Papers by Napatkamon Ayutyanont
Alzheimer Disease and Associated Disorders 2014, Nov 26, 2014
Background: Aim of this study was to compare the performance and power of the best-established di... more Background: Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 5, 2015
This article describes an image-analysis strategy with improved power to track longitudinal amylo... more This article describes an image-analysis strategy with improved power to track longitudinal amyloid-β (Aβ) PET changes and evaluate Aβ-modifying treatments. - To compare the power of template based cerebellar, pontine, and a cerebral white matter reference regions to track 24-month florbetapir standard-uptake-value ratio (SUVR) changes, relate those changes to 24-month clinical decline, and evaluate Aβ-modifying treatments in Aβ positive (Aβ+) and Aβ negative (Aβ-) probable Alzheimer's dementia (pAD) patients, mild cognitive impairment (MCI) patients, and cognitively normal controls (NCs) and in cognitively normal apolipoprotein E4 (APOE4) carriers and non-carriers, we used baseline and approximately 24-month follow-up florbetapir PET scans from 332 Aβ+ and Aβ- subjects from the multi-center Alzheimer's Disease Neuroimaging Initiative (ADNI), including 31 pAD patients, 187 MCI patients and 114 NCs for each of the proposed analyses. Cerebral-to-white matter, cerebellar, and p...
Alzheimer's & Dementia, 2014
Acta Neuropathologica Communications, 2013
Background: Autopsy series commonly report a high percentage of coincident pathologies in demente... more Background: Autopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimer's Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid Aβ, total and phosphorylated tau and α-synuclein and MRI and FDG-PET scans.
Alzheimer Disease & Associated Disorders, 2014
Background: Aim of this study was to compare the performance and power of the best-established di... more Background: Aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI).
There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that... more There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE)ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these
Researchers have begun to characterize the subtle biological and cognitive processes that precede... more Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.
There is growing interest in the evaluation of preclinical Alzheimer&... more There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention…
2009 ICME International Conference on Complex Medical Engineering, 2009
Magnetic resonance imaging (MRI) based whole brain atrophy has been proposed as an imaging marker... more Magnetic resonance imaging (MRI) based whole brain atrophy has been proposed as an imaging marker in clinical trials to evaluate the effects of potential treatments for Alzheimer's disease (AD) due to its objectiveness and sensitivity confirmed by a number of studies. Our study uses an iterative principal component analysis (IPCA) technique to measure whole brain atrophy from sequential MRI scans from Manuscript
2009 ICME International Conference on Complex Medical Engineering, 2009
... 33, no. 1, pp. 94-102, Oct.2006. [9] A. Drzezga, T. Grimmer, G. Henriksen, I. Stangier, R. Pe... more ... 33, no. 1, pp. 94-102, Oct.2006. [9] A. Drzezga, T. Grimmer, G. Henriksen, I. Stangier, R. Perneczky, J. ehl-Schmid, CA Mathis, WE Klunk, J. Price, S. DeKosky, HJ Wester, M. Schwaiger, and A. Kurz, "Imaging of amyloid plaques and Page 5. ...
JAMA Neurology, 2015
IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and com... more IMPORTANCE Age-associated changes in brain imaging and fluid biomarkers are characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and noncarriers from the world's largest known autosomal dominant Alzheimer disease (AD) kindred. OBJECTIVE To characterize and compare age-associated changes in brain imaging and fluid biomarkers in PSEN1 E280A mutation carriers and noncarriers.
Proceedings of the National Academy of Sciences, 2009
Fibrillar amyloid-beta (A) is found in the brains of many cognitively normal older people. Wheth... more Fibrillar amyloid-beta (A) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar A burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar A burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) 4 allele. The 8 4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar A was significantly associated with APOE 4 carrier status and 4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar A burden in cognitively normal older people is associated with APOE 4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar A accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar A, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar A imaging in primary prevention trials.
