Differentiation of hemispheric white matter lesions in migraine and multiple sclerosis with similar radiological features using advanced MRI.

Background and aim: White matter hyperintensities (WMHs), presented on T2-weighted or fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequences, are lesions in the human brain that can be observed in both migraine and multiple sclerosis (MS). Methods: Seventeen migraine patients and 15 patients with relapsing-remitting multiple sclerosis with WMHs, and 17 healthy subjects age-and sex-matched to the migraine group were prospectively enrolled and underwent conventional and advanced MRI studies with diffusion-and perfusion-weighted imaging and single voxel proton magnetic resonance spectroscopy. Results: In both disease groups, elevated T2 relaxation time, apparent diffusion coefficient (ADC) values, and decreased N-acetyl-aspartate levels were found in the intralesional white matter compared to the contralateral normal-appearing white matter (NAWM), while there was no difference between the hemispheres of the control subjects. Migraine patients had the lowest intralesional creatine + phosphocreatine and myo-inositol (mI) values among the three groups, while patients with MS showed the highest intralesional T1 and T2 relaxation times, ADC, and mI values. In the contralateral NAWM, the same trend with mI changes was observed in migraineurs and MS patients. No differences in perfusion variables were observed in any groups. Conclusion: Our multimodal study showed that tissue damage is detectable in both diseases. Despite the differences in various advanced MRI measures, with more severe injury detected in MS lesions, we could not clearly differentiate the two white matter lesion types.

Volumetric alteration of brainstem in female migraineurs with and without aura.

BACKGROUND AND AIM: Brainstem descending modulatory circuits have been postulated to be involved in migraine. Differences in brainstem volume between migraineurs and healthy controls have been demonstrated in previous research, nevertheless, the effect of migraine aura on brainstem volume is still uncertain. The aim of this study was to investigate the brainstem volume in migraineurs and examine the effect of migraine aura on brainstem volume. METHODS: Our study included 90 female migraine patients without white matter lesions. (29 migraine patients with aura (MwA) and 61 migraine patients without aura (MwoA) and 32 age-matched female healthy controls (HC). Using the FreeSurfer image analysis suite, the volumes of the entire brainstem and its subfields (medulla, pons, and midbrain) were measured and compared between migraine subgroups (MwA vs. MwoA) and the healthy control group. The possible effects of migraine characteristics (i.e., disease duration and migraine attack frequency) on brainstem volume were also investigated. RESULTS: Migraineurs had greater medulla volume (MwoA 3552 ± 459 mm3, MwA 3424 ± 448 mm3) than healthy controls (3236 ± 411 mm3). Statistically, MwA vs. HC p = 0.040, MwoA vs. HC p = 0.002, MwA vs. MwoA p = 0.555. A significant positive correlation was found between disease duration and the volume of medulla in the whole migraine group (r = 0.334, p = 0.001). Neither the whole brainstem nor its subfields were significantly different in volume between migraine subgroups. CONCLUSION: Brainstem volume changes in migraine are mainly localized to the medulla and not specific to the presence of aura.

The volume of the thalamus and hippocampus in a right-handed female episodic migraine group.

Background/aim: Migraine is a disabling headache with clinical and radiological complications. The aim of this study was to investigate the volume of the thalamus and hippocampus in migraineurs, the role of white matter lesions (WMLs), and the migraine characteristics in volume changes. Methods: Brain MRIs of 161 right-handed female episodic migraine patients and 40 right-handed, age-related, healthy women were performed. Left and right thalamus segmentation was performed on the 3D MPRAGE images using the Freesurfer 5.3 image analysis suite. Hippocampal subfield segmentation was based on a novel statistical atlas built primarily upon ultra-high-resolution ex vivo MRI data. Results: The left hippocampus had a smaller and the left thalamus had a larger total volume than the right one in both the control (p < 0.001) and migraine groups (p <0.001). Patients with white matter lesions (L+) showed smaller right thalamus and right hippocampal tail volumes than patients without lesions (L-) (p = 0.002 and p = 0.015, respectively) and controls (p = 0.039 and p = 0.025, respectively). For the right hippocampal body, we found significantly smaller volume in L+ patients when compared to L- patients (p = 0.018) and a similar trend when compared to the control group (p = 0.064). Patients without aura (A-) showed a larger right hippocampus (p = 0.029), right hippocampal body (p = 0.012), and tail volumes (p = 0.011) than patients with aura (A+). Inverse correlations were found between attack frequency and the volumes of the left and right hippocampal tails (p = 0.018 and p = 0.008, respectively). Conclusion: These findings indicate that WMLs may influence the volume of the right thalamus and hippocampus, while migraine aura and attack frequency may lead to volume changes in different parts of the hippocampi in migraine patients. These data support the necessity of effective migraine management to limit subcortical volume loss in migraineurs.

