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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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

Results 1-6 (6)