Traumatic brain injury imaging research roadmap.

The past decade has seen impressive advances in the types of neuroimaging information that can be acquired in patients with traumatic brain injury. However, despite this increase in information, understanding of the contribution of this information to prognostic accuracy and treatment pathways for patients is limited. Available techniques often allow us to infer the presence of microscopic changes indicative of alterations in physiology and function in brain tissue. However, because histologic confirmation is typically lacking, conclusions reached by using these techniques remain solely inferential in almost all cases. Hence, a need exists for validation of these techniques by using data from large population samples that are obtained in a uniform manner, analyzed according to well-accepted procedures, and correlated with closely monitored clinical outcomes. At present, many of these approaches remain confined to population-based research rather than diagnosis at an individual level, particularly with regard to traumatic brain injury that is mild or moderate in degree. A need and a priority exist for patient-centered tools that will allow advanced neuroimaging tools to be brought into clinical settings. One barrier to developing these tools is a lack of an age-, sex-, and comorbidities-stratified, sequence-specific, reference imaging data base that could provide a clear understanding of normal variations across populations. Such a data base would provide researchers and clinicians with the information necessary to develop computational tools for the patient-based interpretation of advanced neuroimaging studies in the clinical setting. The recent "Joint ASNR-ACR HII-ASFNR TBI Workshop: Bringing Advanced Neuroimaging for Traumatic Brain Injury into the Clinic" on May 23, 2014, in Montreal, Quebec, Canada, brought together neuroradiologists, neurologists, psychiatrists, neuropsychologists, neuroimaging scientists, members of the National Institute of Neurologic Disorders and Stroke, industry representatives, and other traumatic brain injury stakeholders to attempt to reach consensus on issues related to and develop consensus recommendations in terms of creating both a well-characterized normative data base of comprehensive imaging and ancillary data to serve as a reference for tools that will allow interpretation of advanced neuroimaging tests at an individual level of a patient with traumatic brain injury. The workshop involved discussions concerning the following: 1) designation of the policies and infrastructure needed for a normative data base, 2) principles for characterizing normal control subjects, and 3) standardizing research neuroimaging protocols for traumatic brain injury. The present article summarizes these recommendations and examines practical steps to achieve them.

Analysis of corpus callosum diffusion tensor imaging parameters in infants.

Radial diffusivity is a diffusion tensor imaging (DTI) metric that has received increased attention in recent studies as a parameter that may better reflect myelination than the more commonly-used fractional anisotropy (FA). This study compared rates of radial diffusivity decrease against FA increase and axial diffusivity decrease on DTI maps in the corpus callosum of normal infants during the first postnatal year. Fifty-three normal infants (range: 0-52 weeks adjusted for gestational age) underwent six-direction DTI on a 1.5 Tesla scanner (b= 1,000 s/mm(2), one excitation). A single individual placed regions of interest on FA maps in the genu 1) and radial diffusivity (i.e., λ and splenium to obtain axial (i.e., 3)/2]), FA and ADC. We calculated mean and median values for FA, λ 2+λ[ ADC, radial diffusivity and axial diffusivity in each of four 13-week epochs and measured the percent change over the first year of life. Within the genu, radial diffusivity decreased 36%, FA increased 25%, ADC decreased 22% and axial diffusivity decreased 10%. Within the splenium, radial diffusivity decreased 53%, FA increased 43%, ADC decreased 38%, and axial diffusivity decreased 23%. For both genu and splenium, the greatest difference was seen in radial diffusivity values, followed in order by FA, ADC and axial diffusivity. Furthermore, decreases in radial diffusivity were on the order of two to threefold greater than those in axial diffusivity. The high rate of radial diffusivity decrease compared to axial diffusivity decrease is consistent with myelination. Decreases in radial diffusivity were greater than increases in FA values. This finding is further support of the concept that radial diffusivity and FA values represent two different types of microstructural change during development of white matter.

Research challenges in central nervous system manifestations of inborn errors of metabolism.

