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1.  A Fast Algorithm for Denoising Magnitude Diffusion-Weighted Images with Rank and Edge Constraints 
Magnetic resonance in medicine  2015;75(1):433-440.
Purpose
To accelerate denoising of magnitude diffusion-weighted images subject to joint rank and edge constraints.
Methods
We extend a previously proposed majorize-minimize (MM) method for statistical estimation that involves noncentral χ distributions and joint rank and edge constraints. A new algorithm is derived which decomposes the constrained noncentral χ denoising problem into a series of constrained Gaussian denoising problems each of which is then solved using an efficient alternating minimization scheme.
Results
The performance of the proposed algorithm has been evaluated using both simulated and experimental data. Results from simulations based on ex vivo data show that the new algorithm achieves about a factor of 10 speed up over the original Quasi-Newton based algorithm. This improvement in computational efficiency enabled denoising of large data sets containing many diffusion-encoding directions. The denoising performance of the new efficient algorithm is found to be comparable to or even better than that of the original slow algorithm. For an in vivo high-resolution Q-ball acquisition, comparison of fiber tracking results around hippocampus region before and after denoising will also be shown to demonstrate the denoising effects of the new algorithm.
Conclusion
The optimization problem associated with denoising noncentral χ distributed diffusion-weighted images subject to joint rank and edge constraints can be solved efficiently using an MM-based algorithm.
doi:10.1002/mrm.25643
PMCID: PMC4558386  PMID: 25733066
Diffusion imaging; magnitude image denoising; noncentral χ-distribution; rank constraint; edge constraint; majorize-minimize algorithm
2.  Progression of Regional Microstructural Degeneration in Parkinson’s Disease: A Multicenter Diffusion Tensor Imaging Study 
PLoS ONE  2016;11(10):e0165540.
This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson’s disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression.
doi:10.1371/journal.pone.0165540
PMCID: PMC5087900  PMID: 27798653
3.  Diagnostic utility of ASL‐MRI and FDG‐PET in the behavioral variant of FTD and AD 
Abstract
Objective
To compare the values of arterial spin‐labeled (ASL) MRI and fluorodeoxyglucose (FDG) PET in the diagnosis of behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD).
Methods
Partial least squares logistic regression was used to identify voxels with diagnostic value in cerebral blood flow (CBF) and cerebral metabolic rate of glucose (CMRgl) maps from patients with bvFTD (n = 32) and AD (n = 28), who were compared with each other and with cognitively normal controls (CN, n = 15). Diagnostic values of these maps were compared with each other.
Results
Regions that differentiated each disorder from controls were similar for CBF and CMRgl. For differentiating AD from CN, the areas under the curve (AUC) for CBF (0.89) and CMRgl (0.91) were similar, with similar sensitivity (CBF: 86%, CMRgl: 78%) and specificity (CBF: 92%, CMRgl: 100%). Likewise, for differentiating bvFTD from CN performances of CBF (AUC = 0.83) and CMRgl (AUC = 0.85) were equivalent, with similar sensitivity (CBF: 78%, CMRgl: 79%) and specificity (CBF: 92%, CMRgl: 100%). In differentiating bvFTD from AD, classification was again similar for CBF (AUC = 0.87) and CMRgl (AUC = 0.79), as were sensitivity (CBF: 83%, CMRgl: 89%) and specificity (CBF: 93%, CMRgl: 78%). None of the differences in any performance measure were statistically significant.
Interpretation
ASL‐MRI has similar diagnostic utility as FDG‐PET in the diagnosis of AD and bvFTD. Continued development of ASL‐MRI as a diagnostic tool for neurodegenerative dementias is warranted.
doi:10.1002/acn3.330
PMCID: PMC5048385  PMID: 27752510
4.  Diffusion Tensor Imaging of the Nigrostriatal Fibers in Parkinson’s Disease 
Background
Parkinson’s disease (PD) is histopathologically characterized by the loss of dopamine neurons in the substantia nigra pars compacta. The depletion of these neurons is thought to reduce the dopaminergic function of the nigrostriatal pathway, as well as the neural fibers that link the substantia nigra to the striatum (putamen and caudate), causing a dysregulation in striatal activity that ultimately leads to lack of movement control. Based on diffusion tensor imaging, visualizing this pathway and measuring alterations of the fiber integrity remain challenging. The objectives were to: 1) develop a diffusion tensor tractography protocol for reliably tracking the nigrostriatal fibers on multicenter data; 2) test whether the integrities measured by diffusion tensor imaging of the nigrostriatal fibers are abnormal in PD; 3) test if abnormal integrities of the nigrostriatal fibers in PD patients are associated with the severity of motor disability and putaminal dopamine binding ratios.
