Publications

2022
Alosco ML, Su Y, Stein TD, Protas H, Cherry JD, Adler CH, Balcer LJ, Bernick C, Pulukuri SV, Abdolmohammadi B, et al. Associations Between Near End-of-Life Flortaucipir PET and Postmortem CTE-Related Tau Neuropathology in Six Former American Football Players. Eur J Nucl Med Mol Imaging. 2022.Abstract
PURPOSE: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players. METHODS: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs). RESULTS: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions. CONCLUSIONS: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed.
Kaufmann E, Rojczyk P, Sydnor VJ, Guenette JP, Tripodis Y, Kaufmann D, Umminger L, Seitz-Holland J, Sollmann N, Rathi Y, et al. Association of War Zone-Related Stress With Alterations in Limbic Gray Matter Microstructure. JAMA Netw Open. 2022;5 (9) :e2231891.Abstract
Importance: Military service members returning from theaters of war are at increased risk for mental illness, but despite high prevalence and substantial individual and societal burden, the underlying pathomechanisms remain largely unknown. Exposure to high levels of emotional stress in theaters of war and mild traumatic brain injury (mTBI) are presumed factors associated with risk for the development of mental disorders. Objective: To investigate (1) whether war zone-related stress is associated with microstructural alterations in limbic gray matter (GM) independent of mental disorders common in this population, (2) whether associations between war zone-related stress and limbic GM microstructure are modulated by a history of mTBI, and (3) whether alterations in limbic GM microstructure are associated with neuropsychological functioning. Design, Setting, and Participants: This cohort study was part of the TRACTS (Translational Research Center for TBI and Stress Disorders) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. Participants included male veterans (aged 18-65 years) with available diffusion tensor imaging data enrolled in the TRACTS study. Data analysis was performed between December 2017 to September 2021. Exposures: The Deployment Risk and Resilience Inventory (DRRI) was used to measure exposure to war zone-related stress. The Boston Assessment of TBI-Lifetime was used to assess history of mTBI. Stroop Inhibition (Stroop-IN) and Inhibition/Switching (Stroop-IS) Total Error Scaled Scores were used to assess executive or attentional control functions. Main Outcomes and Measures: Diffusion characteristics (fractional anisotropy of tissue [FAT]) of 16 limbic and paralimbic GM regions and measures of functional outcome. Results: Among 384 male veterans recruited, 168 (mean [SD] age, 31.4 [7.4] years) were analyzed. Greater war zone-related stress was associated with lower FAT in the cingulate (DRRI-combat left: P = .002, partial r = -0.289; DRRI-combat right: P = .02, partial r = -0.216; DRRI-aftermath left: P = .004, partial r = -0.281; DRRI-aftermath right: P = .02, partial r = -0.219), orbitofrontal (DRRI-combat left medial orbitofrontal cortex: P = .02, partial r = -0.222; DRRI-combat right medial orbitofrontal cortex: P = .005, partial r = -0.256; DRRI-aftermath left medial orbitofrontal cortex: P = .02, partial r = -0.214; DRRI-aftermath right medial orbitofrontal cortex: P = .005, partial r = -0.260; DRRI-aftermath right lateral orbitofrontal cortex: P = .03, partial r = -0.196), and parahippocampal (DRRI-aftermath right: P = .03, partial r = -0.191) gyrus, as well as with higher FAT in the amygdala-hippocampus complex (DRRI-combat: P = .005, partial r = 0.254; DRRI-aftermath: P = .02, partial r = 0.223). Lower FAT in the cingulate-orbitofrontal gyri was associated with impaired response inhibition (Stroop-IS left cingulate: P < .001, partial r = -0.440; Stroop-IS right cingulate: P < .001, partial r = -0.372; Stroop-IS left medial orbitofrontal cortex: P < .001, partial r = -0.304; Stroop-IS right medial orbitofrontal cortex: P < .001, partial r = -0.340; Stroop-IN left cingulate: P < .001, partial r = -0.421; Stroop-IN right cingulate: P < .001, partial r = -0.300; Stroop-IN left medial orbitofrontal cortex: P = .01, partial r = -0.223; Stroop-IN right medial orbitofrontal cortex: P < .001, partial r = -0.343), whereas higher FAT in the mesial temporal regions was associated with improved short-term memory and processing speed (left amygdala-hippocampus complex: P < .001, partial r = -0.574; right amygdala-hippocampus complex: P < .001, partial r = 0.645; short-term memory left amygdala-hippocampus complex: P < .001, partial r = 0.570; short-term memory right amygdala-hippocampus complex: P < .001, partial r = 0.633). A history of mTBI did not modulate the association between war zone-related stress and GM diffusion. Conclusions and Relevance: This study revealed an association between war zone-related stress and alteration of limbic GM microstructure, which was associated with cognitive functioning. These results suggest that altered limbic GM microstructure may underlie the deleterious outcomes of war zone-related stress on brain health. Military service members may benefit from early therapeutic interventions after deployment to a war zone.
