Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

Intensity warping for multisite MRI harmonization.

In multisite neuroimaging studies there is often unwanted technical variation across scanners and sites. These "scanner effects" can hinder detection of biological features of interest, produce inconsistent results, and lead to spurious associations. We propose mica (multisite image harmonization by cumulative distribution function alignment), a tool to harmonize images taken on different scanners by identifying and removing within-subject scanner effects. Our goals in the present study were to (1) establish a method that removes scanner effects by leveraging multiple scans collected on the same subject, and, building on this, (2) develop a technique to quantify scanner effects in large multisite studies so these can be reduced as a preprocessing step. We illustrate scanner effects in a brain MRI study in which the same subject was measured twice on seven scanners, and assess our method's performance in a second study in which ten subjects were scanned on two machines. We found that unharmonized images were highly variable across site and scanner type, and our method effectively removed this variability by aligning intensity distributions. We further studied the ability to predict image harmonization results for a scan taken on an existing subject at a new site using cross-validation.

Longitudinal quantitative magnetic resonance imaging in adrenomyeloneuropathy.

BACKGROUND AND PURPOSE: Adrenomyeloneuropathy (AMN) is the most frequent metabolic hereditary spastic paraplegia. Accordingly, its main site of pathological changes is the spinal cord. It is difficult to quantify AMN progression because commonly used clinical scales have limitations and reliable biomarkers are lacking. The goal was to investigate whether spinal cord and brain quantitative magnetic resonance imaging may assess structural changes in AMN over a relatively short time period. METHODS: In this longitudinal observational study, the total cord areas (TCAs) from the C2-C3 to T2-T3 level and diffusion tensor imaging (DTI) metrics of the cervical spinal cord and brain portion of the corticospinal tracts in six AMN and six age-matched control subjects at baseline and at a mean follow-up of 22.6 months were assessed. RESULTS: A significant reduction of the mean TCA at the T1-T2 level (-3.79%) and a trend of reduction at the lowest cervical levels were observed only in AMN patients. Additionally, DTI metrics revealed significant changes in fractional anisotropy (-8.84%), mean diffusivity (+12.62%) and radial diffusivity (+25.91%) at the C2-C3 level. DISCUSSION: The study encourages the assessment of TCAs and spinal cord DTI metrics as surrogate outcome measures in AMN, by focusing on the cervical-thoracic junction and the uppermost part of the cervical spinal cord. Despite the limitation of the results due to the small number of investigated subjects, these observations are useful for forthcoming clinical trials in AMN and possibly other hereditary diseases with predominant spinal cord involvement.

An Automated Statistical Technique for Counting Distinct Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: Lesion load is a common biomarker in multiple sclerosis, yet it has historically shown modest association with clinical outcome. Lesion count, which encapsulates the natural history of lesion formation and is thought to provide complementary information, is difficult to assess in patients with confluent (ie, spatially overlapping) lesions. We introduce a statistical technique for cross-sectionally counting pathologically distinct lesions. MATERIALS AND METHODS: MR imaging was used to assess the probability of a lesion at each location. The texture of this map was quantified using a novel technique, and clusters resembling the center of a lesion were counted. Validity compared with a criterion standard count was demonstrated in 60 subjects observed longitudinally, and reliability was determined using 14 scans of a clinically stable subject acquired at 7 sites. RESULTS: The proposed count and the criterion standard count were highly correlated (r = 0.97, P < .001) and not significantly different (t59 = -.83, P = .41), and the variability of the proposed count across repeat scans was equivalent to that of lesion load. After accounting for lesion load and age, lesion count was negatively associated (t58 = -2.73, P < .01) with the Expanded Disability Status Scale. Average lesion size had a higher association with the Expanded Disability Status Scale (r = 0.35, P < .01) than lesion load (r = 0.10, P = .44) or lesion count (r = -.12, P = .36) alone. CONCLUSIONS: This study introduces a novel technique for counting pathologically distinct lesions using cross-sectional data and demonstrates its ability to recover obscured longitudinal information. The proposed count allows more accurate estimation of lesion size, which correlated more closely with disability scores than either lesion load or lesion count alone.

Spinal cord microstructure integrating phase-sensitive inversion recovery and diffusional kurtosis imaging.

