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1.  Brain imaging and neurodevelopment in HIV-uninfected Thai children born to HIV-infected mothers 
Perinatal use of combination antiretroviral therapy dramatically reduces vertical (mother-to-child) transmission of HIV, but has led to a growing population of children with perinatal HIV-exposure but uninfected (HEU). HIV can cause neurological injury among children born with infection, but the neuroanatomical and developmental effects in HEU children are poorly understood.
We used structural magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) to compare brain anatomy between 30 HEU and 33 age-matched HIV-unexposed and uninfected (HUU) children from Thailand. Maps of brain volume and microstructural anatomy were compared across groups; associations were tested between neuroimaging measures and concurrent neuropsychological test performance.
Mean (SD) age of children was 10.3 (2.8) years and 58% were male. All were enrolled in school and lived with family members. Intelligence quotient (IQ) did not differ between groups. Caretaker education levels did not differ, but income was higher for HUU (p<0.001). We did not detect group differences in brain volume or DTI metrics, after controlling for sociodemographic factors. The mean (95% confidence interval) fractional anisotropy (FA) in the corpus callosum was 0.375 (0.368–0.381) in HEU compared to 0.370 (0.364–0.375) in HUU. Higher FA and lower mean diffusivity were each associated with higher IQ scores in analyses with both groups combined.
No differences in neuroanatomical or brain integrity measures were detectable in HEU children compared to age- and sex-matched controls (HUU children). Expected associations between brain integrity measures and IQ scores were identified suggesting sufficient power to detect subtle associations that were present.
PMCID: PMC4575227  PMID: 26090574
HIV; brain injuries; maternal exposure; children; diffusion tensor imaging
2.  Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network 
Human brain mapping  2015;36(8):3087-3103.
Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3-Tesla whole-brain diffusion-weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative – 50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the ‘rich-club’ – a network property where high-degree network nodes are more interconnected than expected by chance. We calculated the rich-club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length and efficiency. Network disruptions predominated in the low-degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step-wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich-club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline.
PMCID: PMC4504816  PMID: 26037224
Alzheimer's disease; Mild Cognitive Impairment; MRI; DWI; rich club; graph theory
3.  Information-Theoretic Characterization of Blood Panel Predictors for Brain Atrophy and Cognitive Decline in the Elderly 
Cognitive decline in old age is tightly linked with brain atrophy, causing significant burden. It is critical to identify which biomarkers are most predictive of cognitive decline and brain atrophy in the elderly. In 566 older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we used a novel unsupervised machine learning approach to evaluate an extensive list of more than 200 potential brain, blood and cerebrospinal fluid (CSF)-based predictors of cognitive decline. The method, called CorEx, discovers groups of variables with high multivariate mutual information and then constructs latent factors that explain these correlations. The approach produces a hierarchical structure and the predictive power of biological variables and latent factors are compared with regression. We found that a group of variables containing the well-known AD risk gene APOE and CSF tau and amyloid levels were highly correlated. This latent factor was the most predictive of cognitive decline and brain atrophy.
PMCID: PMC4578218  PMID: 26413208
Magnetic resonance imaging (MRI); Brain; Cells & molecules; Genes; Machine learning
Diffusion tensor imaging (DTI) has recently been added to several large-scale studies of Alzheimer’s disease (AD), such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI), to investigate white matter (WM) abnormalities not detectable on standard anatomical MRI. Disease effects can be widespread, and the profile of WM abnormalities across tracts is still not fully understood. Here we analyzed image-wide measures from DTI fractional anisotropy (FA) maps to classify AD patients (n=43), mild cognitive impairment (n=114) and cognitively healthy elderly controls (n=70). We used voxelwise maps of FA along with averages in WM regions of interest (ROI) to drive a Support Vector Machine. We further used the ReliefF algorithm to select the most discriminative WM voxels for classification. This improved accuracy for all classification tasks by up to 15%. We found several clusters formed by the ReliefF algorithm, highlighting specific pathways affected in AD but not always captured when analyzing ROIs.
