusions
Clinicians may find autobiographical memories an important indicator of clinical memory function and the autobiographical query a useful tool when assessing for dementia.
doi:10.1001/archneurol.2010.145
PMCID: PMC2904638  PMID: 20625094
19.  Unified Parkinson’s Disease Rating Scale-Motor Exam: Inter-rater reliability of advanced practice nurse and neurologist assessments 
Journal of advanced nursing  2010;66(6):1382-1387.
Aim
This paper is a report of a study to establish the inter-rater reliability of advanced practice nurse and neurologist neurological assessments which included ratings with the Unified Parkinson’s Disease Rating Scale-Motor Exam.
Background
Around the world, advanced practice nurses are performing tasks once completed by only physicians. To promote consumer and provider confidence, it is important to establish that nurse and physician ratings using assessment tools are similar. In addition in research settings, when different raters are used, establishment of inter-rater reliability for study assessments is needed.
Method
Advanced practice nurses and neurologists independently recorded findings on neurological examinations of 46 participants in a study conducted between August 2007 and January 2008. An intraclass correlation coefficient was calculated to estimate overall agreement between the nurse and neurologist ratings. Agreement for individual items measured on a dichotomous scale was assessed by calculating Cohen’s kappa.
Results
There was substantial agreement between advanced practice nurses and neurologists on the mean Unified Parkinson’s Disease Rating Scale-Motor Exam ratings (intraclass correlation coefficient = 0.65) and the U.S. National Alzheimer’s Coordinating Center Uniform Data Set neurological examination ratings of unremarkable findings (kappa = 0.74) and of gait disorder (kappa = 0.73). Moderate agreement (kappa = 0.53) was reached for the rating of whether all Unified Parkinson’s Disease Rating Scale-Motor Exam items were normal.
Conclusion
These findings are consistent with studies of the inter-rater agreement of the Unified Parkinson’s Disease Rating Scale-Motor Exam and support the conduct of neurological assessments by advanced practice nurses.
doi:10.1111/j.1365-2648.2010.05313.x
PMCID: PMC2903978  PMID: 20546368
Unified Parkinson’s Disease Rating Scale; advanced practice nurse; neurologist; inter-rater reliability; neurological examination
20.  Thyroid medication use and subsequent development of dementia of the Alzheimer type 
Associations between medication use and the development of Alzheimer’s disease have been investigated since the late 1900s. Thyroid hormone supplementation is rarely a studied medication class in this area of research. We examined data from participants enrolled in longitudinal studies at the Washington University Alzheimer’s Disease Research Center for associations between thyroid disease, thyroid hormone supplementation therapy, and subsequent development of dementia of the Alzheimer type (DAT). Data collected between April 1992 and June 2008 from 499 participants, 184 men and 315 women, were analyzed. Mean age was 76.9 years (S.D. = 9.2). At baseline, 61 participants reported thyroid medication use and 87 were identified as having a history of thyroid dysfunction. These participants progressed to a DAT diagnosis more rapidly than individuals not taking thyroid medication (HR: 1.67, 95% CI: 0.99–2.78, p = 0.054). While an interesting trend was seen, baseline thyroid disease was not significantly (p=.093) associated with time to DAT diagnosis. Our findings suggest that utilization of thyroid medication may be associated with the development of DAT.
doi:10.1177/0891988709342723
PMCID: PMC2820146  PMID: 19666883
thyroid; dysfunction; hormone replacement; Alzheimer’s; dementia
21.  Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease 
PLoS ONE  2011;6(1):e16032.
Background
Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the ‘preclinical’ stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.
Methods and Findings
CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85–0.94 95% confidence interval [CI]) and 0.88 (0.81–0.94 CI), respectively.
Conclusions
Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.
doi:10.1371/journal.pone.0016032
PMCID: PMC3020224  PMID: 21264269
22.  A brief clinical tool to assess physical function: The mini physical performance test 
The aim was to develop a brief physical performance assessment tool that can be reliably used to detect physical impairment in older adults with and without mild dementia. Scores on the 9-item physical performance test (PPT) from non-demented participants were used to develop and validate the 4-item mini-PPT. The validated mini-PPT was then used to predict total PPT score and functional physical status in participants with mild dementia. Receiver Operating Curve (ROC) analyses were used to generate a cut off score that classifies participants as functional vs. not functional. The setting was in the Alzheimer’s Disease Research Center (Washington University). A total of 1,199 participants met inclusion criteria: 574 non demented participants, 436 with very mild dementia, measured by the clinical dementia rating (CDR) = 0.5 and 189 with mild dementia (CDR = 1). The mean age of the sample was 76.4 years, mean educational attainment was 14 years, 58% were women, and 11% were African American. A 4-item scale, the mini-PPT, was developed (based on the results of multiple regression analyses and clinical meaningfulness) that highly correlated with total PPT score (r = 0.917, p < 0.0001) in the non-demented sample The correlation of the mini-PPT with total PPT was 0.90 among those with very mild, and 0.91 among those with mild dementia. Using the ROCs, a cut off score of 12 correctly classified at least 85% of non demented and demented persons. The 4-item mini-PPT is highly correlated with the 9-item PPT in non demented and mildly demented persons. This brief tool may be useful in detecting early physical impairment in the clinical setting.
