E. Mark Haacke

YNIMG Journal 2026 Journal Article

Partial volume correction for quantifying venous oxygen saturation levels using contrast-enhanced MRI

• Sagar Buch
• Yifan Lv
• Mingming Wang
• Bo Wu
• Ryan M. Smith
• Yu Luo
• E. Mark Haacke

Quantifying brain oxygenation is crucial for diagnosing and managing neurological conditions like stroke. Quantitative susceptibility mapping (QSM), an MRI technique, can measure venous oxygen saturation (Yv) but is hampered by partial volume effects (PVEs) in small vessels, leading to inaccurate measurements. This study aims to develop a robust method to mitigate these PVEs for the QSM-derived Yv and oxygen extraction fraction (OEF) in small cerebral veins. We integrated QSM with high-resolution, contrast-enhanced T1-weighted imaging to generate regional cerebral blood volume (rCBV) maps, which were used to correct for PVEs in QSM data from 30 stroke patients. The corrected QSM images showed a significant increase in venous susceptibility (Δχ) values compared to the uncorrected images (441.46 ± 61.14 ppb vs. 163.26 ± 19.66 ppb; p < 0.001), translating to a physiologically plausible mean Yv of 70.42 ± 4.09%. The method also improved the distinction of asymmetrically prominent cortical veins (APCVs), revealing lower Yv values in these areas for some cases, consistent with reduced oxygenation. Our findings demonstrate that using contrast-enhanced rCBV maps can correct PVEs in QSM, providing more reliable measurements of Yv and OEF in small cerebral veins. This approach offers valuable clinical insight into assessing cerebral hemodynamics in patients with stroke and other neurological conditions.

YNIMG Journal 2025 Journal Article

Optimizing the visualization of the locus coeruleus using magnetization transfer contrast 3D imaging

• Haiying Lyu
• Naying He
• Bo Wu
• Paula Trujillo
• Fuhua Yan
• Yong Lu
• E. Mark Haacke

BACKGROUND: The locus coeruleus (LC) is a key noradrenergic nucleus of the brain. Its dysfunction is implicated in neurodegenerative diseases like Alzheimer's disease and Parkinson's disease, as well as in psychiatric disorders. However, imaging the LC with sufficient contrast-to-noise ratio (CNR) is challenging due to its small size and deep location in the brainstem. This study optimizes a 3D gradient echo (GRE) sequence with magnetization transfer contrast (MTC) to enable rapid, high-resolution LC imaging in under five minutes. METHODS: A high-resolution 3D-GRE-MTC sequence was optimized on a 3T scanner in 11 healthy volunteers (6 young and 5 older adults). Tissue properties were measured using in vivo MRI data, and simulations were performed to identify the optimal flip angle. LC visualization was evaluated by two independent raters using relative contrast ratio (rCR) and CNR. The diameter and the length of the LC were also evaluated. Each volunteer underwent MRI sessions over three days to assess test-retest reliability. The intra-class correlation coefficient (ICC) for inter-rater reliability and the mean ± standard deviation of LC rCR across sessions for test-retest reproducibility were calculated. RESULTS: A total of 98 scans were collected. The optimized protocol achieved 0.67 × 0.73 × 2 mm³ resolution with an 18° flip angle, 6.18 ms first echo, 52 ms repetition time, flow compensation, arterial suppression, and strict head immobilization. The LC exhibited a CNR of 8.27 ± 1.03, and rCR of 16.70% ± 1.77% (left) and 13.97% ± 2.19% (right), with good inter-rater reliability (ICC = 88.51%). Contrast stability between scans had a variability of 4%-11%. The bilateral LC was visible across 3-6 slices (6-12 mm). Using the full width at quarter maximum measure, the LC diameter was 1.94 ± 0.40 mm for the left side and 1.67 ± 0.34 mm for the right side. CONCLUSION: The optimized protocol enabled reliable, high-resolution LC imaging in under five minutes, providing a valuable tool for clinical and research applications.

YNIMG Journal 2025 Journal Article

White matter hyperintensity tissue property spatial variations as a function of cognitive status in Parkinson’s disease

• Mariyemuguli Reheman
• Sagar Buch
• Naying He
• Pei Huang
• Qiurong Yu
• Xinhui Wang
• Yu Liu
• Youmin Zhang

BACKGROUND AND PURPOSE: The pathological relationship between white matter hyperintensities (WMH) and cognitive impairment in Parkinson's disease (PD) remains unclear due to their variable locations, heterogeneity, and limited assessment of underlying tissue properties. This study integrates T2-FLAIR and quantitative MRI (qMRI) to investigate burden, spatial distribution, and extent of tissue alterations in WMH, aiming to elucidate their role in cognitive decline among PD patients. METHODS: A total of 122 age- and sex-matched PD patients and 65 healthy controls (HC) were recruited, with PD patients grouped by Montreal Cognitive Assessment (MoCA) score including normal, mild cognitive impairment (MCI) or PD with dementia (PDD). WMH burden was compared across groups and cognitive status. Water content, T1, and T2* measures were derived from qMRI data and tissue property heatmaps and periventricular distance profiles were constructed for all groups to visualize location-dependent tissue alterations of WMH relative to the lateral ventricles. In addition, voxel-wise analysis was performed to examine the correlation between WMH lesion tissue properties and MoCA scores. RESULTS: WMH volume was significantly higher in PDD compared to other groups (p < 0.05) and negatively correlated with MoCA scores (r = -0.352, p < 0.001). WMH appeared predominantly around the lateral ventricles, with anterior horn involvement common to all groups and posterior horn involvement specific to PDD. qMRI measures were significantly elevated in WMH compared to normal appearing white matter (NAWM) (p < 0.001), with heatmaps showing a negative gradient of tissue property changes from the lateral ventricles to the NAWM. Voxel-wise analysis revealed a significant negative correlation between the qMRI tissue properties of periventricular WMH and MoCA scores, with the strongest association observed in the periventricular WM situated just beyond the boundary of the lateral ventricles. CONCLUSION: Over and above volume differences, the spatial distribution and tissue property variations of WMH were closely linked to cognitive impairment in PD patients, with distinct patterns across different cognitive stages.

