Remyelination in the human central nervous system.

Remyelination, albeit incomplete, has been demonstrated in human central nervous system (CNS). However, information about the initial stage and the final extent of such remyelination is not available. We describe the morphologic findings of a demyelinating lesion with evidence of early remyelination in a biopsy obtained from a 15-year-old boy about two weeks after the onset of neurologic symptoms. The demyelinated area appeared hypercellular with a relatively large number of oligodendrocytes frequently seen in the process of new myelin formation. In addition to the usual reactive changes, the astrocytes were often seen to contain otherwise normal-looking oligodendrocytes within their cytoplasm. In the ensuing months, the patient made apparently total functional recovery accompanied by nearly complete resolution of the white matter lesions demonstrated by the subsequent magnetic resonance studies. These observations suggested that the initial remyelination seen in the biopsy eventually succeeded in producing extensive remyelination in the lesion. Although the exact nature of the demyelinating disorder in our patient remains undetermined, this study indicates that clinically significant remyelination is possible in human CNS. Also, our findings appeared strikingly similar to those described in certain experimental animal models in which widespread remyelination is known to occur.

Magnetic resonance imaging and other techniques in the diagnosis of multiple sclerosis.

We evaluated 35 patients with multiple sclerosis (MS) by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, evoked potential testing, and computed tomographic (CT) scanning. As classified by the McAlpine et al and McDonald and Halliday criteria, 27 patients had definite MS, three had probable MS, and five had possible MS. All of the patients had multiple white matter lesions detectable by MRI that were evident predominantly in the periventricular areas but also in the cerebral or cerebellar white matter. The severity of the MRI abnormality, as judged by the number and size of the lesions, correlated with the likelihood of a positive CT scan but not with the duration of disease, the degree of disability, or positive CSF oligoclonal banding. Magnetic resonance imaging successfully demonstrated brain-stem lesions in 15 patients (none were seen on CT scans). Magnetic resonance imaging seems to be a sensitive indicator of MS lesions, but clinical assessment will continue to be crucial to the diagnosis of MS.

Contrast enhanced MRI. Evaluation of a canine model of osmotic blood-brain barrier disruption.

An osmotic model of blood-brain barrier (BBB) disruption was studied by magnetic resonance (MR) imaging (0.5 T) in 17 canines. The animals were killed after imaging and the lesions confirmed on gross pathology by the presence of Evans blue dye. No accompanying cerebral edema was demonstrated on histologic examination. The disrupted BBB could be identified in only one of five control animals on unenhanced MRI, despite the use of calculated T1 and T2 images. In a second group of five animals, the area of abnormal vascular permeability was consistently demonstrated after IV injection of 0.25 mmol/kg Gd DTPA. The time course of enhancement was evaluated in four additional animals. The brain tissue concentration of the gadolinium ion responsible for the observed enhancement was determined by ion coupled plasma analysis in the last three canines. In a study of pulse techniques, spin echo sequences with both short TRs and TEs (ie, SE 500/30) and inversion recovery techniques proved to be most efficacious for the detection of contrast enhancement. However, contrast could be demonstrated on more T2 weighted sequences.

Early changes in experimental hydrocephalus.

In acute obstruction of the cerebral spinal fluid (CSF) absorption pathways, fluid is produced more rapidly than it is absorbed, and the ventricles enlarge proximal to the obstructions. Communicating hydrocephalus results from a difference between the rates of production and absorption of cerebrospinal fluid. In animals with chronic communicating hydrocephalus, the initial pathologic changes appear to involve the periventricular tissue near the angles of the lateral ventricles. The present investigation was designed to identify the various changes associated with the production of communicating hydrocephalus in acutely hydrocephalic preparations and to relate these findings to those found in experimental animals with chronic communicating hydrocephalus. The results of this study seem to confirm that the changes noted in the chronically hydrocephalic animals occur as early as 12 hours after the restriction of the normal flow of CSF.

Neuroradiologic applications of intraarterial digital subtraction angiography.

