Publications

2017
Oestreich LKL, Lyall AE, Pasternak O, Kikinis Z, Newell DT, Savadjiev P, Bouix S, Shenton ME, Kubicki M, Kubicki M, Whitford TJ, et al. Characterizing White Matter Changes in Chronic Schizophrenia: A Free-water Imaging Multi-site Study. Schizophr Res. 2017;189 :153-61.Abstract
Diffusion tensor imaging (DTI) studies in chronic schizophrenia have found widespread but often inconsistent patterns of white matter abnormalities. These studies have typically used the conventional measure of fractional anisotropy, which can be contaminated by extracellular free-water. A recent free-water imaging study reported reduced free-water corrected fractional anisotropy (FAT) in chronic schizophrenia across several brain regions, but limited changes in the extracellular volume. The present study set out to validate these findings in a substantially larger sample. Tract-based spatial statistics (TBSS) was performed in 188 healthy controls and 281 chronic schizophrenia patients. Forty-two regions of interest (ROIs), as well as average whole-brain FAT and FW were extracted from free-water corrected diffusion tensor maps. Compared to healthy controls, reduced FAT was found in the chronic schizophrenia group in the anterior limb of the internal capsule bilaterally, the posterior thalamic radiation bilaterally, as well as the genu and body of the corpus callosum. While a significant main effect of group was observed for FW, none of the follow-up contrasts survived correction for multiple comparisons. The observed FAT reductions in the absence of extracellular FW changes, in a large, multi-site sample of chronic schizophrenia patients, validate the pattern of findings reported by a previous, smaller free-water imaging study of a similar sample. The limited number of regions in which FAT was reduced in the schizophrenia group suggests that actual white matter tissue degeneration in chronic schizophrenia, independent of extracellular FW, might be more localized than suggested previously.
Ofori E, Krismer F, Burciu RG, Pasternak O, McCracken JL, Lewis MM, Du G, McFarland NR, Okun MS, Poewe W, et al. Free Water Improves Detection of Changes in the Substantia Nigra in Parkinsonism: A Multisite Study. Mov Disord. 2017;32 (10) :1457-64.Abstract
BACKGROUND: Imaging markers that are sensitive to parkinsonism across multiple sites are critically needed for clinical trials. The objective of this study was to evaluate changes in the substantia nigra using single- and bi-tensor models of diffusion magnetic resonance imaging in PD, MSA, and PSP. METHODS: The study cohort (n = 425) included 107 healthy controls and 184 PD, 63 MSA, and 71 PSP patients from 3 movement disorder centers. Bi-tensor free water, free-water-corrected fractional anisotropy, free-water-corrected mean diffusivity, single-tensor fractional anisotropy, and single-tensor mean diffusivity were computed for the anterior and posterior substantia nigra. Correlations were computed between diffusion MRI measures and clinical measures. RESULTS: In the posterior substantia nigra, free water was greater for PSP than MSA and PD patients and controls. PD and MSA both had greater free water than controls. Free-water-corrected fractional anisotropy values were greater for PSP patents than for controls and PD patients. PSP and MSA patient single-tensor mean diffusivity values were greater than controls, and single-tensor fractional anisotropy values were lower for PSP patients than for healthy controls. The parkinsonism effect size for free water was 0.145 in the posterior substantia nigra and 0.072 for single-tensor mean diffusivity. The direction of correlations between single-tensor mean diffusivity and free-water values and clinical scores was similar at each site. CONCLUSIONS: Free-water values in the posterior substantia nigra provide a consistent pattern of findings across patients with PD, MSA, and PSP in a large cohort across 3 sites. Free water in the posterior substantia nigra relates to clinical measures of motor and cognitive symptoms in a large cohort of parkinsonism. © 2017 International Parkinson and Movement Disorder Society.
Chen Y, Georgiou TT, Ning L, Tannenbaum A. Matricial Wasserstein-1 Distance. IEEE Control Syst Lett. 2017;1 (1) :14-9.Abstract
We propose an extension of the Wasserstein 1-metric (W1) for density matrices, matrix-valued density measures, and an unbalanced interpretation of mass transport. We use duality theory and, in particular, a "dual of the dual" formulation of W1. This matrix analogue of the Earth Mover's Distance has several attractive features including ease of computation.
