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Published online before print August 9, 2007, 10.1148/radiol.2443051171
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(Radiology 2007;244:823-831.)
© RSNA, 2007

Neuroradiology

Multiple Sclerosis: Hyperintense Lesions in the Brain on Nonenhanced T1-weighted MR Images Evidenced as Areas of T1 Shortening1

Vallabh Janardhan, MD, Sonu Suri, MD, and Rohit Bakshi, MD

1 From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (V.J.); Department of Radiology, University at Buffalo, State University of New York, Buffalo, NY (S.S.); and Departments of Neurology and Radiology, Center for Neurological Imaging, Partners Multiple Sclerosis Center, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115 (R.B.). Received July 14, 2005; revision requested September 21; revision received August 31, 2006; accepted October 5; final version accepted February 7, 2007. R.B. supported in part by research grants from the National Institutes of Health–National Institute of Neurological Disorders and Stroke (1 K23 NS42379-01), National Multiple Sclerosis Society (RG 3258A2/1, RG 3574A1), and National Science Foundation (DBI-0234895). Address correspondence to R.B. (e-mail: rbakshi{at}bwh.harvard.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To retrospectively document hyperintense lesions on nonenhanced T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) and study their relationship to physical disability, disease course, and other MR markers of tissue damage (brain atrophy).

Materials and Methods: Institutional review board approval was obtained; informed consent was waived for this HIPAA-compliant study, with 145 patients with MS (mean age, 43 years). Patients had relapsing-remitting (RR) (n = 92) or secondary-progressive (SP) (n = 49) MS; clinical course was unknown in four. Mean Expanded Disability Status Scale (EDSS) score was 3.5. T1 lesions were compared with normal white matter on nonenhanced images and judged hyperintense. Spearman rank correlation, Wilcoxon rank sum, and Fisher exact probability tests and analysis of variance and analysis of covariance (ANCOVA) were employed.

Results: At least one T1 hyperintense lesion was found in 113 patients (total, 340 lesions). Two-thirds of lesions had hyperintense rim; others were uniformly hyperintense. Lesions were more common in patients with SP MS (P = .003, Wilcoxon test) and correlated with EDSS score (Spearman {rho} = 0.19, P = .04) and brain atrophy measures (total cortical atrophy, Spearman {rho} = 0.42, P < .001; third ventricular width, Spearman {rho} = 0.40, P < .001) but not disease duration (Spearman {rho} = 0.038, P = .69). Lesions were more likely multiple in the SP versus RR group (P < .001, Fisher test). After adjustment for disease course, T1 hyperintense lesions remained associated with brain atrophy (P ≤ .001, ANCOVA). No independent effect of imager type (ANCOVA F value = 1.4, P = .24) or spin-echo method (P = .67, Wilcoxon test) on number of lesions was detected. An effect of other MR protocol adjustments (analysis of variance F value = 5.6, P = .001) was unconfirmed after clinical characteristic adjustment (ANCOVA F value = 1.1, P = .35).

Conclusion: Hyperintense MS plaques on T1-weighted MR images are common and associated with brain atrophy, disability, and advancing disease; a hyperintense lesion may be a clinically relevant biomarker.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Hyperintense lesions on T2-weighted magnetic resonance (MR) images are helpful in diagnosing and monitoring patients with multiple sclerosis (MS) (1,2). However, suggestions have been made that these lesions are nonspecific for the underlying pathologic findings, and correlations with clinical status seem to be weak (3). Clearly, there is a need for better MR imaging markers of disease activity and tissue damage (4).

Hyperintense lesions in the brain that are revealed on nonenhanced T1-weighted MR images (areas of T1 shortening) have been reported to occur in various disease states (5), such as with processes that result in the deposition of paramagnetic substances (methemoglobin and non-heme iron such as ferritin) (6,7), minerals (such as calcium) (5), fat (8), melanin (9), and proteinaceous material (10) and in remyelination (11). This phenomenon also has been reported in the rim of cerebral abscesses and is thought to represent the effect of free radicals generated by macrophages during phagocytosis (12,13). Because remyelination (11,14), macrophage infiltration (14), free radical generation (15), and ferritin accumulation associated with lipid peroxidation (16) probably occur in patients with MS, T1 hyperintense lesions could represent an underrecognized biomarker of MS disease activity and/or tissue damage.