PURPOSE: The aim of this prospective study was to determine the feasibility in terms of repeatability and reproducibility of diffusional kurtosis imaging (DKI) for microstructural assessment of the normal cervical spinal cord (cSC) using a phase-sensitive inversion recovery (PSIR) sequence as the anatomical reference for accurately defining white-matter (WM) and gray-matter (GM) regions of interests (ROIs). METHODS: Thirteen young healthy subjects were enrolled to undergo DKI and PSIR sequences in the cSC. The repeatability and reproducibility of kurtosis metrics and fractional anisotropy (FA) were calculated in GM, WM, and cerebral-spinal-fluid (CSF) ROIs drawn by two independent readers on PSIR images of three different levels (C1-C4). The presence of statistically significant differences in DKI metrics for levels, ROIs (GM, WM, and CSF) repeatability, reproducibility, and inter-reader agreement was evaluated. RESULTS: Intra-class correlation coefficients between the two readers ranged from good to excellent (0.75 to 0.90). The inferior level consistently had the highest concordance. The lower values of scan-rescan variability for all DKI parameters were found for the inferior level. Statistically significant differences in kurtosis values were not found in the lateral white-matter bundles of the spinal cord. CONCLUSION: The integration of DKI and PSIR sequences in a clinical MR acquisition to explore the regional microstructure of the cSC in healthy subjects is feasible, and the results obtainable are reproducible. Further investigation will be required to verify the possibility to translate this method to a clinical setting to study patients with SC involvement especially in the absence of MRI abnormalities on standard sequences.

Volumetric Analysis from a Harmonized Multisite Brain MRI Study of a Single Subject with Multiple Sclerosis.

BACKGROUND AND PURPOSE: MR imaging can be used to measure structural changes in the brains of individuals with multiple sclerosis and is essential for diagnosis, longitudinal monitoring, and therapy evaluation. The North American Imaging in Multiple Sclerosis Cooperative steering committee developed a uniform high-resolution 3T MR imaging protocol relevant to the quantification of cerebral lesions and atrophy and implemented it at 7 sites across the United States. To assess intersite variability in scan data, we imaged a volunteer with relapsing-remitting MS with a scan-rescan at each site. MATERIALS AND METHODS: All imaging was acquired on Siemens scanners (4 Skyra, 2 Tim Trio, and 1 Verio). Expert segmentations were manually obtained for T1-hypointense and T2 (FLAIR) hyperintense lesions. Several automated lesion-detection and whole-brain, cortical, and deep gray matter volumetric pipelines were applied. Statistical analyses were conducted to assess variability across sites, as well as systematic biases in the volumetric measurements that were site-related. RESULTS: Systematic biases due to site differences in expert-traced lesion measurements were significant (P < .01 for both T1 and T2 lesion volumes), with site explaining >90% of the variation (range, 13.0-16.4 mL in T1 and 15.9-20.1 mL in T2) in lesion volumes. Site also explained >80% of the variation in most automated volumetric measurements. Output measures clustered according to scanner models, with similar results from the Skyra versus the other 2 units. CONCLUSIONS: Even in multicenter studies with consistent scanner field strength and manufacturer after protocol harmonization, systematic differences can lead to severe biases in volumetric analyses.

Application of quantitative DTI metrics in sporadic CJD.

Diffusion Weighted Imaging is extremely important for the diagnosis of probable sporadic Jakob-Creutzfeldt disease, the most common human prion disease. Although visual assessment of DWI MRI is critical diagnostically, a more objective, quantifiable approach might more precisely identify the precise pattern of brain involvement. Furthermore, a quantitative, systematic tracking of MRI changes occurring over time might provide insights regarding the underlying histopathological mechanisms of human prion disease and provide information useful for clinical trials. The purposes of this study were: 1) to describe quantitatively the average cross-sectional pattern of reduced mean diffusivity, fractional anisotropy, atrophy and T1 relaxation in the gray matter (GM) in sporadic Jakob-Creutzfeldt disease, 2) to study changes in mean diffusivity and atrophy over time and 3) to explore their relationship with clinical scales. Twenty-six sporadic Jakob-Creutzfeldt disease and nine control subjects had MRIs on the same scanner; seven sCJD subjects had a second scan after approximately two months. Cortical and subcortical gray matter regions were parcellated with Freesurfer. Average cortical thickness (or subcortical volume), T1-relaxiation and mean diffusivity from co-registered diffusion maps were calculated in each region for each subject. Quantitatively on cross-sectional analysis, certain brain regions were preferentially affected by reduced mean diffusivity (parietal, temporal lobes, posterior cingulate, thalamus and deep nuclei), but with relative sparing of the frontal and occipital lobes. Serial imaging, surprisingly showed that mean diffusivity did not have a linear or unidirectional reduction over time, but tended to decrease initially and then reverse and increase towards normalization. Furthermore, there was a strong correlation between worsening of patient clinical function (based on modified Barthel score) and increasing mean diffusivity.

Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias.

BACKGROUND: Diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) MRI have high sensitivity and specificity for Creutzfeldt-Jakob disease (CJD). No studies, however, have demonstrated how MRI can distinguish CJD from nonprion causes of rapidly progressive dementia (npRPD). We sought to determine the diagnostic accuracy of MRI for CJD compared to a cohort of npRPD subjects. METHODS: Two neuroradiologists blinded to diagnosis assessed DWI and FLAIR images in 90 patients with npRPD (n = 29) or prion disease (sporadic CJD [sCJD], n = 48, or genetic prion disease [familial CJD, n = 6, and Gerstmann-Sträussler-Scheinker, n = 7]). Thirty-one gray matter regions per hemisphere were assessed for abnormal hyperintensities. The likelihood of CJD was assessed using our previously published criteria. RESULTS: Gray matter hyperintensities (DWI > FLAIR) were found in all sCJD cases, with certain regions preferentially involved, but never only in limbic regions, and rarely in the precentral gyrus. In all sCJD cases with basal ganglia or thalamic DWI hyperintensities, there was associated restricted diffusion (apparent diffusion coefficient [ADC] map). This restricted diffusion, however, was not seen in any npRPD cases, in whom isolated limbic hyperintensities (FLAIR > DWI) were common. One reader's sensitivity and specificity for sCJD was 94% and 100%, respectively, the other's was 92% and 72%. After consensus review, the readers' combined MRI sensitivity and specificity for sCJD was 96% and 93%, respectively. Familial CJD had overlapping MRI features with sCJD. CONCLUSIONS: The pattern of FLAIR/DWI hyperintensity and restricted diffusion can differentiate sCJD from other RPDs with a high sensitivity and specificity. MRI with DWI and ADC should be included in sCJD diagnostic criteria. New sCJD MRI criteria are proposed.

Diffusion-weighted imaging in fetuses with severe congenital heart defects.

Fetal diffusion MR imaging was performed in 3 fetuses with CHD. ADC values in the periatrial WM, thalamus, and basal ganglia were compared with those in a control population of fetuses. Diffusivity in the periatrial WM and thalamus was higher for the fetuses with CHD compared with controls. These observations support the finding of abnormal in utero brain development in fetuses with CHD.

Quantitative fiber tracking of the optic radiation is correlated with visual-evoked potential amplitude in preterm infants.

BACKGROUND AND PURPOSE: Children born preterm are at risk for adverse outcome, including visual impairment. We examined the relationship between neonatal DTI and sVEP in children born preterm to determine whether visual outcomes are related to early measurements of brain microstructure. MATERIALS AND METHODS: Subjects were born at <34 weeks gestation and imaged before term-equivalent age. DTI fiber tracking was used to delineate the optic radiations and measure tract-specific average FA, D(av), and parallel and transverse diffusivity. Visual-evoked response amplitudes were measured as a function of spatial frequency, contrast, and vernier offset size with sVEP at 6-20 months after birth. The association between DTI and sVEP was assessed by using the Spearman correlation coefficient and linear regression for repeated measures. RESULTS: Nine children with 15 scans were included. The peak response amplitudes for spatial frequency sweeps were associated with increasing FA and decreasing D(av) and transverse diffusivity (P ≤ .006) but not with parallel diffusivity (P = 1). There was only modest association with the swept contrast condition and no detectable association with the vernier offset sweeps. CONCLUSIONS: Microstructure of the optic radiations measured shortly after birth is associated with quantitatively measured responses elicited by moderate-to-high contrast spatiotemporal gratings in infancy. These findings are in keeping with studies showing a relationship between brain microstructure and function. While the clinical impact is not known, quantitative neuroimaging of white matter may ultimately be important for predicting outcome in preterm neonates.

Quantitative fiber tracking analysis of the optic radiation correlated with visual performance in premature newborns.