The Research Challenges in CNS Manifestations of Inborn Errors of Metabolism workshop was designed to address challenges in translating potential therapies for these rare disorders, and to highlight novel therapeutic strategies and innovative approaches to CNS delivery, assessment of effects and directions for the future in the treatment of these diseases. Therapies for the brain in inborn errors represent some of the greatest challenges to translational research due to the special properties of the brain, and of inborn errors themselves. This review covers the proceedings of this workshop as submitted by participants. Scientific, ethical and regulatory issues are discussed, along with ways to measure outcomes and the conduct of clinical trials. Participants included regulatory and funding agencies, clinicians, scientists, industry and advocacy groups.

Sixty-four-section multidetector CT angiography of carotid arteries: a systematic analysis of image quality and artifacts.

BACKGROUND AND PURPOSE: Sixty-four-section CT scanners have recently been introduced for vascular imaging. Before such scanners reach widespread use, scanning protocol should be optimized and image quality assessed. The goals of this study were to systematically measure image quality and determine the prevalence of various types of artifacts produced by a 64-section scanner. MATERIALS AND METHODS: We retrospectively reviewed CT angiography (CTA) scans obtained on a 64-section CT scanner in 100 consecutive patients presenting to the emergency department during a 2-month period with a suspected acute cerebrovascular event. We evaluated scan quality by using 2 different methods: First, we quantitatively assessed arterial opacification by measuring attenuation values in 9 arterial segments from the aortic arch to the distal cervical internal carotid artery, by using a threshold of 150 HU as an indicator of good opacification. Second, we assessed image contrast between arteries and veins by measuring attenuation within venous segments and recording the number of artery-vein-segment pairs in which the attenuation difference was 150 HU). Image contrast between artery and vein segments was also good, with 714 of 763 analyzable segment pairs (85.6%) having >50 HU difference. Artifacts obscuring arterial evaluation included streak from contrast material in the subclavian/brachiocephalic vein (32% of patients), attenuation of the x-ray beam between the shoulders (28%), beam-hardening from metallic hardware (26%), and contrast material reflux into neck veins (16%). The most clinically relevant artifacts were flow artifacts, mimicking dissection or vascular occlusion; they were seen in 14% of patients and likely are related to the rapid data acquisition for CTA on 64-section scanners (compared with the circulation of contrast material in the cervical arteries). None of the patients in our historical control group who underwent 16-section CT had flow artifacts on their CTA studies; the incidence of the other types of artifacts in this group was similar to that in patients imaged with 64-section CT. CONCLUSIONS: The 64-section CTA imaging protocol for carotid arteries yields high-quality studies in >95% of cases.

Uses of nanoparticles for central nervous system imaging and therapy.

SUMMARY: Applications of nanotechnology to medicine are leading to novel means of imaging living systems and of delivering therapy. Much nanotechnology research is focused on methods for imaging central nervous system functions and disease states. In this review, the principles of nanoparticle design and function are discussed with specific emphasis on applications to neuroradiology. In addition to innovative forms of imaging, this review describes therapeutic uses of nanoparticles, such as drug delivery systems, neuroprotection devices, and methods for tissue regeneration.

Systematic review of CT and MR perfusion imaging for assessment of acute cerebrovascular disease.

BACKGROUND AND PURPOSE: Perfusion imaging sequences are an important part of imaging studies designed to provide information to guide therapy for treatment of cerebrovascular disease. The purpose of this study was to perform a meta-analysis of the medical literature on perfusion imaging to determine its role in clinical decision making for patients with acute cerebral ischemia. MATERIALS AND METHODS: We searched MEDLINE by using a strategy that combined terms related to perfusion imaging with terms related to acute cerebral ischemia and brain tumors. We identified 658 perfusion imaging articles and classified them according to the clinical usefulness criteria of Thornbury and Fryback. We found 59 articles with promise of indicating usefulness in clinical decision making. We devised and implemented a clinical decision making scoring scale more appropriate to the topic of acute cerebral ischemia. RESULTS: Several articles provided important insights into the physiologic processes underlying acute cerebral ischemia by correlation of initial perfusion imaging deficits with clinical outcome or ultimate size of the infarct. However, most articles showed relatively low relevance to influencing decisions in implementing treatment. CONCLUSION: Most perfusion imaging articles are oriented toward important topics such as optimization of imaging parameters, determination of ischemia penumbra, and prediction of outcome. However, information as to the role of perfusion imaging in clinical decision making is lacking. Studies are needed to demonstrate that use of perfusion imaging changes outcome of patients with acute cerebral ischemia.