PMCID: PMC4578229  PMID: 26413201
diffusion tensor imaging; fractional anisotropy; Alzheimer’s disease; voxel-based analysis; support vector machines
Our understanding of network breakdown in Alzheimer’s disease (AD) is likely to be enhanced through advanced mathematical descriptors. Here, we applied spectral graph theory to provide novel metrics of structural connectivity based on 3-Tesla diffusion weighted images in 42 AD patients and 50 healthy controls. We reconstructed connectivity networks using whole-brain tractography and examined, for the first time here, cortical disconnection based on the graph energy and spectrum. We further assessed supporting metrics - link density and nodal strength - to better interpret our results. Metrics were analyzed in relation to the well-known APOE-4 genetic risk factor for late-onset AD. The number of disconnected cortical regions increased with the number of copies of the APOE-4 risk gene in people with AD. Each additional copy of the APOE-4 risk gene may lead to more dysfunctional networks with weakened or abnormal connections, providing evidence for the previously hypothesized “disconnection syndrome”.
PMCID: PMC4578320  PMID: 26413205
graph spectrum; energy; Alzheimer’s disease; APOE-4; disconnection syndrome
6.  Connectivity network measures predict volumetric atrophy in mild cognitive impairment 
Neurobiology of aging  2014;36(0 1):S113-S120.
Alzheimer’s disease (AD) is characterized by cortical atrophy and disrupted anatomical connectivity, and leads to abnormal interactions between neural systems. Diffusion weighted imaging (DWI) and graph theory can be used to evaluate major brain networks, and detect signs of a breakdown in network connectivity. In a longitudinal study using both DWI and standard MRI, we assessed baseline white matter connectivity patterns in 30 subjects with mild cognitive impairment (MCI; mean age: 71.8+/−7.5 yrs; 18M/12F) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Using both standard MRI-based cortical parcellations and whole-brain tractography, we computed baseline connectivity maps from which we calculated global “small-world” architecture measures, including mean clustering coefficient (MCC) and characteristic path length (CPL). We evaluated whether these baseline network measures predicted future volumetric brain atrophy in MCI subjects, who are at risk for developing AD, as determined by 3D Jacobian “expansion factor maps” between baseline and 6-month follow-up anatomical scans. This study suggests that DWI-based network measures may be a novel predictor of AD progression.
PMCID: PMC4276308  PMID: 25444606
Graph theory; brain networks; white matter; DTI; tractography; ADNI; TBM; small worldness; connectivity
7.  Seemingly Unrelated Regression empowers detection of network failure in dementia 
Neurobiology of aging  2014;36(0 1):S103-S112.
Brain connectivity is progressively disrupted in Alzheimer’s disease (AD). Here we used a seemingly unrelated regression (SUR) model to enhance the power to identify structural connections related to cognitive scores. We simultaneously solved regression equations with different predictors and used correlated errors among the equations to boost power for associations with brain networks. Connectivity maps were computed to represent the brain’s fiber networks from diffusion-weighted MRI scans of 200 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We first identified a pattern of brain connections related to clinical decline using standard regressions powered by this large sample size. As AD studies with a large number of DTI scans are rare, it is important to detect effects in smaller samples using simultaneous regression modeling like SUR. Diagnosis of MCI or AD is well known to be associated with ApoE genotype and educational level. In a subsample with no apparent associations using the general linear model, power was boosted with our SUR model--combining genotype, educational level, and clinical diagnosis.
PMCID: PMC4276318  PMID: 25257986
Brain connectivity; neuroimaging genetics; HARDI tractography; seemingly unrelated regression (SUR); APOE4; multivariate analysis
8.  Brain connectivity and novel network measures for Alzheimer’s disease classificationa 
Neurobiology of aging  2014;36(0 1):S121-S131.
