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1.  The future of blood-based biomarkers for Alzheimer’s disease 
Treatment of Alzheimer’s disease (AD) is significantly hampered by the lack of easily accessible biomarkers that can detect disease presence and predict disease risk reliably. Fluid biomarkers of AD currently provide indications of disease stage; however, they are not robust predictors of disease progression or treatment response, and most are measured in cerebrospinal fluid, which limits their applicability. With these aspects in mind, the aim of this article is to underscore the concerted efforts of the Blood-Based Biomarker Interest Group, an international working group of experts in the field. The points addressed include: (1) the major challenges in the development of blood-based biomarkers of AD, including patient heterogeneity, inclusion of the “right” control population, and the blood– brain barrier; (2) the need for a clear definition of the purpose of the individual markers (e.g., prognostic, diagnostic, or monitoring therapeutic efficacy); (3) a critical evaluation of the ongoing biomarker approaches; and (4) highlighting the need for standardization of preanalytical variables and analytical methodologies used by the field.
PMCID: PMC4128378  PMID: 23850333
2.  Association of plasma and cortical beta-amyloid is modulated by APOE ε4 status 
APOE ε4’s role as a modulator of the relationship between soluble plasma beta-amyloid (Aβ) and fibrillar brain Aβ measured by Pittsburgh Compound-B positron emission tomography ([11C]PiB PET) has not been assessed.
Ninety-six Alzheimer’s Disease Neuroimaging Initiative participants with [11C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at time of scan were included. Regional and voxel-wise analyses of [11C]PiB data were used to determine the influence of APOE ε4 on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [11C]PiB uptake.
In APOE ε4− but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [11C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [11C]PiB binding compared to using APOE and plasma Aβ1-40/Aβ1-42 as separate terms.
The results suggest that plasma Aβ is a potential Alzheimer’s disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
PMCID: PMC3750076  PMID: 23541187
Alzheimer’s disease (AD); mild cognitive impairment (MCI); Alzheimer’s Disease Neuroimaging Initiative (ADNI); beta-amyloid (Aβ); plasma beta-amyloid; positron emission tomography (PET); Pittsburgh Compound-B ([11C]PiB); Apolipoprotein E (APOE)
3.  In-vivo investigation of the human cingulum bundle using the optimization of MR diffusion spectrum imaging 
European journal of radiology  2009;75(1):e29-e36.
Diffusion spectrum imaging (DSI) is a generalization of diffusion tensor imaging to map fibrous structure of white matter and potentially very sensitive to alterations of the cingulum bundles in dementia. In this in-vivo 4T study, DSI parameters especially spatial resolution and diffusion encoding bandwidth were optimized on humans to segment the cingulum bundles for tract level measurements of diffusion. The careful tailoring of the DSI acquisitions in conjunction with fiber tracking provided an optimal DSI setting for a reliable quantification of the cingulum bundle tracts. The optimization of tracking the cingulum bundle was verified using fiber tract quantifications, including coefficients of variability of DSI measurements along the fibers between and within healthy subjects in back-to-back studies and variogram analysis of spatial correlations between diffusion orientation distribution functions (ODF) along the cingulum bundle tracts. The results demonstrate identification of the cingulum bundle in human brain is reproducible using an optimized DSI parameter for maximum b-value and high spatial resolution of the DSI acquisition with a feasible acquisition time of whole brain in clinical practice. This optimized DSI setting should be useful for detecting alterations along the cingulum bundle in Alzheimer disease and related neurodegenerative disorders.
PMCID: PMC4266695  PMID: 19615838
MR diffusion; Diffusion spectrum imaging; optimization; cingulum bundle; Alzheimer
4.  Genetic Analysis of Quantitative Phenotypes in AD and MCI: Imaging, Cognition and Biomarkers 
Brain imaging and behavior  2014;8(2):183-207.
The Genetics Core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer’s disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g. APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g. FRMD6) that were later replicated on different data sets. Several other genes (e.g. APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.
PMCID: PMC3976843  PMID: 24092460
Alzheimer’s disease; genetic association study; quantitative traits; neuroimaging; biomarker; cognition
5.  Locally Linear Embedding (LLE) for MRI based Alzheimer’s Disease Classification 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.06.033.
