Alzheimer Disease: Xiong C

Ringman JM, Grill J, Rodriguez-Agudelo Y, Chavez M, Xiong C. · Mary S. Easton Center for Alzheimer's Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA. · Alzheimers Dement. · Pubmed #19328453 No free full text.

This publication has no abstract.

Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, Xiong C, Morris JC, Holtzman DM. · Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S Euclid, St Louis, MO 63110, USA. · Arch Neurol. · Pubmed #19433664 No free full text.

Abstract: BACKGROUND: Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. OBJECTIVE: To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). DESIGN: Retrospective analysis of CSF biomarkers and clinical data. SETTING: An academic Alzheimer disease research center. PARTICIPANTS: Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). MAIN OUTCOME MEASURES: Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. RESULTS: The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values. CONCLUSIONS: In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

Price JL, McKeel DW, Buckles VD, Roe CM, Xiong C, Grundman M, Hansen LA, Petersen RC, Parisi JE, Dickson DW, Smith CD, Davis DG, Schmitt FA, Markesbery WR, Kaye J, Kurlan R, Hulette C, Kurland BF, Higdon R, Kukull W, Morris JC. · Department of Anatomy and Neurobiology, Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA. · Neurobiol Aging. · Pubmed #19376612 No free full text.

Abstract: 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.

Roe CM, Mintun MA, D'Angelo G, Xiong C, Grant EA, Morris JC. · Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, USA. · Arch Neurol. · Pubmed #19001165 No free full text.

Abstract: 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 levels. Design, Setting, and PARTICIPANTS: Uptake of carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) 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 [(11)C]PiB uptake interacted with level of educational attainment to predict cognitive function. MAIN OUTCOME MEASURES: Scores on the Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, and Short Blessed Test and individual measures from a psychometric battery. RESULTS: Uptake of [(11)C]PiB interacted with years of education in predicting scores on the Clinical Dementia Rating sum of boxes (P = .003), the Mini-Mental State Examination (P < .001), the Short Blessed Test (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. CONCLUSION: The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition.

Roe CM, Xiong C, Miller JP, Cairns NJ, Morris JC. · Alzheimer's Disease Research Center, Washington University School of Medicine, 4488 Forest Park Avenue, St Louis, MO 63108, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18525294 No free full text.

Abstract: 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.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #18334827 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the quality of longitudinal statistical applications in published studies on Alzheimer's disease (AD). METHODS: A 21-item instrument, the Quality of Longitudinal AD Studies (QLADS), was developed by the research team (4 biostatisticians, 1 neuroepidemiologist, and 1 neurologist). All items were extensively discussed within the team for content validity. After pilot testing on 5 publications, the instrument was revised and tested for reliability with a sample of 40 published longitudinal AD studies randomly sampled from MEDLINE. RESULTS: Item-specific test-retest reliability coefficients for QLADS ranged from 0.53 to 1.00 with the associated standard error (SE) ranging from 0.02 to 0.13. The test-retest reliability for the overall score over the 21 items was high (intraclass correlation coefficient (ICC) = 0.94, 95% CI 0.90, 0.97). Item-specific inter-rater reliability coefficients for QLADS ranged from 0.46 to 1.00 with the associated SE ranging from 0.07 to 0.18. The inter-rater reliability for the overall score was also high (ICC = 0.87, 95% CI 0.77, 0.93). CONCLUSIONS: This study indicates that the quality of longitudinal statistical applications in AD publications can be reliably assessed.

Roe CM, Xiong C, Grant E, Miller JP, Morris JC. · Division of Biostatistics, Alzheimer's Disease Research Center, Washington University School of Medicine, St Louis, Missouri 63108, USA. · Arch Neurol. · Pubmed #18195147 links to  free full text

Abstract: OBJECTIVES: To examine whether reported age at onset of dementia symptoms among participants with Alzheimer disease (AD) is later for those with fewer years of education and, if so, to see if education 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=1449 participants). RESULTS: Reported age at onset of dementia symptoms is slightly younger in participants with more education. Participants with fewer years of education show greater clinical severity of Alzheimer disease at first assessment. CONCLUSION: Symptoms of Alzheimer disease are recognized later among those with less education.

Carpenter BD, Xiong C, Porensky EK, Lee MM, Brown PJ, Coats M, Johnson D, Morris JC. · Department of Psychology, Washington University, St. Louis, Missouri 63130, USA. · J Am Geriatr Soc. · Pubmed #18194228 No free full text.