In the neuroradiologic evaluation of 118 patients using intraarterial digital subtraction angiography definite advantages and disadvantages were defined. Advantages include reduction of contrast medium volume, catheter time, and patient risk and discomfort. It also aids in angiographic planning. The paramount disadvantage is less spatial resolution compared with conventional film angiography.

Dyke Award. Evaluation of contrast-enhanced MR imaging in a brain-abscess model.

An alpha-streptococcus brain abscess was produced in five dogs and studied with magnetic resonance (MR) imaging (0.5 T) and computed tomography (CT). Non-contrast- and contrast-enhanced CT scans were obtained using gadolinium diethylenetriamine-pentaacetic acid (Gd DTPA) for MR imaging and meglumine iothalamate for CT scanning. Each animal was evaluated in the early and later cerebritis stages of abscess evolution. On MR, the area of cerebritis enhanced after administration of Gd DTPA in a manner similar to that observed with contrast-enhanced CT. However, contrast enhancement was greater on the MR examination. Early lesions in two animals were detected only with contrast-enhanced MR imaging. This experience suggests that intravenously administered agents such as Gd DTPA should increase the diagnostic potential of MR imaging in neurologic diseases, especially those altering the blood-brain barrier.

Phase III multicenter trial of high-dose gadoteridol in MR evaluation of brain metastases.

PURPOSE: To assess the efficacy and safety profile of high-dose (0.3 mmol/kg cumulative dose) gadoteridol in patients with suspected central nervous system metastatic disease. METHODS: We studied 67 patients using an incremental-dose technique. Patient monitoring included a medical history, physical examination, vital signs, and extensive laboratory tests within 24 hours before and after the MR examination. Precontrast T1- and T2-weighted spin-echo studies were performed, followed by intravenous injection of 0.1 mmol/kg of gadoteridol. T1-weighted images were acquired immediately after and at 10 and 20 minutes after injection. At 30 minutes an additional 0.2 mmol/kg of gadoteridol was administered (0.3-mmol/kg cumulative dose), and T1-weighted images were acquired. Cases demonstrating abnormal MR findings were assessed for efficacy by unblinded and blinded reviewers and were analyzed quantitatively. RESULTS: Three adverse effects in two patients were considered to be related to gadoteridol administration. No adverse effects were serious; all self-resolved. Forty-nine cases showed abnormal MR findings and were included in the efficacy analysis. A significantly greater number of lesions was seen on the high-dose as opposed to the standard-dose images. Blinded and unblinded readers identified 5 and 8 patients, respectively, with solitary lesions on standard-dose examination and multiple lesions on high-dose examination. Two patients who had normal standard-dose findings had lesions identified on high-dose studies. Quantitative analysis of 133 lesions in 45 patients demonstrated significant increases in lesion signal intensity on high-dose studies when compared with standard-dose studies. CONCLUSION: Gadoteridol can be safely administered up to a cumulative dose of 0.3 mmol/kg. High-dose contrast studies provide improved lesion detectability and additional diagnostic information over studies performed in the same patients with a 0.1-mmol/kg dose and aid in patient diagnosis and treatment. High-dose gadoteridol study may facilitate the care of patients with suspected central nervous system metastasis.

Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review).

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.

A fatal case of sclerosing mesenteritis.

A 22-year-old patient was admitted because of abdominal pain and vomiting. Computed tomography diagnosed small intestinal malignancy. Ileal resection was performed, and the histological findings were consistent with sclerosing mesenteritis. The patient was treated with enteral nutrition, corticosteroids, azathioprine and methotrexate, but died 2 years later.

The prospective evaluation of Gd-DTPA in 225 consecutive cranial cases: adverse reactions and diagnostic value.