We compare a variety of different anatomical connectivity measures, including several novel ones, that may help in distinguishing Alzheimer’s disease patients from controls. We studied diffusion-weighted MRI from 200 subjects scanned as part of the Alzheimer’s disease Neuroimaging Initiative (ADNI). We first evaluated measures derived from connectivity matrices based on whole-brain tractography; next, we studied additional network measures based on a novel flow-based measure of brain connectivity, computed on a dense 3D lattice. Based on these two kinds of connectivity matrices, we computed a variety of network measures. We evaluated the measures’ ability to discriminate disease with a repeated stratified 10-fold cross-validated classifier, using support vector machines (SVMs), a supervised learning algorithm. We tested the relative importance of different combinations of features based on the accuracy, sensitivity, specificity, and feature ranking of the classification of 200 people into normal healthy controls, and people with early- or late-stage mild cognitive impairment (MCI), or Alzheimer’s disease (AD).
PMCID: PMC4276322  PMID: 25264345
SVM; classification; sensitivity; specificity; maximum flow; connectivity matrix; Alzheimer’s disease; network measures; graph; ranking
9.  DTI-based maximum density path analysis and classification of Alzheimer’s disease 
Neurobiology of aging  2014;36(0 1):S132-S140.
Characterizing brain changes in Alzheimer’s disease (AD) is important for patient prognosis, and for assessing brain deterioration in clinical trials. In this diffusion tensor imaging study, we used a new fiber-tract modeling method to investigate white matter integrity in 50 elderly controls (CTL), 113 people with mild cognitive impairment (MCI), and 37 AD patients. After clustering tractography using an ROI atlas, we used a shortest path graph search through each bundle’s fiber density map to derive maximum density paths (MDPs), which we registered across subjects. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) along all MDPs and found significant MD and FA differences between AD patients and CTL subjects as well as MD differences between CTL and late MCI subjects. MD and FA were also associated with widely used clinical scores (MMSE). As an MDP is a compact, low-dimensional representation of white matter organization, we tested the utility of DTI measures along these MDPs as features for support vector machine (SVM) based classification of AD.
PMCID: PMC4283487  PMID: 25444597
ADNI; tractography; DTI; fiber tract modeling; white matter; connectivity; SVM; classification
10.  Algebraic connectivity of brain networks shows patterns of segregation leading to reduced network robustness in Alzheimer's disease 
Measures of network topology and connectivity aid the understanding of network breakdown as the brain degenerates in Alzheimer's disease (AD). We analyzed 3-Tesla diffusion-weighted images from 202 patients scanned by the Alzheimer's Disease Neuroimaging Initiative – 50 healthy controls, 72 with early- and 38 with late-stage mild cognitive impairment (eMCI/lMCI) and 42 with AD. Using whole-brain tractography, we reconstructed structural connectivity networks representing connections between pairs of cortical regions. We examined, for the first time in this context, the network's Laplacian matrix and its Fiedler value, describing the network's algebraic connectivity, and the Fiedler vector, used to partition a graph. We assessed algebraic connectivity and four additional supporting metrics, revealing a decrease in network robustness and increasing disarray among nodes as dementia progressed. Network components became more disconnected and segregated, and their modularity increased. These measures are sensitive to diagnostic group differences, and may help understand the complex changes in AD.
PMCID: PMC4669194  PMID: 26640830
brain network; algebraic connectivity; Fiedler value; modularity; Alzheimer's disease
11.  Obesity Gene NEGR1 Associated with White Matter Integrity in Healthy Young Adults 
NeuroImage  2014;102(0 2):548-557.
Obesity is a crucial public health issue in developed countries, with implications for cardiovascular and brain health as we age. A number of commonly-carried genetic variants are associated with obesity. Here we aim to see whether variants in obesity-associated genes - NEGR1, FTO, MTCH2, MC4R, LRRN6C, MAP2K5, FAIM2, SEC16B, ETV5, BDNF-AS, ATXN2L, ATP2A1, KCTD15, and TNN13K - are associated with white matter microstructural properties, assessed by high angular resolution diffusion imaging (HARDI) in young healthy adults between 20–30 years of age from the Queensland Twin Imaging study (QTIM). We began with a multi-locus approach testing how a number of common genetic risk factors for obesity at the single nucleotide polymorphism (SNP) level may jointly influence white matter integrity throughout the brain and found a wide spread genetic effect. Risk allele rs2815752 in NEGR1 was most associated with lower white matter integrity across a substantial portion of the brain. Across the area of significance in the bilateral posterior corona radiata, each additional copy of the risk allele was associated with a 2.2% lower average FA. This is the first study to find an association between an obesity risk gene and differences in white matter integrity. As our subjects were young and healthy, our results suggest that NEGR1 has effects on brain structure independent of its effect on obesity.
