Seth A. Smith

RETINAL NERVE FIBER LAYER IS ASSOCIATED WITH BRAIN ATROPHY IN MULTIPLE SCLEROSIS

Objective: Optical coherence tomography (OCT) noninvasively quantifies retinal nerve fiber layer (RNFL) thickness. Studies show RNFL thinning in multiple sclerosis (MS), and we assessed its association with brain atrophy. Methods: RNFL thickness was measured in 40 patients with MS and 15 controls. Brain parenchymal fraction (BPF) and partial brain volumes were estimated from cranial MRI scans using SIENA-X. Multiple linear regression modeling assessed the association between OCT and MRI measures of atrophy. Results: Minimum RNFL thickness and subject age together predict 21% (p = 0.005) of the variance in BPF in all patients with MS and 43% (p = 0.003) of the variance in BPF in the subgroup with relapsing remitting MS (RRMS; n = 20). The partial correlation coefficient between BPF and minimum RNFL thickness, controlling for age, is 0.46 (p = 0.003) in all patients with MS and 0.69 (p = 0.001) in patients with RRMS. These associations are driven by CSF volume but not by gray or white matter volume. There is no significant association of these variables among controls. Conclusions: In multiple sclerosis (MS), retinal nerve fiber layer thickness is associated with brain parenchymal fraction and CSF volume. These data suggest that quantification of axonal thickness in the retina by optical coherence tomography (OCT) provides concurrent information about MRI brain abnormality in MS. OCT should be examined in longitudinal studies to determine if it could be used as an outcome measure in clinical trials of neuroprotective drugs. GLOSSARY: BPF = brain parenchymal fraction; EDSS = Expanded Disability Status Scale; KKI = Kennedy Krieger Institute; MNI = Montreal Neurological Institute; MPRAGE = magnetization-prepared rapid gradient echo; MS = multiple sclerosis; OCT = optical coherence tomography; PPMS = primary progressive MS; RNFL = retinal nerve fiber layer; RRMS = relapsing remitting MS; SPMS = secondary progressive MS; TMV = total macular volume.

Effects of signal‐to‐noise ratio on the accuracy and reproducibility of diffusion tensor imaging–derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5T

To develop an experimental protocol to calculate the precision and accuracy of fractional anisotropy (FA), mean diffusivity (MD), and the orientation of the principal eigenvector (PEV) as a function of the signal‐to‐noise ratio (SNR) in vivo.

Effects of diffusion weighting schemes on the reproducibility of DTI-derived fractional anisotropy, mean diffusivity, and principal eigenvector measurements at 1.5T

Diffusion tensor imaging (DTI) is used to study tissue composition and architecture in vivo. To increase the signal to noise ratio (SNR) of DTI contrasts, studies typically use more than the minimum of 6 diffusion weighting (DW) directions or acquire repeated observations of the same set of DW directions. Simulation-based studies have sought to optimize DTI acquisitions and suggest that increasing the directional resolution of a DTI dataset (i.e., the number of distinct directions) is preferable to repeating observations, in an equal scan time comparison. However, it is not always clear how to translate these recommendations into practice when considering physiological noise and scanner stability. Furthermore, the effect of different DW schemes on in vivo DTI findings is not fully understood. This study characterizes how the makeup of a DW scheme, in terms of the number of directions, impacts the precision and accuracy of in vivo fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) findings. Orientation dependence of DTI reliability is demonstrated in vivo and a principled theoretical framework is provided to support and interpret findings with simulation results. As long as sampling orientations are well balanced, differences in DTI contrasts due to different DW schemes are shown to be small relative to intra-session variability. These differences are accentuated at low SNR, while minimized at high SNR. This result suggests that typical clinical studies, which use similar protocols but different well-balanced DW schemes, are readily comparable within the experimental precision.

Quantitative Description of the Asymmetry in Magnetization Transfer Effects around the Water Resonance in the Human Brain

Magnetization transfer (MT) imaging provides a unique method of tissue characterization by capitalizing on the interaction between solid‐like tissue components and bulk water. We used a continuous‐wave (CW) MT pulse sequence with low irradiation power to study healthy human brains in vivo at 3 T and quantified the asymmetry of the MT effects with respect to the water proton frequency. This asymmetry was found to be a difference of approximately a few percent from the water signal intensity, depending on both the RF irradiation power and the frequency offset. The experimental results could be quantitatively described by a modified two‐pool MT model extended with a shift contribution for the semisolid pool with respect to water. For white matter, this shift was fitted to be 2.34 ± 0.17 ppm (N = 5) upfield from the water signal. Magn Reson Med 58:786–793, 2007.

Damage to the Optic Radiation in Multiple Sclerosis Is Associated With Retinal Injury and Visual Disability