Methods
Diffusion tensor tractography was performed on 50 drug naïve PD patients and 27 healthy control subjects from the international multicenter Parkinson’s Progression Marker Initiative.
Results
Tractography consistently detected the nigrostriatal fibers, yielding reliable diffusion measures. Fractional anisotropy, along with radial and axial diffusivity of the nigrostriatal tract, showed systematic abnormalities in patients. In addition, variations in fractional anisotropy and radial diffusivity of the nigrostriatal tract were associated with the degree of motor deficits in PD patients.
Conclusion
Taken together, the findings imply that the diffusion tensor imaging characteristic of the nigrostriatal tract is potentially an index for detecting and staging of early PD.
doi:10.1002/mds.26251
PMCID: PMC4418199  PMID: 25920732
Parkinson’s disease; MRI; diffusion tensor imaging; diffusion tensor tractography; nigrostriatal pathway
5.  Magnetic Resonance Imaging in ADNI 
INTRODUCTION
ADNI is now in its 10th year. The primary objective of the MRI core of ADNI has been to improve methods for clinical trials in Alzheimer’s disease and related disorders.
METHODS
We review the contributions of the MRI core from present and past cycles of ADNI (ADNI 1, GO and 2). We also review plans for the future – ADNI 3.
RESULTS
Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials.
DISCUSSION
Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in Alzheimer’s disease and will continue to do so in the future.
doi:10.1016/j.jalz.2015.05.002
PMCID: PMC4523217  PMID: 26194310
6.  Progression of Microstructural Degeneration in Progressive Supranuclear Palsy and Corticobasal Syndrome: A Longitudinal Diffusion Tensor Imaging Study 
PLoS ONE  2016;11(6):e0157218.
Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are both 4 microtubule binding repeat tauopathy related disorders. Clinical trials need new biomarkers to assess the effectiveness of tau-directed therapies. This study investigated the regional distribution of longitudinal diffusion tensor imaging changes, measured by fractional anisotropy, radial and axial diffusivity over 6 months median interval, in 23 normal control subjects, 35 patients with PSP, and 25 patients with CBS. A mixed-effects framework was used to test longitudinal changes within and between groups. Correlations between changes in diffusion variables and clinical progression were also tested. The study found that over a 6 month period and compared to controls, the most prominent changes in PSP were up to 3±1% higher rates of FA reduction predominantly in superior cerebellar peduncles, and up to 18±6% higher rates of diffusivity increases in caudate nuclei. The most prominent changes in CBS compared to controls were up to 4±1% higher rates of anisotropy reduction and 18±6% higher rates of diffusivity increase in basal ganglia and widespread white matter regions. Compared to PSP, CBS was mainly associated with up to 3±1% greater rates of anisotropy reduction around the central sulci, and 11±3% greater rates of diffusivity increase in superior fronto-occipital fascicules. Rates of diffusivity increases in the superior cerebellar peduncle correlated with rates of ocular motor decline in PSP patients. This study demonstrated that longitudinal diffusion tensor imaging measurement is a promising surrogate marker of disease progression in PSP and CBS over a relatively short period.
doi:10.1371/journal.pone.0157218
PMCID: PMC4911077  PMID: 27310132
7.  Bayesian segmentation of brainstem structures in MRI 
NeuroImage  2015;113:184-195.
