Publications by authors named "Steven R Kecskemeti"

11 Publications

  • Page 1 of 1

Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults.

Alzheimers Dement 2021 May 13. Epub 2021 May 13.

Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Introduction: Neurite orientation dispersion and density imaging (NODDI), a multi-compartment diffusion-weighted imaging (DWI) model, may be useful for detecting early cortical microstructural alterations in Alzheimer's disease prior to cognitive impairment.

Methods: Using neuroimaging (NODDI and T1-weighted magnetic resonance imaging [MRI]) and cerebrospinal fluid (CSF) biomarker data (measured using Elecsys® CSF immunoassays) from 219 cognitively unimpaired participants, we tested the main and interactive effects of CSF amyloid beta (Aβ) /Aβ and phosphorylated tau (p-tau) on cortical NODDI metrics and cortical thickness, controlling for age, sex, and apolipoprotein E ε4.

Results: We observed a significant CSF Aβ /Aβ × p-tau interaction on cortical neurite density index (NDI), but not orientation dispersion index or cortical thickness. The directionality of these interactive effects indicated: (1) among individuals with lower CSF p-tau, greater amyloid burden was associated with higher cortical NDI; and (2) individuals with greater amyloid and p-tau burden had lower cortical NDI, consistent with cortical neurodegenerative changes.

Discussion: NDI is a particularly sensitive marker for early cortical changes that occur prior to gross atrophy or development of cognitive impairment.
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May 2021

Test-retest of automated segmentation with different motion correction strategies: A comparison of prospective versus retrospective methods.

Neuroimage 2020 04 30;209:116494. Epub 2019 Dec 30.

University of Wisconsin-Madison, USA.

Test-retest of automated image segmentation algorithms (FSL FAST, FSL FIRST, and FREESURFER) are computed on magnetic resonance images from 12 unsedated children aged 9.4±2.6 years ([min,max] ​= ​[6.5 years, 13.8 years]) using different approaches to motion correction (prospective versus retrospective). The prospective technique, PROMO MPRAGE, dynamically estimates motion using specially acquired navigator images and adjusts the remaining acquisition accordingly, whereas the retrospective technique, MPnRAGE, uses a self-navigation property to retrospectively estimate and account for motion during image reconstruction. To increase the likelihood and range of motions, participants heads were not stabilized with padding during repeated scans. When motion was negligible both techniques had similar performance. When motion was not negligible, the automated image segmentation and anatomical labeling software tools showed the most consistent performance with the retrospectively corrected MPnRAGE technique (≥80% volume overlaps for 15 of 16 regions for FIRST and FREESURFER, with greater than 90% volume overlaps for 12 regions with FIRST and 11 regions with FREESURFER). Prospectively corrected MPRAGE with linear view-ordering also demonstrated lower performance than MPnRAGE without retrospective motion correction.
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April 2020

Optimizing the intrinsic parallel diffusivity in NODDI: An extensive empirical evaluation.

PLoS One 2019 25;14(9):e0217118. Epub 2019 Sep 25.

Department of Medical Physics, University of Wisconsin - Madison, Madison, WI, United States of America.

Purpose: NODDI is widely used in parameterizing microstructural brain properties. The model includes three signal compartments: intracellular, extracellular, and free water. The neurite compartment intrinsic parallel diffusivity (d∥) is set to 1.7 μm2⋅ms-1, though the effects of this assumption have not been extensively explored. This work investigates the optimality of d∥ = 1.7 μm2⋅ms-1 under varying imaging protocol, age groups, sex, and tissue type in comparison to other biologically plausible values of d∥.

Methods: Model residuals were used as the optimality criterion. The model residuals were evaluated in function of d∥ over the range from 0.5 to 3.0 μm2⋅ms-1. This was done with respect to tissue type (i.e., white matter versus gray matter), sex, age (infancy to late adulthood), and diffusion-weighting protocol (maximum b-value). Variation in the estimated parameters with respect to d∥ was also explored.

Results: Results show d∥ = 1.7 μm2⋅ms-1 is appropriate for adult brain white matter but it is suboptimal for gray matter with optimal values being significantly lower. d∥ = 1.7 μm2⋅ms-1 was also suboptimal in the infant brain for both white and gray matter with optimal values being significantly lower. Minor optimum d∥ differences were observed versus diffusion protocol. No significant sex effects were observed. Additionally, changes in d∥ resulted in significant changes to the estimated NODDI parameters.

Conclusion: The default (d∥) of 1.7 μm2⋅ms-1 is suboptimal in gray matter and infant brains.
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March 2020

Topographic organization of connections between prefrontal cortex and mediodorsal thalamus: Evidence for a general principle of indirect thalamic pathways between directly connected cortical areas.

Neuroimage 2019 04 1;189:832-846. Epub 2019 Feb 1.

