Non-Gaussian diffusion MRI of gray matter is associated with cognitive impairment in multiple sclerosis.

BACKGROUND: Non-Gaussian diffusion imaging by using diffusional kurtosis imaging (DKI) allows assessment of isotropic tissue as of gray matter (GM), an important limitation of diffusion tensor imaging (DTI). OBJECTIVE: In this study, we describe DKI and DTI metrics of GM in multiple sclerosis (MS) patients and their association with cognitive deficits. METHODS: Thirty-four patients with relapsing-remitting MS and 17 controls underwent MRI on a 3T scanner including a sequence for DKI with 30 diffusion directions and 3b values for each direction. Mean kurtosis (MK), mean diffusivity and fractional anisotropy (FA) of cortical and subcortical GM were measured using histogram analysis. Spearman rank correlations were used to characterize associations among imaging measures and clinical/neuropsychological scores. RESULTS: In cortical GM, a significant decrease of MK (0.68 vs. 0.73; p < 0.001) and increase of FA (0.16 vs. 0.13; p < 0.001) was found in patients compared to controls. Decreased cortical MK was correlated with poor performance on the Delis-Kaplan Executive Function System test (r = 0.66, p = 0.01). CONCLUSION: Mean kurtosis is sensitive to abnormality in GM of MS patients and can provide information that is complementary to that of conventional DTI-derived metrics. The association between MK and cognitive deficits suggests that DKI might serve as a clinically relevant biomarker for cortical injury.

Imaging the effects of oxygen saturation changes in voluntary apnea and hyperventilation on susceptibility-weighted imaging.

BACKGROUND AND PURPOSE: Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T. MATERIALS AND METHODS: We performed SWI scans (3T; acquisition time of 1 minute, 28 seconds; centered on the anterior commissure and the posterior commissure) on 10 healthy male volunteers during baseline breathing as well as during simple voluntary hyperventilation and apnea challenges. The hyperventilation and apnea tasks were separated by a 5-minute resting period. SWI venograms were generated, and the signal changes on SWI before and after the respiratory stress tasks were compared by means of a paired Student t test. RESULTS: Changes in venous vasculature visibility caused by the respiratory challenges were directly visualized on the SWI venograms. The venogram segmentation results showed that voluntary apnea decreased the mean venous blood voxel number by 1.6% (P < .0001), and hyperventilation increased the mean venous blood voxel number by 2.7% (P < .0001). These results can be explained by blood CO2 changes secondary to the respiratory challenges, which can alter cerebrovascular tone and cerebral blood flow and ultimately affect venous oxygen levels. CONCLUSIONS: These results highlight the sensitivity of SWI to simple and noninvasive respiratory challenges and its potential utility in assessing cerebral hemodynamics and vasomotor responses.

Functional homotopic changes in multiple sclerosis with resting-state functional MR imaging.

BACKGROUND AND PURPOSE: CC is extensively involved in MS with interhemispheric dysfunction. The purpose of this study was to determine whether interhemispheric correlation is altered in MS by use of a recently developed RS-fMRI homotopy technique and whether these homotopic changes correlate with CC pathology. MATERIALS AND METHODS: Twenty-four patients with relapsing-remitting MS and 24 age-matched healthy volunteers were studied with RS-fMRI and DTI acquired at 3T. The Pearson correlation of each pair of symmetric interhemispheric voxels of RS-fMRI time-series data was performed to compute VMHC, and z-transformed for subsequent group-level analysis. In addition, 5 CC segments in the midsagittal area and DTI-derived FA were measured to quantify interhemispheric microstructural changes and correlate with global and regional VMHC in MS. RESULTS: Relative to control participants, patients with MS exhibited an abnormal homotopic pattern with decreased VMHC in the primary visual, somatosensory, and motor cortices and increased VMHC in several regions associated with sensory processing and motor control including the insula, thalamus, pallidum, and cerebellum. The global VMHC correlates moderately with the average FA of the entire CC for all participants in both groups (r = 0.3; P = .03). CONCLUSIONS: Our data provide preliminary evidence of the potential usefulness of VMHC analyses for the detection of abnormalities of interhemispheric coordination in MS. We demonstrated that the whole-brain homotopic RS-fMRI pattern was altered in patients with MS, which was partially associated with the underlying structural degenerative changes of CC measured with FA.