YNIMG Journal 2024 Journal Article

In vivo mapping of hippocampal venous vasculature and oxygenation using susceptibility imaging at 7T

• Chenyang Li
• Sagar Buch
• Zhe Sun
• Marco Muccio
• Li Jiang
• Yongsheng Chen
• E. Mark Haacke
• Jiangyang Zhang

Mapping the small venous vasculature of the hippocampus in vivo is crucial for understanding how functional changes of hippocampus evolve with age. Oxygen utilization in the hippocampus could serve as a sensitive biomarker for early degenerative changes, surpassing hippocampal tissue atrophy as the main source of information regarding tissue degeneration. Using an ultrahigh field (7T) susceptibility-weighted imaging (SWI) sequence, it is possible to capture oxygen-level dependent contrast of submillimeter-sized vessels. Moreover, the quantitative susceptibility mapping (QSM) results derived from SWI data allow for the simultaneous estimation of venous oxygenation levels, thereby enhancing the understanding of hippocampal function. In this study, we proposed two potential imaging markers in a cohort of 19 healthy volunteers aged between 20 and 74 years. These markers were: 1) hippocampal venous density on SWI images and 2) venous susceptibility ( Δ χ vein ) in the hippocampus-associated draining veins (the inferior ventricular veins (IVV) and the basal veins of Rosenthal (BVR) using QSM images). They were chosen specifically to help characterize the oxygen utilization of the human hippocampus and medial temporal lobe (MTL). As part of the analysis, we demonstrated the feasibility of measuring hippocampal venous density and Δ χ vein in the IVV and BVR at 7T with high spatial resolution (0. 25 × 0. 25 × 1 mm3). Our results demonstrated the in vivo reconstruction of the hippocampal venous system, providing initial evidence regarding the presence of the venous arch structure within the hippocampus. Furthermore, we evaluated the age effect of the two quantitative estimates and observed a significant increase in Δ χ vein for the IVV with age (p = 0. 006, r2 = 0. 369). This may suggest the potential application of Δ χ vein in IVV as a marker for assessing changes in atrophy-related hippocampal oxygen utilization in normal aging and neurodegenerative diseases such as AD and dementia.

YNIMG Journal 2024 Journal Article

In Vivo visualization of white matter fiber tracts in the brainstem using low flip angle double echo 3D gradient echo imaging at 3T

• Qiuyun Xu
• Yongsheng Chen
• Stephan Miller
• Kunal Bajaj
• Jairo Santana
• Mohamed Badawy
• Haiying Lyu
• Yu Liu

BACKGROUND: White matter (WM) fiber tracts in the brainstem communicate with various regions in the cerebrum, cerebellum, and spinal cord. Clinically, small lesions, malformations, or histopathological changes in the brainstem can cause severe neurological disorders. A direct and non-invasive assessment approach could bring valuable information about the intricate anatomical variations of the white matter fiber tracts and nuclei. Although tractography from diffusion tensor imaging has been commonly used to map the WM fiber tracts connectivity, it is difficult to differentiate the complex WM tracts anatomically. Both high field MRI methods and ultrahigh-field MRI methods at 7T and 11.7 T have been used to enhance the contrast of WM fiber tracts. Despite their promising results, it is still challenging to achieve wide clinical adoption at 3T. In this study, we explored a clinically feasible method using a proton density weighted (PDW) 3D gradient echo (GRE) sequence to directly image the WM fiber tracts in the brainstem at 3T in vivo. METHODS: We optimized a 3D high resolution, double echo, short TR, PDW GRE sequence on 5 healthy volunteers using a clinical 3T scanner to visualize the complicated anatomy of WM fiber tracts in the brain stem. Tissue properties including T1, proton density and T2* from in vivo quantitative MRI data were used for simulations to determine the optimal flip angle for the sequence. The visualization of multiple WM fiber tracts in the brainstem was assessed qualitatively and quantitatively using relative contrast and contrast-to-noise ratio (CNR). To improve the CNR, the final images were created by averaging over all echoes from two consecutive scans at the optimal flip angle. The results were compared to anatomical atlases and histology sections to identify the major fiber tracts. All the identified major fiber tracts were labeled on axial, sagittal and coronal slices. RESULTS: The WM fiber tracts were found to have distinct hypointense signal throughout the brainstem and most of the major WM fiber tracts, such as the corticospinal tract, medial lemniscus, medial longitudinal fasciculus, and central tegmental tract, in the brainstem up to and including the thalamus were identified in all subjects. Both qualitative and quantitative evaluations showed that the 3° scan offered the best contrast for WM fiber tracts for a TR of 20 ms. The average over the first two echo times and two consecutive 3° scans gave a CNR of 47.8 ± 6.2 for the pyramidal tracts in particular and CNRs values greater than 6.5 ± 2.4 for the rest of the fiber tracts. CONCLUSIONS: All the major fiber tracts in the brainstem could be visualized. Given the reasonably short scan time of 10 min at 3T, double echo PDW GRE sequence is a very practical approach for clinical adoption.

