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1.  Amyloid-β Dynamics in Human Plasma 
Archives of neurology  2012;69(12):10.1001/archneurol.2012.18107.
Background
A marked decrease of Aβ42 in the cerebrospinal fluid (CSF) of patients with incipient Alzheimer's Disease (AD) has been well documented. However, contradictory results have been reported from studies on plasma Aβ levels as diagnostic markers for AD.
Objective
To investigate dynamic changes in human plasma Aβ levels, evaluate the effects of aging and amyloidosis on these dynamics, and determine their correlation with CSF Aβ levels.
Design, Settings, and Participants
This was a repeated plasma and CSF sampling study conducted at the Washington University School of Medicine in St. Louis. Older adults with amyloid deposition (Amyloid +), age-matched controls without amyloid deposition (Amyloid −), and younger normal controls (YNC) were enrolled for the study.
Main Outcome Measures
Hourly measurements of plasma Aβ were compared between groups by age and amyloidosis. Plasma Aβ and CSF Aβ levels were compared for correlation, linear increase, and circadian patterns.
Results
Circadian patterns were observed in plasma Aβ, with diminished amplitudes with aging. Linear increase of Aβ was only observed for CSF Aβ in YNC and Amyloid − groups, but not in the Amyloid + group. No linear increase was observed for plasma Aβ. No significant correlations were found between plasma and CSF Aβ levels.
Conclusions
Plasma Aβ, like CSF, demonstrates a circadian pattern which is reduced in amplitude with increasing age but is unaffected by amyloid deposition. However, we found no evidence that plasma and CSF Aβ levels were related on an hourly or individual basis.
doi:10.1001/archneurol.2012.18107
PMCID: PMC3808092  PMID: 23229043
2.  Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia 
Archives of neurology  2012;69(6):700-708.
Objective
To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a Workgroup sponsored by the National Institute on Aging and the Alzheimer’s Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.
Design
Retrospective review of ratings of functional impairment across diagnostic categories. Participants: The functional ratings of individuals (N = 17,535) with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer’s Disease Centers and submitted to the National Alzheimer’s Coordinating Center were assessed in accordance with the definition of “functional independence” allowed by the revised criteria.
Methods
Pairwise demographic differences between the 3 diagnostic groups were tested using t-tests for continuous variables and chi-square for categorical variables.
Results
Almost all (99.8%) of individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these AD dementia individuals also meet the revised “functional independence” criterion for MCI as measured by the Functional Assessment Questionnaire.
Conclusions
The categorical distinction between MCI and milder stages of Alzheimer dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that “MCI due to AD” represents the earliest symptomatic stage of AD.
doi:10.1001/archneurol.2011.3152
PMCID: PMC3423496  PMID: 22312163
Dementia Diagnosis; Alzheimer disease; MCI
3.  Exercise engagement as a moderator of APOE effects on amyloid deposition 
Archives of neurology  2012;69(5):636-643.
Objective
APOE ε4 status has been associated with greater cortical amyloid deposition whereas exercise has been associated with less in cognitively normal adults. The primary objective here was to examine whether physical exercise moderates the association between APOE genotype and amyloid deposition in cognitively normal adults.
Method
APOE genotyping and a questionnaire on physical exercise engagement over the last decade were obtained in conjunction with cerebrospinal fluid (CSF) samples and amyloid imaging with PET-PIB. Participants were classified as either low or high exercisers based on exercise guidelines of the American Heart Association.
Subjects
201 cognitively normal adults (135 females) aged 45–88 were recruited from the Knight Alzheimer Disease Research Center at Washington University. CSF samples were collected from 165 participants. Amyloid imaging was performed on 163 participants.
Results
APOE ε4 carriers evidenced higher PIB binding (p<.001) and lower CSF Aβ42 levels (p<.001) than non-carriers. Our previous findings of higher PIB binding (p=.005) and lower CSF Aβ42 levels (p=.009) in more sedentary individuals were replicated. Most importantly, we observed a novel interaction between APOE status and exercise engagement for PIB binding (p=.008) such that a more sedentary lifestyle was significantly associated with higher PIB binding for ε4 carriers (p=.013) but not for ε4 non-carriers (p=.208). All findings remained significant after controlling for age, gender, education, hypertension, body mass index, diabetes, heart problems, history of depression and interval between assessments.