Zhang W, Paatero J, Leppänen A-P, Møller B, Jensen LK, Gudnason K, Sofiev M, Anderson Pål, Sickel M, Burakowska A, et al. Evaluation of 137Cs, 133Xe and 3H Activity Concentrations Monitored in the Arctic Atmosphere. J Environ Radioact. 2022;253-254 :107013.Abstract
This paper provides a brief introduction to the Arctic atmospheric radioactivity monitoring network. A decade of monitoring results have shown the 137Cs background levels in Arctic air range from 0.05 to 1.50 μBq/m3. The monitoring stations have sufficient sensitivity to detect 137Cs brought to the atmosphere due to resuspension in local soil and reemissions from biomass burning in a daily temporal resolution. These observations can be used as tracers for atmospheric processes. The 133Xe measurements obtained at Yellowknife, Resolute and Spitsbergen could support other research into how air pollution problems arise across intercontinental distances. It will help develop and improve models capable of predicting the long-distance transport and deposition of trace gases in the Arctic. Rainwater monitoring data collected in Finnish Lapland since the 1960's indicate that 3H radioactivity concentrations reached natural background levels in early 2000s, typically around 1-2 Bq/L monthly, with an annual seasonal variation cycle consistent with the observed of other cosmogenic radionuclides.
Spotorno N, Strandberg O, Vis G, Stomrud E, Nilsson M, Hansson O. Measures of Cortical Microstructure Are Linked to Amyloid Pathology in Alzheimer's Disease. Brain. 2022.Abstract
Markers of downstream events are a key component of clinical trials of disease-modifying therapies for Alzheimer's disease. Morphological metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ-related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion-MRI can provide sensitive markers of cortical microstructural changes and to test their associations with multiple aspects of the Alzheimer's disease pathological cascade, including both Aβ and tau accumulation, astrocytic activation and cognitive deficits. We applied the mean apparent diffusion propagator model to diffusion-MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER-2 cohort. Participants were stratified in Aβ-negative/tau-negative, Aβ-positive/tau-negative, and Aβ-positive/tau-positive based on Aβ- and tau-PET uptake. Cortical regional values of diffusion-MRI metrics and cortical thickness were compared across groups. Associations between regional values of diffusion-MRI metrics and both Aβ- and tau-PET uptake were also investigated along with the association with plasma level of glial fibrillary acidic protein (GFAP), a marker of astrocytes activation (available in 292 participants). Mean squared displacement revealed widespread microstructural differences already between Aβ-negative/tau-negative and Aβ-positive/tau-negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness were clearly more limited. Mean squared displacement was also correlated with both Aβ- and tau-PET uptake even independently from one another and from cortical thickness. Further, the same metric exhibited significantly stronger correlations with PET uptake than cortical thickness (p < 0.05). Mean squared displacement was also positively correlated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ accumulation and mean squared displacement. Further, impairments in executive functions were significantly more associated with mean squared displacement values extracted from a meta-ROI encompassing regions accumulating Aβ early in the disease process, than with cortical thickness (p < 0.05). Similarly, impairments in memory functions were significantly more associated with mean squared displacement values extracted from a temporal meta-ROI, than with cortical thickness (p < 0.05). Metrics of cortical microstructural alteration derived from diffusion-MRI are highly sensitive to multiple aspects of the Alzheimer's disease pathological cascade. Of particular interest is the link with both Aβ-PET and GFAP suggesting diffusion-MRI might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, metrics of cortical diffusion might be important outcome measures in anti-Aβ treatments clinical trials for detecting drug-induced changes in cortical microstructure.
