Abstract
Background: High angular resolution diffusion tensor imaging (HARD) is an MRI technique that exploits the mobility of water molecules to yield maps of structural order and directionality of white matter tracts with greater precision than six-direction diffusion tensor imaging (DTI) schemes.
Objective: To assess whether HARD is more sensitive than conventional MRI or neurologic assessment in detecting the upper motor neuron (UMN) pathology of patients with ALS.
Methods: Twenty-five patients with definite UMN clinical signs and 23 healthy volunteers underwent conventional MRI. HARD datasets were collected from a subset of these participants plus four patients with isolated lower motor neuron (LMN) signs. ALS symptom severity was assessed by a neurologist, the conventional MR images were reviewed by neuroradiologists, and the DTI maps were subject to quantitative region of interest analysis.
Results: Motor cortex hypointensity on T2-weighted images and corona radiata hyperintensity on proton density-weighted images distinguished patients with UMN involvement from volunteers with 100% specificity, but only 20% sensitivity. Fractional anisotropy (FA) was reduced in the posterior limb of the internal capsule in patients with UMN involvement compared to volunteers. A FA threshold value with a sensitivity of 95% to detect patients with ALS (including those with isolated LMN signs) had a specificity of 71%.
Conclusions: High angular resolution diffusion tensor imaging may be more sensitive than conventional MRI or neurologic assessment to the upper motor neuron (UMN) pathology of ALS, but it lacks the specificity required of a diagnostic marker. Instead, it is potentially useful as a quantitative tool for monitoring the progression of UMN pathology.
The clinical subtype of ALS is dependent upon whether the upper motor neurons (UMN) of the motor cortex and the lower motor neurons (LMN) of the brainstem and spinal cord are affected together or in isolation (primary lateral sclerosis [UMN only] and progressive muscular atrophy [LMN only]). Involvement of the LMN is confirmed by EMG and nerve conduction studies,1 but to date, there is no objective technique that can reliably confirm involvement of the UMN.
Brain MRI is primarily used during diagnosis to exclude other conditions. However, both conventional MRI and diffusion tensor imaging (DTI) reveal abnormalities in patients with ALS that may reflect pathologic alteration of the UMN.
On T2-weighted images, a ribbon of signal loss (hypointensity) has been observed in the gray matter of the motor cortex adjacent to the central sulcus in a proportion of patients with ALS.2,3⇓ This may reflect elevated regional iron deposition.2 On T2-weighted, proton density-weighted, and fluid-attenuated inversion recovery (FLAIR) images, signal increase (hyperintensity) has been observed throughout the intracranial corticospinal tract (CST) from the level of the centrum semiovale to the brainstem, in a proportion of patients with UMN signs (figure 1).4,5⇓ Such signal increase is most readily identified at the level of the posterior limb of the internal capsule4 and may reflect demyelination and degeneration of CST fibers.6 Occasionally, similar MRI abnormalities in the CST are also identified on T1-weighted images in association with very pronounced UMN symptoms.3 There is a general lack of agreement regarding how sensitive and specific the presence of these abnormalities is for the detection of UMN involvement. This is because the contrast in conventional MR images varies depending upon the specific sequence parameters used and, in the absence of quantitative relaxation rate determination, the identification of abnormalities is dependent upon the subjective observations of the rater.
Figure 1. Signal hyperintensity in the intracranial corticospinal tract in a patient with amyotrophic lateral sclerosis (proton density-weighted images). (a) Centrum semiovale, (b) corona radiata, (c) posterior limb of the internal capsule, (d) cerebral peduncle.
In contrast, DTI yields objective quantitative measures of the magnitude and directionality of diffusion of water molecules in three-dimensional space.7 When unimpeded, water molecules move in a random manner (isotropic diffusion), however, the presence of obstacles to free motion, such as cell membranes or myelin sheaths, restricts molecular motion in a particular direction resulting in anisotropic diffusion.8 Therefore, a breakdown of the obstacles to free diffusion, as occurs in association with UMN degeneration, may be reflected by reduced diffusion anisotropy.
