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1.  Different Patterns of White Matter Disruption among Amnestic Mild Cognitive Impairment Subtypes: Relationship with Neuropsychological Performance 
Amnestic mild cognitive impairment (aMCI) is recognized as the prodromal phase of Alzheimer’s disease (AD). Evidence showed that patients with multiple-domain (MD) aMCI were at higher risk of converting to dementia and exhibited more severe gray matter atrophy than single-domain (SD) aMCI. The investigation of the microstructural abnormalities of white matter (WM) among different subtypes of aMCI and their relations with cognitive performances can help to understand the variations among aMCI subtypes and to construct potential imaging based biomarkers to monitor the progression of aMCI. Diffusion-weighted MRI data were acquired from 40 patients with aMCI (aMCI-SD: n = 19; aMCI-MD: n= 21) and 37 healthy controls (HC). Voxel-wise and atlas-based analyses of whole-brain WM were performed among three groups. The correlations between the altered diffusion metrics of the WM tracts and the neuropsychological scores in each subtype of aMCI were assessed. The aMCI-MD patients showed disrupted integrity in multiple WM tracts across the whole-brain when compared with HCs or with aMCI-SD. In contrast, only few WM regions with diffusion changes were found in aMCI-SD as compared to HCs and with less significance. For neuropsychological correlations, only aMCI-MD patients exhibited significant associations between disrupted WM connectivity (in the body of the corpus callosum and the right anterior internal capsules) and cognitive impairments (MMSE and Digit Symb-Coding scores), whereas no such correlations were found in aMCI-SD. These findings indicate that the degeneration extensively exists in WM tracts in aMCI-MD that precedes the development of AD, whereas underlying WM pathology in aMCI-SD is imperceptible. The results are consistent with the view that aMCI is not a uniform disease entity and presents heterogeneity in the clinical progression.
doi:10.3233/JAD-122023
PMCID: PMC4085483  PMID: 23603396
Amnestic mild cognitive impairment; diffusion tensor imaging; multiple-domain; single-domain; TBSS; white matter
2.  USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE 
Nature reviews. Neurology  2013;9(7):371-381.
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. Here, 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 these advances 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.
doi:10.1038/nrneurol.2013.107
PMCID: PMC4084675  PMID: 23752908
3.  The Receiver Operational Characteristic for Binary Classification with Multiple Indices and Its Application to the Neuroimaging Study of Alzheimer’s Disease 
Given a single index, the receiver operational characteristic (ROC) curve analysis is routinely utilized for characterizing performances in distinguishing two conditions/groups in terms of sensitivity and specificity. Given the availability of multiple data sources (referred to as multi-indices), such as multimodal neuroimaging data sets, cognitive tests, and clinical ratings and genomic data in Alzheimer’s disease (AD) studies, the single-index-based ROC underutilizes all available information. For a long time, a number of algorithmic/analytic approaches combining multiple indices have been widely used to simultaneously incorporate multiple sources. In this study, we propose an alternative for combining multiple indices using logical operations, such as “AND,” “OR,” and “at least n” (where n is an integer), to construct multivariate ROC (multiV-ROC) and characterize the sensitivity and specificity statistically associated with the use of multiple indices. With and without the “leave-one-out” cross-validation, we used two data sets from AD studies to showcase the potentially increased sensitivity/specificity of the multiV-ROC in comparison to the single-index ROC and linear discriminant analysis (an analytic way of combining multi-indices). We conclude that, for the data sets we investigated, the proposed multiV-ROC approach is capable of providing a natural and practical alternative with improved classification accuracy as compared to univariate ROC and linear discriminant analysis.
doi:10.1109/TCBB.2012.141
PMCID: PMC4085147  PMID: 23702553
Alzheimer’s dementia (AD); multiple indices; multiV-ROC; receiver operational characteristic (ROC)
4.  Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(1):11-22.
IMPORTANCE
Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.
OBJECTIVE
To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
DESIGN, SETTING, AND PARTICIPANTS
Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
MAIN OUTCOMES AND MEASURES
Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
RESULTS
Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
CONCLUSIONS AND RELEVANCE
While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
doi:10.1001/jamaneurol.2013.4544
PMCID: PMC4056558  PMID: 24276092
5.  Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions 
Neurology  2013;80(17):1557-1564.
Objective:
To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD).