This prospective study evaluates two facets of gadopentetate dimeglumine (Gd-DTPA) enhanced MR imaging in 225 consecutive cranial cases in patients greater than 18 years of age: (i) patient and physician perception of adverse reactions, (ii) diagnostic value of the Gd-DTPA enhanced exam. The 225 cases included 173 head cases, 27 IAC cases, and 25 sella cases. Forty-six percent of the cases were abnormal excluding cases of mild atrophy and ischemic white matter disease judged to be related to aging and not pertinent to the patient's presenting complaint. Concerning adverse reactions, 83% of patients had no complaints. Five percent of the patients had reactions that were judged by the physician to be related to Gd-DTPA. All reactions were minor and required no therapy. In a subset of exams (115) that were blindly and independently interpreted by two board-certified, fellowship-trained radiologists, the Gd-DTPA-enhanced exam resulted in a change in diagnosis in 5%-8% of cases. Additionally, a major benefit of Gd-DTPA administration was the increased diagnostic confidence afforded by the addition of a contrast enhanced exam due to improved lesion characterization and exclusion of additional significant intracranial pathology. In 52%-69% of the abnormal cases, Gd-DTPA provided additional diagnostic information and in 26%-39% the absence of enhancement aided in interpretation. The Gd-DTPA-enhanced exam aids in the diagnosis and characterization of neoplastic disease, acoustic neuroma, subacute infarction, inflammatory disease (meningeal and parenchymal), and certain vascular abnormalities.

The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption.

To provide contrast enhancement in magnetic resonance imaging, a new class of compounds has been developed, the paramagnetic metal ion chelates. Gadolinium (Gd) DTPA, a prototype of this class, shows a sufficiently high in vivo stability and low toxicity for use in initial clinical trials. This type of agent, designed for rapid clearance by glomerular filtration, allows the assessment on MRI of renal function, alterations in tissue perfusion, myocardial ischemia, and perhaps most significantly disruption of the blood-brain barrier (BBB). Research at Vanderbilt has demonstrated these applications, with particular emphasis in three areas. Tissue perfusion changes, such as those produced by ligation of the arterial blood supply to portions of the spleen and kidney, cannot easily be detected on unenhanced MRI. These acute tissue infarcts can be readily identified following the administration of Gd DTPA. The question of field strength dependence of Gd DTPA has been addressed by experimentation at 0.15, 0.5, and 1.5 tesla. Furthermore, the ability to detect an alteration of the BBB, when present without associated edema, has been demonstrated with the application of control enhancement. The use of contrast agents in MRI will enhance both the sensitivity and specificity of magnetic resonance imaging.

Paramagnetic contrast agents in magnetic resonance imaging: research at Vanderbilt University.

Experimental studies in animals have demonstrated the application of particulate and chelated paramagnetic oral contrast agents in magnetic resonance imaging (at 0.5 tesla). The ability of a soluble paramagnetic species, ferrous gluconate, to improve imaging studies of the pancreas presently is being evaluated in clinical trials. Two paramagnetic metal ion chelates, Cr EDTA and Gd DTPA, have been evaluated extensively as potential intravascular contrast agents. Renal function, tissue vascularity, abnormalities of the blood-brain barrier, and infarction of myocardial tissue may all be assessed with IV contrast enhanced magnetic resonance imaging. The contrast materials tested all represent first generation compounds. Improved relaxation characteristics, toxicity, distribution, and flexibility will result from development of second generation agents, primarily within the particulate and chelate classes.

Inhibition of monocarboxylate transporter-4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner.