In this paper we present a method to segment four brainstem structures (midbrain, pons, medulla oblongata and superior cerebellar peduncle) from 3D brain MRI scans. The segmentation method relies on a probabilistic atlas of the brainstem and its neighboring brain structures. To build the atlas, we combined a dataset of 39 scans with already existing manual delineations of the whole brainstem and a dataset of 10 scans in which the brainstem structures were manually labeled with a protocol that was specifically designed for this study. The resulting atlas can be used in a Bayesian framework to segment the brainstem structures in novel scans. Thanks to the generative nature of the scheme, the segmentation method is robust to changes in MRI contrast or acquisition hardware. Using cross validation, we show that the algorithm can segment the structures in previously unseen T1 and FLAIR scans with great accuracy (mean error under 1 mm) and robustness (no failures in 383 scans including 168 AD cases). We also indirectly evaluate the algorithm with a experiment in which we study the atrophy of the brainstem in aging. The results show that, when used simultaneously, the volumes of the midbrain, pons and medulla are significantly more predictive of age than the volume of the entire brainstem, estimated as their sum. The results also demonstrate that that the method can detect atrophy patterns in the brainstem structures that have been previously described in the literature. Finally, we demonstrate that the proposed algorithm is able to detect differential effects of AD on the brainstem structures. The method will be implemented as part of the popular neuroimaging package FreeSurfer.
Graphical abstract
doi:10.1016/j.neuroimage.2015.02.065
PMCID: PMC4434226  PMID: 25776214
8.  Joint analysis of structural and perfusion MRI for cognitive assessment and classification of Alzheimer’s disease and normal aging 
NeuroImage  2010;52(1):186-197.
Structural magnetic resonance imaging (MRI) of brain tissue loss and physiological imaging of regional cerebral blood flow (rCBF) can provide complimentary information for the characterization of brain disorders, such as Alzheimer’s disease (AD) but studies into gains in classification power for AD using these image modalities jointly have been limited. Our aim in this study was to determine the joint contribution of structural and perfusion-weighted imaging for the classification of AD in a cross-sectional study using an integrated multimodality MRI processing framework and a cortical surface-based analysis approach. We used logistic regression analysis to determine sequentially the value of cortical thickness, rCBF, and cortical thickness and rCBF jointly for classification for diagnosis of AD compared to controls. We further tested the extent to which cortical thinning and reduced rCBF explain individually or together variability in dementia severity. Separate analysis of structural MRI and perfusion-weighted MRI data yielded the well-established pattern of cortical thinning and rCBF reduction in AD, affecting predominantly temporo-parietal brain regions. Using structural MRI and perfusion-weighted MRI jointly indicated that cortical thinning dominated the classification of AD and controls without significant contributions from rCBF. However there was also a positive interaction between reduced rCBF and cortical thinning in the right superior temporal sulcus, implying that structural and physiological brain alterations in AD can be complementary. Compared to reduced rCBF, regional cortical thinning better explained the variability in dementia severity. In conclusion, structural brain alterations compared to physiological variations are the dominant features of MRI in AD.
doi:10.1016/j.neuroimage.2010.04.033
PMCID: PMC4667806  PMID: 20406691
9.  Sensitive measures of executive dysfunction in non-demented Parkinson’s disease 
Parkinsonism & related disorders  2014;20(12):1430-1433.
Background
We examined the sensitivity of different executive function measures for detecting deficits in Parkinson’s disease patients without dementia.
Methods
Twenty-one non-demented PD subjects and 21 neurologically healthy controls were administered widely used clinical executive functioning measures as well as the NIH EXAMINER battery, which produces Cognitive Control, Working Memory, and Verbal Fluency scores, along with an overall Executive Composite score, using psychometrically matched scales.
Results
No significant differences between groups were observed on widely used clinical measures. The PD patients scored lower than controls on the EXAMINER Executive Composite, Cognitive Control, and Working Memory Scores.
Conclusions
The NIH EXAMINER Executive Composite and Cognitive Control Scores are sensitive measures of executive dysfunction in non-demented PD, and may be more sensitive than several widely used measures. Results highlight the importance of careful test selection when evaluating for mild cognitive impairment in PD.
doi:10.1016/j.parkreldis.2014.10.007
PMCID: PMC4314390  PMID: 25454318
Parkinson’s disease; Mild cognitive impairment; Executive function; Cognitive control; Working memory
10.  Relationship Between CSF Biomarkers of Alzheimer’s Disease and Rates of Regional Cortical Thinning in ADNI Data 
Previously it was reported that Alzheimer’s disease (AD) patients have reduced amyloid (Aβ1–42) and elevated total tau (t-tau) and phosphorylated tau (p-tau181p) in the cerebro-spinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly (CN) and mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Aβ1–42, t-tau, and p-tau181p and ApoE ε4 status, and that the pattern of this association would be diagnosis specific. Our findings primarily showed that lower CSF Aβ1–42 and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in CN and MCI that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Aβ1–42 levels and higher p-tau levels supports the hypothesis that CSF Aβ1–42 and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE ε4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to amyloid and tau mediated pathology is regional and disease stage specific.