Department of Psychology, University of Wisconsin-Madison, United States; Wisconsin National Primate Research Center, University of Wisconsin-Madison, United States. Electronic address:

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas.
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April 2019

Association of Prenatal Maternal Depression and Anxiety Symptoms With Infant White Matter Microstructure.

JAMA Pediatr 2018 10;172(10):973-981

Waisman Center, University of Wisconsin, Madison.

Importance: Maternal depression and anxiety can have deleterious and lifelong consequences on child development. However, many aspects of the association of early brain development with maternal symptoms remain unclear. Understanding the timing of potential neurobiological alterations holds inherent value for the development and evaluation of future therapies and interventions.

Objective: To examine the association between exposure to prenatal maternal depression and anxiety symptoms and offspring white matter microstructure at 1 month of age.

Design, Setting, And Participants: This cohort study of 101 mother-infant dyads used a composite of depression and anxiety symptoms measured in mothers during the third trimester of pregnancy and measures of white matter microstructure characterized in the mothers' 1-month offspring using diffusion tensor imaging and neurite orientation dispersion and density imaging performed from October 1, 2014, to November 30, 2016. Magnetic resonance imaging was performed at an academic research facility during natural, nonsedated sleep.

Main Outcomes And Measures: Brain mapping algorithms and statistical models were used to evaluate the association between maternal depression and anxiety and 1-month infant white matter microstructure as measured by diffusion tensor imaging and neurite orientation dispersion and density imaging findings.

Results: In the 101 mother-infant dyads (mean [SD] age of mothers, 33.22 [3.99] years; mean age of infants at magnetic resonance imaging, 33.07 days [range, 18-50 days]; 92 white mothers [91.1%]; 53 male infants [52.5%]), lower 1-month white matter microstructure (decreased neurite density and increased mean, radial, and axial diffusivity) was associated in right frontal white matter microstructure with higher prenatal maternal symptoms of depression and anxiety. Significant sex × symptom interactions with measures of white matter microstructure were also observed, suggesting that white matter development may be differentially sensitive to maternal depression and anxiety symptoms in males and females during the prenatal period.

Conclusions And Relevance: These data highlight the importance of the prenatal period to early brain development and suggest that the underlying white matter microstructure is associated with the continuum of prenatal maternal depression and anxiety symptoms.
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October 2018

Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease.

JAMA Neurol 2017 Jan;74(1):41-49

Alzheimer Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison5Geriatric Research Education and Clinical Center, William S. Middleton Memorial VA Hospital, Madison, Wisconsin.

Importance: The accumulation of aggregated β-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging.

Objective: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content.

Design, Setting, And Participants: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including β-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals.

Main Outcomes And Measures: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction.

Results: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/β-amyloid 42, suggesting that phosphorylated tau 181/β-amyloid 42 levels modulate age-related changes in myelin water fraction.

Conclusions And Relevance: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.
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January 2017

Sleep reverts changes in human gray and white matter caused by wake-dependent training.

Neuroimage 2016 Apr 23;129:367-377. Epub 2016 Jan 23.

Dept. of Psychiatry, University of Wisconsin, Madison, WI 53719, USA. Electronic address:

Learning leads to rapid microstructural changes in gray (GM) and white (WM) matter. Do these changes continue to accumulate if task training continues, and can they be reverted by sleep? We addressed these questions by combining structural and diffusion weighted MRI and high-density EEG in 16 subjects studied during the physiological sleep/wake cycle, after 12 h and 24 h of intense practice in two different tasks, and after post-training sleep. Compared to baseline wake, 12 h of training led to a decline in cortical mean diffusivity. The decrease became even more significant after 24 h of task practice combined with sleep deprivation. Prolonged practice also resulted in decreased ventricular volume and increased GM and WM subcortical volumes. All changes reverted after recovery sleep. Moreover, these structural alterations predicted cognitive performance at the individual level, suggesting that sleep's ability to counteract performance deficits is linked to its effects on the brain microstructure. The cellular mechanisms that account for the structural effects of sleep are unknown, but they may be linked to its role in promoting the production of cerebrospinal fluid and the decrease in synapse size and strength, as well as to its recently discovered ability to enhance the extracellular space and the clearance of brain metabolites.
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April 2016

Free water elimination diffusion tractography: A comparison with conventional and fluid-attenuated inversion recovery, diffusion tensor imaging acquisitions.

J Magn Reson Imaging 2015 Dec 20;42(6):1572-81. Epub 2015 Apr 20.

Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Purpose: White matter tractography reconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spaces are often adversely affected by CSF partial volume effects (PVEs). This study evaluates the ability of free water elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractography applications.

Materials And Methods: Ten healthy individuals were scanned with "traditional," FLAIR (fluid-attenuated inversion recovery), and FWE DTI scans. The fornix, corpus callosum, and cingulum bundles were reconstructed using deterministic tractography. The FWE DTI scan was performed twice to separately match total acquisition time (long FWE) and number of measurements (encoding directions, short FWE) to the FLAIR and "traditional" DTI scans. PVE resolution was determined based on reconstructed tract volume. All reconstructions underwent blinded review for anatomical correctness, symmetry, and completeness.

