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Published online before print April 26, 2006, 10.1148/radiol.2393050573
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(Radiology 2006;239:831-838.)
© RSNA, 2006

Neuroradiology

Amyotrophic Lateral Sclerosis: Diffusion-Tensor and Chemical Shift MR Imaging at 3.0 T1

Sumei Wang, MD, Harish Poptani, PhD, John H. Woo, MD, Lisa M. Desiderio, RT, Lauren B. Elman, MD, Leo F. McCluskey, MD, Jaroslaw Krejza, MD, PhD and Elias R. Melhem, MD

1 From the Department of Radiology, Division of Neuroradiology (S.W., H.P., J.H.W., L.M.D., J.K., E.R.M.), and Department of Neurology (L.B.E., L.F.M.), Hospital of the University of Pennsylvania, 3400 Spruce St, Dulles 2, Philadelphia, PA 19104; and Medical University of Gdansk, Gdansk, Poland (J.K.). From the 2004 RSNA Annual Meeting. Received April 7, 2005; revision requested June 3; revision received July 18; final version accepted August 15. Address correspondence to E.R.M. (e-mail: elias.melhem{at}uphs.upenn.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively determine whether diffusion-tensor magnetic resonance (MR) imaging in conjunction with two-dimensional chemical shift imaging can assist in identifying upper motor neuron involvement and whether disease severity and duration can be predicted based on imaging parameters in patients with amyotrophic lateral sclerosis (ALS).

Materials and Methods: Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Fifteen patients with ALS (12 men, three women; mean age, 57.3 years) with clinical evidence of upper motor neuron involvement and 10 healthy control subjects (five men and five women; mean age, 49.4 years) were studied. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were measured from the corticospinal tracts at the level of the internal capsule. Average N-acetylaspartate (NAA)/creatine-phosphocreatine (Cr) and NAA/choline-containing compounds (Cho) ratios were calculated from the precentral gyrus. Student t test, multiple linear regression analysis, and Spearman correlation coefficients were employed to quantify relationships between imaging and clinical parameters.

Results: Patients with ALS exhibited significantly reduced FA values and NAA/Cr and NAA/Cho ratios compared with values in control subjects (P < .05) for both affected and nonaffected sides of the brain. ADC was elevated significantly in the affected side (P < .05) and was an independent predictor of disease duration after adjusting for age; however, FA values and NAA/Cr ratios for the affected side were even stronger predictors of disease duration. Moderate but statistically significant correlation was found between the FA values for the affected side and the ALS Functional Rating Scale Revised (ALSFRS-R) score (r = 0.51, P < .05). The NAA/Cr ratio also correlated with both the ALSFRS-R and upper motor neuron scores (r = 0.50 and 0.54, respectively; P < .05).

Conclusion: Diffusion-tensor and two-dimensional chemical shift MR imaging spectroscopy can be used to identify upper motor neuron involvement and predict disease duration in patients with ALS.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of upper and lower motor neurons. While electromyography can be used to identify lower motor neuron involvement, upper motor neuron dysfunction can only be assessed by means of neurologic examination (1,2). Objective and sensitive measures of upper motor neuron dysfunction are needed, since delayed diagnosis can result in loss of motor function that may not be corrected by therapeutic interventions (3).

Diffusion-tensor magnetic resonance (MR) imaging can provide important measures of upper motor neuron dysfunction because it offers insight into microscopic structures in vivo. Diffusion is anisotropic in white matter tracts because axonal membranes and myelin sheaths present barriers to the motion of water molecules. Diffusivity is generally much higher in directions along fiber tracts than in those perpendicular to them (4,5). Fractional anisotropy (FA) is a measure of directionality of diffusion, whereas apparent diffusion coefficient (ADC) is a measure of magnitude of diffusion (6). Corticospinal tract degeneration in ALS modifies diffusion characteristics, which can be reflected in changes in FA and ADC values. Although results of previous studies have shown that diffusion-tensor MR imaging can depict upper motor neuron involvement in ALS (7–12), the researchers in that study, who used a region of interest approach, could not avoid contamination from non–corticospinal tract fibers in their measurements. Such an approach can lead to erroneous interpretation of the diffusion-tensor imaging results.