DTI indices are obtained through the acquisition of diffusion-weighted images along at least six gradient directions, plus an image without diffusion-weighting (b = 0); this is sufficient to yield the six independent tensor elements.9 From the tensor elements, three-dimensional diffusion ellipsoids can be described on a voxel-by-voxel basis.10 The principal axis of each ellipsoid represents the main direction of molecular diffusion within that voxel (principal eigenvector; presumed to be parallel to the path of the white matter tracts) and the length of the ellipsoid represents the magnitude of diffusion in that direction (principal eigenvalue, λ1). The width and height of each ellipsoid represents the magnitude of diffusion in the remaining orthogonal directions. From the diffusion eigenvalues (λ1, λ2, λ3), the invariant indices of relative anisotropy (RA—the ratio of the anisotropic part of the diffusion tensor to the isotropic part) and fractional anisotropy (FA—the fraction of the diffusion tensor that can be ascribed to anisotropic diffusion) can be calculated.11 RA and FA are quantitative measures of diffusion anisotropy, intrinsic to the tissue under examination and independent of the orientation of the subject in the magnet.7 A quantitative measure of the overall presence of obstacles to diffusion (mean diffusivity [MD]) in each voxel, independent of anisotropic diffusion, may be obtained from the trace of the diffusion tensor (trace = λ1 + λ2 + λ3; MD = trace/3).9
DTI investigations of patients with ALS reveal both reduced diffusion anisotropy and increased MD in the intracranial CST compared to healthy volunteers, which may directly reflect the UMN pathology of axonal loss and demyelination.12,13⇓ However, previous studies did not include patients with isolated LMN clinical signs (progressive muscular atrophy variant). Furthermore, the results may be limited by the small number7 of gradient directions used; such sparse sampling of the diffusion tensor is known to cause imprecision in the DTI maps.14
High-angular resolution DTI (HARD) acquires diffusion-weighted images along many (more than six) gradient directions, thus sampling the space of the diffusion ellipsoid with greater density and uniformity. This results in improved resolution of areas where fibers cross (important for analysis by fiber tracking),9 but also improves the precision of the invariant DTI indices (improved signal to noise characteristics).14
Using the more precise DTI indices obtained from HARD, the purpose of this investigation was to evaluate whether conventional MRI or HARD are suitable techniques for the identification of UMN involvement in patients with ALS. In particular, it was hypothesized that DTI indices would distinguish 1) patients with UMN clinical signs from healthy volunteers with greater sensitivity and specificity than conventional MRI techniques and 2) patients with isolated LMN clinical signs from healthy volunteers.
Methods.
The study was approved by the South Sheffield Research Ethics Committee and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants.
Participants.
Twenty-nine patients (nine female) with ALS were recruited from the specialist Motor Neurone Disorders clinic at the Royal Hallamshire Hospital, Sheffield. Patients were diagnosed on the strength of clinical assessment by a consultant neurologist, and a protocol of investigations to exclude other diagnoses including blood and CSF examinations and detailed neurophysiologic assessment. Twenty-five patients had clinically definite UMN signs and were classified, according to the El Escorial diagnostic criteria,15 as definite ALS (15 patients), probable ALS (6 patients), and possible ALS (4 patients). The mean disease duration of these patients was 30.7 months (minimum = 9 months, maximum = 142 months, SD = 30.7 months) and their mean age was 54.4 years (minimum = 28.0 years, maximum = 72.9 years, SD = 11.9 years). The remaining four patients had isolated LMN clinical signs and were diagnosed with the progressive muscular atrophy variant of ALS following exclusion of other LMN syndromes. These patients had a mean disease duration of 74.8 months (minimum = 26 months, maximum = 114 months, SD = 37.5 months) and a mean age of 58.2 years (minimum = 44.5 years, maximum = 72.3 years, SD = 11.4 years). Twenty-three healthy volunteers (six female) were recruited by advertisement from either the Royal Hallamshire Hospital or the Sheffield branch of the Motor Neurone Disease Association. The mean age of the healthy volunteers was 52.9 years (minimum = 28.0 years, maximum = 78.3 years, SD = 12.2 years).
