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To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-L-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials.Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 ± 5 years old (mean ± SD), had a disease duration of 47 ± 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-L-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation.The baseline WBNAA of the patients (10.5 ± 1.7 mM) was significantly lower than that of the controls (12.3 ± 1.3 mM; p0.002) and declined significantly (5%/year, p0.002) vs that for the controls who did not show a decline (0.4%/year, p0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA.WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies.

Objective: The purpose of this study was to develop an algorithm incorporating MRI metrics to classify patients with mild traumatic brain injury (mTBI) and controls. Methods: This was an institutional review board–approved, Health Insurance Portability and Accountability Act–compliant prospective study. We recruited patients with mTBI and healthy controls through the emergency department and general population. We acquired data on a 3.0T Siemens Trio magnet including conventional brain imaging, resting-state fMRI, diffusion-weighted imaging, and magnetic field correlation (MFC), and performed multifeature analysis using the following MRI metrics: mean kurtosis (MK) of thalamus, MFC of thalamus and frontal white matter, thalamocortical resting-state networks, and 5 regional gray matter and white matter volumes including the anterior cingulum and left frontal and temporal poles. Feature selection was performed using minimal-redundancy maximal-relevance. We used classifiers including support vector machine, naive Bayesian, Bayesian network, radial basis network, and multilayer perceptron to test maximal accuracy. Results: We studied 24 patients with mTBI and 26 controls. Best single-feature classification uses thalamic MK yielding 74% accuracy. Multifeature analysis yields 80% accuracy using the full feature set, and up to 86% accuracy using minimal-redundancy maximal-relevance feature selection (MK thalamus, right anterior cingulate volume, thalamic thickness, thalamocortical resting-state network, thalamic microscopic MFC, and sex). Conclusion: Multifeature analysis using diffusion-weighted imaging, MFC, fMRI, and volumetrics may aid in the classification of patients with mTBI compared with controls based on optimal feature selection and classification methods. Classification of evidence: This study provides Class III evidence that classification algorithms using multiple MRI features accurately identifies patients with mTBI as defined by American Congress of Rehabilitation Medicine criteria compared with healthy controls.

Objective: To determine the relationship between gadolinium-enhancing lesions and changes in whole brain parenchymal volume in patients with relapsing-remitting MS, and to test the hypothesis that gadolinium enhancement is a predictor of whole brain atrophy.Methods: Twenty-four patients with clinically definite MS were imaged over 2 years. A computer-assisted segmentation technique based on high-resolution MRI was used to quantify gadolinium-enhancing T1 lesion volume and brain parenchyma and CSF volumes. Percent brain parenchymal volume (PBV) relative to the total intracranial volume was calculated, and changes in PBV were used to represent the degree of whole brain atrophy over 2 years.Results: PBV at baseline was dependent on duration of MS, and a significant decrease in PBV was observed over the course of the study. Changes in enhanced T1 lesion load failed to correlate with changes in PBV, and multiple regression analyses determined that enhanced T1 lesion load at baseline was not a significant predictor of subsequent change in PBV.Conclusions: MR visible inflammation as demonstrated by enhanced T1 lesions is not a significant factor in the pathogenesis of whole brain atrophy in relapsing-remitting MS, suggesting that a more global pathologic process is responsible for the loss of brain parenchymal volume.

We examined the relations between quantitative volumetric estimates of cerebral lesion load based on magnetization transfer imaging (MTI), clinical data, and measures of neuropsychological function in 44 patients with clinically diagnosed MS. In this population we assessed the correlation between several volumetric MTI measures, measures of neurologic function (Kurtzke Expanded Disability Status Scale and Ambulation Index), and disease duration using Spearman's correlation coefficient. Patients were classified on the basis of neuropsychological test performance as severely impaired, moderately impaired, and normal. We assessed differences between these groups with respect to MTI results using the Kruskal-Wallis test. MTI measures corrected for brain volume were found to correlate with disease duration (p0.01) and showed suggestive correlations with measures of neurologic impairment (p0.05). Individual neuropsychological tests correlated with MTI measures corrected and not corrected for brain volume (p0.001). An MTI measure not corrected for brain volume differed (p0.05) between severely impaired, moderately impaired, and normal patients. These preliminary results suggest that volumetric MTI analysis provides new measures that reflect more accurately the global lesion load in the brain of MS patients, and they may serve as a method to study the natural course of the disease and as an outcome measure to evaluate the effect of drugs.