Maier-Hein KH, Neher PF, Houde J-C, Côté M-A, Garyfallidis E, Zhong J, Chamberland M, Yeh F-C, Lin Y-C, Ji Q, et al. The Challenge of Mapping the Human Connectome Based on Diffusion Tractography. Nat Commun. 2017;8 (1) :1349.Abstract
Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.
Norton I, Essayed WI, Zhang F, Pujol S, Yarmarkovich A, Golby AJ, Kindlmann G, Wasserman D, Estepar RSJ, Rathi Y, et al. SlicerDMRI: Open Source Diffusion MRI Software for Brain Cancer Research. Cancer Res. 2017;77 (21) :e101-e103.Abstract
Diffusion MRI (dMRI) is the only noninvasive method for mapping white matter connections in the brain. We describe SlicerDMRI, a software suite that enables visualization and analysis of dMRI for neuroscientific studies and patient-specific anatomic assessment. SlicerDMRI has been successfully applied in multiple studies of the human brain in health and disease, and here, we especially focus on its cancer research applications. As an extension module of the 3D Slicer medical image computing platform, the SlicerDMRI suite enables dMRI analysis in a clinically relevant multimodal imaging workflow. Core SlicerDMRI functionality includes diffusion tensor estimation, white matter tractography with single and multi-fiber models, and dMRI quantification. SlicerDMRI supports clinical DICOM and research file formats, is open-source and cross-platform, and can be installed as an extension to 3D Slicer (www.slicer.org). More information, videos, tutorials, and sample data are available at dmri.slicer.org Cancer Res; 77(21); e101-3. ©2017 AACR.
Dalca AV, Bouman K L, Freeman WT, Rost NS, Sabuncu MR, Golland P. Population Based Image Imputation. Inf Process Med Imaging. 2017;10265 (659-71).
Zhang M, Liao R, Dalca AV, Turk E, Luo J, Grant E, Golland P. Frequency Diffeomorphisms for Efficient Image Registration. Inf Process Med Imaging. 2017;10265 :559-70.
Wachinger C, Brennan M, Sharp GC, Golland P. Efficient Descriptor-Based Segmentation of Parotid Glands With Nonlocal Means. IEEE Trans Biomed Eng. 2017;64 (7) :1492-1502.Abstract
OBJECTIVE: We introduce descriptor-based segmentation that extends existing patch-based methods by combining intensities, features, and location information. Since it is unclear which image features are best suited for patch selection, we perform a broad empirical study on a multitude of different features. METHODS: We extend nonlocal means segmentation by including image features and location information. We search larger windows with an efficient nearest neighbor search based on kd-trees. We compare a large number of image features. RESULTS: The best results were obtained for entropy image features, which have not yet been used for patch-based segmentation. We further show that searching larger image regions with an approximate nearest neighbor search and location information yields a significant improvement over the bounded nearest neighbor search traditionally employed in patch-based segmentation methods. CONCLUSION: Features and location information significantly increase the segmentation accuracy. The best features highlight boundaries in the image. SIGNIFICANCE: Our detailed analysis of several aspects of nonlocal means-based segmentation yields new insights about patch and neighborhood sizes together with the inclusion of location information. The presented approach advances the state-of-the-art in the segmentation of parotid glands for radiation therapy planning.