YNIMG Journal 2024 Journal Article

PENCIL imaging: A novel approach for neuromelanin sensitive MRI in Parkinson's disease

• Peng Liu
• Xinhui Wang
• Youmin Zhang
• Pei Huang
• Zhijia Jin
• Zenghui Cheng
• Yongsheng Chen
• Qiuyun Xu

BACKGROUND: Parkinson's disease (PD) is associated with the loss of neuromelanin (NM) and increased iron in the substantia nigra (SN). Magnetization transfer contrast (MTC) is widely used for NM visualization but has limitations in brain coverage and scan time. This study aimed to develop a new approach called Proton-density Enhanced Neuromelanin Contrast in Low flip angle gradient echo (PENCIL) imaging to visualize NM in the SN. METHODS: This study included 30 PD subjects and 50 healthy controls (HCs) scanned at 3T. PENCIL and MTC images were acquired. NM volume in the SN pars compacta (SNpc), normalized image contrast (Cnorm), and contrast-to-noise ratio (CNR) were calculated. The change of NM volume in the SNpc with age was analyzed using the HC data. A group analysis compared differences between PD subjects and HCs. Receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculations were used to evaluate the diagnostic performance of NM volume and CNR in the SNpc. RESULTS: PENCIL provided similar visualization and structural information of NM compared to MTC. In HCs, PENCIL showed higher NM volume in the SNpc than MTC, but this difference was not observed in PD subjects. PENCIL had higher CNR, while MTC had higher Cnorm. Both methods revealed a similar pattern of NM volume in SNpc changes with age. There were no significant differences in AUCs between NM volume in SNpc measured by PENCIL and MTC. Both methods exhibited comparable diagnostic performance in this regard. CONCLUSIONS: PENCIL imaging provided improved CNR compared to MTC and showed similar diagnostic performance for differentiating PD subjects from HCs. The major advantage is PENCIL has rapid whole-brain coverage and, when using STAGE imaging, offers a one-stop quantitative assessment of tissue properties.

YNIMG Journal 2023 Journal Article

Diagnosing Parkinson's disease by combining neuromelanin and iron imaging features using an automated midbrain template approach

• Mojtaba Jokar
• Zhijia Jin
• Pei Huang
• Ying Wang
• Youmin Zhang
• Yan Li
• Zenghui Cheng
• Yu Liu

BACKGROUND AND PURPOSE: Early diagnosis of Parkinson's disease (PD) is still a clinical challenge. Most previous studies using manual or semi-automated methods for segmenting the substantia nigra (SN) are time-consuming and, despite raters being well-trained, individual variation can be significant. In this study, we used a template-based, automatic, SN subregion segmentation pipeline to detect the neuromelanin (NM) and iron features in the SN and SN pars compacta (SNpc) derived from a single 3D magnetization transfer contrast (MTC) gradient echo (GRE) sequence in an attempt to develop a comprehensive imaging biomarker that could be used to diagnose PD. MATERIALS AND METHODS: volume, SNpc volume and iron content with a variety of thresholds as well as the N1 sign in diagnosing PD. Correlation analyses were performed to study the relationship between these imaging measures and the clinical scales in PD. RESULTS: = 0.04, p = 0.013) in PD patients. CONCLUSION: volume, SNpc volume and iron content) resulted in an AUC of 0.947 and provided a comprehensive set of imaging biomarkers that, potentially, could be used to diagnose PD clinically.

YNIMG Journal 2023 Journal Article

The iron burden of cerebral microbleeds contributes to brain atrophy through the mediating effect of white matter hyperintensity

• Ke Lv
• Yanzhen Liu
• Yongsheng Chen
• Sagar Buch
• Ying Wang
• Zhuo Yu
• Huiying Wang
• Chenxi Zhao

The goal of this work was to explore the total iron burden of cerebral microbleeds (CMBs) using a semi-automatic quantitative susceptibility mapping and to establish its effect on brain atrophy through the mediating effect of white matter hyperintensities (WMH). A total of 95 community-dwelling people were enrolled. Quantitative susceptibility mapping (QSM) combined with a dynamic programming algorithm (DPA) was used to measure the characteristics of 1309 CMBs. WMH were evaluated according to the Fazekas scale, and brain atrophy was assessed using a 2D linear measurement method. Histogram analysis was used to explore the distribution of CMBs susceptibility, volume, and total iron burden, while a correlation analysis was used to explore the relationship between volume and susceptibility. Stepwise regression analysis was used to analyze the risk factors for CMBs and their contribution to brain atrophy. Mediation analysis was used to explore the interrelationship between CMBs and brain atrophy. We found that the frequency distribution of susceptibility of the CMBs was Gaussian in nature with a mean of 201 ppb and a standard deviation of 84 ppb; however, the volume and total iron burden of CMBs were more Rician in nature. A weak but significant correlation between the susceptibility and volume of CMBs was found (r = -0.113, P < 0.001). The periventricular WMH (PVWMH) was a risk factor for the presence of CMBs (number: β = 0.251, P = 0.014; volume: β = 0.237, P = 0.042; total iron burden: β = 0.238, P = 0.020) and was a risk factor for brain atrophy (third ventricle width: β = 0.325, P = 0.001; Evans's index: β = 0.323, P = 0.001). PVWMH had a significant mediating effect on the correlation between CMBs and brain atrophy. In conclusion, QSM along with the DPA can measure the total iron burden of CMBs. PVWMH might be a risk factor for CMBs and may mediate the effect of CMBs on brain atrophy.