ALS symptom assessment.
A single neurologist conducted an assessment of ALS symptomatology, for each patient, on the day of study participation. This comprised 1) the Medical Research Council muscle strength scale, 2) the ALS Functional Rating Scale, which is a validated measure of motor disability in ALS,16 and 3) an assessment of reflexes (the Babinski sign, the Hoffman sign, the jaw reflex, and the deep tendon reflexes of the biceps, triceps, brachioradialis, quadriceps, and ankle), hypertonia (the modified Ashworth spasticity scale17 in the upper limbs, lower limbs, and masseter), fasciculations (in the upper limbs, lower limbs, trunk, and tongue), and atrophy (in the upper limbs, lower limbs, and tongue). From this assessment, summary scores reflecting the degree of involvement of the UMN and the LMN were calculated. The scoring system used for each UMN item was 0 if the response was within the normal range, 1 if the response indicated a possible UMN sign (for example, when a deep tendon reflex was present in an atrophied muscle), and 2 if the response indicated a definite UMN sign. The maximum UMN score was 40. The scoring system for each LMN item was 0 if the response was within the normal range, 1 if the response indicated mild LMN involvement (for example, sporadically present fasciculations), and 2 if the response indicated severe LMN involvement. The maximum LMN score was 14. The rate of symptom progression was calculated as UMN score/ALS duration (LMN score/ALS duration).
MRI.
All imaging took place in the Section of Academic Radiology based at the Royal Hallamshire Hospital, Sheffield, on a 1.5 Tesla MRI system (Eclipse, Philips Medical Systems, Cleveland, OH) equipped with an actively shielded whole-body gradient set (maximum strength per axis of 27 mT/m, slew rate of 72 mT/m/ms). All images were acquired with a cylindrical receive-only head coil with the use of foam padding to reduce the effect of involuntary head movement. All sequences were within FDA guidelines for radiofrequency-specific absorption rate and rate of field change dB/dt, where B is magnetic flux density. Disposable ear protectors were used to reduce acoustic noise by ∼30 dBA.
All conventional MRI sequences were acquired in the axial plane and slices, covering the whole brain, were positioned parallel to a line bisecting the anterior commissure and posterior commissure (AC-PC) defined on a T1-weighted midline sagittal image (repetition time [TR] = 350 msec, echo time [TE] = 16 msec, field of view [FOV] = 250 mm, acquisition matrix = 192 × 256, slice thickness = 4 mm, interslice gap = 5 mm, number of slices = 11). The following sequences were acquired: 1) a dual-echo fast spin echo (DE FSE) sequence, which acquired 60 contiguous slices of both T2- and proton density-weighted images (TR = 8,040 msec, pseudo echo time = 15 and 75 msec, FOV = 230 mm, acquisition matrix = 256 × 256, slice thickness = 2.5 mm); 2) a 20 slice T1-weighted sequence (TR = 501 msec, TE = 16 msec, FOV = 230 mm, acquisition matrix = 256 × 256, slice thickness = 5 mm, interslice gap = 2 mm); and 3) a 30 (contiguous) slice FSE FLAIR sequence (TR = 14,592 msec, pseudo echo time = 95.9 msec, inversion time [TI] = 1,800 msec, FOV = 250 mm, acquisition matrix = 192 × 256, slice thickness = 5 mm, interecho spacing = 13.7 msec, interleave factor = 5).
The DTI acquisition used a single-shot diffusion-weighted (Stejskal-Tanner) spin-echo echoplanar imaging technique. The sequence consisted of diffusion-weighted acquisitions (b = 1,200 seconds/mm2) from 54 distinct, spatially isotropically arranged, diffusion-weighted gradient directions, and four baseline signals with b = 0.18 Duration and temporal spacing of the rectangular diffusion-weighted gradient pulses were 24 msec and 63 msec. The effect of any residual eddy currents was minimized by the application of bipolar gradient waveforms.19 A non-phase encoded reference scan was used to remove residual Nyquist ghosting in the echoplanar images.20 Nineteen contiguous axial slices aligned AC-PC to cover the forebrain were acquired in a total imaging time of 16 minutes (TR = 7,680 msec, TE = 123.1 msec, acquisition matrix = 128 × 128, slice thickness = 5 mm, FOV = 240 mm).
