Microstructural Tissue Changes in Alzheimer Disease Brains: Insights from Magnetization Transfer Imaging

BACKGROUND AND PURPOSE:Reductions in magnetization transfer ratio have been associated with brain microstructural damage. We aim to compare magnetization transfer ratio in global and regional GM and WM between individuals with Alzheimer disease and healthy control participants to analyze the relationship between magnetization transfer ratio and cognitive functioning in Alzheimer disease.MATERIALS AND METHODS:In this prospective study, participants with Alzheimer disease and a group of age-matched healthy control participants underwent clinical examinations and 3T MR imaging. Magnetization transfer ratios were determined in the cortex, AD-signature regions, normal-appearing WM, and WM hyperintensities.RESULTS:Seventy-seven study participants (mean age ± SD, 72 ± 8 years; 47 female) and 77 age-matched healthy control participants (mean age ± SD, 72 ± 8 years; 44 female) were evaluated. Magnetization transfer ratio values were lower in patients with Alzheimer disease than in healthy control participants in all investigated regions. When adjusting for atrophy and extent of WM hyperintensities, significant differences were seen in the global cortex (OR = 0.47; 95% CI: 0.22, 0.97; P = .04), in Alzheimer disease–signature regions (OR = 0.31; 95% CI: 0.14, 0.67; P = .003), in normal-appearing WM (OR = 0.59; 95% CI: 0.39, 0.88; P = .01), and in WM hyperintensities (OR = 0.18; 95% CI: 0.09, 0.33; P ≤ .001). The magnetization transfer ratio in these regions was an independent determinant of AD. When correcting for atrophy and WM hyperintensity extent, lower GM magnetization transfer ratios were associated with poorer global cognition, language function, and constructional praxis.CONCLUSIONS:Alzheimer disease is associated with magnetization transfer ratio reductions in GM and WM regions of the brain. Lower magnetization transfer ratios in the entire cortex and AD-signature regions contribute to cognitive impairment independent of brain atrophy and WM damage.

Alzheimer disease (AD) represents the most common cause of dementia. Only a few neuroimaging biomarkers have been approved for clinical use, and most are still objects of research.¹ Although structural MR imaging contributes to the exclusion of other possible causes of a dementia syndrome, brain atrophy measures have only modest sensitivity and specificity for the differential diagnosis of dementia.² The role of MR imaging techniques that allow assessment of microstructural brain changes, such as DTI and magnetization transfer imaging (MTI) for detecting AD-related tissue abnormalities, is still widely unknown. Numerous DTI studies have reported loss of WM integrity in AD and related this to tau accumulation in AD-specific regions.³ Only a few studies used MTI to explore microstructural tissue abnormalities in AD.The magnetization transfer ratio (MTR), which can be derived from MTI, has been shown to be associated with axonal attenuation and myelin content.^4-6 In patients with AD, MTR reductions were reported in the whole-brain analyses,^7-9 cortical GM,^8,10 global WM,¹⁰ hippocampus,^7,11,12 and temporal lobes.⁸ In a longitudinal study of our own group, patients with AD had significantly lower global MTR values than control participants. MTR declined significantly over a follow-up period of 12 months and was paralleled by a brain tissue loss of 2.2% per year.¹³ So far, only a few studies have explored the association between regional MTR changes and cognition in patients with AD. Van der Flier et al⁹ reported a strong association between whole-brain MTR and global cognitive deterioration in patients with AD, but there was no significant relationship between regional MTR reductions and domain-specific cognitive impairment. In our previous study, we observed direct associations between MTR and Mini-Mental State Examination (MMSE) scores for the hippocampus, putamen, and thalamus. The relationship was stronger in the left than in the right hemisphere.¹³Here we extend previous work by assessing the role of MTR reductions in the GM and WM in distinguishing patients with mild to moderate AD from healthy control participants, and we investigate their associations with cognitive decline independent of atrophy and WM damage.     

Longitudinal Assessment of Enhancing Foci of Abnormal Signal Intensity in Neurofibromatosis Type 1

BACKGROUND AND PURPOSE:Patients with neurofibromatosis 1 are at increased risk of developing brain tumors, and differentiation from contrast-enhancing foci of abnormal signal intensity can be challenging. We aimed to longitudinally characterize rare, enhancing foci of abnormal signal intensity based on location and demographics.MATERIALS AND METHODS:A total of 109 MR imaging datasets from 19 consecutive patients (7 male; mean age, 8.6 years; range, 2.3–16.8 years) with neurofibromatosis 1 and a total of 23 contrast-enhancing parenchymal lesions initially classified as foci of abnormal signal intensity were included. The mean follow-up period was 6.5 years (range, 1–13.8 years). Enhancing foci of abnormal signal intensity were followed up with respect to presence, location, and volume. Linear regression analysis was performed.RESULTS:Location, mean peak volume, and decrease in enhancing volume over time of the 23 lesions were as follows: 10 splenium of the corpus callosum (295 mm³, 5 decreasing, 3 completely resolving, 2 surgical intervention for change in imaging appearance later confirmed to be gangliocytoma and astrocytoma WHO II), 1 body of the corpus callosum (44 mm³, decreasing), 2 frontal lobe white matter (32 mm³, 1 completely resolving), 3 globus pallidus (50 mm³, all completely resolving), 6 cerebellum (206 mm³, 3 decreasing, 1 completely resolving), and 1 midbrain (34 mm³). On average, splenium lesions began to decrease in size at 12.2 years, posterior fossa lesions at 17.1 years, and other locations at 9.4 years of age.CONCLUSIONS:Albeit very rare, contrast-enhancing lesions in patients with neurofibromatosis 1 may regress over time. Follow-up MR imaging aids in ascertaining regression. The development of atypical features should prompt further evaluation for underlying tumors.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant tumor predisposition syndrome characterized by optic pathway gliomas, neurofibromas, skin manifestations, iris hamartomas, and bone lesions, affecting approximately 1 in 3000 individuals.^1,2 Foci of abnormal signal intensity, previously known as unidentified bright objects or neurofibromatosis bright objects of the brain, are not among the diagnostic criteria but can be found in 43%–95% of pediatric patients with NF-1.^3-7 On MR imaging, FASI appear as T2/FLAIR hyperintense lesions of the brain with a predilection for the basal ganglia, cerebellum, and brain stem. Although FASI are not completely understood, myelin vacuolization is commonly considered as an underlying feature of these lesions.^1,4,5,7-9Patients with NF-1 are at an increased risk of developing low- and high-grade brain tumors, including cerebral and cerebellar astrocytomas, ependymomas, and brain stem gliomas, many of which can mimic FASI on MR imaging.^3,10-14 On the other hand, FASI are known for their dynamic properties and may increase or decrease in size or resolve over time.⁸ Although the reference standard for differentiating brain lesions is transcranial biopsy with its own inherent risks, brain signal abnormalities in patients with NF-1 are primarily followed up by MR imaging to screen for possible tumors.^15-18 Contrast enhancement after administration of a gadolinium-based contrast agent is usually considered atypical for FASI and likely to indicate the presence of a brain tumor. Reports considering contrast enhancement in FASI are sparse, limited to case reports and small numbers in cohort studies.^3,6,19-29 We therefore aimed to characterize lesions considered to represent enhancing FASI based on location, volume of enhancement, and demographics to advance the understanding of these rare lesions.     

Automated Detection and Segmentation of Brain Metastases in Malignant Melanoma: Evaluation of a Dedicated Deep Learning Model

BACKGROUND AND PURPOSE:Malignant melanoma is an aggressive skin cancer in which brain metastases are common. Our aim was to establish and evaluate a deep learning model for fully automated detection and segmentation of brain metastases in patients with malignant melanoma using clinical routine MR imaging.MATERIALS AND METHODS:Sixty-nine patients with melanoma with a total of 135 brain metastases at initial diagnosis and available multiparametric MR imaging datasets (T1-/T2-weighted, T1-weighted gadolinium contrast-enhanced, FLAIR) were included. A previously established deep learning model architecture (3D convolutional neural network; DeepMedic) simultaneously operating on the aforementioned MR images was trained on a cohort of 55 patients with 103 metastases using 5-fold cross-validation. The efficacy of the deep learning model was evaluated using an independent test set consisting of 14 patients with 32 metastases. Manual segmentations of metastases in a voxelwise manner (T1-weighted gadolinium contrast-enhanced imaging) performed by 2 radiologists in consensus served as the ground truth.RESULTS:After training, the deep learning model detected 28 of 32 brain metastases (mean volume, 1.0 [SD, 2.4] cm³) in the test cohort correctly (sensitivity of 88%), while false-positive findings of 0.71 per scan were observed. Compared with the ground truth, automated segmentations achieved a median Dice similarity coefficient of 0.75.CONCLUSIONS:Deep learning–based automated detection and segmentation of brain metastases in malignant melanoma yields high detection and segmentation accuracy with false-positive findings of <1 per scan.