YNIMG Journal 2022 Journal Article

Vascular mapping of the human hippocampus using Ferumoxytol-enhanced MRI

• Sagar Buch
• Yongsheng Chen
• Pavan Jella
• Yulin Ge
• E. Mark Haacke

The hippocampus is a small but complex grey matter structure that plays an important role in spatial and episodic memory and can be affected by a wide range of pathologies including vascular abnormalities. In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxide (USPIO) agent, to induce susceptibility in the arteries (as well as increase the susceptibility in the veins) to map the hippocampal micro-vasculature and to evaluate the quantitative change in tissue fractional vascular density (FVD), in each of its subfields. A total of 39 healthy subjects (aged 35. 4 ± 14. 2 years, from 18 to 81 years old) were scanned with a high-resolution (0. 22×0. 44×1 mm3) dual-echo SWI sequence acquired at four time points during a gradual increase in Ferumoxytol dose (final dose = 4 mg/kg). The volumes of each subfield were obtained automatically from the pre-contrast T1-weighted data. The dynamically acquired SWI data were co-registered and adaptively combined to reduce the blooming artifacts from large vessels, preserving the contrast from smaller vessels. The resultant SWI data were used to segment the hippocampal vasculature and to measure the FVD ((volume occupied by vessels)/(total volume)) for each subfield. The hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher micro-vascular FVD than the other parts of hippocampus. The CA1 region exhibited a significant correlation with age (R = −0. 37, p < 0. 05). demonstrating an overall loss of hippocampal vascularity in the normal aging process. Moreover, the vascular density reduction was more prominent than the age correlation with the volume reduction (R = −0. 1, p > 0. 05) of the CA1 subfield, which would suggest that vascular degeneration may precede tissue atrophy.

YNIMG Journal 2021 Journal Article

Imaging iron and neuromelanin simultaneously using a single 3D gradient echo magnetization transfer sequence: Combining neuromelanin, iron and the nigrosome-1 sign as complementary imaging biomarkers in early stage Parkinson's disease

• Naying He
• Kiarash Ghassaban
• Pei Huang
• Mojtaba Jokar
• Ying Wang
• Zenghui Cheng
• Zhijia Jin
• Yan Li

Diagnosing early stage Parkinson's disease (PD) is still a clinical challenge. Previous studies using iron, neuromelanin (NM) or the Nigrosome-1 (N1) sign in the substantia nigra (SN) by themselves have been unable to provide sufficiently high diagnostic performance for these methods to be adopted clinically. Our goal in this study was to extract the NM complex volume, iron content and volume representing the entire SN, and the N1 sign as potential complementary imaging biomarkers using a single 3D magnetization transfer contrast (MTC) gradient echo sequence and to evaluate their diagnostic performance and clinical correlations in early stage PD. A total of 40 early stage idiopathic PD subjects and 40 age- and sex-matched healthy controls (HCs) were imaged at 3T. NM boundaries (representing the SN pars compacta (SNpc) and parabrachial pigmented nucleus) and iron boundaries representing the total SN (SNpc and SN pars reticulata) were determined semi-automatically using a dynamic programming (DP) boundary detection algorithm. Receiver operating characteristic analyses were performed to evaluate the utility of these imaging biomarkers in diagnosing early stage PD. A correlation analysis was used to study the relationship between these imaging measures and the clinical scales. We also introduced the concept of NM and total iron overlap volumes to demonstrate the loss of NM relative to the iron containing SN. Furthermore, all 80 cases were evaluated for the N1 sign independently. The NM and SN volumes were lower while the iron content was higher in the SN for PD subjects compared to HCs. Interestingly, the PD subjects with bilateral loss of the N1 sign had the highest iron content. The area under the curve (AUC) values for the average of both hemispheres for single measures were: .960 for NM complex volume; .788 for total SN volume; .740 for SN iron content and. 891 for the N1 sign. Combining NM complex volume with each of the following measures through binary logistic regression led to AUC values for the averaged right and left sides of: .976 for total iron content; .969 for total SN volume, .965 for overlap volume and. 983 for the N1 sign. We found a negative correlation between SN volume and UPDRS-III (R2 =. 22, p =. 002). While the N1 sign performed well, it does not contain any information about iron content or NM quantitatively, therefore, marrying this sign with the NM and iron measures provides a better physiological explanation of what is happening when the N1 sign disappears in PD subjects. In summary, the combination of NM complex volume, SN volume, iron content and the N1 sign as derived from a single MTC sequence provides complementary information for understanding and diagnosing early stage PD.

YNICL Journal 2021 Journal Article

Revealing vascular abnormalities and measuring small vessel density in multiple sclerosis lesions using USPIO

• Sagar Buch
• Karthikeyan Subramanian
• Pavan K. Jella
• Yongsheng Chen
• Zhen Wu
• Kamran Shah
• Evanthia Bernitsas
• Yulin Ge