Dolliver WR, Wang W, Nardelli P, Rahaghi FN, Orejas JL, Maselli DJ, Yen A, Young K, Kinney G, San José Estépar R, et al. Pulmonary Arterial Pruning Is Associated With CT-Derived Bronchiectasis Progression in Smokers. Respir Med. 2022;202 :106971.Abstract
Loss of small pulmonary arteries measured as the ratio of blood vessel volume in arteries <5 mm2 in cross-section to total arterial blood vessel volume (BV5a/TBVa), with lower values indicating more pruning, was associated with 5-yr progressing CT-derived bronchiectasis in smokers (Odds Ratio (OR) [95% Confidence interval], 1.28 [1.07-1.53] per 5% lower BV5a/TBVa, P = 0.007). Corresponding results in smokers with COPD were: OR 1.45 [1.11-1.89] per 5% lower BV5a/TBVa, P = 0.007. The results support a vascular factor for structural progression of bronchiectasis.
Irimia A, Ngo V, Chaudhari NN, Zhang F, Joshi SH, Penkova AN, O'Donnell LJ, Sheikh-Bahaei N, Zheng X, Chui HC. White Matter Degradation Near Cerebral Microbleeds Is Associated With Cognitive Change After Mild Traumatic Brain Injury. Neurobiol Aging. 2022;120 :68-80.Abstract
To explore how cerebral microbleeds (CMBs) accompanying mild traumatic brain injury (mTBI) reflect white matter (WM) degradation and cognitive decline, magnetic resonance images were acquired from 62 mTBI adults (imaged ∼7 days and ∼6 months post-injury) and 203 matched healthy controls. On average, mTBI participants had a count of 2.7 ± 2.6 traumatic CMBs in WM, located 6.1 ± 4.4 mm from cortex. At ∼6-month follow-up, 97% of CMBs were associated with significant reductions (34% ± 11%, q < 0.05) in the fractional anisotropy of WM streamlines within ∼1 cm of CMB locations. Male sex and older age were significant risk factors for larger reductions (q < 0.05). For CMBs in the corpus callosum, cingulum bundle, inferior and middle longitudinal fasciculi, fractional anisotropy changes were significantly and positively associated with changes in cognitive functions mediated by these structures (q < 0.05). Our findings distinguish traumatic from non-traumatic CMBs by virtue of surrounding WM alterations and challenge the assumption that traumatic CMBs are neurocognitively silent. Thus, mTBI with CMB findings can be described as a clinical endophenotype warranting longitudinal cognitive assessment.
Rajabally YA, Ouaja R, Kasiborski F, Pujol S, Nobile-Orazio E. Assessment Timing and Choice of Outcome Measure in Determining Treatment Response in Chronic Inflammatory Demyelinating Polyneuropathy: A Post-Hoc Analysis of the PRISM Trial. Muscle Nerve. 2022.Abstract
INTRODUCTION/AIMS: Treatment response and its timing are variable in chronic inflammatory demyelinating polyneuropathy (CIDP). We here aimed to study this variability with multiple outcome measures. METHODS: We performed a post-hoc analysis of the PRISM trial, a 24-week prospective, multicenter, single-arm, open-label, phase 3 study of a 10% intravenous immunoglobulin preparation for CIDP. We ascertained timing of response with primary/secondary outcome measures. RESULTS: At 6 weeks post-treatment initiation, 13/40 subjects (32.5%) were defined as responders on the primary outcome measure, the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) scale. This increased to 20/41 (48.8%) at 12 weeks and to 32/42 (76.2%) at 24 weeks. Use of minimal important difference (MID)-determined amelioration of the inflammatory Rasch-built Overall Disability Scale (I-RODS), or of the Medical Research Council Sum Score (MRCSS), or of dominant hand grip strength, in addition to the adjusted INCAT, offered a sensitivity of 41.7% in identifying adjusted INCAT non-responders at week 12 who subsequently responded at week 24. Specificity was 60% versus INCAT non-responders at week 24. Consideration of amelioration of any amplitude on any secondary outcome measure offered a 75% sensitivity but only 30% specificity versus adjusted INCAT non-responders at week 24. DISCUSSION: Immunoglobulin treatment continuation may be justified for up to 24 weeks in CIDP. Additional outcome measures may help in early treatment stages to predict delayed response on the adjusted INCAT. However, their use is limited by high false-positive rates. More robust, reliable and relevant outcome measures are needed to detect early improvement in immunoglobulin-treated CIDP. This article is protected by copyright. All rights reserved.