Malignant melanoma is an aggressive skin cancer associated with high mortality and morbidity rates.^1,2 Brain metastases are common in malignant melanoma,^3,4 subsequently causing potential severe neurologic impairment and worsened outcome. Therefore, it is recommended that melanoma patients with an advanced stage undergo MR imaging of the head for screening purposes to detect metastases.^5-8Owing to an increased workload of radiologists, repetitive evaluation of MR imaging scans can be tiresome, hence bearing an inherent risk of missed diagnosis for subtle lesions, with satisfaction of search effects leading to decreased sensitivity for additional lesions.^9,10 Automatization of detection could serve as an adjunct tool for lesion preselection that can support image evaluation by radiologists and clinicians.^11,12 Furthermore, automated segmentations may be used as a parameter to evaluate therapy response in oncologic follow-up imaging.^13,14 Additionally, exact lesion determination and delineation of size are required for stereotactic radiosurgery.^15,16 In clinical routine, brain lesions have to be segmented manually by the radiosurgeon. This task proves to be time-consuming, in particular if multiple metastases are present. Furthermore, manual segmentation is potentially hampered by interreader variabilities with reduced reproducibility, hence resulting in inaccuracies of lesion delineation.^17,18 In this context, accurate objective and automated segmentations of brain metastases would be highly beneficial.^17-19Recently, deep learning models (DLMs) have shown great potential in detection, segmentation and classification tasks in medical image analysis while having the potential to improve clinical workflow.^20-25 The models apply multiple processing layers that result in deep convolutional neural networks (CNNs). Training data are used to create complex feature hierarchies.^26-28 In general, a DLM includes different layers for convolution, pooling, and classification.²⁸ The required training data are supplied by manual segmentations, which usually serve as the segmentation criterion standard.^18,28,29Previous studies on brain metastases from different tumor entities have demonstrated promising results, reporting a sensitivity for automated deep learning–based detection of lesions of around 80% or higher.^17,30-32 However, the often reported relatively high number of false-positive findings questions their applicability in clinical routine.^17,30The purpose of this study was to develop and evaluate a DLM for automated detection and segmentation of brain metastases in patients with malignant melanoma using heterogeneous MR imaging data from multiple vendors and study centers.     

DTI Values in Key White Matter Tracts from Infancy through Adolescence

BACKGROUND AND PURPOSE:DTI is an advanced neuroimaging technique that allows in vivo quantification of water diffusion properties as surrogate markers of the integrity of WM microstructure. In our study, we investigated normative data from a large number of pediatric and adolescent participants to examine the developmental trends in DTI during this conspicuous WM maturation period.MATERIALS AND METHODS:DTI data in 202 healthy pediatric and adolescent participants were analyzed retrospectively. Fractional anisotropy and mean diffusivity values in the corpus callosum and internal capsule were fitted to an exponential regression model to delineate age-dependent maturational changes across the WM structures.RESULTS:The DTI metrics demonstrated characteristic exponential patterns of progression during development and conspicuous age-dependent changes in the first 36 months, with rostral WM tracts experiencing the highest slope of the exponential function. In contrast, the highest final FA and lowest MD values were detected in the splenium of the corpus callosum and the posterior limb of the internal capsule.CONCLUSIONS:Our analysis shows that the more caudal portions of the corpus callosum and internal capsule begin the maturation process earlier than the rostral regions, but the rostral regions develop at a more accelerated pace, which may suggest that rostral regions rely on development of more caudal brain regions to instigate their development. Our normative DTI can be used as a reference to study normal spatiotemporal developmental profiles in the WM and help identify abnormal WM structures in patient populations.

The behavioral, cognitive, and biologic changes associated with brain development and its aberrations remain poorly understood. The development and maturation of WM tracts during childhood and adolescence are intimately associated with these processes.^1,2 DTI has allowed quantification of the magnitude and direction of water diffusivity in the cerebral WM and, thus, the ability to investigate its development in better detail. Considerable evidence has shown that the diffusion of water in the human brain is a dynamic process, changing with brain maturation and structural integrity of WM. The emerging consensus is that the developing WM is characterized by intrinsic modifications, including an increase in the number of its constituent macromolecules and cytoskeletal microfilaments, and the extrinsic modification of axon caliber resulting in displacement and decrease in brain-water content.^3,4 In addition, constraining changes in tissue macrostructure, including increased WM packing and the activity of sodium channels, have been postulated to play a key role in increasing the nonrandom diffusion of water, or anisotropy.^4–7 These studies have demonstrated a positive correlation between the preferential directionality of water diffusion along WM tracts and age, whereas a negative correlation is demonstrated between the magnitude of water diffusion in specific WM tracts and age.⁶ The most widely adopted scalar DTI metrics to quantify these events are FA, which quantifies the degree of preferential restriction in water diffusion, and MD, which measures the overall magnitude of water diffusion. The quantification of these parameters by DTI has enabled clinicians to construct spatial representations of brain WM structures and to carefully examine their microarchitecture in the developing brain^4,8–10 and the mature brain.^11–13Along with an improved detection of age-related changes in water diffusion–based properties of WM tracts, recent studies have postulated that DTI may be clinically useful in evaluating brain pathologic findings and the subsequent therapeutic response by comparing WM diffusion changes with normative values.^14–16 Previous DTI studies of WM development have been limited by small numbers of pediatric patients, inclusion of data from multiple institutions, combination of adult and pediatric data, or inclusion of potentially biasing pathologies without further follow-up.^{4,8,13,17–22}The aim of our study was, thus, to report a representative dataset of normal age-related changes in FA and MD values detected in the developing brain, derived from 202 healthy participants ranging in age from birth to adolescence. We propose that these normative data represent true age-appropriate DTI values during the development of susceptible and critical WM tracts. The details of these developmental processes are crucial to better understand the mechanisms of WM development, maturation, and its aberrancies caused by various neurologic insults.     

Inversion Recovery Ultrashort TE MR Imaging of Myelin is Significantly Correlated with Disability in Patients with Multiple Sclerosis

BACKGROUND AND PURPOSE:MR imaging has been widely used for the noninvasive evaluation of MS. Although clinical MR imaging sequences are highly effective in showing focal macroscopic tissue abnormalities in the brains of patients with MS, they are not specific to myelin and correlate poorly with disability. We investigated direct imaging of myelin using a 2D adiabatic inversion recovery ultrashort TE sequence to determine its value in assessing disability in MS.MATERIALS AND METHODS:The 2D inversion recovery ultrashort TE sequence was evaluated in 14 healthy volunteers and 31 patients with MS. MPRAGE and T2-FLAIR images were acquired for comparison. Advanced Normalization Tools were used to correlate inversion recovery ultrashort TE, MPRAGE, and T2-FLAIR images with disability assessed by the Expanded Disability Status Scale.RESULTS:Weak correlations were observed between normal-appearing white matter volume (R = –0.03, P = .88), lesion load (R = 0.22, P = .24), and age (R = 0.14, P = .44), and disability. The MPRAGE signal in normal-appearing white matter showed a weak correlation with age (R = –0.10, P = .49) and disability (R = –0.19, P = .31). The T2-FLAIR signal in normal-appearing white matter showed a weak correlation with age (R = 0.01, P = .93) and disability (R = 0.13, P = .49). The inversion recovery ultrashort TE signal was significantly negatively correlated with age (R = –0.38, P = .009) and disability (R = –0.44; P = .01).CONCLUSIONS:Direct imaging of myelin correlates with disability in patients with MS better than indirect imaging of long-T2 water in WM using conventional clinical sequences.

