@article{BelathurSuresh2017,

title = {Factors influencing accuracy of cortical thickness in the diagnosis of Alzheimer's disease},

author = {Mahanand Belathur Suresh and Bruce Fischl and David H. Salat},

doi = {10.1002/hbm.23922},

issn = {1097-0193},

year  = {2018},

date = {2018-04-00},

urldate = {2018-04-00},

journal = {Human Brain Mapping},

volume = {39},

number = {4},

pages = {1500--1515},

publisher = {Wiley},

abstract = {There is great value to use of structural neuroimaging in the assessment of Alzheimer's disease (AD). However, to date, predictive value of structural imaging tend to range between 80% and 90% in accuracy and it is unclear why this is the case given that structural imaging should parallel the pathologic processes of AD. There is a possibility that clinical misdiagnosis relative to the gold standard pathologic diagnosis and/or additional brain pathologies are confounding factors contributing to reduced structural imaging classification accuracy. We examined potential factors contributing to misclassification of individuals with clinically diagnosed AD purely from cortical thickness measures. Correctly classified and incorrectly classified groups were compared across a range of demographic, biological, and neuropsychological data including cerebrospinal fluid biomarkers, amyloid imaging, white matter hyperintensity (WMH) volume, cognitive, and genetic factors. Individual subject analyses suggested that at least a portion of the control individuals misclassified as AD from structural imaging additionally harbor substantial AD biomarker pathology and risk, yet are relatively resistant to cognitive symptoms, likely due to “cognitive reserve,” and therefore clinically unimpaired. In contrast, certain clinical control individuals misclassified as AD from cortical thickness had increased WMH volume relative to other controls in the sample, suggesting that vascular conditions may contribute to classification accuracy from cortical thickness measures. These results provide examples of factors that contribute to the accuracy of structural imaging in predicting a clinical diagnosis of AD, and provide important information about considerations for future work aimed at optimizing structural based diagnostic classifiers for AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Logue2018b,

title = {Smaller Hippocampal Volume in Posttraumatic Stress Disorder: A Multisite ENIGMA-PGC Study: Subcortical Volumetry Results From Posttraumatic Stress Disorder Consortia},

author = {Mark W. Logue and Sanne J.H. van Rooij and Emily L. Dennis and Sarah L. Davis and Jasmeet P. Hayes and Jennifer S. Stevens and Maria Densmore and Courtney C. Haswell and Jonathan Ipser and Saskia B.J. Koch and Mayuresh Korgaonkar and Lauren A.M. Lebois and Matthew Peverill and Justin T. Baker and Premika S.W. Boedhoe and Jessie L. Frijling and Staci A. Gruber and Ilan Harpaz-Rotem and Neda Jahanshad and Sheri Koopowitz and Ifat Levy and Laura Nawijn and Lauren O’Connor and Miranda Olff and David H. Salat and Margaret A. Sheridan and Jeffrey M. Spielberg and Mirjam van Zuiden and Sherry R. Winternitz and Jonathan D. Wolff and Erika J. Wolf and Xin Wang and Kristen Wrocklage and Chadi G. Abdallah and Richard A. Bryant and Elbert Geuze and Tanja Jovanovic and Milissa L. Kaufman and Anthony P. King and John H. Krystal and Jim Lagopoulos and Maxwell Bennett and Ruth Lanius and Israel Liberzon and Regina E. McGlinchey and Katie A. McLaughlin and William P. Milberg and Mark W. Miller and Kerry J. Ressler and Dick J. Veltman and Dan J. Stein and Kathleen Thomaes and Paul M. Thompson and Rajendra A. Morey},

doi = {10.1016/j.biopsych.2017.09.006},

issn = {0006-3223},

year  = {2018},

date = {2018-02-00},

urldate = {2018-02-00},

journal = {Biological Psychiatry},

volume = {83},

number = {3},

pages = {244--253},

publisher = {Elsevier BV},

abstract = {Background 

Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group.



Methods 

We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium.



Results 

In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063).



Conclusions 

Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Waninger2018,

title = {Event‐related potentials during sustained attention and memory tasks: Utility as biomarkers for mild cognitive impairment},

author = {Shani Waninger and Chris Berka and Amir Meghdadi and Marija S. Karic and Kimberly Stevens and Cinthya Aguero and Tatiana Sitnikova and David H. Salat and Ajay Verma},

doi = {10.1016/j.dadm.2018.05.007},

issn = {2352-8729},

year  = {2018},

date = {2018-01-00},

urldate = {2018-01-00},

journal = {Alz & Dem Diag Ass & Dis Mo},

volume = {10},

number = {1},

pages = {452--460},

publisher = {Wiley},

abstract = {Introduction</jats:title><jats:p>The objective of the study is to validate attention and memory tasks that elicit event‐related potentials (ERPs) for utility as sensitive biomarkers for early dementia.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A 3‐choice vigilance task designed to evaluate sustained attention and standard image recognition memory task designed to evaluate attention, encoding, and image recognition memory were administered with concurrent electroencephalography acquisition to elicit ERPs in mild cognitive impairment (MCI) and healthy cohorts. ERPs were averaged, and mean or maximum amplitude of components was measured and compared between and within cohorts.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>There was significant suppression of the amplitude of the late positive potential in the MCI cohort compared with the healthy controls during 3‐choice vigilance task, predominantly over occipital and right temporal‐parietal region, and standard image recognition memory task over all regions. During standard image recognition memory task, diminished performance showed strong correlation with electroencephalography measurements. The old/new effects observed in the healthy controls cohort correlated with performance and were lost in MCI.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>ERPs obtained during cognitive tasks may provide a powerful tool for assessing MCI and have strong potential as sensitive and robust biomarkers for tracking disease progression and evaluating response to investigative therapeutics.</jats:p></jats:sec>},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sitnikova2018,

title = {Short timescale abnormalities in the states of spontaneous synchrony in the functional neural networks in Alzheimer's disease},

author = {Tatiana A. Sitnikova and Jeremy W. Hughes and Seppo P. Ahlfors and Mark W. Woolrich and David H. Salat},

doi = {10.1016/j.nicl.2018.05.028},

issn = {2213-1582},

year  = {2018},

date = {2018-00-00},

urldate = {2018-00-00},

journal = {NeuroImage: Clinical},

volume = {20},

pages = {128--152},

publisher = {Elsevier BV},

abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative condition that can lead to severe cognitive and functional deterioration. Functional magnetic resonance imaging (fMRI) revealed abnormalities in AD in intrinsic synchronization between spatially separate regions in the so-called default mode network (DMN) of the brain. To understand the relationship between this disruption in large-scale synchrony and the cognitive impairment in AD, it is critical to determine whether and how the deficit in the low frequency hemodynamic fluctuations recorded by fMRI translates to much faster timescales of memory and other cognitive processes. The present study employed magnetoencephalography (MEG) and a Hidden Markov Model (HMM) approach to estimate spontaneous synchrony variations in the functional neural networks with high temporal resolution. In a group of cognitively healthy (CH) older adults, we found transient (mean duration of 150–250 ms) network activity states, which were visited in a rapid succession, and were characterized by spatially coordinated changes in the amplitude of source-localized electrophysiological oscillations. The inferred states were similar to those previously observed in younger participants using MEG, and the estimated cortical source distributions of the state-specific activity resembled the classic functional neural networks, such as the DMN. In patients with AD, inferred network states were different from those of the CH group in short-scale timing and oscillatory features. The state of increased oscillatory amplitudes in the regions overlapping the DMN was visited less often in AD and for shorter periods of time, suggesting that spontaneous synchronization in this network was less likely and less stable in the patients. During the visits to this state, in some DMN nodes, the amplitude change in the higher-frequency (8–30 Hz) oscillations was less robust in the AD than CH group. These findings highlight relevance of studying short-scale temporal evolution of spontaneous activity in functional neural networks to understanding the AD pathophysiology. Capacity of flexible intrinsic synchronization in the DMN may be crucial for memory and other higher cognitive functions. Our analysis yielded metrics that quantify distinct features of the neural synchrony disorder in AD and may offer sensitive indicators of the neural network health for future investigations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27298238,

title = {Differential associations between systemic markers of disease and white matter tissue health in middle-aged and older adults},

author = {Chang-Woo Ryu and Jean-Philippe Coutu and Anna Greka and H Diana Rosas and Geon-Ho Jahng and Bruce R Rosen and David H Salat},

doi = {10.1177/0271678X16653613},

issn = {1559-7016},

year  = {2017},

date = {2017-11-01},

journal = {J Cereb Blood Flow Metab},

volume = {37},

number = {11},

pages = {3568--3579},

abstract = {Age-associated cerebrovascular disease impacts brain tissue integrity, but other factors, including normal variation in blood markers of systemic health, may also influence the structural integrity of the brain. This cross-sectional study included 139 individuals between 40 to 86 years old who were physically healthy and cognitively intact. Eleven markers (total-cholesterol, high-density lipoprotein, low-density lipoprotein, triglyceride, insulin, fasting glucose, glycated hemoglobin, creatinine, blood urea nitrogen, albumin, total protein) and five derived indicators (estimated glomerular filtration rate, creatinine clearance rate, insulin-resistance, average glucose, and cholesterol/high-density lipoprotein ratio) were obtained from blood sampling. Diffusion tensor imaging was used to evaluate white matter tissue health. Blood markers were clustered into five factors. The first factor (defined as insulin/high-density lipoprotein factor) was associated with markers of integrity in the deep white matter and projection fiber systems, while the third factor (defined as kidney function factor) was associated with different markers of integrity in the periventricular and watershed white matter regions. Differential segregated associations for insulin and high-density lipoprotein levels and serum markers of kidney function may provide information about distinct mechanisms of brain changes across the lifespan. These results emphasize the need to determine whether therapeutic modulation of systemic health and organ function may prevent decline in brain structural integrity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Schwarz2018,

title = {Differential associations of metabolic risk factors on cortical thickness in metabolic syndrome},

author = {Nicolette F. Schwarz and Leslie K. Nordstrom and Linda H.G. Pagen and Daniela J. Palombo and David H. Salat and William P. Milberg and Regina E. McGlinchey and Elizabeth C. Leritz},

doi = {10.1016/j.nicl.2017.09.022},

issn = {2213-1582},

year  = {2017},

date = {2017-09-28},

urldate = {2017-09-28},

journal = {NeuroImage: Clinical},

volume = {17},

pages = {98--108},

publisher = {Elsevier BV},

abstract = {Objective: Metabolic syndrome (MetS) refers to a cluster of risk factors for cardiovascular disease, including

obesity, hypertension, dyslipidemia, and hyperglycemia. While sizable prior literature has examined associations

between individual risk factors and quantitative measures of cortical thickness (CT), only very limited research

has investigated such measures in MetS. Furthermore, the relative contributions of these risk factors to MetSrelated effects on brain morphology have not yet been studied. The primary goal of this investigation was to

examine how MetS may affect CT. A secondary goal was to explore the relative contributions of individual risk

factors to regional alterations in CT, with the potential to identify risk factor combinations that may underlie

structural changes.