Drayer (17) reported that T1 shortening occurs in MS and might result from abnormal accumulation of protein (albumin) secondary to blood-brain–barrier disruption. Powell et al (15) reported three patients with MS who had T1 shortening in the rim of MS plaques and suggested that this was secondary to paramagnetic free radicals. Guttmann et al (18), while studying the evolution of MS lesions on MR images in five patients, reported ring hyperintensity patterns on nonenhanced T1-weighted MR images that persisted for as long as a year. However, to our knowledge, the frequency, location, and clinical correlation of T1 hyperintense lesions in patients with MS have not been formally studied. Thus the purpose of our study was to retrospectively document the frequency and topography of hyperintense lesions on nonenhanced T1-weighted MR images in patients with MS and to study their relationship to physical disability, disease course, and MR imaging markers of tissue damage, such as brain atrophy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Subjects
We retrospectively reviewed a database of clinical and MR imaging data in consecutive patients with clinically definite MS (19) who were referred to a community-based comprehensive MS academic center from July 1, 1995, to June 30, 1999. We excluded patients with any of the following: (a) primary-progressive MS, (b) poor-quality MR images, (c) other major neurologic and/or systemic diseases, or (d) age older than 60 years (to avoid confounding with findings related to age-related hyperintensities and age-related atrophy on MR images). Patients with primary-progressive MS (n = 3) were excluded, and we planned to ask that they be part of a separate study. We included 145 patients, with a mean age of 43 years ± 9.3 (standard deviation) and an age range of 23–60 years. One-hundred twelve (77%) patients were women, and 33 (23%) patients were men.

The disease duration was known in 72% (n = 104) of patients, and the mean disease duration was 9.6 years (range, 0–38 years). The clinical course was categorized as relapsing-remitting (RR) MS (n = 92, 63%) or secondary-progressive (SP) MS (n = 49, 34%) (20). The clinical course was unknown in four patients. Physical disability was assessed by one author (R.B.), a neurologist and MS specialist with more than 4 years of experience, in 95% (n = 138) of patients by using the Expanded Disability Status Scale (EDSS) (21). The mean EDSS score was 3.5 ± 1.9 (standard deviation), and the range was 0–8.5. Database review was performed by another author (S.S.). Our study was Health Insurance Portability and Accountability Act compliant and had institutional review board approval, but informed consent was waived because of its retrospective nature.

MR Imaging
Transverse brain MR imaging at 1.5 T was performed by using either of two units. Unit A (Signa 4X/LX; GE Healthcare, Milwaukee, Wis) was used in 36 patients. Unit B (ACS NT Gyroscan; Philips Medical Systems, Best, the Netherlands) was used in 109 patients. Several MR protocols were used.

Protocol 1 was performed in 36 patients with unit A and included a conventional spin-echo (SE) T1-weighted MR imaging sequence with repetition time msec/echo time msec of 450/19 and 5-mm section thickness and a dual-echo T2-weighted sequence with 2100/30, 85; a section gap of 2.5 mm; matrix of 256 x 256; two signals acquired; and field of view of 22 cm.

Three MR protocols were performed in patients who underwent imaging with unit B as follows: Protocol 2 was performed in 18 patients and included conventional SE T1-weighted MR imaging with 510/15, matrix of 256 x 256, field of view of 24 cm, and 5-mm section thickness and T2-weighted MR imaging with 2000/120, matrix of 256 x 256, field of view of 23 cm, and no section gap. Protocol 3 was performed in 80 patients and included conventional SE T1-weighted MR imaging with 585/20, one signal acquired, and 5-mm section thickness and fast SE T2-weighted MR imaging with 2300/120, two signals acquired, 6-mm section thickness, section gap of 0.5 mm, and echo train length of 18. Protocol 4 was performed in 11 patients and included fast SE T1-weighted MR imaging with 400/10, matrix of 191 x 256, two signals acquired, field of view of 23 cm, and echo train length of four and T2-weighted MR imaging with 3000/120, matrix of 192 x 256, field of view of 24 cm, echo train length of 12, 5-mm section thickness, and no section gap.