BACKGROUND AND PURPOSE: Many prematurely born neonates have abnormalities of vision or visual processing. This study tests the hypothesis that a correlation exists between the microstructure of the optic radiation and visual performance in premature neonates. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) was performed on 36 premature neonates ranging in age from 29 to 41 weeks of gestational age (GA) at time of MR imaging. DTI fiber tracking methods were developed to delineate the optic radiations and segment the tract into anterior, middle, and posterior regions. Structural development and spatial heterogeneity in the delineated optic radiations were quantitatively assessed with diffusion tensor parameters including fractional anisotropy (FA), directionally averaged diffusivity (D(av)), parallel diffusivity (lambda(1)), and transverse diffusivity (lambda( perpendicular)). Visual maturity of the preterm neonates at the time of MR imaging was assessed with a visual fixation task. Regression analysis was used to examine the relationship between neonatal visual performance and the microstructure of the optic radiation. RESULTS: Fractional anisotropy within the optic radiation was observed to increase with GA (P < .0001). D(av), parallel diffusivity, and transverse diffusivity within the optic radiation each decreased with GA (P < .0003, P < .02, and P < .0001, respectively). The anterior segment of the optic radiation exhibited higher FA and lower D(av), parallel diffusivity, and transverse diffusivity (P < .005 each) than within the middle and posterior segments. Optic radiation fractional anisotropy correlated significantly with scores from the visual fixation tracking assessment, independent of GA (P < .006). CONCLUSIONS: This study detected a significant link between the tissue architecture of the optic radiation and visual function in premature neonates.

Diffusion tensor imaging of the pyramidal tracts in infants with motor dysfunction.

OBJECTIVE: To determine if diffusion tensor imaging (DTI) metrics of the pyramidal tracts correlate with motor outcome in infants presenting with motor dysfunction. METHODS: DTI tractography of the pyramidal tracts was performed in 21 patients with clinical motor dysfunction who were less than 30 months of age and in 22 age-matched controls. We plotted tract-specific DTI metrics (fractional anisotropy, parallel diffusivity, transverse diffusivity, and mean diffusivity) against age for the controls and generated normative curves. For each patient, we calculated the deviation from the normative curves. Patients returned for a neurodevelopmental evaluation when they were over 36 months of age, and motor outcome measures were performed. We analyzed the association between normative deviation in DTI metrics and motor outcome measures using linear and logistic regression models. RESULTS: Normative deviation in fractional anisotropy and transverse diffusivity were significantly correlated with all measures of motor outcome. Lower fractional anisotropy and higher transverse diffusivity compared to controls were associated with worse motor outcome. Furthermore, children who were eventually diagnosed with permanent motor dysfunction had lower fractional anisotropy and higher transverse diffusivity compared with those whose motor dysfunction normalized. CONCLUSIONS: Diffusion tensor imaging metrics correlate with motor outcome in infants presenting with motor dysfunction. The identification of a quantitative imaging marker that can be applied to infants at the time of clinical presentation has implications for the evaluation of early motor dysfunction.

Regional grey matter atrophy in clinically isolated syndromes at presentation.

BACKGROUND: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. METHODS: This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. RESULTS: The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. CONCLUSIONS: Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.

Diffusion tensor MR imaging and fiber tractography: technical considerations.

This second article of the 2-part review builds on the theoretic background provided by the first article to cover the major technical factors that affect image quality in diffusion imaging, including the acquisition sequence, magnet field strength, gradient amplitude, and slew rate as well as multichannel radio-frequency coils and parallel imaging. The sources of many common diffusion image artifacts are also explored in detail. The emphasis is on optimizing these technical factors for state-of-the-art diffusion-weighted imaging and diffusion tensor imaging (DTI) based on the best available evidence in the literature. An overview of current methods for quantitative analysis of DTI data and fiber tractography in clinical research is also provided.

Diffusion tensor MR imaging and fiber tractography: theoretic underpinnings.

In this article, the underlying theory of clinical diffusion MR imaging, including diffusion tensor imaging (DTI) and fiber tractography, is reviewed. First, a brief explanation of the basic physics of diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) mapping is provided. This is followed by an overview of the additional information that can be derived from the diffusion tensor, including diffusion anisotropy, color-encoded fiber orientation maps, and 3D fiber tractography. This article provides the requisite background for the second article in this 2-part review to appear next month, which covers the major technical factors that affect image quality in diffusion MR imaging, including the acquisition sequence, magnet field strength, gradient amplitude and slew rate, and multichannel radio-frequency coils and parallel imaging. The emphasis is on optimizing these factors for state-of-the-art DWI and DTI based on the best available evidence in the literature.

Diffusion tensor MR imaging tractography of the pyramidal tracts correlates with clinical motor function in children with congenital hemiparesis.