doi:10.3233/JAD-2011-0006
PMCID: PMC4587763  PMID: 21971452
MRI; Alzheimer’s disease; cerebrospinal fluid; biomarkers; cortical thickness; atrophy; ApoE
11.  Voxel-wise co-analysis of macro- and microstructural brain alteration in Mild Cognitive Impairment and Alzheimer’s disease using anatomical and diffusion MRI 
Background and Purpose
To determine if a voxel-wise “co-analysis” of structural and diffusion tensor magnetic resonance imaging (MRI) together reveals additional brain regions affected in mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) than voxel-wise analysis of the individual MRI modalities alone.
Methods
Twenty-one patients with MCI, 21 patients with AD, and 21 cognitively normal healthy elderly were studied with MRI. Maps of deformation and fractional anisotropy (FA) were computed and used as dependent variables in univariate and multivariate statistical models.
Results
Univariate voxel-wise analysis of macrostructural changes in MCI showed atrophy in the right anterior temporal lobe, left posterior parietal/precuneus region, WM adjacent to the cingulate gyrus, and dorsolateral prefrontal regions, consistent with prior research. Univariate voxel-wise analysis of microstructural changes in MCI showed reduced FA in the left posterior parietal region extending into the corpus callosum, consistent with previous work. The multivariate analysis, which provides more information than univariate tests when structural and FA measures are correlated, revealed additional MCI-related changes in corpus callosum and temporal lobe.
Conclusion
These results suggest that in corpus callosum and temporal regions macro- and microstructural variations in MCI can be congruent, providing potentially new insight into the mechanisms of brain tissue degeneration.
doi:10.1111/jon.12002
PMCID: PMC3951683  PMID: 23421601
MANOVA; deformation morphometry; fractional anisotropy; multimodality imaging; multivariate statistics; univariate statistics
12.  Numerical modeling of susceptibility-related MR signal dephasing with vessel size measurement: Phantom validation at 3T 
Purpose
MRI is used to obtain quantitative oxygenation and blood volume information from the susceptibility-related MR signal dephasing induced by blood vessels. However, analytical models that fit the MR signal are usually not accurate over the range of small blood vessels. Moreover, recent studies have demonstrated limitations in the simultaneous assessment of oxygenation and blood volume. In this study, a multi-parametric MRI framework that aims to measure vessel radii in addition to magnetic susceptibility and volume fraction was introduced.
Methods
The protocol consisted of gradient-echo sampling of the spin-echo, diffusion, T2 and B0 acquisitions. After correction steps, the data were post-processed with a versatile numerical model of the MR signal. An important analytical model was implemented for comparison. The approach was validated in phantoms with coiling strings as proxy for blood vessels.
Results
The feasibility of the vessel radius measurement is demonstrated. The numerical model shows an improved accuracy compared to the analytical approach. However, both methods overestimate the radius. The simultaneous measurement of the magnetic susceptibility and the volume fraction remains challenging.
Conclusion
The results suggest that this approach could be interesting in vivo to better characterize the microvasculature without contrast agent.
doi:10.1002/mrm.24968
PMCID: PMC3999331  PMID: 24167116
Quantitative BOLD; vessel size measurement; diffusion; magnetic susceptibility; MR numerical model
13.  Data-driven regions of interest for longitudinal change in frontotemporal lobar degeneration 
NeuroImage : Clinical  2015;12:332-340.