Langhein M, Lyall AE, Steinmann S, Seitz-Holland J, Nägele FL, Cetin-Karayumak S, Zhang F, Rauh J, Mußmann M, Billah T, et al. The Decoupling of Structural and Functional Connectivity of Auditory Networks in Individuals at Clinical High-Risk for Psychosis. World J Biol Psychiatry. 2022 :1-13.Abstract
Objectives: Disrupted auditory networks play an important role in the pathophysiology of psychosis, with abnormalities already observed in individuals at clinical high-risk for psychosis (CHR). Here, we examine structural and functional connectivity of an auditory network in CHR utilising state-of-the-art electroencephalography and diffusion imaging techniques.Methods: Twenty-six CHR subjects and 13 healthy controls (HC) underwent diffusion MRI and electroencephalography while performing an auditory task. We investigated structural connectivity, measured as fractional anisotropy in the Arcuate Fasciculus (AF), Cingulum Bundle, and Superior Longitudinal Fasciculus-II. Gamma-band lagged-phase synchronisation, a functional connectivity measure, was calculated between cortical regions connected by these tracts.Results: CHR subjects showed significantly higher structural connectivity in the right AF than HC (p < .001). Although non-significant, functional connectivity between cortical areas connected by the AF was lower in CHR than HC (p = .078). Structural and functional connectivity were correlated in HC (p = .056) but not in CHR (p = .29).Conclusions: We observe significant differences in structural connectivity of the AF, without a concomitant significant change in functional connectivity in CHR subjects. This may suggest that the CHR state is characterised by a decoupling of structural and functional connectivity, possibly due to abnormal white matter maturation.
Chakwizira A, Westin C-F, Brabec J, Lasič S, Knutsson L, Szczepankiewicz F, Nilsson M. Diffusion MRI With Pulsed and Free Gradient Waveforms: Effects of Restricted Diffusion and Exchange. NMR Biomed. 2022 :e4827.Abstract
Monitoring time dependence with diffusion MRI yields observables sensitive to compartment sizes (restricted diffusion) and membrane permeability (water exchange). However, restricted diffusion and exchange have opposite effects on the diffusion-weighted signal, which can lead to errors in parameter estimates. In this work, we propose a signal representation that incorporates the effects of both restricted diffusion and exchange up to second order in b-value and is compatible with gradient waveforms of arbitrary shape. The representation features mappings from a gradient waveform to two scalars that separately control the sensitivity to restriction and exchange. We demonstrate that these scalars span a two-dimensional space that can be used to choose waveforms that selectively probe restricted diffusion or exchange, eliminating the correlation between the two phenomena. We found that waveforms with specific but unconventional shapes provide an advantage over conventional pulsed and oscillating gradient acquisitions. We also show that parametrization of waveforms into a two-dimensional space can be used to understand protocols from other approaches that probe restricted diffusion and exchange. For example, we found that the variation of mixing time in filter-exchange imaging corresponds to variation of our exchange-weighting scalar at a fixed value of the restriction-weighting scalar. The proposed signal representation was evaluated using Monte Carlo simulations in identical parallel cylinders with hexagonal and random packing as well as parallel cylinders with gamma-distributed radii. Results showed that the approach is sensitive to sizes in the interval 4-12 μm $$ \upmu \mathrm{m} $$ and exchange rates in the simulated range of 0 to 20 s - 1 $$ {\mathrm{s}}^{-1} $$ , but also that there is a sensitivity to the extracellular geometry. The presented theory constitutes a simple and intuitive description of how restricted diffusion and exchange influence the signal as well as a guide to protocol design capable of separating the two effects.