Conclusion
Collectively, these results suggest that cognitively normal sedentary APOE ε4+ individuals may be at augmented risk for cerebral amyloid deposition.
doi:10.1001/archneurol.2011.845
PMCID: PMC3583203  PMID: 22232206
4.  HIV Associated Neurocognitive Disorder (HAND) is Not Associated with Increased Fibrillar Amyloid Deposits Using 11C-PiB in Middle-Aged HIV+ Participants 
Archives of neurology  2012;69(1):72-77.
Objectives
Diagnostic challenges exist for differentiating HIV associated neurocognitive disorders (HAND) from symptomatic Alzheimer’s disease (AD) in HIV+ participants. Both disorders have cerebral amyloid containing plaques associated with abnormalities in amyloid beta protein 1–42 (Aβ42) metabolism. We evaluated if the amyloid-binding agent 11C-Pittsburgh compound B (11C-PiB) could discriminate AD from HAND in middle-aged HIV+ participants.
Design
11C-PiB scanning, clinical assessment, and cerebrospinal fluid (CSF) analysis were performed. χ2 and t-tests assessed differences in clinical and demographic variables between HIV+ participants and community-living individuals followed by Alzheimer Disease Research Center (ADRC). An analysis of variance (ANOVA) assessed for regional differences in Aβ42 using 11C-PiB.
Setting
ADRC and HIV clinic
Participants
16 HIV+ participants (11 cognitively normal, 5 with HAND) and 19 ADRC participants (8 cognitively normal, 11 with symptomatic AD).
Main Outcome Measure(s)
Mean and regional 11C-PiB binding potentials
Results
Symptomatic AD were older (p < 0.001), had lower CSF Aβ42 (p < 0.001), and had higher CSF tau levels (p < 0.001) than other groups. Regardless of degree of impairment, HIV+ participants did not have increased 11C-PiB. Mean and regional binding potentials were elevated for symptomatic AD participants (p <0.0001).
Conclusions
Middle-aged HIV+ participants, even with HAND, do not exhibit increased 11C-PiB while symptomatic AD individuals have increased fibrillar Aβ42 deposition in cortical and subcortical regions. Observed dissimilarities between HAND and AD may reflect differences in Aβ42 metabolism. 11C-PiB may provide a diagnostic biomarker for distinguishing symptomatic AD from HAND in middle-aged HIV+ participants. Future cross sectional and longitudinal studies are required to assess utility of 11C-PiB in older HAND individuals.
doi:10.1001/archneurol.2011.761
PMCID: PMC3536500  PMID: 22232345
HIV; Pittsburgh compound B (PIB); amyloid; HIV associated neurocognitive disorders; Alzheimer’s disease
5.  Effects of Age and Amyloid Deposition on Aβ Dynamics in the Human Central Nervous System 
Archives of Neurology  2011;69(1):51-58.
Objective
The amyloid hypothesis predicts that increased production or decreased clearance of amyloid beta (Aβ) leads to amyloidosis, ultimately culminating in Alzheimer’s disease (AD). Dynamic changes in human CNS Aβ levels may be altered by aging or AD pathology and contribute to the risk of AD.
Designs
In this study, hourly cerebrospinal fluid (CSF) Aβ concentrations were compared with age, PIB PET amyloid status and electroencephalography (EEG) and video recording data.
Results
Linear increases of CSF Aβ concentrations over time were observed in younger control participants and older Amyloid- participants, but not in older Amyloid+ participants. Significant CSF Aβ circadian patterns were observed in younger control participants; however circadian amplitudes were decreased in both Amyloid- and Amyloid+ older participants. Aβ diurnal concentrations were correlated to the amount of sleep, but not various awake activities.
Conclusions
Decreased linear rise of CSF Aβ levels associated with amyloid deposition, and decreased CSF Aβ diurnal pattern associated with increasing age disrupt the normal physiology of Aβ dynamics, and may contribute to AD.
doi:10.1001/archneurol.2011.235
PMCID: PMC3254706  PMID: 21911660
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.  Association and Expression analyses with SNPs in TOMM40 in Alzheimer’s Disease 
Archives of neurology  2011;68(8):1013-1019.
Objectives
Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer’s disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all of the association signal is derived from APOE or if there is an independent signal from a nearby gene. In this study we attempted to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset.
Design
We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data and in brain tissue.
Results
We failed to replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk for LOAD among APOE 33 homozygotes but in the opposite direction to the previously reported association (the very-long allele was underrepresented in cases compared to controls in our study (allele frequency: 0.41 vs. 0.48 respectively; p=0.004)). We found no association between rs10524523 and CSF tau or Aβ42 levels or TOMM40 or APOE gene expression.