Modern machine learning algorithms are increasingly being used in neuroimaging studies, such as the prediction of Alzheimer’s disease (AD) from structural MRI. However, finding a good representation for multivariate brain MRI features in which their essential structure is revealed and easily extractable has been difficult. We report a successful application of a machine learning framework that significantly improved the use of brain MRI for predictions. Specifically, we used the unsupervised learning algorithm of locally linear embedding (LLE) to transform multivariate MRI data of regional brain volume and cortical thickness to a locally linear space with fewer dimensions, while also utilizing the global nonlinear data structure. The embedded brain features were then used to train a classifier for predicting future conversion to AD based on a baseline MRI. We tested the approach on 413 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had baseline MRI scans and complete clinical follow-ups over 3 years with following diagnoses: Cognitive normal (CN; n= 137), stable mild cognitive impairment (s-MCI; n=93), MCI converters to AD (c-MCI, n=97), and AD (n=86). We found classifications using embedded MRI features generally outperformed (p < 0.05) classifications using the original features directly. Moreover, the improvement from LLE was not limited to a particular classifier but worked equally well for regularized logistic regressions, support vector machines, and linear discriminant analysis. Most strikingly, using LLE significantly improved (p = 0.007) predictions of MCI subjects who converted to AD and those who remained stable (accuracy/sensitivity/specificity: = 0.68/0.80/0.56). In contrast, predictions using the original features performed not better than by chance (accuracy/sensitivity/specificity: = 0.56/0.65/0.46). In conclusion, LLE is a very effective tool for classification studies of AD using multivariate MRI data. The improvement in predicting conversion to AD in MCI could have important implications for health management and for powering therapeutic trials by targeting non-demented subjects who later convert to AD.
PMCID: PMC3815961  PMID: 23792982
Alzheimer’s disease; locally linear embedding; statistical learning; classification of AD; MRI
6.  Functional Connectivity in Autosomal Dominant and Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(9):1111-1122.
Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in three specific genes, in contrast to late-onset Alzheimer Disease (LOAD), which has a more polygenetic risk profile.
Design, Setting, and Participants
We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of ADAD (N=79) and LOAD (N=444) human participants using resting state functional connectivity MRI (rs-fcMRI) at multiple international academic sites.
Main Outcomes and Measures
For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity as measured by clinical dementia rating (CDR). In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within five RSNs.
Functional connectivity decreases with increasing CDR were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in each type of AD accurately predicted CDR stage in the other, further demonstrating similarity of functional connectivity loss in each disease type. Among ADAD participants, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared to asymptomatic mutation non-carriers.
Conclusions and Relevance
rs-fcMRI changes with progressing AD severity are similar between ADAD and LOAD. Rs-fcMRI may be a useful endpoint for LOAD and ADAD therapy trials. ADAD disease process may be an effective model for LOAD disease process.
PMCID: PMC4240274  PMID: 25069482
Resting-state functional connectivity; autosomal dominant Alzheimer's disease; late-onset Alzheimer's disease; default mode network; apolipoprotein E (APOE)
7.  A Graph-Based Integration of Multimodal Brain Imaging Data for the Detection of Early Mild Cognitive Impairment (E-MCI) 
Alzheimer's disease (AD) is the most common cause of dementia in older adults. By the time an individual has been diagnosed with AD, it may be too late for potential disease modifying therapy to strongly influence outcome. Therefore, it is critical to develop better diagnostic tools that can recognize AD at early symptomatic and especially pre-symptomatic stages. Mild cognitive impairment (MCI), introduced to describe a prodromal stage of AD, is presently classified into early and late stages (E-MCI, L-MCI) based on severity. Using a graph-based semi-supervised learning (SSL) method to integrate multimodal brain imaging data and select valid imaging-based predictors for optimizing prediction accuracy, we developed a model to differentiate E-MCI from healthy controls (HC) for early detection of AD. Multimodal brain imaging scans (MRI and PET) of 174 E-MCI and 98 HC participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were used in this analysis. Mean targeted region-of-interest (ROI) values extracted from structural MRI (voxel-based morphometry (VBM) and FreeSurfer V5) and PET (FDG and Florbetapir) scans were used as features. Our results show that the graph-based SSL classifiers outperformed support vector machines for this task and the best performance was obtained with 66.8% cross-validated AUC (area under the ROC curve) when FDG and FreeSurfer datasets were integrated. Valid imaging-based phenotypes selected from our approach included ROI values extracted from temporal lobe, hippocampus, and amygdala. Employing a graph-based SSL approach with multimodal brain imaging data appears to have substantial potential for detecting E-MCI for early detection of prodromal AD warranting further investigation.