Abstract: OBJECTIVES: To examine short-term changes in depression and anxiety after receiving a dementia diagnosis. DESIGN: Pre/post survey design. SETTING: Alzheimer's Disease Research Center. PARTICIPANTS: Ninety individuals and their companions. MEASUREMENTS: Fifteen-item Geriatric Depression Scale and 20-item "state" version of the State-Trait Anxiety Inventory. RESULTS: Sixty-nine percent of the individuals were diagnosed with dementia; two-thirds of those were in the earliest symptomatic stages of dementia that, in other settings, is considered to represent mild cognitive impairment. No significant changes in depression were noted in individuals or their companions, regardless of diagnostic outcome or dementia severity. Anxiety decreased substantially after diagnostic feedback in most groups. CONCLUSION: Disclosure of a dementia diagnosis does not prompt a catastrophic emotional reaction in most people, even those who are only mildly impaired, and may provide some relief once an explanation for symptoms is known and a treatment plan is developed.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Bergmann KR, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #17878738 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate statistical applications in publications on Alzheimer's disease (AD). METHODS: Three instruments/checklists were developed: Assessment of Statistical Reporting (ASR; 44 items), Survey of Statistical Designs (SSD; 10 items), and Survey of Statistical Methods (SSM; 7 items). After a pilot testing on 5 AD publications, the instruments/checklists were revised and tested for reliability with a sample of 30 AD articles and for validity with another sample of 10 AD articles from MEDLINE. RESULTS: Item-specific test-retest and interrater reliability for ASR ranged from 0.29 to 1.0 with the associated standard errors (SEs) ranging from 0.01 to 0.31. The test-retest reliability (intraclass correlation coefficient = 0.94, 95% CI: 0.88-0.97) and the interrater reliability (intraclass correlation coefficient = 0.84, 95% CI: 0.69-0.92) for the overall score of ASR were high. The correlational validity of the ASR with a published checklist was also high (r = 0.74, SE = 0.24). The item-specific test-retest reliability in SSD and SSM ranged from 0.58 to 1.00 with the associated SEs ranging from 0.01 to 0.32. The item-specific interrater reliability in SSD and SSM ranged from 0.17 to 1.00 with the associated SEs ranging from 0.01 to 0.22. CONCLUSIONS: This study suggested that it was feasible to assess statistical applications in AD publications.

Roe CM, Xiong C, Miller JP, Morris JC. · Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave., Box 8067, St. Louis, MO 63110, USA. · Neurology. · Pubmed #17224578 No free full text.

Abstract: BACKGROUND: Individuals with no cognitive impairment during life but with neuropathologic Alzheimer disease (AD) may represent cases of presymptomatic, or unrecognized early symptomatic, AD. The cognitive reserve hypothesis suggests that at a particular level of AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs less-educated individuals. OBJECTIVE: To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD. METHODS: Samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets. Generalized linear mixed models (using the logit link function) were used in each sample to examine whether years of education was associated with dementia within 1 year of death, adjusting for other relevant variables. RESULTS: Twelve percent of individuals meeting Khachaturian (122/1,009), 19% meeting low, intermediate, or high likelihood for National Institute on Aging/Reagan Institute (320/1,704), and 14% meeting possible, probable, or definite Consortium to Establish a Registry for Alzheimer's Disease (265/1,835) neuropathologic criteria for AD were nondemented at their final clinical assessment. Persons with more education were less likely to have a dementia diagnosis in each sample. CONCLUSIONS: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic Alzheimer disease. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to cope with AD brain pathology without observable deficits in cognition.

Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. · Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Box 8111, St Louis, MO 63110, USA. · Arch Neurol. · Pubmed #17210801 links to  free full text

Abstract: OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Galvin JE, Roe CM, Xiong C, Morris JC. · Departments of Neurology, Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park, Suite 130, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17159098 No free full text.

