Facing privacy in neuroimaging: removing facial features degrades performance of image analysis methods.

BACKGROUND: Recent studies have created awareness that facial features can be reconstructed from high-resolution MRI. Therefore, data sharing in neuroimaging requires special attention to protect participants' privacy. Facial features removal (FFR) could alleviate these concerns. We assessed the impact of three FFR methods on subsequent automated image analysis to obtain clinically relevant outcome measurements in three clinical groups. METHODS: FFR was performed using QuickShear, FaceMasking, and Defacing. In 110 subjects of Alzheimer's Disease Neuroimaging Initiative, normalized brain volumes (NBV) were measured by SIENAX. In 70 multiple sclerosis patients of the MAGNIMS Study Group, lesion volumes (WMLV) were measured by lesion prediction algorithm in lesion segmentation toolbox. In 84 glioblastoma patients of the PICTURE Study Group, tumor volumes (GBV) were measured by BraTumIA. Failed analyses on FFR-processed images were recorded. Only cases in which all image analyses completed successfully were analyzed. Differences between outcomes obtained from FFR-processed and full images were assessed, by quantifying the intra-class correlation coefficient (ICC) for absolute agreement and by testing for systematic differences using paired t tests. RESULTS: Automated analysis methods failed in 0-19% of cases in FFR-processed images versus 0-2% of cases in full images. ICC for absolute agreement ranged from 0.312 (GBV after FaceMasking) to 0.998 (WMLV after Defacing). FaceMasking yielded higher NBV (p = 0.003) and WMLV (p ≤ 0.001). GBV was lower after QuickShear and Defacing (both p < 0.001). CONCLUSIONS: All three outcome measures were affected differently by FFR, including failure of analysis methods and both "random" variation and systematic differences. Further study is warranted to ensure high-quality neuroimaging research while protecting participants' privacy. KEY POINTS: • Protecting participants' privacy when sharing MRI data is important. • Impact of three facial features removal methods on subsequent analysis was assessed in three clinical groups. • Removing facial features degrades performance of image analysis methods.

Reproducibility of Deep Gray Matter Atrophy Rate Measurement in a Large Multicenter Dataset.

BACKGROUND AND PURPOSE: Precise in vivo measurement of deep GM volume change is a highly demanded prerequisite for an adequate evaluation of disease progression and new treatments. However, quantitative data on the reproducibility of deep GM structure volumetry are not yet available. In this paper we aim to investigate this reproducibility using a large multicenter dataset. MATERIALS AND METHODS: We have assessed the reproducibility of 2 automated segmentation software packages (FreeSurfer and the FMRIB Integrated Registration and Segmentation Tool) by quantifying the volume changes of deep GM structures by using back-to-back MR imaging scans from the Alzheimer Disease Neuroimaging Initiative's multicenter dataset. Five hundred sixty-two subjects with scans at baseline and 1 year were included. Reproducibility was investigated in the bilateral caudate nucleus, putamen, amygdala, globus pallidus, and thalamus by carrying out descriptives as well as multilevel and variance component analysis. RESULTS: Median absolute back-to-back differences varied between GM structures, ranging from 59.6-156.4 µL for volume change, and 1.26%-8.63% for percentage volume change. FreeSurfer had a better performance for the outcome of longitudinal volume change for the bilateral amygdala, putamen, left caudate nucleus (P < .005), and right thalamus (P < .001). For longitudinal percentage volume change, Freesurfer performed better for the left amygdala, bilateral caudate nucleus, and left putamen (P < .001). Smaller limits of agreement were found for FreeSurfer for both outcomes for all GM structures except the globus pallidus. Our results showed that back-to-back differences in 1-year percentage volume change were approximately 1.5-3.5 times larger than the mean measured 1-year volume change of those structures. CONCLUSIONS: Longitudinal deep GM atrophy measures should be interpreted with caution. Furthermore, deep GM atrophy measurement techniques require substantially improved reproducibility, specifically when aiming for personalized medicine.

Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis.

Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.

Static and dynamic loading of mandibular condyles and their positional changes after bilateral sagittal split advancement osteotomies.

This study analysed the effects of change of direction of masseter (MAS) and medial pterygoid muscles (MPM) and changes of moment arms of MAS, MPM and bite force on static and dynamic loading of the condyles after surgical mandibular advancement. Rotations of the condyles were assessed on axial MRIs. 16 adult patients with mandibular hypoplasia were studied. The mandibular plane angle (MPA) was <39° in Group I (n=8) and >39° in Group II (n=8). All mandibles were advanced with a bilateral sagittal split osteotomy (BSSO). In Group II, BSSO was combined with Le Fort I osteotomy. Pre and postoperative moment arms of MAS, MPM and bite force were used in a two-dimensional model to assess static loading of the condyles. Pre and postoperative data on muscle cross-sectional area, volume and direction were introduced in three-dimensional dynamic models of the masticatory system to assess the loading of the condyles during opening and closing. Postsurgically, small increases of static condylar loading were calculated. Dynamic loading decreased slightly. Minor rotations of the condyles were observed. The results do not support the idea that increased postoperative condylar loading is a serious cause for condylar resorption or relapse.

Optimizing parameter choice for FSL-Brain Extraction Tool (BET) on 3D T1 images in multiple sclerosis.

BACKGROUND: Brain atrophy studies often use FSL-BET (Brain Extraction Tool) as the first step of image processing. Default BET does not always give satisfactory results on 3DT1 MR images, which negatively impacts atrophy measurements. Finding the right alternative BET settings can be a difficult and time-consuming task, which can introduce unwanted variability. AIM: To systematically analyze the performance of BET in images of MS patients by varying its parameters and options combinations, and quantitatively comparing its results to a manual gold standard. METHODS: Images from 159 MS patients were selected from different MAGNIMS consortium centers, and 16 different 3DT1 acquisition protocols at 1.5 T or 3T. Before running BET, one of three pre-processing pipelines was applied: (1) no pre-processing, (2) removal of neck slices, or (3) additional N3 inhomogeneity correction. Then BET was applied, systematically varying the fractional intensity threshold (the "f" parameter) and with either one of the main BET options ("B" - bias field correction and neck cleanup, "R" - robust brain center estimation, or "S" - eye and optic nerve cleanup) or none. For comparison, intracranial cavity masks were manually created for all image volumes. FSL-FAST (FMRIB's Automated Segmentation Tool) tissue-type segmentation was run on all BET output images and on the image volumes masked with the manual intracranial cavity masks (thus creating the gold-standard tissue masks). The resulting brain tissue masks were quantitatively compared to the gold standard using Dice overlap coefficient (DOC). Normalized brain volumes (NBV) were calculated with SIENAX. NBV values obtained using for SIENAX other BET settings than default were compared to gold standard NBV with the paired t-test. RESULTS: The parameter/preprocessing/options combinations resulted in 20,988 BET runs. The median DOC for default BET (f=0.5, g=0) was 0.913 (range 0.321-0.977) across all 159 native scans. For all acquisition protocols, brain extraction was substantially improved for lower values of "f" than the default value. Using native images, optimum BET performance was observed for f=0.2 with option "B", giving median DOC=0.979 (range 0.867-0.994). Using neck removal before BET, optimum BET performance was observed for f=0.1 with option "B", giving median DOC 0.983 (range 0.844-0.996). Using the above BET-options for SIENAX instead of default, the NBV values obtained from images after neck removal with f=0.1 and option "B" did not differ statistically from NBV values obtained with gold-standard. CONCLUSION: Although default BET performs reasonably well on most 3DT1 images of MS patients, the performance can be improved substantially. The removal of the neck slices, either externally or within BET, has a marked positive effect on the brain extraction quality. BET option "B" with f=0.1 after removal of the neck slices seems to work best for all acquisition protocols.