Methods:
This is a cross-sectional study of 124 cognitively normal persons aged 64 ± 6 years with a first-degree family history of AD, including 61 APOEε4 noncarriers and 63 carriers. An automated brain mapping algorithm characterized and compared correlations between higher fasting serum glucose levels and lower [18F]-fluorodeoxyglucose-PET rCMRgl measurements.
Results:
As predicted, higher fasting serum glucose levels were significantly correlated with lower rCMRgl and were confined to the vicinity of brain regions preferentially affected by AD. A similar pattern of regional correlations occurred in the APOEε4 noncarriers and carriers.
Conclusions:
Higher fasting serum glucose levels in cognitively normal, nondiabetic adults may be associated with AD pathophysiology. Findings suggest that the risk imparted by higher serum glucose levels may be independent of APOEε4 status. This study raises additional questions about the role of the metabolic process in the predisposition to AD and supports the possibility of targeting these processes in presymptomatic AD trials.
doi:10.1212/WNL.0b013e31828f17de
PMCID: PMC3662330  PMID: 23535495
6.  Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition 
Introduction
Based on previous studies, a preclinical classification for Alzheimer’s disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
Results
In the ADNI-1 cohort (median follow-up of 6 years), 6.3% and 17.0% of the CN subjects developed MCI/DAT after 3 and 5 years follow-up, respectively. NI biomarker cutoffs [structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) tau] were established in DAT patients and memory composite scores were calculated in CN subjects in a cross-sectional sample (n = 160). In the complete longitudinally followed CN ADNI cohort (n = 326, median follow-up of 2 years), CSF and MRI values predicted an increased conversion to MCI/DAT. Different NI biomarkers showed important disagreements for classifying subjects as abnormal NI [kappa = (−0.05)-(0.33)] and into AD preclinical groups. SCINIB subjects (5.0%) were more prevalent than AD preclinical stage 3 subjects (3.4%) and showed a trend for increased progression to MCI/DAT.
Conclusions
Different NI biomarkers lead to different classifications of ADNI subjects, while structural MRI and CSF tau measures showed the strongest predictive value for progression to MCI/DAT. The newly defined SCINIB category of ADNI subjects is more prevalent than AD preclinical stage individuals.
doi:10.1186/2051-5960-2-26
PMCID: PMC4008258  PMID: 24602322
Dementia; Alzheimer’s disease; Magnetic resonance imaging; Cerebrospinal fluid; Amyloid beta; Tau
7.  A Sparse Structure Learning Algorithm for Gaussian Bayesian Network Identification from High-Dimensional Data 
Structure learning of Bayesian Networks (BNs) is an important topic in machine learning. Driven by modern applications in genetics and brain sciences, accurate and efficient learning of large-scale BN structures from high-dimensional data becomes a challenging problem. To tackle this challenge, we propose a Sparse Bayesian Network (SBN) structure learning algorithm that employs a novel formulation involving one L1-norm penalty term to impose sparsity and another penalty term to ensure that the learned BN is a Directed Acyclic Graph (DAG)—a required property of BNs. Through both theoretical analysis and extensive experiments on 11 moderate and large benchmark networks with various sample sizes, we show that SBN leads to improved learning accuracy, scalability, and efficiency as compared with 10 existing popular BN learning algorithms. We apply SBN to a real-world application of brain connectivity modeling for Alzheimer’s disease (AD) and reveal findings that could lead to advancements in AD research.
doi:10.1109/TPAMI.2012.129
PMCID: PMC3924722  PMID: 22665720
Bayesian network; machine learning; data mining
8.  A Transfer Learning Approach for Network Modeling 
Networks models have been widely used in many domains to characterize the interacting relationship between physical entities. A typical problem faced is to identify the networks of multiple related tasks that share some similarities. In this case, a transfer learning approach that can leverage the knowledge gained during the modeling of one task to help better model another task is highly desirable. In this paper, we propose a transfer learning approach, which adopts a Bayesian hierarchical model framework to characterize task relatedness and additionally uses the L1-regularization to ensure robust learning of the networks with limited sample sizes. A method based on the Expectation-Maximization (EM) algorithm is further developed to learn the networks from data. Simulation studies are performed, which demonstrate the superiority of the proposed transfer learning approach over single task learning that learns the network of each task in isolation. The proposed approach is also applied to identification of brain connectivity networks of Alzheimer’s disease (AD) from functional magnetic resonance image (fMRI) data. The findings are consistent with the AD literature.