Abstract: OBJECTIVE: To establish the validity, reliability, and discriminative properties of the AD8, a brief informant interview to detect dementia, in a clinic sample. METHODS: We evaluated 255 patient-informant dyads. We compared the number of endorsed AD8 items with an independently derived Clinical Dementia Rating (CDR) and with performance on neuropsychological tests. Construct and concurrent validity, test-retest, interrater and intermodal reliability, and internal consistency of the AD8 were determined. Receiver operator characteristic curves were used to assess the discriminative properties of the AD8. RESULTS: Concurrent validity was strong with AD8 scores correlating with the CDR (r = 0.75, 95% CI 0.63 to 0.88). Construct validity testing showed strong correlation between AD8 scores, CDR domains, and performance on neuropsychological tests. The Cronbach alpha of the AD8 was 0.84 (95% CI 0.80 to 0.87), suggesting excellent internal consistency. The AD8 demonstrated good intrarater reliability and stability (weighted kappa = 0.67, 95% CI 0.59 to 0.75). Both in-person and phone administration showed equal reliability (weighted kappa = 0.65, 95% CI 0.57 to 0.73). Interrater reliability was very good (Intraclass correlation coefficient = 0.80, 95% CI 0.55 to 0.92). The area under the curve was 0.92 (95% CI 0.88 to 0.95), suggesting excellent discrimination between nondemented individuals and those with cognitive impairment regardless of etiology. CONCLUSION: The AD8 is a brief, sensitive measure that validly and reliably differentiates between nondemented and demented individuals. It can be used as a general screening device to detect cognitive change regardless of etiology and with different types of informants.

Williams MM, Xiong C, Morris JC, Galvin JE. · Department of Medicine, Alzheimer Disease Research Center, Washington University School of Medicine, 4488 Forest Park, Suite 130, St. Louis, MO 63108, USA. · Neurology. · Pubmed #17159097 No free full text.

Abstract: OBJECTIVE: To determine whether dementia with Lewy bodies (DLB) progresses more rapidly than Alzheimer disease (AD). METHODS: We compared 315 participants (63 with DLB and 252 with AD) enrolled in a prospective longitudinal study of memory and aging with annual clinical and cognitive assessments and followed until death. The main outcome measure was dementia progression to institutionalization and death. Neuropathologic examinations were performed on all participants in this study. Subject classification (DLB vs AD) was based on neuropathology. RESULTS: Patients with DLB had an increased risk of mortality vs patients with AD (hazard ratio [HR] 1.88, 95% CI: 1.4 to 2.5). The median survival time for DLB was 78.0 years and for AD was 84.6 years (chi(2) = 19.9, p < 0.001) with significant modification effects due to gender (HR 1.51, 95% CI: 1.0 to 2.3) and the presence of at least 1 APOE epsilon4 allele (HR 1.50, 95% CI: 1.0 to 2.2). Survival after dementia onset was also different between DLB and AD (7.3 vs 8.5 years; chi(2) = 5.4, p < 0.02). DLB cases had similar risks of institutionalization and survival in long-term care facilities to AD cases. Self-reports of depression and the presence of extrapyramidal signs were important covariates. The rate of cognitive decline as measured by psychometric performance and clinical staging methods did not differ between DLB and AD. CONCLUSIONS: Dementia with Lewy bodies (DLB) increases the risk of mortality compared with Alzheimer disease (AD), but the two groups did not differ in rate of cognitive decline. The greater risk for noncognitive disease progression for DLB compared with AD suggests clinically meaningful differences for the two disorders.

Csernansky JG, Dong H, Fagan AM, Wang L, Xiong C, Holtzman DM, Morris JC. · Alzheimer's Disease Research Center and the Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. · Am J Psychiatry. · Pubmed #17151169 links to  free full text

Abstract: OBJECTIVE: Studies of subjects with dementia of the Alzheimer type have reported correlations between increases in activity of the hypothalamic-pituitary-adrenal (HPA) axis and hippocampal degeneration. In this study, the authors sought to determine whether increases in plasma cortisol, a marker of HPA activity, were associated with clinical and cognitive measures of the rate of disease progression in subjects with Alzheimer-type dementia. METHOD: Thirty-three subjects with very mild and mild Alzheimer-type dementia and 21 subjects without dementia were assessed annually for up to 4 years with the Clinical Dementia Rating scale and a battery of neuropsychological tests. Plasma was obtained at 8 a.m. on a single day and assayed for cortisol. Rates of change over time in the clinical and cognitive measures were derived from growth curve models. RESULTS: In the subjects with dementia, but not in those without dementia, higher plasma cortisol levels were associated with more rapidly increasing symptoms of dementia and more rapidly decreasing performance on neuropsychological tests associated with temporal lobe function. No associations were observed between plasma cortisol levels and clinical and cognitive assessments obtained at the single assessment closest in time to the plasma collection. CONCLUSIONS: Higher HPA activity, as reflected by increased plasma cortisol levels, is associated with more rapid disease progression in subjects with Alzheimer-type dementia.