BACKGROUND AND PURPOSE: Multiple Sclerosis (MS) is a progressive, inflammatory, neuro-degenerative disease of the central nervous system (CNS) characterized by a wide range of histopathological features including vascular abnormalities. In this study, an ultra-small superparamagnetic iron oxide (USPIO) contrast agent, Ferumoxytol, was administered to induce an increase in susceptibility for both arteries and veins to help better reveal the cerebral microvasculature. The purpose of this work was to examine the presence of vascular abnormalities and vascular density in MS lesions using high-resolution susceptibility weighted imaging (SWI). METHODS: Six subjects with relapsing remitting MS (RRMS, age = 47.3 ± 11.8 years with 3 females and 3 males) and fourteen age-matched healthy controls were scanned at 3 T with SWI acquired before and after the infusion of Ferumoxytol. Composite data was generated by registering the FLAIR data to the high resolution SWI data in order to highlight the vascular information in MS lesions. Both the central vein sign (CVS) and, a new measure, the multiple vessel sign (MVS) were identified, along with any vascular abnormalities, in the lesions on pre- and post-contrast SWI-FLAIR fusion data. The small vessel density within the periventricular normal-appearing white matter (NAWM) and the periventricular lesions were compared for all subjects. RESULTS: Averaged across two independent raters, a total of 530 lesions were identified across all patients. The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM. CONCLUSIONS: By inducing a super-paramagnetic susceptibility in the blood using Ferumoxytol, the vascular abnormalities in the RRMS patients were revealed and small vessel densities were obtained. This approach has the potential to monitor the venous vasculature present in MS lesions, catalogue their characteristics and compare the vascular structures spatially to the presence of lesions. These enhanced vascular features may provide new insight into the pathophysiology of MS.

YNICL Journal 2021 Journal Article

Utility of quantitative susceptibility mapping and diffusion kurtosis imaging in the diagnosis of early Parkinson’s disease

• Samantha Tan
• Septian Hartono
• Thomas Welton
• Chu Ning Ann
• Soo Lee Lim
• Tong San Koh
• Huihua Li
• Fiona Setiawan

OBJECTIVE: To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson's disease (PD) and their clinical correlates to aid in diagnosis of PD. METHOD: Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). RESULTS: There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (β = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p < 0.0001) and had "good" classification performance (AUC = 0.88). CONCLUSIONS: QSM and DKI are complementary tools allowing a better understanding of the complex contribution of iron deposition and microstructural changes in the pathophysiology of PD.

YNICL Journal 2020 Journal Article

Imaging the Nigrosome 1 in the substantia nigra using susceptibility weighted imaging and quantitative susceptibility mapping: An application to Parkinson's disease

• Zenghui Cheng
• Naying He
• Pei Huang
• Yan Li
• Rongbiao Tang
• Sean K. Sethi
• Kiarash Ghassaban
• Kiran Kumar Yerramsetty

Parkinson's disease (PD) is a clinically heterogeneous chronic progressive neuro-degenerative disease with loss of dopaminergic neurons in the nigrosome 1 (N1) territory of the substantia nigra pars compacta (SNpc). To date, there has been a major effort to identify changes in the N1 territory by monitoring increases of iron in the SNpc. However, there is no standard protocol being used to visualize or characterize the N1 territory. Therefore, the purpose of this study was to create a robust high quality, rapid imaging protocol, determine a slice by slice characterization of the appearance of N1 (the "N1 sign") and evaluate the loss of the N1 sign in order to differentiate healthy controls (HCs) from patients with PD. Firstly, one group of 10 HCs was used to determine the choice of imaging parameters. Secondly, another group of 80 HCs was used to characterize the appearance of the N1 sign and train the raters. In this step, the magnitude, susceptibility weighted images (SWI), quantitative susceptibility maps (QSM) and true SWI (tSWI) images were all reviewed using data from a 3D gradient recalled echo sequence. A resolution of 0.67 mm × 0.67 mm × 1.34 mm was chosen based on the ability to cover all the basal ganglia, midbrain and dentate nucleus with good signal-to-noise with echo times of 11 ms and 20 ms. Thirdly, 80 Parkinsonism and related disorders patients [idiopathic Parkinson's disease (IPD): 57; atypical parkinsonian syndromes (APs): 14; essential tremor (ET): 9] and one additional group of 80 age-matched HCs were blindly analyzed for the presence or absence of the N1 sign for a differential diagnosis. From the first group of 80 HCs, all of the 76 (100%) cases (4 were excluded due to motion artifacts) showed the N1 sign in one form or another after reviewing the first 5 caudal slices of the SN. For the second group of 80 HCs, 78 (97.5%) showed the N1 sign in at least 2 slices. Of the 80 Parkinsonism and related disorders patients, 32 (56.1%, 32/57) IPD and 6 (42.9%, 6/14) APs showed a bilateral loss of the N1 sign, 12 (21.1%, 12/57) IPD and 6 (42.9%, 6/14) APs showed the N1 sign unilaterally and 13 (22.8%, 13/57) IPD and 2 (14.2%, 2/14) APs showed the N1 sign bilaterally. Also, all 9 (100%, 9/9) ET patients showed the N1 sign bilaterally. The mean total structure and mean high susceptibility region for the SN for both IPD and APs patients with bilateral loss of N1 were higher than those of the HCs (p < 0.002). In conclusion, the N1 sign can be consistently visualized using tSWI with a resolution of at least 0.67 mm × 0.67 mm × 1.34 mm and can be seen in 95% of HCs.

YNIMG Journal 2020 Journal Article

Optimizing neuromelanin contrast in the substantia nigra and locus coeruleus using a magnetization transfer contrast prepared 3D gradient recalled echo sequence

• Yu Liu
• Junchen Li
• Naying He
• Yongsheng Chen
• Zhijia Jin
• Fuhua Yan
• E. Mark Haacke