T1-weighted MR imaging was performed without magnetization transfer in all these patients. The gradient strengths were similar in the commercial systems used in this study. Transverse fluid-attenuated inversion-recovery (FLAIR) images were also obtained in all patients who underwent imaging with unit B. Because of the retrospective nature of the study, we observed that contrast material–enhanced imaging had not been performed consistently across patients. This inconsistency was noted in the gadolinium-based contrast agents used and in the timing of dose delay, and therefore contrast-enhanced images were not formally considered for this study.

Image Analysis
All MR image analyses were performed in consensus by two observers who were blinded to clinical details. T2 hyperintense lesions, T1 hypointense lesions, and brain atrophy were evaluated by the neurologist-neuroimager who had 4 years of experience (R.B.) and the postdoctoral fellow who had 1 year of experience (V.J.). T1 hyperintense lesions were evaluated by the neurologist-neuroimager and a radiology resident (S.S.).

For the analysis of number and location of lesions and degree of regional brain atrophy, all transverse sections were analyzed. The following regions were identified by using our previously described method (22): superior and inferior frontal lobes, superior and inferior parietal lobes, occipital and temporal lobes, cerebellum, and brainstem. Sulci and fissures were used to separate the lobes, including the central sulcus, lateral fissure, and parieto-occipital sulcus. The third ventricle demarcated superior versus inferior frontal or parietal lobes.

T1 hyperintense lesions were defined on hard-copy images as hyperintense areas versus the normal white matter on nonenhanced T1-weighted MR images that also contained areas of hyperintensity on T2-weighted MR images and areas of at least partial hyperintensity on proton density–weighted or FLAIR images. Areas of hyperintensity on T1-weighted MR images were compared with the intrasubject normal-appearing white matter to adjust for possible differences between subjects in the window and level function, as well as in the system scaling and gain.

Images were analyzed for location, size, and morphology (uniform hyperintensity or rim of hyperintensity) of the lesions. Lesions on T2-weighted MR images were defined as areas of hyperintensity that also contained areas of at least partial hyperintensity on proton density–weighted or FLAIR images. Hypointense lesions on T1-weighted MR images were defined as those that were clearly hypointense versus the normal-appearing white matter and also at least partially hyperintense on proton density–weighted or FLAIR images. The total number of T1 hyperintense, T2 hyperintense, and T1 hypointense lesions was the sum of all the regional numbers of lesions.

Regional cortical atrophy was assessed by using a four-point ordinal rating scale that was based on the enlargement of subarachnoid spaces in the superior and inferior frontal, superior and inferior parietal, temporal, and occipital lobes on nonenhanced T1-weighted MR images by using a previously described method (22). Ratings of atrophy were as follows: normal, grade 1 (mild, <10% atrophy), grade 2 (moderate, 10%–25% atrophy), or grade 3 (severe, >25% atrophy), according to the percentage of parenchymal volume loss (22). Total cortical atrophy was the mean of all regional cortical ratings. Third ventricular width (in millimeters), reflecting central atrophy, was measured from left to right by using our previously described method (23–25).

Because of the retrospective study design, all data were not available in all the patients, and partial sampling of results was performed, when required, for the analyses. In 87 patients, a full data set of all MR imaging lesion variables was available, although in all 145 patients, T1 hyperintense lesions were assessed.