Methods: Eighteen participants with MetS (mean age = 59.78 years) were age-matched with 18 healthy control

participants (mean age = 60.50 years). CT measures were generated from T1-weighted images and groups were

contrasted using whole-brain general linear modeling. A follow-up multivariate partial least squares correlation

(PLS) analysis, including the full study sample with complete risk factor measurements (N = 53), was employed

to examine which risk factors account for variance in group structural differences.

Results: Participants with MetS demonstrated significantly reduced CT in left hemisphere inferior parietal,

rostral middle frontal, and lateral occipital clusters and in a right hemisphere precentral cluster. The PLS analysis

revealed that waist circumference, high-density lipoprotein cholesterol (HDL-C), triglycerides, and glucose were

significant contributors to reduced CT in these clusters. In contrast, diastolic blood pressure showed a significantly positive association with CT while systolic blood pressure did not emerge as a significant contributor.

Age was not associated with CT.

Conclusion: These results indicate that MetS can be associated with regionally specific reductions in CT.

Importantly, a novel link between a risk factor profile comprising indices of obesity, hyperglycemia, dyslipidemia and diastolic BP and localized alterations in CT emerged. While the pathophysiological mechanisms

underlying these associations remain incompletely understood, these findings may be relevant for future investigations of MetS and might have implications for treatment approaches that focus on specific risk factor

profiles with the aim to reduce negative consequences on the structural integrity of the brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28286328,

title = {Two distinct classes of degenerative change are independently linked to clinical progression in mild cognitive impairment},

author = {Jean-Philippe Coutu and Emily R Lindemer and Ender Konukoglu and David H Salat and },

doi = {10.1016/j.neurobiolaging.2017.02.005},

issn = {1558-1497},

year  = {2017},

date = {2017-06-01},

journal = {Neurobiol Aging},

volume = {54},

pages = {1--9},

abstract = {We previously demonstrated 2 statistically distinct factors of degeneration in Alzheimer's disease: one strongly related to white matter damage and age interpreted as "age- and vascular-related", and the other related to cortical atrophy thought to represent "neurodegenerative changes associated with Alzheimer's disease". Those factors are now replicated in a distinct cross-sectional data set of 364 participants from the Alzheimer's Disease Neuroimaging Initiative and their interpretation is improved using correlations with CSF biomarkers. Furthermore, we now show that changes in both factors over 2 years are independently associated with decline in Mini-Mental State Examination score in a longitudinal subset of 116 individuals with mild cognitive impairment. Progression in the "age- and vascular-related" factor was greater for individuals with 2 APOE ε4 alleles and linked to a greater attributable change in Mini-Mental State Examination than the "neurodegenerative" factor. These results suggest benefits of targeting white matter and vascular health to complement interventions focused on the neurodegenerative aspect of the disease, even in individuals with little discernable vascular comorbidity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27847345,

title = {Differential associations between systemic markers of disease and cortical thickness in healthy middle-aged and older adults},

author = {Artur Martins Coutinho and Jean-Philippe Coutu and Emily Rose Lindemer and H Diana Rosas and Bruce R Rosen and David H Salat},

doi = {10.1016/j.neuroimage.2016.11.021},

issn = {1095-9572},

year  = {2017},

date = {2017-02-01},

journal = {Neuroimage},

volume = {146},

pages = {19--27},

abstract = {Aside from cortical damage associated with age, cerebrovascular and neurodegenerative diseases, it's an outstanding question if factors of global health, including normal variation in blood markers of metabolic and systemic function, may also be associated with individual variation in brain structure. This cross-sectional study included 138 individuals between 40 to 86 years old who were physically healthy and cognitively intact. Eleven markers (total cholesterol, HDL, LDL, triglycerides, insulin, fasting glucose, glycated hemoglobin, creatinine, blood urea nitrogen, albumin, total protein) and five derived indicators (estimated glomerular filtration rate, creatinine clearance rate, insulin-resistance, average glucose, and cholesterol/HDL ratio) were obtained from blood sampling of all participants. T1-weighted 3T MRI scans were used to evaluate gray matter cortical thickness. The markers were clustered into five factors, and factor scores were related to cortical thickness by general linear model. Two factors, one linked to insulin/metabolic health and the other to kidney function (KFF) showed regionally selective associations with cortical thickness including lateral and medial temporal, temporoparietal, and superior parietal regions for both factors and frontoparietal regions for KFF. An association between the increasing cholesterol and greater thickness in frontoparietal and occipital areas was also noted. Associations persisted independently of age, presence of cardiovascular risk factors and ApoE gene status. These findings may provide information on distinct mechanisms of inter-individual cortical variation as well as factors contributing to trajectories of cortical thinning with advancing age.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28222518,

title = {Differential Regional Distribution of Juxtacortical White Matter Signal Abnormalities in Aging and Alzheimer's Disease},

author = {Emily R Lindemer and Douglas N Greve and Bruce Fischl and Jean C Augustinack and David H Salat and },

doi = {10.3233/JAD-161057},

issn = {1875-8908},

year  = {2017},

date = {2017-01-01},

journal = {J Alzheimers Dis},

volume = {57},

number = {1},

pages = {293--303},

abstract = {BACKGROUND: White matter signal abnormalities (WMSA) (also known as 'hyperintensities') on MRI are commonly seen in normal aging and increases have been noted in Alzheimer's disease (AD), but whether there is a spatial specificity to these increases is unknown.nnOBJECTIVE: To discern whether or not there is a spatial pattern of WMSA in the brains of individuals with AD that differs from those who exhibit cognitively healthy aging.nnMETHOD: Structural MRI data from the Alzheimer's Disease Neuroimaging Initiative public database were used to quantify WMSA in 35 regions of interest (ROIs). Regional measures were compared between cognitively healthy older controls (OC; n = 107) and individuals with a clinical diagnosis of AD (n = 127). Regional WMSA volume was also assessed in individuals with mild cognitive impairment (MCI; n = 74) who were 6, 12, and 24 months away from AD conversion.nnRESULTS: WMSA volume was significantly greater in AD compared to OC in 24 out of 35 ROIs after controlling for age, and nine were significantly higher after normalizing for total WMSA. Regions with greater WMSA volume in AD included rostral frontal, inferior temporal, and inferior parietal WM. In MCI, frontal and temporal regions demonstrated significantly greater WMSA volume with decreasing time-to-AD-conversion.nnDISCUSSION: Individuals with AD have greater regional volume of WMSA compared to OC regardless of age or total WMSA volume. Accumulation of regional WMSA is linked to time to AD conversion in individuals with MCI. These findings indicate WMSA is an important pathological component of AD development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid28180074,

title = {Regional staging of white matter signal abnormalities in aging and Alzheimer's disease},

author = {Emily R Lindemer and Douglas N Greve and Bruce R Fischl and Jean C Augustinack and David H Salat},

doi = {10.1016/j.nicl.2017.01.022},

issn = {2213-1582},

year  = {2017},

date = {2017-01-01},

journal = {Neuroimage Clin},

volume = {14},

pages = {156--165},

abstract = {White matter lesions, quantified as 'white matter signal abnormalities' (WMSA) on neuroimaging, are common incidental findings on brain images of older adults. This tissue damage is linked to cerebrovascular dysfunction and is associated with cognitive decline. The regional distribution of WMSA throughout the cerebral white matter has been described at a gross scale; however, to date no prior study has described regional patterns relative to cortical gyral landmarks which may be important for understanding functional impact. Additionally, no prior study has described how regional WMSA volume scales with total global WMSA. Such information could be used in the creation of a pathologic 'staging' of WMSA through a detailed regional characterization at the individual level. Magnetic resonance imaging data from 97 cognitively-healthy older individuals (OC) aged 52-90 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study were processed using a novel WMSA labeling procedure described in our prior work. WMSA were quantified regionally using a procedure that segments the cerebral white matter into 35 bilateral units based on proximity to landmarks in the cerebral cortex. An initial staging was performed by quantifying the regional WMSA volume in four groups based on quartiles of total WMSA volume (quartiles I-IV). A consistent spatial pattern of WMSA accumulation was observed with increasing quartile. A clustering procedure was then used to distinguish regions based on patterns of scaling of regional WMSA to global WMSA. Three patterns were extracted that showed high, medium, and non-scaling with global WMSA. Regions in the high-scaling cluster included periventricular, caudal and rostral middle frontal, inferior and superior parietal, supramarginal, and precuneus white matter. A data-driven staging procedure was then created based on patterns of WMSA scaling and specific regional cut-off values from the quartile analyses. Individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) were then additionally staged, and significant differences in the percent of each diagnostic group in Stages I and IV were observed, with more AD individuals residing in Stage IV and more OC and MCI individuals residing in Stage I. These data demonstrate a consistent regional scaling relationship between global and regional WMSA that can be used to classify individuals into one of four stages of white matter disease. White matter staging could play an important role in a better understanding and the treatment of cerebrovascular contributions to brain aging and dementia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27913407,

title = {Whole-brain analysis reveals increased neuroanatomical asymmetries in dementia for hippocampus and amygdala},

author = {Christian Wachinger and David H Salat and Michael Weiner and Martin Reuter and },

doi = {10.1093/brain/aww243},

issn = {1460-2156},

year  = {2016},

date = {2016-12-01},

journal = {Brain},

volume = {139},

number = {Pt 12},

pages = {3253--3266},

abstract = {Structural magnetic resonance imaging data are frequently analysed to reveal morphological changes of the human brain in dementia. Most contemporary imaging biomarkers are scalar values, such as the volume of a structure, and may miss the localized morphological variation of early presymptomatic disease progression. Neuroanatomical shape descriptors, however, can represent complex geometric information of individual anatomical regions and may demonstrate increased sensitivity in association studies. Yet, they remain largely unexplored. In this article, we introduce a novel technique to study shape asymmetries of neuroanatomical structures across subcortical and cortical brain regions. We demonstrate that neurodegeneration of subcortical structures in Alzheimer's disease is not symmetric. The hippocampus shows a significant increase in asymmetry longitudinally and both hippocampus and amygdala show a significantly higher asymmetry cross-sectionally concurrent with disease severity above and beyond an ageing effect. Our results further suggest that the asymmetry in these structures is undirectional and that primarily the anterior hippocampus becomes asymmetric. Based on longitudinal asymmetry measures we subsequently study the progression from mild cognitive impairment to dementia, demonstrating that shape asymmetry in hippocampus, amygdala, caudate and cortex is predictive of disease onset. The same analyses on scalar volume measurements did not produce any significant results, indicating that shape asymmetries, potentially induced by morphometric changes in subnuclei, rather than size asymmetries are associated with disease progression and can yield a powerful imaging biomarker for the early presymptomatic classification and prediction of Alzheimer's disease. Because literature has focused on contralateral volume differences, subcortical disease lateralization may have been overlooked thus far.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid27103138,