Proton (hydrogen 1 [1H]) MR spectroscopy of the brain exhibits three major metabolites: N-acetylaspartate (NAA), choline-containing compounds (Cho), and creatine-phosphocreatine (Cr) (13,14). Hitherto published results of 1H MR spectroscopy studies of ALS have demonstrated that either concentrations of NAA (15,16) or ratios of NAA/Cr (17–19), NAA/Cho (16,20), and NAA/(Cr + Cho) (21) are reduced in the motor cortex, which have been interpreted as evidence of neuronal loss. Most of the studies, however, used a relatively large single-voxel point-resolved spectroscopy pulse sequence (15–20), which encompassed more frontal region than the motor cortex. Thus, results of these studies could only partially reflect changes in the motor cortex. Compared with the single-voxel method, multivoxel (two-dimensional chemical shift) MR imaging provides spectra from an array of voxels, which are much smaller than single voxels used earlier. Thus, the measurements of metabolites can be obtained more precisely from the motor cortex.

A preliminary report (22) suggests that if diffusion-tensor imaging and MR spectroscopy are taken together, better diagnostic information can be obtained. The purpose of our study, therefore, was to prospectively determine whether diffusion-tensor imaging in conjunction with two-dimensional chemical shift MR imaging can be used to identify upper motor neuron involvement and whether disease severity and duration can be predicted based on imaging parameters in patients with ALS.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Subjects
Fifteen patients (12 men, three women; age range, 44–72 years; mean age, 57.3 years ± 6.8 [standard deviation]) with ALS diagnosed clinically by a neurologist (L.F.M., with 19 years of experience) were recruited from our institution between October 2003 and January 2005. Additionally, 10 volunteers (five men, five women; age range, 41–61 years; mean age, 49.4 years ± 8.3) participated in this study as healthy control subjects. These volunteers had no family history of ALS and were considered healthy on the basis of clinical examination and MR imaging findings. All the patients had clinical upper motor neuron signs, and presence of ALS was classified according to the El Escorial criteria (23) as definite (eight patients), probable (five patients), or possible (two patients). The study was approved by the institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Informed consent was obtained from all the participants.

Assessment of ALS Symptoms
All patients underwent physical examination before MR imaging. Disease severity was estimated by a neurologist (L.F.M.) by using two scales—the ALS Functional Rating Scale Revised (ALSFRS-R) and the upper motor neuron involvement score. The ALSFRS-R is a validated measure of motor disability (24). The maximum score on this scale is 48, with lower scores indicating greater impairment. The upper motor neuron involvement score is devised based on the number of segments with upper motor neuron findings at physical examination. Upper motor neuron findings were defined as the presence of pathologic reflexes, hyperactive reflexes (or a missing abdominal reflex), preserved reflexes in a weak or wasted limb, or increased tone and/or spasticity (9). Six segments were considered in total (bulbar, right and left cervical, thoracic, and right and left lumbosacral segments). The upper motor neuron score was reported as the number of segments with upper motor neuron signs, and the score ranged from zero to six. Disease duration was calculated in months from the date of symptom onset to the date of imaging. Clinical characteristics of the patients are provided in Table 1.


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  		Table 1. Clinical Characteristics of Patients with ALS

 
Data Acquisition
MR studies were performed with a 3.0-T whole-body imager (Trio; Siemens, Erlangen, Germany) by using a product transmit-receive head coil. Routine MR pulse sequences included T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo (1620/3.9 [repetition time msec/echo time msec], flip angle of 15°), fast fluid-attenuated inversion recovery (9190/97/2500 [repetition time msec/echo time msec/inversion time msec]), and fast T2-weighted (4000/85) MR imaging.

Diffusion-tensor imaging.—Diffusion-tensor imaging was performed with a 12-direction single-shot spin-echo echo-planar sequence. Imaging parameters were as follows: 6500/99, field of view of 22 x 22 cm, 3-mm section thickness, 128 x 128 matrix, b values of 0 and 1000 sec/mm2, and 40 sections acquired to cover the whole brain. The acquisition time for the diffusion-tensor images was about 8 minutes.