MS is the most common demyelinating disease of the brain.¹ Demyelination affects many aspects of neurologic function, including speech, balance, and cognitive awareness. Across time, this frequently leads to severe and irreversible clinical disability. MR imaging has been widely used for accurate diagnosis of MS, with current techniques focused on imaging the long-T2 water components in WM and GM.^2-4 MS lesions often appear hypointense with T1-weighted gradient recalled-echo sequences² and hyperintense with T2-weighted FSE and T2-weighted FLAIR sequences.³ Active lesions can be highlighted with gadolinium-enhanced imaging.⁴ The magnetization transfer ratio has been used as an indirect marker of myelin disorder in regions of normal-appearing WM (NAWM).⁵ There are also several other advanced imaging techniques for indirect myelin imaging via assessment of myelin water, such as multicomponent T2 or T2* analysis^6,7 and direct visualization of components with short transverse relaxation times.^8,9While conventional MR imaging sequences are highly effective in detecting focal macroscopic brain tissue abnormalities, they are not specific for pathologic substrates of MS lesions such as demyelination and remyelination, and they may not correlate well with patients'' neurologic deficits. Current MR imaging techniques correlate only modestly with disability assessed by the Expanded Disability Status Scale (EDSS).^10-15 The total lesion load showed statistically significant-but-weak correlations with the EDSS score in several large-scale studies (R = 0.1–0.3).^10-12 Composite scores including relaxation times of different tissues and/or volumetric measures generally correlate more strongly with the EDSS score, with a maximum observed correlation of R = 0.34 (P < .001).¹³ Lesions seen with gadolinium-enhanced imaging are only moderately correlated with disability in the first 6 months and are not predictive of changes in the EDSS score in the subsequent 1 or 2 years.¹⁴ A large-scale multicenter study reported very limited correlation between the EDSS score and normalized brain volume (R = –0.18), cross-sectional area (R = –0.26), magnetization transfer ratio of whole-brain tissue (R = –0.16), and GM (R = –0.17).¹⁵The poor performance of conventional MR imaging sequences in assessing disability highlights the need for novel MR imaging techniques that can directly image myelin lipid and enable direct assessment of both myelin damage and repair. However, myelin has an extremely short transverse relaxation time and is not directly detectable with conventional MR images, which typically have TEs of several milliseconds or longer. Ultrashort TE (UTE) sequences can directly detect signal from myelin with ultrashort T2 (ie, excluding water with longer T2s).^16-21 In this study, we describe imaging of WM using a 2D adiabatic inversion recovery prepared UTE (IR-UTE) sequence in healthy volunteers and patients with MS and evaluate its performance in assessing disability in patients with MS compared with 2 conventional clinical sequences.     

Brain and Lung Imaging Correlation in Patients with COVID-19: Could the Severity of Lung Disease Reflect the Prevalence of Acute Abnormalities on Neuroimaging? A Global Multicenter Observational Study

PURPOSE:Our aim was to study the association between abnormal findings on chest and brain imaging in patients with coronavirus disease 2019 (COVID-19) and neurologic symptoms.MATERIALS AND METHODS:In this retrospective, international multicenter study, we reviewed the electronic medical records and imaging of hospitalized patients with COVID-19 from March 3, 2020, to June 25, 2020. Our inclusion criteria were patients diagnosed with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and available chest CT and brain imaging. The 5 lobes of the lungs were individually scored on a scale of 0–5 (0 corresponded to no involvement and 5 corresponded to >75% involvement). A CT lung severity score was determined as the sum of lung involvement, ranging from 0 (no involvement) to 25 (maximum involvement).RESULTS:A total of 135 patients met the inclusion criteria with 132 brain CT, 36 brain MR imaging, 7 MRA of the head and neck, and 135 chest CT studies. Compared with 86 (64%) patients without acute abnormal findings on neuroimaging, 49 (36%) patients with these findings had a significantly higher mean CT lung severity score (9.9 versus 5.8, P < .001). These patients were more likely to present with ischemic stroke (40 [82%] versus 11 [13%], P < .0001) and were more likely to have either ground-glass opacities or consolidation (46 [94%] versus 73 [84%], P = .01) in the lungs. A threshold of the CT lung severity score of >8 was found to be 74% sensitive and 65% specific for acute abnormal findings on neuroimaging. The neuroimaging hallmarks of these patients were acute ischemic infarct (28%), intracranial hemorrhage (10%) including microhemorrhages (19%), and leukoencephalopathy with and/or without restricted diffusion (11%). The predominant CT chest findings were peripheral ground-glass opacities with or without consolidation.CONCLUSIONS:The CT lung disease severity score may be predictive of acute abnormalities on neuroimaging in patients with COVID-19 with neurologic manifestations. This can be used as a predictive tool in patient management to improve clinical outcome.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) began in Wuhan, China, in December 2019 and has rapidly spread around the world to become a pandemic.¹ Extensive studies have described chest and brain imaging characteristics associated with coronavirus disease 2019 (COVID-19).^2-13 The hallmarks of COVID-19 infection on chest imaging are now well-established, including bilateral and peripheral ground-glass and consolidative pulmonary opacities.^2-5 COVID-19-related brain imaging findings such as ischemic infarcts, hemorrhages, and multiple patterns of leukoencephalopathy^6-13 are also well-known. The clinical symptomatology has been linked to the imaging findings with up to 47% of patients with COVID-19 with neurologic symptoms demonstrating acute neuroimaging findings⁶ and patients with high lung severity scores being admitted to the intensive care unit.³ The incidence of neurologic symptoms is higher in patients with more severe respiratory disease.^10,13 There is increasing evidence that patients with acute lung injury are at risk of brain injury through hypoxemia and/or proinflammatory mediators that connect both the brain and the lungs.^14-17 However, little information is available on the potential association between the prevalence of neuroimaging abnormalities and the severity of CT lung findings in patients with COVID-19. The objective of this study was to examine the association between chest and brain imaging abnormalities in patients with COVID-19. We hypothesized that the severity of lung disease may predict acute abnormalities on neuroimaging in patients with COVID-19 with neurologic symptoms.     

Tractography of the Cerebellar Peduncles in Second- and Third-Trimester Fetuses

BACKGROUND AND PURPOSE:Little is known about microstructural development of cerebellar white matter in vivo. This study aimed to investigate developmental changes of the cerebellar peduncles in second- and third-trimester healthy fetuses using motion-corrected DTI and tractography.MATERIALS AND METHODS:3T data of 81 healthy fetuses were reviewed. Structural imaging consisted of multiplanar T2-single-shot sequences; DTI consisted of a series of 12-direction diffusion. A robust motion-tracked section-to-volume registration algorithm reconstructed images. ROI-based deterministic tractography was performed using anatomic landmarks described in postnatal tractography. Asymmetry was evaluated qualitatively with a perceived difference of >25% between sides. Linear regression evaluated gestational age as a predictor of tract volume, ADC, and fractional anisotropy.RESULTS:Twenty-four cases were excluded due to low-quality reconstructions. Fifty-eight fetuses with a median gestational age of 30.6 weeks (interquartile range, 7 weeks) were analyzed. The superior cerebellar peduncle was identified in 39 subjects (69%), and it was symmetric in 15 (38%). The middle cerebellar peduncle was identified in all subjects and appeared symmetric; in 13 subjects (22%), two distinct subcomponents were identified. The inferior cerebellar peduncle was not found in any subject. There was a significant increase in volume for the superior cerebellar peduncle and middle cerebellar peduncle (both, P < .05), an increase in fractional anisotropy (both, P < .001), and a decrease in ADC (both, P < .001) with gestational age. The middle cerebellar peduncle had higher volume (P < .001) and fractional anisotropy (P = .002) and lower ADC (P < .001) than the superior cerebellar peduncle after controlling for gestational age.CONCLUSIONS:A robust motion-tracked section-to-volume registration algorithm enabled deterministic tractography of the superior cerebellar peduncle and middle cerebellar peduncle in vivo and allowed characterization of developmental changes.

In the second half of pregnancy, the cerebellum is growing rapidly and is extremely vulnerable.¹ Despite the increasingly recognized association of antenatal and perinatal cerebellar injury with adverse motor and neurologic outcomes later in life,^2-5 little is known about normal cerebellar developmental in the later part of gestation, in particular with regard to changes in microstructure. In fact, most existing fetal MR imaging data addresses primarily changes in cerebellar volume with gestational age (GA) or changes in volume and their association with specific diseases such as congenital heart disease.^6-8In vivo evaluation of cerebellar microstructure using fetal MR imaging has been limited by the technical challenges related to imaging the gravid abdomen, particularly patient motion. However, data from ex vivo MR imaging studies are promising. For instance, Takahashi et al^9,10 performed high-resolution ex vivo DTI of fetal specimens and demonstrated the feasibility of using tractography to outline the cerebellar peduncles prenatally. Even though tractography of the cerebellar peduncles has been sporadically reported in vivo in technical articles or general review articles on fetal DTI,¹¹ the GA-related microstructural changes that occur in the cerebellar peduncles in the second half of pregnancy remain largely unexplored.Recent advances in hardware and software have improved fetal MR imaging substantially. The use of 3T magnets, which have been shown to be safe, results in improvement of the SNR and spatial resolution, which is advantageous to image the small structures of the fetal brain.^12,13 In addition, postprocessing algorithms that enable reconstruction of motion-corrected fetal DTI data are increasingly available and have been used by several groups to characterize the development of the supratentorial white matter tracts in vivo.^14-16 We hypothesize that fetal DTI performed at 3T and processed with a robust section-to-volume motion-correction and registration¹⁴ algorithm will enable tractography of the cerebellar peduncles in fetuses in the second and third trimesters of pregnancy. We aimed to characterize fetal cerebellar tract microstructure and to investigate tract-specific developmental changes.     