doi:10.1016/j.archger.2009.02.006
PMCID: PMC2787987  PMID: 19282039
physical performance; assessment of physical performance; Alzheimer’s disease; dementia
23.  APOE Predicts Aβ but not Tau Alzheimer’s Pathology in Cognitively Normal Aging 
Annals of neurology  2010;67(1):122-131.
Objective
To examine interactions of Apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer’s disease (AD) in cognitively normal aging.
Methods
Two hundred and 41 cognitively normal individuals, age 45 to 88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta42 (Aβ42), tau, and phosphorylated tau (ptau181). All individuals were genotyped for APOE.
Results
The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Aβ42 appear to begin earlier (18.2% of those age 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There is a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Aβ42 with increased numbers of APOE4 alleles. Individuals with an APOE2 have no increase in MCBP with age and have higher CSF Aβ42 levels than individuals without an APOE2 allele. There is no APOE4 or APOE2 effect on CSF tau or ptau181.
Interpretation
Increasing cerebral Aβ deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Aβ deposition may first be lowered CSF Aβ42, followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.
doi:10.1002/ana.21843
PMCID: PMC2830375  PMID: 20186853
preclinical Alzheimer’s disease; Alzheimer’s biomarkers; Aβ; amyloid imaging (PIB); APOE
24.  PIB Imaging Predicts Progression from Cognitively Normal to Symptomatic Alzheimer’s Disease 
Archives of neurology  2009;66(12):1469-1475.
Objective
To determine whether preclinical Alzheimer’s disease (AD), as detected by the amyloid imaging agent Pittsburgh Compound B (PIB) in cognitively normal older adults, is associated with risk of symptomatic AD.
Design
A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PIB and followed with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT).
Setting
Alzheimer’s Disease Research Center
Participants
One hundred and fifty-nine participants with mean age of 71.5 y in a longitudinal study of memory and aging had a PET PIB scan when cognitively normal with Clinical Dementia Rating (CDR) of 0.
Outcome Measure
Progression from CDR 0 status to CDR 0.5 (very mild dementia).
Results
Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range: 1–5 assessments after PET PIB). Of these, 9 also were diagnosed with DAT. Higher MCBP values for PIB (hazard ratio 4.85, 95% CI, 1.22–19.01, p = .02) and age (hazard ratio 1.14, 95% CI 1.02–1.28, p = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in three cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained CDR 0.
Conclusions
Preclinical AD, as detected by PET PIB, is not benign as it is associated with progression to symptomatic AD.
doi:10.1001/archneurol.2009.269
PMCID: PMC2798814  PMID: 20008650
25.  Neuropathology of Nondemented Aging: Presumptive Evidence for Preclinical Alzheimer Disease 
Neurobiology of aging  2009;30(7):1026-1036.
Objective
To determine the frequency and possible cognitive effect of histological Alzheimer’s disease (AD) in autopsied older nondemented individuals.
Design
Senile plaques (SPs) and neurofibrillary tangles (NFTs) were assessed quantitatively in 97 cases from 7 Alzheimer’s Disease Centers (ADCs). Neuropathological diagnoses of AD (npAD) were also made with four sets of criteria. Adjusted linear mixed models tested differences between participants with and without npAD on the quantitative neuropathology measures and psychometric test scores prior to death. Spearman rank-order correlations between AD lesions and psychometric scores at last assessment were calculated for cases with pathology in particular regions.
Setting
Washington University Alzheimer’s Disease Research Center.
Participants
Ninety-seven nondemented participants who were age 60 years or older at death (mean = 84 years).
Results
About 40% of nondemented individuals met at least some level of criteria for npAD; when strict criteria were used, about 20% of cases had npAD. Substantial overlap of Braak neurofibrillary stages occurred between npAD and no-npAD cases. Although there was no measurable cognitive impairment prior to death for either the no-npAD or npAD groups, cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs.
Conclusions
Neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness. By age 80–85 years, many nondemented older adults have substantial AD pathology.
doi:10.1016/j.neurobiolaging.2009.04.002
PMCID: PMC2737680  PMID: 19376612
preclinical Alzheimer’s disease; nondemented aging; neuropathological Alzheimer’s disease

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