Depression and tryptophan metabolism in patients with primary brain tumors: Clinical and molecular imaging correlates.

Patients with brain tumors have an increased risk for depression, whose underlying pathomechanism may involve dysregulated tryptophan/kynurenine metabolism. In this study, we analyzed the relation of depressive symptoms to clinical and tumor characteristics as well as cerebral and systemic tryptophan metabolism in patients with primary brain tumors. Sixty patients with newly-diagnosed or recurrent primary brain tumor underwent testing with the Beck Depression Inventory-II (BDI-II), and 34 patients also had positron emission tomography (PET) imaging with alpha-[11C]methyl-L-tryptophan (AMT). BDI-II scores were correlated with clinical and tumor-related variables, cerebral regional AMT metabolism measured in the non-tumoral hemisphere, and plasma tryptophan metabolite levels. Sixteen patients (27%) had BDI-II scores indicating depression, including 6 with moderate/severe depression. High BDI-II scores were independent of clinical and tumor-related variables except lower Karnofsky Performance Status scores. In patients with recurrent malignant gliomas, depression was associated with shorter survival (hazard ratio: 3.7; p = 0.048). High BDI-II total and somatic subscale scores were associated with higher frontal cortical and thalamic AMT metabolic values measured on PET. In contrast, plasma tryptophan and kynurenine metabolite levels did not correlate with the BDI-II scores. In conclusion, our results confirm previous data that depression affects more than » of patients with primary brain tumors, it is largely independent of tumor characteristics and is associated with shorter survival in patients with recurrent malignant gliomas. On PET imaging, higher tryptophan metabolism in the frontal cortex and thalamus was found in those with brain tumor-associated depression and supports the role of dysregulated tryptophan/kynurenine metabolism in this condition.

Multimodal neuroimaging of gliomatosis cerebri: a case series of four patients.

In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[11C]methyl-L-tryptophan ([11C]-AMT). Increased uptake of [11C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [11C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors.

Utility of MRI, PET, and ictal SPECT in presurgical evaluation of non-lesional pediatric epilepsy.

Children with epilepsy and normal structural MRI pose a particular challenge in localization of epileptic foci for surgical resection. Many of these patients have subtle structural lesions such as mild cortical dysplasia that can be missed by conventional MRI but may become detectable by optimized and advanced MRI acquisitions and post-processing. Specificity of objective analytic techniques such as voxel-based morphometry remains an issue. Combination of MRI with functional imaging approaches can improve the accuracy of detecting epileptogenic brain regions. Analysis of glucose positron emission tomography (PET) combined with high-resolution MRI can optimize detection of hypometabolic cortex associated with subtle cortical malformations and can also enhance presurgical evaluation in children with epileptic spasms. Additional PET tracers may detect subtle epileptogenic lesions and cortex with enhanced specificity in carefully selected subgroups with various etiologies; e.g., increased tryptophan uptake can identify epileptogenic cortical dysplasia in the interictal state. Subtraction ictal SPECT can be also useful to delineate ictal foci in those with non-localizing PET or after failed surgical resection. Presurgical delineation of language and motor cortex and the corresponding white matter tracts is increasingly reliable by functional MRI and DTI techniques; with careful preparation, these can be useful even in young and sedated children. While evidence-based pediatric guidelines are still lacking, the data accumulated in the last decade strongly indicate that multimodal imaging with combined analysis of MRI, PET, and/or ictal SPECT data can optimize the detection of subtle epileptogenic lesions and facilitate seizure-free outcome while minimizing the postsurgical functional deficit in children with normal conventional MRI.