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS

BACKGROUND AND PURPOSE:MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations.MATERIALS AND METHODS:Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM.RESULTS:The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions.CONCLUSIONS:NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Conventional MR imaging is essential for MS diagnosis and management, specifically for demonstrating WM lesion dissemination in space (involvement of >1 CNS region) and time (across time accumulation).¹ Conventional MR imaging, however, lacks specificity in characterizing MS WM lesions after the acute phase; all lesions show a similar radiologic appearance on T2WI, irrespective of the degree of inflammation, axonal loss, gliosis, demyelination, and remyelination.^2,3 Furthermore, clinical disability shows limited correlation with volume and the number of detectable WM lesions. The different neuropathologic characteristics of WM lesions as well as the accumulation of tissue damage within normal-appearing WM (NAWM) are some of the other factors possibly playing a role in the development of MS disability.⁴Gadolinium-based imaging improves the utility of conventional MR imaging in MS because gadolinium-enhancing lesions (GELs) represent a radiologic correlate of acute inflammation, corresponding to active lesions associated with blood-brain barrier disruption. However, despite its importance for diagnosis (fulfillment of dissemination in time criteria), the application of gadolinium-based contrast agents has raised a number of safety concerns.⁵ Therefore, alternative MR imaging markers of acute inflammation are needed.Neurite orientation dispersion and density imaging (NODDI) is a clinically feasible diffusion MR imaging technique, incorporating multiple shells with different b-values to model brain tissue into 3 compartments showing different diffusion properties.⁶ According to this orientation-dispersed cylindric model, the isotropic diffusion fraction is highly represented only within CSF, whereas within brain parenchyma, the diffusion signal can be either hindered (Gaussian displacement pattern) or restricted (non-Gaussian displacement pattern). The hindered signal is attributed to the extra-neurite compartment (VEC), defining the extracellular volume fraction whereas the restricted signal is attributed to intraneurite spaces and is thought to correspond to the neurite density index (NDI). A Watson distribution is then used to compute the orientation distribution of the cylinders, quantified from 0 to 1 by the orientation dispersion index (ODI). Highly compacted and parallel WM bundles, such as the corpus callosum, generally show lower ODI values compared with the cortical and subcortical regions, characterized by multidirectional dendritic structures.Even though NODDI applications are novel in MS, this technique appears promising in detecting and modeling the complexity of MS pathology, being potentially more specific than DTI in capturing microstructural substrates.^7-12 NODDI has never been used, however, to assess longitudinal changes within MS lesions and NAWM. For animal studies, only a single work, based on a murine model, longitudinally assessed induced demyelinated lesions, correlating NODDI abnormalities with histopathologic changes.¹³ The authors suggested that after a demyelinating event, the combination of decreasing ODI and increasing NDI with time might reflect improvement in fiber coherency due to remyelination.The aim of this work was to cross-sectionally assess the role of NODDI in indicating gadolinium enhancement in acute lesions and to longitudinally assess NODDI and conventional DTI changes in MS lesions and NAWM in the transition from detectable to undetectable gadolinium enhancement. We hypothesized that NODDI-derived metrics may be promising markers to detect acute inflammation as well as heterogeneity among lesions and their evolution with time.     

NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study

BACKGROUND AND PURPOSE:The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive.MATERIALS AND METHODS:A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent ¹H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry.RESULTS:Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06–0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03–0.38) (ρ = 0.19; 95% CI, 0.01–0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = −0.23; 95% CI, −0.39 to −0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = −0.24; 95% CI, −0.40 to −0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis.CONCLUSIONS:This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

Secondary-progressive MS (SPMS) is the dominant progressive form of multiple sclerosis that is characterized by accumulating disability due to a variety of neurodegenerative processes.¹ These include microglial activation with subsequent formation of reactive oxygen species inducing mitochondrial damage, sodium channel dysfunction leading to histotoxic hypoxia and axonal energy failure, and glutaminergic excitotoxicity.^2-4Surrogate markers of brain injury are valuable in improving our understanding of the pathophysiology driving clinical disability in progressive forms of MS (PMS). Surrogate imaging-based markers such as MR imaging–based lesional and atrophy metrics can identify existing inflammatory injury and axonal loss and provide adjunctive prognostic information. Yet existing imaging based–measures are relatively limited in their ability to demonstrate metabolic or microstructural changes and show only a modest association with clinical disability outcomes in PMS.⁵ This is where advanced nonstructural MR imaging techniques such as ¹H-MR spectroscopy are attractive to further understand this neuropathology and its association with clinical disability in progressive forms of MS.By means of ¹H-MR spectroscopy, neurometabolites of interest in MS include the following: N-acetylaspartate plus N-acetylaspartylglutamate (total NAA = tNAA), a marker of neuroaxonal integrity and mitochondrial function;^6,7 Glx, the sum of the excitatory neurotransmitter glutamate and its precursor glutamine;⁴ myo-inositol (mIns), a marker of glial cell activity, most likely astrogliosis; and total choline (tCho = glycerophosphocholine and phosphocholine), a marker of membrane turnover.^7,8 Many studies have demonstrated decreases in tNAA and tNAA/tCr and increases in total creatine (tCr = creatine and phosphocreatine) and inositol in normal-appearing white matter (NAWM) and GM in SPMS.⁹ In a recent meta-analysis of ¹H-MR spectroscopy studies, effect sizes for a reduction in NAA and NAA/Cr were larger in PMS compared with relapsing-remitting MS.⁹ There have been conflicting results from studies examining disability associations in PMS: Several studies showed no association between metabolites (NAA, Glx, mIns, tCho) and the Expanded Disability Status Scale score (EDSS),^10-13 while others showed moderate associations with EDSS, the Nine-Hole Peg Test (9HPT), and the Timed 25-foot Walk Test (T25-FW) in cortical GM and NAWM.^14-16 Of the studies examining cognitive performance (including information processing speed [IPS]) in PMS, no associations were found in sample sizes ranging from 14 to 31, with only 2 of these studies containing pure SPMS cohorts.^13,14,16-18The rationale for this cross-sectional study was to further define metabolite levels and their associations with disability in a much larger sample of individuals with SPMS than has been achieved before.     

Imaging Parameters of the Ipsilateral Medial Geniculate Body May Predict Prognosis of Patients with Idiopathic Unilateral Sudden Sensorineural Hearing Loss on the Basis of Diffusion Spectrum Imaging

BACKGROUND AND PURPOSE:Idiopathic sudden sensorineural hearing loss is an acute unexplained onset of hearing loss. We examined the central auditory pathway abnormalities in patients with unilateral idiopathic sudden sensorineural hearing loss using diffusion spectrum imaging and the relationships between hearing recovery and diffusion spectrum imaging parameters.MATERIALS AND METHODS:Forty-eight patients with unilateral idiopathic sudden sensorineural hearing loss with a duration of ≤2 weeks (range, 8.9 ± 4.3 days) and 20 healthy subjects underwent diffusion spectrum imaging tractography. Hearing levels were evaluated using a pure-tone average at initial presentation and 3-month follow-up. Clinical characteristics and MR imaging findings were assessed.RESULTS:Compared with healthy control subjects, the generalized fractional anisotropy values of patients decreased significantly in the bilateral posterior limbs of the internal capsule, with no differences between the ipsilateral and contralateral sides. The quantitative anisotropy values decreased in the Brodmann area 41, contralateral medial geniculate body, bilateral lateral lemniscus, anterior limb of internal capsule, middle temporal gyrus, and anterior corona radiata. Furthermore, at 3-month follow-up, 14 patients had <15 dB of hearing gain. Receiver operating characteristic curve analysis demonstrated that generalized fractional anisotropy in the ipsilateral medial geniculate body was related to prognosis (sensitivity = 64.7%; specificity = 85.7%; area under the curve = 0.796, 95% CI, 0.661–0.931; P < .01).CONCLUSIONS:Diffusion spectrum imaging can detect abnormalities of white matter microstructure along the central auditory pathway in patients with unilateral idiopathic sudden sensorineural hearing loss. The generalized fractional anisotropy value of the ipsilateral medial geniculate body may help to predict recovery outcomes.