Chemical shift imaging.—Two-dimensional chemical shift imaging was performed by using a spin-echo sequence (point-resolved spectroscopy) with water suppression by means of selective excitation. The volume of interest was centered on the central sulcus, with a section thickness of 20 mm and approximately 80 mm in the anteroposterior and left-right dimensions, respectively, depending on the patient's skull size and shape. Eight outer volume saturation slabs were placed outside the volume of interest to suppress lipid signals from the scalp. Sequence parameters included the following: 1700/30, field of view of 16 x 16–21 x 21 cm, three acquisitions, 16 x 16 phase-encoding, resulting in an approximate voxel size of 11 x 11 x 20 mm. The data set was acquired by using an elliptical k-space sampling with phase weighting, which led to an acquisition time of about 7 minutes. To minimize the effect of increased nominal voxel size by elliptical k-space sampling, a Hanning filter was applied in the spatial dimensions.

The total acquisition time for the entire study was approximately 60 minutes.

Image Processing
Diffusion-tensor imaging.—Three eigenvalues and eigenvectors of diffusion tensor for each pixel were calculated by using multivariate fitting (DTI Task Card version 1.69; Massachusetts General Hospital, Boston, Mass). Subsequently, ADC maps were calculated according to the equation ADC = ({lambda}1 + {lambda}2 + {lambda}3)/3, and FA maps were calculated according to the following equation:

Formula
where {lambda}1, {lambda}2, and {lambda}3 are the three eigenvalues of the diffusion tensor, and {lambda} denotes the mean of the three eigenvalues, a measure of directionally averaged diffusivity.

Color maps were created by mapping the major eigenvector x, y, and z components into red, green, and blue, which were weighted according to FA. Red, green, and blue colors were assigned to right-left, anterior-posterior and superior-inferior orientations, respectively. Fiber tracking was performed by using the fiber assignment by continuous tracking method (25). In brief, tracking was initiated from a "seed" region of interest in both retrograde and antegrade directions defined by the major eigenvector in the region of interest. The propagation was terminated when it reached a voxel with an FA value of less than 0.15 or when the angle between two consecutive steps was greater than 41°. The corticospinal tract was reconstructed by placing a first region of interest at the precentral gyrus and another at the lower pons level.

Regions of interest of uniform size (200–300 mm3) were placed manually by a neuroradiologist (S.W., with 7 years of experience in interpreting brain MR images) in the right and left side of the posterior limb of internal capsule (PLIC) on the transverse sections (Fig 1). All regions of interest were selected by using the fiber tracking images, which helped to identify the corticospinal tract and exclude voxels containing anisotropic fibers inconsistent with known corticospinal tract trajectories. The mean FA and ADC values within the regions of interest were calculated for each subject.


Figure 1
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  		Figure 1: Transverse diffusion-tensor MR section (b = 0 sec/mm2) in a control subject. The corticospinal tracts (green) are reconstructed and overlaid on the image, and regions of interest (red) are placed manually in the left and right side of the PLIC on the basis of the location of corticospinal tracts.

 
Chemical shift MR imaging.—The chemical shift imaging data set was zero filled to 2048 data points, and a Hanning filter (512 msec) was applied to reduce Gibbs ringing prior to Fourier transformation. The Fourier transformed data set was then phase corrected (zero and first order), which was followed by baseline correction. Metabolite areas for NAA, Cr, and Cho in the precentral gyrus were determined by using a frequency domain line-fitting program. The mean NAA/Cr and NAA/Cho ratios were calculated by averaging the NAA/Cr and NAA/Cho ratios for all voxels that included at least 50% of precentral gyrus. Even though eight saturation bands were used to suppress lipid signals from the scalp, some voxels were contaminated by unsuppressed lipid resonances, and, as such, these voxels were excluded from the analysis.

Statistical Analysis
The data were analyzed by using statistical software (Systat for Windows; Systat, Evanston, Ill). The distribution of the measurements was verified by means of the normal plot method, provided by Systat, which showed that distributions of individual values of the imaging parameters could be approximated to a Gaussian distribution. The mean and standard deviation were calculated for FA, ADC, NAA/Cr, and NAA/Cho from both the left and the right side of the brain in patients, as well as in control subjects. Comparisons of the parameters between the two hemispheres in the patient group and between the patients and control subjects were performed with a paired and a nonpaired two-sided Student t test, respectively.