Neuromelanin (NM) loss in the substantia nigra (SN) and locus coeruleus (LC) is being investigated as an imaging biomarker for Parkinson’s disease (PD) using magnetization transfer contrast (MTC) magnetic resonance imaging. The MTC pulse operates in a way to suppress tissue with high macromolecular content thereby highlighting the presence of NM in the LC and the SN. The MTC pulse also leads to a reduction in the effective T1 of the tissue. In the past, a 3D gradient echo (GRE) sequence has usually been run with a single flip angle (FA) generally to highlight the T1 shortening effect when trying to visualize NM. We contend that the NM will be best seen with a low FA (relative to the Ernst angle) because the NM has high water content relative to the surrounding tissues. Therefore, the goal of this paper was to optimize the NM contrast in the SN and LC as a function of flip angle using a 3D GRE MTC strategically acquired gradient echo (STAGE) imaging approach. In order to accomplish this, short repeat time (62 ​ms), 3D GRE imaging data were collected for 7 different flip angles ranging from 5° to 40° for 14 healthy volunteers (age range 24–43 years, mean ​± ​SD ​= ​34. 8 ​± ​6. 0 years, 6 males). By measuring the contrast-to-noise ratio between these structures and the surrounding tissues, we found that the FA showing the best NM contrast was 15° - 20° for the SN and 20° - 25° for the LC. Using STAGE imaging with just two flip angles (15° and 30°) made it possible to quantify not only tissue properties such as T1 and proton density but also to generate synthetic MTC images at an arbitrary FA. These synthetic images make it possible to optimize the contrast for any changes in tissue property that might occur in the LC or SN as a function of age or disease. In conclusion, practically, two scans could be collected in roughly 7 ​min each for both FAs in a standard clinical imaging setting to evaluate the signal intensity and volume of the NM in the LC and SN.

YNIMG Journal 2020 Journal Article

Subvoxel vascular imaging of the midbrain using USPIO-Enhanced MRI

• Sagar Buch
• Ying Wang
• Min-Gyu Park
• Pavan K. Jella
• Jiani Hu
• Yongsheng Chen
• Kamran Shah
• Yulin Ge

There is an urgent need for better detection and understanding of vascular abnormalities at the micro-level, where critical vascular nourishment and cellular metabolic changes occur. This is especially the case for structures such as the midbrain where both the feeding and draining vessels are quite small. Being able to monitor and diagnose vascular changes earlier will aid in better understanding the etiology of the disease and in the development of therapeutics. In this work, thirteen healthy volunteers were scanned with a dual echo susceptibility weighted imaging (SWI) sequence, with a resolution of 0. 22 ​× ​0. 44 ​× ​1 ​mm3 at 3T. Ultra-small superparamagnetic iron oxides (USPIO) were used to induce an increase in susceptibility in both arteries and veins. Although the increased vascular susceptibility enhances the visibility of small subvoxel vessels, the accompanying strong signal loss of the large vessels deteriorates the local tissue contrast. To overcome this problem, the SWI data were acquired at different time points during a gradual administration (final concentration ​= ​4 ​mg/kg) of the USPIO agent, Ferumoxytol, and the data was processed to combine the SWI data dynamically, in order to see through these blooming artifacts. The major vessels and their tributaries (such as the collicular artery, peduncular artery, peduncular vein and the lateral mesencephalic vein) were identified on the combined SWI data using arterio-venous maps. Dynamically combined SWI data was then compared with previous histological work to validate that this protocol was able to detect small vessels on the order of 50 ​μm–100 ​μm. A complex division-based phase unwrapping was also employed to improve the quality of quantitative susceptibility maps by reducing the artifacts due to aliased voxels at the vessel boundaries. The smallest detectable vessel size was then evaluated by revisiting numerical simulations, using estimated true susceptibilities for the basal vein and the posterior cerebral artery in the presence of Ferumoxytol. These simulations suggest that vessels as small as 50 ​μm should be visible with the maximum dose of 4 ​mg/kg.

YNIMG Journal 2019 Journal Article

Cerebral microbleed detection using Susceptibility Weighted Imaging and deep learning

• Saifeng Liu
• David Utriainen
• Chao Chai
• Yongsheng Chen
• Lin Wang
• Sean K. Sethi
• Shuang Xia
• E. Mark Haacke

Detecting cerebral microbleeds (CMBs) is important in diagnosing a variety of diseases including dementia, stroke and traumatic brain injury. However, manual detection of CMBs can be time-consuming and prone to errors, whereas the current automatic algorithms for CMB detection are usually limited by large number of false positives. In this study, we present a two-stage CMB detection framework which contains a candidate detection stage based on a 3D fast radial symmetry transform of the composite images from Susceptibility Weighted Imaging (SWI), and a false positive reduction stage based on deep residual neural networks using both the SWI and the high-pass filtered phase images. While the SWI images provide exquisite sensitivity to the presence of blood products, the high-pass filtered phase images enable the differentiation of diamagnetic calcifications from paramagnetic microbleeds. The deep learning model was trained using 154 data sets, and the best models were selected using 25 validation data sets. Finally, the models were tested using 41 cases, including 13 hemodialysis cases, 9 traumatic brain injury cases, 9 stroke cases and 10 healthy controls. Using 3D SWI and high-pass filtered phase images as input, the best model led to a sensitivity of 95. 8%, a precision of 70. 9%, and 1. 6 false positives per case. This model achieved similar performance to the most experienced human rater and outperformed recently reported CMB detection methods. This study demonstrates the potential of applying deep learning techniques to medical imaging for improving efficiency and accuracy in diagnosis.

YNIMG Journal 2019 Journal Article

Quantifying iron content in magnetic resonance imaging

• Kiarash Ghassaban
• Saifeng Liu
• Caihong Jiang
• E. Mark Haacke

Measuring iron content has practical clinical indications in the study of diseases such as Parkinson's disease, Huntington's disease, ferritinopathies and multiple sclerosis as well as in the quantification of iron content in microbleeds and oxygen saturation in veins. In this work, we review the basic concepts behind imaging iron using T2, T2*, T2′, phase and quantitative susceptibility mapping in the human brain, liver and heart, followed by the applications of in vivo iron quantification in neurodegenerative diseases, iron tagged cells and ultra-small superparamagnetic iron oxide (USPIO) nanoparticles.

