Value of 7T MRI and post-processing in patients with nonlesional 3T MRI undergoing epilepsy presurgical evaluation.

OBJECTIVE: Ultra-high-field 7-Tesla (7T) magnetic resonance imaging (MRI) offers increased signal-to-noise and contrast-to-noise ratios, which may improve visualization of cortical malformations. We aim to assess the clinical value of in vivo structural 7T MRI and its post-processing for the noninvasive identification of epileptic brain lesions in patients with pharmacoresistant epilepsy and nonlesional 3T MRI who are undergoing presurgical evaluation. METHODS: Sixty-seven patients were included who had nonlesional 3T MRI by official radiology report. Epilepsy protocols were used for the 3T and 7T acquisitions. Post-processing of the 7T T1-weighted magnetization-prepared two rapid acquisition gradient echoes sequence was performed using the morphometric analysis program (MAP) with comparison to a normal database consisting of 50 healthy controls. Review of 7T was performed by an experienced board-certified neuroradiologist and at the multimodal patient management conference. The clinical significance of 7T findings was assessed based on intracranial electroencephalography (ICEEG) ictal onset, surgery, postoperative seizure outcomes, and histopathology. RESULTS: Unaided visual review of 7T detected previously unappreciated subtle lesions in 22% (15/67). When aided by 7T MAP, the total yield increased to 43% (29/67). The location of the 7T-identified lesion was identical to or contained within the ICEEG ictal onset in 13 of 16 (81%). Complete resection of the 7T-identified lesion was associated with seizure freedom (P = .03). Histopathology of the 7T-identified lesions encountered mainly focal cortical dysplasia (FCD). 7T MAP yielded 25% more lesions (6/24) than 3T MAP, and showed improved conspicuity in 46% (11/24). SIGNIFICANCE: Our data suggest a major benefit of 7T with post-processing for detecting subtle FCD lesions for patients with pharmacoresistant epilepsy and nonlesional 3T MRI.

Development of high-resolution 3D MR fingerprinting for detection and characterization of epileptic lesions.

BACKGROUND: Conventional MRI can be limited in detecting subtle epileptic lesions or identifying active/epileptic lesions among widespread, multifocal lesions. PURPOSE: We developed a high-resolution 3D MR fingerprinting (MRF) protocol to simultaneously provide quantitative T1 , T2 , proton density, and tissue fraction maps for detection and characterization of epileptic lesions. STUDY TYPE: Prospective. POPULATION: National Institute of Standards and Technology (NIST) / International Society for Magnetic Resonance in Medicine (ISMRM) phantom, five healthy volunteers and 15 patients with medically intractable epilepsy undergoing presurgical evaluation with noninvasive or invasive electroclinical data. FIELD STRENGTH/SEQUENCE: 3D MRF scans and routine clinical epilepsy MR protocols were acquired at 3 T. ASSESSMENT: The accuracy of the T1 and T2 values were first evaluated using the NIST/ISMRM phantom. The repeatability was then estimated with both phantom and volunteers based on the coefficient of variance (CV). For epilepsy patients, all the maps were qualitatively reviewed for lesion detection by three independent reviewers (S.E.J., M.L., I.N.) blinded to clinical data. Region of interest (ROI) analysis was performed on T1 and T2 maps to quantify the multiparametric signal differences between lesion and normal tissues. Findings from qualitative review and quantitative ROI analysis were compared with patients' electroclinical data to assess concordance. STATISTICAL TESTS: Phantom results were compared using R-squared, and patient results were compared using linear regression models. RESULTS: The phantom study showed high accuracy with the standard values, with an R2 of 0.99. The volunteer study showed high repeatability, with an average CV of 4.3% for T1 and T2 in various tissue regions. For the 15 patients, MRF showed additional findings in four patients, with the remaining 11 patients showing findings consistent with conventional MRI. The additional MRF findings were highly concordant with patients' electroclinical presentation. DATA CONCLUSION: The 3D MRF protocol showed potential to identify otherwise inconspicuous epileptogenic lesions from the patients with negative conventional MRI diagnosis, as well as to correlate with different levels of epileptogenicity when widespread lesions were present. LEVEL OF EVIDENCE: 3. Technical Efficacy Stage: 3. J. Magn. Reson. Imaging 2019;49:1333-1346.