Herz C, Fillion-Robin J-C, Onken M, Riesmeier J, Lasso A, Pinter C, Fichtinger G, Pieper S, Clunie D, Kikinis R, et al. DCMQI: An Open Source Library for Standardized Communication of Quantitative Image Analysis Results using DICOM. Cancer Research. 2017;77 (21) :e87-e90.Abstract
Quantitative analysis of clinical image data is an active area of research that holds promise for precision medicine, early assessment of treatment response, and objective characterization of the disease. Interoperability, data sharing, and the ability to mine the resulting data are of increasing importance, given the explosive growth in the number of quantitative analysis methods being proposed. The Digital Imaging and Communications in Medicine (DICOM) standard is widely adopted for image and metadata in radiology. dcmqi (DICOM for Quantitative Imaging) is a free, open source library that implements conversion of the data stored in commonly used research formats into the standard DICOM representation. dcmqi source code is distributed under BSD-style license. It is freely available as a precompiled binary package for every major operating system, as a Docker image, and as an extension to 3D Slicer. Installation and usage instructions are provided on Harvard DASH.
Halle M, Talos I-F, Jakab M, Makris N, Meier D, Wald LL, Fischl B, Kikinis R. Multi-modality MRI-based Atlas of the Brain. Surgical Planning Laboratory, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; 2017. Publisher's VersionAbstract
The Neuroimage Analysis Center's Computational Clinical Anatomy Core and the Surgical Planning Laboratory at Brigham and Women's Hospital is pleased to make available a multi-modality MRI-based atlas of the brain. Data was acquired at the Martinos Center for Biomedical Imaging (courtesy Dr. Lawrence Wald) on a Siemens 3T scanner, using a multi-array head coil, in a healthy, 42 year old male. The data set consists of : 1. a volumetric whole head MPRAGE series (voxel size 0.75 mm isotropic). 2. a volumetric whole head T2-weighted series (voxel size 0.75 mm isotropic). 3. a downsampled version of both acquisitions at 1mm isotropic resolution. 4. a per voxel labeling of the structures based on the 1mm volumes. 5. a color file mapping label values to RadLex-ontology derived names and colors suitable for display. 6. MRML files for displaying the volumes in 3D Slicer version 3.6 or greater, available for download. The atlas data is made available under terms of the 3D Slicer License section B.
The Slicer4 version also consists of 1. hypotalamic parcellation (courtesy Nikos Makris [Neuroimage. 2013]) 2. cerebellar parcellation (courtesy Nikos Makris [J Cogn Neurosci. 2003], [Neuroimage. 2005]) 3.head and neck muscles segmentation 4. anatomical model hierarchy 5. several pre-defined Scene Views (“anatomy teaching files”). All in a mrb (Medical Reality Bundle) archive file that contains the mrml scene file and all data for loading into Slicer 4 for displaying the volumes in 3D Slicer version 4.0 or greater, available for download.
This work is funded as part of the Neuroimaging Analysis Center, grant number P41 RR013218, by the NIH's National Center for Research Resources (NCRR) and grant number P41 EB015902, by the NIH's National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the Google Faculty Research Award.
Contributors: Ilwoo Lyu and Martin Styner: Sulcal Curves, Samira Farough: Ventricular System, Ibraheem Naeem and Maria Naeem: Head and Neck Muscles, George Papadimitriou: Cerebellar Parcellation, Madiha Tahir: White Matter.
This atlas maybe viewed with our Open Anatomy Browser.
Kapur T, Tempany CM. Proceedings of the 9th Image Guided Therapy Workshop. 2017;9 :1-54. 2017 IGT Workshop Proceedings
Niethammer M, Pohl KM, Janoos F, Wells WM. Active Mean Fields for Probabilistic Image Segmentation: Connections with Chan-Vese and Rudin-Osher-Fatemi Models. SIAM J. Imaging Sci. 2017;10 (3) :1069-1103.Abstract
Segmentation is a fundamental task for extracting semantically meaningful regions from an image. The goal of segmentation algorithms is to accurately assign object labels to each image location. However, image noise, shortcomings of algorithms, and image ambiguities cause uncertainty in label assignment. Estimating this uncertainty is important in multiple application domains, such as segmenting tumors from medical images for radiation treatment planning. One way to estimate these uncertainties is through the computation of posteriors of Bayesian models, which is computationally prohibitive for many practical applications. However, most computationally efficient methods fail to estimate label uncertainty. We therefore propose in this paper the active mean fields (AMF) approach, a technique based on Bayesian modeling that uses a mean-field approximation to efficiently compute a segmentation and its corresponding uncertainty. Based on a variational formulation, the resulting convex model combines any label-likelihood measure with a prior on the length of the segmentation boundary. A specific implementation of that model is the Chan-Vese segmentation model, in which the binary segmentation task is defined by a Gaussian likelihood and a prior regularizing the length of the segmentation boundary. Furthermore, the Euler-Lagrange equations derived from the AMF model are equivalent to those of the popular Rudin-Osher-Fatemi (ROF) model for image denoising. Solutions to the AMF model can thus be implemented by directly utilizing highly efficient ROF solvers on log-likelihood ratio fields. We qualitatively assess the approach on synthetic data as well as on real natural and medical images. For a quantitative evaluation, we apply our approach to the tt icgbench dataset.
