Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis.

BACKGROUND: The relationship of gray and white matter atrophy in multiple sclerosis (MS) to neuropsychological and neuropsychiatric impairment has not been examined. METHODS: In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain whole brain normalized volumes of gray and white matter, as well as measured conventional lesion burden (total T1 hypointense and FLAIR hyperintense lesion volume). The whole brain segmentation was corrected for misclassification related to MS brain lesions. To compare the effects of gray matter, white matter, and lesion volumes with respect to brain-behavior relationships, the MS group (disease duration = 11.2 +/- 8.8 years; EDSS score = 3.3 +/- 1.9) underwent neuropsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83). RESULTS: The MS group had smaller gray (p = 0.009) and white matter volume (p = 0.018), impaired cognitive performance (verbal memory, visual memory, processing speed, and working memory) (all p < 0.0001), and greater neuropsychiatric symptoms (depression, p < 0.0001; dysphoria, p < 0.0001; irritability, p < 0.0001; anxiety, p < 0.0001; euphoria, p = 0.006; agitation, p = 0.02; apathy, p = 0.02; and disinhibition, p = 0.11) vs controls. Hierarchical stepwise regression analysis revealed that whole gray and white matter volumes accounted for greater variance than lesion burden in explaining cognitive performance and neuropsychiatric symptoms. White matter volume was the best predictor of mental processing speed and working memory, whereas gray matter volume predicted verbal memory, euphoria, and disinhibition. CONCLUSION: Both gray and white brain matter atrophy contribute to neuropsychological deficits in multiple sclerosis.

The relationship between whole brain volume and disability in multiple sclerosis: a comparison of normalized gray vs. white matter with misclassification correction.

We used SPM99 to obtain normalized whole brain volumes of gray matter, white matter, and total parenchyma in patients with multiple sclerosis (MS) (n = 41) and age-/sex-matched normal controls (n = 18). As SPM99's automated gray/white matter volumes were significantly influenced by tissue compartment misclassification due to the effect of MS-related brain lesions, we corrected these automated volumes for misclassification before performing our primary analyses. For MS patients (disease duration = 9.5 +/- 6.3 years; EDSS score = 3.2 +/- 1.8; 25FTW = 6.6 +/- 3.1 s), we also measured lesion load (total T1 hypointense [T1LV] and FLAIR hyperintense lesion volume [FLLV]), central brain atrophy (third ventricular width [TVW] and bicaudate ratio [BCR]), and clinical status (Expanded Disability Status Scale [EDSS] and 25-ft timed walk [25FTW]). Patients with MS had lower gray matter (707 +/- 33 cm(3) [-3.9%], P = 0.003) and total parenchymal volume (1088 +/- 48 cm(3) [-3.8%], P = 0.003), but only a trend for lower white matter volume (381 +/- 25 cm(3) [-3.7%], P = 0.052) relative to normal controls (gray matter: 736 +/- 33 cm(3); total parenchyma: 1132 +/- 49 cm(3); white matter: 396 +/- 26 cm(3)). Gray matter atrophy was related to clinical status (EDSS, 25FTW, and disease duration), lesion load (T1LV and FLLV), and central brain atrophy (TVW and BCR), whereas white matter atrophy was related to only central brain atrophy. These findings suggest that gray matter loss is related to other aspects of brain pathology and has more clinical relevance than white matter atrophy in MS.

Correction for intracranial volume in analysis of whole brain atrophy in multiple sclerosis: the proportion vs. residual method.

Two techniques that correct (normalize) regional and whole brain volumes according to head size-the proportion method (tissue-to-intracranial volume ratio) and the residual method (regression-based predicted brain tissue volumes)-are used pervasively in neuroimaging research, but have received little critical evaluation or direct comparison. Using a quantitatively derived MRI data set of patients with multiple sclerosis (n = 18) and age-/sex-matched normal controls (n = 18), we introduced various types of error into estimates of intracranial volume (ICV) and absolute parenchymal volume (APV) to observe how this error affected the final outcome of normalized brain measures and their ability to detect group differences, as computed by a proportion (brain parenchymal fraction [BPF]) and residual method (predicted parenchymal volume [PPV]). The results indicated that systemic error in ICV and APV values considerably affected BPF means based on the proportion method, except with dependent-related systematic APV error, but essentially did not change statistical power associated with group differences in BPF. Random error altered BPF means to a much smaller extent, but was associated with moderate reductions in statistical power. On the other hand, PPV estimates based on the residual method were unaffected by these same ICV and APV errors, except with dependent-related systematic APV error, and were not associated with reductions in statistical power. Our findings suggest that head size correction of brain regions with the residual method generally may provide advantages over the proportion method.

Whole-brain atrophy in multiple sclerosis measured by automated versus semiautomated MR imaging segmentation.

BACKGROUND AND PURPOSE: Semiautomated and automated methods are used to measure whole-brain atrophy in multiple sclerosis (MS), but their comparative reliability, sensitivity, and validity are unknown. METHODS: Brain parenchymal fraction (BPF) was measured in patients with MS (n = 52) and healthy control subjects (n = 17) by four methods: semiautomated or automated segmentation and 2D or 3D pulse sequences. Linear measures of atrophy, whole-brain lesion volumes, and clinical data were used to explore validity. RESULTS: The 2D automated method yielded unreliable segmentation and was discarded. The three other BPF methods produced data that were highly intercorrelated and indistinguishable by analysis of variance. In the MS group, semiautomated (2D: 0.84 +/- 0.04, P <.001; 3D: 0.84 +/- 0.05, P =.04) and automated 3D (0.83 +/- 0.05, P =.002) BPFs were lower than controls (semiautomated 2D: 0.88 +/- 0.02; 3D: 0.88 +/- 0.03; automated 3D: 0.88 +/- 0.03). In the MS group, the semiautomated (r = -.79 to -.82) and automated 3D (r = -.81) BPFs inversely correlated with third ventricular width and showed similarly robust correlations with the bicaudate ratio (all r = -.74). The semiautomated and automated BPFs showed similar, moderate correlations with T1 hypointense and FLAIR hyperintense lesion volume, physical disability (Expanded Disability Status Scale) score, and disease duration and similar differences between secondary progressive and relapsing-remitting patients. The intraobserver, interobserver, and test-retest reliability was somewhat higher for the automated than for the semiautomated methods. CONCLUSION: These automated and semiautomated measures of whole-brain atrophy provided similar and nearly interchangeable data regarding MS. They discriminated MS from healthy individuals and showed similar relationships to established disease variables.