Conclusions
Although we were not able to replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we did observe that the polyT polymorphism is associated with risk for LOAD among APOE 33 homozygotes in a large case-control series, but in the opposite direction to the previous report. Additional studies in very large samples will be needed to confirm this association.
doi:10.1001/archneurol.2011.155
PMCID: PMC3204798  PMID: 21825236
8.  TMEM106B gene polymorphism is associated with age at onset in granulin mutation carriers and plasma granulin protein levels 
Archives of neurology  2011;68(5):581-586.
Objective
A recent genome-wide association study for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP), identified rs1990622 (TMEM106B) as a risk factor for FTLD-TDP. In this study we tested whether rs1990622 is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy elderly individuals.
Design
Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier and a Cox proportional hazards model.
Subjects
We analyzed 50 affected and unaffected GRN mutation carriers from four previously reported FTLD-TDP families (HDDD1, FD1, HDDD2 and the Karolinska family). GRN plasma levels were also measured in 73 healthy, elderly individuals.
Results
The risk allele of rs1990622 is associated with a mean decrease of the age at onset of thirteen years (p=9.9×10−7), with lower plasma granulin levels in both healthy older adults (p = 4×10−4) and GRN mutation carriers (p=0.0027). Analysis of the HAPMAP database identified a non-synonymous single nucleotide polymorphism, rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622.
Conclusions
The association of rs1990622 with AAO explains, in part, the wide range in the age at onset of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer’s disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.
doi:10.1001/archneurol.2010.350
PMCID: PMC3090529  PMID: 21220649
9.  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
10.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
11.  Ascertainment Bias in the Clinical Diagnosis of Alzheimer's Disease 
Archives of neurology  2010;67(11):1364-1369.
Objective:
The clinical diagnosis of Alzheimer's disease is often based, at least in part, on poor cognitive test performance compared with normative values. The presence and extent of an ascertainment bias (omission of affected individuals) produced by such criteria when applied as early as possible in the course of the disease was examined.
Design:
Longitudinal study from 1979 to 2008.
Setting:
Washington University in St. Louis Alzheimer Disease Research Center.
Participants:
Of 78 individuals aged 65 to 101 years enrolled as healthy controls 55 later developed autopsy-confirmed AD; 23 remained cognitively healthy and did not have neuropathologic AD.
Main Outcome Measures:
Criteria for diagnosis of Alzheimer disease based on various cut-points (1.5, 1.0, and 0.5 standard deviations below the mean for robust test norms) for two standard psychometric measures from each of three cognitive domains (episodic memory, visusospatial ability, working memory) were applied to data from the first assessment associated with an independent clinical diagnosis of cognitive impairment for those who developed symptomatic AD and the last assessment for those who did not.
Results:
Areas under the curve from ROC analyses ranged from .71 to .49; sensitivities and specificities were unsatisfactory even after adjusting for age and education, using combinations of tests, or examining longitudinal decline prior to clinical diagnosis.
Conclusions:
Reliance on divergence from group normative values to determine initial cognitive decline caused by Alzheimer disease results in failure to include people in the initial symptomatic stage of the illness.
doi:10.1001/archneurol.2010.272
PMCID: PMC2999470  PMID: 21060013
12.  Comparison of analytical platforms for cerebrospinal fluid measures of Aβ1-42, total tau and p-tau181 for identifying Alzheimer’s disease amyloid plaque pathology 
Archives of neurology  2011;68(9):1137-1144.
OBJECTIVE
Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are currently being considered for inclusion in revised diagnostic criteria for research and/or clinical purposes to increase the certainty of ante-mortem diagnosis. Establishing biomarker validity requires demonstration that the assays are true markers of underlying disease pathology (e.g., amyloid plaques and/or neurofibrillary tangles) in living individuals.
DESIGN
We compared the performances of the two most commonly used platforms, INNOTEST® ELISA and INNO-BIA AlzBio3 for measurement of CSF amyloid-beta (Aβ) and tau(s), for identifying the presence of amyloid plaques in a research cohort (n=103). Values obtained for CSF Aβ1-42, total tau and phosphorylated tau181 (p-tau181) using the two assay platforms were compared to brain amyloid load as assessed by positron emission tomography using the amyloid imaging agent, Pittsburgh Compound B (PIB).
SUBJECTS
Research volunteers who are cognitively normal or have very mild to moderate AD dementia.