Chen Y, Georgiou T, Pavon M, Tannenbaum A. Robust Transport over Networks. IEEE Trans Automat Contr. 2017;62 (9) :4675-82.Abstract
We consider transportation over a strongly connected, directed graph. The scheduling amounts to selecting transition probabilities for a discrete-time Markov evolution which is designed to be consistent with initial and final marginal constraints on mass transport. We address the situation where initially the mass is concentrated on certain nodes and needs to be transported in a certain time period to another set of nodes, possibly disjoint from the first. The random evolution is selected to be closest to a prior measure on paths in the relative entropy sense-such a construction is known as a Schrödinger bridge between the two given marginals. It may be viewed as an atypical stochastic control problem where the control consists in suitably modifying the prior transition mechanism. The prior can be chosen to incorporate constraints and costs for traversing specific edges of the graph, but it can also be selected to allocate equal probability to all paths of equal length connecting any two nodes (i.e., a uniform distribution on paths). This latter choice for prior transitions relies on the so-called Ruelle-Bowen random walker and gives rise to scheduling that tends to utilize all paths as uniformly as the topology allows. Thus, this Ruelle-Bowen law (Ruelle-Bowen Law) taken as prior, leads to a transportation plan that tends to lessen congestion and ensures a level of robustness. We also show that the distribution Ruelle-Bowen Law on paths, which attains the maximum entropy rate for the random walker given by the topological entropy, can itself be obtained as the time-homogeneous solution of a maximum entropy problem for measures on paths (also a Schrödinger bridge problem, albeit with prior that is not a probability measure). Finally we show that the paradigm of Schrödinger bridges as a mechanism for scheduling transport on networks can be adapted to graphs that are not strongly connected, as well as to weighted graphs. In the latter case, our approach may be used to design a transportation plan which effectively compromises between robustness and other criteria such as cost. Indeed, we explicitly provide a robust transportation plan which assigns maximum probability to minimum cost paths and therefore compares favourably with Optimal Mass Transportation strategies.
Otake Y, Yokota F, Fukuda N, Takao M, Takagi S, Yamamura N, O'Donnell L, Carl-Fredrik W, Sugano N, Sato Y. Patient-Specific Skeletal Muscle Fiber Modeling from Structure Tensor Field of Clinical CT Images. Int Conf Med Image Comput Comput Assist Interv. 2017;20 (Pt1) :656-63.Abstract
We propose an optimization method for estimating patient- specific muscle fiber arrangement from clinical CT. Our approach first computes the structure tensor field to estimate local orientation, then a geometric template representing fiber arrangement is fitted using a B- spline deformation by maximizing fitness of the local orientation using a smoothness penalty. The initialization is computed with a previously proposed algorithm that takes account of only the muscle’s surface shape. Evaluation was performed using a CT volume (1.0mm3/voxel) and high resolution optical images of a serial cryosection (0.1mm3/voxel). The mean fiber distance error at the initialization of 6.00 mm was decreased to 2.78mm after the proposed optimization for the gluteus maximus muscle, and from 5.28 mm to 3.09 mm for the gluteus medius muscle. The result from 20 patient CT images suggested that the proposed algorithm reconstructed an anatomically more plausible fiber arrangement than the previous method.