PMCID: PMC4224282  PMID: 25383392
Mild Cognitive Impairment; Multimodal Brain Imaging Data; Data Integration; Graph-based Semi-Supervised Learning; Alzheimer's Disease
8.  Denoising Diffusion-Weighted Magnitude MR Images using Rank and Edge Constraints 
To improve signal-to-noise ratio (SNR) for diffusion-weighted MR images.
A new method is proposed for denoising diffusion-weighted magnitude images. The proposed method formulates the denoising problem as an maximum a posteriori estimation problem based on Rician/noncentral χ likelihood models, incorporating an edge prior and a low-rank model. The resulting optimization problem is solved efficiently using a half-quadratic method with an alternating minimization scheme.
The performance of the proposed method has been validated using simulated and experimental data. Diffusion-weighted images and noisy data were simulated based on the diffusion tensor imaging (DTI) model and Rician/noncentral χ distributions. The simulation study (with known gold standard) shows substantial improvements in SNR and diffusion tensor es-timation after denoising. In-vivo diffusion imaging data at different b-values were acquired. Based on the experimental data, qualitative improvement in image quality and quantitative im-provement in diffusion tensor estimation were demonstrated. Additionally, the proposed method is shown to outperform one of the state-of-the-art non-local means based denoising algorithms, both qualitatively and quantitatively.
The SNR of diffusion-weighted images can be effectively improved with rank and edge constraints, resulting in an improvement in diffusion parameter estimation accuracy.
PMCID: PMC3796128  PMID: 23568755
Diffusion-weighted imaging; diffusion tensor imaging; Rician distribution; noncentral χ distribution; low-rank approximation; edge constraints
9.  Focal Hemosiderin Deposits and β-Amyloid Load in the ADNI Cohort 
Prevalence and risk factors for focal hemosiderin deposits are important considerations when planning amyloid–modifying trials for treatment and prevention of Alzheimer’s disease (AD).
Subjects were cognitively normal (n=171), early-mild cognitive impairment (MCI) (n=240), late-MCI (n=111) and AD (n=40) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Microhemorrhages and superficial siderosis were assessed at baseline and on all available MRIs at 3, 6 and 12 months. β-amyloid load was assessed with 18F-florbetapir PET.
Prevalence of superficial siderosis was 1% and prevalence of microhemorrhages was 25% increasing with age (p<0.001) and β-amyloid load (p<0.001). Topographic densities of microhemorrhages were highest in the occipital lobes and lowest in the deep/infratentorial regions. A greater number of microhemorrhages at baseline was associated with a greater annualized rate of additional microhemorrhages by last follow-up (rank correlation=0.49;P<0.001).
Focal hemosiderin deposits are relatively common in the ADNI cohort and are associated with β-amyloid load.
PMCID: PMC3770782  PMID: 23375568
ADNI; microhemorrhage; superficial siderosis; MRI; Amyloid; PET; Florbetapir; Alzheimer’s disease; mild cognitive impairment; early mild cognitive impairment
10.  APOE and BCHE as modulators of cerebral amyloid deposition: a florbetapir PET genome-wide association study 
Molecular psychiatry  2013;19(3):351-357.
Deposition of amyloid-β (Aβ) in the cerebral cortex is thought to be a pivotal event in Alzheimer’s disease (AD) pathogenesis with a significant genetic contribution. Molecular imaging can provide an early noninvasive phenotype but small samples have prohibited genome-wide association studies (GWAS) of cortical Aβ load until now. We employed florbetapir (18F) positron emission tomography (PET) imaging to assess brain Aβ levels in vivo for 555 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). More than six million common genetic variants were tested for association to quantitative global cortical Aβ load controlling for age, gender, and diagnosis. Independent genome-wide significant associations were identified on chromosome 19 within APOE (rs429358, p = 5.5 × 10−14) and on chromosome 3 upstream of BCHE (rs509208, p = 2.7 × 10−8) in a region previously associated with serum butyrylcholinesterase activity. Together, these loci explained 15% of the variance in cortical Aβ levels in this sample (APOE 10.7%, BCHE 4.3%). Suggestive associations were identified within ITGA6, near EFNA5, EDIL3, ITGA1, PIK3R1, NFIB, and ARID1B, and between NUAK1 and C12orf75. These results confirm the association of APOE with Aβ deposition and represent the largest known effect of BCHE on an AD-related phenotype. Butyrylcholinesterase has been found in senile plaques and this new association of genetic variation at the BCHE locus with Aβ burden in humans may have implications for potential disease-modifying effects of butyrylcholinesterase-modulating agents in the AD spectrum.