doi:10.1080/0740817X.2011.649390
PMCID: PMC3920601  PMID: 24526804
9.  Aging Influence on Gray Matter Structural Associations within the Default Mode Network Utilizing Bayesian Network Modeling 
Recent neuroimaging studies have revealed normal aging-related alterations in functional and structural brain networks such as the default mode network (DMN). However, less is understood about specific brain structural dependencies or interactions between brain regions within the DMN in the normal aging process. In this study, using Bayesian network (BN) modeling, we analyzed gray matter volume data from 109 young and 82 old subjects to characterize the influence of aging on associations between core brain regions within the DMN. Furthermore, we investigated the discriminability of the aging-associated BN models for the young and old groups. Compared to their young counterparts, the old subjects showed significant reductions in connections from right inferior temporal cortex (ITC) to medial prefrontal cortex (mPFC), right hippocampus (HP) to right ITC, and mPFC to posterior cingulate cortex and increases in connections from left HP to mPFC and right inferior parietal cortex to right ITC. Moreover, the classification results showed that the aging-related BN models could predict group membership with 88.48% accuracy, 88.07% sensitivity, and 89.02% specificity. Our findings suggest that structural associations within the DMN may be affected by normal aging and provide crucial information about aging effects on brain structural networks.
doi:10.3389/fnagi.2014.00105
PMCID: PMC4038778  PMID: 24910613
normal aging; Bayesian network modeling; default mode network; structural associations; gray matter
10.  Combining Multiple Markers to Improve the Longitudinal Rate of Progression-Application to Clinical Trials on the Early Stage of Alzheimer’s Disease 
Statistics in biopharmaceutical research  2013;5(1):10.1080/19466315.2012.756662.
Clinical trials on early stage Alzheimer’s disease (AD) are reaching a bottleneck because none of the current disease markers changes appreciably early in the disease process and therefore a huge sample is required to adequately power such trials. We propose a method to combine multiple markers so that the longitudinal rate of progression can be improved. The criterion is to maximize the probability that the combined marker will be decreased over time (assuming a negative mean slope for each marker). We propose estimates to the weights of markers in the optimum combination and a confidence interval estimate to the combined rate of progression through the maximum likelihood estimates and a bootstrap procedure. We conduct simulations to assess the performance of our estimates and compare our approach with the first principal component from a principal component analysis. The proposed method is applied to a real world sample of individuals with preclinical AD to combine measures from two cognitive domains. The combined cognitive marker is finally used to design future clinical trials on preclinical AD, demonstrating a significant improvement in reducing the sample sizes needed to power such trials when compared with individual markers alone.
doi:10.1080/19466315.2012.756662
PMCID: PMC3868484  PMID: 24363827
Bootstrap estimate; Delta method; Multivariate random coefficients models; Power; Preclinical Alzheimer’s disease (AD); Randomized clinical trials (RCT); Sample size
11.  Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study 
Lancet neurology  2012;11(12):10.1016/S1474-4422(12)70227-2.
Summary
Background
Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease.
Methods
Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition.
Findings
We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F florbetapir binding rose steeply over the next 9·4 years and plateaued at a mean age of 37·6 years (95% CI 35·3–40·2), about 6 and 11 years before the expected respective median ages at mild cognitive impairment and dementia onset. Prominent florbetapir binding was seen in the anterior and posterior cingulate, precuneus, and parietotemporal and frontal grey matter, as well as in the basal ganglia. Binding in the basal ganglia was not seen earlier or more prominently than in other regions.
Interpretation
These findings contribute to the understanding of preclinical familial Alzheimer’s disease and help set the stage for assessment of amyloid-modifying treatments in the prevention of familial Alzheimer’s disease.
Funding
Avid Radiopharmaceuticals, Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Colciencias, National Institute on Aging, and the State of Arizona.
doi:10.1016/S1474-4422(12)70227-2
PMCID: PMC3515078  PMID: 23137949
12.  Gray matter network associated with risk for Alzheimer's disease in young to middle-aged adults 
Neurobiology of aging  2012;33(12):2723-2732.