YNICL Journal 2019 Journal Article

Quantitative susceptibility mapping based hybrid feature extraction for diagnosis of Parkinson's disease

• Bin Xiao
• Naying He
• Qian Wang
• Zenghui Cheng
• Yining Jiao
• E. Mark Haacke
• Fuhua Yan
• Feng Shi

Parkinson's disease is the second most common neurodegenerative disease in the elderly after Alzheimer's disease. The aetiology and pathogenesis of Parkinson's disease (PD) are still unclear, but the loss of dopaminergic cells and the excessive iron deposition in the substantia nigra (SN) are associated with the pathophysiology. As an imaging technique that can quantitatively reflect the amount of iron deposition, Quantitative Susceptibility Mapping (QSM) has been shown to be a promising modality for the diagnosis of PD. In the present work, we propose a hybrid feature extraction method for PD diagnosis using QSM images. First, we extract radiomics features from the SN using QSM and employ machine learning algorithms to classify PD and normal controls (NC). This approach allows us to investigate which features are most vulnerable to the effects of the disease. Along with this approach, we propose a Convolutional Neural Network (CNN) based method which can extract different features from the QSM image to further support the diagnosis of PD. Finally, we combine these two types of features and we find that the radiomics features and CNN features are complementary to each other, which helps further improve the classification (diagnostic) performance. We conclude that: (1) radiomics features from QSM data have significant clinical value for the diagnosis of PD; (2) CNN features are also useful in the diagnosis of PD; and (3) the combination of radiomics features and CNN features can enhance the diagnostic accuracy.

YNICL Journal 2017 Journal Article

Decreased susceptibility of major veins in mild traumatic brain injury is correlated with post-concussive symptoms: A quantitative susceptibility mapping study

• Chao Chai
• Rui Guo
• Chao Zuo
• Linlin Fan
• Saifeng Liu
• Tianyi Qian
• E. Mark Haacke
• Shuang Xia

Cerebral venous oxygen saturation (SvO2) is an important biomarker of brain function. In this study, we aimed to explore the relative changes of regional cerebral SvO2 among axonal injury (AI) patients, non-AI patients and healthy controls (HCs) using quantitative susceptibility mapping (QSM). 48 patients and 32 HCs were enrolled. The patients were divided into two groups depending on the imaging based evidence of AI. QSM was used to measure the susceptibility of major cerebral veins. Nonparametric testing was performed for susceptibility differences among the non-AI patient group, AI patient group and healthy control group. Correlation was performed between the susceptibility of major cerebral veins, elapsed time post trauma (ETPT) and post-concussive symptom scores. The ROC analysis was performed for the diagnostic efficiency of susceptibility to discriminate mTBI patients from HCs. The susceptibility of the straight sinus in non-AI and AI patients was significantly lower than that in HCs (P <0. 001, P =0. 004, respectively, Bonferroni corrected), which may indicate an increased regional cerebral SvO2 in patients. The susceptibility of the straight sinus in non-AI patients positively correlated with ETPT (r =0. 573, P =0. 003, FDR corrected) while that in AI patients negatively correlated with the Rivermead Post Concussion Symptoms Questionnaire scores (r =−0. 582, P =0. 018, FDR corrected). The sensitivity, specificity and AUC values of susceptibility for the discrimination between mTBI patients and HCs were 88%, 69% and 0. 84. In conclusion, the susceptibility of the straight sinus can be used as a biomarker to monitor the progress of mild TBI and to differentiate mTBI patients from healthy controls.

YNICL Journal 2016 Journal Article

Connectome-scale assessment of structural and functional connectivity in mild traumatic brain injury at the acute stage

• Armin Iraji
• Hanbo Chen
• Natalie Wiseman
• Tuo Zhang
• Robert Welch
• Brian O'Neil
• Andrew Kulek
• Syed Imran Ayaz

Mild traumatic brain injury (mTBI) accounts for over one million emergency visits each year in the United States. The large-scale structural and functional network connectivity changes of mTBI are still unknown. This study was designed to determine the connectome-scale brain network connectivity changes in mTBI at both structural and functional levels. 40 mTBI patients at the acute stage and 50 healthy controls were recruited. A novel approach called Dense Individualized and Common Connectivity-based Cortical Landmarks (DICCCOLs) was applied for connectome-scale analysis of both diffusion tensor imaging and resting state functional MRI data. Among 358 networks identified on DICCCOL analysis, 41 networks were identified as structurally discrepant between patient and control groups. The involved major white matter tracts include the corpus callosum, and superior and inferior longitudinal fasciculi. Functional connectivity analysis identified 60 connectomic signatures that differentiate patients from controls with 93.75% sensitivity and 100% specificity. Analysis of functional domains showed decreased intra-network connectivity within the emotion network and among emotion-cognition interactions, and increased interactions among action-emotion and action-cognition as well as within perception networks. This work suggests that mTBI may result in changes of structural and functional connectivity on a connectome scale at the acute stage.