Current research is investigating the potential utility of longitudinal measurement of brain structure as a marker of drug effect in clinical trials for neurodegenerative disease. Recent studies in Alzheimer's disease (AD) have shown that measurement of change in empirically derived regions of interest (ROIs) allows more reliable measurement of change over time compared with regions chosen a-priori based on known effects of AD on brain anatomy. Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disorder for which there are no approved treatments. The goal of this study was to identify an empirical ROI that maximizes the effect size for the annual rate of brain atrophy in FTLD compared with healthy age matched controls, and to estimate the effect size and associated power estimates for a theoretical study that would use change within this ROI as an outcome measure. Eighty six patients with FTLD were studied, including 43 who were imaged twice at 1.5 T and 43 at 3 T, along with 105 controls (37 imaged at 1.5 T and 67 at 3 T). Empirically-derived maps of change were generated separately for each field strength and included the bilateral insula, dorsolateral, medial and orbital frontal, basal ganglia and lateral and inferior temporal regions. The extent of regions included in the 3 T map was larger than that in the 1.5 T map. At both field strengths, the effect sizes for imaging were larger than for any clinical measures. At 3 T, the effect size for longitudinal change measured within the empirically derived ROI was larger than the effect sizes derived from frontal lobe, temporal lobe or whole brain ROIs. The effect size derived from the data-driven 1.5 T map was smaller than at 3 T, and was not larger than the effect size derived from a-priori ROIs. It was estimated that measurement of longitudinal change using 1.5 T MR systems requires approximately a 3-fold increase in sample size to obtain effect sizes equivalent to those seen at 3 T. While the results should be confirmed in additional datasets, these results indicate that empirically derived ROIs can reduce the number of subjects needed for a longitudinal study of drug effects in FTLD compared with a-priori ROIs. Field strength may have a significant impact on the utility of imaging for measuring longitudinal change.
Highlights
•Identified regions of increased change in a longitudinal cohort of FTLD patients•Data-driven ROIs outperform anatomically predefined regions.•Effect size derived from data-driven 1.5 T map was smaller and less robust than 3 T.
doi:10.1016/j.nicl.2015.08.002
PMCID: PMC4983147  PMID: 27547726
Frontotemporal dementia; Magnetic resonance imaging
14.  Directed Progression Brain Networks in Alzheimer's Disease: Properties and Classification 
Brain Connectivity  2014;4(5):384-393.
Abstract
This article introduces a new approach in brain connectomics aimed at characterizing the temporal spread in the brain of pathologies like Alzheimer's disease (AD). The main instrument is the development of “directed progression networks” (DPNets), wherein one constructs directed edges between nodes based on (weakly) inferred directions of the temporal spreading of the pathology. This stands in contrast to many previously studied brain networks where edges represent correlations, physical connections, or functional progressions. In addition, this is one of a few studies showing the value of using directed networks in the study of AD. This article focuses on the construction of DPNets for AD using longitudinal cortical thickness measurements from magnetic resonance imaging data. The network properties are then characterized, providing new insights into AD progression, as well as novel markers for differentiating normal cognition (NC) and AD at the group level. It also demonstrates the important role of nodal variations for network classification (i.e., the significance of standard deviations, not just mean values of nodal properties). Finally, the DPNets are utilized to classify subjects based on their global network measures using a variety of data-mining methodologies. In contrast to most brain networks, these DPNets do not show high clustering and small-world properties.
doi:10.1089/brain.2014.0235
PMCID: PMC4064803  PMID: 24901258
Alzheimer's disease; amyloid plaques; brain connectomics; cortical thickness; directed networks
15.  Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer’s disease and mild cognitive impairment 
Brain  2014;137(5):1550-1561.
Patients with Alzheimer’s disease show reduced cerebral blood flow, but it is unclear how this relates to β-amyloid pathology. By comparing patients with Alzheimer’s dementia, mild cognitive impairment, and controls, Mattsson et al. show that high β-amyloid load is associated with increased atrophy and reduced perfusion, independent of diagnosis.
Patients with Alzheimer’s disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer’s Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer’s disease with dementia (n = 24). Based on the theory that Alzheimer’s disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. Global amyloid-β load was measured by florbetapir positron emission tomography, and regional blood flow and volume were measured in eight a priori defined regions of interest. Cerebral blood flow was reduced in patients with dementia in most brain regions. Higher amyloid-β load was related to lower cerebral blood flow in several regions, independent of diagnostic group. When comparing amyloid-β-positive subjects with -negative controls, we found reductions of cerebral blood flow in several diagnostic groups, including in precuneus, entorhinal cortex and hippocampus (dementia), inferior parietal cortex (late mild cognitive impairment and dementia), and inferior temporal cortex (early and late mild cognitive impairment and dementia). The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.
doi:10.1093/brain/awu043
PMCID: PMC3999717  PMID: 24625697
Alzheimer’s disease; beta-amyloid; PET imaging; perfusion imaging; magnetic resonance imaging
16.  Directed Network Motifs in Alzheimer’s Disease and Mild Cognitive Impairment 
PLoS ONE  2015;10(4):e0124453.