The apolipoprotein E (APOE) ε4 allele increases the risk for late-onset Alzheimer's disease (AD) and age-related cognitive decline. We investigated whether ε4 carriers show reductions in gray matter volume compared to ε4 non-carriers decades prior to the potential onset of AD dementia or healthy cognitive aging. Fourteen cognitively normal ε4 carriers, ages 26 to 45, were compared with 10 age-matched, ε4 non-carriers using T1-weighted volumetric magnetic resonance imaging (MRI) scans. All had reported first or second-degree family histories of dementia. Group differences in gray matter were tested using voxel-based morphometry (VBM) and a multivariate model of regional covariance, the Scaled Subprofile Model (SSM). A combination of the first two SSM MRI gray matter patterns distinguished the APOE ε4 carriers from non-carriers. This combined pattern showed gray matter reductions in bilateral dorsolateral and medial frontal, anterior cingulate, parietal, and lateral temporal cortices with co-varying relative increases in cerebellum, occipital, fusiform, and hippocampal regions. With these gray matter differences occurring decades prior to the potential onset of dementia or cognitive aging, the results suggest longstanding, gene-associated differences in brain morphology that may lead to preferential vulnerability for the later effects of late onset AD or healthy brain aging.
doi:10.1016/j.neurobiolaging.2012.01.014
PMCID: PMC3398228  PMID: 22405043
Apolipoprotein E; Late-Onset Alzheimer's Disease; Magnetic Resonance Imaging; Voxel-Based Morphometry; Multivariate Analysis; Gray Matter Volume
13.  Separating lexical-semantic access from other mnemonic processes in picture-name verification 
We present a novel paradigm to identify shared and unique brain regions underlying non-semantic, non-phonological, abstract, audio-visual (AV) memory vs. naming using a longitudinal functional magnetic resonance imaging experiment. Participants were trained to associate novel AV stimulus pairs containing hidden linguistic content. Half of the stimulus pairs were distorted images of animals and sine-wave speech versions of the animal's name. Images and sounds were distorted in such a way as to make their linguistic content easily recognizable only after being made aware of its existence. Memory for the pairings was tested by presenting an AV pair and asking participants to verify if the two stimuli formed a learned pairing. After memory testing, the hidden linguistic content was revealed and participants were tested again on their recollection of the pairings in this linguistically informed state. Once informed, the AV verification task could be performed by naming the picture. There was substantial overlap between the regions involved in recognition of non-linguistic sensory memory and naming, suggesting a strong relation between them. Contrasts between sessions identified left angular gyrus and middle temporal gyrus as key additional players in the naming network. Left inferior frontal regions participated in both naming and non-linguistic AV memory suggesting the region is responsible for AV memory independent of phonological content contrary to previous proposals. Functional connectivity between angular gyrus and left inferior frontal gyrus and left middle temporal gyrus increased when performing the AV task as naming. The results are consistent with the hypothesis that, at the spatial resolution of fMRI, the regions that facilitate non-linguistic AV associations are a subset of those that facilitate naming though reorganized into distinct networks.
doi:10.3389/fpsyg.2013.00706
PMCID: PMC3795327  PMID: 24130539
fMRI; memory; crossmodal; language
14.  Clinical and multimodal biomarker correlates of ADNI neuropathological findings 
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.
Results
Clinical diagnosis was either probable DAT or Alzheimer’s disease (AD)-type mild cognitive impairment (MCI) at last evaluation prior to death. All patients had a pathological diagnosis of AD, but only four had pure AD. A coincident pathological diagnosis of dementia with Lewy bodies (DLB), medial temporal lobe pathology (TDP-43 proteinopathy, argyrophilic grain disease and hippocampal sclerosis), referred to collectively here as MTL, and vascular pathology were present in 45.5%, 40.0% and 22.7% of these patients, respectively. Hallucinations were a strong predictor of coincident DLB (100% specificity) and a more severe dysexecutive profile was also a useful predictor of coincident DLB (80.0% sensitivity and 83.3% specificity). Occipital FDG-PET hypometabolism accurately classified coincident DLB (80% sensitivity and 100% specificity). Subjects with coincident MTL showed lower hippocampal volume.
Conclusions
Biomarkers can be used to independently predict coincident AD and DLB pathology, a common finding in amnestic MCI and DAT patients. Cohorts with comprehensive neuropathological assessments and multimodal biomarkers are needed to characterize independent predictors for the different neuropathological substrates of cognitive impairment.
doi:10.1186/2051-5960-1-65
PMCID: PMC3893373  PMID: 24252435
Alzheimer’s disease; Mild cognitive impairment; CSF; MRI; Autopsy; Neuropathology; Dementia; Biomarkers; Amyloid; Tau
15.  Structural Interactions within the Default Mode Network Identified by Bayesian Network Analysis in Alzheimer’s Disease 
PLoS ONE  2013;8(8):e74070.
