Abstract
Objective: To study the time-related changes in cerebral metabolic rate of glucose (CMRglc) in MS patients and to correlate these with changes in MRI lesion load and disability.
Background: Measurements of MRI lesion load and neurologic disability are used widely to monitor disease progression in longitudinal studies of MS patients, but little is known about the associated changes in cerebral neural function.
Methods: The authors studied 10 patients with clinically definite MS who underwent serial measurements of CMRglc, MRI T2-weighted total lesion area (TLA), and clinical evaluation of disability (Expanded Disability Status Scale [EDSS]) over a period of approximately 2 years (three examinations). CMRglc was calculated using PET and 18-fluorodeoxyglucose (FDG).
Results: The global cortical CMRglc decreased with time (p < 0.001) and the most pronounced reductions of CMRglc were detected in frontal and parietal cortical areas. There was a statistically significant increase of disability (p < 0.01) and TLA (p < 0.05) measurements during the study, but changes in CMRglc were not correlated to changes in TLA and EDSS.
Conclusions: Global cortical cerebral metabolism in MS is decreased significantly during a 2-year observation period, suggesting a deterioration of cortical activity with disease progression. The time-related changes of cortical CMRglc are statistically stronger than changes in TLA measurements and neurologic disability, and might be a useful secondary measure of treatment efficacy.
MRI is useful in monitoring disease progression in MS patients using quantitative measurements of the total lesion area (TLA) on T2-weighted images.1 Additionally, there is a consistent relationship between TLA and cognitive dysfunction,2-4 although neurologic disability has a stronger association with other MRI measures, such as cerebral and spinal cord atrophy,5,6 and diffuse white matter magnetization transfer ratios.7 These results imply that there could be a simple relation between lesion load and neural function, although disability seems to be determined by spinal and diffuse white matter disease involvement as well.
Although conventional MRI measures structural changes, functional brain imaging has provided insight into the pathophysiologic consequences of focal and diffuse brain disorders. In MS, PET and SPECT studies have shown that regional reductions in cerebral blood flow and metabolism are associated with cognitive dysfunction,8-13 whereas the relationship between neurologic disability and regional cerebral blood flow or metabolism is controversial.9,11,13 Thus far, PET studies have been cross-sectional, presumably due to their high cost and logistics. We performed a longitudinal PET study of cerebral metabolism and compared our results with changes in MRI lesion load and neurologic disability.
Methods.
Patients.
We studied 11 patients (5 men, 6 women) with clinically definite MS14 in a remittent state of the disease, who were selected randomly from the MS clinic at the Copenhagen University Hospital, Rigshospitalet. Informed consent was obtained after written information was disseminated, according to the declaration of Helsinki II, and the study was approved by the Central Scientific Ethical Committee of Denmark. All patients were studied with their eyes closed in a darkened, quiet room and were instructed not to smoke, or to consume carbohydrates or coffee within 3 hours before the examination. Mean age was 42 years (range, 32 to 56 years) and mean disease duration was 12 years (range, 4 to 19 years). The patients underwent neurologic examination, MRI, and PET three times during a period of approximately 2 years.
Positron emission tomography.
We used a GE 4096-15 WB tomograph15 (General Electric, Milwaukee, WI) yielding 15 consecutive image slices parallel to the canthomeatal line and separated by 6.5 mm. Spatial resolution in the image plane was approximately 7 mm and the axial field of view was 97.5 mm. The head was fixed using an individually molded head holder of polystyrene foam and positioned in the PET scanner. A transmission scan was performed immediately before tracer injection for attenuation correction. A dose of approximately 200 MBq 18-fluorodeoxyglucose was administered as a slow bolus through an antecubital vein, and arterial blood samples were drawn manually from the distal part of the radial artery. Blood glucose was monitored throughout the examination. Global cerebral metabolic rate of glucose (CMRglc) was calculated by the autoradiographic single-scan method as described by Sokoloff et al.16 and revised by Huang et al.17 A 15-minute scan obtained from 45 to 60 minutes postinjection was used for calculation. We used a lumped constant of 0.8218 and kinetic rate constants determined for normal gray matter.19 The following image analysis was therefore restricted to gray matter regions, which are rarely affected by the pathophysiologic processes in MS.20 To test our data for underestimation of CMRglc in hypometabolic regions, due to the use of fixed kinetic rate constants, we calculated the kinetic rate constants in a cortical region of five patients with high as well as low CMRglc. The largest relative difference between CMRglc calculated with individual rate constants and CMRglc calculated with standard rate constants was 2.6%, and therefore was considered negligible.
