Lois J. Mannon

Total brain N-acetylaspartate A new measure of disease load in MS

Objective: To quantitate the extent of neuronal cell loss in MS via the whole brain’s N-acetylaspartate (NAA) concentration (WBNAA). Methods: Because NAA is assumed to be present only in neuronal cell bodies and their axons, we measured WBNAA as a marker for viable neurons in 12 patients (9 women and 3 men, 26 to 53 years of age) suffering from relapsing-remitting (RR) MS for at least 5 years and compared them with 13 age- and sex-matched normal controls. Total brain NAA was determined with proton MR spectroscopy, and WBNAA was obtained by dividing it by the total brain volume, calculated from high resolution MRI. Results: The WBNAA of the RR MS patients was lower than their matched controls (p < 0.005). This difference was greater among older than younger subjects. The linear prediction equations of WBNAA with age indicate a faster, ×10, decline in the patients, ∼0.8% per year of age (p = 0.022). Conclusion: The age-dependent decrease of whole brain N-acetylaspartate (WBNAA) in the patients suggests that progressive neuronal cell loss is a cardinal feature of this disease. WBNAA offers a quick, highly reproducible measure of disease progression and may be an important marker of treatment efficacy in MS as well as other neurodegenerative diseases.

Glatiramer acetate (Copaxone) treatment in relapsing–remitting MS: Quantitative MR assessment

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.

Magnetization transfer ratio histogram analysis of normal-appearing gray matter and normal-appearing white matter in multiple sclerosis.

Purpose The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Method Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Results Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p ≤ 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p ≤ 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Conclusion Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

Preferential occult injury of corpus callosum in multiple sclerosis measured by diffusion tensor imaging

To investigate the feasibility of diffusion tensor imaging (DTI) assessment of microscopic fiber tract injury in the corpus callosum (CC) and other normal‐appearing white matter (NAWM) in patients with early multiple sclerosis (MS).

Isolated U-fiber involvement in MS : preliminary observations

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.

Olfactory dysfunction in multiple sclerosis: relation to longitudinal changes in plaque numbers in central olfactory structures.

Article abstract Scores on the University of Pennsylvania Smell Identification Test (UPSIT), as well as the numbers of MRI-determined plaques within the inferior frontal and temporal lobes, were obtained on three or four separate occasions in each of five MS patients over an 18- to 20-month period. A close association was observed, longitudinally, between the remission and exacerbation of plaque numbers and UPSIT scores, with more plaques reflecting lower UPSIT scores. These observations further support the hypothesis that olfactory loss in MS is associated with fluctuations in plaque numbers in central olfactory brain regions.

Three-dimensional proton spectroscopy of deep gray matter nuclei in relapsing-remitting MS.

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).

Olfactory Dysfunction in Multiple Sclerosis

To the Editor: Multiple sclerosis, the most common neurologic disease in young adults, is accompanied by focal demyelinating plaques within the central nervous system, which can be quantified in vi...

The effect of gadolinium-enhancing lesions on whole brain atrophy in relapsing-remitting MS

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.

Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals.

A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies of MS families, has been proposed for decades. Few reports provide detailed neurological as well as neuroradiological findings on these patients. We report total T2-weighted intracranial lesion volumes on members of three familial MS cohorts: a mother and father with conjugal MS with one affected son and a neurologically normal son and daughter, one pair of monozygotic twin sisters with MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings in a family with two affected parents and another affected child might demonstrate clinically silent T2-weighted lesions; and that monozygotic twins with MS are more likely to express similar T2-weighted lesion volumes than non-twin sibling pairs. We found clinically silent lesions in unaffected children of the symptomatic parent couple, with a significant difference in total T2 lesion volume between these unaffected siblings and their parents, as well as their affected brother. In our other sibling pairs, T2 lesion volumes were similar between the twins and significantly different in the non-twin pair, despite similar levels of clinical functioning as determined by EDSS scoring. These results suggest that foci of demyelination might be expected in clinically normal offspring of parents with MS, possibly reflecting a genetic predisposition to subsequent development of MS.