Ashish Arora

Iron in chronic brain disorders: imaging and neurotherapeutic implications.

SummaryIron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurological disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathological processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article, we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis.

Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical‐MRI correlations.

Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis.

To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI).

MRI in multiple sclerosis: What’s inside the toolbox?

SummaryMagnetic resonance imaging (MRI) has played a central role in the diagnosis and management of multiple sclerosis (MS). In addition, MRI metrics have become key supportive outcome measures to explore drug efficacy in clinical trials. Conventional MRI measures have contributed to the understanding of MS pathophysiology at the macroscopic level yet have failed to provide a complete picture of underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical progression. Advanced quantitative MRI measures such as magnetization transfer, spectroscopy, diffusion imaging, and relaxometry techniques are somewhat more specific and sensitive for underlying pathology. These measures are particularly useful in revealing diffuse damage in cerebral white and gray matter and therefore may help resolve the dissociation between clinical and conventional MRI findings. In this article, we provide an overview of the array of tools available with brain and spinal cord MRI technology as it is applied to MS. We review the most recent data regarding the role of conventional and advanced MRI techniques in the assessment of MS. We focus on the most relevant pathologic and clinical correlation studies relevant to these measures.

The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis

To determine the interrelationships between MRI‐defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (MS).

Spinal cord lesions and clinical status in multiple sclerosis: A 1.5 T and 3 T MRI study

OBJECTIVE Assess the relationship between spinal cord T2 hyperintense lesions and clinical status in multiple sclerosis (MS) with 1.5 and 3 T MRI. METHODS Whole cord T2-weighted fast spin-echo MRI was performed in 32 MS patients [Expanded Disability Status Scale (EDSS) score (mean+/-SD: 2+/-1.9), range 0-6.5]. Protocols at 1.5 T and 3 T were optimized and matched on voxel size. RESULTS Moderate correlations were found between whole cord lesion volume and EDSS score at 1.5 T (r(s)=.36, p=0.04), but not at 3 T (r(s)=0.13, p=0.46). Pyramidal Functional System Score (FSS) correlated with thoracic T2 lesion number (r(s)=.46, p=0.01) and total spinal cord lesion number (r(s)=0.37, p=0.04) and volume (r(s)=0.37, p=0.04) at 1.5 T. Bowel/bladder FSS correlated with T2 lesion volume and number in the cervical, thoracic, and total spine at 1.5 T (r(s) 0.40-0.57, all p<0.05). These MRI-FSS correlations were non-significant at 3 T. However, these correlation coefficients did not differ significantly between platforms (Chois test p>0.05). Correlations between whole cord lesion volume and timed 25-foot walk were non-significant at 1.5 T and 3 T (p>0.05). Lesion number and volume did not differ between MRI platforms in the MS group (p>0.05). CONCLUSIONS Despite the use of higher field MRI strength, the link between spinal lesions and MS disability remains weak. The 1.5 T and 3 T protocols yielded similar results for many comparisons.

T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis.

Background Gray matter (GM) magnetic resonance imaging (MRI) T2 hypointensity, a putative marker of iron deposition, commonly occurs in multiple sclerosis (MS). However, GM T2 hypointensity in benign MS (BMS) has not yet been characterized. Objective To determine the presence of deep GM T2 hypointensity in BMS, compare it to secondary progressive (SP) MS and assess its association with clinical and diffusion tensor (DT) MRI measures. Methods Thirty-five cognitively unimpaired BMS, 26 SPMS patients, and 25 healthy controls were analyzed for normalized T2-intensity in the basal ganglia and thalamus, global T2 hyperintense lesion volume, global atrophy, and white matter and GM DT metrics. Results BMS and SPMS patients showed deep GM T2 hypointensity compared with controls. T2 hypointensity was similar in both MS subgroups and moderately correlated (r = −0.45 to 0.42) with DT MRI metrics. GM T2 hypointensity in BMS showed a weak to moderate correlation (r = −0.44 to −0.35) with disability. Conclusions GM in BMS is not spared from structural change including iron deposition. However, while T2 hypointensity is related to global tissue disruption reflected in DT MRI, the expression of benign versus non-benign MS is likely related to other factors.

Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis.