Statistical Analysis
The number of T1 hyperintense lesions was correlated with age, disease duration, EDSS score, and MR measures of brain atrophy (cortical brain atrophy rating and third ventricular width) by using the Spearman rank correlation test. Because of the exploratory nature of the study and as lesion counts were not normally distributed, we used the Spearman rank correlation test instead of linear regression modeling for all correlations involving lesion counts. Group differences were assessed by using the Wilcoxon rank sum test for two groups or analysis of variance for more than two groups. Differences in frequencies among groups were evaluated by using the Fisher exact probability test. Analysis of covariance (ANCOVA) was performed for regression analysis when the dependent variable was continuous and the independent variables were nominal or continuous. As a result of the exploratory nature of this study, a difference with P < .05 was considered statistically significant. We used software (StatView, version 5.0; SAS Institute, Cary, NC) for the statistical analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
T1 Hyperintense Lesions: Frequency and Topography
T1 hyperintense lesions were seen in 113 (78%) patients (Table 1, Figs 1–4), and a total of 340 lesions were observed. The mean number of lesions per patient was 2.3 (range, 0–9 lesions) (Table 1). T1 hyperintense lesions were less common than T2 hyperintense and T1 hypointense lesions (Table 1). T1 hyperintense lesions occurred typically in the supratentorial regions, most commonly in the superior and inferior frontal lobes and in the superior parietal lobe (Table 1), whereas infratentorial T1 hyperintense lesions were noted in only one patient (one lesion in the brainstem). Areas of uniform hyperintensity (Figs 1, 4) were noted in 130 (38%) lesions, and areas of peripheral (rim) hyperintensity (Figs 2–4) were noted in the remaining 210 (62%) lesions. The lesions averaged 0.8 cm in diameter (range, 0.2–2.0 cm).


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  		Table 1. Frequency and Topography of Brain MR Lesions in Patients with MS

 

Figure 1
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  		Figure 1: Transverse MR images in a 50-year-old woman with RR MS. Left: Lesion (arrow) of right centrum semiovale shows uniform hyperintensity on the nonenhanced T1-weighted image (400/10) (protocol 4). Right: Lesion (arrow) also is seen on FLAIR image (repetition time msec/echo time msec/inversion time msec, 8000/150/2200).

 

Figure 2
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  		Figure 2: Transverse nonenhanced T1-weighted MR images (585/20) (protocol 2) in a 41-year-old man with RR MS and mild to moderate physical disability (EDSS score, 3.5). Uniformly hyperintense lesions (arrows) are seen. Lesions have corresponding hyperintensity on FLAIR images (not shown).

 

Figure 3
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  		Figure 3: Transverse nonenhanced T1-weighted MR images (450/19) (protocol 1) in a 40-year-old woman with SP MS and severe physical disability (EDSS score, 6.5). Significant central and cortical atrophy and hyperintense lesions characterized by rim hyperintensity (arrows) are seen. The lesions have corresponding hyperintensity on proton density–weighted MR images (not shown).

 

Figure 4
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  		Figure 4: Transverse nonenhanced T1-weighted MR images (400/10) (protocol 4) in a 36-year-old woman with RR MS. Hyperintense lesions with rim of hyperintensity (periventricular and centrum semiovale lesions [vertical arrow on left image and arrow on right image]) or uniform hyperintensity (frontal pole [horizontal arrow on left image]) are seen. The lesions have corresponding hyperintensity on FLAIR images (not shown).

 
T1 Hyperintense Lesions: Clinical Correlations
Age, sex, and disease duration.—The total number of T1 hyperintense lesions (sum of all regions) was not significantly associated with age (Spearman rank correlation test {rho} = 0.02, P = .83), sex (Wilcoxon rank sum test: in 112 women, sum rank = 8300; in 33 men, sum rank = 2285; P = .55), or disease duration (Spearman rank correlation test {rho} = 0.038, P = .69) (Table 2).