BACKGROUND AND PURPOSE: Children with congenital hemiparesis have greater asymmetry in diffusion parameters of the pyramidal tracts compared with control subjects. We hypothesized that the asymmetry correlates with the severity of hemiparesis and that diffusion metrics would be abnormal in the affected tracts and normal in the unaffected tracts. MATERIALS AND METHODS: Fifteen patients with congenital hemiparesis and 17 age-matched control subjects were studied with diffusion tensor MR imaging tractography. Hemipareses were scored as mild, moderate, or severe. We measured tract-specific diffusion parameters (fractional anisotropy, mean, and directional diffusion coefficients) of the pyramidal tracts. We compared tract-specific parameters and asymmetry between the right and left tracts of the differing severity groups and control subjects. RESULTS: We observed many different causes of congenital hemiparesis including venous infarction, arterial infarction, and polymicrogyria. Clinical severity of hemiparesis correlated with asymmetry in fractional anisotropy (P < .0001), transverse diffusivity (P < .0001), and mean diffusivity (P < .03). With increasing severity of hemiparesis, fractional anisotropy decreased (P < .0001) and transverse diffusivity (P < .0001) and mean diffusivity (P < .02) increased in the affected pyramidal tract compared with controls. Diffusion metrics in the unaffected tract were similar to those in the control subjects. CONCLUSION: Asymmetry in fractional anisotropy, transverse diffusivity, and mean diffusivity, as well as the degree of abnormality in the actual values of the affected pyramidal tracts themselves, correlates with the severity of motor dysfunction in infants and children with congenital hemiparesis from different causes. This suggests that abnormalities detected by diffusion tensor MR imaging tractography in the affected pyramidal tract are related to the functional ability of the affected pyramidal tract, regardless of the etiology of motor dysfunction.

Estimation of metabolite T1 relaxation times using tissue specific analysis, signal averaging and bootstrapping from magnetic resonance spectroscopic imaging data.

OBJECT: A novel method of estimating metabolite T1 relaxation times using MR spectroscopic imaging (MRSI) is proposed. As opposed to conventional single-voxel metabolite T1 estimation methods, this method investigates regional and gray matter (GM)/white matter (WM) differences in metabolite T1 by taking advantage of the spatial distribution information provided by MRSI. MATERIAL AND METHODS: The method, validated by Monte Carlo studies, involves a voxel averaging to preserve the GM/WM distribution, a non-linear least squares fit of the metabolite T1 and an estimation of its standard error by bootstrapping. It was applied in vivo to estimate the T1 of N-acetyl compounds (NAA), choline, creatine and myo-inositol in eight normal volunteers, at 1.5 T, using a short echo time 2D-MRSI slice located above the ventricles. RESULTS: WM-T 1,NAA was significantly (P < 0.05) longer in anterior regions compared to posterior regions of the brain. The anterior region showed a trend of a longer WM T1 compared to GM for NAA, creatine and myo-Inositol. Lastly, accounting for the bootstrapped standard error estimate in a group mean T1 calculation yielded a more accurate T1 estimation. CONCLUSION: The method successfully measured in vivo metabolite T1 using MRSI and can now be applied to diseased brain.

A voxel-based morphometry study of patterns of brain atrophy in ALS and ALS/FTLD.

OBJECTIVE: To investigate the patterns of MRI brain atrophy in patients with ALS with and without clinically evident frontotemporal lobar dementia (FTLD) using voxel-based morphometry (VBM). METHODS: Voxel-based morphometry was used to compare T1-weighted MRI images obtained from ten ALS patients with FTLD, ten ALS patients who were cognitively and behaviorally normal, and 22 control subjects. Images from patients and controls were spatially pre-processed using a study-specific, customized template and a priori images. A statistical threshold of p < 0.05 corrected for multiple comparisons determined significance. RESULTS: A common pattern of gray matter atrophy was seen in both ALS and ALS/FTLD patients when compared to controls that involved the bilateral motor/premotor cortices, the left middle and inferior frontal gyri, the anterior portion of the superior frontal gyri, the superior temporal gyri, the temporal poles and left posterior thalamus. Most of the frontal regions were significantly more atrophied in the ALS/FTLD group than in the ALS group. No significant differences were found in white matter volumes. CONCLUSIONS: Patients with ALS and ALS associated with frontotemporal lobar degeneration exhibit widespread gray matter atrophy in frontotemporal regions. This finding supports the idea of a clinical and anatomic continuum between ALS and frontotemporal lobar degeneration.