PMCID: PMC3661739  PMID: 23419831
Alzheimer’s disease (AD); amyloid; apolipoprotein E (APOE); butyrylcholinesterase (BCHE); florbetapir (AV-45); genome-wide association study (GWAS)
11.  The Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception 
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.
PMCID: PMC4108198  PMID: 23932184
Alzheimer's disease; Mild cognitive impairment; Amyloid; Tau; Biomarker
12.  Mapping Dynamic Changes in Ventricular Volume onto Baseline Cortical Surfaces in Normal Aging, MCI, and Alzheimer’s Disease* 
Ventricular volume (VV) is a powerful global indicator of brain tissue loss on MRI in normal aging and dementia. VV is used by radiologists in clinical practice and has one of the highest obtainable effect sizes for tracking brain change in clinical trials, but it is crucial to relate VV to structural alterations underlying clinical symptoms. Here we identify patterns of thinner cortical gray matter (GM) associated with dynamic changes in lateral VV at 1-year (N=677) and 2-year (N=536) intervals, in the ADNI cohort. People with faster VV loss had thinner baseline cortical GM in temporal, inferior frontal, inferior parietal, and occipital regions (controlling for age, sex, diagnosis). These findings show the patterns of relative cortical atrophy that predict later ventricular enlargement, further validating the use of ventricular segmentations as biomarkers. We may also infer specific patterns of regional cortical degeneration (and perhaps functional changes) that relate to VV expansion.
PMCID: PMC4138607  PMID: 25152934
imaging biomarkers*; brain imaging; magnetic resonance imaging; quantitative image analysis; statistical analysis; temporal/longitudinal image series analysis
13.  Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers 
Brain Imaging and Behavior  2013;8(2):183-207.
The Genetics Core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer’s disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development.
Electronic supplementary material
The online version of this article (doi:10.1007/s11682-013-9262-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3976843  PMID: 24092460
Alzheimer’s disease; Genetic association study; Quantitative traits; Neuroimaging; Biomarker; Cognition
14.  Breakdown of Brain Connectivity Between Normal Aging and Alzheimer's Disease: A Structural k-Core Network Analysis 
Brain Connectivity  2013;3(4):407-422.
Brain connectivity analyses show considerable promise for understanding how our neural pathways gradually break down in aging and Alzheimer's disease (AD). Even so, we know very little about how the brain's networks change in AD, and which metrics are best to evaluate these changes. To better understand how AD affects brain connectivity, we analyzed anatomical connectivity based on 3-T diffusion-weighted images from 111 subjects (15 with AD, 68 with mild cognitive impairment, and 28 healthy elderly; mean age, 73.7±7.6 SD years). We performed whole brain tractography based on the orientation distribution functions, and compiled connectivity matrices showing the proportions of detected fibers interconnecting 68 cortical regions. We computed a variety of measures sensitive to anatomical network topology, including the structural backbone—the so-called “k-core”—of the anatomical network, and the nodal degree. We found widespread network disruptions, as connections were lost in AD. Among other connectivity measures showing disease effects, network nodal degree, normalized characteristic path length, and efficiency decreased with disease, while normalized small-worldness increased, in the whole brain and left and right hemispheres individually. The normalized clustering coefficient also increased in the whole brain; we discuss factors that may cause this effect. The proportions of fibers intersecting left and right cortical regions were asymmetrical in all diagnostic groups. This asymmetry may intensify as disease progressed. Connectivity metrics based on the k-core may help understand brain network breakdown as cognitive impairment increases, revealing how degenerative diseases affect the human connectome.