To determine whether the sample size (m) is appropriate to be confident within the required confidence ranges, power analysis for comparison of means (µ1 and µ2 for unpaired data) was performed by using the following formula: m = 2(z{alpha} + z2ß)2{sigma}2/{delta}2, where {delta} = µ2 – µ1. The calculation was performed for a significance level at {alpha} = .05 and a power of 80% (1 – ß), and thus (z{alpha} + z2ß)2 = 7.849, where z{alpha} and z2ß are the ordinates for the normal distribution; {sigma} = standard deviation (the larger value of {sigma} from both groups was taken for the power analysis).

Distributions of clinical parameters, such as duration of disease and ALSFRS-R and upper motor neuron score were skewed, so the data were transformed to a logarithmic scale. Multiple linear regression analysis was performed to quantify the relationships between clinical parameters, such as ALSFRS-R, upper motor neuron score, and duration of disease (dependent variables), and imaging parameters, as well as age and sex. Separate analyses were performed for affected and nonaffected hemispheres, as well as for summed values of imaging parameters from both sides. In case of bilateral involvement, one hemisphere was assigned to the affected group and the other to the nonaffected group, depending on the severity of the involvement. In addition, the Spearman correlation coefficient was used to quantify associations between imaging parameters and clinical status as assessed by means of ALSFRS-R and upper motor neuron scores. A probability level less than .05 was considered to indicate a significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
In all subjects, we were able to create fiber tracking images of the corticospinal tracts, which was helpful in placing regions of interest in the PLIC.

In patients with ALS, the interhemispheric differences in FA, ADC, and NAA/Cr values obtained for the affected and nonaffected sides were not significant, while the NAA/Cho value was substantially lower in the affected hemisphere in comparison with the nonaffected hemisphere, as determined by using a paired t test (P = .036). The FA values for nonaffected and affected sides of the PLIC were significantly reduced in patients with ALS compared with healthy subjects (P < .05). ADC values for patients were significantly elevated only in the affected side of the brain compared with the right (P < .05) or left (P < .05) side of the brain in healthy subjects. NAA/Cr and NAA/Cho ratios for the precentral gyrus were lower for affected and nonaffected hemispheres in patients compared with respective values in healthy subjects (Fig 2, Table 2). Power analysis showed that for a significance level of {alpha} = .05 and a power of 80% (1 – ß), the total number of patients required for obtained size effects and standard deviations is 12 (Table 2).


Figure 2
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  		Figure 2a: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

Figure 2
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  		Figure 2b: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

Figure 2
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  		Figure 2c: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

Figure 2
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  		Figure 2d: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

Figure 2
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  		Figure 2e: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

Figure 2
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  		Figure 2f: MR images and spectra from two-dimensional chemical shift imaging spectroscopy (point-resolved spectroscopy localized) of the motor cortex in (a–c) a patient with ALS and (d–f) a control subject. Transverse T2-weighted (4000/85) MR images show the grid and volume of interest (rectangle) for the chemical shift study in the patient (a) and control subject (d). Representative spectra of the motor cortex from the ALS patient (b, c, voxel size of 11 x 10 x 20 mm) demonstrate reduced NAA/Cr and NAA/Cho ratios compared with the control subject (e, f, voxel size of 11 x 11 x 20 mm).

 

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  		Table 2. FA and ADC Values from the PLIC and Metabolite Ratios from the Motor Cortex in Patients with ALS and Control Subjects

 
Regression analysis showed that the age of patients was an independent predictor of disease duration (duration [log] = –1.93 + 0.079 [age]; F = 6.5, P = .024). Also, the sum of ADC values from affected and nonaffected sides was found to be an independent predictor of disease duration after adjusting for age (duration [log] = –15.58 + 0.055 [age, P = .079] + 0.997 [ADC, P = .041]; F = 6.93, P = .01). The disease duration was best predicted with ADC values from the affected side after adjusting for age and controlling for side (duration [log] = –5.86 + 0.05 [age, P = .094] + 1.37 [ADC, P = .146] – 0.392 [side, P = .106]; F = 7.62, P = .005), where a value of 1 was assigned to the left side, 2 to the right side, and 3 to the both sides.