Positional changes of the masseter and medial pterygoid muscles after surgical mandibular advancement procedures: an MRI study.

This study evaluated whether surgical mandibular advancement procedures induced a change in the direction and the moment arms of the masseter (MAS) and medial pterygoid (MPM) muscles. Sixteen adults participated in this study. The sample was divided in two groups: Group I (n=8) with a mandibular plane angle (mpa) <39° and Group II (n=8) with an mpa >39°. Group I patients were treated with a bilateral sagittal split osteotomy (BSSO). Those in Group II were treated with a BSSO combined with a Le Fort I osteotomy. Pre- and postoperative direction and moment arms of MAS and MPM were compared in these groups. Postsurgically, MAS and MPM in Group II showed a significantly more vertical direction in the sagittal plane. Changes of direction in the frontal plane and changes of moment arms were insignificant in both groups. This study demonstrated that bimaxillary surgery in patients with an mpa >39° leads to a significant change of direction of MAS and MPM in the sagittal plane.

Spinal cord grey matter lesions in multiple sclerosis detected by post-mortem high field MR imaging.

BACKGROUND: Post-mortem studies demonstrate extensive grey matter demyelination in MS, both in the brain and in the spinal cord. However the clinical significance of these plaques is unclear, largely because they are grossly underestimated by MR imaging at conventional field strengths. Indeed post-mortem MR studies suggest the great majority of lesions in the cerebral cortex go undetected, even when performed at high field. Similar studies have not been performed using post-mortem spinal cord material. AIM: To assess the sensitivity of high field post-mortem MRI for detecting grey matter lesions in the spinal cord in MS. METHODS: Autopsy material was obtained from 11 MS cases and 2 controls. Proton Density-weighted images of this formalin-fixed material were acquired at 4.7 Tesla before the tissue was sectioned and stained for Myelin Basic Protein. Both the tissue sections and the MR images were scored for grey matter and white matter plaques, with the readers of the MR images being blinded to the histopathology results. RESULTS: Our results indicate that post-mortem imaging at 4.7 Tesla is highly sensitive for cord lesions, detecting 87% of white matter lesions and 73% of grey matter lesions. The MR changes were highly specific for demyelination, with all lesions scored on MRI corresponding to areas of demyelination. CONCLUSION: Our work suggests that spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the functional consequences of grey matter demyelination in MS.

A comparison of human jaw muscle cross-sectional area and volume in long- and short-face subjects, using MRI.

OBJECTIVE: In humans, the vertical craniofacial dimensions vary significantly with the size of the jaw muscles, which are regarded as important controlling factors of craniofacial growth. The functional relevance of the maximum cross-sectional area (CSA), indicating maximum muscle strength, is questionable since peak forces are generated only a fraction of the day. Alternatively, muscle volume (indicating the generated loads) might be a more meaningful functional variable. Therefore, the aim of this study was to investigate if jaw muscle volume is stronger related with vertical craniofacial dimensions than with jaw muscle CSA. DESIGN: Thirty-one adult healthy subjects with varying vertical craniofacial morphology participated in this study. Axial magnetic resonance imaging (MRI) scans were used for segmentation of the masseter (Mas) and medial pterygoid muscles (MPM). This enabled measurements of the muscle CSA and volume. Cephalometric analysis was performed using lateral radiographs. With factor analysis, the number of cephalometric variables was reduced into two factors that represented the anterior face height and the posterior face height (PFH), respectively. Subsequently, mutual relationships between these factors and muscular variables were assessed using a multiple regression analysis. RESULTS: It was found that vertical craniofacial dimensions were significantly better (up to 12%) related with muscle volume rather than with CSA. Furthermore, it was shown that especially the PFH factor was significantly correlated with the Mas and MPM. CONCLUSION: Vertical craniofacial dimensions are stronger related with jaw muscle volume than with CSA. Tentatively, it can be assumed that the generated muscle loads, rather than maximum forces, influence vertical craniofacial growth.