Central nervous system extraosseous Ewing sarcoma: radiologic manifestations of this newly defined pathologic entity.

Although these entities are histologically similar, recent advances in molecular genetics have allowed the distinction of central nervous system extraosseous Ewing sarcoma (CNS-EES) from central primitive neuroectodermal tumors (c-PNET) including medulloblastoma and supratentorial PNET. We present 2 cases of pathologically confirmed CNS-EES. Knowledge of CNS-EES as a distinct entity enables the neuroradiologist to suggest the proper diagnosis and the need for special immuno-histochemical and molecular studies to confirm the diagnosis. Because treatment and prognosis are vastly different, the proper diagnosis of CNS-EES versus c-PNET is critical.

Cerebral blood flow, blood volume, and vascular permeability of cerebral glioma assessed with dynamic CT perfusion imaging.

We report dynamic CT perfusion imaging assessment of hemodynamics in a patient with a high-grade cerebral glioma and compare our results to those of previously published studies.

Analysis of normal-appearing white matter in multiple sclerosis: comparison of diffusion tensor MR imaging and magnetization transfer imaging.

BACKGROUND AND PURPOSE: Our purpose was to compare diffusion tensor MR and magnetization transfer imaging in assessing normal-appearing white matter (WM) regions in multiple sclerosis (MS). METHODS: Diffusion tensor, magnetization transfer, and conventional MR imaging were performed in 12 patients with MS. Fractional anisotropy, apparent diffusion coefficients (ADCs), and magnetization transfer ratios (MTRs) were measured in plaques, normal-appearing periplaque WM (PWM) regions, and normal-appearing WM regions remote from plaques. Mean fractional anisotropy, ADCs, and MTRs were calculated and compared in WM regions. RESULTS: Fractional anisotropy was lower in normal-appearing PWM regions than in remote WM regions (P <.001) but higher than in plaques (P <.001). MTRs were lower (not significantly, P =.19) in normal-appearing PWM regions than in remote regions. MTRs were higher in normal-appearing PWM regions than in plaques (P <.001). ADCs were higher in normal-appearing PWM regions than in remote regions (P =.008) but lower than in plaques (P =.001). Correlation between fractional anisotropy and MTRs of individual lesions was poor (r = 0.18) and between fractional anisotropy and ADC, modest (r = -0.39). CONCLUSION: In MS, diffusion tensor MR imaging can depict differences between WM regions that are not apparent on conventional MR images. Anisotropy measurements may be more sensitive than those of MTRs in detecting subtle abnormalities in PWM.

Human herpesvirus 6 limbic encephalitis after stem cell transplantation.

Central nervous system complications are common in stem cell transplant recipients, but selective involvement of the medial temporal area is unusual. The 5 patients reported here presented after stem cell transplantation with increased hippocampal T2 signal on magnetic resonance imaging and increased hippocampal glucose uptake on [F-18]fluorodeoxyglucose-positron emission tomography (FDG-PET) associated with short-term memory loss, insomnia, and temporal lobe electrographic seizure activity. The initial scalp electroencephalograms (EEGs) failed to detect seizure activity in these patients, although the memory dysfunction along with the magnetic resonance imaging and FDG-PET findings suggested subcortical seizure activity. However, extended EEG monitoring revealed repetitive temporal lobe electrographic seizure activity. Follow-up MRIs in 2 patients and postmortem findings on 1 patient suggested that hippocampal sclerosis had developed following the clinical syndrome. Cerebrospinal fluid studies revealed the presence of human herpesvirus 6, variant B, DNA in all of 3 patients who had lumbar punctures. Immunohistochemical staining for the P41 and P101 human herpesvirus 6 protein antigens showed numerous immunoreactive astrocytes and neurons in the hippocampus of 1 of the patients who died from other causes. Because of its subtle clinical presentation, this syndrome may be underrecognized, but can be diagnosed with appropriate magnetic resonance imaging techniques, EEG monitoring, and cerebrospinal fluid viral studies.

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

Quantitative assessment of diffusion abnormalities in posterior reversible encephalopathy syndrome.