Hearing plays a crucial role in communication with the outside world. Idiopathic sudden sensorineural hearing loss (ISSHL) is an acute unexplained onset of hearing loss from a cochlear or retrocochlear origin.^1,2 Sudden sensorineural hearing loss affects approximately 5−27 per 100,000 people annually, and the incidence has increased across recent decades.^3,4 Viral infections, cochlear ischemia, autoimmune processes, and metabolic derangement have been proposed as potential etiologies. Treatment options include steroids and other medications, hyperbaric oxygen therapy, and other complementary and alternative treatments. However, selection of treatments may be difficult due to the variety of possible etiologies.² Additionally, the hearing prognosis in individual cases is quite uncertain.High-resolution MR imaging can detect the pathologic changes in the inner ear and the cochlea, providing new insights into the etiology of ISSHL.⁵ A number of studies have examined the prognostic value of white matter abnormalities in hearing loss using T2WI or FLAIR sequences with conflicting results.^6,7 White matter microstructural changes along the auditory pathway have not been well-evaluated, but DTI is becoming a method to study the central auditory pathways.^8,9 DTI is sensitive to the highly directional structure of white matter, which can reflect the structural or functional changes of white matter. Fractional anisotropy (FA), as a DTI parameter, is considered a marker of fiber tract integrity. On the basis of a recent systematic review, white matter changes can be detected by DTI in patients with sensorineural hearing loss.¹⁰ However, DTI needs larger sample sizes for standardization, and the spatial resolution limits the further use of DTI in the auditory pathway. By contrast, diffusion spectrum imaging (DSI) generalizes DTI by acquiring more directions in q-space, either by high-angular-resolution diffusion imaging shells, a cube on a Cartesian grid, or Q-ball imaging.¹¹ Also compared with DTI, DSI can provide a better estimate of areas of crossing or kissing fibers, demyelination, and axonal remodeling.¹²The aim of the present study was to investigate the value of DSI in detecting microstructural abnormalities of the central auditory pathway in patients with ISSHL and to assess the correlations between clinical outcomes and DSI parameters.     

Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up

BACKGROUND AND PURPOSE:Although developmental venous anomalies have been frequently studied in adults and occasionally in children, data regarding these entities are scarce in neonates. We aimed to characterize clinical and neuroimaging features of neonatal developmental venous anomalies and to evaluate any association between MR imaging abnormalities in their drainage territory and corresponding angioarchitectural features.MATERIALS AND METHODS:We reviewed parenchymal abnormalities and angioarchitectural features of 41 neonates with developmental venous anomalies (20 males; mean corrected age, 39.9 weeks) selected through a radiology report text search from 2135 neonates who underwent brain MR imaging between 2008 and 2019. Fetal and longitudinal MR images were also reviewed. Neurologic outcomes were collected. Statistics were performed using χ², Fisher exact, Mann-Whitney U, or t tests corrected for multiple comparisons.RESULTS:Developmental venous anomalies were detected in 1.9% of neonatal scans. These were complicated by parenchymal/ventricular abnormalities in 15/41 cases (36.6%), improving at last follow-up in 8/10 (80%), with normal neurologic outcome in 9/14 (64.2%). Multiple collectors (P = .008) and larger collector caliber (P < .001) were significantly more frequent in complicated developmental venous anomalies. At a patient level, multiplicity (P = .002) was significantly associated with the presence of ≥1 complicated developmental venous anomaly. Retrospective fetal detection was possible in 3/11 subjects (27.2%).CONCLUSIONS:One-third of neonatal developmental venous anomalies may be complicated by parenchymal abnormalities, especially with multiple and larger collectors. Neuroimaging and neurologic outcomes were favorable in most cases, suggesting a benign, self-limited nature of these vascular anomalies. A congenital origin could be confirmed in one-quarter of cases with available fetal MR imaging.

Developmental venous anomalies (DVAs) are the most frequently diagnosed intracranial vascular malformations, often encountered as incidental neuroimaging findings.^1,2 On MR imaging, DVAs are recognized on postcontrast T1WI as radially oriented veins with a “caput medusae” pattern converging into 1 (or rarely more) dilated venous collector.^3,4 These features may be also detected on precontrast MR images,^3-5 especially if T2*-weighted sequences such as high-resolution SWI are included in the protocol.⁵ In addition, DVAs may be occasionally recognized in utero using fetal MR imaging.⁶DVAs are usually considered benign anatomic variants.⁷ However, they represent areas of venous fragility that can become symptomatic through diverse pathomechanisms.^8,9 Indeed, DVA-associated brain abnormalities are frequently depicted, including-but-not limited-to sporadic cerebral cavernous malformations (CCMs).^8-16 Moreover, a higher prevalence of DVAs has been described in patients with different pathologies and/or genetic conditions.^17-21Although DVAs are widely described and characterized in adults, they remain under-reported in the pediatric population. Indeed, there are noticeably fewer studies focusing exclusively on DVAs in this age group, especially in the neonatal period.^17,18,21-24 In particular, the largest case series of neonatal DVAs described so far included 14 neonates, mostly detected using ultrasound during routine scanning for other reasons,²² with limited information on the prevalence and perinatal characteristics of these vascular abnormalities, including complications and longitudinal evolution. Moreover, additional data on neonatal and fetal DVAs would be of great interest because there is an ongoing debate regarding their congenital or postnatal etiology.²⁵In this study, we aimed to describe the pre- and postnatal appearance of DVAs and associated brain anomalies in a relatively large single-center group of neonates, providing information on their imaging and clinical follow-up. In addition, we tested a possible association between parenchymal and ventricular abnormalities in the drainage territory of neonatal DVAs and their angioarchitectural features.     

Glioma-Induced Disruption of Resting-State Functional Connectivity and Amplitude of Low-Frequency Fluctuations in the Salience Network

BACKGROUND AND PURPOSE:Cognitive challenges are prevalent in survivors of glioma, but their neurobiology is incompletely understood. The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on resting-state functional connectivity and amplitude of low-frequency fluctuations of the salience network, a key neural network associated with cognition.MATERIALS AND METHODS:Sixty-nine patients with glioma (mean age, 48.74 [SD, 14.32] years) who underwent resting-state fMRI were compared with 31 healthy controls (mean age, 49.68 [SD, 15.54] years). We identified 4 salience network ROIs: left/right dorsal anterior cingulate cortex and left/right anterior insula. Average salience network resting-state functional connectivity and amplitude of low-frequency fluctuations within the 4 salience network ROIs were computed.RESULTS:Patients with gliomas showed decreased overall salience network resting-state functional connectivity (P = .001) and increased amplitude of low-frequency fluctuations in all salience network ROIs (P < .01) except in the left dorsal anterior cingulate cortex. Compared with controls, patients with left-sided gliomas showed increased amplitude of low-frequency fluctuations in the right dorsal anterior cingulate cortex (P = .002) and right anterior insula (P < .001), and patients with right-sided gliomas showed increased amplitude of low-frequency fluctuations in the left anterior insula (P = .002). Anterior tumors were associated with decreased salience network resting-state functional connectivity (P < .001) and increased amplitude of low-frequency fluctuations in the right anterior insula, left anterior insula, and right dorsal anterior cingulate cortex. Patients with high-grade gliomas had decreased salience network resting-state functional connectivity compared with healthy controls (P < .05). The right anterior insula showed increased amplitude of low-frequency fluctuations in patients with grade II and IV gliomas compared with controls (P < .01).CONCLUSIONS:By demonstrating decreased resting-state functional connectivity and an increased amplitude of low-frequency fluctuations related to the salience network in patients with glioma, this study adds to our understanding of the neurobiology underpinning observable cognitive deficits in these patients. In addition to more conventional functional connectivity, amplitude of low-frequency fluctuations is a promising functional-imaging biomarker of tumor-induced vascular and neural pathology.

Detrimental effects of cancer on cognitive function and, consequently, on the quality of life are emerging as a key focus of cancer survivorship both in research and clinical practice.^1,2 Brain tumors have been shown to affect memory, processing, and attention in patients; however, their underlying neurobiology is incompletely understood.³ Using resting-state functional MR imaging (rsfMRI) to evaluate changes in cognitive resting-state networks may provide a better understanding of the pathology underlying the observable cognitive disruptions in gliomas, the most common primary brain tumor in adults.A “triple network model” of neurocognitive pathology has been proposed, which encompasses the default mode network, involved in mind wandering; the central executive network, involved in decision-making; and the salience network (SN), implicated in modulating activation of the default mode network and central executive network by detecting the presence of salient stimuli.^4-8 While previous rsfMRI research has largely focused on tumor-induced changes in the default mode network,^9,10 our study examined the less-studied SN, a network rooted in the anterior insula and the dorsal anterior cingulate cortex.⁶Prior studies evaluating gliomas and SN resting-state functional connectivity (RSFC) provided conflicting results in small patient samples: Maesawa et al¹⁰ found no significant differences in the SN in 12 patients, while Liu et al¹¹ more recently found decreased SN connectivity in 13 patients. Gliomas impact the integrity of the neurovascular unit to varying degrees, resulting in neurovascular uncoupling that has been reported to confound fMRI interpretations in patients with brain tumors.^12-14 Additionally, research has reported neuronal plasticity manifested by structural reorganization and functional remodeling of neural networks in patients with gliomas with possible alterations in clinically observable cognitive manifestations.^15-17 An rsfMRI metric, the amplitude of low-frequency fluctuations (ALFF), has recently shown promise as a biomarker for brain plasticity and hemodynamic characterization, including neurovascular uncoupling in patients with gliomas.^15-19The purpose of this study was to investigate the effect of glioma presence and tumor characteristics on overall RSFC and regional normalized ALFF within the SN in a large patient population. We hypothesized that there would be decreased average SN RSFC and altered ALFF in patients with gliomas compared with healthy controls. Recent studies have acknowledged that gliomas have variable effects on network integrity based on lesion location and proximity to network ROIs,^20-22 and unilateral gliomas can be associated with plasticity in both the ipsilateral and contralateral hemispheres.^11,17 Research also supports differences in resting-state network reorganization in aggressive high-grade gliomas compared with slower-growing low-grade gliomas.^20,23 Therefore, we also hypothesized that there would be differences in average SN RSFC and regional ALFF in patients based on the anterior-versus-posterior location, hemispheric side, and grade of glioma.     

