Statistics for Investigation of Multimodal MR Imaging Data and an Application to Multiple Sclerosis Patients

Abstract

Magnetic resonance spectroscopy can image axonal damage specifically based on changes in N‐acetyl aspartate (NAA), a neuronal marker. We have developed statistical methods for multimodal analysis of MR spectroscopic images. These methods, which are extensions of mixed‐effect models, have allowed us to quantify differences in images from different subgroups of patients with multiple sclerosis (MS) and to determine the dependence of chemical pathology on clinical disability, duration of disease and lesions on T2‐weighted MRI. Statistical power was improved by using all reliable resonance intensities in the spectroscopic images while taking into consideration the intra‐subject correlations. We studied 17 normal subjects, 14 patients with relapsing remitting (RR) MS and 21 patients with chronic progressive (CP) MS. The ratio of resonance intensities of N‐acetylaspartate over creatine (Cr) was found to be significantly lower than normal in normal appearing white matter (NAWM) of both RR and CP patients (19.6% in RR, 28.8% in CP). NAA/Cr was decreased even more in MS plaques than in NAWM (44.2% in RR, 17.7% in CP). NAA/Cr was correlated with clinical disability (p<0.02) and disease duration (p<0.1). Our results suggest that, in this setting, MRS reflects accumulated neuronal loss or damage and can be used as a measure of disease severity. The methods developed provide opportunities to evaluate the relationship between inflammation, demyelination, axonal loss and clinical disability in future studies.

Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis

“…This may not be the case in the long-term: absolute axonal and neuronal loss may be more important as the disease progresses. This may, in part, explain the discrepancy between the present results and those from some previous studies that have investigated cohorts with longer disease durations and shown a correlation between disability and reductions in NAA:Cr ratios (Fu et al, 1996(Fu et al, , 1998De Stefano et al, 1998.…”

Multiple sclerosis

“…[20][21][22] Remarkably, when we analyzed correlations between the anti-NfL index and MRI measures in the different subgroups of MS (RR vs SP vs PP), we especially found significant correlations in the RR phase of the disease. Even though measurement of atrophy reflects the end stage of the process that underlies irreversible disability, it is not pathologically specific because both demyelination and axonal loss can inevitably lead to tissue loss.…”

Axonal Injury or Loss in the Internal Capsule and Motor Impairment in Multiple Sclerosis

“…Results of in vivo MRS studies demonstrated reduced NAA levels in chronic 10,11 and acute 12,13 lesions. Moreover, results of MRS studies [12][13][14][15] showed a significant reduction in NAA concentration in normalappearing white matter (NAWM), suggesting damage to axons distant from areas of focal inflammation. Although the conventionally obvious pathological features in MS lie in macroscopic lesions, significant and functionally important axonal damage might also occur within the more extensive NAWM.…”