Directed network motifs are the building blocks of complex networks, such as human brain networks, and capture deep connectivity information that is not contained in standard network measures. In this paper we present the first application of directed network motifs in vivo to human brain networks, utilizing recently developed directed progression networks which are built upon rates of cortical thickness changes between brain regions. This is in contrast to previous studies which have relied on simulations and in vitro analysis of non-human brains. We show that frequencies of specific directed network motifs can be used to distinguish between patients with Alzheimer’s disease (AD) and normal control (NC) subjects. Especially interesting from a clinical standpoint, these motif frequencies can also distinguish between subjects with mild cognitive impairment who remained stable over three years (MCI) and those who converted to AD (CONV). Furthermore, we find that the entropy of the distribution of directed network motifs increased from MCI to CONV to AD, implying that the distribution of pathology is more structured in MCI but becomes less so as it progresses to CONV and further to AD. Thus, directed network motifs frequencies and distributional properties provide new insights into the progression of Alzheimer’s disease as well as new imaging markers for distinguishing between normal controls, stable mild cognitive impairment, MCI converters and Alzheimer’s disease.
doi:10.1371/journal.pone.0124453
PMCID: PMC4400037  PMID: 25879535
17.  Voxelwise multivariate analysis of multimodality magnetic resonance imaging 
Human brain mapping  2013;35(3):831-846.
Most brain magnetic resonance imaging (MRI) studies concentrate on a single MRI contrast or modality, frequently structural MRI. By performing an integrated analysis of several modalities, such as structural, perfusion-weighted, and diffusion-weighted MRI, new insights may be attained to better understand the underlying processes of brain diseases. We compare two voxelwise approaches: (1) fitting multiple univariate models, one for each outcome and then adjusting for multiple comparisons among the outcomes and (2) fitting a multivariate model. In both cases, adjustment for multiple comparisons is performed over all voxels jointly to account for the search over the brain. The multivariate model is able to account for the multiple comparisons over outcomes without assuming independence because the covariance structure between modalities is estimated. Simulations show that the multivariate approach is more powerful when the outcomes are correlated and, even when the outcomes are independent, the multivariate approach is just as powerful or more powerful when at least two outcomes are dependent on predictors in the model. However, multiple univariate regressions with Bonferroni correction remains a desirable alternative in some circumstances. To illustrate the power of each approach, we analyze a case control study of Alzheimer's disease, in which data from three MRI modalities are available.
doi:10.1002/hbm.22217
PMCID: PMC4324330  PMID: 23408378
multivariate analysis; multiple comparisons; multimodality imaging; diffusion tensor imaging; structural magnetic resonance imaging; perfusion weighted magnetic resonance imaging; Alzheimer's disease
18.  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.
doi:10.1016/j.ejrad.2009.06.019
PMCID: PMC4266695  PMID: 19615838
MR diffusion; Diffusion spectrum imaging; optimization; cingulum bundle; Alzheimer
19.  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.
doi:10.1016/j.neuroimage.2013.06.033
PMCID: PMC3815961  PMID: 23792982
Alzheimer’s disease; locally linear embedding; statistical learning; classification of AD; MRI
20.  Denoising Diffusion-Weighted Magnitude MR Images using Rank and Edge Constraints 
Purpose
To improve signal-to-noise ratio (SNR) for diffusion-weighted MR images.
Methods
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.
Results
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.
Conclusion
The SNR of diffusion-weighted images can be effectively improved with rank and edge constraints, resulting in an improvement in diffusion parameter estimation accuracy.
doi:10.1002/mrm.24728
PMCID: PMC3796128  PMID: 23568755
Diffusion-weighted imaging; diffusion tensor imaging; Rician distribution; noncentral χ distribution; low-rank approximation; edge constraints
21.  Patterns of Reduced Cortical Thickness in Late Life Depression and Relationship to Psychotherapeutic Response 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jagp.2013.01.013
PMCID: PMC3732520  PMID: 23567394
22.  Standardization of Analysis Sets for Reporting Results from ADNI MRI Data 
The ADNI 3D T1-weighted MRI acquisitions provide a rich dataset for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising: screening visits, 1 year completers (subjects who all have screening, 6 and 12 month scans), two year annual completers (screening, 1, and 2 year scans), two year completers (screening, 6 months, 1 year, 18 months (MCI only) and 2 years) and complete visits (screening, 6 months, 1 year, 18 months (MCI only), 2, and 3 year (normal and MCI only) scans). As the ADNI-GO/ADNI-2 data becomes available, updated standard analysis sets will be posted regularly.