Alzheimer’s disease (AD) is a well-known neurodegenerative disease that is associated with dramatic morphological abnormalities. The default mode network (DMN) is one of the most frequently studied resting-state networks. However, less is known about specific structural dependency or interactions among brain regions within the DMN in AD. In this study, we performed a Bayesian network (BN) analysis based on regional grey matter volumes to identify differences in structural interactions among core DMN regions in structural MRI data from 80 AD patients and 101 normal controls (NC). Compared to NC, the structural interactions between the medial prefrontal cortex (mPFC) and other brain regions, including the left inferior parietal cortex (IPC), the left inferior temporal cortex (ITC) and the right hippocampus (HP), were significantly reduced in the AD group. In addition, the AD group showed prominent increases in structural interactions from the left ITC to the left HP, the left HP to the right ITC, the right HP to the right ITC, and the right IPC to the posterior cingulate cortex (PCC). The BN models significantly distinguished AD patients from NC with 87.12% specificity and 81.25% sensitivity. We then used the derived BN models to examine the replicability and stability of AD-associated BN models in an independent dataset and the results indicated discriminability with 83.64% specificity and 80.49% sensitivity. The results revealed that the BN analysis was effective for characterising regional structure interactions and the AD-related BN models could be considered as valid and predictive structural brain biomarker models for AD. Therefore, our study can assist in further understanding the pathological mechanism of AD, based on the view of the structural network, and may provide new insights into classification and clinical application in the study of AD in the future.
doi:10.1371/journal.pone.0074070
PMCID: PMC3755999  PMID: 24015315
16.  Regional Neural Response Differences in the Determination of Faces or Houses Positioned in a Wide Visual Field 
PLoS ONE  2013;8(8):e72728.
In human visual cortex, the primary visual cortex (V1) is considered to be essential for visual information processing; the fusiform face area (FFA) and parahippocampal place area (PPA) are considered as face-selective region and places-selective region, respectively. Recently, a functional magnetic resonance imaging (fMRI) study showed that the neural activity ratios between V1 and FFA were constant as eccentricities increasing in central visual field. However, in wide visual field, the neural activity relationships between V1 and FFA or V1 and PPA are still unclear. In this work, using fMRI and wide-view present system, we tried to address this issue by measuring neural activities in V1, FFA and PPA for the images of faces and houses aligning in 4 eccentricities and 4 meridians. Then, we further calculated ratio relative to V1 (RRV1) as comparing the neural responses amplitudes in FFA or PPA with those in V1. We found V1, FFA, and PPA showed significant different neural activities to faces and houses in 3 dimensions of eccentricity, meridian, and region. Most importantly, the RRV1s in FFA and PPA also exhibited significant differences in 3 dimensions. In the dimension of eccentricity, both FFA and PPA showed smaller RRV1s at central position than those at peripheral positions. In meridian dimension, both FFA and PPA showed larger RRV1s at upper vertical positions than those at lower vertical positions. In the dimension of region, FFA had larger RRV1s than PPA. We proposed that these differential RRV1s indicated FFA and PPA might have different processing strategies for encoding the wide field visual information from V1. These different processing strategies might depend on the retinal position at which faces or houses are typically observed in daily life. We posited a role of experience in shaping the information processing strategies in the ventral visual cortex.
doi:10.1371/journal.pone.0072728
PMCID: PMC3749153  PMID: 23991147
17.  Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease 
JAMA neurology  2013;70(3):320-325.
Objective
To characterize and compare measurements of the posterior cingulate glucose metabolism, the hippocampal glucose metabolism, and hippocampal volume so as to distinguish cognitively normal, late-middle-aged persons with 2, 1, or 0 copies of the apolipoprotein E (APOE) ε4 allele, reflecting 3 levels of risk for late-onset Alzheimer disease.
Design
Cross-sectional comparison of measurements of cerebral glucose metabolism using 18F-fluorodeoxy-glucose positron emission tomography and measurements of brain volume using magnetic resonance imaging in cognitively normal ε4 homozygotes, ε4 heterozygotes, and noncarriers.
Setting
Academic medical center.
Participants
A total of 31 ε4 homozygotes, 42 ε4 heterozygotes, and 76 noncarriers, 49 to 67 years old, matched for sex, age, and educational level.
