Faculty Bibliography

Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention

BACKGROUND AND PURPOSE: Magnetization transfer ratio (MTR) histogram analysis and volumetric MR imaging are sensitive tools with which to quantify the tissue destructive effects in patients with white matter or neurodegenerative disease. Our purpose was to determine whether whole brain MTR and fractional brain parenchyma volume measurements are altered in HIV-1-infected patients who are neurologically symptomatic and in those who are asymptomatic. METHODS: We performed MR imaging and MTR studies of 15 neurologically symptomatic (seven patients) and asymptomatic (eight patients) HIV-1-seropositive patients and compared their findings with those of 10 seronegative normal control participants. MTR was computed on the basis of whole brain parenchyma segmented by using thin section dual echo MR images. RESULTS: The loss of brain tissue, indicated by fractional brain parenchyma volume, was more pronounced in neurologically symptomatic patients (P =.003) but not in asymptomatic patients (P =.23) when compared with control participants. As for whole brain MTR histogram analysis, both patient groups showed significant decrease in mean (P =.02) and median (P < or =.009) values, compared with normal control participants. There was a trend toward positive correlation (r > or = 0.56) between MTR histogram statistics and fractional brain parenchyma volume. CONCLUSION: Our results suggest that MTR histogram analysis is sensitive in detecting early involvement in neurologically asymptomatic patients with HIV and may, therefore, be used as a combined tool with volumetric measurement, which showed significant tissue loss only in symptomatic patients, to assess various stages of brain damage induced by HIV

BACKGROUND AND PURPOSE: Persistent T1-hypointense lesions ('black holes') are thought to represent permanent damage of brain parenchyma. We attempted to ascertain whether the metabolic profiles of these hypointense areas support this hypothesis and whether these profiles correlate with these hypointense findings. METHODS: Four patients with relapsing-remitting multiple sclerosis and four matched control volunteers underwent MR imaging and 3D proton MR spectroscopy. Absolute levels of N-acetylaspartate (NAA), creatine, and choline (Cho) were obtained in 0.19 cm(3) voxels containing 14 T1-hypointense lesions (average volume, 0.4 cm(3); range, 0.2-1.0 cm(3)) in patients. Metabolite levels were analyzed, by using Pearson correlation, against their respective lesions' hypointensity relative to the surrounding normal-appearing white matter. RESULTS: Moderate correlation, r = 0.56, was found between the NAA level and MR imaging hypointensity. Of the 14 lesions studied, 12 were deficient in NAA and 11 had excess Cho compared with corresponding brain regions in control volunteers. Only one lesion was significantly deficient in all three metabolites, indicative of total damage or matrix loss. CONCLUSION: No relationship was found between the hypointensity of the lesions and their metabolic profile. Specifically, lesions with the same hypointensity on T1-weighted MR images were metabolically variable (ie, displayed disparate metabolite levels and behavior). Also, although 86% of the lesions exhibited abnormally low NAA, 71% also had increased Cho. This indicates that although neuronal damage had already occurred (lower NAA), these lesions were still 'smoldering' with active membrane turnover (high Cho), most likely because of de- and remyelination, indicative of shadow plaques (remyelinated lesions). Consequently, relapsing-remitting hypointense lesions represent neither final-stage nor static pathologic abnormality

X-linked Charcot-Marie-Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet. Magnetic resonance imaging studies in both patients showed nonenhancing, confluent, and symmetrical white matter abnormalities that were more pronounced posteriorly and that resolved over several months. Magnetic transfer images in one patient demonstrated increased magnetization transfer ratios distinct from that seen in demyelination or edema. Both patients returned to their normal baseline within 2 to 3 weeks. These cases suggest that CMTX patients are at risk for developing an acute, transient, neurological syndrome when they travel to places at high altitudes and return to sea level. Cx32 mutations may cause central nervous system dysfunction by reducing the number of functioning gap junctions between oligodendrocytes and astrocytes, making both cells more susceptible to abnormalities of intercellular exchange of ions and small molecules in situations of metabolic stress