Quantitative positron emission tomography-guided magnetic resonance imaging postprocessing in magnetic resonance imaging-negative epilepsies.

OBJECTIVE: Detection of focal cortical dysplasia (FCD) is of paramount importance in epilepsy presurgical evaluation. Our study aims at utilizing quantitative positron emission tomography (QPET) analysis to complement magnetic resonance imaging (MRI) postprocessing by a morphometric analysis program (MAP) to facilitate automated identification of subtle FCD. METHODS: We retrospectively included a consecutive cohort of surgical patients who had a negative preoperative MRI by radiology report. MAP was performed on T1-weighted volumetric sequence and QPET was performed on PET/computed tomographic data, both with comparison to scanner-specific normal databases. Concordance between MAP and QPET was assessed at a lobar level, and the significance of concordant QPET-MAP+ abnormalities was confirmed by postresective seizure outcome and histopathology. QPET thresholds of standard deviations (SDs) of -1, -2, -3, and -4 were evaluated to identify the optimal threshold for QPET-MAP analysis. RESULTS: A total of 104 patients were included. When QPET thresholds of SD = -1, -2, and -3 were used, complete resection of the QPET-MAP+ region was significantly associated with seizure-free outcome when compared with the partial resection group (P = 0.023, P < 0.001, P = 0.006) or the no resection group (P = 0.002, P < 0.001, P = 0.001). The SD threshold of -2 showed the best combination of positive rate (55%), sensitivity (0.68), specificity (0.88), positive predictive value (0.88), and negative predictive value (0.69). Surgical pathology of the resected QPET-MAP+ areas revealed mainly FCD type I. Multiple QPET-MAP+ regions were present in 12% of the patients at SD = -2. SIGNIFICANCE: Our study demonstrates a practical and effective approach to combine quantitative analyses of functional (QPET) and structural (MAP) imaging data to improve identification of subtle epileptic abnormalities. This approach can be readily adopted by epilepsy centers to improve postresective seizure outcomes for patients without apparent lesions on MRI.

Amyloid-ß deposition in mild cognitive impairment is associated with increased hippocampal activity, atrophy and clinical progression.

Cross-sectional functional magnetic resonance imaging studies using a memory task in patients with mild cognitive impairment have produced discordant results, with some studies reporting increased hippocampal activity--consistent with findings in genetic at-risk populations--and other studies reporting decreased hippocampal activity, relative to normal controls. However, previous studies in mild cognitive impairment have not included markers of amyloid-ß, which may be particularly important in prediction of progression along the Alzheimer's disease continuum. Here, we examine the contribution of amyloid-ß deposition to cross-sectional and longitudinal measures of hippocampal functional magnetic resonance imaging activity, hippocampal volume, global cognition and clinical progression over 36 months in 33 patients with mild cognitive impairment. Amyloid-ß status was examined with positron emission tomography imaging using Pittsburg compound-B, hippocampal functional magnetic resonance imaging activity was assessed using an associative face-name memory encoding task, and hippocampal volume was quantified with structural magnetic resonance imaging. Finally global cognition was assessed using the Mini-Mental State Examination and clinical progression was assessed using the Clinical Dementia Rating (Sum of Boxes). At baseline, amyloid-ß positive patients with mild cognitive impairment showed increased hippocampal activation, smaller hippocampal volumes, and a trend towards lower Mini-Mental State Examination scores and higher Clinical Dementia Ratings compared to amyloid-ß negative patients with mild cognitive impairment. Longitudinally, amyloid-ß positive patients with mild cognitive impairment continued to show high levels of hippocampal activity, despite increasing rates of hippocampal atrophy, decline on the Mini-Mental State Examination and faster progression on the Clinical Dementia Ratings. When entered simultaneously into the same linear mixed model, amyloid-ß status, hippocampal activation, and hippocampal volume independently predicted clinical progression. These results indicate that amyloid-ß positive patients with mild cognitive impairment are more likely on a path towards Alzheimer's disease dementia than amyloid-ß negative patients. Increased hippocampal activity is discussed in relation to neuronal compensation and/or amyloid-ß induced excitoxicity.

Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC).

Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC.

Characterization of white matter lesions in multiple sclerosis using proton density and T1-relaxation measures.

PURPOSE: Although lesion dissemination in time is a defining characteristic of multiple sclerosis (MS), there is a limited understanding of lesion heterogeneity. Currently, conventional sequences such as fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W) data are used to assess MS lesions qualitatively. Estimating water content could provide a measure of local tissue rarefaction, or reduced tissue density, resulting from chronic inflammation. Our goal was to utilize the proton spin density (PD), derived from a rapid, multi-contrast STAGE (strategically acquired gradient echo) protocol to characterize white matter (WM) lesions seen on T2W, FLAIR and T1W data. MATERIALS AND METHODS: Twenty (20) subjects with relapsing-remitting MS were scanned at 3 T using T1W, T2-weighted, FLAIR and strategically acquired gradient echo (STAGE) sequences. PD and T1 maps were derived from the STAGE data. Disease severity scores, including Extended Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), were correlated with total, high PD and high T1 lesion volumes. A probability map of high PD regions and all lesions across all subjects was generated. Five perilesional normal appearing WM (NAWM) bands surrounding the lesions were generated to compare the median PD and T1 values in each band with the lesional values and the global WM. RESULTS: T1W intensity was negatively correlated with PD as expected (R = -0.87, p < 0.01, R2 = 0.756) and the FLAIR signal was suppressed for high PD volumes within the lesions, roughly for PD ≥ 0.85. The threshold for high PD and T1 regions was set to 0.909 and 1953.6 ms, respectively. High PD regions showed a high probability of occurrence near the boundary of the lateral ventricles. EDSS score and nine-hole peg test (dominant and non-dominant hand) were significantly correlated with the total lesion volume and the volumes of high PD and T1 regions (p < 0.05). There was a significant difference in PD/T1 values between the high PD/T1 regions within the lesions and the remaining lesional tissue (p < 0.001). In addition, the PD values of the first NAWM perilesional band directly adjacent to the lesional boundary displayed a significant difference (p < 0.05) compared to the global WM. CONCLUSION: Lesions with high PD and T1s had the highest probability of occurrence at the boundary of the lateral ventricles and likely represent chronic lesions with significant local tissue rarefaction. Moreover, the perilesional NAWM exhibited subtly increasing PD and T1 values from the NAWM up to the lesion boundary. Unlike on the T1 maps, the perilesional band adjacent to the lesion boundary possessed a significantly higher PD value than the global WM PD values. This shows that PD maps were sensitive to the subtle changes in NAWM surrounding the lesions.

PET tracers in glioblastoma: Toward neurotheranostics as an individualized medicine approach.

Over the past decade, theragnostic radiopharmaceuticals have been used in nuclear medicine for both diagnosis and treatment of various tumors. In this review, we carried out a literature search to investigate and explain the role of radiotracers in the theragnostic approach to glioblastoma multiform (GBM). We primarily focused on basic and rather common positron emotion tomography (PET) radiotracers in these tumors. Subsequently, we introduced and evaluated the preclinical and clinical results of theranostic-based biomarkers including integrin receptor family, prostate-specific membrane antigen (PSMA), fibroblast activated protein (FAP), somatostatin receptors (SRS), and chemokine receptor-4 (CXCR4) for patients with GBM to confer the benefit of personalized therapy. Moreover, promising research opportunities that could have a profound impact on the treatment of GBM over the next decade are also highlighted. Preliminary results showed the potential feasibility of the theragnostic approach using theses biomarkers in GBM patients.

Structure of the extracellular portion of CD46 provides insights into its interactions with complement proteins and pathogens.