Cognitive impairment in mild traumatic brain injury: a longitudinal diffusional kurtosis and perfusion imaging study.

BACKGROUND AND PURPOSE: Cognitive impairment is frequent among patients with mild traumatic brain injury despite the absence of detectable damage on conventional MR imaging. In this study, the quantitative MR imaging techniques DTI, DKI, and ASL were used to measure changes in the structure and function in the thalamus and WM of patients with MTBI during a short follow-up period, to determine whether these techniques can be used to investigate relationships with cognitive performance and to predict outcome. MATERIALS AND METHODS: Twenty patients with MTBI and 16 controls underwent MR imaging at 3T and a neuropsychological battery designed to yield measures for attention, concentration, executive functioning, memory, learning, and information processing. MK, FA, MD, and CBF were measured in the thalamus by using region-of-interest analysis and in WM by using tract-based spatial statistics. Analyses were performed comparing regional imaging measures of subject groups and the results of testing of their associations with neuropsychological performance. RESULTS: Patients with MTBI exhibited significant differences from controls for DTI, DKI, and ASL measures in the thalamus and various WM regions both within 1 month after injury and >9 months after injury. At baseline, DTI and DKI measures in the thalamus and various WM regions were significantly associated with performance in different neuropsychological domains, and cognitive impairment was significantly associated with MK in the thalamus and FA in optic radiations. CONCLUSIONS: Combined application of DTI, DKI, and ASL to study MTBI might be useful for investigating dynamic changes in the thalamus and WM as well as cognitive impairment during a short follow-up period, though the small number of patients examined did not predict outcome.

Two-year serial whole-brain N-acetyl-L-aspartate in patients with relapsing-remitting multiple sclerosis.

OBJECTIVES: To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-L-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials. METHODS: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 ± 5 years old (mean ± SD), had a disease duration of 47 ± 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-L-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation. RESULTS: The baseline WBNAA of the patients (10.5 ± 1.7 mM) was significantly lower than that of the controls (12.3 ± 1.3 mM; p < 0.002) and declined significantly (5%/year, p < 0.002) vs that for the controls who did not show a decline (0.4%/year, p > 0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p < 0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA. CONCLUSIONS: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies.

Brain iron quantification in mild traumatic brain injury: a magnetic field correlation study.

BACKGROUND AND PURPOSE: Experimental studies have suggested a role for iron accumulation in the pathology of TBI. Magnetic field correlation MR imaging is sensitive to the presence of non-heme iron. The aims of this study are to 1) assess the presence, if any, and the extent of iron deposition in the deep gray matter and regional white matter of patients with mTBI by using MFC MR imaging; and 2) investigate the association of regional brain iron deposition with cognitive and behavioral performance of patients with mTBI. MATERIALS AND METHODS: We prospectively enrolled 28 patients with mTBI. Eighteen healthy subjects served as controls. The subjects were administered the Stroop color word test, the Verbal Fluency Task, and the Post-Concussion Symptoms Scale. The MR imaging protocol (on a 3T imager) consisted of conventional brain imaging and MFC sequences. After the calculation of parametric maps, MFC was measured by using a region of interest approach. MFC values across groups were compared by using analysis of covariance, and the relationship of MFC values and neuropsychological tests were evaluated by using Spearman correlations. RESULTS: Compared with controls, patients with mTBI demonstrated significant higher MFC values in the globus pallidus (P = .002) and in the thalamus (P = .036). In patients with mTBI, Stroop test scores were associated with the MFC value in frontal white matter (r = -0.38, P = .043). CONCLUSIONS: MFC values were significantly elevated in the thalamus and globus pallidus of patients with mTBI, suggesting increased accumulation of iron. This supports the hypothesis that deep gray matter is a site of injury in mTBI and suggests a possible role for iron accumulation in the pathophysiological events after mTBI.