Hypoxic regions are frequent in glioblastoma (GBM), the most common type of malignant adult brain tumor, and increased levels of tumor hypoxia have been associated with worse clinical outcomes. To unmask genes important in hypoxia, we treated GBM neurospheres in hypoxia and identified monocarboxylate transporter-4 (MCT4) as one of the most upregulated genes. To investigate the clinical importance of MCT4 in GBM, we examined clinical outcomes and found that MCT4 overexpression is associated with shorter patient survival. Consistent with this, MCT4 upregulation correlated with the aggressive mesenchymal subset of GBM, and MCT4 downregulation correlated with the less aggressive G-CIMP (Glioma CpG Methylator Phenotype) subset of GBM. Immunohistochemical analysis of tissue microarrays confirmed that MCT4 protein levels were increased in high-grade as compared with lower-grade astrocytomas, further suggesting that MCT4 is a clinically relevant target. To test the requirement for MCT4 in vitro, we transduced neurospheres with lentiviruses encoding short-hairpin RNAs (shRNAs) against MCT4, resulting in growth inhibition of 50-80% under hypoxia in two lines. MCT4 knockdown was associated with a decreased percentage of cells expressing the stem-cell marker CD133 and increased apoptotic fraction. We also found that flow-sorted CD133-positive cells had almost sixfold higher MCT4 levels than CD133-negative cells, suggesting that the stem-like population might have a greater requirement for MCT4. Most importantly, MCT4 silencing also slowed GBM intracranial xenograft growth in vivo. Interestingly, whereas MCT4 is a well-characterized lactate exporter, we found that both intracellular and extracellular lactate levels did not change following MCT4 silencing, suggesting a novel lactate export-independent mechanism for growth inhibition in GBMs. To identify this potential mechanism, we performed microarray analysis on control and shMCT4-expressing neurospheres and found a dramatic reduction in the expression of multiple Hypoxia-Inducible Factor (HIF)-regulated genes following MCT4 knockdown. The overall reduction in HIF transcriptional response was further validated using a hypoxia response element (HRE)-dependent green-fluorescent protein (GFP) reporter line.

Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis.

The mechanisms for motor neuron degeneration and regeneration in adult spinal cord following axotomy and target deprivation are not fully understood. We used a unilateral sciatic nerve avulsion model in adult rats to test the hypothesis that retrograde degeneration of motor neurons resembles apoptosis. By 21 days postlesion, the number of large motor neurons in lumbar spinal cord was reduced by approximately 30%. The death of motor neurons was confirmed using the terminal transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling method for detecting fragmentation of nuclear DNA. Motor neuron degeneration was characterized by aberrant accumulation of perikaryal phosphorylated neurofilaments. Structurally, motor neuron death was apoptosis. Apoptotic motor neurons undergo chromatolysis followed by progressive cytoplasmic and nuclear condensation with chromatin compaction into uniformly large round clumps. Prior to apoptosis, functionally active mitochondria accumulate within chromatolytic motor neurons, as determined by cytochrome c oxidase activity. These dying motor neurons sustain oxidative damage to proteins and nucleic acids within the first 7 days after injury during the progression of apoptosis, as identified by immunodetection of nitrotyrosine and hydroxyl-modified deoxyguanosine and guanosine. We conclude that the retrograde death of motor neurons in the adult spinal cord after sciatic nerve avulsion is apoptosis. Accumulation of active mitochondria within the perikaryon and oxidative damage to nucleic acids and proteins may contribute to the mechanisms for apoptosis of motor neurons in the adult spinal cord.

Craniopharyngioma: CT and MR imaging in nine cases.

Magnetic resonance (MR) imaging and CT examinations were performed in nine patients with surgically proven craniopharyngioma. Computed tomography was found to be superior to MR in detection of calcification and cyst formation. Extent of involvement of adjacent structures (e.g., optic chiasm, third ventricle, and intracavernous carotid artery) was more clearly delineated by MR. Craniopharyngioma fluid collections were found to be uniformly bright on T2-weighted sequences. However, on T1-weighted sequences, the signal intensity of the fluid ranged from hypointense to hyperintense, reflecting the heterogeneous contents of cysts in these tumors. Since calcification and cyst formation are hallmarks of craniopharyngiomas, we believe that CT is more specific than MR in diagnosis of craniopharyngiomas. Magnetic resonance, however, offers a more accurate assessment of the tumor extent.

Gd DTPA. Future applications with advanced imaging techniques.

In this admittedly preliminary view of the future, the authors present a number of new concepts in MR imaging and consider their possible advantages and limitations.