YNIMG Journal 2016 Journal Article

Database integration of protocol-specific neurological imaging datasets

• Emil E. Pacurar
• Sean K. Sethi
• Charbel Habib
• Marius O. Laze
• Rachel Martis-Laze
• E. Mark Haacke

For many years now, Magnetic Resonance Innovations (MR Innovations), a magnetic resonance imaging (MRI) software development, technology, and research company, has been aggregating a multitude of MRI data from different scanning sites through its collaborations and research contracts. The majority of the data has adhered to neuroimaging protocols developed by our group which has helped ensure its quality and consistency. The protocols involved include the study of: traumatic brain injury, extracranial venous imaging for multiple sclerosis and Parkinson's disease, and stroke. The database has proven invaluable in helping to establish disease biomarkers, validate findings across multiple data sets, develop and refine signal processing algorithms, and establish both public and private research collaborations. Myriad Masters and PhD dissertations have been possible thanks to the availability of this database. As an example of a project that cuts across diseases, we have used the data and specialized software to develop new guidelines for detecting cerebral microbleeds. Ultimately, the database has been vital in our ability to provide tools and information for researchers and radiologists in diagnosing their patients, and we encourage collaborations and welcome sharing of similar data in this database.

YNIMG Journal 2016 Journal Article

The connectivity domain: Analyzing resting state fMRI data using feature-based data-driven and model-based methods

• Armin Iraji
• Vince D. Calhoun
• Natalie M. Wiseman
• Esmaeil Davoodi-Bojd
• Mohammad R.N. Avanaki
• E. Mark Haacke
• Zhifeng Kou

Spontaneous fluctuations of resting state functional MRI (rsfMRI) have been widely used to understand the macro-connectome of the human brain. However, these fluctuations are not synchronized among subjects, which leads to limitations and makes utilization of first-level model-based methods challenging. Considering this limitation of rsfMRI data in the time domain, we propose to transfer the spatiotemporal information of the rsfMRI data to another domain, the connectivity domain, in which each value represents the same effect across subjects. Using a set of seed networks and a connectivity index to calculate the functional connectivity for each seed network, we transform data into the connectivity domain by generating connectivity weights for each subject. Comparison of the two domains using a data-driven method suggests several advantages in analyzing data using data-driven methods in the connectivity domain over the time domain. We also demonstrate the feasibility of applying model-based methods in the connectivity domain, which offers a new pathway for the use of first-level model-based methods on rsfMRI data. The connectivity domain, furthermore, demonstrates a unique opportunity to perform first-level feature-based data-driven and model-based analyses. The connectivity domain can be constructed from any technique that identifies sets of features that are similar across subjects and can greatly help researchers in the study of macro-connectome brain function by enabling us to perform a wide range of model-based and data-driven approaches on rsfMRI data, decreasing susceptibility of analysis techniques to parameters that are not related to brain connectivity information, and evaluating both static and dynamic functional connectivity of the brain from a new perspective.

YNIMG Journal 2013 Journal Article

Measuring iron in the brain using quantitative susceptibility mapping and X-ray fluorescence imaging

• Weili Zheng
• Helen Nichol
• Saifeng Liu
• Yu-Chung N. Cheng
• E. Mark Haacke

Measuring iron content in the brain has important implications for a number of neurodegenerative diseases. Quantitative susceptibility mapping (QSM), derived from magnetic resonance images, has been used to measure total iron content in vivo and in post mortem brain. In this paper, we show how magnetic susceptibility from QSM correlates with total iron content measured by X-ray fluorescence (XRF) imaging and by inductively coupled plasma mass spectrometry (ICPMS). The relationship between susceptibility and ferritin iron was estimated at 1. 10±0. 08ppb susceptibility per μg iron/g wet tissue, similar to that of iron in fixed (frozen/thawed) cadaveric brain and previously published data from unfixed brains. We conclude that magnetic susceptibility can provide a direct and reliable quantitative measurement of iron content and that it can be used clinically at least in regions with high iron content.

YNIMG Journal 2012 Journal Article

The role of susceptibility weighted imaging in functional MRI

• E. Mark Haacke
• Yongquan Ye

The development of functional brain magnetic resonance imaging (fMRI) has been a boon for neuroscientists and radiologists alike. It provides for fundamental information on brain function and better diagnostic tools to study disease. In this paper, we will review some of the early concepts in high resolution gradient echo imaging with a particular emphasis on susceptibility weighted imaging (SWI) and MR angiography (MRA). We begin with the history of our own experience in this area, followed by a discussion of the role of high resolution in studying the vasculature of the brain and how this relates to the BOLD (blood oxygenation level dependent) signal. We introduce the role of SWI and susceptibility mapping (SWIM) in fMRI and close with recommendations for future high resolution experiments.

YNIMG Journal 2011 Journal Article

Differential effects of age and history of hypertension on regional brain volumes and iron

• Karen M. Rodrigue
• E. Mark Haacke
• Naftali Raz

Aging affects various structural and metabolic properties of the brain. However, associations among various aspects of brain aging are unclear. Moreover, those properties and associations among them may be modified by age-associated increase in vascular risk. In this study, we measured volume of brain regions that vary in their vulnerability to aging and estimated local iron content via T2* relaxometry. In 113 healthy adults (19–83years old), we examined prefrontal cortex (PFC), primary visual cortex (VC), hippocampus (HC), entorhinal cortex (EC), caudate nucleus (Cd), and putamen (Pt). In some regions (PFC, VC, Cd, and Pt) age-related differences in iron and volume followed similar patterns. However, in the medial–temporal structures, volume and iron content exhibited different age trajectories. Whereas age-related volume reduction was mild in HC and absent in EC, iron content evidenced significant age-related declines. In hypertensive participants significantly greater iron content was noted in all examined regions. Thus, iron content as measured by T2* may be a sensitive index of regional brain aging and may reveal declines that are more prominent than gross anatomical shrinkage.

YNIMG Journal 1996 Journal Article

Experimental and statistical assessment of EKG gated acquisition of functional magnetic resonance brain images

• K. Kuppusamy
• W. Lin
• E. Mark Haacke