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  		Table 2. Association between T1 Hyperintense Lesions and Other Variables

 
Physical disability (EDSS score).—In the univariate analysis, the total number (sum of all regions) of T1 hyperintense lesions (Spearman rank correlation test {rho} = 0.19, P = .04) (Table 2) and total number of T1 hypointense lesions (Spearman rank correlation test {rho} = 0.28, P = .01) were significantly correlated with physical disability (higher EDSS score). The total number of T2 hyperintense lesions (Spearman rank correlation test {rho} = 0.16, P = .14) was not significantly associated with physical disability.

MS clinical disease course.—Hyperintense lesions on T1-weighted MR images were more likely to be multiple than single (P < .001, Fisher exact probability test) in patients with SP MS (multiple, 71% [35 of 49]; single, 8% [four of 49]) compared with those with RR MS (multiple, 46% [42 of 92]; single, 30% [28 of 92]). In the univariate analysis, the total number (sum of all regions) of T1 hyperintense lesions was significantly higher in SP MS than in RR MS (P = .003, Wilcoxon rank sum test); however, no group significant differences between SP MS and RR MS were noted for total number (sum of all regions) of T2 hyperintense lesions (P = .141, Wilcoxon rank sum test) or T1 hypointense lesions (P = .059, Wilcoxon rank sum test) (Table 3). Thus, only the T1 hyperintense lesion subtype was associated with advancing clinical disease course.


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  		Table 3. Association between Brain MR Lesions and MS Clinical Disease Course

 
Imaging Correlations
The total number (sum of all regions) of T1 hyperintense lesions was significantly associated with MR imaging measures of brain atrophy: For total cortical brain atrophy, Spearman rank correlation test {rho} was 0.42 and P was less than .001, and for third ventricular width, Spearman rank correlation test {rho} was 0.40 and P was less than .001 (Tables 2 and 4, Figs 3 and 4). In the multivariable analysis (ANCOVA), after adjustment for MS disease course, total T1 hyperintense lesions remained significantly associated with MR imaging measures of brain atrophy (for total cortical brain atrophy, F value = 11.8 and P = .001; for third ventricular width, F value = 10.9 and P = .001) (Table 4).


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  		Table 4. Association between Brain MR Lesions and Brain Atrophy

 
MR Imaging Technical Considerations
The total number of T1 hyperintense lesions was significantly higher (P = .001, Wilcoxon rank sum test) in patients who were imaged by using the unit A platform (n = 33 of 36; median ± length of IQR, 3.0 ± 2.0; sum rank, 3313.5; mean rank, 92.04) compared with patients who underwent imaging by using the unit B platform (n = 80 of 109; median ± length of IQR, 1.0 ± 3.0; sum rank, 7271.5; mean rank, 66.71). However, in the multivariable analysis (ANCOVA) accounting for physical disability, there was no significant difference in the total number of hyperintense lesions on T1-weighted MR images on the basis of imager type (F value = 1.4, P = .24). There was no significant difference (P = .67, Wilcoxon rank sum test) in the total number of hyperintense lesions on T1-weighted MR images on the basis of whether MR imaging was performed by using conventional SE (n = 106 of 134; median ± length of IQR, 2.0 ± 3.0; sum rank, 9837.0; mean rank, 73.41) or fast SE (n = six of 11; median ± length of IQR, 2.0 ± 3.75; sum rank, 748.0; mean rank, 68.0) T1-weighted sequences.