PMCID: PMC3749712  PMID: 23701292
Alzheimer's disease; asymmetry; brain connectivity; diffusion tensor imaging; efficiency; k-core; mild cognitive impairment; nodal degree; small-world; tractography
15.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Cortical atrophy has been associated with late life depression (LLD) and recent findings suggest that reduced right hemisphere cortical thickness is associated with familial risk for major depressive disorder but cortical thickness abnormalities in LLD have not been explored. Further, cortical atrophy has been posited as a contributor to poor antidepressant treatment response in LLD but the impact of cortical thickness on psychotherapy response is unknown. This study was conducted to evaluate patterns of cortical thickness in LLD and in relation to psychotherapy treatment outcomes.
Participants included 22 individuals with LLD and 12 age matched comparison subjects. LLD participants completed 12 weeks of psychotherapy and treatment response was defined as a 50% reduction in depressive symptoms. All participants participated in Magnetic Resonance Imaging (MRI) of the brain and cortical mapping of grey matter tissue thickness was calculated.
LLD individuals demonstrated thinner cortex than controls prominently in the right frontal, parietal, and temporal brain regions. Eleven participants (50%) exhibited positive psychotherapy response after 12 weeks of treatment. Psychotherapy non-responders demonstrated thinner cortex in bilateral posterior cingulate and parahippocampal cortices, left paracentral, precuneus, cuneus, and insular cortices, and the right medial orbito-frontal and lateral occipital cortices relative to treatment responders.
Our findings suggest more distributed right hemisphere cortical abnormalities in LLD than have been previously reported. Additionally, our findings suggest that reduced bilateral cortical thickness may be an important phenotypic marker of individuals at higher risk for poor response to psychotherapy.
PMCID: PMC3732520  PMID: 23567394
16.  Exhaustive search of the SNP-SNP interactome identifies epistatic effects on brain volume in two cohorts 
The SNP-SNP interactome has rarely been explored in the context of neuroimaging genetics mainly due to the complexity of conducting ∼1011 pairwise statistical tests. However, recent advances in machine learning, specifically the iterative sure independence screening (SIS) method, have enabled the analysis of datasets where the number of predictors is much larger than the number of observations. Using an implementation of the SIS algorithm (called EPISIS), we used exhaustive search of the genome-wide, SNP-SNP interactome to identify and prioritize SNPs for interaction analysis. We identified a significant SNP pair, rs1345203 and rs1213205, associated with temporal lobe volume. We further examined the full-brain, voxelwise effects of the interaction in the ADNI dataset and separately in an independent dataset of healthy twins (QTIM). We found that each additional loading in the epistatic effect was associated with ∼5% greater brain regional brain volume (a protective effect) in both the ADNI and QTIM samples.
PMCID: PMC4109883  PMID: 24505811
epistasis; interaction; genome; sure independence; tensor-based morphometry
17.  Alzheimer's Disease Disrupts Rich Club Organization in Brain Connectivity Networks 
Diffusion imaging and brain connectivity analyses can monitor white matter deterioration, revealing how neural pathways break down in aging and Alzheimer's disease (AD). Here we tested how AD disrupts the ‘rich club’ effect – a network property found in the normal brain – where high-degree nodes in the connectivity network are more heavily interconnected with each other than expected by chance. We analyzed 3-Tesla whole-brain diffusionweighted images (DWI) from 66 subjects (22 AD/44 normal elderly). We performed whole-brain tractography based on the orientation distribution functions. Connectivity matrices were compiled, representing the proportion of detected fibers interconnecting 68 cortical regions. As expected, AD patients had a lower nodal degree (average number of connections) in cortical regions implicated in the disease. Unexpectedly, the normalized rich club coefficient was higher in AD. AD disrupts cortical networks by removing connections; when these networks are thresholded, organizational properties are disrupted leading to additional new biomarkers of AD.
PMCID: PMC4063983  PMID: 24953139
18.  A Commonly Carried Genetic Variant in the Delta Opioid Receptor Gene, OPRD1, is Associated with Smaller Regional Brain Volumes: Replication in Elderly and Young Populations 
Human brain mapping  2013;35(4):1226-1236.