Global N-acetylaspartate declines even in benign multiple sclerosis.

BACKGROUND AND PURPOSE: Neuro-axonal damage is a well known sequelae of MS pathogeneses. Consequently, our aim was to test whether the ∼20% of patients with MS exhibiting a clinically benign disease course also have minimal neural dysfunction as reflected by the global concentration of their MR imaging marker NAA. MATERIALS AND METHODS: Q(NAA) was obtained with nonlocalizing whole-head (1)H-MR spectroscopy in 43 patients with benign RRMS (30 women, 13 men; mean age, 44.7 ± 7.3 years of age) with 21.0 ± 4.4 years (range, 15-35 years) of disease duration from the first symptom and an EDSS score of 1.9 (range, 0-3). Q(NAA) was by divided by the brain volume (from MR imaging segmentation) to normalize it into WBNAA. All participants gave institutional review board-approved written informed consent, and the study was HIPAA compliant. RESULTS: The patients' lesion load was 12.2 ± 7.7 cm(3). Their 8.3 ± 1.8 mmol/L WBNAA was 35% lower than that in controls (P < .001). Individual average loss rates (absolute loss compared with controls divided by disease duration) clustered around 0.22 ± 0.09 mmol/L/year (1.7%/year, assuming monotonic decline). This rate could be extrapolated from that already reported for patients with RRMS of much shorter disease duration. WBNAA did not correlate with lesion load or EDSS. CONCLUSIONS: Normal WBNAA is not characteristic of benign MS and is not an early predictor of its course. These patients, therefore, probably benefit from successful compensation and sparing of eloquent regions. Because they may ultimately have a rapid decline once their brain plasticity is exhausted, they may benefit from treatment options offered to more affected patients.

Whole-brain N-acetylaspartate MR spectroscopic quantification: performance comparison of metabolite versus lipid nulling.

BACKGROUND AND PURPOSE: Despite the prominent peak of N-acetylaspartate (NAA) in proton MR spectroscopy ((1)H-MR spectroscopy) of the adult brain and its almost exclusive presence in neuronal cells, the total amount of NAA, regarded as their marker, is difficult to obtain due to signal contamination from the skull lipids. This article compares the performance of 2 methods that overcome this difficulty to yield the whole-brain NAA signal, important for the assessment of the total disease load in diffuse neurologic disorders. MATERIALS AND METHODS: The heads of 12 healthy volunteers, 3 women and 9 men, 31.0 +/- 7.1 years of age, were scanned at 3T by using 2 nonlocalizing (1)H-MR spectroscopy sequences: One nulls the NAA (TI = 940 ms) every second acquisition by inversion-recovery to cancel the signals of the lipids (T1 << TI) in an add-subtract scheme. The other nulls the signal of the lipids (TI = 155 ms) directly after each acquisition, requiring half as many averages for the same signal-to-noise ratio. Each sequence was repeated 3 times back-to-back on 3 occasions, and the comparison criteria were intrasubject precision (reproducibility) and total measurement duration. RESULTS: NAA nulling is nearly twice as precise in its intrinsic back-to-back (5.8% versus 8.6%) as well as longitudinal (10.6% versus 19.7%) coefficients of variation compared with lipid nulling, but at the cost of double the acquisition time. CONCLUSION: When speed is a more stringent requirement than precision, the new lipid-nulling sequence is a viable alternative. For precision in cross-sectional or longitudinal global NAA quantification, however, NAA nulling is still the approach of choice despite its x2 ( approximately 5 minutes) time penalty compared with the lipid-nulling approach.

Serial whole-brain N-acetylaspartate concentration in healthy young adults.