Improved reliability of hippocampal atrophy rate measurement in mild cognitive impairment using fluid registration.

MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval+/-SD: 2.01+/-0.11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean+/-SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2.13+/-1.62; right: 2.36+/-1.78 and for regional fluid registration: forward: left: 2.39+/-1.68; right: 2.49+/-1.52 and backward: left: 2.21+/-1.51; right: 2.42+/-1.49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0.99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0.798; right: 0.850) compared with regional fluid registration (forward: left: 0.985; right: 0.988 and backward: left: 0.975; right: 0.989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.

Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease.

PURPOSE: Mild cognitive impairment (MCI) is thought to be the prodromal phase to Alzheimer's disease (AD). We analyzed patterns of gray matter (GM) loss to examine what characterizes MCI and what determines the difference with AD. MATERIALS AND METHODS: Thirty-three subjects with AD, 14 normal elderly controls (NCLR), and 22 amnestic MCI subjects were included and underwent brain MR imaging. Global GM volume was assessed using segmentation and local GM volume was assessed using voxel-based morphometry (VBM); VBM was optimized for template mismatch and statistical mass. RESULTS: AD subjects had significantly (12.3%) lower mean global GM volume when compared to controls (517 +/- 58 vs. 590 +/- 52 ml; P < 0.001). Global GM volume in the MCI group (552 +/- 52) was intermediate between these two: 6.2% lower than AD and 6.5% higher than the controls but not significantly different from either group. VBM showed that subjects with MCI had significant local reductions in gray matter in the medial temporal lobe (MTL), the insula, and thalamus compared to NCLR subjects. By contrast, when compared to subjects with AD, MCI subjects had more GM in the parietal association areas and the anterior and the posterior cingulate. CONCLUSION: GM loss in the MTL characterizes MCI, while GM loss in the parietal and cingulate cortices might be a feature of AD.

Measuring progression of cerebral white matter lesions on MRI: visual rating and volumetrics.

OBJECTIVE: To evaluate the concordance of a volumetric method for measuring white matter lesion (WML) change with visual rating scales. METHODS: The authors selected a stratified sample of 20 elderly people (mean age 72 years, range 61 to 88 years) with an MRI examination at baseline and at 3-year follow-up from the community-based Rotterdam Scan Study (RSS). Four raters assessed WML change with four different visual rating scales: the Fazekas scale, the Scheltens scale, the RSS scale, and a new visual rating scale that was designed to measure change in WML. The authors assessed concordance with a volumetric method with scatter plots and correlations, and interobserver agreement with intraclass correlation coefficients. RESULTS: For assessment of change in WML, the Fazekas, Scheltens, and periventricular part of the RSS scale showed little correlation with volumetrics, and low interobserver agreement. The authors' new WML change scale and the subcortical part of the RSS scale showed good correlation with volumetrics. After additional training, the new WML change scale showed good interobserver agreement for measuring WML change. CONCLUSIONS: Commonly used visual rating scales are not well suited for measuring change in white matter lesion severity. The authors' new white matter lesion change scale is more accurate and precise, and may be of use in studies focusing on progression of white matter lesions.

A comprehensive study of gray matter loss in patients with Alzheimer's disease using optimized voxel-based morphometry.

Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimer's disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

Isotropic 3D fast FLAIR imaging of the brain in multiple sclerosis patients: initial experience.