Otake-MICCAI2017.pdf
Hong Y, Golland P, Zhang M. Fast Geodesic Regression for Population-Based Image Analysis. Int Conf Med Image Comput Comput Assist Interv. 2017;20 (Pt1) :317-25.Abstract
Geodesic regression on images enables studies of brain development and degeneration, disease progression, and tumor growth. The high-dimensional nature of image data presents significant computational challenges for the current regression approaches and prohibits large scale studies. In this paper, we present a fast geodesic regression method that dramatically decreases the computational cost of the inference procedure while maintaining prediction accuracy. We employ an efficient low dimensional representation of diffeomorphic transformations derived from the image data and characterize the regressed trajectory in the space of diffeomorphisms by its initial conditions, i.e., an initial image template and an initial velocity field computed as a weighted average of pairwise diffeomorphic image registration results. This construction is achieved by using a first-order approximation of pairwise distances between images. We demonstrate the efficiency of our model on a set of 3D brain MRI scans from the OASIS dataset and show that it is dramatically faster than the state-of-the-art regression methods while producing equally good regression results on the large subject cohort.
Hong-MICCAI2017.pdf
Lipeng N, Rathi Y. Dynamic Regression for Partial Correlation and Causality Analysis of Functional Brain Networks. Int Conf Med Image Comput Comput Assist Interv. 2017;20 (Pt1) :365-72.Abstract
We propose a general dynamic regression framework for partial correlation and causality analysis of functional brain networks. Using the optimal prediction theory, we present the solution of the dynamic regression problem by minimizing the entropy of the associated stochastic process. We also provide the relation between the solutions and the linear dependence models of Geweke and Granger and derive novel expressions for computing partial correlation and causality using an optimal prediction filter with minimum error variance. We use the proposed dynamic framework to study the intrinsic partial correlation and causal- ity between seven different brain networks using resting state functional MRI (rsfMRI) data from the Human Connectome Project (HCP) and compare our results with those obtained from standard correlation and causality measures. The results show that our optimal prediction filter explains a significant portion of the variance in the rsfMRI data at low frequencies, unlike standard partial correlation analysis.
Ning-MICCAI2017.pdf
Fan Z, Weining W, Lipeng N, Gloria MA, Deborah W, Gagoski B, Kiera S, Hesham M H, Yang S, Weidong C, et al. Supra-Threshold Fiber Cluster Statistics for Data-Driven Whole Brain Tractography Analysis. Int Conf Med Image Comput Comput Assist Interv. 2017;20 (Pt1) :556-65.Abstract
This work presents a supra-threshold fiber cluster (STFC) analysis that leverages the whole brain fiber geometry to enhance sta- tistical group difference analysis. The proposed method consists of (1) a study-specific data-driven tractography parcellation to obtain white matter (WM) tract parcels according to the WM anatomy and (2) a nonparametric permutation-based STFC test to identify significant dif- ferences between study populations (e.g. disease and healthy). The basic idea of our method is that a WM parcel’s neighborhood (parcels with similar WM anatomy) can support the parcel’s statistical significance when correcting for multiple comparisons. The method is demonstrated by application to a multi-shell diffusion MRI dataset from 59 individuals, including 30 attention deficit hyperactivity disorder (ADHD) patients and 29 healthy controls (HCs). Evaluations are conducted using both synthetic and real data. The results indicate that our STFC method gives greater sensitivity in finding group differences in WM tract parcels compared to several traditional multiple comparison correction methods.