Impact of Kidney Function on CNS Gadolinium Deposition in Patients Receiving Repeated Doses of Gadobutrol

BACKGROUND AND PURPOSE:Studies associate repeat gadolinium-based contrast agent administration with T1 shortening in the dentate nucleus and globus pallidus, indicating CNS gadolinium deposition, most strongly with linear agents but also reportedly with macrocyclics. Renal impairment effects on long-term CNS gadolinium deposition remain underexplored. We investigated the relationship between signal intensity changes and renal function in patients who received ≥10 administrations of the macrocyclic agent gadobutrol.MATERIALS AND METHODS:Patients who underwent ≥10 brain MR imaging examinations with administration of intravenous gadobutrol between February 1, 2014, and January 1, 2018, were included in this retrospective study. Dentate nucleus-to-pons and globus pallidus-to-thalamus signal intensity ratios were calculated, and correlations were calculated between the estimated glomerular filtration rate (minimum and mean) and the percentage change in signal intensity ratios from the first to last scan. Partial correlations were calculated to control for potential confounders.RESULTS:One hundred thirty-one patients (73 women; mean age at last scan, 55.9 years) showed a mean percentage change of the dentate nucleus-to-pons of 0.31%, a mean percentage change of the globus pallidus-to-thalamus of 0.15%, a mean minimum estimated glomerular filtration rate of 69.65 (range, 10.16–132.26), and a mean average estimated glomerular filtration rate at 89.48 (range, 38.24–145.93). No significant association was found between the estimated glomerular filtration rate and percentage change of the dentate nucleus-to-pons (minimum estimated glomerular filtration rate, r = –0.09, P = .28; average estimated glomerular filtration rate, r = –0.09, P = .30,) or percentage change of the globus pallidus-to-thalamus (r = 0.07, P = .43; r = 0.07, P = .40). When we controlled for age, sex, number of scans, and total dose, there were no significant associations between the estimated glomerular filtration rate and the percentage change of the dentate nucleus-to-pons (r = 0.16, P = .07; r = 0.15, P = .08) or percentage change of the globus pallidus-to-thalamus (r = –0.14, P = .12; r = –0.15, P = .09).CONCLUSIONS:In patients receiving an average of 12 intravenous gadobutrol administrations, no correlation was found between renal function and signal intensity ratio changes, even in those with mild or moderate renal impairment.

Gadolinium-based contrast agents (GBCAs) are commonly used in imaging to increase conspicuity and reveal enhancement characteristics of lesions. GBCAs can have either a macrocyclic or a linear molecular structure. Recent studies investigating CNS gadolinium deposition following repeat GBCA administrations showed measurable T1 shortening in the dentate nucleus and globus pallidus in patients who received GBCAs with a linear molecular structure.^1-12 Postmortem studies in patients who received linear agents have documented gadolinium deposition in the CNS, again most prominently in the dentate nucleus and globus pallidus, lending further credibility to imaging findings.^13-15The underlying mechanism of gadolinium retention remains unknown, as does the chemical formulation of the accumulated gadolinium. Despite these unknown mechanisms, gadolinium deposition is thought to involve dissociation of gadolinium from its chelating ligand, so macrocyclic agents are thought to be more stable than linear GBCAs due to their lower dissociation constants.¹⁶ Although the CNS deposition of linear GBCAs has been demonstrated previously, most studies failed to show increased signal intensity in the dentate nucleus and globus pallidus^2-10,17-27 after the use of macrocyclic GBCAs. Nevertheless, a few studies do report increased signal in the brain,^20,27-29 including a postmortem study that detected brain gadolinium, even in the setting of macrocyclic GBCA use.³⁰ On the other hand, two studies using highly sensitive inductively coupled plasma mass spectrometry to measure gadolinium in the brain in animal models did not find significant deposition with macrocyclic agents in the parenchyma, so the picture remains mixed.^31,32GBCAs undergo primary renal clearance;³³ hence, determining whether renal impairment could predispose a patient to gadolinium deposition is important. Patients on hemodialysis receiving a linear GBCA have a greater increase in dentate nucleus signal intensity (SI) compared with controls not on dialysis.¹¹ In 2017, Lee et al²⁰ showed that in a subgroup of 28 patients, there was a significant change in SI ratios in patients with estimated glomerular filtration rates (eGFR) between 45 and 60 mL/min/m² who received the macrocyclic agent gadoterate meglumine. Although much has been discussed regarding nephrogenic systemic fibrosis in the context of renal impairment, there is surprisingly little known regarding the potential effects of abnormal renal function on long-term CNS gadolinium deposition.The purpose of this study was to specifically investigate whether a relationship exists between SI and renal function in patients receiving a large number (≥10) of administrations of the macrocyclic GBCA gadobutrol.     

Quantitative fiber tracking in the corpus callosum and internal capsule reveals microstructural abnormalities in preterm infants at term-equivalent age

BACKGROUND AND PURPOSE:Signal-intensity abnormalities in the PLIC and thinning of the CC are often seen in preterm infants and associated with poor outcome. DTI is able to detect subtle abnormalities. We used FT to select bundles of interest (CC and PLIC) to acquire additional information on the WMI.MATERIALS AND METHODS:One hundred twenty preterm infants born at <31 weeks'' gestation with 3T DTI at TEA entered this prospective study. Quantitative information (ie, volume, length, anisotropy, and MD) was obtained from fiber bundles passing through the PLIC and CC. A general linear model was used to assess the effects of factor (sex) and variables (GA, BW, HC, PMA, and WMI) on FT-segmented parameters.RESULTS:Seventy-two CC and 85 PLIC fiber bundles were assessed. For the CC, increasing WMI and decreasing FA (P = .038), bundle volume (P < .001), and length (P = .001) were observed, whereas MD increased (P = .001). For PLIC, MD increased with increasing WMI (P = .002). Higher anisotropy and larger bundle length were observed in the left PLIC compared with the right (P = .003, P = .018).CONCLUSIONS:We have shown that in the CC bundle, anisotropy was decreased and diffusivity was increased in infants with high WMI scores. A relation of PLIC with WMI was also shown but was less pronounced. Brain maturation is affected more if birth was more premature.

Premature birth of <30 weeks'' gestation is associated with a high risk of neurodevelopmental impairments, including cognitive and motor disabilities.^1–3 The underlying neuropathology for cognitive disabilities is largely unknown, though it has been suggested that disturbances in the WM maturation play a role.^4,5 In teenagers, the effects of preterm birth are associated with thinning of the CC, widening of the ventricles, reduced volumes of the WM, and microstructural changes in the PLIC and the CC.^6–9MR imaging is commonly performed in preterm infants around TEA to detect brain injury. Different scoring systems have been developed to quantify MR imaging findings.^2,10 Although these scoring systems were related to outcome, they did not provide information about the pathology on a microstructural level. WM maturation may best be followed with DTI because this technique uses both information on the diffusion properties of water molecules that are restricted in tissue and information on the direction of diffusion (anisotropy). DTI has been shown to be sensitive to microstructural WM changes, like myelination.^11,12 Most information concerning DTI changes in relation to brain maturation is available from studies assessing selected ROIs in the WM.¹¹ It has been shown that the anisotropy in preterm infants is decreased at TEA in certain brain regions (among these, the CC and the frontal WM) compared with term-born controls.¹³Instead of measuring local effects in selected ROIs, FT can be applied to measure changes in bundles of WM. FT is a 3D visualization technique that reconstructs the underlying linear structure defined by the diffusion tensor.¹⁴ Quantification of WM tracts in infants has been performed previously^15–23 and is based on calculating an average of a certain DTI parameter over the complete bundle. Axial and radial diffusivity over specific tracts have been shown to be differentially affected by bundle maturation with age,^20,21 and DTI parameters quantifying the corticospinal tract are affected in preterm infants with WMI.²² Only 1 study recently investigated the genu and splenium of the CC in premature infants at TEA by using FT.²³ The CC is of interest because reduced callosal volumes have been shown to correlate with motor function and cognitive impairment.^24,25The aim of our study was to investigate whether diffusion tensor parameters, abstracted by using FT to select complete CC and PLIC bundles, display WM abnormalities in the premature infant at TEA. The WMI score² (as measured with conventional MR imaging) was used as a reference index.We hypothesized that WMI would be better detected with DTI and that it would give more information on the microstructure. We investigated, furthermore, how the DTI parameters were affected by GA at birth, BW, HC, sex, and the PMA, defined here as the age at the time of scanning.     