title = {Multivariate statistical analysis of diffusion imaging parameters using partial least squares: Application to white matter variations in Alzheimer's disease},

author = {Ender Konukoglu and Jean-Philippe Coutu and David H Salat and Bruce Fischl and },

doi = {10.1016/j.neuroimage.2016.04.038},

issn = {1095-9572},

year  = {2016},

date = {2016-07-01},

journal = {Neuroimage},

volume = {134},

pages = {573--586},

abstract = {Diffusion magnetic resonance imaging (dMRI) is a unique technology that allows the noninvasive quantification of microstructural tissue properties of the human brain in healthy subjects as well as the probing of disease-induced variations. Population studies of dMRI data have been essential in identifying pathological structural changes in various conditions, such as Alzheimer's and Huntington's diseases (Salat et al., 2010; Rosas et al., 2006). The most common form of dMRI involves fitting a tensor to the underlying imaging data (known as diffusion tensor imaging, or DTI), then deriving parametric maps, each quantifying a different aspect of the underlying microstructure, e.g. fractional anisotropy and mean diffusivity. To date, the statistical methods utilized in most DTI population studies either analyzed only one such map or analyzed several of them, each in isolation. However, it is most likely that variations in the microstructure due to pathology or normal variability would affect several parameters simultaneously, with differing variations modulating the various parameters to differing degrees. Therefore, joint analysis of the available diffusion maps can be more powerful in characterizing histopathology and distinguishing between conditions than the widely used univariate analysis. In this article, we propose a multivariate approach for statistical analysis of diffusion parameters that uses partial least squares correlation (PLSC) analysis and permutation testing as building blocks in a voxel-wise fashion. Stemming from the common formulation, we present three different multivariate procedures for group analysis, regressing-out nuisance parameters and comparing effects of different conditions. We used the proposed procedures to study the effects of non-demented aging, Alzheimer's disease and mild cognitive impairment on the white matter. Here, we present results demonstrating that the proposed PLSC-based approach can differentiate between effects of different conditions in the same region as well as uncover spatial variations of effects across the white matter. The proposed procedures were able to answer questions on structural variations such as: "are there regions in the white matter where Alzheimer's disease has a different effect than aging or similar effect as aging?" and "are there regions in the white matter that are affected by both mild cognitive impairment and Alzheimer's disease but with differing multivariate effects?"},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26915497,

title = {Different partial volume correction methods lead to different conclusions: An (18)F-FDG-PET study of aging},

author = {Douglas N Greve and David H Salat and Spencer L Bowen and David Izquierdo-Garcia and Aaron P Schultz and Ciprian Catana and J Alex Becker and Claus Svarer and Gitte M Knudsen and Reisa A Sperling and Keith A Johnson},

doi = {10.1016/j.neuroimage.2016.02.042},

issn = {1095-9572},

year  = {2016},

date = {2016-05-01},

journal = {Neuroimage},

volume = {132},

pages = {334--343},

abstract = {A cross-sectional group study of the effects of aging on brain metabolism as measured with (18)F-FDG-PET was performed using several different partial volume correction (PVC) methods: no correction (NoPVC), Meltzer (MZ), Müller-Gärtner (MG), and the symmetric geometric transfer matrix (SGTM) using 99 subjects aged 65-87years from the Harvard Aging Brain study. Sensitivity to parameter selection was tested for MZ and MG. The various methods and parameter settings resulted in an extremely wide range of conclusions as to the effects of age on metabolism, from almost no changes to virtually all of cortical regions showing a decrease with age. Simulations showed that NoPVC had significant bias that made the age effect on metabolism appear to be much larger and more significant than it is. MZ was found to be the same as NoPVC for liberal brain masks; for conservative brain masks, MZ showed few areas correlated with age. MG and SGTM were found to be similar; however, MG was sensitive to a thresholding parameter that can result in data loss. CSF uptake was surprisingly high at about 15% of that in gray matter. The exclusion of CSF from SGTM and MG models, which is almost universally done, caused a substantial loss in the power to detect age-related changes. This diversity of results reflects the literature on the metabolism of aging and suggests that extreme care should be taken when applying PVC or interpreting results that have been corrected for partial volume effects. Using the SGTM, significant age-related changes of about 7% per decade were found in frontal and cingulate cortices as well as primary visual and insular cortices.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26324104,

title = {SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans},

author = {N Sadeh and J M Spielberg and M W Logue and E J Wolf and A K Smith and J Lusk and J P Hayes and E Sperbeck and W P Milberg and R E McGlinchey and D H Salat and W C Carter and A Stone and S A Schichman and D E Humphries and M W Miller},

doi = {10.1038/mp.2015.134},

issn = {1476-5578},

year  = {2016},

date = {2016-03-01},

journal = {Mol Psychiatry},

volume = {21},

number = {3},

pages = {357--363},

abstract = {Methylation of the SKA2 (spindle and kinetochore-associated complex subunit 2) gene has recently been identified as a promising biomarker of suicide risk. Based on this finding, we examined associations between SKA2 methylation, cortical thickness and psychiatric phenotypes linked to suicide in trauma-exposed veterans. About 200 trauma-exposed white non-Hispanic veterans of the recent conflicts in Iraq and Afghanistan (91% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. Of all, 145 participants also had neuroimaging data available. Based on previous research, we examined DNA methylation at the cytosine-guanine locus cg13989295 as well as DNA methylation adjusted for genotype at the methylation-associated single nucleotide polymorphism (rs7208505) in relationship to whole-brain cortical thickness, posttraumatic stress disorder symptoms (PTSD) and depression symptoms. Whole-brain vertex-wise analyses identified three clusters in prefrontal cortex that were associated with genotype-adjusted SKA2 DNA methylation (methylation(adj)). Specifically, DNA methylation(adj) was associated with bilateral reductions of cortical thickness in frontal pole and superior frontal gyrus, and similar effects were found in the right orbitofrontal cortex and right inferior frontal gyrus. PTSD symptom severity was positively correlated with SKA2 DNA methylation(adj) and negatively correlated with cortical thickness in these regions. Mediation analyses showed a significant indirect effect of PTSD on cortical thickness via SKA2 methylation status. Results suggest that DNA methylation(adj) of SKA2 in blood indexes stress-related psychiatric phenotypes and neurobiology, pointing to its potential value as a biomarker of stress exposure and susceptibility.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26006791,

title = {Glucose Dysregulation Interacts With APOE-∊4 to Potentiate Temporoparietal Cortical Thinning},

author = {Jessica M Foley and David H Salat and Nikki H Stricker and Regina E McGlinchey and William P Milberg and Laura J Grande and Elizabeth C Leritz},

doi = {10.1177/1533317515587084},

issn = {1938-2731},

year  = {2016},

date = {2016-02-01},

journal = {Am J Alzheimers Dis Other Demen},

volume = {31},

number = {1},

pages = {76--86},

abstract = {We examined the interactive effects of apolipoprotein ∊4 (APOE-∊4), a risk factor for Alzheimer's disease (AD), and diabetes risk on cortical thickness among 107 healthy elderly participants; in particular, participants included 27 APOE-∊4+ and 80 APOE-∊4- controls using T1-weighted structural magnetic resonance imaging. Regions of interests included select frontal, temporal, and parietal cortical regions. Among APOE-∊4, glucose abnormalities independently predicted reduced cortical thickness among temporoparietal regions but failed to predict changes for noncarriers. However, among noncarriers, age independently predicted reduced cortical thickness among temporoparietal and frontal regions. Diabetes risk is particularly important for the integrity of cortical gray matter in APOE-∊4 and demonstrates a pattern of thinning that is expected in preclinical AD. However, in the absence of this genetic factor, age confers risk for reduced cortical thickness among regions of expected compromise. This study supports aggressive management of cerebrovascular factors and earlier preclinical detection of AD among individuals presenting with genetic and metabolic risks.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25904759,

title = {Mild Cognitive Impairment is Associated With White Matter Integrity Changes in Late-Myelinating Regions Within the Corpus Callosum},

author = {Nikki H Stricker and David H Salat and Taylor P Kuhn and Jessica M Foley and Jenessa S Price and Lars T Westlye and Michael S Esterman and Regina E McGlinchey and William P Milberg and Elizabeth C Leritz},

doi = {10.1177/1533317515578257},

issn = {1938-2731},

year  = {2016},

date = {2016-02-01},

journal = {Am J Alzheimers Dis Other Demen},

volume = {31},

number = {1},

pages = {68--75},

abstract = {Degenerative brain changes in Alzheimer's disease may occur in reverse order of normal brain development based on the retrogenesis model. This study tested whether evidence of reverse myelination was observed in mild cognitive impairment (MCI) using a data-driven analytic approach based on life span developmental data. Whole-brain high-resolution diffusion tensor imaging scans were obtained for 31 patients with MCI and 79 demographically matched healthy older adults. Comparisons across corpus callosum (CC) regions of interest (ROIs) showed decreased fractional anisotropy (FA) in the body but not in the genu or splenium; early-, middle-, and late-myelinating ROIs restricted to the CC revealed decreased FA in late- but not early- or middle-myelinating ROIs. Voxelwise group differences revealed areas of lower FA in MCI, but whole-brain differences were equally distributed across early-, middle-, and late-myelinating regions. Overall, results within the CC support the retrogenesis model, although caution is needed when generalizing these results beyond the CC.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26447678,

title = {Accelerated DNA methylation age: Associations with PTSD and neural integrity},

author = {Erika J Wolf and Mark W Logue and Jasmeet P Hayes and Naomi Sadeh and Steven A Schichman and Annjanette Stone and David H Salat and William Milberg and Regina McGlinchey and Mark W Miller},

doi = {10.1016/j.psyneuen.2015.09.020},

issn = {1873-3360},

year  = {2016},

date = {2016-01-01},

journal = {Psychoneuroendocrinology},

volume = {63},

pages = {155--162},

abstract = {BACKGROUND: Accumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline.nnMETHODS: This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging.nnRESULTS: Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ∼.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (β=.13, p=.032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (β=-.17, p=.009) and indirectly linked to poorer working memory performance via this region (indirect β=-.05, p=.029). Horvath DNAm age estimates were not associated with PTSD or neural integrity.nnCONCLUSIONS: Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26497829,