When considered separately, FA value, metabolite ratios, and sex were not significant predictors of disease duration, although NAA/Cr ratio showed a trend toward significance after being adjusted for age (duration [log] = –5.53 + 0.86 [age, P = .011] + 0.989 [sum of NAA/Cr from both sides, P = .083]; F = 5.68, P = .018). However, when FA value and NAA/Cr ratio for the affected side were taken together, the disease duration could be well predicted on the basis of these parameters after adjusting for age and side (duration [log] = 5.477 + 0.08 [age, P = .007] – 16.96 [FA, P = .018] + 2.11 [NAA/Cr, P = .05] – 0.223 [side, P = .32]; F = 9.4, P = .002), where a value of 1 was assigned to the left side, 2 to the right side, and 3 to both sides. These two parameters were the strongest predictors of disease duration for all the parameters studied. Adding ADC value to the model only weakened the prediction power of the model. The NAA/Cr ratios and FA values from the affected side were not significantly correlated (Pearson correlation coefficient, r = 0.33, P > .05).

No one imaging parameter in any combination was a significant predictor of ALSFRS-R or upper motor neuron scores. However, a moderate but statistically significant correlation, as determined with Spearman correlation coefficient, was found between FA values for the affected side and ALSFRS-R score (r = 0.51, P < .05) and between the sum of FA values for both sides and ALSFRS-R score (r = 0.51, P < .05). Also, NAA/Cr ratio was found to correlate with both ALSFRS-R and upper motor neuron score (r = 0.50, P < .05 and r = 0.54, P < .05, respectively). The other imaging parameters were not correlated with clinical scores.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Results of our study show that diffusion-tensor imaging and MR spectroscopy parameters can be used to identify upper motor neuron involvement and predict disease duration in patients with ALS. We observed a significant reduction of FA value in the PLIC of patients with ALS, which indicates a breakdown of the barriers that restrict free water movement, probably reflecting axonal degeneration (1,26). An increase in ADC values with disease duration at the same location may represent an increase in the extracellular water volume secondary to axonal loss. These findings are consistent with corticospinal tract degeneration—the main pathologic feature of ALS. This result is also in line with results of previous studies in which diffusion-tensor MR imaging was used to quantify water diffusion changes in ALS (7–12). Although other brain disorders, such as Wallerian degeneration, might also affect PLIC and lead to similar findings at diffusion-tensor MR imaging, results of these studies and of our study suggest that quantification of corticospinal tract damage in the PLIC with diffusion-tensor MR imaging can be useful for the diagnosis of ALS.

Diffusion-tensor studies in patients with ALS have generally been focused on the measurements of FA and ADC values along corticospinal tracts, such as in the PLIC (7–12), cerebral peduncle (9,11), corona radiata (10,22), pons, and pyramids (10,11). Authors of these studies reported decreased FA and elevated ADC values only in the PLIC. Differences in diffusion characteristics observed at various anatomic levels of the corticospinal tract may be related to its architecture and/or to the unequal distribution of pathologic damage in ALS (11,27). Diffusion anisotropy is high in the internal capsule, which contains very coherent and tightly packed corticospinal tract fibers, whereas it is low in the pons and medulla, where the corticospinal tract fibers are less coherent owing to the presence of transverse pontine fibers, as well as nuclei and roots of cranial nerves (28). Reports of several postmortem studies have described uneven involvement of corticospinal tracts and variable patterns of degeneration (29,30). Despite widespread loss of myelin throughout the corticospinal tracts, almost all patients with ALS had degeneration of myelin in the PLIC (29,30). Therefore, we believe that the PLIC is the optimal site for the quantification of corticospinal tract degeneration.