PMCID: PMC4269485  PMID: 25072390
12.  Serum Cholesterol and Variant in Cholesterol-Related Gene CETP Predict White Matter Microstructure 
Neurobiology of aging  2014;35(11):2504-2513.
Several common genetic variants influence cholesterol levels, which play a key role in overall health. Myelin synthesis and maintenance are highly sensitive to cholesterol concentrations, and abnormal cholesterol levels increase the risk for various brain diseases, including Alzheimer's disease (AD). We report significant associations between higher serum cholesterol (CHOL) levels and high-density lipoproteins (HDL) and higher fractional anisotropy in 403 young adults (23.8±2.4 years) scanned with diffusion imaging and anatomical MRI at 4 Tesla. By fitting a multi-locus genetic model within white matter areas associated with CHOL, we found that a set of 18 cholesterol-related SNPs implicated in AD risk predicted FA. We focused on the SNP with the largest individual effects - CETP (rs5882) – and found that increased G-allele dosage was associated with higher FA and lower radial and mean diffusivities in voxel-wise analyses of the whole brain. A follow-up analysis detected WM associations with rs5882 in the opposite direction in 78 older individuals (74.3±7.3 years). Cholesterol levels may influence WM integrity, and cholesterol-related genes may exert age-dependent effects.
PMCID: PMC4198330  PMID: 24997672
brain structure; DTI; imaging genetics; cholesterol; development; aging
13.  Mapping White Matter Integrity in Elderly People with HIV 
Human brain mapping  2013;35(3):975-992.
People with HIV are living longer as combination antiretroviral therapy (cART) becomes more widely available. However, even when plasma viral load is reduced to untraceable levels, chronic HIV infection is associated with neurological deficits and brain atrophy beyond that of normal aging. HIV is often marked by cortical and subcortical atrophy, but the integrity of the brain’s white matter (WM) pathways also progressively declines. Few studies focus on older cohorts where normal aging may be compounded with HIV infection to influence deficit patterns. In this relatively large diffusion tensor imaging (DTI) study, we investigated abnormalities in WM fiber integrity in 56 HIV+ adults with access to cART (mean age: 63.9 ± 3.7 years), compared to 31 matched healthy controls (65.4 ± 2.2 years). Statistical 3D maps revealed the independent effects of HIV diagnosis and age on fractional anisotropy (FA) and diffusivity, but we did not find any evidence for an age by diagnosis interaction in our current sample. Compared to healthy controls, HIV patients showed pervasive FA decreases and diffusivity increases throughout WM. We also assessed neuropsychological (NP) summary z-score associations. In both patients and controls, fiber integrity measures were associated with NP summary scores. The greatest differences were detected in the corpus callosum and in the projection fibers of the corona radiata. These deficits are consistent with published NP deficits and cortical atrophy patterns in elderly people with HIV.
PMCID: PMC3775847  PMID: 23362139
brain integrity; white matter; diffusion tensor imaging; cognition; HIV; cART
14.  Registering Cortical Surfaces Based on Whole-Brain Structural Connectivity and Continuous Connectivity Analysis 
We present a framework for registering cortical surfaces based on tractography-informed structural connectivity. We define connectivity as a continuous kernel on the product space of the cortex, and develop a method for estimating this kernel from tractography fiber models. Next, we formulate the kernel registration problem, and present a means to non-linearly register two brains’ continuous connectivity profiles. We apply theoretical results from operator theory to develop an algorithm for decomposing the connectome into its shared and individual components. Lastly, we extend two discrete connectivity measures to the continuous case, and apply our framework to 98 Alzheimer’s patients and controls. Our measures show significant differences between the two groups.
