Normal-appearing White Matter Of Patients Research Articles

Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study.

In spite of marked disability, patients with primary progressive multiple sclerosis (PPMS) display smaller lesion volumes on conventional magnetic resonance imaging (MRI) compared with other forms of multiple sclerosis (MS). Hence, damage to the normal-appearing brain tissue (NABT) may play an important role in explaining the pathogenesis of disability in PPMS. Diffusion-weighted MRI (DW-MRI) probes water diffusion in vivo that can be altered by pathologic changes. Using DW-MRI we investigated diffusion in the NABT of 15 patients with PPMS over one year. The average apparent diffusion coefficient (ADCav) was measured in 10 regions of interest located in the normal-appearing thalamus and the normal-appearing white matter (NAWM). Six healthy subjects served as a reference. In contrast to healthy subjects, patients with PPMS showed an increment within 12 months of the ADCav in NAWM which was associated with an increase of the T2- and T1-lesion volumes. The ADCav in frontal NAWM was associated with disability as measured by the MS Functional Composite Measure. Serial DW-MRI depicts progressive changes in the NAWM of patients with PPMS. Our preliminary findings suggest that the processes causing structural damage in NAWM and lesions in patients with PPMS are partially linked and that changes of water diffusion in NAWM depicted by DW-MRI are clinically relevant.

Biophysical changes in normal-appearing white matter and subcortical nuclei in late-life major depression detected using magnetization transfer

Neuroanatomical changes have been identified in patients diagnosed with late-life major depressive disorder (MDD) compared with controls. These primarily comprise a decrease in focal brain volumes and an increase in MRI-determined high intensity lesions that are largely confined to the white matter. The physiological status of normal-appearing white matter in patients with MDD remains unknown. Magnetization transfer (MT) is a relatively new neuroimaging technique that permits us to examine the biophysical characteristics of specific brain regions. Using MT, we studied eight patients with late-life MDD and eight non-depressed controls. MT ratios (MTR), which reflect the integrity of the macromolecular protein pool, were ascertained in normal-appearing white matter and subcortical nuclei. Patients had significantly lower MTRs in the genu and splenium of the corpus callosum, the right caudate nucleus and putamen, and the occipital white matter compared with controls. The findings indicate that the structure of the macromolecular protein matrix may be compromised in normal-appearing white matter and critical subcortical nuclei in patients with late-life major depression. These changes may provide important substrates to mood disorders and have implications for neuronal connectivity and its role in the pathophysiology of late-life depression.

A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis

Background and purpose: The stage at which normal appearing white matter (NAWM) abnormalities first appear in multiple sclerosis (MS) is not clear. The aim of our study was to monitor water diffusion changes over time in NAWM of patients with early MS. Methods: Out of a consecutive series of patients enrolled in a MR study on clinically isolated syndrome (CIS), we selected 19 subjects who had completed a one year follow-up. The MR scans obtained at baseline and at 12 months were reviewed according to the new criteria on the diagnosis of MS. Lesion load on T2 and T1 weighted images and the trace of the apparent diffusion coefficient in NAWM were measured both at baseline and at 12 months in patients and in 12 healthy controls. Results: In three patients the diagnosis of MS was done at baseline based on MR. Thirteen patients developed MS during the study and in three patients the diagnosis remained “possible MS.” TADC in NAWM in patients was significantly higher than in controls at the 12 months’ follow-up but not at baseline (controls mean tADC ± sd = 0.745 ± 0.02 mm 2/sec × 10 −3; patients mean tADC 12 ± sd = 0.767 ± 0.02 mm 2/sec × 10 −3; p < 0.02). TADC and T2 lesion load at 12 months were significantly correlated (p < 0.01). Patients exhibiting tADC 12 above a confidence interval had a significantly greater EDSS score at the same time period (EDSS 12 ± sd = 1.9 ± 0.5 and = 1.1 ± 0.4 respectively; p < 0.01). Conclusions: This study suggests that diffusion MR cannot detect alterations in NAWM of patients with a CIS suggestive of MS. After one year, when most patients develop MS, diffusion MR abnormalities in NAWM become apparent. These abnormalities are correlated with T2 lesion load and may contribute to neurological impairment.