RESULTS
The two assay platforms yielded different (~2–6-fold) absolute values for the various analytes, but relative values were highly correlated. CSF Aβ1-42 correlated inversely, and tau and p-tau181 correlated positively, with the amount of cortical PIB binding, albeit to differing degrees. Both assays yielded similar patterns of CSF biomarker correlations with amyloid load. The ratios of total tau/Aβ1-42 and p-tau181/Aβ1-42 outperformed any single analyte, including Aβ1-2, in discriminating individuals with versus without cortical amyloid.
CONCLUSIONS
The INNOTEST® and INNO-BIA CSF platforms performed equally well in identifying individuals with underlying amyloid plaque pathology. Differences in absolute values, however, point to the need for assay-specific diagnostic cut-point values.
doi:10.1001/archneurol.2011.105
PMCID: PMC3154969  PMID: 21555603
Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; imaging (PET, MRI) in dementias; Pittsburgh Compound B
13.  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
14.  DONEPEZIL TREATMENT AND CHANGES IN HIPPOCAMPAL STRUCTURE IN VERY MILD ALZHEIMER DISEASE 
Archives of neurology  2010;67(1):99-106.
Objective
We compared longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil, untreated very mild DAT subjects and nondemented controls.
Design
MPRAGE sequences were collected approximately two years apart on two 1.5T Siemens Vision systems, yielding two cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.
Subjects
Subjects came from two sources: 18 untreated DAT subjects and 26 controls were drawn from a previous longitudinal study; 18 treated DAT subjects were studied prospectively, and 44 controls were drawn from a longitudinal study from the same time period.
Interventions
Patients attending a dementia clinic at Washington University School of Medicine were prescribed Donepezil by their physician.
Results
There was no significant cohort effect at baseline; therefore the two groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate-of-change of hippocampal volume or subfields deformation. Further exploration showed that compared with the untreated DAT subjects, the treated DAT subjects did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated DAT subjects differed from the controls in the rates-of-change of hippocampal volume, CA1 and subiculum subfield deformations.
Conclusions
Treatment with donepezil did not alter the progression of hippocampal deformation in DAT subjects in this study. Small sample size may have contributed to this outcome.
doi:10.1001/archneurol.2009.292
PMCID: PMC2855123  PMID: 20065136
donepezil; Alzheimer’s disease; hippocampus; magnetic resonance imaging
15.  Cognitive decline and brain volume loss are signatures of cerebral Aβ deposition identified with PIB 
Archives of neurology  2009;66(12):1476-1481.
Objective
To examine the relation of amyloid-beta (Aβ) levels in cerebral cortex with structural brain integrity and cognitive performance in older people with a Clinical Dementia Rating (CDR) of 0 (cognitively normal).
Methods
The relations between mean cortical [11C] PIB binding potential values, proportional to the density of fibrillar Aβ binding sites in the brain, concurrent regional brain volumes as assessed by magnetic resonance imaging, and both concurrent and longitudinal (up to 19 years) cognitive performance in multiple domains were examined in 135 CDR 0 individuals aged 65 to 88 years.
Results
Elevated cerebral Aβ levels, in some cases comparable to that seen in individuals with Alzheimer's disease, were observed in 29 CDR 0 individuals. Significantly smaller regional volumes in the hippocampus, temporal neocortex, anterior cingulate, and posterior cingulate were observed in these CDR 0 individuals with elevated Aβ levels. Concurrent cognitive performance was unrelated to Aβ levels but was related to regional brain volumes with the exception of caudate. Longitudinal cognitive decline was associated with elevated Aβ levels and decreased hippocampal volume. Decline was not limited to episodic memory but included working memory and visuospatial abilities as well.
Interpretation
[11C] PIB, an in vivo measure of cerebral amyloidosis, is associated with regionally specific brain atrophy cross-sectionally and a pattern of longitudinal cognitive decline in multiple cognitive domains that occurs prior to the clinical diagnosis of Alzheimer' disease. These findings contribute to the understanding of the cognitive and structural consequences of Aβ levels in CDR 0 older adults.
doi:10.1001/archneurol.2009.272
PMCID: PMC2796577  PMID: 20008651
Cognitive decline; cerebral Aβ; PIB; brain volumetry; preclinical Alzheimer's disease
16.  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
17.  Stability of the Clinical Dementia Rating: 1979–2007 
Archives of neurology  2009;66(6):773-777.
Background
Diagnostic drift characterizes change in diagnosis and diagnostic classification over time. The Clinical Dementia Rating (CDR) is used commonly in dementia diagnosis and staging of dementia severity. Whether increasing efforts to diagnose dementia at earlier symptomatic stages has led to diagnostic drift in the CDR is unknown.