Zhang-MICCAI2017.pdf
Yip SSF, Parmar C, Blezek D, Estepar RSJ, Pieper S, Kim J, Aerts HJWL. Application of the 3D Slicer Chest Imaging Platform Segmentation Algorithm for Large Lung Nodule Delineation. PLoS One. 2017;12 (6) :e0178944.Abstract
PURPOSE: Accurate segmentation of lung nodules is crucial in the development of imaging biomarkers for predicting malignancy of the nodules. Manual segmentation is time consuming and affected by inter-observer variability. We evaluated the robustness and accuracy of a publically available semiautomatic segmentation algorithm that is implemented in the 3D Slicer Chest Imaging Platform (CIP) and compared it with the performance of manual segmentation. METHODS: CT images of 354 manually segmented nodules were downloaded from the LIDC database. Four radiologists performed the manual segmentation and assessed various nodule characteristics. The semiautomatic CIP segmentation was initialized using the centroid of the manual segmentations, thereby generating four contours for each nodule. The robustness of both segmentation methods was assessed using the region of uncertainty (δ) and Dice similarity index (DSI). The robustness of the segmentation methods was compared using the Wilcoxon-signed rank test (pWilcoxon<0.05). The Dice similarity index (DSIAgree) between the manual and CIP segmentations was computed to estimate the accuracy of the semiautomatic contours. RESULTS: The median computational time of the CIP segmentation was 10 s. The median CIP and manually segmented volumes were 477 ml and 309 ml, respectively. CIP segmentations were significantly more robust than manual segmentations (median δCIP = 14ml, median dsiCIP = 99% vs. median δmanual = 222ml, median dsimanual = 82%) with pWilcoxon~10-16. The agreement between CIP and manual segmentations had a median DSIAgree of 60%. While 13% (47/354) of the nodules did not require any manual adjustment, minor to substantial manual adjustments were needed for 87% (305/354) of the nodules. CIP segmentations were observed to perform poorly (median DSIAgree≈50%) for non-/sub-solid nodules with subtle appearances and poorly defined boundaries. CONCLUSION: Semi-automatic CIP segmentation can potentially reduce the physician workload for 13% of nodules owing to its computational efficiency and superior stability compared to manual segmentation. Although manual adjustment is needed for many cases, CIP segmentation provides a preliminary contour for physicians as a starting point.
Kikinis Z, Muehlmann M, Pasternak O, Peled S, Kulkarni P, Ferris C, Bouix S, Rathi Y, Koerte IK, Pieper S, et al. Diffusion Imaging of Mild Traumatic Brain Injury in the Impact Accelerated Rodent Model: A Pilot Study. Brain Inj. 2017;31 (10) :1376-81.Abstract
PRIMARY OBJECTIVE: There is a need to understand pathologic processes of the brain following mild traumatic brain injury (mTBI). Previous studies report axonal injury and oedema in the first week after injury in a rodent model. This study aims to investigate the processes occurring 1 week after injury at the time of regeneration and degeneration using diffusion tensor imaging (DTI) in the impact acceleration rat mTBI model. RESEARCH DESIGN: Eighteen rats were subjected to impact acceleration injury, and three rats served as sham controls. Seven days post injury, DTI was acquired from fixed rat brains using a 7T scanner. Group comparison of Fractional Anisotropy (FA) values between traumatized and sham animals was performed using Tract-Based Spatial Statistics (TBSS), a method that we adapted for rats. MAIN OUTCOMES AND RESULTS: TBSS revealed white matter regions of the brain with increased FA values in the traumatized versus sham rats, localized mainly to the contrecoup region. Regions of increased FA included the pyramidal tract, the cerebral peduncle, the superior cerebellar peduncle and to a lesser extent the fibre tracts of the corpus callosum, the anterior commissure, the fimbria of the hippocampus, the fornix, the medial forebrain bundle and the optic chiasm. CONCLUSION: Seven days post injury, during the period of tissue reparation in the impact acceleration rat model of mTBI, microstructural changes to white matter can be detected using DTI.
Ji F, Pasternak O, Liu S, Loke YM, Choo BL, Hilal S, Xu X, Ikram MK, Venketasubramanian N, Chen CL-H, et al. Distinct White Matter Microstructural Abnormalities and Extracellular Water Increases Relate to Cognitive Impairment in Alzheimer's Disease with And without Cerebrovascular Disease. Alzheimers Res Ther. 2017;9 (1) :63.Abstract
BACKGROUND: Mixed vascular and neurodegenerative dementia, such as Alzheimer's disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. METHODS: We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. RESULTS: The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. CONCLUSIONS: Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.

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