Magnetization transfer measurements of cerebral white matter in patients with myotonic dystrophy

To determine whether patients with myotonic dystrophy (MyD) have structural changes in the cerebral white matter, we performed magnetization transfer (MT) imaging of the cerebral white matter in 14 MyD patients and 11 age-matched normal controls. We calculated MT ratios in both the white matter lesions (WMLs) and the normal-appearing white matter (NAWM) of MyD patients using region of interest (ROI) analysis. MT ratios in WMLs were markedly decreased, and all ROIs in NAWM also showed significantly lower MT ratios in MyD patients than in normal controls. The average MT ratio of all ROIs in WMLs and NAWM in each patient showed a significant negative correlation with duration of illness, but not with the patient's age or age at onset. The results of the present study indicate not only the presence of pathological changes in WMLs but also the widespread involvement of NAWM in MyD patients. The results also suggest that structural changes in the white matter may be progressive during the clinical course of MyD.

Diffusion tensor magnetic resonance imaging in multiple sclerosis.

To quantify, using diffusion tensor imaging (DTI), the tissue damage in lesions and normal-appearing white matter (NAWM) from a large cohort of patients with MS and to investigate the magnitude of the correlation between DTI-derived metrics and clinical disability. Dual-echo and DTI scans were obtained from 78 patients with relapsing-remitting, secondary progressive, or primary progressive MS and from 20 normal control participants. Post-contrast T1-weighted images were also obtained from the patients. After creating mean diffusivity (D) and fractional anisotropy (FA) images and image coregistration, D and FA values were measured for 4846 lesions (3207 nonenhancing T1-isointense, 1511 nonenhancing T1-hypointense, and 128 enhancing), 497 NAWM areas from patients, and 160 white matter areas from the controls. The average lesion D was higher and the average lesion FA was lower than the corresponding quantities of the NAWM (p < 0.001). The values of enhancing and nonenhancing lesions were not different, whereas enhancing lesions had lower FA (p < 0.001). T1-hypointense lesions had higher D and lower FA than T1-isointense lesions (p < 0.001). NAWM of patients had higher and lower FA than white matter of controls (p = 0.01). Significant correlations were found between T1 and T2 lesion volume and and FA of lesions and NAWM. In the overall patient sample, a moderate correlation was also found between lesion D and the Expanded Disability Status Scale score (r = 0.28, p = 0.01). However, the r value of this correlation was 0.48 in patients with secondary progressive MS, whose disability was also correlated with average lesion FA (r = -0.50). The results of this study show that DTI is able to identify MS lesions with severe tissue damage and to detect changes in the NAWM. They also indicate that DTI-derived measures are correlated with clinical disability, especially in patients with secondary progressive MS, thus suggesting a role for DTI in monitoring advanced phases of the disease.

Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI.

To compare diffusion characteristics of MS lesions, normal-appearing white matter (NAWM) from patients, and normal white matter from control subjects, and to investigate the correlations between the magnetization transfer ratio (MTR) and a directionally averaged tissue water diffusion coefficient (D) in patients. MS and other pathologic processes that modify tissue integrity can result in abnormal diffusion of water molecules detectable by diffusion-weighted imaging (DWI). Conventional dual-echo and DWI scans were obtained from 35 patients with relapsing-remitting MS and 24 healthy control subjects. MT scans were also obtained from the patients. After coregistration of all scans, MTR and D values from MS lesions and NAWM in different regions were marked using the dual-echo scans as a reference. D values from the same brain regions in control subjects were acquired. Histograms of MTR and D were also produced. Patients with MS had significantly higher D values in all the areas studied. Moreover, histogram metrics (peak height, peak site, and average D) from patients were substantially different from those of control subjects. In patients, average lesion D and MTR were markedly different from those in the NAWM. There was an inverse correlation between average lesion MTR and D inside lesions, whereas no correlation was found for average MTR and D taken from the histograms. DWI detects severe tissue disruption inside lesions and subtle widespread abnormalities in NAWM in patients with relapsing-remitting MS. MT and DWI may provide information about different aspects of brain pathology in MS.

1H magnetic resonance spectroscopy of normal appearing white matter in primary progressive multiple sclerosis.

