The driven-equilibrium single-pulse observation of T 1 (DES-POT1) and T 2 (DESPOT2) are rapid, accurate, and precise methods for voxelwise determination of the longitudinal and transverse relaxation times. A limitation of the methods, however, is the inherent assumption of single-component relaxation. In a variety of biological tissues, in particular human white matter (WM) and gray matter (GM), the relaxation has been shown to be more completely characterized by a summation of two or more relaxation components, or species, each believed to be associated with unique microanatomical domains or water pools. Unfortunately, characterization of these components on a voxelwise, whole-brain basis has traditionally been hindered by impractical acquisition times. In this work we extend the conventional DESPOT1 and DESPOT2 approaches to include multicomponent relaxation analysis. The driven-equilibrium single-pulse observation of T 1 (DESPOT1) and T 2 (DESPOT2) (1,2) methods afford rapid, accurate, and precise evaluation of the longitudinal and transverse relaxation times. As previously described (1,2), unlike the more common spin-echo (SE)-based relaxometry approaches that sample multiple time points along the T 1 recovery or T 2 decay curves, DESPOT1 and DESPOT2 derive T 1 and T 2 information from sets of spoiled gradientrecalled echo (SPGR) and fully-balanced steady-state free precession (bSSFP) data acquired over a range of flip angles, ␣, with constant interpulse spacing, TR. With TR values of less than 10 ms, whole-brain and high-spatialresolution quantitative T 1 and T 2 maps can be acquired in less than 15 min (2,3), a time frame comparable to that of clinical T 1 -or T 2 -weighted acquisitions.Despite the advantages of DESPOT1 and DESPOT2 over alternative relaxometry techniques, both methods are based on the premise that the relaxation of magnetization in each imaging voxel is characterized by a single T 1 and T 2 combination, i.e., that the MR signal arises from a single microanatomical domain or water pool. This proposition, however, overlooks the complex microstructural organization of tissue. Although information related to tissue microstructure has broad clinical utility (for example, in identifying tissue change associated with disease), obtaining such information generally requires invasive or destructive techniques, such as histological analysis. Analysis of transverse relaxation data, however, has shown considerable promise for elucidating tissue microstructure noninvasively by enabling the decomposition of the measured MR signal into multiple components, each believed to originate from distinct tissue subdomains (4 -10). T 2 data obtained from a variety of neural tissues have consistently revealed the presence of at least two relaxation components: a fast-relaxing species with T 2 Ͻ 50 ms, and a slower-relaxing species with T 2 Ͼ 70 ms. Based on histological correlations (11,12), the fast-relaxing species is broadly attributed to water trapped between the lipid bilayers of the myelin sheath, while the s...

Neurodegeneration is the main cause for permanent disability in multiple sclerosis. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, we showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.

ObjectiveTo characterize a cohort of patients with neurosarcoidosis with particular focus on CSF analysis and to investigate whether CSF values could help in distinguishing it from multiple sclerosis (MS).MethodsThis retrospective cohort study enrolled 85 patients with a diagnosis of neurosarcoidosis (possible, probable, or definite). CSF total protein, white cell count, and angiotensin-converting enzyme levels were measured. CSF and serum oligoclonal immunoglobulin G (IgG) patterns were analyzed with the use of odds ratios and binary logistic regression.ResultsEighty patients had a probable (nonneural positive histology) or definite (neural positive histology) diagnosis of neurosarcoidosis. Most frequent findings on MRI were leptomeningeal enhancement (35%) and white matter and spinal cord involvement (30% and 23%). PET scan showed avid areas in 74% of cases. CSF analysis frequently showed lymphocytosis (63%) and elevated protein (62%), but CSF-selective oligoclonal bands were rare (3%). Serum ACE levels were elevated in 51% of patients but in only 14% of those with isolated neurosarcoidosis. Elevated CSF ACE was not found in any patient.ConclusionsLarge elevations in total protein, white cell count, and serum ACE occur in neurosarcoidosis but are rare in MS. The diagnostic use of these tests is, however, limited because minimal changes may occur in both. MS clinical mimics in neurosarcoidosis are not common, and intrathecal synthesis of oligoclonal IgG is a powerful discriminator because it is rare in neurosarcoidosis but occurs in 95% to 98% cases of MS. We suggest caution in making a diagnosis of neurosarcoidosis when intrathecal oligoclonal IgG synthesis is found.