Fluorine-18-Labeled PET Radiotracers for Imaging Tryptophan Uptake and Metabolism: a Systematic Review.

Due to its metabolism via the serotonin and kynurenine pathways, tryptophan plays a key role in multiple disease processes including cancer. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative positron emission tomography (PET) radiotracers. While human studies with such tracers have been confined to C-11-labeled compounds, preclinical development of F-18-labeled tryptophan-based radiotracers has surged in recent years. We performed a systematic review of studies reporting on such F-18-labeled tryptophan tracers to summarize and compare their biological characteristics and their potential for tumor imaging, with a particular focus on key enzymes of the kynurenine pathway (indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]), which play an important role in tumoral immune resistance. From a PubMed search, English language articles including data on the preparation and radiochemical and/or biological characteristics of F-18-labeled tryptophan derivative radiotracers were reviewed. A total of 19 original papers included data on 15 unique radiotracers, the majority of which were synthesized with an adequate radiochemical yield. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer thus far. Biodistribution studies showed high uptake in the pancreas, while the L-type amino acid transporter was the dominant transport mechanism for most of the reviewed tracers. Tracers tested for tumor uptake showed accumulation in tumor cell lines in vitro and in xenografts in vivo, often with favorable tumor-to-background uptake ratios in comparison with clinically used F-18-labeled radiotracers. Five tracers showed promise for imaging IDO activity, including 1-(2-[18F]fluoroethyl)-L-tryptophan and a F-18-labeled analog of alpha-[11C]methyl-L-tryptophan tested clinically in previous studies. Two radiotracers were metabolized by TDO but showed defluorination in vivo. In summary, most F-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several reported tracers could be candidates for further testing and validation toward PET imaging applications in a variety of human diseases.

Multimodal Imaging of Nonenhancing Glioblastoma Regions.

BACKGROUND: Clinical glioblastoma treatment mostly focuses on the contrast-enhancing tumor mass. Amino acid positron emission tomography (PET) can detect additional, nonenhancing glioblastoma-infiltrated brain regions that are difficult to distinguish on conventional magnetic resonance imaging (MRI). We combined MRI with perfusion imaging and amino acid PET to evaluate such nonenhancing glioblastoma regions. METHODS: Structural MRI, relative cerebral blood volume (rCBV) maps from perfusion MRI, and α-[11C]-methyl-l-tryptophan (AMT)-PET images were analyzed in 20 patients with glioblastoma. The AMT uptake and rCBV (expressed as tumor to normal [T/N] ratios) were compared in nonenhancing tumor portions showing increased signal on T2/fluid-attenuated inversion recovery (T2/FLAIR) images. RESULTS: Thirteen (65%) tumors showed robust heterogeneity in nonenhancing T2/FLAIR hyperintense areas on AMT-PET, whereas the nonenhancing regions in the remaining 7 cases had homogeneous AMT uptake (low in 6, high in 1). AMT and rCBV T/N ratios showed only a moderate correlation in the nonenhancing regions (r = 0.41, P = .017), but regions with very low rCBV (<0.79 T/N ratio) had invariably low AMT uptake. CONCLUSIONS: The findings demonstrate the metabolic and perfusion heterogeneity of nonenhancing T2/FLAIR hyperintense glioblastoma regions. Amino acid PET imaging of such regions can detect glioma-infiltrated brain for treatment targeting; however, very low rCBV values outside the contrast-enhancing tumor mass make increased AMT uptake in nonenhancing glioblastoma regions unlikely.

Influence of hemispheric white matter lesions and migraine characteristics on cortical thickness and volume.