Ten patients completed the study, although one subject did not participate in the intermediate examination. One patient refused the final examination and was excluded from the study.
Image analysis.
PET image analysis was performed using a computerized brain atlas (CBA).21 All images were reformatted (normalized) to a standard stereotactic space and thereby aligned to the intercommissural (anterior commissure/posterior commissure [AC/PC]) line. Regions of interest were applied guided by the anatomic information of the CBA. Global and lobar (frontal, temporal, parietal, and occipital) cortical values of CMRglc were obtained. Because all regions extended through several image slices, weighted average values were calculated.
Magnetic resonance imaging.
MRI studies were made on a Siemens Magnetom SP 4000 1.5-T scanner (slice thickness, 5 mm; double-spin echoes, 15 and 90 msec; repetition time [TR] 2,500 msec) and a Siemens H15 1.5-T (slice thickness, 4 mm; double-spin echoes, 15 and 90 msec; TR, 1,800 msec) scanner (Erlangen, Germany).
MR images were obtained in the intercommisural horizontal image plane. If the images deviated from the AC/PC line they were aligned using a three-dimensional algorithm (automated image registration software, version 2.0)22 on a voxel-by-voxel basis. The following data analysis was carried out by a radiologist using DispImage, version 4.5 (Display Image Software),23 and the TLA of the T2-weighted images were calculated. The ratio between the MRI brain volume of each patient and the mean brain volume of all patients was used to normalize the TLA to compare the MRI data with the stereotactically normalized PET data.
Two patients could not complete the MRI examinations because of claustrophobia.
Statistical analysis.
For each subject a regression line was calculated using the CMRglc as the dependent variable and time as the independent variable. The slope of the 10 individual regression lines was compared with zero, using the t-statistic. If the t-test of the individual regression lines was significantly different from zero, we concluded that there was a linear dependence between cerebral metabolism and time.24 This was also carried out for the MRI and the clinical measures, with time as the independent variable. We used Spearman’s correlation coefficient to determine the association between changes in MRI, Expanded Disability Status Scale (EDSS) score, and PET.
Results.
The results of the PET examination (CMRglc), the MR images, and the clinical examination (EDSS25) are shown in table 1. There is a uniform trend in the distribution of the EDSS, PET, and MRI data (differences between the first and the last examination are all unchanged or have the same sign; all slopes of the regression lines have the same sign), although the disability of the patients did not change over time in three patients and only increased one or more steps in three patients on the EDSS.
Data from the three examinations of each patient in the study showing measurements of physical disability (EDSS), MRI T2-weighted TLA, and CMRglc
Linear regression was performed between the different measurements and time for each subject (table 2). There was a significant dependence of changes in disability (p < 0.01) as well as in TLA (p < 0.05) with time. The dependence of CMRglc on time was highly significant in global as well as frontal and parietal cortical areas (p < 0.001). In temporal lobe measurements this relationship was weaker although still significant, whereas in occipital regions there were no statistical association with time. PET images showing the time-related changes in CMRglc in a single subject is visualized in figure 1, and the association between global cortical CMRglc and time is shown for each individual in figure 2. Changes in global CMRglc were not correlated with changes in TLA and EDSS (table 3).
Changes in disability (EDSS), MRI total lesion area, and CMRglc with time
Figure 1. PET scan (canthomeatal + 50 mm) showing reductions of cerebral glucose metabolism in an MS subject during the study. Global cortical cerebral metabolic rate of glucose (μmol/100 g/min) is listed below each PET image.
Figure 2. The relation between cerebral metabolic rate of glucose (CMRglc) and time (examination) is shown for each MS patient (n = 10). Furthermore, a mean regression line is shown (dashed line).
Correlations between changes in CMRglc and disability (EDSS), and MRI T2-weighted TLA
Discussion.