BACKGROUND AND PURPOSE: Previous studies have shown that lesions in posterior reversible encephalopathy syndrome are often isointense on diffusion-weighted MR images. We hypothesized that 1) apparent diffusion coefficient (ADC) maps using various thresholds would show larger abnormalities in posterior white matter (WM) and 2) isointense appearance of lesions on isotropic diffusion-weighted images results from a balance of T2 prolongation effects and diffusibility effects. METHODS: T2-weighted MR images from 11 patients were reviewed. Hyperintense lesions were located in both anterior and posterior WM in eight patients and solely in posterior WM in three patients. The ADC maps were produced by use of ADC values > or = 3 SD and > or = 10 SD above the mean value of normal WM. Lesions on diffusion-weighted images were classified as isointense or hypointense. ADC values within lesions (ADC(L)) were compared with those of normal WM (ADC(N)), and compared for isointense lesions and hypointense lesions. RESULTS: The distribution of lesions with ADC values > or = 3 SD was essentially identical to that on T2-weighted images. Regions with ADC values > or = 10 SD were found in both anterior WM and posterior WM in two patients and solely in posterior WM in nine patients. On diffusion-weighted images, lesions appeared isointense in seven patients and hypointense in four patients. Mean ADC(L)/ADC(N) for all lesions was 1.81; for hypointense lesions, 2.30. CONCLUSION: Vasogenic edema was more severe in posterior WM. Isointense lesions result from a balance of T2 effects and increased water diffusibility. Hypointense lesions have higher ADC values, which are not balanced by T2 effects.

(18)F-fluorodeoxyglucose positron emission tomography and MR imaging findings in Rasmussen encephalitis.

BACKGROUND AND PURPOSE: Rasmussen encephalitis is a chronic, progressive encephalitis that manifests as an abrupt-onset, intractable seizure disorder in previously developmentally normal children. The objectives of the current study were to characterize the (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and MR imaging findings in Rasmussen encephalitis and to test the hypotheses that data from both imaging techniques are required to establish the diagnosis and identify the affected cerebral hemisphere in some cases. METHODS: Eleven patients with Rasmussen encephalitis were identified from a review of a computer database. The MR (n = 10) and PET (n = 11) imaging data were reviewed retrospectively and conjointly. RESULTS: On MR images, nine of 10 patients manifested bilateral cerebral atrophy that predominantly involved one hemisphere. One patient had purely unilateral cerebral atrophy. We observed foci of abnormally increased T2 signal intensity in nine of 10 patients. On FDG PET images, all patients showed extensive regions of hypometabolism within the cerebral hemisphere that showed the greatest atrophy. Discrete foci of hypermetabolism, indicative of seizure activity, were observed in six patients. The FDG PET and MR imaging findings were either stable or gradually progressive in patients with multiple imaging studies (MR, n = 5; FDG PET, n = 5). CONCLUSION: Rasmussen encephalitis is characterized by diffuse, unilateral cerebral hypometabolism on FDG PET images, with corresponding regions of cerebral atrophy on MR images. Although MR imaging data alone are sufficient to suggest a diagnosis of Rasmussen encephalitis in many cases, correlation with FDG PET data increases diagnostic confidence and allows the unequivocal identification of the affected cerebral hemisphere in patients whose MR imaging findings are subtle or distributed bilaterally.

Evidence of white matter tract disruption in MRI hyperintensities.

BACKGROUND: Diffusion tensor imaging (DTI) of brain tissue measures the apparent diffusion coefficient (ADC), or isotropic diffusion, and anisotropy, or diffusion as influenced by tissue structure. We hypothesized that hyperintensities, when compared with normal tissue by DTI, would show evidence of damage through an increased ADC and decreased anisotropy. We also hypothesized that DTI changes in hyperintensities would be similar between depressed subjects and control subjects. METHODS: Fourteen depressed geriatric patients and nineteen control subjects received DTI. The ADC and aniso-tropy of normal tissue from standard regions were compared with hyperintensities from these regions. The Students' t test compared individual regions and averaged white matter results. RESULTS: Hyperintensities showed higher ADC and lower anisotropy than normal regions. Gray matter exhibited similar trends. There was no significant difference in diffusion characteristics of hyperintensities between subjects and control subjects. CONCLUSIONS: Hyperintensities damage the structure of brain tissue, and do so comparably in depressed subjects and control subjects.