Main Outcome Measures
The measurements of posterior cingulate and hippocampal glucose metabolism were characterized using automated region-of-interest algorithms and normalized for whole-brain measurements. The hippocampal volume measurements were characterized using a semiautomated algorithm and normalized for total intracranial volume.
Results
Although there were no significant differences among the 3 groups of participants in their clinical ratings, neuropsychological test scores, hippocampal volumes (P=.60), or hippocampal glucose metabolism measurements (P = .12), there were significant group differences in their posterior cingulate glucose metabolism measurements (P=.001). The APOE ε4 gene dose was significantly associated with posterior cingulate glucose metabolism (r=0.29, P=.0003), and this association was significantly greater than those with hippocampal volume or hippocampal glucose metabolism (P<.05, determined by use of pairwise Fisher z tests).
Conclusions
Although our findings may depend in part on the analysis algorithms used, they suggest that a reduction in posterior cingulate glucose metabolism precedes a reduction in hippocampal volume or metabolism in cognitively normal persons at increased genetic risk for Alzheimer disease.
doi:10.1001/2013.jamaneurol.286
PMCID: PMC3745014  PMID: 23599929
18.  Association between an Alzheimer’s Disease-Related Index and APOE ε4 Gene Dose 
PLoS ONE  2013;8(6):e67163.
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 ε4 (APOE ε4) 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 ε4 homozygotes, heterozygotes, and non-carriers.
Methods
An algorithm was used to characterize and compare AD-related HCIs in cognitively normal individuals, including 36 ε4 homozygotes, 46 heterozygotes, and 78 non-carriers.
Results
These three groups differed significantly in their HCIs (ANOVA, p = 0.004), and there was a significant association between HCIs and gene dose (linear trend, p = 0.001).
Conclusions
The HCI is associated with three levels of genetic risk for late-onset AD. This supports the possibility of using a single FDG PET measurement to help in the preclinical detection and tracking of AD.
doi:10.1371/journal.pone.0067163
PMCID: PMC3694066  PMID: 23840615
19.  A method of generating image derived input function in quantitative 18F-FDG PET study based on the monotonicity of the input and output function curve 
Nuclear medicine communications  2012;33(4):10.1097/MNM.0b013e32834f262e.
Objective
A method for defining image-derived input function (IDIF) has been introduced and evaluated for the quantification of the regional cerebral metabolic rate of glucose in positron emission tomography studies.
Methods
The voxels in the brain vasculature are extracted based on the different monotonicity between the input and output function curves. The TACs of such voxels are averaged to get the uncorrected TAC of the brain vasculature. The IDIF was obtained from the raw TAC after correcting for the partial volume and spillover effects by an empirical formula in conjunction with single blood sample and the TAC of the brain tissue. Data from 16 human subjects were used to test the proposed method. The Patlak approach is used to calculate the net FDG clearance with plasma-derived input function (PDIF) and our generated IDIF, respectively.
Results
the net FDG clearances calculated with the image-derived input function generated by our approach are not only highly correlated (correlation coefficients close to 1) to, but also highly comparable (regression slopes close to 1, and intercepts close to 0) with those calculated with plasma-derived input function.
Conclusion
The method used in the present work is feasible and accurate.
doi:10.1097/MNM.0b013e32834f262e
PMCID: PMC3654793  PMID: 22262245
regional cerebral metabolic rate of glucose; 18F-fluoro-2-deoxyglucose; image derived input function; positron emission tomography
20.  Mapping joint grey and white matter reductions in Alzheimer's disease using joint independent component analysis 
Neuroscience letters  2012;531(2):10.1016/j.neulet.2012.10.038.
Alzheimer's disease (AD) is a neurodegenerative disease concomitant with grey and white matter damages. However, the interrelationship of volumetric changes between grey and white matter remains poorly understood in AD. Using joint independent component analysis, this study identified joint grey and white matter volume reductions based on structural magnetic resonance imaging data to construct the covariant networks in twelve AD patients and fourteen normal controls (NC). We found that three networks showed significant volume reductions in joint grey–white matter sources in AD patients, including (1) frontal/parietal/temporal-superior longitudinal fasciculus/corpus callosum, (2) temporal/parietal/occipital-frontal/occipital, and (3) temporal-precentral/postcentral. The corresponding expression scores distinguished AD patients from NC with 85.7%, 100% and 85.7% sensitivity for joint sources 1, 2 and 3, respectively; 75.0%, 66.7% and 75.0% specificity for joint sources 1, 2 and 3, respectively. Furthermore, the combined source of three significant joint sources best predicted the AD/NC group membership with 92.9% sensitivity and 83.3% specificity. Our findings revealed joint grey and white matter loss in AD patients, and these results can help elucidate the mechanism of grey and white matter reductions in the development of AD.