Xiong C, van Belle G, Miller JP, Morris JC. · Division of Biostatistics, Washington University in St. Louis, St. Louis, MO 63110, USA. · Stat Med. · Pubmed #16345029 No free full text.

Abstract: This article studies the problem of measuring and estimating the diagnostic accuracy when there are three ordinal diagnostic groups. We use a receiver operating characteristic (ROC) surface to describe the probabilities of correct classifications into three diagnostic groups based on various sets of diagnostic thresholds of a test and propose to use the entire and the partial volume under the surface to measure the diagnostic accuracy. Mathematical properties and probabilistic interpretations of the proposed measure of diagnostic accuracy are discussed. Under the assumption of normal distributions of the diagnostic test from three diagnostic groups, we present the maximum likelihood estimate to the volume under the ROC surface and give the asymptotic variance to the estimate. We further propose several asymptotic confidence interval estimates to the volume under the ROC surface. The performance of these confidence interval estimates is evaluated in terms of attaining the nominal coverage probability based on a simulation study. In addition, we develop a method of sample size determination to achieve an adequate accuracy of the confidence interval estimate. Finally, we demonstrate the proposed methodology by applying it to the clinical diagnosis of early stage Alzheimer's disease based on the neuropsychological database of the Washington University Alzheimer's Disease Research Center.

Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF, Snyder AZ, Morris JC, Buckner RL. · Department of Neurology, Washington University, St Louis, MO, USA. · Arch Neurol. · Pubmed #16344345 links to  free full text

Abstract: BACKGROUND: White matter lesions (WMLs) are prevalent in nondemented aging and in Alzheimer disease (AD). Their relationship with cognition in the earliest stages of AD is unknown. OBJECTIVE: To assess the relationship between WMLs and cognition in nondemented aging and in early-stage AD. DESIGN: Cross-sectional study. SETTING: Alzheimer Disease Research Center, St Louis, MO. PARTICIPANTS: Participants were nondemented (n = 88) or had very mild (n = 48) or mild (n = 20) AD. MAIN OUTCOME MEASURES: Regression coefficients for deep WMLs and periventricular WMLs (PVWMLs) as predictors of cognition, after controlling for age, educational achievement, brain atrophy, and infarctlike lesions. RESULTS: White matter lesions were present in nondemented aging and in early-stage AD, with no group differences in deep WML burden and a modest PVWML burden increase in the AD group. The prevalence of infarctlike lesions was equivalent between groups. Age and hypertension were related to deep WML burden and PVWML burden. Deep WML burden and PVWML burden were associated with reduced global cognition in AD but not in nondemented aging. A PVWML x AD status interaction for global cognition suggests that the relationship between PVWMLs and cognition is modified by AD. In AD, global cognitive reductions were related to impairments in visual memory, processing speed, and executive function. CONCLUSIONS: White matter lesions are prevalent in nondemented aging and in early-stage AD, and their presence influences cognitive impairment in the earliest stages of AD. Individuals with early-stage AD may be more vulnerable to the cognitive effect of WMLs than nondemented aging individuals with similar WML burden.

Xiong C, Yu K, Gao F, Yan Y, Zhang Z. · Division of Biostatistics, Washington University in St Louis, MO 63110, USA. · Clin Trials. · Pubmed #16317808 No free full text.

Abstract: BACKGROUND: When the efficacy of a treatment in a randomized controlled trial is required for multiple primary endpoints, trial design and analysis differ from trial requiring efficacy in only one of the multiple endpoints. METHODS: We consider a two-arm clinical trial requiring efficacy analysis for multiple primary endpoints, formulating the appropriate null and alternative hypotheses for the test of treatment efficacy. We study the significance level/statistical power of an intersection-union test (IUT) in this situation. We compare IUT with the intuitive approach (selecting the maximum sample size over those obtained from testing individual primary endpoints one by one) for determination of sample size. RESULTS: The proposed IUT reserves the same Type I error rate as shared by all endpoint-specific tests. The statistical power of the proposed IUT is no more than the minimum from the individual tests. The maximum sample size from multiple endpoint-specific tests is often inadequate for the test of treatment efficacy, especially when the standardized effect sizes are similar. Finally, the IUT can be applied to Alzheimer's disease treatment trials in which two primary endpoints are typically used. CONCLUSIONS: The IUT is a valid method for use in the design and analysis of clinical trials requiring efficacy at multiple primary endpoints.