Patients in whom MR images were obtained by using protocol 1 had a significantly higher total number of hyperintense lesions on T1-weighted MR images (n = 33 of 36; mean, 3.3 ± 0.4 [standard error of the mean]) compared with those in whom MR images were obtained with other protocols, whereas those in whom MR images were obtained by using protocol 3 had a significantly lower total number of hyperintense lesions on T1-weighted MR images (n = 58 of 80; mean, 1.8 ± 0.2 [standard error of the mean]) compared with those in whom images were obtained by using other protocols (analysis of variance, F value = 5.6; P = .001). However, in the multivariable analysis (ANCOVA) accounting for physical disability, there was no significant difference in the total number of hyperintense lesions on T1-weighted MR images on the basis of the type of MR imaging protocol (F value = 1.1, P = .35).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Our study findings suggest that T1 hyperintense lesions commonly occur in patients with MS. T1 hyperintense lesions are more commonly associated with an advancing clinical disease course. These lesions also show a weak-to-moderate but significant relationship with physical disability and brain atrophy. More important, the T1 hyperintense lesions are better correlated with disability than are T2 hyperintense lesions. Moreover, the lesions show better differentiation between RR and SP MS groups than do either T2 hyperintense or T1 hypointense lesions. In summary, hyperintense MS plaques on T1-weighted images are common and are associated with brain atrophy, disability, and MS disease course (SP), and these findings suggest that such hyperintensity may be a clinically relevant biomarker of the MS disease process.

To our knowledge, ours is the first study to formally document the frequency and topography of T1 hyperintense lesions and their clinical correlation in patients with MS. However, T1 hyperintense lesions have been reported in various other processes that are associated with the following: (a) proteinaceous material such as colloid cysts (10), craniopharyngiomas (26), and pituitary tumors (5); (b) melanin (9); (c) dystrophic parenchymal mineralization (predominantly calcium) (5) or trace element deposition (27); (d) remyelination or hypermyelination that occurs in neurofibromatosis type 1 (11); (e) alterations of the cellular architecture in nonhemorrhagic cerebral infarction (6); (f) chronic hepatic failure (28,29); (g) paramagnetic substances such as methemoglobin (7) and nonheme iron, namely ferritin (30,31); (h) hypoxic-ischemic injury (5); (i) increased lipid or cholesterol content (8); and (j) macrophage infiltration in the rim of cerebral abscesses with phagocytosis and generation of paramagnetic free radicals, which carry strong paramagnetic properties as a result of an unpaired outer shell electron (12,13).

Some of these processes, such as macrophage infiltration (14), the production of free radicals (15), ferritin accumulation associated with lipid peroxidation (16), and remyelination (11,14), probably occur in MS lesions and may help one to understand the clinical importance of T1 hyperintense lesions in patients with MS. Pathologic studies have shown that the inflammatory infiltrate in MS plaques and periplaque regions of the brain in patients with MS consist of both T lymphocytes (CD8+ and CD4+) and macrophages (14). During phagocytosis, infiltrated lipid-laden macrophages (phagocytic cells) require large amounts of oxygen and undergo a respiratory burst at the cell membrane, activity that thus produces superoxide (O2–), a less reactive normal cellular metabolite (32). However, highly reactive and toxic free radicals, hydroxyl radicals (·OH), can be produced when superoxide reacts with hydrogen peroxide (H2O2). This process is known as the Haber-Weiss reaction (33), which has been shown to be thermodynamically unfavorable in biologic systems and is rate limited by the need for a metal ion catalyst, such as iron, to proceed (33).

In disease states such as MS, iron deposition has been shown to occur in the brains of patients and in animal models (16,34,35). Iron deposits have been observed to surround demyelinated plaques (34). Myelinated white matter near MS lesions has been shown to contain numerous ovoid-bodied axons that stain positively for iron (34). Iron deposition also has been found within blood vessels of gray matter near lesions (34). This iron deposition could represent a disease epiphenomenon. However, it is also plausible that iron accumulation plays a more direct role in MS-associated tissue damage (16,35). Studies have shown that the iron-catalyzed Haber-Weiss reaction, which makes use of the Fenton reaction, is now considered the major mechanism by which highly reactive and toxic hydroxyl radicals are generated in biologic systems, and these free radicals can initiate lipid peroxidation and neuronal death (36).