DTI was performed on a subset of 36 of the study participants: 16 patients with UMN signs, 4 patients with isolated LMN signs, and 16 healthy volunteers. Total imaging time for the full protocol of conventional MRI sequences and axial DTI was approximately 50 minutes. (The remaining study participants were imaged under an alternative protocol that contained the conventional imaging sequences, the PRIME sequence,21 and MRI spectroscopy in the motor cortex [manuscript in preparation]. The addition of the DTI sequence to this protocol was not feasible because the imaging session would have become intolerably long for many of the patients with ALS.)
MR image analysis.
Each participant was given a unique code number to ensure that all data analysis was conducted without knowledge of his or her clinical status.
The conventional MR images were printed onto films (to standardize the windowing level of the images) and rated by two neuroradiologists independently. Brain regions were classified as definitely normal, definitely abnormal, or borderline abnormal at six levels through the CST (the precentral gyrus, the centrum semiovale, the corona radiata, the posterior limb of the internal capsule, the cerebral peduncle, and the pons), in the postcentral gyrus, and in two control brain regions (the frontal deep white matter at the level of the centrum semiovale and the anterior limb of the internal capsule). A consensus rating scheme was employed, in which brain regions were classified as either normal or abnormal by the following method: inter-rater disagreements of definitely normal/borderline abnormality were classified as normal; disagreements of borderline abnormality/definitely abnormal were classified as abnormal; and when both raters indicated the region was borderline abnormality or there was total disagreement (definitely normal/definitely abnormal), the raters reviewed the images together to reach a consensus opinion.
The DTI datasets were fitted to the diffusion tensor equations to yield six independent tensor elements using a non-linear least-squares fitting routine.14 From these elements, maps of MD and the rotationally invariant anisotropy indices of RA and FA were calculated.11 Region of interest analysis of the DTI maps was conducted by two independent raters. Regions were positioned at three levels through the CST (in the subcortical white matter of the precentral gyrus, the corona radiata, and the posterior limb of the internal capsule), in the subcortical white matter of the postcentral gyrus, and in three control brain regions (the frontal white matter at the level of the corona radiata, the genu, and splenium, of the corpus callosum). All regions were 5 × 5 pixels in size except those positioned in the internal capsule, which were 3 × 12 pixels (figure 2 illustrates typical region of interest placement). The RA maps were used for region placement because these images offer the best compromise between visual contrast and anatomic detail (resolving areas of mild anisotropy and showing acceptable signal-to-noise ratio in areas of high anisotropy).22 These regions were then transposed into identical positions on the FA maps (which offer the smoothest intensity variations within anisotropic structures22) and the MD maps; mean values were recorded. It has recently been recognized that certain white matter tracts show more alignment in the right, than the left, hemisphere in neurologically healthy individuals.23 To avoid this potential bias, the FA and MD values from the right and left hemispheres were averaged before any statistical group comparisons were made.
Figure 2. Region of interest positioning for the diffusion tensor imaging analysis. (a) Subcortical white matter of the precentral and postcentral gyri, (b) deep white matter of the parietal and frontal lobe at the level of the corona radiata, (c) genu and splenium of the corpus callosum, (d) posterior limb of the internal capsule (which was aligned medial to the signal void of the globus pallidus on the relative anisotropy maps).
Statistical analysis.
All statistical analyses, unless otherwise specified, were conducted using SPSS for Windows Version 11.0. The neuroradiologists’ ratings of the conventional MR images were compared between patients with UMN signs and healthy volunteers using a series of χ2 analyses. Quantitative anisotropy and MD values were compared between the groups using independent samples t-tests. In an exploratory analysis, the group of patients with isolated LMN signs was compared to both the patients with UMN signs and the healthy volunteers using non-parametric procedures. The relationship between the DTI indices and the measures of ALS symptom severity were explored using the Pearson Product-Moment correlation technique. The degree of agreement between the raters of the DTI maps was examined using intraclass correlation.