title = {White matter abnormalities are associated with chronic postconcussion symptoms in blast-related mild traumatic brain injury},

author = {Danielle R Miller and Jasmeet P Hayes and Ginette Lafleche and David H Salat and Mieke Verfaellie},

doi = {10.1002/hbm.23022},

issn = {1097-0193},

year  = {2016},

date = {2016-01-01},

journal = {Hum Brain Mapp},

volume = {37},

number = {1},

pages = {220--229},

abstract = {Blast-related mild traumatic brain injury (mTBI) is a common injury among Iraq and Afghanistan military veterans due to the frequent use of improvised explosive devices. A significant minority of individuals with mTBI report chronic postconcussion symptoms (PCS), which include physical, emotional, and cognitive complaints. However, chronic PCS are nonspecific and are also associated with mental health disorders such as posttraumatic stress disorder (PTSD). Identifying the mechanisms that contribute to chronic PCS is particularly challenging in blast-related mTBI, where the incidence of comorbid PTSD is high. In this study, we examined whether blast-related mTBI is associated with diffuse white matter changes, and whether these neural changes are associated with chronic PCS. Ninety Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans were assigned to one of three groups including a blast-exposed no--TBI group, a blast-related mTBI without loss of consciousness (LOC) group (mTBI--LOC), and a blast-related mTBI with LOC group (mTBI + LOC). PCS were measured with the Rivermead Postconcussion Questionnaire. Results showed that participants in the mTBI + LOC group had more spatially heterogeneous white matter abnormalities than those in the no--TBI group. These white matter abnormalities were significantly associated with physical PCS severity even after accounting for PTSD symptoms, but not with cognitive or emotional PCS severity. A mediation analysis revealed that mTBI + LOC significantly influenced physical PCS severity through its effect on white matter integrity. These results suggest that white matter abnormalities are associated with chronic PCS independent of PTSD symptom severity and that these abnormalities are an important mechanism explaining the relationship between mTBI and chronic physical PCS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26444767,

title = {White Matter Changes are Associated with Ventricular Expansion in Aging, Mild Cognitive Impairment, and Alzheimer's Disease},

author = {Jean-Philippe Coutu and Alison Goldblatt and H Diana Rosas and David H Salat and },

doi = {10.3233/JAD-150306},

issn = {1875-8908},

year  = {2016},

date = {2016-01-01},

journal = {J Alzheimers Dis},

volume = {49},

number = {2},

pages = {329--342},

abstract = {White matter lesions are highly prevalent in individuals with Alzheimer's disease (AD). Although these lesions are presumed to be of vascular origin and linked to small vessel disease in older adults, little information exists about their relationship to markers of classical AD neurodegeneration. Thus, we examined the link between these white matter changes (WMC) segmented on T1-weighted MRI and imaging markers presumed to be altered due to primary AD neurodegenerative processes. Tissue microstructure of WMC was quantified using diffusion tensor imaging and the relationship of WMC properties and volume to neuroimaging markers was examined in 219 cognitively healthy older adults and individuals with mild cognitive impairment and AD using data from the Alzheimer's Disease Neuroimaging Initiative. No significant group differences in WMC properties were found. However, there were strong associations between diffusivity of WMC and ventricular volume, volume of WMC and total WM volume. In comparison, group differences in parahippocampal white matter microstructure were found for all diffusion metrics and were largely explained by hippocampal volume. Factor analysis on neuroimaging markers suggested two independent sets of covarying degenerative changes, with potentially age- and vascular-mediated tissue damage contributing to one factor and classical neurodegenerative changes associated with AD contributing to a second factor. These data demonstrate two potentially distinct classes of degenerative change in AD, with one factor strongly linked to aging, ventricular expansion, and both volume and tissue properties of white matter lesions, while the other factor related to classical patterns of cortical and hippocampal neurodegeneration in AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26095760,

title = {White matter signal abnormality quality differentiates mild cognitive impairment that converts to Alzheimer's disease from nonconverters},

author = {Emily R Lindemer and David H Salat and Eric E Smith and Khoa Nguyen and Bruce Fischl and Douglas N Greve and },

doi = {10.1016/j.neurobiolaging.2015.05.011},

issn = {1558-1497},

year  = {2015},

date = {2015-09-01},

journal = {Neurobiol Aging},

volume = {36},

number = {9},

pages = {2447--2457},

abstract = {The objective of this study was to assess how longitudinal change in the quantity and quality of white matter signal abnormalities (WMSAs) contributes to the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). The Mahalanobis distance of WMSA from normal-appearing white matter using T1-, T2-, and proton density-weighted MRI was defined as a quality measure for WMSA. Cross-sectional analysis of WMSA volume in 104 cognitively healthy older adults, 116 individuals with MCI who converted to AD within 3 years (mild cognitive impairment converter [MCI-C]), 115 individuals with MCI that did not convert in that time (mild cognitive impairment nonconverter [MCI-NC]), and 124 individuals with AD from the Alzheimer's Disease Neuroimaging Initiative revealed that WMSA volume was substantially greater in AD relative to the other groups but did not differ between MCI-NC and MCI-C. Longitudinally, MCI-C exhibited faster WMSA quality progression but not volume compared with matched MCI-NC beginning 18 months before MCI-C conversion to AD. The strongest difference in rate of change was seen in the time period starting 6 months before MCI-C conversion to AD and ending 6 months after conversion (p < 0.001). The relatively strong effect in this time period relative to AD conversion in the MCI-C was similar to the relative rate of change in hippocampal volume, a traditional imaging marker of AD pathology. These data demonstrate changes in white matter tissue properties that occur within WMSA in individuals with MCI that will subsequently obtain a clinical diagnosis of AD within 18 months. Individuals with AD have substantially greater WMSA volume than all MCI suggesting that there is a progressive accumulation of WMSA with progressive disease severity, and that quality change predates changes in this total volume. Given the timing of the changes in WMSA tissue quality relative to the clinical diagnosis of AD, these findings suggest that WMSAs are a critical component for this conversion and are a critical component of this clinical syndrome.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25818631,

title = {Brain network disturbance related to posttraumatic stress and traumatic brain injury in veterans},

author = {Jeffrey M Spielberg and Regina E McGlinchey and William P Milberg and David H Salat},

doi = {10.1016/j.biopsych.2015.02.013},

issn = {1873-2402},

year  = {2015},

date = {2015-08-01},

journal = {Biol Psychiatry},

volume = {78},

number = {3},

pages = {210--216},

abstract = {BACKGROUND: Understanding the neural causes and consequences of posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) is a high research priority, given the high rates of associated disability and suicide. Despite remarkable progress in elucidating the brain mechanisms of PTSD and mTBI, a comprehensive understanding of these conditions at the level of brain networks has yet to be achieved. The present study sought to identify functional brain networks and topological properties (measures of network organization and function) related to current PTSD severity and mTBI.nnMETHODS: Graph theoretic tools were used to analyze resting-state functional magnetic resonance imaging data from 208 veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn, all of whom had experienced a traumatic event qualifying for PTSD criterion A. Analyses identified brain networks and topological network properties linked to current PTSD symptom severity, mTBI, and the interaction between PTSD and mTBI.nnRESULTS: Two brain networks were identified in which weaker connectivity was linked to higher PTSD re-experiencing symptoms, one of which was present only in veterans with comorbid mTBI. Re-experiencing was also linked to worse functional segregation (necessary for specialized processing) and diminished influence of key regions on the network, including the hippocampus.nnCONCLUSIONS: Findings of this study demonstrate that PTSD re-experiencing symptoms are linked to weakened connectivity in a network involved in providing contextual information. A similar relationship was found in a separate network typically engaged in the gating of working memory, but only in veterans with mTBI.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26033970,

title = {Military blast exposure, ageing and white matter integrity},

author = {Benjamin B Trotter and Meghan E Robinson and William P Milberg and Regina E McGlinchey and David H Salat},

doi = {10.1093/brain/awv139},

issn = {1460-2156},

year  = {2015},

date = {2015-08-01},

journal = {Brain},

volume = {138},

number = {Pt 8},

pages = {2278--2292},

abstract = {Mild traumatic brain injury, or concussion, is associated with a range of neural changes including altered white matter structure. There is emerging evidence that blast exposure-one of the most pervasive causes of casualties in the recent overseas conflicts in Iraq and Afghanistan-is accompanied by a range of neurobiological events that may result in pathological changes to brain structure and function that occur independently of overt concussion symptoms. The potential effects of brain injury due to blast exposure are of great concern as a history of mild traumatic brain injury has been identified as a risk factor for age-associated neurodegenerative disease. The present study used diffusion tensor imaging to investigate whether military-associated blast exposure influences the association between age and white matter tissue structure integrity in a large sample of veterans of the recent conflicts (n = 190 blast-exposed; 59 without exposure) between the ages of 19 and 62 years. Tract-based spatial statistics revealed a significant blast exposure × age interaction on diffusion parameters with blast-exposed individuals exhibiting a more rapid cross-sectional age trajectory towards reduced tissue integrity. Both distinct and overlapping voxel clusters demonstrating the interaction were observed among the examined diffusion contrast measures (e.g. fractional anisotropy and radial diffusivity). The regions showing the effect on fractional anisotropy included voxels both within and beyond the boundaries of the regions exhibiting a significant negative association between fractional anisotropy and age in the entire cohort. The regional effect was sensitive to the degree of blast exposure, suggesting a 'dose-response' relationship between the number of blast exposures and white matter integrity. Additionally, there was an age-independent negative association between fractional anisotropy and years since most severe blast exposure in a subset of the blast-exposed group, suggesting a specific influence of time since exposure on tissue structure, and this effect was also independent of post-traumatic stress symptoms. Overall, these data suggest that blast exposure may negatively affect brain-ageing trajectories at the microstructural tissue level. Additional work examining longitudinal changes in brain tissue integrity in individuals exposed to military blast forces will be an important future direction to the initial findings presented here.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25959594,

title = {Neurobiological indicators of disinhibition in posttraumatic stress disorder},

author = {Naomi Sadeh and Jeffrey M Spielberg and Mark W Miller and William P Milberg and David H Salat and Melissa M Amick and Catherine B Fortier and Regina E McGlinchey},