Delta opioid receptors are implicated in a variety of psychiatric and neurological disorders. These receptors play a key role in the reinforcing properties of drugs of abuse, and polymorphisms in OPRD1 (the gene encoding delta opioid receptors) are associated with drug addiction. Delta opioid receptors are also involved in protecting neurons against hypoxic and ischemic stress. Here, we first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer’s Disease Neuroimaging Initiative. We hypothesized that common variants in OPRD1 would be associated with differences in brain structure, particularly in regions relevant to addictive and neurodegenerative disorders. One very common variant (rs678849) predicted differences in regional brain volumes. We replicated the association of this single-nucleotide polymorphism with regional tissue volumes in a large sample of young participants in the Queensland Twin Imaging study. Although the same allele was associated with reduced volumes in both cohorts, the brain regions affected differed between the two samples. In healthy elderly, exploratory analyses suggested that the genotype associated with reduced brain volumes in both cohorts may also predict cerebrospinal fluid levels of neurodegenerative biomarkers, but this requires confirmation. If opiate receptor genetic variants are related to individual differences in brain structure, genotyping of these variants may be helpful when designing clinical trials targeting delta opioid receptors to treat neurological disorders.
PMCID: PMC4046708  PMID: 23427138
neuroimaging; genetics; neurodegeneration; drug addiction; opiates
19.  Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N=1345 young and elderly subjects 
Brain imaging and behavior  2013;7(2):102-115.
Deficits in lentiform nucleus volume and morphometry are implicated in a number of genetically influenced disorders, including Parkinson’s disease, schizophrenia, and ADHD. Here we performed genome-wide searches to discover common genetic variants associated with differences in lentiform nucleus volume in human populations. We assessed structural MRI scans of the brain in two large genotyped samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; N=706) and the Queensland Twin Imaging Study (QTIM; N=639). Statistics of association from each cohort were combined meta-analytically using a fixed-effects model to boost power and to reduce the prevalence of false positive findings. We identified a number of associations in and around the flavin-containing monooxygenase (FMO) gene cluster. The most highly associated SNP, rs1795240, was located in the FMO3 gene; after meta-analysis, it showed genome-wide significant evidence of association with lentiform nucleus volume (PMA=4.79×10−8). This commonly-carried genetic variant accounted for 2.68 % and 0.84 % of the trait variability in the ADNI and QTIM samples, respectively, even though the QTIM sample was on average 50 years younger. Pathway enrichment analysis revealed significant contributions of this gene to the cytochrome P450 pathway, which is involved in metabolizing numerous therapeutic drugs for pain, seizures, mania, depression, anxiety, and psychosis. The genetic variants we identified provide replicated, genome-wide significant evidence for the FMO gene cluster’s involvement in lentiform nucleus volume differences in human populations.
PMCID: PMC3779070  PMID: 22903471
Basal ganglia; Genome-wide association study (GWAS); MRI; Replication; Morphometry; Drug metabolism
20.  Three-Class Differential Diagnosis among Alzheimer Disease, Frontotemporal Dementia, and Controls 
Biomarkers derived from brain magnetic resonance (MR) imaging have promise in being able to assist in the clinical diagnosis of brain pathologies. These have been used in many studies in which the goal has been to distinguish between pathologies such as Alzheimer’s disease and healthy aging. However, other dementias, in particular, frontotemporal dementia, also present overlapping pathological brain morphometry patterns. Hence, a classifier that can discriminate morphometric features from a brain MRI from the three classes of normal aging, Alzheimer’s disease (AD), and frontotemporal dementia (FTD) would offer considerable utility in aiding in correct group identification. Compared to the conventional use of multiple pair-wise binary classifiers that learn to discriminate between two classes at each stage, we propose a single three-way classification system that can discriminate between three classes at the same time. We present a novel classifier that is able to perform a three-class discrimination test for discriminating among AD, FTD, and normal controls (NC) using volumes, shape invariants, and local displacements (three features) of hippocampi and lateral ventricles (two structures times two hemispheres individually) obtained from brain MR images. In order to quantify its utility in correct discrimination, we optimize the three-class classifier on a training set and evaluate its performance using a separate test set. This is a novel, first-of-its-kind comparative study of multiple individual biomarkers in a three-class setting. Our results demonstrate that local atrophy features in lateral ventricles offer the potential to be a biomarker in discriminating among AD, FTD, and NC in a three-class setting for individual patient classification.