Objective
To examine dementia severity as determined by the CDR over time.
Design
Secondary analysis of data from longitudinal studies of aging and dementia.
Setting
An Alzheimer’s Disease Research Center (ADRC), where a variety of clinicians contributed CDR ratings over the course of the study.
Participants
Adults aged 63 to 83 years with no (CDR 0), very mild (CDR 0.5) or mild (CDR 1) dementia enrolled in the ADRC at any time from August 1979 to May 2007.
Main Outcome Measures
Within each CDR group changes in scores on standardized psychometric tests with time were examined using multiple linear regression analyses. These tests included the Mini Mental State Examination, Short Blessed Test, Wechsler Memory Scale Logical Memory IA-Immediate, Blessed Dementia Scale, and a psychometric composite score.
Results
A total of 1768 participants met inclusion criteria. Over time, participants were older, more educated, more likely to be minorities, and less likely to be male. Statistically significant change in psychometric test performance over time occurred only within the CDR 1 group for Logical Memory and the psychometric composite, but the degree of change was minimal.
Conclusion
Despite changes in participant characteristics, the CDR demonstrates general stability for assessment of dementia over almost three decades.
doi:10.1001/archneurol.2009.69
PMCID: PMC2779108  PMID: 19506139
18.  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
19.  Absence of PIttsburgh Compound B Detection of CerebralAmyloid Beta in a Patient With Clinical, Cognitive, and Cerebrospinal FluidMarkers of Alzheimer Disease 
Archives of neurology  2009;66(12):1557-1562.
Objective
To determine the temporal relationships of clinical, cognitive, Pittsburgh Compound-B (PiB) amyloid imaging, and cerebrospinal fluid (CSF) markers of Alzheimer’s disease (AD).
Design
A case report of a longitudinally assessed participant in a memory and aging study who had serial clinical and psychometric assessments over 6 years, in addition to PiB imaging and CSF biomarker assays, prior to coming to autopsy.
Setting
Alzheimer’s Disease Research Center
Findings
An 85-year old individual was cognitively normal at his initial and next 3 annual assessments. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB-PET amyloid imaging was negative at age 88.5 years, but at age 89.5 years there was reduced amyloid-beta 42 (Aβ42) and elevated levels of tau in the CSF. At his 6th assessment, when he was 90 years old, he was diagnosed with very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse Aβ plaques, sufficient to fulfill Khachaturian neuropathologic criteria for AD, but neuritic plaques and neurofibrillary tangles were sparse. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB-PET-binding was below the level needed for in vivo detection.
Conclusion
Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral Aβ with amyloid imaging agents such as PiB, which primarily label fibrillar Aβ plaques.
doi:10.1001/archneurol.2009.279
PMCID: PMC2796200  PMID: 20008664
20.  Longitudinal Study of the Transition From Healthy Aging to Alzheimer Disease 
Archives of neurology  2009;66(10):1254-1259.
Background
Detection of the earliest cognitive changes signifying Alzheimer disease is difficult.
Objective
To model the cognitive decline in preclinical Alzheimer disease.
Design
Longitudinal archival study comparing individuals who became demented during follow-up and people who remained nondemented on each of 4 cognitive factors: global, verbal memory, visuospatial, and working memory.
Setting
Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri.
Participants
One hundred thirty-four individuals who became demented during follow-up and 310 who remained nondemented.
Main Outcome Measures
Inflection point in longitudinal cognitive performance.
Results
The best-fitting model for each of the 4 factors in the stable group was linear, with a very slight downward trend on all but the Visuospatial factor. In contrast, a piecewise model with accelerated slope after a sharp inflection point provided the best fit for the group that progressed. The optimal inflection point for all 4 factors was prior to diagnosis of dementia: Global, 2 years; Verbal and Working Memory, 1 year; and Visuospatial, 3 years. These results were also obtained when data were limited to the subset (n=44) with autopsy-confirmed Alzheimer disease.
Conclusions
There is a sharp inflection point followed by accelerating decline in multiple domains of cognition, not just memory, in the preclinical period in Alzheimer disease when there is insufficient cognitive decline to warrant clinical diagnosis using conventional criteria. Early change was seen in tests of visuospatial ability, most of which were speeded. Research into early detection of cognitive disorders using only episodic memory tasks may not be sensitive to all of the early manifestations of disease.
doi:10.1001/archneurol.2009.158
PMCID: PMC2795328  PMID: 19822781
21.  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

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