BACKGROUND/AIM: Migraine-related intracerebral white matter lesions (WMLs) are likely to be microvascular in nature and can be found in all hemispheric lobes. The aim of this study was to investigate migraine patients with or without WMLs to see the effects of these tissue damages on cortical thickness and volume. The role of migraine characteristics (duration of headache, attack frequency, estimated lifetime attack number, aura) was also tested. METHODS: As study participants, 161 female migraine patients (63 with aura; 52 with WMLs) and 40 age-matched healthy female subjects were enrolled in the study. None of the included migraine patients' headache or aura (where present) was unilaterally side-locked. Patients and controls were all right handed. Except for migraine, patients were free of any medical comorbidity. Cortical reconstruction and segmentation were performed on the 3D T1-weighted images using Freesurfer 5.3 image analysis suite. The automatic cortical parcellation was based on Freesurfer's Desikan-Killiany-Tourville atlas, which has 31 cortical regions per hemisphere. The segmented regions were divided into five lobes (frontal, parietal, temporal, occipital, insula). Since the left and right differences in lobar and insular volumes/thicknesses were not different among our groups, volume and cortical thickness were calculated for corresponding bilateral lobes. RESULTS: There was no significant difference in age between the whole migraine and the control groups. Migraineurs with WMLs (L+ patients) were significantly older than lesion-free (L-) patients (P = 0.0003) and controls (P = 0.018). Disease duration (P = 0.003), the total number of migraine attacks (P = 0.022) and the rate of aura (P = 0.0003) were significantly higher in L+ patients than in L- patients. Cortical thickness and volume measurements of lobes were not statistically different between the three groups (L+, L-, control). Age showed a significant negative association with both thickness and volume in each examined lobe (P < 0.001). Intracranial volume (ICV) showed a significant positive association with all regional volumes (P < 0.001). There were no significant group*age, group*ICV, or age*ICV interactions. None of the migraine characteristics were selected by stepwise linear regression as significant predictors of cortical thickness or volume. Only age (for both thickness and volume) and ICV (for volume) were identified as significant predictors (P < 0.001). When the L + group was divided into two subgroups by median split of total and lobar lesion number and volume, the cortical measures did not show any significant difference between the groups with low vs. high lesion number/volume by stepwise linear regression. CONCLUSIONS: In a female migraine group, we found that the WMLs and clinical migraine characteristics have no effect on cortical thickness and volume of bilateral lobes. Lobar cortical thicknesses were equivalent within the range of ±0.1 mm. Only age and ICV proved to be significant predictors; the former for both cortical thickness and volume, while the latter for cortical volume.

Feasibility of Multimodal MRI-Based Deep Learning Prediction of High Amino Acid Uptake Regions and Survival in Patients With Glioblastoma.

Purpose: Amino acid PET has shown high accuracy for the diagnosis and prognostication of malignant gliomas, however, this imaging modality is not widely available in clinical practice. This study explores a novel end-to-end deep learning framework ("U-Net") for its feasibility to detect high amino acid uptake glioblastoma regions (i.e., metabolic tumor volume) using clinical multimodal MRI sequences. Methods: T2, fluid-attenuated inversion recovery (FLAIR), apparent diffusion coefficient map, contrast-enhanced T1, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 21 patients with newly-diagnosed glioblastoma. U-Net system with data augmentation was implemented to deeply learn non-linear voxel-wise relationships between intensities of multimodal MRI as the input and metabolic tumor volume from AMT-PET as the output. The accuracy of the MRI- and PET-based volume measures to predict progression-free survival was tested. Results: In the augmented dataset using all four MRI modalities to investigate the upper limit of U-Net accuracy in the full study cohort, U-Net achieved high accuracy (sensitivity/specificity/positive predictive value [PPV]/negative predictive value [NPV]: 0.85/1.00/0.81/1.00, respectively) to predict PET-defined tumor volumes. Exclusion of FLAIR from the MRI input set had a strong negative effect on sensitivity (0.60). In repeated hold out validation in randomly selected subjects, specificity and NPV remained high (1.00), but mean sensitivity (0.62), and PPV (0.68) were moderate. AMT-PET-learned MRI tumor volume from this U-net model within the contrast-enhancing volume predicted 6-month progression-free survival with 0.86/0.63 sensitivity/specificity. Conclusions: These data indicate the feasibility of PET-based deep learning for enhanced pretreatment glioblastoma delineation and prognostication by clinical multimodal MRI.

Multimodal imaging-defined subregions in newly diagnosed glioblastoma: impact on overall survival.

BACKGROUND: Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value. METHODS: Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined. RESULTS: A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = -0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98-31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients. CONCLUSIONS: Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival.