Heller C, Kimmig A-CS, Kubicki MR, Derntl B, Kikinis Z. Imaging the Human Brain on Oral Contraceptives: A Review of Structural Imaging Methods and Implications for Future Research Goals. Front Neuroendocrinol. 2022;67 :101031.Abstract
Worldwide over 150 million women use oral contraceptives (OCs), which are the most prescribed form of contraception in both the United States and in European countries. Sex hormones, such as estradiol and progesterone, are important endogenous hormones known for shaping the brain across the life span. Synthetic hormones, which are present in OCs, interfere with the natural hormonal balance by reducing the endogenous hormone levels. Little is known how this affects the brain, especially during the most vulnerable times of brain maturation. Here, we review studies that investigate differences in brain gray and white matter in women using OCs in comparison to naturally cycling women. We focus on two neuroimaging methods used to quantify structural gray and white matter changes, namely structural MRI and diffusion MRI. Finally, we discuss the potential of these imaging techniques to advance knowledge about the effects of OCs on the brain and wellbeing in women.
Seitz-Holland J, Wojcik JD, Cetin-Karayumak S, Lyall AE, Pasternak O, Rathi Y, Vangel M, Pearlson G, Tamminga C, Sweeney JA, et al. Cognitive Deficits, Clinical Variables, and White Matter Microstructure in Schizophrenia: A Multisite Harmonization Study. Mol Psychiatry. 2022.Abstract
Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).
Rodriguez GG, Yu Z, O Donnell LF, Calderon L, Cloos MA, Madelin G. Repeatability of Simultaneous 3D H MRF/Na MRI in Brain at 7T. Sci Rep. 2022;12 (1) :14156.Abstract
Proton MRI can provide detailed morphological images, but it reveals little information about cell homeostasis. On the other hand, sodium MRI can provide metabolic information but cannot resolve fine structures. The complementary nature of proton and sodium MRI raises the prospect of their combined use in a single experiment. In this work, we assessed the repeatability of normalized proton density (PD), T1, T2, and normalized sodium density-weighted quantification measured with simultaneous 3D 1H MRF/23Na MRI in the brain at 7 T, from ten healthy volunteers who were scanned three times each. The coefficients of variation (CV) and the intra-class correlation (ICC) were calculated for the mean and standard deviation (SD) of these 4 parameters in grey matter, white matter, and cerebrospinal fluid. As result, the CVs were lower than 3.3% for the mean values and lower than 6.9% for the SD values. The ICCs were higher than 0.61 in all 24 measurements. We conclude that the measurements of normalized PD, T1, T2, and normalized sodium density-weighted from simultaneous 3D 1H MRF/23Na MRI in the brain at 7 T showed high repeatability. We estimate that changes > 6.6% (> 2 CVs) in mean values of both 1H and 23Na metrics could be detectable with this method.
Alosco ML, Tripodis Y, Baucom ZH, Adler CH, Balcer LJ, Bernick C, Mariani ML, Au R, Banks SJ, Barr WB, et al. White Matter Hyperintensities in Former American Football Players. Alzheimers Dement. 2022.Abstract
INTRODUCTION: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION: In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.