Results: Reconstructions of the fornix demonstrated that the FWE and FLAIR scans produce more complete, anatomically plausible reconstructions than "traditional" DTI. Additionally, the tract reconstructions using FWE-DTI were significantly larger than when FLAIR was used with DTI (P < 0.0005). FLAIR and the FWE methods led to signal-to-noise ratio (SNR) reductions of 33% and 11%, respectively, compared with conventional DTI. The long and short FWE acquisitions did not significantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts.

Conclusion: The FWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penalties inherent to FLAIR DTI.
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December 2015

Optimization of a free water elimination two-compartment model for diffusion tensor imaging.

Neuroimage 2014 Dec 28;103:323-333. Epub 2014 Sep 28.

Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA; Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, USA; Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Blvd, Madison, WI 53719, USA.

Diffusion tensor imaging is used to measure the diffusion of water in tissue. The diffusion properties carry information about the relative organization and structure of the underlying tissue. In the case of a single voxel containing both tissue and a fast diffusing component such as free water, a single diffusion tensor is no longer appropriate. A two-tensor free water elimination model has previously been proposed to correct for the case of volume mixing. Here, this model was implemented in a straightforward but novel manner without the use of spatial constraints. The optimal acquisition parameters were investigated through Monte Carlo simulations and human brain imaging studies. At a signal-to-noise ratio of 40 with 64 diffusion-weighted encoding images, the most accurate estimates of fast diffusion signal were obtained with two diffusion-weighted shells (b-value in s/mm(2)×number of directions) of 500×32 and 1500×32. The potential bias in fractional anisotropy induced by this two-compartment model was more than an order of magnitude less than the error of using the single diffusion tensor model in the presence of partial volume effects with free water. This strategy may be useful for characterizing the diffusion of tissues adjacent to cerebral spinal fluid (CSF), tissues affected by edema, and removing artifacts from blurring and ghosting of the CSF signal.
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December 2014

Time resolved contrast enhanced intracranial MRA using a single dose delivered as sequential injections and highly constrained projection reconstruction (HYPR CE).

Magn Reson Med 2011 Apr 17;65(4):956-63. Epub 2011 Feb 17.

Department of Medical Physics, University of Wisconsin, Madison, Wisconsin 53705, USA.

Time-resolved contrast-enhanced magnetic resonance angiography of the brain is challenging due to the need for rapid imaging and high spatial resolution. Moreover, the significant dispersion of the intravenous contrast bolus as it passes through the heart and lungs increases the overlap between arterial and venous structures, regardless of the acquisition speed and reconstruction window. An innovative technique is presented that divides a single dose contrast into two injections. Initially a small volume of contrast material (2-3 mL) is used to acquiring time-resolved weighting images with a high frame rate (2 frames/s) during the first pass of the contrast agent. The remaining contrast material is used to obtain a high resolution whole brain contrast-enhanced (CE) magnetic resonance angiography (0.57 × 0.57 × 1 mm(3) ) that is used as the spatial constraint for Local Highly Constrained Projection Reconstruction (HYPR LR) reconstruction. After HYPR reconstruction, the final dynamic images (HYPR CE) have both high temporal and spatial resolution. Furthermore, studies of contrast kinetics demonstrate that the shorter bolus length from the reduced contrast volume used for the first injection significantly improves the arterial and venous separation.
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April 2011

HYPR TOF: time-resolved contrast-enhanced intracranial MR angiography using time-of-flight as the spatial constraint.

J Magn Reson Imaging 2011 Mar 1;33(3):719-23. Epub 2011 Feb 1.

Department of Medical Physics, University of Wisconsin, Madison, Wisconsin, USA.

Purpose: To investigate the feasibility of using time-of-flight (TOF) images as a constraint in the reconstruction of a series of highly undersampled time-resolved contrast-enhanced MR images (HYPR TOF), to allow simultaneously high temporal and spatial resolution and increased SNR.

Materials And Methods: Ten healthy volunteers and three patients with aneurysms underwent a HYPR TOF study, which includes a clinical routine TOF scan followed by a first pass time-resolved contrast-enhanced exam using an undersampled three-dimensional (3D) projection trajectory (VIPR). Image quality, waveform fidelity and signal to background variation ratio measurements were compared between HYPR TOF images and VIPR images without HYPR reconstruction.

Results: Volunteer results demonstrated the feasibility of using the clinical routine TOF as the spatial constraint to reconstruct the first pass time-resolved contrast-enhanced MRA acquired using highly undersampled 3D projection trajectory (VIPR). All the HYPR TOF images are superior to the corresponding VIPR images with the same temporal reconstruction window on both spatial resolution and SNR.

Conclusion: HYPR TOF improves the spatial resolution and SNR of the rapidly acquired dynamic images without losing the temporal information.
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March 2011