Results.
Conventional MRI.
The patients with UMN signs were matched to the healthy volunteers with respect to sex (χ2 = 0.203, p = 0.653) and age (t = 0.446, p = 0.658).
The consensus ratings revealed that abnormal signal hypointensity in the motor cortex on T2-weighted images (χ2 = 5.135, p = 0.023) and abnormal signal hyperintensity in the corona radiata on proton density-weighted images (χ2 = 4.015, p = 0.045) distinguished patients with UMN signs from healthy volunteers (table 1). There was also a trend for the patient group to show more signal hyperintensity in the posterior limb of the internal capsule on FLAIR images (χ2 = 2.901, p = 0.089). Table 1 illustrates that there were no other differences between patients with UMN signs and healthy volunteers on any type of conventional MR image, in any other brain region examined.
Table 1 Number (%) of subjects with abnormal conventional MR scans according to the consensus ratings (* p < 0.05; † p < 0.10)
Nonparametric analysis revealed that the patients with identifiable signal loss in the motor cortex on T2-weighted images (n = 5) did not differ from those without this abnormality (n = 20) on any measure of symptom severity. However, the patients with abnormal signal hyperintensity in the corona radiata on proton density-weighted images (n = 4) had a faster rate of UMN symptom progression than those without (n = 21) (Mann Whitney U = 12.5, p = 0.038). There was also a corresponding trend toward a shorter symptom duration in these patients (Mann Whitney U = 16.0, p = 0.074).
DTI region of interest analysis.
Of the 36 DTI datasets collected, 3 were of very poor quality due to subject motion between DTI acquisitions and were consequently excluded from the region of interest analysis (1 from a patient with UMN signs and 2 from healthy volunteers). The remaining 33 participants in this section of the study comprised 15 patients with UMN signs (mean disease duration = 33.7 months, SD = 33.2 months; mean age = 55.5 years, SD = 13.3 years), 4 patients with isolated LMN signs (as detailed previously). and 14 age-matched healthy volunteers (mean age = 53.7 years, SD = 14.0 years). These groups were matched for sex (χ2 = 0.161, p = 0.923) and age (F = 0.192, p = 0.827).
Figure 3 illustrates the typical FA maps obtained from the 54-direction HARD sequence used in this investigation. There was no obvious difference between the maps from patients with ALS and healthy volunteers upon visual inspection. However, quantitative region of interest analysis revealed that FA was reduced in the posterior limb of the internal capsule in patients with UMN signs compared to healthy volunteers (t = 3.594, p = 0.001) (table 2). There was also a trend toward reduced FA in the subcortical white matter of the precentral gyrus in patients (t = 1.739, p = 0.094). The groups did not differ in any other brain region examined. FA in the posterior limb of the internal capsule was correlated with clinical symptom severity as measured by the Medical Research Council scale (Pearson correlation coefficient = 0.562, p = 0.037). There was also a trend toward a similar relationship with functional disability as measured by the ALS rating scale (Pearson correlation coefficient = 0.514, p = 0.060). FA in the subcortical white matter of the precentral gyrus correlated with both the Medical Research Council scale (Pearson correlation coefficient = 0.584, p = 0.028) and the ALS rating scale (Pearson correlation coefficient = 0.559, p = 0.038). FA was unrelated to age in the healthy volunteers.
Figure 3. Typical fractional anisotropy map obtained from a patient with amyotrophic lateral sclerosis.
Table 2 Mean (SD) FA and MD values from the region of interest analysis (* p < 0.10, † p < 0.01)
Table 2 also illustrates that MD was equivalent in patients with UMN signs and healthy volunteers in all brain regions examined. Furthermore, MD was unrelated to any clinical measure of ALS symptom severity in the patients, or to age in the healthy volunteers. These observations were further explored by examination of the individual eigenvalues of the diffusion tensor in the brain regions with reduced anisotropy (the posterior limb of the internal capsule and the subcortical white matter of the precentral gyrus). Table 3 reveals that λ2 was greater in the posterior limb of the internal capsule in patients with UMN signs than in healthy volunteers (t = 2.354, p = 0.026). The eigenvalues were not correlated with any clinical measure of symptom severity in the patient group, or with age in the healthy volunteers.