doi = {10.1002/hbm.22829},

issn = {1097-0193},

year  = {2015},

date = {2015-08-01},

journal = {Hum Brain Mapp},

volume = {36},

number = {8},

pages = {3076--3086},

abstract = {Deficits in impulse control are increasingly recognized in association with posttraumatic stress disorder (PTSD). To our further understanding of the neurobiology of PTSD-related disinhibition, we examined alterations in brain morphology and network connectivity associated with response inhibition failures and PTSD severity. The sample consisted of 189 trauma-exposed Operation Enduring Freedom/Operation Iraqi Freedom veterans (89% male, ages 19-62) presenting with a range of current PTSD severity. Disinhibition was measured using commission errors on a Go/No-Go (GNG) task with emotional stimuli, and PTSD was assessed using a measure of current symptom severity. Whole-brain vertex-wise analyses of cortical thickness revealed two clusters associated with PTSD-related disinhibition (Monte Carlo cluster corrected P < 0.05). The first cluster included portions of right inferior and middle frontal gyri and frontal pole. The second cluster spanned portions of left medial orbital frontal, rostral anterior cingulate, and superior frontal gyrus. In both clusters, commission errors were associated with reduced cortical thickness at higher (but not lower) levels of PTSD symptoms. Resting-state functional magnetic resonance imaging analyses revealed alterations in the functional connectivity of the right frontal cluster. Together, study findings suggest that reductions in cortical thickness in regions involved in flexible decision-making, emotion regulation, and response inhibition contribute to impulse control deficits in PTSD. Furthermore, aberrant coupling between frontal regions and networks involved in selective attention, memory/learning, and response preparation suggest disruptions in functional connectivity may also play a role.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lee2015,

title = {Tract-based analysis of white matter degeneration in Alzheimer’s disease},

author = {S.-H. Lee and J.-P. Coutu and P. Wilkens and A. Yendiki and H.D. Rosas and D.H. Salat},

doi = {10.1016/j.neuroscience.2015.05.049},

issn = {0306-4522},

year  = {2015},

date = {2015-08-00},

journal = {Neuroscience},

volume = {301},

pages = {79--89},

publisher = {Elsevier BV},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26125043,

title = {Cardiorespiratory fitness is associated with white matter integrity in aging},

author = {Scott M Hayes and David H Salat and Daniel E Forman and Reisa A Sperling and Mieke Verfaellie},

doi = {10.1002/acn3.204},

issn = {2328-9503},

year  = {2015},

date = {2015-06-01},

journal = {Ann Clin Transl Neurol},

volume = {2},

number = {6},

pages = {688--698},

abstract = {OBJECTIVE: Aging is associated with reduced neural integrity, yet there are remarkable individual differences in brain health among older adults (OA). One factor that may attenuate age-related neural decline is cardiorespiratory fitness (CRF). The primary aim of this study was to link CRF to neural white matter microstructure using diffusion tensor imaging in OA.nnMETHODS: Young adults (YA; n = 32) and OA (n = 27) completed a graded maximal exercise test to evaluate CRF and diffusion tensor magnetic resonance imaging to examine neural white matter integrity.nnRESULTS: As expected, pervasive age-related declines in white matter integrity were observed when OA were compared to YA. Further, peak VO2 was positively associated with fractional anisotropy (FA), an indicator of white matter integrity, in multiple brain regions in OA, but not YA. In multiple posterior regions such as the splenium, sagittal stratum, posterior corona radiata, and superior parietal white matter, FA values were similar in YA and OA classified as higher fit, with both groups having greater FA than lower fit OA. However, age-related differences in FA values remained in other regions, including the body and genu of the corpus callosum, precuneus, and superior frontal gyrus.nnINTERPRETATION: CRF is positively associated with neural white matter microstructure in aging. The relationship between peak VO2 and FA appears to be tract-specific, as equivalent FA values were observed in higher fit OA and YA in some white matter tracts, but not others. Further, the association between peak VO2 and FA appears to be age-dependent.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25366378,

title = {Close-range blast exposure is associated with altered functional connectivity in Veterans independent of concussion symptoms at time of exposure},

author = {Meghan E Robinson and Emily R Lindemer and Jennifer R Fonda and William P Milberg and Regina E McGlinchey and David H Salat},

doi = {10.1002/hbm.22675},

issn = {1097-0193},

year  = {2015},

date = {2015-03-01},

journal = {Hum Brain Mapp},

volume = {36},

number = {3},

pages = {911--922},

abstract = {Although there is emerging data on the effects of blast-related concussion (or mTBI) on cognition, the effects of blast exposure itself on the brain have only recently been explored. Toward this end, we examine functional connectivity to the posterior cingulate cortex, a primary region within the default mode network (DMN), in a cohort of 134 Iraq and Afghanistan Veterans characterized for a range of common military-associated comorbidities. Exposure to a blast at close range (<10 meters) was associated with decreased connectivity of bilateral primary somatosensory and motor cortices, and these changes were not different from those seen in participants with blast-related mTBI. These results remained significant when clinical factors such as sleep quality, chronic pain, or post traumatic stress disorder were included in the statistical model. In contrast, differences in functional connectivity based on concussion history and blast exposures at greater distances were not apparent. Despite the limitations of a study of this nature (e.g., assessments long removed from injury, self-reported blast history), these data demonstrate that blast exposure per se, which is prevalent among those who served in Iraq and Afghanistan, may be an important consideration in Veterans' health. It further offers a clinical guideline for determining which blasts (namely, those within 10 meters) are likely to lead to long-term health concerns and may be more accurate than using concussion symptoms alone.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25595222,

title = {Comparison of grey matter volume and thickness for analysing cortical changes in chronic schizophrenia: a matter of surface area, grey/white matter intensity contrast, and curvature},

author = {Li Kong and Christina J Herold and Frank Zöllner and David H Salat and Marc M Lässer and Lena A Schmid and Iven Fellhauer and Philipp A Thomann and Marco Essig and Lothar R Schad and Kirk I Erickson and Johannes Schröder},

doi = {10.1016/j.pscychresns.2014.12.004},

issn = {1872-7123},

year  = {2015},

date = {2015-02-01},

journal = {Psychiatry Res},

volume = {231},

number = {2},

pages = {176--183},

abstract = {Grey matter volume and cortical thickness are the two most widely used measures for detecting grey matter morphometric changes in various diseases such as schizophrenia. However, these two measures only share partial overlapping regions in identifying morphometric changes. Few studies have investigated the contributions of the potential factors to the differences of grey matter volume and cortical thickness. To investigate this question, 3T magnetic resonance images from 22 patients with schizophrenia and 20 well-matched healthy controls were chosen for analyses. Grey matter volume and cortical thickness were measured by VBM and Freesurfer. Grey matter volume results were then rendered onto the surface template of Freesurfer to compare the differences from cortical thickness in anatomical locations. Discrepancy regions of the grey matter volume and thickness where grey matter volume significantly decreased but without corresponding evidence of cortical thinning involved the rostral middle frontal, precentral, lateral occipital and superior frontal gyri. Subsequent region-of-interest analysis demonstrated that changes in surface area, grey/white matter intensity contrast and curvature accounted for the discrepancies. Our results suggest that the differences between grey matter volume and thickness could be jointly driven by surface area, grey/white matter intensity contrast and curvature.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25277041,

title = {Reduction in the retinotopic early visual cortex with normal aging and magnitude of perceptual learning},

author = {Li-Hung Chang and Yuko Yotsumoto and David H Salat and George J Andersen and Takeo Watanabe and Yuka Sasaki},

doi = {10.1016/j.neurobiolaging.2014.08.025},

issn = {1558-1497},

year  = {2015},

date = {2015-01-01},

journal = {Neurobiol Aging},

volume = {36},

number = {1},

pages = {315--322},

abstract = {Although normal aging is known to reduce cortical structures globally, the effects of aging on local structures and functions of early visual cortex are less understood. Here, using standard retinotopic mapping and magnetic resonance imaging morphologic analyses, we investigated whether aging affects areal size of the early visual cortex, which were retinotopically localized, and whether those morphologic measures were associated with individual performance on visual perceptual learning. First, significant age-associated reduction was found in the areal size of V1, V2, and V3. Second, individual ability of visual perceptual learning was significantly correlated with areal size of V3 in older adults. These results demonstrate that aging changes local structures of the early visual cortex, and the degree of change may be associated with individual visual plasticity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25367025,

title = {Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy},

author = {Yael D Reijmer and Panagiotis Fotiadis and Sergi Martinez-Ramirez and David H Salat and Aaron Schultz and Ashkan Shoamanesh and Alison M Ayres and Anastasia Vashkevich and Diana Rosas and Kristin Schwab and Alexander Leemans and Geert-Jan Biessels and Jonathan Rosand and Keith A Johnson and Anand Viswanathan and M Edip Gurol and Steven M Greenberg},

doi = {10.1093/brain/awu316},

issn = {1460-2156},

year  = {2015},

date = {2015-01-01},

journal = {Brain},

volume = {138},

number = {Pt 1},

pages = {179--188},

abstract = {Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid26106539,

title = {The nature of white matter abnormalities in blast-related mild traumatic brain injury},

author = {Jasmeet P Hayes and Danielle R Miller and Ginette Lafleche and David H Salat and Mieke Verfaellie},

doi = {10.1016/j.nicl.2015.04.001},

issn = {2213-1582},

year  = {2015},

date = {2015-01-01},

journal = {Neuroimage Clin},

volume = {8},

pages = {148--156},

abstract = {Blast-related traumatic brain injury (TBI) has been a common injury among returning troops due to the widespread use of improvised explosive devices in the Iraq and Afghanistan Wars. As most of the TBIs sustained are in the mild range, brain changes may not be detected by standard clinical imaging techniques such as CT. Furthermore, the functional significance of these types of injuries is currently being debated. However, accumulating evidence suggests that diffusion tensor imaging (DTI) is sensitive to subtle white matter abnormalities and may be especially useful in detecting mild TBI (mTBI). The primary aim of this study was to use DTI to characterize the nature of white matter abnormalities following blast-related mTBI, and in particular, examine the extent to which mTBI-related white matter abnormalities are region-specific or spatially heterogeneous. In addition, we examined whether mTBI with loss of consciousness (LOC) was associated with more extensive white matter abnormality than mTBI without LOC, as well as the potential moderating effect of number of blast exposures. A second aim was to examine the relationship between white matter integrity and neurocognitive function. Finally, a third aim was to examine the contribution of PTSD symptom severity to observed white matter alterations. One hundred fourteen OEF/OIF veterans underwent DTI and neuropsychological examination and were divided into three groups including a control group, blast-related mTBI without LOC (mTBI - LOC) group, and blast-related mTBI with LOC (mTBI + LOC) group. Hierarchical regression models were used to examine the extent to which mTBI and PTSD predicted white matter abnormalities using two approaches: 1) a region-specific analysis and 2) a measure of spatial heterogeneity. Neurocognitive composite scores were calculated for executive functions, attention, memory, and psychomotor speed. Results showed that blast-related mTBI + LOC was associated with greater odds of having spatially heterogeneous white matter abnormalities. Region-specific reduction in fractional anisotropy (FA) in the left retrolenticular part of the internal capsule was observed in the mTBI + LOC group as the number of blast exposures increased. A mediation analysis revealed that mTBI + LOC indirectly influenced verbal memory performance through its effect on white matter integrity. PTSD was not associated with spatially heterogeneous white matter abnormalities. However, there was a suggestion that at higher levels of PTSD symptom severity, LOC was associated with reduced FA in the left retrolenticular part of the internal capsule. These results support postmortem reports of diffuse axonal injury following mTBI and suggest that injuries with LOC involvement may be particularly detrimental to white matter integrity. Furthermore, these results suggest that LOC-associated white matter abnormalities in turn influence neurocognitive function.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25406797,