PMCID: PMC4283762  PMID: 25320795
Diffusion MRI; Cortical Surface Registration; Connectivity Analysis; Data Fusion
15.  Comparison of nine tractography algorithms for detecting abnormal structural brain networks in Alzheimer’s disease 
Alzheimer’s disease (AD) involves a gradual breakdown of brain connectivity, and network analyses offer a promising new approach to track and understand disease progression. Even so, our ability to detect degenerative changes in brain networks depends on the methods used. Here we compared several tractography and feature extraction methods to see which ones gave best diagnostic classification for 202 people with AD, mild cognitive impairment or normal cognition, scanned with 41-gradient diffusion-weighted magnetic resonance imaging as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) project. We computed brain networks based on whole brain tractography with nine different methods – four of them tensor-based deterministic (FACT, RK2, SL, and TL), two orientation distribution function (ODF)-based deterministic (FACT, RK2), two ODF-based probabilistic approaches (Hough and PICo), and one “ball-and-stick” approach (Probtrackx). Brain networks derived from different tractography algorithms did not differ in terms of classification performance on ADNI, but performing principal components analysis on networks helped classification in some cases. Small differences may still be detectable in a truly vast cohort, but these experiments help assess the relative advantages of different tractography algorithms, and different post-processing choices, when used for classification.
PMCID: PMC4396191  PMID: 25926791
Alzheimer’s disease; brain network; tractography; classification; PCA; GLRAM; diffusion MRI
Brain connectivity declines in Alzheimer’s disease (AD), both functionally and structurally. Connectivity maps and networks derived from diffusion-based tractography offer new ways to track disease progression and to understand how AD affects the brain. Here we set out to identify (1) which fiber network measures show greatest differences between AD patients and controls, and (2) how these effects depend on the density of fibers extracted by the tractography algorithm. We computed brain networks from diffusion-weighted images (DWI) of the brain, in 110 subjects (28 normal elderly, 56 with early and 11 with late mild cognitive impairment, and 15 with AD). We derived connectivity matrices and network topology measures, for each subject, from whole-brain tractography and cortical parcellations. We used an ODF lookup table to speed up fiber extraction, and to exploit the full information in the orientation distribution function (ODF). This made it feasible to compute high density connectivity maps. We used accelerated tractography to compute a large number of fibers to understand what effect fiber density has on network measures and in distinguishing different disease groups in our data. We focused on global efficiency, transitivity, path length, mean degree, density, modularity, small world, and assortativity measures computed from weighted and binary undirected connectivity matrices. Of all these measures, the mean nodal degree best distinguished diagnostic groups. High-density fiber matrices were most helpful for picking up the more subtle clinical differences, e.g. between mild cognitively impaired (MCI) and normals, or for distinguishing subtypes of MCI (early versus late). Care is needed in clinical analyses of brain connectivity, as the density of extracted fibers may affect how well a network measure can pick up differences between patients and controls.
PMCID: PMC4232938  PMID: 25404994
tractography; Hadoop; MapReduce; network measures; connectivity matrix; Alzheimer’s disease; ODF
17.  A Dynamical Clustering Model of Brain Connectivity Inspired by the N -Body Problem 
We present a method for studying brain connectivity by simulating a dynamical evolution of the nodes of the network. The nodes are treated as particles, and evolved under a simulated force analogous to gravitational acceleration in the well-known N -body problem. The particle nodes correspond to regions of the cortex. The locations of particles are defined as the centers of the respective regions on the cortex and their masses are proportional to each region’s volume. The force of attraction is modeled on the gravitational force, and explicitly made proportional to the elements of a connectivity matrix derived from diffusion imaging data. We present experimental results of the simulation on a population of 110 subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), consisting of healthy elderly controls, early mild cognitively impaired (eMCI), late MCI (LMCI), and Alzheimer’s disease (AD) patients. Results show significant differences in the dynamic properties of connectivity networks in healthy controls, compared to eMCI as well as AD patients.