Galvin JE, Powlishta KK, Wilkins K, McKeel DW, Xiong C, Grant E, Storandt M, Morris JC. · Department of Neurology, Alzheimer's Disease Research Center, School of Medicine, Washington University, St Louis, MO 63108, USA. · Arch Neurol. · Pubmed #15883263 links to  free full text

Abstract: BACKGROUND: To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy. OBJECTIVE: To determine clinical and cognitive features associated with the development of AD or other dementias in older adults. DESIGN: Longitudinal study of memory and aging. SETTING: Alzheimer's Disease Research Center, St Louis, Mo. MAIN OUTCOME MEASURES: Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia. PARTICIPANTS: Eighty control participants who eventually came to autopsy. RESULTS: Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating = 0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34% of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing. CONCLUSIONS: Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals without dementia who develop dementia. Older adults who do not develop dementia have stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may reflect a preclinical stage of the illness.

Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. · Division of Biostatistics, Washington University School of Medicine, 660 South Euclid Avenue, Box 8067, St. Louis, MO 63110, USA. · Neurology. · Pubmed #15753432 No free full text.

Abstract: Cross-sectional studies raise the possibility of protective relationships between, or a common mechanism underlying, the development of dementia of the Alzheimer type (DAT) and cancer. Using a prospective longitudinal design, the authors found that the risk of developing cancer is less among participants with DAT vs nondemented participants (p < 0.001) and that the risk of developing DAT may be less for participants with a history of cancer (p = 0.060).

McKeel DW, Price JL, Miller JP, Grant EA, Xiong C, Berg L, Morris JC. · Dept. of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA. · J Neuropathol Exp Neurol. · Pubmed #15535130 No free full text.

Abstract: Universally accepted neuropathologic criteria for differentiating Alzheimer disease (AD) from healthy brain aging do not exist. We tested the hypothesis that Bielschowsky silver stained total, cored, and neuritic senile plaques (TSPs, CSPs, and NSPs, respectively), rather than neurofibrillary tangles (NFTs), best discriminate between the 2 conditions using rigorously defined nondemented (n = 7) and AD (n = 35) subjects with no known co-morbidities. We compared lesions in 3 neocortical regions, in hippocampal CA1, and in entorhinal cortex in 19 men and 13 women between 74 and 86 years at death. The Clinical Dementia Rating (CDR) was used to assess degree of cognitive impairment within a year of demise. Neocortical TSP measures provided the highest correlation with expiration CDR: area under the curve (AUC) = 0.986 with 97.8% sensitivity at 90% specificity with an estimated cut-point of 6.0 TSP/ mm2. All SP measures yielded higher estimated AUC and sensitivity for 90% specificity compared to NFTs. Derived TSP cut-points applied to 149 persons with clinical AD regardless of their neuropathologic diagnosis yielded a sensitivity of 97% and specificity of 84% for TSPs in the 3 neocortical areas. Thus cut-points based on both diffuse and neuritic SP in neocortical regions distinguished nondemented and AD subjects with high sensitivity and specificity.

Xiong C, McKeel DW, Miller JP, Morris JC. · Division of Biostatistics, Washington University in St. Louis, Missouri 63110, USA. · Med Decis Making. · Pubmed #15534346 No free full text.

Abstract: This article studies the problem of combining correlated diagnostic tests to maximize the discriminating power between the diseased population and the healthy population. The authors consider all possible linear combinations of multiple diagnostic tests and search for the one that achieves the largest area under the receiver operating characteristic (ROC) curve. They discuss the statistical estimation of the optimum linear combination test and the associated maximum area under the ROC curve. Their approach is based on the assumption of multivariate normal distribution of the multiple diagnostic tests. They also present the application of the proposed techniques to the neuropathologic diagnosis of Alzheimer's disease based on brain lesions from 5 different brain locations using a data set from the Washington University Alzheimer's Disease Research Center.

Xiong C, Miller JP, Morris JC. · Division of Biostatistics, Washington University in St Louis, St Louis, MO 63110, USA. · J Alzheimers Dis. · Pubmed #14646032 No free full text.