Recent magnetic resonance imaging (MRI) and pathological studies have indicated that axonal loss is a major contributor to disease progression in multiple sclerosis. 1H magnetic resonance spectroscopy (MRS), through measurement of N-acetyl aspartate (NAA), a neuronal marker, provides a unique tool to investigate this. Patients with primary progressive multiple sclerosis have few lesions on conventional MRI, suggesting that changes in normal appearing white matter (NAWM), such as axonal loss, may be particularly relevant to disease progression in this group. To test this hypothesis NAWM was studied with MRS, measuring the concentration of N-acetyl derived groups (NA, the sum of NAA and N-acetyl aspartyl glutamate). Single-voxel MRS using a water-suppressed PRESS sequence was carried out in 24 patients with primary progressive multiple sclerosis and in 16 age-matched controls. Ratios of metabolite to creatine concentration (Cr) were calculated in all subjects, and absolute concentrations were measured in 18 patients and all controls. NA/Cr (median 1.40, range 0.86-1.91) was significantly lower in NAWM in patients than in controls (median 1.70, range 1.27-2.14; P = 0.006), as was the absolute concentration of NA (patients, median 6.90 mM, range 4.62-10.38 mM; controls, median 7.77 mM, range 6.60-9.71 mM; P = 0.032). There was no significant difference in the absolute concentration of creatine between the groups. This study supports the hypothesis that axonal loss occurs in NAWM in primary progressive multiple sclerosis and may well be a mechanism for disease progression in this group.

Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis.

To determine the efficacy of MRS in discriminating between relapsing remitting (RR) and secondary progressive (SP) MS. MRS at long and short echo times was carried out in 104 patients with MS stratified for clinical course (RR or SP), and the results were compared with those of 15 control subjects. Normal-appearing white matter (NAWM) was studied in 55 patients, and a high-T2-signal area on MRI in 49 others. At long echo times, there was a highly significant decrease in the ratios N-acetyl-aspartate/creatine (NAA/Cr) and NAA/ choline (Cho) in high-T2-signal areas and in the NAWM in patients with an SP course compared with control subjects and patients with an RR course. There was a significant negative correlation between these ratios and clinical disability measured by Expanded Disability Status Scale score, which was independent of disease duration. Discriminant values between patients with RR and SP courses were found in the NAWM (NAA/Cr = 1.75 and NAA/Cho = 1.5), but not in high-T2-signal areas. At short echo times, there was a significant increase in the ratio myoinositol/Cr in high-signal areas of patients with an SP course compared with control subjects, and the presence of abnormal resonances in the lesions and NAWM for free amino acids and lipids (in 30% and 8%, respectively) and GLX complex (glutamine, glutamate, gamma-aminobutyric acid; 16% and 20%, respectively). Studying normal-appearing white matter on MRI with MRS allows discrimination between relapsing remitting and secondary progressive patients. In the NAWM of patients with MS and an SP course, severe axonal loss/dysfunction is negatively correlated to clinical disability and independent of the duration of the disease.

Proton MR spectroscopy in clinically isolated syndromes suggestive of multiple sclerosis.

The concentration of the metabolite N-acetyl aspartate (NAA), thought to be a marker of axonal loss or damage, has been shown to be reduced in lesions, as demonstrated by high signal areas on T2-weighted MRI, and in normal-appearing white matter (NAWM) in established multiple sclerosis (MS). The stage of the disease when these changes first appear is not known. To try to determine this we studied 20 patients with clinically isolated syndromes, many of whom will be at the earliest clinical stages of MS, and 20 age- and sex-matched controls with single-voxel proton magnetic spectroscopy (MRS). MRS was performed using a General Electric 1.5T Signa EchoSpeed scanner (TR 3000 ms, TE 30 ms, PRESS). Absolute metabolite concentrations were determined using the LCModel fitting software. No significant reduction of NAA concentration was evident in the NAWM of the patients (patients: median 7.3 mM; controls: median 7.7 mM; P=0.19). There was, however, a significantly lower concentration of NAA in lesions (median 6.6 mM, P=0.015). Absolute values of choline-containing compounds, creatine and myo-inositol were significantly raised in the lesions (P=0.007, P=0.011 and P=0.002 respectively). The low NAA in lesions is consistent with axonal loss, damage or dysfunction occurring focally at the earliest clinical phase of the disease. The lack of any significant reduction in NAA in patient NAWM demonstrates that more widespread axonal changes are not yet detectable at this early clinical stage. A larger cohort and follow-up will be necessary to determine whether or not MRS findings have any prognostic significance for individual patients or sub-groups. This will also enable the clarification of the time course, pathogenesis and pathophysiological significance of the development of the low NAA, which is found in the NAWM of many patients with established MS.

Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis.