We studied the frequency and location of isolated U-fiber involvement in MS and correlated these findings exploratively with physical disability and neuropsychological impairment. Fifty-three MS patients were examined. Three-millimeter-thick, fast spin-echo T2-weighted MR images and spin-echo postgadolinium T1-weighted images were obtained. Computer software that which had been validated previously for quantitation of MS lesions was used to detect lesions on the T2-weighted images. The Expanded Disability Status Scale (EDSS), Ambulation Index (AI), and a battery of neurocognitive tests were performed on each patient. Forty-two arcuate hyperintensities along the U-fiber were detected by the software in 28 patients (53%). Twenty-seven lesions (64.3%) were seen in the frontal lobe, eight (19.0%) in the temporal lobe, three (7.1%) in the parietal lobe, three (7.1%) in the occipital lobe, and one (2.4%) in both frontal and parietal lobes. Four lesions (9.5%) showed gadolinium enhancement. Seventeen lesions (40%) were hypointense on the T1-weighted images. Scores of three of the 11 neuropsychological tests reflecting performance in executive control and memory were significantly different at least at the p = 0.05 level between the eight patients with multiple, isolated U-fiber lesions and the 45 patients without any or with only a single U-fiber lesion. No significant difference was noted for EDSS or AI. Isolated U-fiber involvement is an underappreciated MR finding in MS. Our preliminary hypothesis is that U-fiber lesions may contribute to neuropsychological impairment, although our observation requires confirmation.

The metabolic changes in the deep gray matter (GM) nuclei, thalamus, and basal ganglia of patients with relapsing-remitting multiple sclerosis were investigated with quantitative, multivoxel, three-dimensional proton MR spectroscopy. This technique facilitated the study of several bilateral structures in a single session at sub-cubic centimeter spatial resolution. Compared with 9 matched control subjects, the deep GM nuclei of 11 patients showed 7% lower N-acetylaspartate and 14% higher choline levels (p = 0.02 for both).

Global brain atrophy estimated using MRI and whole brain N-acetylaspartate (WBNAA) concentration measured with proton MR spectroscopy were obtained in 42 patients with relapsing-remitting multiple sclerosis and 41 matched control subjects. Patients exhibited cross-sectional atrophy (0.5%; p = 0.033) and WBNAA decline (1.8%/y; p = 0.005) vs disease duration. The 3.6-fold rate disparity between the two processes suggests that neuronal/axonal dysfunction (N-acetylaspartate decline) precedes parenchyma loss, not its consequence (i.e., is an earlier, more sensitive specific metric of the ongoing disease activity).

Conventional MRI (cMRI) is limited in its ability to provide specific information about pathology in MS. Measures commonly derived from cMRI include T2 lesions, T1-enhanced lesions, atrophy, and possibly T1-hypointense lesions, which have been extensively investigated in many clinical trials. Better MRI measures are needed to advance our understanding of MS and design ideal clinical trials. This article reviews the strengths and weaknesses of the major MRI-based methods used to monitor MS evolution and submits that 1) metrics derived from magnetization transfer MRI, diffusion-weighted MRI, and proton MRS should be implemented to achieve reliable specific in vivo quantification of MS pathology; 2) targeted multiparametric MRI protocols rather than generic application of cMRI should be used in all possible clinical circumstances and trials; and 3) reproducible quantitative MR measures should ideally be used for the assessment of patients but are essential for clinical trials.

Objective: To evaluate the efficacy of glatiramer acetate (GA, Copaxone; Teva Pharmaceutical Industries, Ltd., Petah Tiqva, Israel) by MRI-based measures in patients with relapsing–remitting (RR) MS. Methods: Twenty-seven patients with clinically definite RR-MS were treated with either 20 mg of GA by daily subcutaneous self-injection (n = 14) or placebo (n = 13) for approximately 24 months. Axial dual-echo fast-spin-echo T2-weighted images and T1-weighted images before and after gadolinium (Gd) were acquired at 1.5 tesla and transferred into an image processing computer system. The main outcome measures were the number of Gd-enhanced T1 and T2 lesions and their volume as well as brain parenchyma volume. Results: The values of age, disease duration, Expanded Disability Status Scale (EDSS) score, the number of T1- and T2-weighted lesions, and their volume were similar between GA- and placebo-receiving groups at the entry of this study. There was a decrease in the number of T1-enhanced lesions ( p = 0.03) and a significant percent annual decrease of their volume in GA recipients compared with those of placebo recipients. There were no significant differences between changes in the two groups in the number of T2 lesions and their volume. The loss of brain tissue was significantly smaller in the GA group compared with that of the placebo group. Conclusions: These results show that GA treatment may decrease both lesion inflammation and the rate of brain atrophy in RR-MS.

Article abstract A 36-year-old man presented with spinal myoclonus, ataxia, hearing loss, and unilateral pupillary dilation. MRI demonstrated hemosiderin deposition along the superficial surfaces of the brain, brainstem, cerebellum, and spine. The pupillary changes were localized to the preganglionic oculomotor nerve. In contrast to vasculopathic oculomotor nerve palsies, superficial siderosis may cause selective involvement of the superficially located pupillary fibers.