The human membrane cofactor protein (MCP, CD46) is a central component of the innate immune system. CD46 protects autologous cells from complement attack by binding to complement proteins C3b and C4b and serving as a cofactor for their cleavage. Recent data show that CD46 also plays a role in mediating acquired immune responses, and in triggering autophagy. In addition to these physiologic functions, a significant number of pathogens, including select adenoviruses, measles virus, human herpes virus 6 (HHV-6), Streptococci, and Neisseria, use CD46 as a cell attachment receptor. We have determined the crystal structure of the extracellular region of CD46 in complex with the human adenovirus type 11 fiber knob. Extracellular CD46 comprises four short consensus repeats (SCR1-SCR4) that form an elongated structure resembling a hockey stick, with a long shaft and a short blade. Domains SCR1, SCR2 and SCR3 are arranged in a nearly linear fashion. Unexpectedly, however, the structure reveals a profound bend between domains SCR3 and SCR4, which has implications for the interactions with ligands as well as the orientation of the protein at the cell surface. This bend can be attributed to an insertion of five hydrophobic residues in a SCR3 surface loop. Residues in this loop have been implicated in interactions with complement, indicating that the bend participates in binding to C3b and C4b. The structure provides an accurate framework for mapping all known ligand binding sites onto the surface of CD46, thereby advancing an understanding of how CD46 acts as a receptor for pathogens and physiologic ligands of the immune system.

Mannose-binding lectin binds to amyloid ß protein and modulates inflammation.

Mannose-binding lectin (MBL), a soluble factor of the innate immune system, is a pattern recognition molecule with a number of known ligands, including viruses, bacteria, and molecules from abnormal self tissues. In addition to its role in immunity, MBL also functions in the maintenance of tissue homeostasis. We present evidence here that MBL binds to amyloid ß peptides. MBL binding to other known carbohydrate ligands is calcium-dependent and has been attributed to the carbohydrate-recognition domain, a common feature of other C-type lectins. In contrast, we find that the features of MBL binding to Aß are more similar to the reported binding characteristics of the cysteine-rich domain of the unrelated mannose receptor and therefore may involve the MBL cysteine-rich domain. Differences in MBL ligand binding may contribute to modulation of inflammatory response and may correlate with the function of MBL in processes such as coagulation and tissue homeostasis.

Theranostics in Brain Tumors.

Theranostic nuclear oncology, mainly in neuro-oncology (neurotheranostics), aims to combine cancer imaging and therapy using the same targeting molecule. This approach tries to identify patients who are most likely to benefit from tumor molecular radionuclide therapy. The ability of radioneurotheranostic agents to interact with cancer cells at the molecular level with high specificity can significantly improve the effectiveness of cancer therapy. A variety of biologic targets are under investigation for treating brain tumors. PET-based precision imaging can substantially improve the therapeutic efficacy of radiotheranostic approach in brain tumors.

Multimodal assessment of regional gray matter integrity in early relapsing-remitting multiple sclerosis patients with normal cognition: a voxel-based structural and perfusion approach.

OBJECTIVE: There is increasing evidence that gray matter (GM) impairment is strongly associated with clinical performance decline. We aim to perform a voxelwise analysis between regional GM (rGM) perfusion and structural abnormalities in early relapsing-remitting multiple sclerosis patients with normal cognition (RRMS-IC) and explore clinical correlate of early rGM abnormalities. METHODS AND MATERIALS: We studied 14 early RRMS-IC patients and 14 healthy age- and sex-matched controls. Brain perfusion single photon emission computed tomography (SPECT), structural MRI, and a comprehensive neuropsychological examination were acquired from all participants. Neuropsychological tests include expanded disability status scale, minimal mental status examination, short physical performance battery, Wechsler memory scale, and quick smell test. Voxel-based morphometry was used for analyzing SPECT and T1-MR images to identify rGM hypoperfusion and atrophy, respectively (RRMS-IC vs controls (group analysis), and also, each patient vs controls (individual analysis)) (p < 0.001). Then, anatomical location of impaired regions was acquired by automated anatomical labeling software. RESULTS: There was no significant difference in total GM volume between RRMS-IC and healthy controls, however, rGM atrophy and hypoperfusion were detected. Individual analysis revealed more rGM impairment compared with group analysis. rGM hypoperfusion was more extensive rather than rGM atrophy in RRMS-IC. There was no spatial association between rGM atrophy and rGM hypoperfusion (p > 0.05). rGM abnormalities correlated with several relevant minimal clinical deficits. CONCLUSION: Lack of spatial correlation between rGM atrophy and hypoperfusion might suggest that independent mechanisms might underlie atrophy and hypoperfusion. Perfusion SPECT may provide supplementary information along with MRI. ADVANCES IN KNOWLEDGE: Association between rGM atrophy and rGM hypoperfusion and their clinical significance in early RRMS-IC is not well described yet. Our study showed that there is spatial dissociation between rGM atrophy and rGM hypoperfusion, suggesting that different mechanisms might underlie these pathologies.