PMCID: PMC4203319  PMID: 25340177
gravity; n-body simulation; diffusion; connectivity; MRI
18.  The Chimpanzee Brain Shows Human-Like Perisylvian Asymmetries in White Matter 
Modern neuroimaging technologies allow scientists to uncover inter-species differences and similarities in hemispheric asymmetries that may shed light onto the origin of brain asymmetry and its functional correlates. We analyzed asymmetries in white to grey matter ratios of the lateral aspect of the lobes of the brains of chimpanzees. We found marked leftward asymmetries for all lobar regions. This asymmetry was particularly pronounced in the frontal region and was found to be related to handedness for communicative manual gestures as well as for tool use. These results point to a continuity in asymmetry patterns between the human and chimpanzee brain, and support the notion that the anatomical substrates for lateralization of communicative functions and complex manipulative activities may have been present in the common hominid ancestor.
PMCID: PMC4195238  PMID: 19614754
hemispheric asymmetry; white matter; gray matter; tool use; handedness; chimpanzee
19.  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
We present a new flow-based method for modeling brain structural connectivity. The method uses a modified maximum-flow algorithm that is robust to noise in the diffusion data and guided by biologically viable pathways and structure of the brain. A flow network is first created using a lattice graph by connecting all lattice points (voxel centers) to all their neighbors by edges. Edge weights are based on the orientation distribution function (ODF) value in the direction of the edge. The maximum-flow is computed based on this flow graph using the flow or the capacity between each region of interest (ROI) pair by following the connected tractography fibers projected onto the flow graph edges. Network measures such as global efficiency, transitivity, path length, mean degree, density, modularity, small world, and assortativity are computed from the flow connectivity matrix. We applied our method to diffusion-weighted images (DWIs) from 110 subjects (28 normal elderly, 56 with early and 11 with late mild cognitive impairment, and 15 with AD) and segmented co-registered anatomical MRIs into cortical regions. Experimental results showed better performance compared to the standard fiber-counting methods when distinguishing Alzheimer’s disease from normal aging.
PMCID: PMC4109645  PMID: 25067993
maximum flow; tractography; connectivity matrix; Alzheimer’s disease; ODF; projection; network measures; graph
21.  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
22.  Disrupted Brain Networks in the Aging HIV+ Population 
Brain Connectivity  2012;2(6):335-344.
Antiretroviral therapies have become widely available, and as a result, individuals infected with the human immunodeficiency virus (HIV) are living longer, and becoming integrated into the geriatric population. Around half of the HIV+ population shows some degree of cognitive impairment, but it is unknown how their neural networks and brain connectivity compare to those of noninfected people. Here we combined magnetic resonance imaging-based cortical parcellations with high angular resolution diffusion tensor imaging tractography in 55 HIV-seropositive patients and 30 age-matched controls, to map white matter connections between cortical regions. We set out to determine selective virus-associated disruptions in the brain's structural network. All individuals in this study were aged 60–80, with full access to antiretroviral therapy. Frontal and motor connections were compromised in HIV+ individuals. HIV+ people who carried the apolipoprotein E4 allele (ApoE4) genotype—which puts them at even greater risk for neurodegeneration—showed additional network structure deficits in temporal and parietal connections. The ApoE4 genotype interacted with duration of illness. Carriers showed greater brain network inefficiencies the longer they were infected. Neural network deficiencies in HIV+ populations exceed those typical of normal aging, and are worse in those genetically predisposed to brain degeneration. This work isolates neuropathological alterations in HIV+ elders, even when treated with antiretroviral therapy. Network impairments may contribute to the neuropsychological abnormalities in elderly HIV patients, who will soon account for around half of all HIV+ adults.
PMCID: PMC3621327  PMID: 23240599
ApoE4; diffusion tensor imaging (DTI); fractional anisotropy (FA); geriatrics; high angular resolution diffusion imaging; imaging genetics; structural brain networks
23.  Effectiveness of regional DTI measures in distinguishing Alzheimer's disease, MCI, and normal aging☆ 
NeuroImage : Clinical  2013;3:180-195.