Diagnostic Accuracy of Arterial Spin-Labeling MR Imaging in Detecting the Epileptogenic Zone: Systematic Review and Meta-analysis

BACKGROUND:A noninvasive, safe, and economic imaging technique is required to identify epileptogenic lesions in the brain.PURPOSE:Our aim was to perform a meta-analysis evaluating the accuracy of arterial spin-labeling in localizing the epileptic focus in the brain and the changes in the blood perfusion in these regions.DATA SOURCES:Our sources were the PubMed and EMBASE data bases.STUDY SELECTION:English language studies that assessed the diagnostic accuracy of arterial spin-labeling for detecting the epileptogenic zone up to July 2019 were included.DATA ANALYSIS:The symptomatogenic foci of seizures in the brain were determined and used as the references. The relevant studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The outcomes were evaluated using the pooled sensitivity, pooled specificity, pooled accuracy, diagnostic odds ratio, area under the summary receiver operating characteristic curve, and likelihood ratio.DATA SYNTHESIS:Six studies that included 174 patients qualified for this meta-analysis. The pooled sensitivity, pooled specificity, and area under the summary receiver operating characteristic curve were 0.74 (95% CI, 0.65–0.82), 0.35 (95% CI, 0.03–0.90), and 0.73 (95% CI, 0.69–0.76), respectively. The accuracy of arterial spin-labeling for localizing the epileptic focus was 0.88 (accuracy in arterial spin-labeling/all perfusion changes in arterial spin-labeling) in cases of a positive arterial spin-labeling result. The epileptogenic zone exhibited hyperperfusion or hypoperfusion.LIMITATIONS:Only a few studies were enrolled due to the strict inclusion criteria.CONCLUSIONS:Arterial spin-labeling can be used for assessing, monitoring, and reviewing, postoperatively, patients with epilepsy. Blood perfusion changes in the brain may be closely related to the seizure time and pattern.

Epilepsy is the most common chronic neurologic disease, characterized by the occurrence of repeat seizures. Several diseases, including brain tumors, hypoxia-related brain diseases, and cerebral cortical dysplasia, can cause epilepsy. Electroencephalography, which identifies the epileptic discharges in the brain, was the earliest method applied for the diagnosis and localization of epileptic disorders.^1,2 The development of imaging technology in recent years has enabled the use of conventional (structural) MR imaging and CT, which can locate and visualize the structural brain lesions responsible for epilepsy. However, not all patients with epilepsy exhibit structural changes in their brain tissue. Several animal and clinical studies have found that seizures can alter the metabolism and vascular perfusion in the brain tissue.^3-8 Therefore, PET and SPECT can be used to locate lesions with metabolic abnormalities and an abnormal blood supply.Currently, the treatment of epilepsy is mainly based on pharmacotherapy, and 20%–40% of patients may have refractory seizures. Surgery is the treatment of choice in patients with refractory epilepsy.^9,10 Patients who are not drug-resistant with surgical conditions can also benefit from surgery.¹¹ The accurate detection of the epileptic lesion is the key to the effectiveness of surgery. The surgical treatment plan mainly depends on the consistency of the clinical symptoms of the seizure and the findings of electroencephalography and structural MR imaging.¹² PET and SPECT are used if both electroencephalography and structural MR imaging fail to identify the lesion.^13-15 However, the radiation exposure associated with PET and SPECT can have adverse effects on human health. Therefore, a noninvasive, safe, and economic imaging technique is required to identify the brain lesions responsible for epilepsy.The development of functional MR imaging technology has made it possible to visualize the change in the CBF using arterial spin-labeling (ASL) (without the use of contrast agents) because ASL can magnetize protons in the circulating blood as an endogenous perfusion tracer.^16,17 Several studies of neurologic diseases have shown a good correlation among ASL, DSC-perfusion MR imaging, and PET for evaluating the changes in CBF perfusion, and they support the credibility and feasibility of the clinical applications of ASL.^18-21ASL can be used to identify the location of epileptic lesions, with the potential to replace interventional examinations. However, most published research on this subject consists of experimental studies, with small samples and different results. There is controversy about the changes in the blood perfusion in the lesion area; some believe that perfusion is increased, and some believe that perfusion is reduced. The purpose of our study was to conduct a systematic review and meta-analysis of studies assessing the ability of ASL to locate epileptogenic foci. We aimed to obtain a clear idea of the accuracy of ASL for the localization of the epileptogenic focus and the changes of the blood perfusion of the lesion.     

Utility of Contrast-Enhanced T2 FLAIR for Imaging Brain Metastases Using a Half-dose High-Relaxivity Contrast Agent

BACKGROUND AND PURPOSE:Efficient detection of metastases is important for patient’ treatment. This prospective study was to explore the clinical value of contrast-enhanced T2 FLAIR in imaging brain metastases using half-dose gadobenate dimeglumine.MATERIALS AND METHODS:In vitro signal intensity of various gadolinium concentrations was explored by spin-echo T1-weighted imaging and T2 FLAIR. Then, 46 patients with lung cancer underwent nonenhanced T2 FLAIR before administration of half-dose gadobenate dimeglumine and 3 consecutive contrast-enhanced T2 FLAIR sequences followed by 1 spin-echo T1WI after administration of half-dose gadobenate dimeglumine. After an additional dose of 0.05 mmol/kg, 3D brain volume imaging was performed. All brain metastases were classified as follows: solid-enhancing, ≥ 5 mm (group A); ring-enhancing, ≥ 5 mm (group B); and lesion diameter of <5 mm (group C). The contrast ratio of the lesions on 3 consecutive phases of contrast-enhanced T2 FLAIR was measured, and the percentage increase of contrast-enhanced T2 FLAIR among the 3 groups was compared.RESULTS:In vitro, the maximal signal intensity was achieved in T2 FLAIR at one-eighth to one-half of the contrast concentration needed for maximal signal intensity in T1WI. In vivo, the mean contrast ratio values of metastases on contrast-enhanced T2 FLAIR for the 3 consecutive phases ranged from 63.64% to 83.05%. The percentage increase (PI) values of contrast-enhanced T2 FLAIR were as follows: PI_A < PI_B (P = .001) and PI_A < PI_C (P < .001). The degree of enhancement of brain metastases on contrast-enhanced T2 FLAIR was lower than on 3D brain volume imaging (P < .001) in group A, and higher than on 3D brain volume imaging (P < .001) in group C.CONCLUSIONS:Small or ring-enhancing metastases can be better visualized on delayed contrast-enhanced T2 FLAIR using a half-dose high-relaxivity contrast agent.

Brain metastases occur in approximately 25% of patients with cancer and account for 40% of adult brain tumors.¹ The incidence of brain metastases in patients with lung cancer is highest (19.9%),² resulting in high morbidity and mortality.³ Small metastases, not combined with vasogenic edema or mass effects, are often missed.¹ Improvement of the early detection of small brain metastases will contribute to developing treatment protocols and will affect the outcomes⁴ because small lesions effectively respond to therapies and can be controlled at a substantially higher rate compared with larger lesions.^5,6 For patients with metastases, contrast-enhanced T1WI (CE-T1WI) should be repeatedly performed to assess the progress of brain metastases^7,8 or the efficacy of treatment.^9,10 The conspicuity and detection rate of brain metastases can be improved with a higher dose of gadolinium-based contrast agents (GBCA).¹¹ However, multiple enhanced examinations or use of higher contrast doses may increase the potential adverse effects, such as nephrogenic systemic fibrosis,^12,13 and may lead to higher gadolinium deposition in the brain¹⁴ or other tissues.^15,16Therefore, reducing the gadolinium-based contrast agent dose may decrease the adverse effects produced by gadolinium accumulation, which is crucial to the patient’s health. T2 FLAIR is an inversion recovery pulse sequence that is sensitive to low concentrations of GBCA in the tissue.¹⁷ It is reported that only one-quarter of the routine dose of GBCA is needed for CE-T2 FLAIR to achieve a signal enhancement comparable with that of CE-T1WI; moreover, CE-T2 FLAIR may offer additional morphologic information compared with CE-T1WI alone.^17,18 Due to the suppression of intravascular and CSF signal,¹⁹ CE-T2 FLAIR imaging has been used in the detection of various intra- and extra-axial brain lesions, eg, the delineation of meningeal lesions including meningoencephalitis and leptomeningeal metastases.^20-22Previous studies mostly focused on the use of CE-T2 FLAIR after use of the normal GBCA dose; no studies were performed to assess the utility of low-dose CE-T2 FLAIR in the detection of brain metastases. Additionally, an increased delay of CE-T2 FLAIR scanning can improve the diagnosis of leptomeningeal infectious or tumoral diseases,²³ which means CE-T2 FLAIR has a relationship with scanning time. The purpose of the present study was to investigate the value of delayed low-dose CE-T2 FLAIR compared with routine-dose CE brain volume imaging (BRAVO; GE Healthcare) for contrast enhancement in brain metastases.     