The application of image registration and subtraction to detect change in multiple sclerosis (MS) disease burden on serial MR scans benefits from the use of isotropic voxels. An optimised 3D fast fluid-attenuated inversion recovery (FLAIR) sequence with 1.2- and 1.8-mm cubic voxels was compared with a 2D T2 SE sequence using standard 3-mm slices. Three-dimensional fast FLAIR and T2 SE series were obtained in 20 MS patients and 15 controls. Whole brain acquisition times for the 1.2- and 1.8-mm FLAIR were 21 and 10.5 min, respectively, for the interleaved T2 SE 16 min. Brain lesions were marked in consensus by two radiologists and the CNR was calculated in ten lesions. The mean number of lesions detected with the 1.2-mm FLAIR sequence was 115 +/- 76, compared with 85 +/- 59 for the T2 SE series ( p<0.001). The 1.8-mm FLAIR detected only 73 +/- 46 lesions. The CNR of the 1.2-mm FLAIR was significantly better than the T2 SE ( p<0.01), but not as good as the 1.8-mm FLAIR. In conclusion, isotropic 3D fast FLAIR using 1.2-mm cubic voxels is superior to the 2D T2 SE in the detection of brain lesions in MS patients. The isotropic 1.8-mm FLAIR is faster and has better contrast characteristics but lacks sensitivity.

Improved interobserver agreement for visual detection of active T2 lesions on serial MR scans in multiple sclerosis using image registration.

The aim of this study was to analyse the effect of image registration on interobserver agreement in the visual detection of active multiple sclerosis (MS) lesions from serial magnetic resonance (MR) scans. T2W spin-echo MR scans (3-mm slices) of 16 MS patients participating in a treatment trial were selected. For each patient, two pairs of scans were used: an original (i. e., non-registered) and a registered pair. For the original pair, baseline and month 6 were used, and for the registered pair month 3 and 9. For registration an automatic matching algorithm based on Mutual Information was used. Six observers identified active lesions on both original and registered scans. Kappa values were calculated to assess interobserver agreement. Reslicing caused a slight blurring of the images, but near perfect registration. The kappa value of 0.35 +/- 0.07 for new lesions on original images improved to 0.62 (+/- 0.06) by registration (p = 0.004). For enlarging lesions on original images it was extremely poor (kappa 0.11 +/- 0.05), and did not benefit much by registration (kappa 0.20 +/- 0.11). Thus, image registration improved interobserver agreement for visual detection of new lesions. For enlarging lesions, registration improved agreement but still not to a satisfactory level.

Magnetization transfer histogram parameters reflect all dimensions of MS pathology, including atrophy.

INTRODUCTION: Magnetization transfer ratio (MTR) histogram analysis can be used as a method for quantifying overall disease burden in MS. We studied correlations between MTR histogram and clinical parameters in MS subgroups. Contrary to earlier studies we placed special emphasis on the lower MTR range, to explore the effect of partial volume averaging effects with CSF. METHODS: Seventy-nine patients with MS [26 primary progressive (PP), and 53 'relapse-onset', including 26 secondary progressive (SP)], and 23 healthy individuals were studied. MR imaging included 3 mm 2D gradient-echo images with and without an off-resonance MT pulse. According to the visually determined cut-off, histogram parameters were classified as parenchymal or CSF-related variables. Clinical measurements included the Expanded Disability Status Scale (EDSS) as a measure of global impairment/disability and the Paced Auditory Serial Addition Test (PASAT) as a measure of cognition. RESULTS: SP MS patients differed from the other subgroups on many MTR variables, originating from both the lower and the higher MTR range. CSF-related low MTRs were clearly over-represented in SP patients, and showed a significant distinction between the SP and PP MS group. In the total group, as well as in the relapse-onset patients, significant correlations were found between MTR parameters and clinical parameters. No associations were found in the PP group. CONCLUSION: This explorative study suggests that MTR histogram analysis can distinguish between MS patients and controls, and best identifies the SP phenotype, partly as a result of increased CSF volume (atrophy). In addition, we show that MTR histogram analysis gives information about the level of impairment and disability in patients with a 'relapse-onset' course of MS, and therefore provides a useful tool to monitor the evolution of the disease in these patients.

MR venography of multiple sclerosis.