Although the concentration of N-acetylaspartate (NAA) is often used as a neuronal integrity marker, its normal temporal variations are not well documented. To assess them over the 1-2 year periods of typical clinical trials, the whole-brain NAA concentration was measured longitudinally, over 4 years, in a cohort of healthy young adults. No significant change (adjusted for both sex and age) was measured either interpersonally or intrapersonally over the entire duration of the study.

Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging.

BACKGROUND AND PURPOSE: Deposition of iron has been recognized recently as an important factor of pathophysiologic change including neurodegenerative processes in multiple sclerosis (MS). We propose that there is an excess accumulation of iron in the deep gray matter in patients with MS that can be measured with a newly developed quantitative MR technique--magnetic field correlation (MFC) imaging. MATERIALS AND METHODS: With a 3T MR system, we studied 17 patients with relapsing-remitting MS and 14 age-matched healthy control subjects. We acquired MFC imaging using an asymmetric single-shot echo-planar imaging sequence. Regions of interest were selected in both deep gray matter and white matter regions, and the mean MFC values were compared between patients and controls. We also correlated the MFC data with lesion load and neuropsychologic tests in the patients. RESULTS: MFC measured in the deep gray matter in patients with MS was significantly higher than that in the healthy controls (P < or = .03), with an average increase of 24% in the globus pallidus, 39.5% in the putamen, and 30.6% in the thalamus. The increased iron deposition measured with MFC in the deep gray matter in the patients correlated positively with the total number of MS lesions (thalamus: r = 0.61, P = .01; globus pallidus: r = 0.52, P = .02). A moderate but significant correlation between the MFC value in the deep gray matter and the neuropsychologic tests was also found. CONCLUSION: Quantitative measurements of iron content with MFC demonstrate increased accumulation of iron in the deep gray matter in patients with MS, which may be associated with the disrupted iron outflow pathway by lesions. Such abnormal accumulation of iron may contribute to neuropsychologic impairment and have implications for neurodegenerative processes in MS.

Proton MR spectroscopy and MRI-volumetry in mild traumatic brain injury.

BACKGROUND AND PURPOSE: More than 85% of brain traumas are classified as "mild"; MR imaging findings are minimal if any and do not correspond to clinical symptoms. Our goal, therefore, was to quantify the global decline of the neuronal marker N-acetylaspartate (NAA), as well as gray (GM) and white matter (WM) atrophy after mild traumatic brain injury (mTBI). MATERIALS AND METHODS: Twenty patients (11 male, 9 female; age range, 19-57 years; median, 35 years) with mTBI (Glasgow Coma Scale score 13-15 with loss of consciousness for at least 30 seconds) and 19 age- and sex-matched control subjects were studied. Seven patients were studied within 9 days of TBI; the other 13 ranged from 1.2 months to 31.5 years (average and median of 4.6 and 1.7 years, respectively) after injury. Whole-brain NAA (WBNAA) concentration was obtained in all subjects with nonlocalizing proton MR spectroscopy. Brain volume and GM and WM fractions were segmented from T1-weighted MR imaging and normalized to the total intracranial volume, suitable for intersubject comparisons. The data were analyzed with least squares regression. RESULTS: Patients with mTBI exhibited, on average, a 12% WBNAA deficit that increased with age, compared with the control subjects (p<.05). Adjusted for age effects, patients also suffered both global atrophy (-1.09%/year; P=.029) and GM atrophy (-0.89%/year; P=.042). Patients with and without visible MR imaging pathology, typically punctate foci of suspected shearing injury, were indistinguishable in both atrophy and WBNAA. CONCLUSION: WBNAA detected neuronal/axonal injury beyond the minimal focal MR-visible lesions in mTBI. Combined with GM atrophy, the findings may provide further, noninvasive insight into the nature and progression of mTBI.

Correlation of diffusion tensor and dynamic perfusion MR imaging metrics in normal-appearing corpus callosum: support for primary hypoperfusion in multiple sclerosis.