We have employed fiber tracking images to map corticospinal tract location and used this as an unbiased guide to place regions of interest. This method is more objective than previous methods (7–12) and thus provides reproducible quantitative assessment of corticospinal tract involvement. In previous studies (7–12), no anatomic landmark was used to study the changes of FA and ADC; thus, additional interobserver variability was introduced to the measurements in these studies.

The characteristic MR spectroscopic features from the motor cortex in patients with ALS include a reduction of NAA concentrations (15,16) or NAA/Cho (16,20) or NAA/Cr (17–19) ratios. NAA is present primarily in neurons; thus, these metabolite changes reflect a loss or dysfunction of motor neurons. NAA concentration appears to be the most attractive surrogate marker for upper motor neuron degeneration; however, use of metabolite ratios can be more valid because standardization to Cr and Cho minimizes the interindividual differences that may occur in computing absolute concentrations. There is no consensus on which metabolite ratios can accurately reflect upper motor neuron involvement (17–19). A decrease in NAA/Cho and NAA/Cr ratios along with a constant Cho/Cr ratio in our study suggest a decrease in NAA level in patients with ALS. This NAA reduction might reflect cortical Betz cell loss or dysfunction, including dendrite atrophy, since histologic studies demonstrated loss of the giant pyramidal Betz cells with astrogliosis in the motor cortex in patients with ALS. These cells account for about 5% of the total pyramidal cells in the precentral gyrus and are responsible for shrinkage of the remaining neurons (31).

Only moderate correlations between FA values, NAA/Cr ratios, and disease severity were observed in our study. This may be due to the fact that separation of the relative contributions of upper and lower motor neuron dysfunction to overall disability is difficult to achieve by using functional scales (1,26,32). The ALSFRS-R is not specific for the detection of upper motor neuron disease. In general, associations between clinical symptoms and pathologic findings are weak, because it has been shown that prominent clinical disability during life may occur even in the absence of corticospinal tract involvement; the reverse has also been reported (1,26).

ADC value in the PLIC was significantly correlated with disease duration in our study. This result is consistent with the observation of Ellis et al (7). The pathologic process in ALS may affect the FA early in the disease process, whereas the elevation in ADC represents more chronic change with loss of neurons. Our study also demonstrated that the ADC value from the affected side was an independent predictor of disease duration, while the disease duration was best predicted based on FA and NAA/Cr values from the affected side after adjusting for age and controlling for side. In general, this observation is consistent with the pathologic features of ALS, because the longer the disease duration, the more severe the neuronal loss and axonal degeneration (29). Therefore, FA and ADC values and NAA/Cr ratios can provide important prognostic information.

The limitation of our study was the relatively small sample size, especially the number of patients in whom ALS was probable or possible. While a study with a larger population is warranted, one has to take into account that the prevalence of the disease is low, and collection of a more numerous and homogeneous group of patients with ALS can be difficult. Future directions include longitudinal studies in patients with ALS and studying patients with clinical lower motor neuron disease who lack apparent upper motor neuron disease.

In conclusion, results of our study show that FA and ADC values from the PLIC that are based on the tractography technique can be used to assess corticospinal tract degeneration, whereas two-dimensional chemical shift MR imaging spectroscopy can depict neuronal loss in the motor cortex. These results indicate that abnormality in either diffusion-tensor MR imaging or two-dimensional chemical shift MR imaging is suggestive of upper motor neuron involvement, regardless of clinical findings. A combination of FA, ADC, and NAA/Cr ratios can help predict disease duration. Therefore, diffusion-tensor MR imaging in conjunction with two-dimensional chemical shift MR imaging can be used to identify upper motor neuron involvement and yield diagnostic and prognostic information in patients with ALS.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: ADC = apparent diffusion coefficient • ALS = amyotrophic lateral sclerosis • ALSFRS-R = ALS Functional Rating Scale Revised • Cho = choline-containing compounds • Cr = creatine-phosphocreatine • FA = fractional anisotropy • NAA = N-acetylaspartate • PLIC = posterior limb of internal capsule

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, S.W., H.P., E.R.M.; 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, S.W., H.P., E.R.M.; clinical studies, S.W., H.P., J.H.W., L.M.D., L.B.E., L.F.M., E.R.M.; statistical analysis, S.W., H.P., J.K., E.R.M.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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