doi:10.1016/j.jalz.2012.06.004
PMCID: PMC3891834  PMID: 23110865
23.  T2-based Arterial Spin Labeling measurements of blood to tissue water transfer in human brain 
Purpose
To investigate blood to tissue water transfer in human brain, in vivo and spatially resolved using a T2-based arterial spin labeling (ASL) method with 3D readout.
Materials and Methods
A T2-ASL method is introduced to measure the water transfer processes between arterial blood and brain tissue based on a 3D-GRASE pulsed ASL sequence with multi-echo readout. An analytical mathematical model is derived based on the General Kinetic Model, including blood- and tissue compartment, T1 and T2 relaxation and a blood-to-tissue transfer term. Data has been collected from healthy volunteers on a 3 Tesla system. The mean transfer time parameter Tbl→ex (blood- to extravascular compartment transfer time) has been derived voxel-wise by non-linear least-squares fitting.
Results
Whole-brain maps of Tbl→ex show stable results in cortical regions, yielding different values depending on brain region. The mean value across subjects and ROIs in grey matter is 440±30 ms.
Conclusion
A novel method to derive whole-brain maps of blood to tissue water transfer dynamics is demonstrated. It is promising for the investigation of underlying physiological mechanisms and development of diagnostic applications in cerebro-vascular diseases.
doi:10.1002/jmri.23822
PMCID: PMC3554863  PMID: 23019041
Arterial Spin Labeling; two-compartment model; water transfer; transverse relaxation; T2; 3D-GRASE
24.  Improved Diffusion Imaging through SNR-Enhancing Joint Reconstruction 
Quantitative diffusion imaging is a powerful technique for the characterization of complex tissue microarchitecture. However, long acquisition times and limited signal-to-noise ratio (SNR) represent significant hurdles for many in vivo applications. This paper presents a new approach to reduce noise while largely maintaining resolution in diffusion weighted images, using a statistical reconstruction method that takes advantage of the high level of structural correlation observed in typical datasets. Compared to existing denoising methods, the proposed method performs reconstruction directly from the measured complex k-space data, allowing for Gaussian noise modeling and theoretical characterizations of the resolution and SNR of the reconstructed images. In addition, the proposed method is compatible with many different models of the diffusion signal (e.g., diffusion tensor modeling, q-space modeling, etc.). The joint reconstruction method can provide significant improvements in SNR relative to conventional reconstruction techniques, with a relatively minor corresponding loss in image resolution. Results are shown in the context of diffusion spectrum imaging tractography and diffusion tensor imaging, illustrating the potential of this SNR-enhancing joint reconstruction approach for a range of different diffusion imaging experiments.
doi:10.1002/mrm.24229
PMCID: PMC3407310  PMID: 22392528
Diffusion imaging; denoising; statistical reconstruction; feature preservation
25.  Diffusion MRI Registration Using Orientation Distribution Functions 
We propose a linear-elastic registration method to register diffusion-weighted MRI (DW-MRI) data sets by mapping their diffusion orientation distribution functions (ODFs). The ODFs were reconstructed using a q-ball imaging (QBI) technique to resolve intravoxel fiber crossing. The registration method is based on mapping the ODF maps represented by spherical harmonics which yield analytic solutions and reduce the computational complexity. ODF reorientation is required to maintain the consistency with transformed local fiber directions. The reorientation matrices are extracted from the local Jacobian and directly applied to the coefficients of spherical harmonics. The similarity cost of the registration is defined by the ODF shape distance calculated from the spherical harmonic coefficients. The transformation fields are regularized by linear elastic constraints. The proposed method was validated using both synthetic and real data sets. Experimental results show that the elastic registration improved the affine alignment by further reducing the ODF shape difference; reorientation during the registration produced registered ODF maps with more consistent principle directions compared to registrations without reorientation or simultaneous reorientation.
PMCID: PMC3860746  PMID: 19694299

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