Masquelin AH, Alshaabi T, Cheney N, San José Estépar R, Bates JHT, Kinsey MC. Perinodular Parenchymal Features Improve Indeterminate Lung Nodule Classification. Acad Radiol. 2022.Abstract
BACKGROUND: Radiomics, defined as quantitative features extracted from images, provide a non-invasive means of assessing malignant versus benign pulmonary nodules. In this study, we evaluate the consistency with which perinodular radiomics extracted from low-dose computed tomography images serve to identify malignant pulmonary nodules. MATERIALS AND METHODS: Using the National Lung Screening Trial (NLST), we selected individuals with pulmonary nodules between 4mm to 20mm in diameter. Nodules were segmented to generate four distinct datasets; 1) a Tumor dataset containing tumor-specific features, 2) a 10 mm Band dataset containing parenchymal features between the segmented nodule boundary and 10mm out from the boundary, 3) a 15mm Band dataset, and 4) a Tumor Size dataset containing the maximum nodule diameter. Models to predict malignancy were constructed using support-vector machine (SVM), random forest (RF), and least absolute shrinkage and selection operator (LASSO) approaches. Ten-fold cross validation with 10 repetitions per fold was used to evaluate the performance of each approach applied to each dataset. RESULTS: With respect to the RF, the Tumor, 10mm Band, and 15mm Band datasets achieved areas under the receiver-operator curve (AUC) of 84.44%, 84.09%, and 81.57%, respectively. Significant differences in performance were observed between the Tumor and 15mm Band datasets (adj. p-value <0.001). However, when combining tumor-specific features with perinodular features, the 10mm Band + Tumor and 15mm Band + Tumor datasets (AUC 87.87% and 86.75%, respectively) performed significantly better than the Tumor Size dataset (66.76%) or the Tumor dataset. Similarly, the AUCs from the SVM and LASSO were 84.71% and 88.91%, respectively, for the 10mm Band + Tumor. CONCLUSIONS: The combined 10mm Band + Tumor dataset improved the differentiation between benign and malignant lung nodules compared to the Tumor datasets across all methodologies. This demonstrates that parenchymal features capture novel diagnostic information beyond that present in the nodule itself. (data agreement: NLST-163).
Lefebvre TL, Ueno Y, Dohan A, Chatterjee A, Vallières M, Winter-Reinhold E, Saif S, Levesque IR, Zeng XZ, Forghani R, et al. Development and Validation of Multiparametric MRI-based Radiomics Models for Preoperative Risk Stratification of Endometrial Cancer. Radiology. 2022 :212873.Abstract
Background Stratifying high-risk histopathologic features in endometrial carcinoma is important for treatment planning. Radiomics analysis at preoperative MRI holds potential to identify high-risk phenotypes. Purpose To evaluate the performance of multiparametric MRI three-dimensional radiomics-based machine learning models for differentiating low- from high-risk histopathologic markers-deep myometrial invasion (MI), lymphovascular space invasion (LVSI), and high-grade status-and advanced-stage endometrial carcinoma. Materials and Methods This dual-center retrospective study included women with histologically proven endometrial carcinoma who underwent 1.5-T MRI before hysterectomy between January 2011 and July 2015. Exclusion criteria were tumor diameter less than 1 cm, missing MRI sequences or histopathology reports, neoadjuvant therapy, and malignant neoplasms other than endometrial carcinoma. Three-dimensional radiomics features were extracted after tumor segmentation at MRI (T2-weighted, diffusion-weighted, and dynamic contrast-enhanced MRI). Predictive features were selected in the training set with use of random forest (RF) models for each end point, and trained RF models were applied to the external test set. Five board-certified radiologists conducted MRI-based staging and deep MI assessment in the training set. Areas under the receiver operating characteristic curve (AUCs) were reported with balanced accuracies, and radiologists' readings were compared with radiomics with use of McNemar tests. Results In total, 157 women were included: 94 at the first institution (training set; mean age, 66 years ± 11 [SD]) and 63 at the second institution (test set; 67 years ± 12). RF models dichotomizing deep MI, LVSI, high grade, and International Federation of Gynecology and Obstetrics (FIGO) stage led to AUCs of 0.81 (95% CI: 0.68, 0.88), 0.80 (95% CI: 0.67, 0.93), 0.74 (95% CI: 0.61, 0.86), and 0.84 (95% CI: 0.72, 0.92), respectively, in the test set. In the training set, radiomics provided increased performance compared with radiologists' readings for identifying deep MI (balanced accuracy, 86% vs 79%; P = .03), while no evidence of a difference was observed in performance for advanced FIGO stage (80% vs 78%; P = .27). Conclusion Three-dimensional radiomics can stratify patients by using preoperative MRI according to high-risk histopathologic end points in endometrial carcinoma and provide nonsignificantly different or higher performance than radiologists in identifying advanced stage and deep myometrial invasion, respectively. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Kido and Nishio in this issue.