Table 3 Principal diffusivities in the motor cortex and posterior limb of the internal capsule (* p < 0.05)
The greatest degree of reliability between the two independent raters was achieved in the posterior limb of the internal capsule (intraclass correlation coefficient = 0.79) and the subcortical white matter of the precentral gyrus (intraclass correlation coefficient = 0.74).
Figure 4 reveals that patients with clinical signs of isolated LMN involvement had FA values in the posterior limb of the internal capsule that were more similar to those displayed by patients with UMN signs than those of healthy volunteers. Nonparametric tests revealed that there was a trend (which just failed to reach significance) toward reduced FA in the posterior limb of the internal capsule in patients with isolated LMN signs compared to healthy volunteers (mean FA LMN patients = 0.695, SD = 0.017, Mann-Whitney U = 10.00, p = 0.056). The FA values of the patients with isolated LMN signs were equivalent to those of the patients with UMN signs (Mann-Whitney U = 25.00, p = 0.617).
Figure 4. Mean fractional anisotropy in the posterior limb of the internal capsule by group (error bars indicate the SD of the mean). UMN = upper motor neuron; LMN = lower motor neuron.
An upper threshold FA value in the posterior limb of the internal capsule of 0.72 (selected because it was 1 SD above the mean FA of patients with UMN signs) correctly classified 95% of patients with ALS (including those with isolated LMN signs), but also incorrectly included 29% of healthy volunteers. As a test for the presence of UMN corticospinal tract pathology, this threshold value had a sensitivity of 95%, a specificity of 71%, and a positive predictive value of 82%.
Discussion.
FA was significantly reduced in the posterior limb of the internal capsule in patients with UMN clinical signs compared to age-matched healthy volunteers. Patients also showed a trend toward reduced FA in the subcortical white matter of the precentral gyrus and, in both regions, FA was related to the degree of ALS symptom severity. The posterior third of the posterior limb of the internal capsule contains the densely packed projection fibers of the CST,24 an area in which water diffusion is highly anisotropic in the healthy human brain.25 Reduced FA indicates that there has been a breakdown of the barriers that restrict the free motion of water. On a microscopic scale, it has been established that intact axonal membranes are the most important determinant of anisotropic diffusion in neural tissues, but there is also a smaller moderating effect on anisotropy of the myelin coating of the axons.8 Therefore, it is likely that the reduced FA in the posterior limb of the internal capsule in patients with ALS reflects the axonal fiber degeneration, and myelin pallor observed in this region in histologic investigations.26,27⇓ The idea that reduced FA reflects the UMN pathology of ALS is also supported by the observed relationship between FA and motor disability.
The trend toward reduced FA in the subcortical white matter of the precentral gyrus may also reflect the UMN pathology of ALS. This area contains the axonal contribution to the CST from the large pyramidal motor neurons (Betz cells), which have been shown to be reduced in number in patients with ALS.28 Shrinkage of the remaining Betz cells29 and degeneration of the dendrites30 has also been identified. Histologically, white matter involvement is less obvious in the precentral gyrus than at lower levels of the CST in patients with ALS, but when present, shows the same type of alterations (i.e., axonal degeneration, demyelination, and gliosis).31 In addition, the subcortical white matter of the healthy human brain is less anisotropic than the tightly packed fiber tracts of the internal capsule.25 These observations may explain why the difference in FA between patients and healthy volunteers was less obvious in the subcortical white matter of the precentral gyrus than in the internal capsule.
MD did not differ between patients with UMN clinical signs and healthy volunteers, which indicates that the groups did not differ in the overall magnitude of displacement of water molecules in either the posterior limb of the internal capsule or the subcortical white matter of the precentral gyrus. It may be speculated that reduced FA in the absence of increased MD indicates that directional organization of the tract has been lost, but that absolute cell density remains unchanged.32 Pathologic processes that independently increase and decrease the magnitude of diffusion of water molecules, but which have the common effect of reducing directionality, may explain this effect.33 For example, axonal loss leads to expansion of the extracellular matrix resulting in increased diffusivity, but gliosis is a dense cellular process that leads to reduced diffusivity. Therefore, cell density may be preserved in the CST in patients with ALS because the extracellular spaces created through axonal degeneration are filled by a proliferation of glial cells. The opposing influences of these pathologic processes on MD may also account for the lack of observed relationship with ALS symptom severity.
