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issn:0003-99.2
1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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

Results 1-7 (7)