title = {Widespread effects of alcohol on white matter microstructure},

author = {Catherine B Fortier and Elizabeth C Leritz and David H Salat and Emily Lindemer and Arkadiy L Maksimovskiy and Juli Shepel and Victoria Williams and Jonathan R Venne and William P Milberg and Regina E McGlinchey},

doi = {10.1111/acer.12568},

issn = {1530-0277},

year  = {2014},

date = {2014-12-01},

journal = {Alcohol Clin Exp Res},

volume = {38},

number = {12},

pages = {2925--2933},

abstract = {BACKGROUND: Evidence suggests that chronic misuse of alcohol may preferentially affect the integrity of frontal white matter (WM) tracts, which can impact executive functions important to achieve and maintain abstinence.nnMETHODS: Global and regional WM microstructure was assessed using diffusion magnetic resonance measures of fractional anisotropy (FA) for 31 abstinent alcoholics (ALC) with an average of 25 years of abuse and approximately 5 years of sobriety and 20 nonalcoholic control (NC) participants. Data processing was conducted with FreeSurfer and FSL processing streams. Voxelwise processing of the FA data was carried out using tract-based spatial statistics. Clusters of significance were created to provide a quantitative summary of highly significant regions within the voxelwise analysis.nnRESULTS: Widespread, bilateral reductions in FA were observed in ALC as compared to NC participants in multiple frontal, temporal, parietal, and cerebellar WM tracts. FA in the left inferior frontal gyrus was associated with drinking severity.nnCONCLUSIONS: This study found widespread reductions in WM integrity in a group of ALC compared to NC participants, with most pronounced effects in frontal and superior tracts. Decreased FA throughout the frontostriatal circuits that mediate inhibitory control may result in impulsive behavior and inability to maintain sobriety.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25154857,

title = {H.M.'s contributions to neuroscience: a review and autopsy studies},

author = {Jean C Augustinack and André J W van der Kouwe and David H Salat and Thomas Benner and Allison A Stevens and Jacopo Annese and Bruce Fischl and Matthew P Frosch and Suzanne Corkin},

doi = {10.1002/hipo.22354},

issn = {1098-1063},

year  = {2014},

date = {2014-11-01},

journal = {Hippocampus},

volume = {24},

number = {11},

pages = {1267--1286},

abstract = {H.M., Henry Molaison, was one of the world's most famous amnesic patients. His amnesia was caused by an experimental brain operation, bilateral medial temporal lobe resection, carried out in 1953 to relieve intractable epilepsy. He died on December 2, 2008, and that night we conducted a wide variety of in situ MRI scans in a 3 T scanner at the Massachusetts General Hospital (Mass General) Athinoula A. Martinos Center for Biomedical Imaging. For the in situ experiments, we acquired a full set of standard clinical scans, 1 mm isotropic anatomical scans, and multiple averages of 440 μm isotropic anatomical scans. The next morning, H.M.'s body was transported to the Mass General Morgue for autopsy. The photographs taken at that time provided the first documentation of H.M.'s lesions in his physical brain. After tissue fixation, we obtained ex vivo structural data at ultra-high resolution using 3 T and 7 T magnets. For the ex vivo acquisitions, the highest resolution images were 210 μm isotropic. Based on the MRI data, the anatomical areas removed during H.M.'s experimental operation were the medial temporopolar cortex, piriform cortex, virtually all of the entorhinal cortex, most of the perirhinal cortex and subiculum, the amygdala (except parts of the dorsal-most nuclei-central and medial), anterior half of the hippocampus, and the dentate gyrus (posterior head and body). The posterior parahippocampal gyrus and medial temporal stem were partially damaged. Spared medial temporal lobe tissue included the dorsal-most amygdala, the hippocampal-amygdalo-transition-area, ∼2 cm of the tail of the hippocampus, a small part of perirhinal cortex, a small portion of medial hippocampal tissue, and ∼2 cm of posterior parahippocampal gyrus. H.M.'s impact on the field of memory has been remarkable, and his contributions to neuroscience continue with a unique dataset that includes in vivo, in situ, and ex vivo high-resolution MRI.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24650791,

title = {Genetic variation of oxidative phosphorylation genes in stroke and Alzheimer's disease},

author = {Alessandro Biffi and Mert R Sabuncu and Rahul S Desikan and Nick Schmansky and David H Salat and Jonathan Rosand and Christopher D Anderson and },

doi = {10.1016/j.neurobiolaging.2014.01.141},

issn = {1558-1497},

year  = {2014},

date = {2014-08-01},

journal = {Neurobiol Aging},

volume = {35},

number = {8},

pages = {1956.e1--1956.e8},

abstract = {Previous research implicates alterations in oxidative phosphorylation (OXPHOS) in the development of Alzheimer's disease (AD). We sought to test whether genetic variants within OXPHOS genes increase the risk of AD. We first used gene-set enrichment analysis to identify associations, and then applied a previously replicated stroke genetic risk score to determine if OXPHOS genetic overlap exists between stroke and AD. Gene-set enrichment analysis identified associations between variation in OXPHOS genes and AD versus control status (p = 0.012). Conversion from cognitively normal controls to mild cognitive impairment was also associated with the OXPHOS gene-set (p = 0.045). Subset analyses demonstrated association for complex I genes (p < 0.05), but not for complexes II-V. Among neuroimaging measures, hippocampal volume and entorhinal cortex thickness were associated with OXPHOS genes (all p < 0.025). The stroke genetic risk score demonstrated association with clinical status, baseline and longitudinal imaging measures (p < 0.05). OXPHOS genetic variation influences clinical status and neuroimaging intermediates of AD. OXPHOS genetic variants associated with stroke are also linked to AD progression. Further studies are needed to explore functional consequences of these OXPHOS variants.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24862391,

title = {Reduced cortical thickness in veterans exposed to early life trauma},

author = {Vincent Corbo and David H Salat and Melissa M Amick and Elizabeth C Leritz and William P Milberg and Regina E McGlinchey},

doi = {10.1016/j.pscychresns.2014.04.013},

issn = {1872-7123},

year  = {2014},

date = {2014-08-01},

journal = {Psychiatry Res},

volume = {223},

number = {2},

pages = {53--60},

abstract = {Studies have shown that early life trauma may influence neural development and increase the risk of developing psychological disorders in adulthood. We used magnetic resonance imaging to examine the impact of early life trauma on the relationship between current posttraumatic stress disorder (PTSD) symptoms and cortical thickness/subcortical volumes in a sample of deployed personnel from Operation Enduring Freedom/Operation Iraqi Freedom. A group of 108 service members enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders (TRACTS) were divided into those with interpersonal early life trauma (EL-Trauma+) and Control (without interpersonal early life trauma) groups based on the Traumatic Life Events Questionnaire. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale. Cortical thickness and subcortical volumes were analyzed using the FreeSurfer image analysis package. Thickness of the paracentral and posterior cingulate regions was positively associated with PTSD severity in the EL-Trauma+ group and negatively in the Control group. In the EL-Trauma+ group, both the right amygdala and the left hippocampus were positively associated with PTSD severity. This study illustrates a possible influence of early life trauma on the vulnerability of specific brain regions to stress. Changes in neural morphometry may provide information about the emergence and maintenance of symptoms in individuals with PTSD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24378085,

title = {Non-Gaussian water diffusion in aging white matter},

author = {Jean-Philippe Coutu and J Jean Chen and H Diana Rosas and David H Salat},

doi = {10.1016/j.neurobiolaging.2013.12.001},

issn = {1558-1497},

year  = {2014},

date = {2014-06-01},

journal = {Neurobiol Aging},

volume = {35},

number = {6},

pages = {1412--1421},

abstract = {Age-associated white matter degeneration has been well documented and is likely an important mechanism contributing to cognitive decline in older adults. Recent work has explored a range of noninvasive neuroimaging procedures to differentially highlight alterations in the tissue microenvironment. Diffusional kurtosis imaging (DKI) is an extension of diffusion tensor imaging (DTI) that accounts for non-Gaussian water diffusion and can reflect alterations in the distribution and diffusion properties of tissue compartments. We used DKI to produce whole-brain voxel-based maps of mean, axial, and radial diffusional kurtoses, quantitative indices of the tissue microstructure's diffusional heterogeneity, in 111 participants ranging from the age of 33 to 91 years. As suggested from prior DTI studies, greater age was associated with alterations in white-matter tissue microstructure, which was reflected by a reduction in all 3 DKI metrics. Prominent effects were found in prefrontal and association white matter compared with relatively preserved primary motor and visual areas. Although DKI metrics co-varied with DTI metrics on a global level, DKI provided unique regional sensitivity to the effects of age not available with DTI. DKI metrics were additionally useful in combination with DTI metrics for the classification of regions according to their multivariate "diffusion footprint", or pattern of relative age effect sizes. It is possible that the specific multivariate patterns of age-associated changes measured are representative of different types of microstructural pathology. These results suggest that DKI provides important complementary indices of brain microstructure for the study of brain aging and neurologic disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24381137,

title = {Interactive effects of apolipoprotein E4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults},

author = {Jessica M Foley and David H Salat and Nikki H Stricker and Tyler A Zink and Laura J Grande and Regina E McGlinchey and William P Milberg and Elizabeth C Leritz},