Closer examination of the individual directional components of MD revealed that there was a statistically significant increase in λ2 in the posterior limb of the internal capsule and a corresponding, albeit non-significant, decrease in λ1 in patients with UMN signs compared to healthy volunteers. This suggests that, although there is no overall difference in the magnitude of diffusion, there has been an orthogonal shift in the direction of molecular motion away from the long axis of the tract. This interpretation is compatible with the observed decrease in FA. However, caution should be exercised in any anatomic interpretation of the individual eigenvalues because the measures are inherently susceptible to noise contamination.7
There have been two previous DTI investigations of patients with ALS, both of which employed seven-direction DTI schemes. The first of these studies used a less anatomically specific measure of the CST than that of the current investigation because it was created from the average of six regions of interest positioned from the centrum semiovale to the posterior limb of the internal capsule in each cerebral hemisphere.12 In common with the current investigation, reduced FA was observed in the CST in patients with ALS compared to age-matched healthy volunteers and FA in this region was correlated with ALS clinical symptom severity.12 The second of these previous studies investigated the CST at four discrete levels; the posterior limb of the internal capsule, the cerebral peduncles, the pons, and the pyramids.13 As in the current study, FA was reduced in the posterior limb of the internal capsule (and was also reduced at all lower levels of the CST) in patients with ALS compared to healthy volunteers.13 However, in this investigation, the association between FA in the CST and ALS clinical symptom severity was not detected, possibly owing to the lack of statistical power associated with the low angular resolution DTI scheme that was employed.
The main difference between the previous studies and the current investigation was the observation of increased MD in the CST in patients with ALS compared to healthy volunteers. Very little is known about the precise mechanism by which UMNs degenerate in ALS, however, from the established pattern of Betz cell loss from the primary motor cortex combined with more apparent axonal degeneration at the lowest levels of the CST, a dying-back process of axonal degeneration may be hypothesized.31 Astrocytic gliosis and demyelination are secondary responses to axonal degeneration; they begin several months after axonal degeneration and are associated with the eventual deposition of a dense astrocytic scar and complete loss of myelin.34 Therefore, the observation of increased MD in the CST in previous DTI investigations, but not in the current study, may be accounted for by the stage of progression of UMN pathology of the specific patients included in the study. In patients with early UMN involvement, axonal degeneration may have reached the height of the posterior limb of the internal capsule (resulting in reduced FA) but the associated gliosis may not yet have reached a density to impair molecular diffusion (resulting in increased MD). In chronic UMN involvement, both axonal degeneration and gliosis may be well established, resulting in reduced FA without any apparent increase in MD. In the previous DTI study that evaluated the lower levels of the CST in patients with ALS, such a pattern of DTI changes was observed; in the cerebral peduncles, pons, and pyramids, reduced FA was observed in the absence of increased MD; and at the higher level of the posterior limb of the internal capsule, reduced FA was observed with an increase in MD.13 Furthermore, the patients included in the current study had a longer ALS duration than those included in either of the previous investigations. This explanation is highly speculative, but may be objectively evaluated by a longitudinal DTI investigation of the progression of UMN pathology in a group of patients with ALS.