PMCID: PMC4026692  PMID: 24860545
differential diagnosis; Alzheimer; frontotemporal disease; multi-class; ventricle
21.  Maximizing power to track Alzheimer’s disease and MCI progression by LDA-based weighting of longitudinal ventricular surface features 
NeuroImage  2013;70:386-401.
We propose a new method to maximize biomarker efficiency for detecting anatomical change over time in serial MRI. Drug trials using neuroimaging become prohibitively costly if vast numbers of subjects must be assessed, so it is vital to develop efficient measures of brain change. A popular measure of efficiency is the minimal sample size (n80) needed to detect 25% change in a biomarker, with 95% confidence and 80% power. For multivariate measures of brain change, we can directly optimize n80 based on a Linear Discriminant Analysis (LDA). Here we use a supervised learning framework to optimize n80, offering two alternative solutions. With a new medial surface modeling method, we track 3D dynamic changes in the lateral ventricles in 2065 ADNI scans. We apply our LDA-based weighting to the results. Our best average n80—in two-fold nested cross-validation—is 104 MCI subjects (95% CI: [94,139]) for a 1-year drug trial, and 75 AD subjects [64,102]. This compares favorably with other MRI analysis methods. The standard “statistical ROI” approach applied to the same ventricular surfaces requires 165 MCI or 94 AD subjects. At 2 years, the best LDA measure needs only 67 MCI and 52 AD subjects, versus 119 MCI and 80 AD subjects for the stat-ROI method. Our surface-based measures are unbiased: they give no artifactual additive atrophy over three time points. Our results suggest that statistical weighting may boost efficiency of drug trials that use brain maps.
PMCID: PMC3942253  PMID: 23296188
Linear Discriminant Analysis; Shape analysis; ADNI; Lateral ventricles; Alzheimer’s disease; Mild cognitive impairment; Biomarker; Drug trial; Machine learning
22.  Mapping creatinine and cystatin C related white matter brain deficits in the elderly 
Neurobiology of aging  2012;34(4):1221-1230.
Poor kidney function is associated with increased risk of cognitive decline and generalized brain atrophy. Chronic kidney disease impairs glomerular filtration rate (eGFR), and this deterioration is indicated by elevated blood levels of kidney biomarkers such as creatinine (SCr) and cystatin C (CysC). Here we hypothesized that impaired renal function would be associated with brain deficits in regions vulnerable to neurodegeneration.
Using tensor-based morphometry, we related patterns of brain volumetric differences to SCr, CysC levels, and eGFR in a large cohort of 738 (mean age: 75.5±6·8 years; 438 men/300 women) elderly Caucasian subjects scanned as part of the Alzheimer’s Disease Neuroimaging Initiative.
Elevated kidney biomarkers were associated with volume deficits in the white matter region of the brain. All the three renal parameters in our study showed significant associations consistently with a region that corresponds with the anterior limb of internal capsule, bilaterally.
This is the first study to report a marked profile of structural alterations in the brain associated with elevated kidney biomarkers; helping us explain the cognitive deficits.
PMCID: PMC3603573  PMID: 23182131
creatinine; cystatin C; GFR; kidney function; brain volumes; brain structure; brain atrophy; neuroimaging; cognitive deficits
23.  The Aging Brain and Cognition 
JAMA neurology  2013;70(4):488-495.
β-Amyloid (Aβ) deposition and vascular brain injury (VBI) frequently co-occur and are both associated with cognitive decline in aging. Determining whether a direct relationship exists between them has been challenging. We sought to understand VBI’s influence on cognition and clinical impairment, separate from and in conjunction with pathologic changes associated with Alzheimer disease (AD).
To examine the relationship between neuroimaging measures of VBI and brain Aβ deposition and their associations with cognition.
Design and Setting
A cross-sectional study in a community- and clinic-based sample recruited for elevated vascular disease risk factors.
Clinically normal (mean age, 77.1 years [N=30]), cognitively impaired (mean age, 78.0 years [N=24]), and mildly demented (mean age, 79.8 years [N=7]) participants.
Magnetic resonance imaging, Aβ (Pitts-burgh Compound B–positron emission tomographic [PiB-PET]) imaging, and cognitive testing.