doi:10.1016/j.neulet.2012.10.038
PMCID: PMC3652975  PMID: 23123779
Alzheimer's disease; Joint source; Joint independent component analysis; Structural MRI; Voxel-based morphometry
21.  Correlations between FDG PET glucose uptake-MRI gray matter volume scores and apolipoprotein E ε4 gene dose in cognitively normal adults: a cross-validation study using voxel-based multi-modal partial least squares 
Neuroimage  2012;60(4):2316-2322.
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, late-middle-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.
doi:10.1016/j.neuroimage.2012.02.005
PMCID: PMC3325642  PMID: 22348880
22.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
Objective:
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
Methods:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
Results:
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
Conclusion:
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
doi:10.1212/WNL.0b013e318253d5b3
PMCID: PMC3345787  PMID: 22491869
23.  Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers☆ 
NeuroImage : Clinical  2013;2:512-520.
Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimer's disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of 18F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.
Highlights
•Codon 66 BDNF polymorphisms have been associated with various cerebral effects.•Community-recruited cognitively intact older adults underwent amyloid PET.•Recruitment was stratified factorially with APOE and BDNF as factors.•Aβ load in BDNF met carriers was higher but only in the presence of APOE ε4.•Aβ load was associated with worse episodic memory but only in BDNF met/APOE ε4.
doi:10.1016/j.nicl.2013.04.001
PMCID: PMC3777754  PMID: 24179803
BDNF, brain-derived neurotrophic factor; APOE, apolipoprotein E; SUVR, standardized uptake value ratio; SUVRcomp, SUVR in composite cortical volume of interest; val, valine; met, methionine; MRI, magnetic resonance imaging; PET, positron emission tomography; VOI, volume-of-interest; AD, Alzheimer's disease; PVC, partial volume correction; BDNF; APOE; Amyloid PET; Alzheimer; Flutemetamol
24.  Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons 
Neurobiology of Aging  2011;33(4):827.e11-827.e19.
Epidemiological studies suggest that elevated blood pressure (BP) in mid-life is associated with increased risk of Alzheimer’s disease (AD) in late-life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late-middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and non-carriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB DVRs and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower CMRgl in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late-mid-life may be associated with increased risk of presymptomatic AD.
doi:10.1016/j.neurobiolaging.2011.06.020
PMCID: PMC3236809  PMID: 21821316
APOE; blood pressure; arterial stiffness; brain imaging; PET; Alzheimer’s disease; amyloid; PiB; Pittsburgh Compound-B
25.  Identifying effective connectivity parameters in simulated fMRI: a direct comparison of switching linear dynamic system, stochastic dynamic causal, and multivariate autoregressive models 
The number and variety of connectivity estimation methods is likely to continue to grow over the coming decade. Comparisons between methods are necessary to prune this growth to only the most accurate and robust methods. However, the nature of connectivity is elusive with different methods potentially attempting to identify different aspects of connectivity. Commonalities of connectivity definitions across methods upon which base direct comparisons can be difficult to derive. Here, we explicitly define “effective connectivity” using a common set of observation and state equations that are appropriate for three connectivity methods: dynamic causal modeling (DCM), multivariate autoregressive modeling (MAR), and switching linear dynamic systems for fMRI (sLDSf). In addition while deriving this set, we show how many other popular functional and effective connectivity methods are actually simplifications of these equations. We discuss implications of these connections for the practice of using one method to simulate data for another method. After mathematically connecting the three effective connectivity methods, simulated fMRI data with varying numbers of regions and task conditions is generated from the common equation. This simulated data explicitly contains the type of the connectivity that the three models were intended to identify. Each method is applied to the simulated data sets and the accuracy of parameter identification is analyzed. All methods perform above chance levels at identifying correct connectivity parameters. The sLDSf method was superior in parameter estimation accuracy to both DCM and MAR for all types of comparisons.
doi:10.3389/fnins.2013.00070
PMCID: PMC3653105  PMID: 23717258
effective connectivity; fMRI BOLD; modeling and simulation; parameter estimation

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