doi = {10.1177/1533317513517045},

issn = {1938-2731},

year  = {2014},

date = {2014-05-01},

journal = {Am J Alzheimers Dis Other Demen},

volume = {29},

number = {3},

pages = {222--235},

abstract = {Possession of the apolipoprotein E4 (APOE4) allele and diabetes risk are independently related to reduced white matter (WM) integrity that may contribute to the development of Alzheimer's disease (AD). The purpose of this study is to examine the interactive effects of APOE4 and diabetes risk on later myelinating WM regions among healthy elderly individuals at risk of AD. A sample of 107 healthy elderly (80 APOE4-/27 APOE4+) individuals underwent structural magnetic resonance imaging/diffusion tensor imaging (DTI). Data were prepared using Tract-Based Spatial Statistics, and a priori regions of interest (ROIs) were extracted from T1-based WM parcellations. Regions of interest included later myelinating frontal/temporal/parietal WM regions and control regions measured by fractional anisotropy (FA). There were no APOE group differences in DTI for any ROI. Within the APOE4 group, we found negative relationships between hemoglobin A1c/fasting glucose and APOE4 on FA for all later myelinating WM regions but not for early/middle myelinating control regions. Results also showed APOE4/diabetes risk interactions for WM underlying supramarginal, superior temporal, precuneus, superior parietal, and superior frontal regions. Results suggest interactive effects of APOE4 and diabetes risk on later myelinating WM regions, which supports preclinical detection of AD among this particularly susceptible subgroup.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24771537,

title = {Effects of insulin resistance on white matter microstructure in middle-aged and older adults},

author = {Seon Young Ryu and Jean-Philippe Coutu and H Diana Rosas and David H Salat},

doi = {10.1212/WNL.0000000000000452},

issn = {1526-632X},

year  = {2014},

date = {2014-05-01},

journal = {Neurology},

volume = {82},

number = {21},

pages = {1862--1870},

abstract = {OBJECTIVE: To investigate the potential relationship between insulin resistance (IR) and white matter (WM) microstructure using diffusion tensor imaging in cognitively healthy middle-aged and older adults.nnMETHODS: Diffusion tensor imaging was acquired from 127 individuals (age range 41-86 years). IR was evaluated by the homeostasis model assessment of IR (HOMA-IR). Participants were divided into 2 groups based on HOMA-IR values: "high HOMA-IR" (≥2.5, n = 27) and "low HOMA-IR" (<2.5, n = 100). Cross-sectional voxel-based comparisons were performed using Tract-Based Spatial Statistics and anatomically defined regions of interest analysis.nnRESULTS: The high HOMA-IR group demonstrated decreased axial diffusivity broadly throughout the cerebral WM in areas such as the corpus callosum, corona radiata, cerebral peduncle, posterior thalamic radiation, and right superior longitudinal fasciculus, and WM underlying the frontal, parietal, and temporal lobes, as well as decreased fractional anisotropy in the body and genu of corpus callosum and parts of the superior and anterior corona radiata, compared with the low HOMA-IR group, independent of age, WM signal abnormality volume, and antihypertensive medication status. These regions additionally demonstrated linear associations between diffusion measures and HOMA-IR across all subjects, with higher HOMA-IR values being correlated with lower axial diffusivity.nnCONCLUSIONS: In generally healthy adults, greater IR is associated with alterations in WM tissue integrity. These cross-sectional findings suggest that IR contributes to WM microstructural alterations in middle-aged and older adults.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23362153,

title = {Associations between T1 white matter lesion volume and regional white matter microstructure in aging},

author = {Elizabeth C Leritz and Juli Shepel and Victoria J Williams and Lewis A Lipsitz and Regina E McGlinchey and William P Milberg and David H Salat},

doi = {10.1002/hbm.22236},

issn = {1097-0193},

year  = {2014},

date = {2014-03-01},

journal = {Hum Brain Mapp},

volume = {35},

number = {3},

pages = {1085--1100},

abstract = {White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24510496,

title = {PRECREST: a phase II prevention and biomarker trial of creatine in at-risk Huntington disease},

author = {Herminia D Rosas and Gheorghe Doros and Sona Gevorkian and Keith Malarick and Martin Reuter and Jean-Philippe Coutu and Tyler D Triggs and Paul J Wilkens and Wayne Matson and David H Salat and Steven M Hersch},

doi = {10.1212/WNL.0000000000000187},

issn = {1526-632X},

year  = {2014},

date = {2014-03-01},

journal = {Neurology},

volume = {82},

number = {10},

pages = {850--857},

abstract = {OBJECTIVE: To assess the safety and tolerability of high-dose creatine, the feasibility of enrolling premanifest and 50% at-risk subjects in a prevention trial, and the potential of cognitive, imaging, and blood markers.nnMETHODS: Sixty-four eligible consenting participants were randomly allocated (1:1) to 15 g twice daily of creatine monohydrate or placebo for a 6-month double-blind phase followed by a 12-month open-label extension. Subjects included premanifest (tested) and at-risk (not tested) individuals without clinical symptoms or signs of Huntington disease (HD). Primary outcomes were safety and tolerability. Exploratory endpoints included fine motor, visuospatial, and memory performance; structural and diffusion MRI; and selected blood markers.nnRESULTS: Forty-seven HD carriers and 17 non-HD controls were enrolled. Fifteen discontinued treatment (2 assigned to placebo); all were followed for the entire study period. Primary analysis was by intent to treat. The most common adverse events were gastrointestinal. Neuroimaging demonstrated treatment-related slowing of cortical and striatal atrophy at 6 and 18 months.nnCONCLUSION: We describe a design that preserves the autonomy of subjects not wanting genetic testing while including controls for assessing the specificity of treatment effects. Our results demonstrate the feasibility of prevention trials for HD and the safety of high-dose creatine, provide possible evidence of disease modification, support future studies of creatine, and illustrate the value of prodromal biomarkers.nnCLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose creatine is safe and tolerable.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24129749,

title = {Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage},

author = {Sushmita Purkayastha and Otite Fadar and Aujan Mehregan and David H Salat and Nicola Moscufo and Dominik S Meier and Charles Rg Guttmann and Naomi Dl Fisher and Lewis A Lipsitz and Farzaneh A Sorond},

doi = {10.1038/jcbfm.2013.180},

issn = {1559-7016},

year  = {2014},

date = {2014-02-01},

journal = {J Cereb Blood Flow Metab},

volume = {34},

number = {2},

pages = {228--234},

abstract = {White matter hyperintensities (WMH) in elderly individuals with vascular diseases are presumed to be due to ischemic small vessel diseases; however, their etiology is unknown. We examined the cross-sectional relationship between cerebrovascular hemodynamics and white matter structural integrity in elderly individuals with vascular risk factors. White matter hyperintensity volumes, fractional anisotropy (FA), and mean diffusivity (MD) were obtained from MRI in 48 subjects (75±7years). Pulsatility index (PI) and dynamic cerebral autoregulation (dCA) was assessed using transcranial Doppler ultrasound of the middle cerebral artery. Dynamic cerebral autoregulation was calculated from transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations in the low (LF, 0.03 to 0.15 Hz) and high (HF, 0.16 to 0.5 Hz) frequency ranges. Higher PI was associated with greater WMH (P<0.005). Higher phase across all frequency ranges was associated with greater FA and lower MD (P<0.005). Lower gain was associated with higher FA in the LF range (P=0.001). These relationships between phase and FA were significant in the territories limited to the middle cerebral artery as well as across the entire brain. Our results show a strong relationship between impaired cerebrovascular hemodynamics (PI and dCA) and loss of cerebral white matter structural integrity (WMH and DTI metrics) in elderly individuals.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24795629,

title = {Fluid intelligence and brain functional organization in aging yoga and meditation practitioners},

author = {Tim Gard and Maxime Taquet and Rohan Dixit and Britta K Hölzel and Yves-Alexandre de Montjoye and Narayan Brach and David H Salat and Bradford C Dickerson and Jeremy R Gray and Sara W Lazar},

doi = {10.3389/fnagi.2014.00076},

issn = {1663-4365},

year  = {2014},

date = {2014-01-01},

journal = {Front Aging Neurosci},

volume = {6},

pages = {76},

abstract = {Numerous studies have documented the normal age-related decline of neural structure, function, and cognitive performance. Preliminary evidence suggests that meditation may reduce decline in specific cognitive domains and in brain structure. Here we extended this research by investigating the relation between age and fluid intelligence and resting state brain functional network architecture using graph theory, in middle-aged yoga and meditation practitioners, and matched controls. Fluid intelligence declined slower in yoga practitioners and meditators combined than in controls. Resting state functional networks of yoga practitioners and meditators combined were more integrated and more resilient to damage than those of controls. Furthermore, mindfulness was positively correlated with fluid intelligence, resilience, and global network efficiency. These findings reveal the possibility to increase resilience and to slow the decline of fluid intelligence and brain functional architecture and suggest that mindfulness plays a mechanistic role in this preservation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24855633,

title = {White Matter and Cognitive Changes in Veterans Diagnosed with Alcoholism and PTSD},

author = {Arkadiy L Maksimovskiy and Regina E McGlinchey and Catherine B Fortier and David H Salat and William P Milberg and Marlene Oscar-Berman},

doi = {10.4172/2329-6488.1000144},

issn = {2329-6488},

year  = {2014},

date = {2014-01-01},

journal = {J Alcohol Drug Depend},

volume = {2},

number = {1},

pages = {144},

abstract = {Alcoholism frequently occurs in returning U.S. Veterans, and is often comorbid with Post Traumatic Stress Disorder (PTSD). The goal of this study was to investigate the relationship between white matter changes and neuropsychological alterations in Operation Enduring Freedom, and/or Operation Iraqi Freedom (OEF/OIF) alcoholic Veterans with two primary aims: (1) to examine the relationship of alcoholism to brain structure and function while controlling for the potential effects of comorbid PTSD, and (2) to examine whether the effects of alcoholism are moderated by the quantity of lifetime alcohol consumption. Our sample consisted of 71 deployed OEF/OIF Veterans stratified into four groups: alcoholics without PTSD, alcoholics with PTSD, participants with PTSD without comorbid alcoholism, and control participants without alcoholism or PTSD. Participants were given an extensive neuropsychological and psychiatric assessment battery, as well as Magnetic Resonance Diffusion Tensor Imaging (DT-MRI) scans. Results showed that disruption of executive functioning, and abnormal fractional anisotropy (FA; a measure of axonal integrity) within the frontal subcortical and dorsolateral frontal-parietal regions, occurred independently of the effects of PTSD. Furthermore, these cognitive and neuronal alterations were unique to the most severe subgroup of alcoholics who consumed the greatest amount of alcohol over the course of their lifetime, as compared to the rest of the sample. Axonal integrity within this subgroup, in regions underlying the frontal subcortical area, was shown to be decreased independently of cognitive changes. Integrity of axons underlying the dorsolateral frontal-parietal region, however, was increased. We hypothesized that this is a compensatory mechanism for executive dysfunction.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23809097,