To determine whether diffusion tensor imaging (DTI) can detect structural changes in normal-appearing white matter, and to distinguish between plaques of different pathologic severity, in patients with MS. Conventional MRI detects lesions sensitively in MS but has limited pathologic specificity. The diffusion of water molecules in brain tissue, most fully expressed mathematically by a tensor quantity, reflects its intrinsic microstructure. It is now possible to estimate the diffusion tensor noninvasively in the human brain using MR DTI. This method is unique in providing precise and rotationally invariant measurements of the amount and directional bias (anisotropy) of diffusion in white matter tracts relating to tissue integrity and orientation. DTI was performed in six patients with MS and in six age-matched control subjects. Diffusion was characterized in normal-appearing white matter in both groups, and in lesions of different pathologic subtypes (inflammatory, noninflammatory, T1 hypointense, and T1 isointense). DTI identified significantly altered water diffusion properties in the normal-appearing white matter of patients compared with control subjects (p < 0.001), and distinguished between lesion types. The highest diffusion was seen in destructive (T1 hypointense) lesions, whereas the greatest change in anisotropy was found in inflammatory (gadolinium-enhancing) lesions. DTI detects diffuse abnormalities in the normal-appearing white matter of MS patients, and the findings in lesions appear to relate to pathologic severity. Its use in serial studies and in larger clinical cohorts may increase our understanding of pathogenetic mechanisms of reversible and persistent disability.

Magnetization transfer changes in the normal appearing white matter precede the appearance of enhancing lesions in patients with multiple sclerosis.

Serial monthly magnetization transfer (MT) imaging was performed to evaluate whether a change of the normal appearing white matter (NAWM), which precedes the appearance of enhancing lesions, is seen in patients with multiple sclerosis (MS). Every 4 weeks for 3 months, 10 patients with relapsing-remitting MS were scanned with a T1-weighted sequence, 20 minutes after injection with 0.3 mmol/kg gadolinium-DTPA (Gd-DTPA). During each of the monthly sessions, MT and dual echo scans were also performed before Gd-DTPA injection. On coregistered images, the MT ratio (MTR) was measured in NAWM subsequently involved by enhancing lesions, in NAWM areas on the same slices but outside any present or future MR abnormality, and in enhancing lesions at the time of their appearance. Forty-eight new enhancing lesions with no corresponding abnormalities on previous scans were identified. Their average MTR was 33.1% (+/-8.4%). Three, 2, and 1 month before enhancement appearance, the mean MTR in NAWM, measured from areas corresponding to future enhancing lesions, was significantly lower than the mean MTR in NAWM outside enhancing areas; the MTR decreased steadily as the time when the enhanced lesion approached. These results suggest that changes in the NAWM of patients with MS occur before lesions become evident on conventional MRI scans.

Magnetization transfer contrast (MTC) and long repetition time spin-echo MR imaging in multiple sclerosis

Purpose: To study whether application of magnetization transfer contrast (MTC) improves visibility and detection of multiple sclerosis (MS) lesions on long repetition time (TR) conventional spin-echo (CSE) or fast spin-echo (FSE) magnetic resonance (MR) imaging. Material and methods: In 20 patients and 5 controls, MR images were obtained using long repetition time CSE and FSE sequences with and without MTC. Signal-to-noise ratios of normal appearing white matter (NAWM) and selected lesions, and contrast-to-noise ratios between lesions and NAWM, were calculated. Lesions were counted and total lesion volume was measured in a blinded fashion for each sequence. Results: In controls, MT effect in white matter (16.3% vs. 12.2%) was higher for CSE than for FSE ( p < 0.01). Application of MTC to either CSE or FSE resulted in a significantly lower decrease in signal intensity of NAWM in patients compared to white matter in controls ( p < 0.01). Furthermore, in patients signal intensity of lesions was less decreased than signal intensity of NAWM ( p < 0.01). Compared to sequences without MTC, contrast-to-noise ratios were significantly higher on both CSE (10.9%) and FSE (6.3%) when MTC was applied ( p < 0.01). Despite better visibility, the number of lesions detected on either sequences did not increase when MTC was applied. For CSE with MTC, we found an almost equal number of lesions and for FSE with MTC, we found even less lesions ( p < 0.01). Total lesion volume did not change significantly when MTC was applied. Conclusion: Although contrast between lesions and NAWM improved when magnetization transfer contrast was applied, this did not increase detection of MS lesions on either CSE or FSE MR imaging.