Value of Emergent Neurovascular Imaging for “Seat Belt Injury”: A Multi-institutional Study

BACKGROUND AND PURPOSE:Screening for blunt cerebrovascular injury in patients after motor vehicle collision (MVC) solely based on the presence of cervical seat belt sign has been debated in the literature without consensus. Our aim was to assess the value of emergent neurovascular imaging in patients after an MVC who present with a seat belt sign through a large-scale multi-institutional study.MATERIALS AND METHODS:The electronic medical records of patients admitted to the emergency department with CTA/MRAs performed with an indication of seat belt injury of the neck were retrospectively reviewed at 5 participating institutions. Logistic regression analysis was used to determine the association among age, sex, and additional trauma-related findings with blunt cerebrovascular injury.RESULTS:Five hundred thirty-five adult and 32 pediatric patients from June 2003 until March 2020 were identified. CTA findings were positive in 12/567 (2.1%) patients for the presence of blunt cerebrovascular injury of the vertebral (n = 8) or internal carotid artery (n = 4) in the setting of acute trauma with the seat belt sign. Nine of 12 patients had symptoms, signs, or risk factors for cervical blunt cerebrovascular injury other than the seat belt sign. The remaining 3 patients (3/567, 0.5%) had Biffl grades I–II vascular injury with no neurologic sequelae. The presence of at least 1 additional traumatic finding or the development of a new neurologic deficit was significantly associated with the presence of blunt cerebrovascular injury among adult patients, with a risk ratio of 11.7 (P = .001). No children had blunt cerebrovascular injury.CONCLUSIONS:The risk of vascular injury in the presence of the cervical seat belt sign is small, and most patients diagnosed with blunt cerebrovascular injury have other associated findings. Therefore, CTA based solely on this sign has limited value (3/567 =  a 0.5% positivity rate). We suggest that in the absence of other clinical findings, the seat belt sign does not independently justify neck CTA in patients after trauma.

Motor vehicle collision (MVC) is a major cause of blunt cerebrovascular injury (BCVI).¹ Historically, the incidence of BCVI was reported to be as low as 0.1%–0.67% among patients with blunt trauma.^2,3 However, implementation of more rigorous screening protocols in trauma centers has revealed a 10-fold higher rate of BCVI, as high as 2.7%, among severely injured patients.^4-6 Although uncommon, the neurologic sequelae of BCVI are potentially serious. Many patients do not manifest stroke symptoms until hours to days after the injury,⁷ and when not treated in a timely fashion, up to 80% develop permanent neurologic sequelae with an estimated 40% mortality rate.^3,8,9 Thus, screening CTA or MRA for BCVI has become commonplace in the management of patients after an MVC.^10,11 However, the selection of which patients to screen has been a controversial topic during the past 4 decades.⁶Various screening algorithms, including the modified Memphis and Denver criteria or the Western Trauma Association algorithm, may be used as guidelines (Online Supplemental Data). These guidelines, developed on the basis of observational studies and expert opinion, have adopted a liberal approach to imaging patients with possible BCVI.^7,12,13 Although this approach helps avoid missing occult injuries, it may lead to unnecessary imaging, discovery of incidental findings, increased radiation exposure, and low-value health care expenditures.^14-17 Many believe that advanced imaging studies are being overused in many medical centers, in part, due to a “defensive medicine” mentality. It is estimated that up to 50% of ordered studies lead to no improvement in patient welfare.^15,18One of the controversial indications for BCVI is the physical sign of neck abrasion or contusion caused by a seat belt, the so-called cervical seat belt sign. Screening for BCVI solely based on the presence of this sign has been debated in the literature without consensus.^19-22 The existing guidelines also recommend contradictory approaches regarding the use of the seat belt sign as a sole indicator to stratify patients for screening (Online Supplemental Data). Despite some single-center studies suggesting that discoloration of the skin from the seat belt is not a reliable indicator of risk to the cervical vessels,^23-25 many trauma centers persist in ordering emergent CTAs to exclude BCVI in patients with this finding because of continued debate as to the validity of the seat belt sign as an indicator of vascular injury. To address this controversy, we aimed to assess the value of emergent neurovascular imaging in patients with a seat belt sign after an MVC through a large-scale multi-institutional study that would identify the situations in which the seat belt sign may be predictive of cervical vascular injury. We hypothesized that cervical CTA performed solely on the basis of a seat belt sign has limited value.     

Peak Width of Skeletonized Mean Diffusivity as Neuroimaging Biomarker in Cerebral Amyloid Angiopathy

BACKGROUND AND PURPOSE:Whole-brain network connectivity has been shown to be a useful biomarker of cerebral amyloid angiopathy and related cognitive impairment. We evaluated an automated DTI-based method, peak width of skeletonized mean diffusivity, in cerebral amyloid angiopathy, together with its association with conventional MRI markers and cognitive functions.MATERIALS AND METHODS:We included 24 subjects (mean age, 74.7 [SD, 6.0] years) with probable cerebral amyloid angiopathy and mild cognitive impairment and 62 patients with MCI not attributable to cerebral amyloid angiopathy (non-cerebral amyloid angiopathy–mild cognitive impairment). We compared peak width of skeletonized mean diffusivity between subjects with cerebral amyloid angiopathy–mild cognitive impairment and non-cerebral amyloid angiopathy–mild cognitive impairment and explored its associations with cognitive functions and conventional markers of cerebral small-vessel disease, using linear regression models.RESULTS:Subjects with Cerebral amyloid angiopathy–mild cognitive impairment showed increased peak width of skeletonized mean diffusivity in comparison to those with non-cerebral amyloid angiopathy–mild cognitive impairment (P < .001). Peak width of skeletonized mean diffusivity values were correlated with the volume of white matter hyperintensities in both groups. Higher peak width of skeletonized mean diffusivity was associated with worse performance in processing speed among patients with cerebral amyloid angiopathy, after adjusting for other MRI markers of cerebral small vessel disease. The peak width of skeletonized mean diffusivity did not correlate with cognitive functions among those with non-cerebral amyloid angiopathy–mild cognitive impairment.CONCLUSIONS:Peak width of skeletonized mean diffusivity is altered in cerebral amyloid angiopathy and is associated with performance in processing speed. This DTI-based method may reflect the degree of white matter structural disruption in cerebral amyloid angiopathy and could be a useful biomarker for cognition in this population.

Sporadic cerebral amyloid angiopathy (CAA) is a highly prevalent cerebral small-vessel disease (cSVD) in the elderly.¹ CAA is a well-known cause of lobar intracerebral hemorrhage (ICH) and is also increasingly recognized as a major contributor to vascular cognitive impairment and dementia.^2,3 Although underlying mechanisms leading to cognitive impairment in CAA remain uncertain, it has been hypothesized that recurrent vascular lesions cause progressive disruption of the brain''s structural connectivity, compromising network efficiency.^4,5 Conventional MR imaging markers of CAA, including lobar cerebral microbleeds (CMB),⁶ cortical superficial siderosis (cSS),⁷ white matter hyperintensities (WMH),⁸ and cortical microinfarcts ⁹ have been linked to cognitive functions. However, these associations are mostly weak and inconsistent across studies, suggesting that these markers may reflect only the tip of the iceberg in the whole spectrum of vascular pathology.¹⁰Accumulating evidence suggests that DTI methods detect loss of microstructural integrity and other abnormalities not captured by structural MRI and tend to show stronger associations with cognition in subjects with cSVD.^11,12 Yet, the direct application of DTI in routine clinical practice is hampered by highly variable, complex, and time-consuming processing techniques.Peak width of skeletonized mean diffusivity (PSMD) is a recently developed, fully automated DTI marker based on the skeletonization of white matter tracts and histogram analysis of mean diffusivity (MD).¹³ PSMD has been shown to be particularly sensitive to vascular-related white matter abnormalities, demonstrating consistent associations with processing speed in subjects with cSVD.¹³ However, despite the common nature and high prevalence of CAA in aging populations, potential applications of PSMD in CAA have been scarcely investigated.In the current study, we tested whether PSMD reflects the burden of underlying cSVD and cognitive dysfunctions in subjects with CAA. Among subjects with mild cognitive impairment (MCI) recruited specifically from a memory clinic setting, we explored the following: 1) whether PSMD is increased in subjects with CAA compared with those with non-CAA, 2) whether it is associated with structural MRI markers of CAA, and 3) whether it is correlated with cognitive functions.