PLoS ONE, 2013
Background: We introduced a hypometabolic convergence index (HCI) to characterize in a single mea... more Background: We introduced a hypometabolic convergence index (HCI) to characterize in a single measurement the extent to which a person's fluorodeoxyglucose positron emission tomogram (FDG PET) corresponds to that in Alzheimer's disease (AD). Apolipoprotein E e4 (APOE e4) gene dose is associated with three levels of risk for late-onset AD. We explored the association between gene dose and HCI in cognitively normal e4 homozygotes, heterozygotes, and non-carriers.
NeuroImage, 2011
This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's... more This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer's disease (AD), compares it to other biological, cognitive and clinical measures, and demonstrate its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual's fluorodeoxyglucose positron emission tomography (FDG PET) image corresponds to that in probable AD patients, and is generated using a fully automated voxel-based image analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18 months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p = 9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCI's or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, have the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.
NeuroImage, 2012
We previously introduced a voxel-based, multi-modal application of the partial least square algor... more We previously introduced a voxel-based, multi-modal application of the partial least square algorithm (MMPLS) to characterize the linkage between patterns in a person's complementary complex datasets without the need to correct for multiple regional comparisons. Here we used it to demonstrate a strong correlation between MMPLS scores to characterize the linkage between the covarying patterns of fluorodeoxyglucose positron emission tomography (FDG PET) measurements of regional glucose metabolism and magnetic resonance imaging (MRI) measurements of regional gray matter associated with apolipoprotein E (APOE) ε4 gene dose (i.e., three levels of genetic risk for late-onset Alzheimer's disease (AD)) in cognitively normal, latemiddle-aged persons. Coregistered and spatially normalized FDG PET and MRI images from 70% of the subjects (27 ε4 homozygotes, 36 ε4 heterozygotes and 67 ε4 non-carriers) were used in a hypothesis-generating MMPLS analysis to characterize the covarying pattern of regional gray matter volume and cerebral glucose metabolism most strongly correlated with APOE-ε4 gene dose. Coregistered and spatially normalized FDG PET and MRI images from the remaining 30% of the subjects were used in a hypothesis-testing MMPLS analysis to generate FDG PET-MRI gray matter MMPLS scores blind to their APOE genotype and characterize their relationship to APOE-ε4 gene dose. The hypothesis-generating analysis revealed covarying regional gray matter volume and cerebral glucose metabolism patterns that resembled those in traditional univariate analyses of AD and APOE-ε4 gene dose and PET-MRI scores that were strongly correlated with APOE-ε4 gene dose (p<1×10 −16 ). The hypothesis-testing analysis results showed strong correlations between FDG PET-MRI gray matter scores and APOE-ε4 gene dose (p=8.7×10 −4 ). Our findings support the possibility of using the MMPLS to analyze complementary datasets from the same person in the presymptomatic detection and tracking of AD.
NeuroImage, 2009
In this article, we introduce a multimodal multivariate network analysis to characterize the link... more In this article, we introduce a multimodal multivariate network analysis to characterize the linkage between the patterns of information from the same individual's complementary brain images, and illustrate its potential by showing its ability to distinguish older from younger adults with greater power than several previously established methods. Our proposed method uses measurements from every brain voxel in each person's complementary co-registered images and uses the partial least square (PLS) algorithm to form a combined latent variable that maximizes the covariance among all of the combined variables. It represents a new way to calculate the singular value decomposition from the high-dimensional covariance matrix in a computationally feasible way. Analyzing fluorodeoxyglucose positron emission tomography (PET) and volumetric magnetic resonance imaging (MRI) images, this method distinguished 14 older adults from 15 younger adults (p = 4e-12) with no overlap between groups, no need to correct for multiple comparisons, and greater power than the univariate Statistical Parametric Mapping (SPM), multimodal SPM or multivariate PLS analysis of either imaging modality alone. This technique has the potential to link patterns of information among any number of complementary images from an individual, to use other kinds of complementary complex datasets besides brain images, and to characterize individual state-or traitdependent brain patterns in a more powerful way.
NeuroImage, 2010
Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxygl... more Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically predefined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.
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Papers by Napatkamon Ayutyanont