Seitz-Holland J, Nägele FL, Kubicki M, Pasternak O, Cho KIK, Hough M, Mulert C, Shenton ME, Crow TJ, James ACD, et al. Shared and Distinct White Matter Abnormalities in Adolescent-Onset Schizophrenia and Adolescent-Onset Psychotic Bipolar Disorder. Psychol Med. 2022 :1-13.Abstract
BACKGROUND: While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. METHODS: Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. RESULTS: Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.
Wang S, Zhang F, Huang P, Hong H, Jiaerken Y, Yu X, Zhang R, Zeng Q, Zhang Y, Kikinis R, et al. Superficial White Matter Microstructure Affects Processing Speed in Cerebral Small Vessel Disease. Hum Brain Mapp. 2022.Abstract
White matter hyperintensities (WMH) are a typical feature of cerebral small vessel disease (CSVD), which contributes to about 50% of dementias worldwide. Microstructural alterations in deep white matter (DWM) have been widely examined in CSVD. However, little is known about abnormalities in superficial white matter (SWM) and their relevance for processing speed, the main cognitive deficit in CSVD. In 141 CSVD patients, processing speed was assessed using Trail Making Test Part A. White matter abnormalities were assessed by WMH burden (volume on T2-FLAIR) and diffusion MRI measures. SWM imaging measures had a large contribution to processing speed, despite a relatively low SWM WMH burden. Across all imaging measures, SWM free water (FW) had the strongest association with processing speed, followed by SWM mean diffusivity (MD). SWM FW was the only marker to significantly increase between two subgroups with the lowest WMH burdens. When comparing two subgroups with the highest WMH burdens, the involvement of WMH in the SWM was accompanied by significant differences in processing speed and white matter microstructure. Mediation analysis revealed that SWM FW fully mediated the association between WMH volume and processing speed, while no mediation effect of MD or DWM FW was observed. Overall, results suggest that the SWM has an important contribution to processing speed, while SWM FW is a sensitive imaging marker associated with cognition in CSVD. This study extends the current understanding of CSVD-related dysfunction and suggests that the SWM, as an understudied region, can be a potential target for monitoring pathophysiological processes.
Langhein M, Seitz-Holland J, Lyall AE, Pasternak O, Chunga-Iturry N, Cetin Karayumak S, Kubicki A, Mulert C, Espinoza RT, Narr KL, et al. Association Between Peripheral Inflammation and Free-Water Imaging in Major Depressive Disorder Before and After Ketamine Treatment - a Pilot Study. J Affect Disord. 2022;314 :78-85.Abstract
BACKGROUND: Alterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD. METHODS: Ten individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion. RESULTS: The MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043). LIMITATIONS: The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD. CONCLUSIONS: This pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment.