Free radicals have an unpaired outer shell electron and are paramagnetic. This factor could be causing T1 shortening in MS (15). Ferritin is paramagnetic and has been suggested as a cause for the T2 shortening in the brain of patients with MS (16). Ferritin is water soluble and has significant dipole-dipole interactions and also a large surface area, factors which could be possible reasons for an additional T1-shortening effect (30). This finding suggests that ferritin-associated T1 shortening, like T2 shortening (16,23), could represent a marker of MS-associated tissue damage. In addition, remyelinated regions in the brain result in T1 shortening (11). Terada et al (11) have shown that T1 shortening occurs in patients with neurofibromatosis type 1 and usually occurs before the T2-shortening effect, and this finding suggests that this activity represents remyelination or any early phase of repair. Therefore, the T1 hyperintense lesions in patients with MS noted in our study may also represent an early marker of remyelination. Other explanations for this T1-shortening effect include lipid-laden macrophages or paramagnetic substances other than iron. MR imaging–pathologic finding correlation studies are warranted for further elucidation.

The type of MR imager and the MR imaging protocols used for obtaining images might play a role in the T1-shortening effect. T1 hyperintense lesions were more commonly seen in patients whose MR images were obtained by using unit A compared with patients whose MR images were obtained by using unit B. However, there was no statistically significant difference in results of multivariable analysis after we controlled for disease severity. There did not seem to be any significant differences in the frequency of T1 hyperintense lesions on the basis of whether conventional SE or fast SE sequences were employed. There was also no effect of sections with a gap versus those without a gap on the sensitivity for detection of these lesions, and this lack of effect suggests that the finding is not the result of cross-talk between image sections.

The limitations of our study included (a) its retrospective nature, (b) the cross-sectional design that did not allow study of the evolution of T1 hyperintense lesions, and (c) the lack of a quantitative analysis of T1 hyperintensity or relaxation time. In addition, the P values and relationships derived in the ANCOVA and analysis of variance were potentially limited, as these normality-based methods were applied to nonnormal count data. Another limitation was that various MR imaging protocols were used across the cohort and therefore there is clearly a need for a prospective study with multiple T1 protocols to see whether the effect is technically dependent. In addition, fairly thick sections were employed and were obtained in only one section plane. Therefore, partial averaging errors could confound the results. The results of our study were qualitative and should be confirmed by quantitative techniques, such as T1 relaxometry (37). Future studies with newer techniques such as diffusion-tensor imaging that can be used to assess the integrity of white matter tracts (38) and MR spectroscopy that can be useful in studying axonal loss, metabolic changes, and membrane turnover may help us to better understand the pathophysiology of these lesions (39). On the basis of these limitations, we urge caution that the results and conclusion of this study should be treated as exploratory and require confirmation in a larger prospective study.

In conclusion, hyperintense plaques on nonenhanced T1-weighted MR images are common in patients with MS and are associated with brain atrophy, disability, and advancing disease course, and these findings suggest that a hyperintense lesion may be a clinically relevant biomarker. The lesions are more commonly associated with SP MS compared with RR MS and show a weak-to-moderate but significant relationship with physical disability and brain atrophy. The T1 hyperintense lesions are correlated with disability better than are T2 hyperintense lesions and show better differentiation between RR and SP MS groups than do either T2 hyperintense or T1 hypointense lesions. We conclude that a T1 hyperintense lesion deserves further study as a potentially clinically relevant biomarker of the disease process. Further prospective studies are warranted to assess the evolution of these lesions with time and their use for the prediction of clinical progression. Future studies should also correlate the MR imaging findings with histologic findings to define the pathologic substrate underlying this T1 hyperintense signal change. Further studies are warranted to determine whether T1 hyperintensity adds specificity for the diagnosis of MS versus other multifocal brain diseases.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   FOOTNOTES
 

Abbreviations: ANCOVA = analysis of covariance • EDSS = Expanded Disability Status Scale • FLAIR = fluid-attenuated inversion recovery • IQR = interquartile range • MS = multiple sclerosis • RR = relapsing remitting • SE = spin echo • SP = secondary progressive

Authors stated no financial relationship to disclose.

Author contributions:Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, V.J., R.B.; clinical studies, all authors; statistical analysis, V.J., S.S.; and manuscript editing, V.J., R.B.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

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