The exploratory analysis of DTI in four patients with isolated LMN clinical signs revealed a trend toward reduced FA in the posterior limb of the internal capsule compared to age-matched healthy volunteers. Figure 4 illustrates that the FA values from these patients were more similar to those obtained from patients with UMN clinical signs than from those of healthy volunteers. Therefore, patients with isolated LMN clinical signs may also have pathologic changes in the UMN. This hypothesis is consistent with the findings of autopsy investigations that identified intracranial CST degeneration in patients with isolated LMN clinical signs during life.35
Our findings suggest that diffusion anisotropy measures may be more sensitive to the detection of UMN involvement in patients with prominent LMN signs than neurologic assessment. The sensitivity of neurologic assessment is limited in such patients because pathologically brisk reflexes (UMN sign) are difficult to detect in muscles that are already weak, atrophic, and fasciculating (LMN signs).35 Diffusion anisotropy measures are free from this confound because changes in the UMN are evaluated independently from changes in the LMN. Early detection of UMN involvement has therapeutic implications for patients with motor neuron degeneration because, according to the current recommendations of the National Institute for Clinical Excellence (NICE), only patients with identifiable UMN clinical signs should be prescribed riluzole therapy (NICE, 2003). Riluzole is a neuroprotective glutamatergic inhibitor, which has been proven to modestly extend survival in ALS.36 The identification of UMN involvement in patients with isolated LMN clinical signs strongly suggests that the progressive muscular atrophy subgroup of patients may also derive therapeutic benefit from riluzole. Therefore, it is important to confirm the findings of this preliminary DTI investigation in a larger sample of patients showing isolated LMN signs clinically, with the aim of proposing a change in the current prescribing guidelines.
Conventional MRI revealed two abnormalities that distinguished patients with UMN signs from healthy volunteers. A ribbon of signal hypointensity was identified in the motor cortex on T2-weighted MR images in 20% of patients with UMN signs and in none of the healthy volunteers. This probably reflects elevated iron deposition, because T2-weighted relaxation time is known to shorten in approximate proportion to tissue iron content37 and ferric iron-laden astrocytes and macrophages have been identified in the motor cortex of patients with ALS.2 Previous studies have found that T2-weighted signal loss in the motor cortex has 100% specificity for, and greater than 20% sensitivity to, the UMN pathology of patients with ALS,4,38⇓ but in contrast, other studies also identify this MRI abnormality in up to 38% of healthy volunteers.3 Such inconsistency between studies may be explained by the natural accumulation of iron in the motor cortex with advancing age,39 a confounding factor that limits the reliability of this MRI abnormality as a marker for the UMN pathology of ALS.
Abnormal MRI signal hyperintensity was identified in the corona radiata (at the position of the CST) on proton density-weighted images in 16% of patients with UMN signs and in none of the healthy volunteers. This confirms, as previously reported, that CST abnormalities (including those in the posterior limb of the internal capsule) on proton density-weighted images are specific for, but not sensitive to, the UMN alteration of patients with ALS, compared to healthy volunteers.40 Also in accordance with previous observations, it was further identified that corona radiata hyperintensity was more related to the rate of ALS progression than to the absolute degree of symptom severity.4 Therefore, this MRI abnormality may reflect the current level of active demyelination and gliosis, rather than the absolute degree of CST axonal degeneration.
To evaluate whether conventional MRI or HARD is more sensitive to the presence of UMN pathology, it was necessary to convert the FA data into categorical format. This was achieved by selecting a FA threshold value that was 1 SD above the mean FA in the posterior limb of the internal capsule in patients with UMN signs. This value resulted in 95% sensitivity and 71% specificity for the identification of patients with ALS (including the progressive muscular atrophy subgroup with isolated LMN clinical signs), which is far more sensitive than either of the conventional MRI abnormalities discussed above. The lack of 100% specificity rules out the use of diffusion anisotropy as a diagnostic marker for ALS, but low FA values in the posterior limb of the internal capsule may be a valuable addition to the process of reaching diagnostic certainty.
Part of the attraction of DTI is that the anisotropy indices are rotationally invariant, that is, they are insensitive to the orientation of: the subject in the scanner, the diffusion gradients, and the laboratory coordinate system. As such, the quantitative anisotropy values obtained from different patients, at different times, and from different MRI systems should be directly comparable provided the same acquisition scheme is always used.9 Therefore, diffusion anisotropy measures are suited to monitoring the progression of UMN involvement over time, which is helpful in evaluating the efficacy of novel pharmaceutical compounds.
- Received March 4, 2004.
- Accepted August 12, 2004.
References
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