BACKGROUND AND PURPOSE: Hypoperfusion of the normal-appearing white matter in multiple sclerosis (MS) may be related to ischemia or secondary to hypometabolism from wallerian degeneration (WD). This study evaluated whether correlating perfusion and diffusion tensor imaging (DTI) metrics in normal-appearing corpus callosum could provide support for an ischemic mechanism for hypoperfusion. MATERIALS AND METHODS: Fourteen patients with relapsing-remitting MS (RRMS) and 17 control subjects underwent perfusion MR imaging and DTI. Absolute measures of cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) were calculated. Mean diffusivity (MD) and fractional anisotropy (FA) maps were computed from DTI data. After visual coregistration of perfusion and DTI images, regions of interest were placed in the genu, central body, and splenium of normal-appearing corpus callosum. Pearson product-moment correlation coefficients were calculated using mean DTI and perfusion measures in each region. RESULTS: In the RRMS group, CBF and CBV were significantly correlated with MD in the splenium (r = 0.83 and r = 0.63, respectively; both P < .001) and in the central body (r = 0.86 and r = 0.65, respectively; both P < .001), but not in the genu (r = 0.23 and 0.25, respectively; both P is nonsignificant). No significant correlations were found between MTT and DTI measures or between FA and any perfusion measure in the RRMS group. No significant correlations between diffusion and perfusion metrics were found in control subjects. CONCLUSION: In the normal-appearing corpus callosum of patients with RRMS, decreasing perfusion is correlated with decreasing MD. These findings are more consistent with what would be expected in primary ischemia than in secondary hypoperfusion from WD.

Reproducibility of three whole-brain N-acetylaspartate decline cohorts in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: The cross-sectional rate of whole-brain N-acetylaspartate (NAA, a neuronal cell marker) loss in clinically similar relapsing-remitting multiple sclerosis (RRMS) patients has recently been shown to fall into 3 distinct decline rate strata. Our goal was to test the reproducibility of this observation in a new cohort of RRMS patients. MATERIALS AND METHODS: Sixteen serial patients (12 women, 4 men, median age 38 [27-55] years) with clinically definite RRMS for an average of 5 (0.3-18) years' disease duration and a mean Expanded Disability Status Score of 2.0 (0-6) were studied, once each. Their whole-brain NAA (WBNAA) amounts, obtained with proton MR spectroscopy, were divided by brain volumes (segmented from MR imaging) to yield concentrations suitable for cross-sectional comparisons. RESULTS: Three distinct strata of cross-sectional NAA decline rates were found: -0.031, -0.32, and -1.71 mmol/L/y when disease duration was estimated from confirmed diagnosis, or -0.057, -0.20, and -1.38 mmol/L/y when measured from the first clinical symptom. These rates and their corresponding fractions of the study population were indistinguishable from those reported previously in a different group of 49 clinically similar (mean Expanded Disability Status Score also 2.0) RRMS patients. CONCLUSION: Reproducing the previous cohort's cross-sectional WBNAA decline characteristics in this new group of clinically similar RRMS patients indicates that 3 WBNAA loss strata may be a general attribute of MS. Consequently, WBNAA could serve as a surrogate marker for the global load of neuronal and axonal dysfunction and damage in this disease.

Reproducibility of the whole-brain N-acetylaspartate level across institutions, MR scanners, and field strengths.

BACKGROUND AND PURPOSE: Radiologic markers in multicenter trials are often confounded by different instrumentation used. Our goal was to estimate the variance of the global concentration of the neuronal cell marker N-acetylaspartate (NAA) among research centers using MR imaging scanners of different models, from different manufacturers, and of different magnetic field strength. MATERIALS AND METHODS: Absolute millimolar amounts of whole-brain NAA (WBNAA) were quantified with nonlocalizing proton MR spectroscopy in the brains of 101 healthy subjects (53 women, 48 men) aged 16-59 years (mean, 34.2 years). Twenty-three were scanned at 1 institute in a 1.5T Siemens Vision; 31 from another institute were studied with a 1.5T Siemens SP63; 36 were scanned at a third institute (24 with a 1.5T Vision, 12 with a 3T Siemens Trio); and 11 were obtained at a fourth institute using a 4T GE Signa 5.x. The NAA amounts were quantified with phantom-replacement and divided by the brain volume, segmented from MR imaging, to yield the concentration, a metric independent of brain size suitable for cross-sectional comparison. RESULTS: The average WBNAA concentration among institutions was 12.2 +/- 1.2 mmol/L. The subjects' WBNAA distributions did not differ significantly (p > .237) among the 4 centers, regardless of scanner manufacturer, model, or field strength and irrespective of whether adjustments were made for age or sex. CONCLUSION: Absolute quantification against a standard makes the WBNAA concentration insensitive to the MR hardware used to acquire it. This important attribute renders it a robust surrogate marker for multicenter neurologic trials.