Gray matter (GM) magnetic resonance imaging (MRI) T2 hypointensity, a putative marker of iron deposition, is a frequent finding in patients with clinically definite (CD) multiple sclerosis (MS). The objective of this study was to assess: (a) how early deep GM T2 hypointensity occurs in MS, by studying patients with clinically isolated syndromes (CIS) suggestive of MS, and (b) whether they contribute to predict subsequent evolution to CDMS. Dual-echo scans using two different acquisition protocols were acquired from 47 CIS patients and 13 healthy controls (HC). Normalized T2-intensity of the basal ganglia and thalamus was quantified. Patients were assessed clinically at the time of MRI acquisition and after three years. During the observation period, 18 patients (38%) evolved to CDMS. At the baseline, only the GM T2-intensity of the left caudate nucleus was significantly reduced in CIS patients in comparison with the HC (p = 0.04). At the baseline, the T2 intensity of the left caudate nucleus was significantly lower (p = 0.01) in CIS patients with disease dissemination in space (DIS), but not in those without DIS, compared to the HC. The baseline T2 lesion volume, but not GM T2 hypointensity, was associated with evolution to CDMS (hazard ratio = 1.60, 95% confidence interval (CI) = 1.05—2.42; p = 0.02). In CIS patients, deep GM is not spared, suggesting that iron-related changes and neurodegeneration occurs early. The magnitude of such damage is only minor and not associated with an increased risk of evolution to CDMS.

The impact of lesion in-painting and registration methods on voxel-based morphometry in detecting regional cerebral gray matter atrophy in multiple sclerosis.

BACKGROUND AND PURPOSE: VBM has been widely used to study GM atrophy in MS. MS lesions lead to segmentation and registration errors that may affect the reliability of VBM results. Improved segmentation and registration have been demonstrated by WM LI before segmentation. DARTEL appears to improve registration versus the USM. Our aim was to compare the performance of VBM-DARTEL versus VBM-USM and the effect of LI in the regional analysis of GM atrophy in MS. MATERIALS AND METHODS: 3T T1 MR imaging scans were acquired from 26 patients with RRMS and 28 age-matched NC. LI replaced WM lesions with normal-appearing WM intensities before image segmentation. VBM analysis was performed in SPM8 by using DARTEL and USM with and without LI, allowing the comparison of 4 VBM methods (DARTEL + LI, DARTEL − LI, USM + LI, and USM − LI). Accuracy of VBM was assessed by using NMI, CC, and a simulation analysis. RESULTS: Overall, DARTEL + LI yielded the most accurate GM maps among the 4 methods (highest NMI and CC, P < .001). DARTEL + LI showed significant GM loss in the bilateral thalami and caudate nuclei in patients with RRMS versus NC. The other 3 methods overestimated the number of regions of GM loss in RRMS versus NC. LI improved the accuracy of both VBM methods. Simulated data suggested the accuracy of the results provided from patient MR imaging analysis. CONCLUSIONS: We introduce a pipeline that shows promise in limiting segmentation and registration errors in VBM analysis in MS.

Normal Findings on Brain Fluid-Attenuated Inversion Recovery MR Images at 3T

BACKGROUND AND PURPOSE: Fluid attenuated inversion recovery (FLAIR) MR imaging of the brain has become a routine tool for assessing lesions in patients with suspected neurologic disorders. There is growing interest in 3T brain FLAIR MR imaging but little normative data are available. The purpose of this study was to evaluate the frequency and topography of cerebral hyperintensities seen with FLAIR MR imaging of the brain at 3T in a normal population and compare those findings to 1.5T. MATERIALS AND METHODS: Whole-brain 2D FLAIR MR imaging was performed in 22 healthy controls (mean age, 44 ± 8 years; range, 30–53 years) at 3T. Fifteen of these subjects also underwent 2D FLAIR at 1.5T, with similar optimized parameters and voxel size. Cerebral hyperintense areas, including discrete foci, anterior and posterior periventricular capping, diffuse parenchymal hyperintensity, septal hyperintensity, corticospinal tract hyperintensity, and CSF flow artifacts were assessed. The Spearman rank test assessed the correlation between discrete hyperintense foci and age. The Wilcoxon signed rank test compared foci detectability at 3T versus 1.5T. RESULTS: FLAIR at 3T commonly showed hyperintensities such as discrete foci (mean, 10.68 per subject; at least 1 present in 68% of subjects), anterior and posterior periventricular capping, diffuse posterior white matter hyperintensity, septal hyperintensity, corticospinal tract hyperintensity, and ventricular CSF flow artifacts. FLAIR at 3T showed a higher hyperintense foci volume (170 ± 243 versus 93 ± 152 mm3, P < .01) and number (9.4 ± 13 versus 5.5 ± 9.2, P < .01) than at 1.5T. No significant differences (P = .68) in the length/diameter of individual discrete hyperintense foci were seen between 3T and 1.5T. Discrete foci volume (r = 0.72 at 3T, r = 0.70 at 1.5T) and number (r = 0.74 at 3T; r = 0.69 at 1.5T) correlated with age to a similar degree on both platforms. All discrete foci were confined to the noncallosal supratentorial white matter. The other nonfocal hyperintensities (anterior and posterior periventricular capping, diffuse parenchymal hyperintensity, septal hyperintensity, corticospinal tract hyperintensity, and CSF flow artifacts) were generally more common and prominent at 3T than at 1.5T. CONCLUSIONS: Discrete and diffuse parenchymal brain white matter FLAIR hyperintensities are more common and prominent at 3T than at 1.5T in healthy volunteers.