Article abstract-We report a patient with biopsy-proven progressive multifocal leukoencephalopathy (PML) who was serially imaged with MRI and magnetization transfer imaging. The magnetization transfer ratio (MTR) was profoundly and significantly diminished when compared with normal control subjects. The pattern of MTR was distinct from that of MS and periventricular ischemic white matter disease. Magnetization transfer imaging techniques may aid in the differential diagnosis of PML. NEUROLOGY 1997;48: 534-536

A healthy adult volunteers to serve as a control subject in an fMRI study. The subject provides informed consent, and a tailored protocol designed for the particular study then is executed. In most cases, the research subject altruistically assumes that the result will benefit science in some way. However, does science owe the volunteer a fair assessment of the information not relevant to the focus of the investigation (i.e., should the images be read by a capable individual who has facility to detect abnormalities and can render an opinion of what constitutes normal)? In the article by Illes et al.1 in this issue of Neurology , the incidence of abnormal findings in 151 research scans, requiring physician referral, was 6.6%. The authors state that most of the findings were not detected or reported to the participants. This is a problem and highlights several issues associated with imaging research. First, some MR research—particularly fMRI—is performed by scientists who are not skilled at image …

MRI is very sensitive in showing MS lesions throughout the CNS. Using MRI for diagnostic purposes, however useful, is a complex issue because of limited specificity of findings and a variety of options as to when, how, and which patients to examine. Comparability of data and a common view regarding the impact of MRI are needed. Following a review of the typical appearance and pattern of MS lesions including differential diagnostic considerations, we suggest economic MRI examination protocols for the brain and spine. Recommendations for referral to MRI consider the need to avoid misdiagnosis and the probability of detecting findings of diagnostic relevance. We also suggest MRI classes of evidence for MS to determine the diagnostic weight of findings and their incorporation into the clinical evaluation. These proposals should help to optimize and standardize the use of MRI in the diagnosis of MS.

Neurologists are familiar with MRI as T1-, T2-, and proton density–weighted images, and, recently, magnetic resonance angiography (MRA). Here, we draw attention to newer MRI methods—diffusion-weighted imaging (DWI) and perfusion imaging (PI)—that are unique among all imaging methods in their sensitivity to pathophysiologic changes underlying acute stroke. Documentation in clinical studies is now sufficiently compelling to warrant careful consideration of DWI and PI by all physicians who care for patients with acute stroke syndrome. Conventional MRI methods usually detect ischemic lesions after a few hours, well before clear changes appear on x-ray CT, and with much greater anatomic resolution. The increased sensitivity is particularly obvious in the posterior fossa, where imaging artifacts can mask acute CT changes. However, the advantages of MRI for stroke diagnosis have not yet been documented by clinical outcome studies comparing it directly with CT, which led Powers and Zivin to express well-reasoned reservations about whether MRI is so clearly superior as to justify the costs in money and procedural adjustment that its rapid general adoption would require.1 We believe that recent literature on DWI and PI has tipped the balance definitively in favor of accelerated implementation of MRI as the principal imaging modality for initial evaluation of acute stroke syndrome. This issue of Neurology contains two articles2,3 and a review4 providing new support for that position. Their independent submission to a single journal within a few weeks of each other accurately reflects the pace of development in the field. Diffusion-weighted imaging. Diffusion in liquids occurs by Brownian motion, the random process of molecular displacements caused by thermal agitation. DWI measures the diffusive motion of water molecules as an apparent diffusion coefficient (ADC), which varies with location in biologic tissue. The anatomic differences can be rendered as an image by standard …

Cerebral aspergillosis currently occurs most frequently with disseminated aspergillosis in immunocompromised hosts. Twelve patients with cerebral aspergillosis in this setting were seen over 10 years. Underlying illnesses were renal transplantation in six cases and one case each of subacute hepatic necrosis, head trauma, glioblastoma, microglioma, and esthesioneuroblastoma. All patients were receiving high dose steroid therapy except one who had ectopic ACTH syndrome. Eleven patients were receiving broad spectrum antibiotics. All patients were febrile and developed progressive pulmonary infiltrates preceding or coincident with neurologic symptoms. Sudden onset of neurologic deficits or seizures occurred in nine of 11 clinically analyzable cases. Brainstem or cerebellar signs and symptoms were a presenting feature in three cases and were eventually seen in five cases. Cranial computerized tomography in four cases showed low absorption areas with minimal enhancement and little mass effect. Neurologic deterioration was rapid with nine of 11 patients dying within 6 days of onset. Neuropathologic examination showed multiple abscess formation in 11 cases and prominent blood vessel invasion in all cases. The sudden onset of stroke-like deficits and brainstem findings in a febrile immunocompromised host with pulmonary infiltrates suggests the diagnosis of cerebral aspergillosis. Two cases of aspergillus meningitis were also seen, one postoperatively.

High field strength magnetic resonance imaging (MRI) provides a noninvasive means of evaluating patients with parkinsonism. Using strict clinical criteria, we began a prospective study of patients with Parkinson's disease (PD) and parkinsonian syndromes (PS) including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and atypical parkinsonism (ATYP). We detected moderate to severe putaminal hypointensity more frequently in PS than in PD and controls, although putaminal hypointensity did not distinguish between MSA, PSP, or ATYP. Signal intensity in the lateral substantia nigra did not differ significantly among patients with PD, PS, or controls and was therefore not a useful MRI marker. Pars compacta width was significantly narrower in both PD and PS. Subcortical and periventricular hyperintense foci were more abundant in PD and PS than controls. Atrophy of the brainstem occurred only in patients with PS.