Deep cerebral vein expansion with metabolic and neurocognitive recovery in Sturge-Weber syndrome.

We present longitudinal imaging data of a child with Sturge-Weber syndrome (SWS). At age 8 months, 3 weeks after initial seizures and prolonged motor deficit, MRI showed extensive right hemispheric SWS involvement with severe glucose hypometabolism on PET. She was treated with levetiracetam and aspirin. Follow-up imaging at age 29 months showed a robust interval expansion of enlarged deep medullary veins throughout the affected hemisphere along with a dramatic recovery of hemispheric metabolism and normalized neurocognitive functioning. These findings demonstrate a robust, multilobar hemispheric remodeling of deep venous collaterals that likely contributed to reversal of initial metabolic and neurocognitive deficits.

Iron Concentration in Deep Gray Matter Structures is Associated with Worse Visual Memory Performance in Healthy Young Adults.

Abnormally high deposition of iron can contribute to neurodegenerative disorders with cognitive impairment. Since previous studies investigating cognition-brain iron accumulation relationships focused on elderly people, our aim was to explore the association between iron concentration in subcortical nuclei and two types of memory performances in a healthy young population. Gender difference was found only in the globus pallidus. Our results showed that iron load characterized by R2* value on the MRI in the caudate and putamen was related to visual memory, while verbal memory was unrelated to iron concentration.

Age at onset and seizure frequency affect white matter diffusion coefficient in patients with mesial temporal lobe epilepsy.

In mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), structural abnormalities are present not only in the hippocampus but also in the white matter with ipsilateral predominance. Although the timing of epilepsy onset is commonly associated with clinical and semiological dissimilarities, limited data exist regarding white matter diffusion changes with respect to age at epilepsy onset. The aim of this study was to investigate diffusion changes in the white matter of patients with unilateral MTLE-HS with respect to clinical parameters and to compare them with an age- and sex-matched healthy control group. Apparent diffusion coefficients (ADCs) were derived using monoexponential approaches from 22 (11 early and 11 late age at onset) patients with unilateral MTLE-HS and 22 age- and sex-matched control subjects after acquiring diffusion-weighted images on a 3T MRI system. Data were analyzed using two-tailed t-tests and multiple linear regression models. In the group with early onset MTLE-HS, ADC was significantly elevated in the ipsilateral hemispheric (p=0.04) and temporal lobe white matter (p=0.01) compared with that in controls. These differences were not detectable in late onset MTLE-HS patients. Apparent diffusion coefficient of the group with early onset MTLE-HS was negatively related to age at epilepsy onset in the ipsilateral hemispheric white matter (p=0.03) and the uncinate fasciculus (p=0.03), while in patients with late onset MTLE-HS, ADC was no longer dependent on age at epilepsy onset itself but rather on the seizure frequency in the ipsilateral uncinate fasciculus (p=0.03). Such diffusivity pattern has been associated with chronic white matter degeneration, reflecting myelin loss and higher extracellular volume which are more pronounced in the frontotemporal regions and also depend on clinical features. In the group with early onset MTLE-HS, the timing of epilepsy seems to be the major cause of white matter abnormalities while in late onset disease, it has a secondary role in provoking diffusion changes.

White-matter microstructure and language lateralization in left-handers: a whole-brain MRI analysis.

Most people are left-hemisphere dominant for language. However the neuroanatomy of language lateralization is not fully understood. By combining functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), we studied whether language lateralization is associated with cerebral white-matter (WM) microstructure. Sixteen healthy, left-handed women aged 20-25 were included in the study. Left-handers were targeted in order to increase the chances of involving subjects with atypical language lateralization. Language lateralization was determined by fMRI using a verbal fluency paradigm. Tract-based spatial statistics analysis of DTI data was applied to test for WM microstructural correlates of language lateralization across the whole brain. Fractional anisotropy and mean diffusivity were used as indicators of WM microstructural organization. Right-hemispheric language dominance was associated with reduced microstructural integrity of the left superior longitudinal fasciculus and left-sided parietal lobe WM. In left-handed women, reduced integrity of the left-sided language related tracts may be closely linked to the development of right hemispheric language dominance. Our results may offer new insights into language lateralization and structure-function relationships in human language system.