BACKGROUND AND PURPOSE: The distribution of multiple sclerosis (MS) lesions in the brain follows a specific pattern, with most lesions in the periventricular regions and in the deep white matter; histopathologic studies have shown a perivenous distribution. The aim of this study was to illustrate these distribution patterns in vivo using high-resolution MR venography. METHODS: Seventeen MS patients underwent MR imaging at 1.5 T. Venographic studies were obtained with a 3D gradient-echo technique. MS lesions were identified on T2-weighted images, and their shape, orientation, and location were compared with the venous anatomy on the venograms. RESULTS: The use of contrast material facilitated the visualization of small veins and increased the number of veins seen. A total of 95 MS lesions could be identified on both the T2-weighted series and the venograms; a central vein was visible in all 43 periventricular lesions and in all but one of the 52 focal deep white matter lesions. The typical ovoid shape and orientation of the long axis of the MS lesions correlated well with the course of these veins. CONCLUSION: With MR venography, the perivenous distribution of MS lesions in the brain can be visualized in vivo. The venous anatomy defines the typical form and orientation of these lesions.

Sensitivity and reproducibility of volume change measurements of different brain portions on magnetic resonance imaging in patients with multiple sclerosis.

The course of multiple sclerosis (MS) can be monitored by measuring changes in brain volume, but consensus is still lacking on the best strategy to be adopted. We compared the reproducibility and sensitivity of volume measurements from different brain portions for detecting changes on magnetic resonance imaging (MRI) in patients with MS. T1-weighted MRI of the brain was performed in 50 patients with relapsing-remitting MS at study entry and after an average follow-up of 18.4 months. Using a semiautomated technique for brain parenchyma segmentation, the volumes of the following brain portions were measured: (a) the whole brain (whole-brain volume, WBV), (b) the seven slices rostral to the velum interpositum (seven-slice volume, SSV), (c) the central slice of the image set (central-slice volume, CSV) and (d) the infratentorial regions (infratentorial-brain volume, IBV). All these measurements were carried out by a single observer and were repeated twice on ten randomly selected scans to test the intra-observer reproducibility using the four strategies. At follow-up there was a significant decrease in all the measures of brain volume (P ranged from 0.002 to < 0.001). The univariate correlations between changes in WBV, SSV, CSV and IBV were all statistically significant, with the exception of that between changes in CSV and IBV; r values ranged from 0.34 (for the WBV/IBV correlation) to 0.80 (for the WBV/SSV correlation). The mean intra-observer coefficient of variations were 1.9% for WBV, 1.5% for SSV, 2.9% for CSV and 2.2% for IBV measurements. The measurement of volume on a portion of brain selectively including the regions in which MS pathology is more diffuse is as reliable and sensitive to disease-related changes as that on the whole brain, with significant time saving for processing.

Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy.

Hypointense T1 lesions in multiple sclerosis patients correlate with axonal loss at autopsy and biopsy. We evaluated the chemical substrate of hypointense T1 lesions by using in vivo proton magnetic resonance spectroscopy, and analyzed the spectroscopic correlate of increased T1-relaxation time measurements. Localized proton magnetic resonance spectroscopy and T1-relaxation time measurements were performed in lesions, selected on T1-weighted spin-echo magnetic resonance images according to degree of hypointensity, in normal appearing white matter (NAWM) and in normal white matter of controls. In NAWM, prolongation of T1-relaxation time and a decrease in N-acetylaspartate (NAA) were present, compared with normal white matter. Severely hypointense lesions showed a lower concentration of NAA and creatine compared with NAWM and a lower concentration of NAA compared with isointense to mildly hypointense lesions. NAA concentration correlated with degree of hypointensity of lesions and with T1-relaxation time within the spectroscopic voxel. Our results provide the first in vivo evidence of axonal damage in severely hypointense T1 lesions in multiple sclerosis patients. T1-relaxation time correlates with the concentration of NAA in both multiple sclerosis lesions and NAWM, indicating that this parameter deserves further evaluation to monitor disease progression.