Abstract: This paper studies the correlation of cognitive progression for subjects whose dementia has made a transition from a milder stage of severity to the next stage of impairment. We model the progression of cognitive decline at adjacent stages of dementia by using a general linear mixed model. We also propose a three-step procedure to detect the best configuration of the covariance matrices for the random components in the model. After the best configuration of covariance matrices for the random components in the model is determined, we then recommend another two-step process to test whether there exists a significant correlation between the rate of cognitive decline before the transition, the cognitive status at the transition time, and the rate of cognitive decline after the transition. In addition, we present asymptotic confidence interval estimates for the correlations associated with a transition. This method is applied to several composite psychometric factor scores in the longitudinal database from the Alzheimer's Disease Research Center (ADRC) at Washington University in St. Louis.

Ji M, Xiong C, Grundman M. · Division of Epidemiology and Bisotatistics, Graduate School of Public Health, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-4162, USA. · J Alzheimers Dis. · Pubmed #14646028 No free full text.

Abstract: In this paper, we present a statistical hypothesis test for detecting a change point over the course of cognitive decline among Alzheimer's disease patients. The model under the null hypothesis assumes a constant rate of cognitive decline over time and the model under the alternative hypothesis is a general bilinear model with an unknown change point. When the change point is unknown, however, the null distribution of the test statistics is not analytically tractable and has to be simulated by parametric bootstrap. When the alternative hypothesis that a change point exists is accepted, we propose an estimate of its location based on the Akaike's Information Criterion. We applied our method to a data set from the Neuropsychological Database Initiative by implementing our hypothesis testing method to analyze Mini Mental Status Exam scores based on a random-slope and random-intercept model with a bilinear fixed effect. Our result shows that despite large amount of missing data, accelerated decline did occur for MMSE among AD patients. Our finding supports the clinical belief of the existence of a change point during cognitive decline among AD patients and suggests the use of change point models for the longitudinal modeling of cognitive decline in AD research.

Duchek JM, Carr DB, Hunt L, Roe CM, Xiong C, Shah K, Morris JC. · Department of Psychology, Washington University School of Medicine, St. Louis, Missouri 63130, USA. · J Am Geriatr Soc. · Pubmed #14511152 No free full text.

Abstract: OBJECTIVES: To longitudinally assess on-road driving performance in healthy older adults and those with early-stage dementia of the Alzheimer type (DAT). DESIGN: A prospective longitudinal study. SETTING: Large urban medical center and surrounding area. PARTICIPANTS: A sample of 58 healthy controls, 21 participants with very mild DAT, and 29 participants with mild DAT participated. DAT was diagnosed using validated clinical diagnostic criteria and staged according to the Clinical Dementia Rating (CDR) Scale. MEASUREMENTS: Healthy controls and individuals with very mild DAT and mild DAT were administered a standardized on-road driving assessment over repeated times of testing. RESULTS: Subjects in the CDR=1 group (mild DAT) had a faster rate of receiving a rating of not safe on the driving test than subjects in the CDR=0 group (healthy controls; log rank test, P=.006), and the survival function of the CDR=0.5 group (very mild DAT) fell between those of the CDR=0 and CDR=1 groups. A Cox proportional hazards model indicated a significant difference in survival functions between the CDR=0 and CDR=1 groups after baseline age was controlled for (P<.001). Cox regression analysis also indicated that baseline age was a significant risk factor for a rating of "not safe" (P=.002). CONCLUSION: This study provides longitudinal evidence for a decline in driving performance over time, primarily in early-stage DAT, and supports the need not only for driving assessments, but also for reevaluation of individuals with very mild and mild DAT.

Han X, Fagan AM, Cheng H, Morris JC, Xiong C, Holtzman DM. · Division of Bioorganic Chemistry and Molecular Pharmacology, and the Departments of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. · Ann Neurol. · Pubmed #12838527 No free full text.

Abstract: We recently noted a profound decline in brain sulfatides (ST) in subjects who died with incipient dementia due to Alzheimer's disease. Herein, we measured ST levels in cerebrospinal fluid in cognitively normal elderly and in subjects with mild cognitive impairment due to incipient demenia of the Alzheimer type. There was a significant decrease in cerebrospinal fluid ST and in the ST to phosphatidylinositol ratio in MCI subjects. The ST to phosphatidylinositol ratio accurately differentiated very mildly impaired subjects from controls on an individual basis. The cerebrospinal fluid ST to phosphatidylinositol ratio may be a very useful biomarker for the earliest clinical stage of Alzheimer's disease.