Diffusion tensor imaging in multiple sclerosis: assessment of regional differences in the axial plane within normal-appearing cervical spinal cord.

BACKGROUND AND PURPOSE: Evaluation of the spinal cord is important in the diagnosis and follow-up of patients with multiple sclerosis. Our purpose was to investigate diffusion tensor imaging (DTI) changes in different regions of normal-appearing spinal cord (NASC) in relapsing-remitting multiple sclerosis (RRMS). METHODS: Axial DTI of the cervical spinal cord was performed in 24 patients with RRMS and 24 age- and sex-matched control subjects. Fractional anisotropy (FA) and mean diffusivity (MD) were calculated in separate regions of interest (ROIs) in the anterior, lateral, and posterior spinal cord, bilaterally, and the central spinal cord, at the C2-C3 level. Patients and control subjects were compared with respect to FA and MD with the use of an exact Mann-Whitney test. Logistic regression and receiver operating characteristic (ROC) curve analysis assessed the utility of each measure for the diagnosis of RRMS. RESULTS: DTI metrics in areas of NASC in MS were significantly different in patients compared with control subjects; FA was lower in the lateral (mean +/- SD of 0.56 +/- 0.10 versus 0.69 +/- 0.09 in control subjects, P < .0001), posterior (0.52 +/- 0.11 versus 0.63 +/- 0.10, P < .0001), and central (0.53 +/- 0.10 versus 0.58 +/- 0.10, P = .049) NASC ROIs. Assessing DTI metrics in the diagnosis of MS, a sensitivity of 87.0% (95% confidence interval [CI], 66.4 to 97.1) and a specificity of 91.7% (95% CI, 73.0 to 98.7) were demonstrated. CONCLUSION: The NASC in RRMS demonstrates DTI changes. This may prove useful in detecting occult spinal cord pathology, predicting clinical course, and monitoring disease progression and therapeutic effect in MS.

Three-dimensional proton spectroscopy of deep gray matter nuclei in relapsing-remitting MS.

The metabolic changes in the deep gray matter (GM) nuclei, thalamus, and basal ganglia of patients with relapsing-remitting multiple sclerosis were investigated with quantitative, multivoxel, three-dimensional proton MR spectroscopy. This technique facilitated the study of several bilateral structures in a single session at sub-cubic centimeter spatial resolution. Compared with 9 matched control subjects, the deep GM nuclei of 11 patients showed 7% lower N-acetylaspartate and 14% higher choline levels (p = 0.02 for both).

Neuronal cell injury precedes brain atrophy in multiple sclerosis.

Global brain atrophy estimated using MRI and whole brain N-acetylaspartate (WBNAA) concentration measured with proton MR spectroscopy were obtained in 42 patients with relapsing-remitting multiple sclerosis and 41 matched control subjects. Patients exhibited cross-sectional atrophy (0.5%; p = 0.033) and WBNAA decline (1.8%/y; p = 0.005) vs disease duration. The 3.6-fold rate disparity between the two processes suggests that neuronal/axonal dysfunction (N-acetylaspartate decline) precedes parenchyma loss, not its consequence (i.e., is an earlier, more sensitive specific metric of the ongoing disease activity).

The utility of MRI in suspected MS: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis.

Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.