MRI correlates of suicide attempt history in unipolar depression.

BACKGROUND: Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS: In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS: Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS: Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Cerebral abscesses: investigation using apparent diffusion coefficient maps.

The combination of high signal and reduced apparent diffusion coefficients (ADC) within abscesses on diffusion-weighted MRI (DWI) has been reported as characteristic of abscesses, and useful for distinguishing them from cystic or necrotic neoplasms. To assess whether these are consistent findings in abscesses, we used DWI-derived ADC to investigate changes in water diffusibility in cerebral abscesses. We reviewed the MRI studies and clinical records of five patients with brain abscesses, who underwent DWI. Regions of interest were drawn within the abscesses on ADC maps, to obtain the ADC. The center of all five abscesses gave signal higher than that of white matter on DWI. The three largest also appeared bright on ADC maps, i. e., showed ADC substantially lower than those of normal white matter, consistent with restricted diffusion. However, the two smaller abscesses were not visible on ADC maps because their ADC were essentially the same as that of white matter; they did not show restricted diffusion. The absence of restricted diffusion within small abscesses may be related to intrinsic differences in molecular microenvironment between small and large abscesses, or to greater influence of volume averaging with surrounding edema on the ADC in smaller abscesses.

Long term response in a patient with neoplastic meningitis secondary to melanoma treated with (131)I-radiolabeled antichondroitin proteoglycan sulfate Mel-14 F(ab')(2): a case study.

Even with novel chemotherapeutic agents and external beam radiation therapy, the prognosis of neoplastic meningitis secondary to malignant melanoma is still dismal. The authors report a case study of a 46-year-old white female who presented with progressive hearing loss, severe headaches, nausea, vomiting, and a rapid decline in neurologic status. She was referred to Duke University Medical Center after conventional chemotherapy for malignant melanoma failed. She was enrolled in a Phase I trial of (131)I-labeled monoclonal antibody Mel-14 F(ab')(2) fragment administered intrathecally. Within a year after her treatment, she recovered, having a normal neurologic exam except for residual bilateral hearing loss. The authors discuss dosimetry, preclinical, and clinical studies conducted with Mel-14 F(ab')(2) and introduce a potentially promising therapy option in the treatment of neoplastic meningitis in patients with malignant melanoma. Currently, the patient remains neurologically normal except for a mild bilateral hearing loss more than 4 years after treatment and has no radiographic evidence of neoplastic meningitis.

Use of exponential diffusion imaging to determine the age of ischemic infarcts.

OBJECTIVE: Diffusion-weighted magnetic resonance imaging (DWI) detects acute ischemic infarcts with high lesion conspicuity. Determination of infarct age is difficult on DWI alone because infarct signal intensity (SIinfarct) on DWI is influenced by T2 properties ("T2 shine-through"). Maps of the apparent diffusion coefficient (ADC) reflect pure diffusion characteristics without T2 effects but have low lesion conspicuity. Thus, in clinical practice, combined use of DWI and ADC maps is required. Exponential DWI (eDWI) is an innovative means of MRI-diffusion data analysis that merges the advantages of DWI and ADC maps. The authors hypothesized that SIinfarct on eDWI would correlate with infarct age. The authors studied 114 consecutive patients who had 120 ischemic strokes with clearly determined onset times and who underwent echo-planar DWI. The eDWI were generated by dividing the signal intensity on DWI by that on the corresponding T2 image on a pixel-by-pixel basis. SIinfarct on eDWI was measured in the lesion core and expressed as a percentage of contralateral control tissue. On eDWI, relative SIinfarct changed significantly with infarct age (P < .0001). When patients were sorted in infarct-age groups, no significant differences were found within the first 120 hours. However, for patients studied within 5 days, the mean relative SIinfarct was significantly higher compared with patients studied > or = 8 days after stroke (P < .05). For all infarcts up to 5 days old, the eDWI signal intensity was higher than control tissue (hyperintense appearance). All infarcts > 10 days old had an eDWI signal intensity lower than control tissue (hypointense appearance). The authors concluded that the use of eDWI, as a single set of images, reliably differentiates acute infarcts (< or = 5 days old) from infarcts > 10 days old. This feature would be expected to be helpful when the distinction between acute and nonacute infarction cannot be determined on clinical grounds.