The use of PET in longitudinal studies of degenerative neurologic diseases depends on absolute physiologic measurements, although the test–retest variance is reported as high as 10%.26-28 Despite this we found a statistically significant reduction in global cortical metabolism with time in MS patients during an observation period of approximately 2 years. It has been described that cerebral metabolism is reduced by age during a time span of approximately six decades,29,30 although this effect is observed primarily in the frontal lobes whereas other cerebral lobes are not affected significantly. Taking the short time interval of our study into account, we regarded changes in CMRglc due to normal aging as negligible. The time-related reductions of CMRglc in lobar subdivisions of the cerebral cortex was strongest in the frontal and parietal regions, and weakest in the occipital regions. This discrepancy could be explained by the characteristic topographic distribution of MS plaques, which is most pronounced in periventricular and frontoparietal subcortical areas, and reduced in the occipital lobe.20 However, it should be mentioned that the data variance was increased in the occipital region, presumably caused by accidental activation of the visual cortex, because several MS patients opened their eyes during the experiment.
PET studies of CMRglc are time-consuming, unpleasant (puncture of artery and vein), and incorporate administration of radioactive isotopes, which increases the demand for experimental compliance and makes recruitment difficult in longitudinal studies. For these reasons we accepted a small data sample size, although we were aware that the statistics of the study would be weakened in this regard.
MRI offers a different and more feasible approach because it is not time-consuming or unpleasant, which allows serial studies on larger groups of patients, using changes in lesion load as an outcome parameter in clinical and prospective trials.1,31 The clinical relevance of measuring T2-weighted lesion load is to some extent still an issue of controversy, although the relationship with cognitive dysfunction2-4 as well as disability32 has been shown in large selections. A recent cross-sectional MRI/PET study8 has shown that there is a weak statistical association between T2 lesion load and cortical CMRglc in MS, and these two approaches could therefore be regarded as characterizing different aspects of the degenerative processes of the disease. In our study, the average T2-weighted lesion load increased during the observation period as expected from previous studies,1,31 although this relationship was statistically weaker than the association between CMRglc changes and time. These data indicate that cortical CMRglc is a more direct measure of neural deterioration, reflecting the irreversible axonal damage and neuronal degeneration, which have been described recently in MS.33 Theoretically, a quantitative measure of cortical neural function is preferable in the evaluation of disease progression and could encourage the use of PET in future clinical trials. We found no correlation between changes in PET and MRI (see table 3), and in this way our data support the notion that T2 lesion burden and cerebral neural function is not related in a simple matter. It should be mentioned, however, that both MRI and PET results incorporate considerable biological and measurement variability, and due to the small sample size this conclusion should be taken with reservation.
The increase of clinical disability (EDSS) during the relatively short observation period was small, as expected from studies of the natural history of MS.34 Our data showed that the time-related changes were statistically significant for the group but there was no correlation between EDSS and global cortical CMRglc. EDSS measurements are rough estimates of the clinical status summarized in an ordinal scale score, and in the interval between four and seven it is relying on gait, and therefore primarily reflects spinal cord function. Therefore, we did not expect to find a simple relationship between reductions in cortical CMRglc and clinical status, because spinal cord lesions presumably have a proportionally larger effect on the EDSS score. Although it has been shown that global CMRglc is reduced in paraplegic and tetraplegic patients,35 we did not see this effect in our data.
Cognitive dysfunction has been associated consistently with MRI lesion burden2-4 as well as decreased cerebral blood flow and CMR.8-13 Therefore, it would have been relevant to study the associated changes in cognition, although we did not have the opportunity to do so. We still believe that this is a subject for further study.
Acknowledgments
Acknowledgment
The authors acknowledge The John and Birthe Meyer Foundation for their donation of the cyclotron and the PET scanner. Thanks are extended to Dr. Steen G. Hasselbalch and Dr. Henrik B. Larsson for revision of the manuscript regarding PET and MRI methodology, respectively.
Footnotes
-
Supported in part with grants from Alfred Benzons Fond, Direktør J.P.A. Espersens Fond, Kong Christian den Tiendes Fond, and Kong Christian IX og Dronning Louises Jubilæumslegat.
- Received November 13, 1998.
- Accepted February 13, 1999.
References
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