title = {Decreased white matter integrity in neuropsychologically defined mild cognitive impairment is independent of cortical thinning},

author = {Nikki H Stricker and David H Salat and Jessica M Foley and Tyler A Zink and Ida L Kellison and Craig P McFarland and Laura J Grande and Regina E McGlinchey and William P Milberg and Elizabeth C Leritz},

doi = {10.1017/S1355617713000660},

issn = {1469-7661},

year  = {2013},

date = {2013-09-01},

journal = {J Int Neuropsychol Soc},

volume = {19},

number = {8},

pages = {925--937},

abstract = {Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer’s disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for corticalthic kness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23925758,

title = {Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people},

author = {Farzaneh A Sorond and Shelley Hurwitz and David H Salat and Douglas N Greve and Naomi D L Fisher},

doi = {10.1212/WNL.0b013e3182a351aa},

issn = {1526-632X},

year  = {2013},

date = {2013-09-01},

journal = {Neurology},

volume = {81},

number = {10},

pages = {904--909},

abstract = {OBJECTIVE: To investigate the relationship between neurovascular coupling and cognitive function in elderly individuals with vascular risk factors and to determine whether neurovascular coupling could be modified by cocoa consumption.nnMETHODS: Sixty older people (aged 72.9 ± 5.4 years) were studied in a parallel-arm, double-blind clinical trial of neurovascular coupling and cognition in response to 24 hours and 30 days of cocoa consumption. Cognitive measures included Mini-Mental State Examination and Trail Making Test A and B. Neurovascular coupling was measured from the beat-to-beat blood flow velocity responses in the middle cerebral arteries to the N-Back Task. In a subset of MRI-eligible participants, cerebral white matter structural integrity was also measured.nnRESULTS: Neurovascular coupling was associated with Trails B scores (p = 0.002) and performance on the 2-Back Task. Higher neurovascular coupling was also associated with significantly higher fractional anisotropy in cerebral white matter hyperintensities (p = 0.02). Finally, 30 days of cocoa consumption was associated with increased neurovascular coupling (5.6% ± 7.2% vs -2.4% ± 4.8%; p = 0.001) and improved Trails B times (116 ± 78 seconds vs 167 ± 110 seconds; p = 0.007) in those with impaired neurovascular coupling at baseline.nnCONCLUSION: There is a strong correlation between neurovascular coupling and cognitive function, and both can be improved by regular cocoa consumption in individuals with baseline impairments. Better neurovascular coupling is also associated with greater white matter structural integrity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22438182,

title = {Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults},

author = {Victoria J Williams and Elizabeth C Leritz and Juli Shepel and Regina E McGlinchey and William P Milberg and James L Rudolph and Lewis A Lipsitz and David H Salat},

doi = {10.1002/hbm.22030},

issn = {1097-0193},

year  = {2013},

date = {2013-08-01},

journal = {Hum Brain Mapp},

volume = {34},

number = {8},

pages = {1826--1841},

abstract = {Prior research has demonstrated links among vascular health and the occurrence of stroke, mild cognitive decline, and dementia in older adults. However, little is known about whether normal variation in vascular indicators may be related to changes in neural tissue integrity. Even less is known about how the brain is affected by cholesterol levels in the normal to moderate risk range, leading up to overt disease pathology. This study examined associations between serum lipid levels and DTI indicators of white matter (WM) structural integrity in a sample of 125 generally healthy older adults aged 43-87 years. Whole-brain voxelwise analysis, controlling for age and gender, revealed low density lipoprotein levels (LDL) as the most robust correlate of regional WM structural integrity of the measured lipids. Higher LDL was associated with decreased WM integrity in right frontal and temporal regions, the superior longitudinal fasciculus and internal/external capsules. Increasing LDL was associated with increased radial and axial diffusivity; however, more widespread statistical effects were found for radial diffusivity. These findings suggest that normal interindividual variation in lipid levels is associated with compromised regional WM integrity, even in individuals below clinical thresholds for hyperlipidemia. Given the prevalence of cholesterol-associated sequelae in older adults, and mounting evidence suggesting a vascular role in the etiology of dementia, the current data suggest that understanding the relationship between cholesterol and brain tissue microstructure may have important clinical implications for early detection of vascular-related cognitive disorders and optimal regulation of serum lipids to maintain neural health in older adults.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid21954054,

title = {Association between white matter microstructure, executive functions, and processing speed in older adults: the impact of vascular health},

author = {Heidi I L Jacobs and Elizabeth C Leritz and Victoria J Williams and Martin P J Van Boxtel and Wim van der Elst and Jelle Jolles and Frans R J Verhey and Regina E McGlinchey and William P Milberg and David H Salat},

doi = {10.1002/hbm.21412},

issn = {1097-0193},

year  = {2013},

date = {2013-01-01},

journal = {Hum Brain Mapp},

volume = {34},

number = {1},

pages = {77--95},

abstract = {Cerebral white matter damage is not only a commonly reported consequence of healthy aging, but is also associated with cognitive decline and dementia. The aetiology of this damage is unclear; however, individuals with hypertension have a greater burden of white matter signal abnormalities (WMSA) on MR imaging than those without hypertension. It is therefore possible that elevated blood pressure (BP) impacts white matter tissue structure which in turn has a negative impact on cognition. However, little information exists about whether vascular health indexed by BP mediates the relationship between cognition and white matter tissue structure. We used diffusion tensor imaging to examine the impact of vascular health on regional associations between white matter integrity and cognition in healthy older adults spanning the normotensive to moderate-severe hypertensive BP range (43-87 years; N = 128). We examined how white matter structure was associated with performance on tests of two cognitive domains, executive functioning (EF) and processing speed (PS), and how patterns of regional associations were modified by BP and WMSA. Multiple linear regression and structural equation models demonstrated associations between tissue structure, EF and PS in frontal, temporal, parietal, and occipital white matter regions. Radial diffusivity was more prominently associated with performance than axial diffusivity. BP only minimally influenced the relationship between white matter integrity, EF and PS. However, WMSA volume had a major impact on neurocognitive associations. This suggests that, although BP and WMSA are causally related, these differential metrics of vascular health may act via independent pathways to influence brain structure, EF and PS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24179811,

title = {Reduced cortical thickness with increased lifetime burden of PTSD in OEF/OIF Veterans and the impact of comorbid TBI},

author = {Emily R Lindemer and David H Salat and Elizabeth C Leritz and Regina E McGlinchey and William P Milberg},

doi = {10.1016/j.nicl.2013.04.009},

issn = {2213-1582},

year  = {2013},

date = {2013-01-01},

journal = {Neuroimage Clin},

volume = {2},

pages = {601--611},

abstract = {Posttraumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) in military personnel is increasing dramatically following the OEF/OIF conflicts and is associated with alterations to brain structure. The present study examined the relationship between PTSD and cortical thickness, and its possible modification by mTBI, in a 104-subject OEF/OIF veteran cohort ranging in age from 20 to 62 years. For each participant, two T1-weighted scans were averaged to create high-resolution images for calculation of regional cortical thickness. PTSD symptoms were assessed using the Clinician Administered PTSD Scale (CAPS) and scores were derived based on the previous month's symptoms ("current") and a Cumulative Lifetime Burden of PTSD (CLB-P) reflecting the integral of CAPS scores across the lifetime. Mild TBI was diagnosed using the Boston Assessment of TBI-Lifetime (BAT-L). Results demonstrated a clear negative relationship between current PTSD severity and thickness in both postcentral gyri and middle temporal gyri. This relationship was stronger and more extensive when considering lifetime burden (CLB-P), demonstrating the importance of looking at trauma in the context of an individual's lifetime, rather than only at their current symptoms. Finally, interactions with current PTSD only and comorbid current PTSD and mTBI were found in several regions, implying an additive effect of lifetime PTSD and mTBI on cortical thickness.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23437228,

title = {The relationship between cortical blood flow and sub-cortical white-matter health across the adult age span},

author = {J Jean Chen and H Diana Rosas and David H Salat},

doi = {10.1371/journal.pone.0056733},

issn = {1932-6203},

year  = {2013},

date = {2013-01-01},

journal = {PLoS One},

volume = {8},

number = {2},

pages = {e56733},

abstract = {Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid23077048,

title = {Default network connectivity in medial temporal lobe amnesia},

author = {Scott M Hayes and David H Salat and Mieke Verfaellie},

doi = {10.1523/JNEUROSCI.0700-12.2012},

issn = {1529-2401},

year  = {2012},

date = {2012-10-01},

journal = {J Neurosci},

volume = {32},

number = {42},

pages = {14622--14629},

abstract = {There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans, the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting fMRI was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex were observed in amnesic patients. In contrast, somatomotor network connectivity was intact in amnesic patients, indicating that bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid22393169,

title = {Alterations in brain transition metals in Huntington disease: an evolving and intricate story},

author = {H Diana Rosas and Y Iris Chen and Gheorghe Doros and David H Salat and Nan-kuei Chen and Ken K Kwong and Ashley Bush and Jonathan Fox and Steven M Hersch},

doi = {10.1001/archneurol.2011.2945},

issn = {1538-3687},

year  = {2012},

date = {2012-07-01},

journal = {Arch Neurol},

volume = {69},

number = {7},

pages = {887--893},

abstract = {BACKGROUND: Aberrant accumulation of transition metals in the brain may have an early and important role in the pathogenesis of several neurodegenerative disorders, including Huntington disease (HD).nnOBJECTIVE: To comprehensively evaluate and validate the distribution of metal deposition in the brain using advanced magnetic resonance imaging methods from the premanifest through symptomatic stages of HD.nnDESIGN: Observational study.nnSETTING: University imaging center.nnPARTICIPANTS: Twenty-eight HD expanded gene carriers, 34 patients with symptomatic HD, and 56 age- and sex-matched healthy control subjects were included in the study.nnINTERVENTIONS: Participants underwent magnetic resonance imaging for the quantification of the phase evolution of susceptibility-weighted images.nnMAIN OUTCOME MEASURES: To verify the identity of the metals responsible for the changes in the phase evolution of the susceptibility signal in the brain and to assess correlations with systemic levels. Inductively coupled plasma mass spectrometry was used to measure transition metal concentrations in postmortem brains.nnRESULTS: In the basal ganglia, progressive increases in the phase evolution were found in HD, beginning in premanifest individuals who were far from expected onset and increasing with proximity to expected onset and thereafter. Increases in the cerebral cortex were regionally selective and present only in symptomatic HD. Increases were verified by excessive deposition of brain iron, but a complex alteration in other transition metals was found.nnCONCLUSION: An important and early role of altered metal homeostasis is suggested in the pathogenesis of HD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}