The Alzheimer's Disease Neuroimaging Initiative (ADNI) recently added diffusion tensor imaging (DTI), among several other new imaging modalities, in an effort to identify sensitive biomarkers of Alzheimer's disease (AD). While anatomical MRI is the main structural neuroimaging method used in most AD studies and clinical trials, DTI is sensitive to microscopic white matter (WM) changes not detectable with standard MRI, offering additional markers of neurodegeneration. Prior DTI studies of AD report lower fractional anisotropy (FA), and increased mean, axial, and radial diffusivity (MD, AxD, RD) throughout WM. Here we assessed which DTI measures may best identify differences among AD, mild cognitive impairment (MCI), and cognitively healthy elderly control (NC) groups, in region of interest (ROI) and voxel-based analyses of 155 ADNI participants (mean age: 73.5 ± 7.4; 90 M/65 F; 44 NC, 88 MCI, 23 AD). Both VBA and ROI analyses revealed widespread group differences in FA and all diffusivity measures. DTI maps were strongly correlated with widely-used clinical ratings (MMSE, CDR-sob, and ADAS-cog). When effect sizes were ranked, FA analyses were least sensitive for picking up group differences. Diffusivity measures could detect more subtle MCI differences, where FA could not. ROIs showing strongest group differentiation (lowest p-values) included tracts that pass through the temporal lobe, and posterior brain regions. The left hippocampal component of the cingulum showed consistently high effect sizes for distinguishing groups, across all diffusivity and anisotropy measures, and in correlations with cognitive scores.
•DTI scans in ADNI2 provide numerous biomarkers of Alzheimer's disease.•FA, MD, AxD, and RD measures all detect MCI and AD white matter deficits.•DTI FA and diffusivity measures are correlated with clinical cognitive scores.•FA is the least sensitive DTI measure for detecting AD related differences.•WM in the temporal lobe, corpus callosum and cingulum is repeatedly implicated.
PMCID: PMC3792746  PMID: 24179862
NC, normal control; RD, radial diffusivity; AxD, axial diffusivity; ADNI, Alzheimer's Disease Neuroimaging Initiative; DTI; Alzheimer's disease; MCI; White matter; Clinical scores; Biomarkers
Alzheimer’s Disease (AD) has long been considered a cortical degenerative disease, but impaired brain connectivity, due to white matter injury, may exacerbate cognitive problems. Predicting brain changes is critically important for early treatment. In a longitudinal diffusion tensor imaging study, we investigated white matter fiber integrity in 19 patients (mean age: 74.7 +/− 8.4 yrs at baseline) displaying early signs of mild cognitive impairment (eMCI). We first examined whether baseline average fractional anisotropy (FA) measures in the corpus callosum (CC) predicted changes in white matter integrity over the following 6 months. We then examined whether “small world” architecture measures - calculated from baseline connectivity maps - predicted white matter changes over the next 6 months. While average CC FA measures at baseline were not associated with future changes in FA, network measures were a sensitive biomarker for predicting white matter changes during this critical time before AD strikes.
PMCID: PMC3420972  PMID: 22903203
diffusion imaging; graph theory; connectivity; predictive models; Alzheimer’s disease
25.  A Voxel-Based Morphometry Analysis of White Matter Asymmetries in Chimpanzees (Pan troglodytes) 
Brain, Behavior and Evolution  2010;76(2):93-100.
Voxel-based morphometry (VBM) has become an increasingly common method for assessing neuroanatomical asymmetries in human in vivo magnetic resonance imaging (MRI). Here, we employed VBM to examine asymmetries in white matter in a sample of 48 chimpanzees (15 males and 33 females). T1-weighted MRI scans were segmented into white matter using FSL and registered to a common template. The segmented volumes were then flipped in the left-right axis and registered back to the template. The mirror image white matter volumes were then subtracted from the correctly oriented volumes and voxel-by-voxel t tests were performed. Twenty-seven significant lateralized clusters were found, including 18 in the left hemisphere and 9 in the right hemisphere. Several of the asymmetries were found in regions corresponding to well-known white matter tracts including the superior longitudinal fasciculus, inferior longitudinal fasciculus and corticospinal tract.
PMCID: PMC3202944  PMID: 20881357
Chimpanzees; Brain asymmetry; White matter; Language evolution

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