Imaging axonal damage of normal-appearing white matter in multiple sclerosis.

The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease.

Microscopic disease in normal-appearing white matter on conventional MR images in patients with multiple sclerosis: assessment with magnetization-transfer measurements.

To assess for the presence of microscopic abnormalities in otherwise normal-appearing white matter on T2-weighted images in patients with multiple sclerosis (MS) by using magnetization-transfer (MT) measurements. Twenty-three patients with MS and nine healthy control subjects underwent magnetic resonance (MR) imaging with a 1.5-T system. MT ratios (MTRs) were measured in 16 areas of normal-appearing white matter identified on conventional T2-weighted images in patients with MS. MTRs in the same white-matter locations in control subjects were determined. The two groups were compared. The mean whole-brain MTR of normal-appearing white matter in patients was 40.13% +/- 1.37 (standard deviation; range, 36.31%-42.09%); in control subjects, 42.93% +/- 0.95 (range, 41.62%-44.50%). The difference was statistically significant (P < or = .001). Except for the internal capsules, the difference in mean MTRs in each sublocation of the brain between patients and control subjects was statistically significant (P < or = .05). MT measurements are more sensitive than conventional MR imaging in the detection of abnormalities beyond the resolution of T2-weighted imaging.

Biochemical alterations in multiple sclerosis lesions and normal-appearing white matter detected by in vivo 31P and 1H spectroscopic imaging.

The goals of the current study were threefold: first, to confirm previous single volume proton (1H) magnetic resonance spectroscopy results of reduced N-acetyl aspartate (NAA, a putative marker of neurons) in multiple sclerosis (MS) white matter lesions using multiple volume 1H magnetic resonance spectroscopic imaging (MRSI); second, to measure the phospholipid metabolites phosphomonoesters and phosphodiesters in such lesions using phosphorus (31P) MRSI; and third, to test the hypothesis that biochemical changes occur in the normal-appearing (on spin echo T2-weighted magnetic resonance images) white matter in patients with MS. Thirteen subjects with clinically definite MS were studied with both 1H and 31P MRSI, and 19 controls were studied with either 1H MRSI, 31P MRSI, or both. MS lesion, MS normal-appearing white matter, and region-matched control spectra from the centrum semiovale were analyzed. The major findings of this study were that in both white matter lesions and normal-appearing white matter in patients with MS, the metabolite ratio NAA/creatine and the total 31P peak integrals were significantly reduced compared with controls. In addition, in MS lesions NAA/choline and phosphodiesters/total 31P were significantly reduced compared with controls, and in MS normal-appearing white matter there was a trend for NAA/choline to be reduced compared with controls. In normal-appearing white matter in patients with MS, total creatine and phosphocreatine were significantly increased compared to controls, as detected with both 1H (total creatine peak integrals) and 31P (phosphocreatine/total 31P) MRSI techniques. These results suggest reduced neuronal density and altered phospholipid metabolites in white matter lesions in patients with MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Magnetic resonance relaxation time mapping in multiple sclerosis: Normal appearing white matter and the “invisible” lesion load

Prolonged T 1 and/or T 2 relaxation times (RT) in the normal appearing white matter (NAWM) of patients with multiple sclerosis (MS) have been attributed either to a diffuse abnormality, or to “small lesions” undetected by visual inspection of conventional MR images. In a comparison of brain slices from five MS patients and five healthy control subjects, we have confirmed that the average T 1 and T 2 RTs obtained from NAWM in patients with MS are significantly prolonged ( p < .04). Quantitative pixel-by-pixel mapping shows that this overall prolongation is due to the averaging of RTs from two subfractions of NAWM. In all patients a proportion (average 54% for T 1 and 63% for T 2) of the total white matter pixel sample from each MR brain slice had RT values indistinguishable from those found in the white matter of matched healthy control subjects (i.e., “normal normal appearing white matter”, NNAWM). Scattered throughout the NAWM were multiple small areas, often of only one or two pixels, with abnormal RT values. These lesions, which were revealed only by pixel-by-pixel mapping of RT, made up a significant proportion (average 47% for T 1 or 57% for T 2 estimates) of the total (visible plus “invisible”) lesion load per slice, and of the NAWM (average 36% for T 1, 27% for T 2), with wide interpatient variability. Further studies of these minute lesions are required to determine their total volume in the brain, their precise nature, evolution and relevance to the functional deficit in MS.