Main Outcome Measures
Magnetic resonance images were rated for the presence and location of infarct (34 infarct-positive participants, 27 infarct-negative participants) and were used to quantify white matter lesion volume. The PiB-PET uptake ratios were used to create a PiB index by averaging uptake across regions vulnerable to early Aβ deposition; PiB positivity (29 PiB-positive participants, 32 PiB-negative participants) was determined from a data-derived threshold. Standardized composite cognitive measures included executive function and verbal and nonverbal memory.
Vascular brain injury and Aβ were independent in both cognitively normal and impaired participants. Infarction, particularly in cortical and subcortical gray matter, was associated with lower cognitive performance in all domains (P<.05 for all comparisons). Pittsburgh Compound B positivity was neither a significant predictor of cognition nor interacted with VBI.
Conclusions and Relevance
In this elderly sample with normal cognition to mild dementia, enriched for vascular disease, VBI was more influential than Aβ in contemporaneous cognitive function and remained predictive after including the possible influence of Aβ. There was no evidence that VBI increases the likelihood of Aβ deposition. This finding highlights the importance of VBI in mild cognitive impairment and suggests that the impact of cerebrovascular disease should be considered with respect to defining the etiology of mild cognitive impairment.
PMCID: PMC3771392  PMID: 23400560
24.  Cognitive reserve associated with FDG-PET in preclinical Alzheimer disease 
Neurology  2013;80(13):1194-1201.
To examine the effect of education (a surrogate measure of cognitive reserve) on FDG-PET brain metabolism in elderly cognitively healthy (HC) subjects with preclinical Alzheimer disease (AD).
Fifty-two HC subjects (mean age 75 years) with FDG-PET and CSF measurement of Aβ1-42 were included from the prospective Alzheimer's Disease Neuroimaging Initiative biomarker study. HC subjects received a research classification of preclinical AD if CSF Aβ1-42 was <192 pg/mL (Aβ1-42 [+]) vs HC with normal Aβ (Aβ1-42 [−]). In regression analyses, we tested the interaction effect between education and CSF Aβ1-42 status (Aβ1-42 [+] vs Aβ1-42 [−]) on FDG-PET metabolism in regions of interest (ROIs) (posterior cingulate, angular gyrus, inferior/middle temporal gyrus) and the whole brain (voxel-based).
An interaction between education and CSF Aβ1-42 status was observed for FDG-PET in the posterior cingulate (p < 0.001) and angular gyrus ROIs (p = 0.03), but was not significant for the inferior/middle temporal gyrus ROI (p = 0.06), controlled for age, sex, and global cognitive ability (Alzheimer’s Disease Assessment Scale–cognitive subscale). The interaction effect was such that higher education was associated with lower FDG-PET in the Aβ1-42 (+) group, but with higher FDG-PET in the Aβ1-42 (−) group. Voxel-based analysis showed that this interaction effect was primarily restricted to temporo-parietal and ventral prefrontal brain areas.
Higher education was associated with lower FDG-PET in preclinical AD (Aβ1-42 [+]), suggesting that cognitive reserve had a compensatory function to sustain cognitive ability in presence of early AD pathology that alters FDG-PET metabolism.
PMCID: PMC3691784  PMID: 23486873
25.  Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology 
NeuroImage : Clinical  2014;4:508-516.
The relationships between clinical phenotype, β-amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aβ deposition measured by (11C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aβ deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA–AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 ± 7.7, Mini-Mental State Examination 22.0 ± 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Aβ deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E ε4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD-language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Aβ deposition and glucose metabolism in partially overlapping brain regions suggests that Aβ may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology.
•Multivariate approaches may be best suited to study links between biomarkers.•This is the first effort to apply pICA to FDG and PiB data in three groups with AD.•Hypometabolism was focal but amyloid binding was similar across conditions.•Results provide support for involvement of functional networks in variants of AD.•Aβ may exert both local and remote effects on brain metabolism.
PMCID: PMC3984448  PMID: 24818077
Multivariate data analysis; Parallel ICA; Alzheimer's disease; Amyloid imaging; PiB-PET; FDG-PET; Functional connectivity; Networks; AD or AD-memory, Alzheimer's disease; AUC, area under the curve; AD-language or LPA, logopenic variant primary progressive aphasia; PCA or AD-visuospatial, posterior cortical atrophy; PCC, posterior cingulate cortex; PPC, posterior parietal cortex

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