Amyloid Precursor Protein Variant, E665D, Associated With Unique Clinical and Biomarker Phenotype.

We describe a clinical, imaging and biomarker phenotype associated with an amyloid precursor gene (APP) E665D variant in a 45-year-old man with progressive cognitive and behavioral dysfunction. Brain MRI showed bilateral, confluent T2 hyperintensities predominantly in the anterior white matter. Amyloid imaging and CSF testing were consistent with amyloid deposition. 7 Tesla MRI revealed cerebral microhemorrhages suggestive of cerebral amyloid angiopathy (CAA). Contrary to previous reports, this case raises the possibility that the APP E665D genetic change may be pathogenic, particularly given the abnormal Alzheimer's disease biomarkers observed in the cerebrospinal fluid, positive amyloid imaging and imaging evidence for CAA in a relatively young patient with progressive cognitive decline.

Radiological and Clinical Value of 7T MRI for Evaluating 3T-Visible Lesions in Pharmacoresistant Focal Epilepsies.

Objective: The recent FDA approval of the first 7T MRI scanner for clinical diagnostic use in October 2017 will likely increase the utilization of 7T for epilepsy presurgical evaluation. This study aims at accessing the radiological and clinical value of 7T in patients with pharmacoresistant focal epilepsy and 3T-visible lesions. Methods: Patients with pharmacoresistant focal epilepsy were included if they had a lesion on pre-operative standard-of-care 3T MRI and also a 7T research MRI. An epilepsy protocol was used for the acquisition of the 7T MRI. Prospective visual analysis of 7T MRI was performed by an experienced board-certified neuroradiologist and communicated to the patient management team. The clinical significance of the additional 7T findings was assessed by intracranial EEG (ICEEG) ictal onset, surgical resection, post-operative seizure outcome and histopathology. A subset of lesions were demarked with arrows for subsequent, retrospective comparison between 3T and 7T by 7 neuroradiologists using a set of quantitative scales: lesion presence, conspicuity, boundary, gray-white tissue contrast, artifacts, and the most helpful sequence for diagnosis. Conger's kappa for multiple raters was performed for chance-adjusted agreement statistics. Results: A total of 47 patients were included, with the main pathology types of focal cortical dysplasia (FCD), hippocampal sclerosis, periventricular nodular heterotopia (PVNH), tumor and polymicrogyria (PMG). 7T detected additional smaller lesions in 19% (9/47) of patients, who had extensive abnormalities such as PMG and PVNH; however, these additional findings were not necessarily epileptogenic. 3T-7T comparison by the neuroradiologist team showed that lesion conspicuity and lesion boundary were significantly better at 7T (p < 0.001), particularly for FCD, PVNH and PMG. Chance-adjusted agreement was within the fair range for lesion presence, conspicuity and boundary. Gray-white contrast was significantly improved at 7T (p < 0.001). Significantly more artifacts were encountered at 7T (p < 0.001). Significance: For patients with 3T-visible lesions, 7T MRI may better elucidate the extent of multifocal abnormalities such as PVNH and PMG, providing potential targets to improve ICEEG implantation. Patients with FCD, PVNH and PMG would likely benefit the most from 7T due to improved lesion conspicuity and boundary. Pathologies in the antero-inferior temporal regions likely benefit less due to artifacts.