De Luca A, Cetin Karayumak S, Leemans A, Rathi Y, Swinnen S, Gooijers J, Clauwaert A, Bahr R, Sandmo SB, Sochen N, et al. Cross-Site Harmonization of Multi-Shell Diffusion MRI Measures Based on Rotational Invariant Spherical Harmonics (RISH). Neuroimage. 2022;259 :119439.Abstract
Quantification methods based on the acquisition of diffusion magnetic resonance imaging (dMRI) with multiple diffusion weightings (e.g., multi-shell) are becoming increasingly applied to study the in-vivo brain. Compared to single-shell data for diffusion tensor imaging (DTI), multi-shell data allows to apply more complex models such as diffusion kurtosis imaging (DKI), which attempts to capture both diffusion hindrance and restriction effects, or biophysical models such as NODDI, which attempt to increase specificity by separating biophysical components. Because of the strong dependence of the dMRI signal on the measurement hardware, DKI and NODDI metrics show scanner and site differences, much like other dMRI metrics. These effects limit the implementation of multi-shell approaches in multicenter studies, which are needed to collect large sample sizes for robust analyses. Recently, a post-processing technique based on rotation invariant spherical harmonics (RISH) features was introduced to mitigate cross-scanner differences in DTI metrics. Unlike statistical harmonization methods, which require repeated application to every dMRI metric of choice, RISH harmonization is applied once on the raw data, and can be followed by any analysis. RISH features harmonization has been tested on DTI features but not its generalizability to harmonize multi-shell dMRI. In this work, we investigated whether performing the RISH features harmonization of multi-shell dMRI data removes cross-site differences in DKI and NODDI metrics while retaining longitudinal effects. To this end, 46 subjects underwent a longitudinal (up to 3 time points) two-shell dMRI protocol at 3 imaging sites. DKI and NODDI metrics were derived before and after harmonization and compared both at the whole brain level and at the voxel level. Then, the harmonization effects on cross-sectional and on longitudinal group differences were evaluated. RISH features averaged for each of the 3 sites exhibited prominent between-site differences in the frontal and posterior part of the brain. Statistically significant differences in fractional anisotropy, mean diffusivity and mean kurtosis were observed both at the whole brain and voxel level between all the acquisition sites before harmonization, but not after. The RISH method also proved effective to harmonize NODDI metrics, particularly in white matter. The RISH based harmonization maintained the magnitude and variance of longitudinal changes as compared to the non-harmonized data of all considered metrics. In conclusion, the application of RISH feature based harmonization to multi-shell dMRI data can be used to remove cross-site differences in DKI metrics and NODDI analyses, while retaining inherent relations between longitudinal acquisitions.
Giganti F, Cole AP, Fennessy FM, Clinton T, Moreira PLDF, Bernardes MC, Westin C-F, Krishnaswamy D, Fedorov A, Wollin DA, et al. Promoting the use of the PI-QUAL score for prostate MRI quality: results from the ESOR Nicholas Gourtsoyiannis teaching fellowship. Eur Radiol. 2022 :1-11.Abstract
OBJECTIVES: The Prostate Imaging Quality (PI-QUAL) score is a new metric to evaluate the diagnostic quality of multiparametric magnetic resonance imaging (MRI) of the prostate. This study assesses the impact of an intervention, namely a prostate MRI quality training lecture, on the participant's ability to apply PI-QUAL. METHODS: Sixteen participants (radiologists, urologists, physicists, and computer scientists) of varying experience in reviewing diagnostic prostate MRI all assessed the image quality of ten examinations from different vendors and machines. Then, they attended a dedicated lecture followed by a hands-on workshop on MRI quality assessment using the PI-QUAL score. Five scans assessed by the participants were evaluated in the workshop using the PI-QUAL score for teaching purposes. After the course, the same participants evaluated the image quality of a new set of ten scans applying the PI-QUAL score. Results were assessed using receiver operating characteristic analysis. The reference standard was the PI-QUAL score assessed by one of the developers of PI-QUAL. RESULTS: There was a significant improvement in average area under the curve for the evaluation of image quality from baseline (0.59 [95 % confidence intervals: 0.50-0.66]) to post-teaching (0.96 [0.92-0.98]), an improvement of 0.37 [0.21-0.41] (p < 0.001). CONCLUSIONS: A teaching course (dedicated lecture + hands-on workshop) on PI-QUAL significantly improved the application of this scoring system to assess the quality of prostate MRI examinations. KEY POINTS: • A significant improvement in the application of PI-QUAL for the assessment of prostate MR image quality was observed after an educational intervention. • Appropriate training on image quality can be delivered to those involved in the acquisition and interpretation of prostate MRI. • Further investigation will be needed to understand the impact on improving the acquisition of high-quality diagnostic prostate MR examinations.

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