OBJECTIVEnTo determine whether damage to the optic radiation (OR) in multiple sclerosis (MS) is associated with optic nerve injury and visual dysfunction.nnnDESIGNnCase-control study.nnnSETTINGnReferral center.nnnPARTICIPANTSnNinety referred patients with MS and 29 healthy volunteers.nnnMAIN OUTCOME MEASURESnMagnetic resonance imaging indices along the OR were reconstructed with diffusion tensor tractography. Retinal nerve fiber layer thickness and visual acuity at high and low contrast were measured in a subset of the MS group (n = 36).nnnRESULTSnAll tested magnetic resonance imaging indices (fractional anisotropy [FA]; mean, parallel, and perpendicular [lambda( perpendicular)] diffusivity; T2 relaxation time; and magnetization transfer ratio) were significantly abnormal in patients with MS. Mean retinal nerve fiber layer thickness was significantly correlated with FA (r = 0.55; P < .001) and lambda( perpendicular) (r = -0.37; P = .001). The retinal nerve fiber layer thickness in the nasal retinal quadrant was also specifically correlated with FA and lambda( perpendicular) in the synaptically connected contralateral OR. In individuals with less severely damaged optic nerves (mean retinal nerve fiber layer thickness >80 mum), letter acuity scores at 2.5% contrast were correlated with OR-specific FA (r = 0.55; P = .004), lambda( perpendicular) (r = -0.40; P = .04), and magnetization transfer ratio (r = 0.54; P = .01), as well as the fraction of OR volume made up of lesions (r = -0.69; P < .001).nnnCONCLUSIONSnFractional anisotropy and lambda( perpendicular) are potentially useful quantitative magnetic resonance imaging biomarkers of OR-specific damage in MS. Such damage is associated with retinal injury and visual disability.

MRI of the Corpus Callosum in Multiple Sclerosis: Association with Disability

Inflammatory demyelination and axon damage in the corpus callosum are prominent features of multiple sclerosis (MS) and may partially account for impaired performance on complex tasks. The objective of this article was to characterize quantitative callosal MRI abnormalities and their association with disability. In 69 participants with MS and 29 healthy volunteers, lesional and extralesional callosal MRI indices were estimated via diffusion tensor tractography. expanded disability status scale (EDSS) and MS functional composite (MSFC) scores were recorded in 53 of the participants with MS. All tested callosal MRI indices were diffusely abnormal in MS. EDSS score was correlated only with age (r = 0.51). Scores on the overall MSFC and its paced serial auditory addition test (PASAT) and 9-hole peg test components were correlated with callosal fractional anisotropy (r = 0.27, 0.35, and 0.31, respectively) and perpendicular diffusivity (r = —0.29, —0.30, and —0.31) but not with overall callosal volume or callosal lesion volume; the PASAT score was more weakly correlated with callosal magnetization-transfer ratio (r = 0.21). Anterior callosal abnormalities were associated with impaired PASAT performance and posterior abnormalities with slow performance on the 9-hole peg test. In conclusion, abnormalities in the corpus callosum can be assessed with quantitative MRI and are associated with cognitive and complex upper-extremity dysfunction in MS.

Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord

The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = -0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R(2) = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R(2) = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

High b‐value q‐space diffusion‐weighted MRI of the human cervical spinal cord in vivo: Feasibility and application to multiple sclerosis

Q‐space analysis is an alternative analysis technique for diffusion‐weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q‐space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q‐space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zero‐displacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q‐space contrasts showed a significant (P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q‐space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. The conspicuity of lesions compared favorably with magnetization transfer (MT)‐weighted images and quantitative CSF‐normalized MT measurements. Thus, q‐space DWI can be used to study water diffusion in the human spinal cord in vivo and is well suited to assess white matter damage. Magn Reson Med 59:1079–1089, 2008.

Multiparametric magnetic resonance imaging analysis of the corticospinal tract in multiple sclerosis

BACKGROUND/PURPOSEnMuscle weakness is an important feature of multiple sclerosis and is responsible for much of the disability associated with that condition. Here, we describe the quantitative magnetic resonance imaging (MRI) attributes of the major intracerebral motor pathway--the corticospinal tract--in multiple sclerosis. To do so, we develop an intuitive method for creating and displaying spatially normalized tract-specific imaging data.nnnMETHODSnIn 75 individuals with multiple sclerosis and 29 healthy controls, the corticospinal tracts were reconstructed from diffusion tensor imaging at 3 T. Multiple MRI indices--T2 relaxation time; fractional anisotropy; mean, longitudinal, and transverse diffusivity; and magnetization transfer ratio--were examined within the reconstructed tracts. Spatially normalized tract profiles were created to compare, across subjects, the variation in MRI index as a function of tract position.nnnRESULTSnEach indexs tract profile had a characteristic shape. Individual subjects had markedly abnormal tract profiles, particularly at lesion sites. On average, tract profiles were different between patients and controls, particularly in the subcortical white matter and corona radiata, for all indices examined except for fractional anisotropy. Magnetization transfer ratio was further decreased in subjects with secondary progressive disease. Tract asymmetry was increased in multiple sclerosis compared to controls.nnnCONCLUSIONnMultiparametric MRI allows rapid detection, localization, and characterization of tract-specific abnormalities in multiple sclerosis. Tract profiles bridge the gap between whole-brain imaging of neurological disease and the interrogation of individual, functionally relevant subsystems.

Reproducibility of tract-specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla.

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)‐ and magnetization transfer (MT)‐derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column‐specific parallel (λ||) and perpendicular (λ⟂) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT‐weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time‐points separated by more than 1u2009week. Cross‐sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ||: 2.13u2009±u20090.14 and 2.14u2009±u20090.11u2009μm2/ms; λ⟂: 0.67u2009±u20090.16 and 0.61u2009±u20090.09u2009μm2/ms; MD: 1.15u2009±u20090.15 and 1.12u2009±u20090.08u2009μm2/ms; FA: 0.68u2009±u20090.06 and 0.68u2009±u20090.05; MTCSF: 0.52u2009±u20090.05 and 0.50u2009±u20090.05. We examined the variability and interrater and test‐retest reliability for each metric. These column‐specific MR measurements are expected to enhance understanding of the intimate structure‐function relationship in the cervical spinal cord and may be useful for the assessment of disease progression. Copyright