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Published online before print October 1, 2001, 10.1148/radiol.2212001648
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(Radiology. 2001;221:327-331.)
© RSNA, 2001

Neuroradiology

Quantifying Radiation Therapy–induced Brain Injury with Whole-Brain Proton MR Spectroscopy: Initial Observations1

Benjamin Movsas, MD, Belinda S. Y. Li, PhD, James S. Babb, PhD, Barbara L. Fowble, MD, Nicos Nicolaou, MD and Oded Gonen, PhD

1 From the Departments of Radiation Oncology (B.M., B.S.Y.L., B.L.F., N.N., O.G.) and Biostatistics (J.S.B.), Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111. From the 2000 RSNA scientific assembly. Received October 11, 2000; revision requested November 26; revision received February 28, 2001; accepted April 9. Supported by National Institutes of Health grants RO1 NS33385, NS37739, and NS29029. Address correspondence to B.M. (e-mail: b_movsas@fccc.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To quantify the extent of neuronal cell loss imparted to the brain by means of radiation therapy through the decline of the amino acid derivative N-acetylaspartate (NAA) by using proton (hydrogen 1) magnetic resonance (MR) spectroscopy.

MATERIALS AND METHODS: Proton MR spectroscopy in a clinical MR imager was used to ascertain the amount of whole-brain NAA before and immediately after whole-brain radiation therapy 3–4 weeks later. Eight patients (four women, four men; median age, 55 years; age range, 39–70 years) were studied. All subjects had lung cancer (non–small cell lung cancer [n = 5], small-cell lung cancer [n = 3]) and received either palliative or prophylactic whole-brain radiation therapy. Six of them also underwent a Mini-Mental Status Examination (MMSE) for correlation with the whole-brain NAA. Two-tailed Student t tests were used to evaluate the data.

RESULTS: A significant (P = .042) average decline in whole-brain NAA of -0.91 mmol per person was observed in the cohort. No corresponding changes occurred in MMSE scores. There was no significant difference in whole-brain NAA decline between prophylactic and therapeutic whole-brain radiation therapy.

CONCLUSION: Since whole-brain NAA loss was detected even when MMSE scores were unchanged, the former seems to be a more sensitive measure of radiation therapy injury than is the latter.

Index terms: Brain, injuries, 13.47 • Brain, MR, 13.12145 • Magnetic resonance (MR), spectroscopy, 13.12145 • Radiations, injurious effects, complications of therapeutic radiology, 13.47


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Radiation therapy, either alone or in combination with chemotherapy and/or surgery, is commonly used in the treatment of primary and/or metastatic brain tumors. Even in the absence of brain disease, prophylactic cranial irradiation is routinely offered to certain patients with small-cell lung cancer (1). Although neurotoxicity is always a concern in brain radiation therapy, there is currently no direct method to quantify its damage to the central nervous system. Such knowledge is critical for risk-to-benefit assessment and dose determination. Presently, this assessment can be achieved only indirectly by using neurocognitive tests, the outcomes of which are often confounded by other factors, such as language barriers and the patient’s state of mind and/or level of fatigue. Clearly, an objective, preferably instrumental, noninvasive and, most importantly, sensitive method to quantify radiation neurotoxicity is essential.

A probe to assess brain damage is the amino acid derivative N-acetylaspartate (NAA), present almost exclusively in neuronal cells (2,3). Although its precise role remains unclear, NAA decreases have been reported in multiple sclerosis, strokes, primary or metastatic brain tumors, trauma, Alzheimer disease, and acquired immunodeficiency syndrome (4–13). Its methyl group yields the most prominent peak in brain proton (hydrogen 1) magnetic resonance (MR) spectrum detectable noninvasively with common MR imagers (14). By using whole-brain NAA acquisition, which is not susceptible to the partial coverage or serial misalignment problems that beset localized proton MR spectroscopy, results of two recent studies (15,16) have shown that global NAA level variations in healthy subjects 18–55 years of age are small (<5%; P < .01). Thus, the purpose of our study was to quantify the extent of neuronal cell loss imparted to the brain by means of radiation therapy through the decline of NAA by using proton MR spectroscopy.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Human Subjects
Eligible subjects for this study were patients undergoing any whole-brain radiation therapy, including prophylactic cranial irradiation, aimed at either primary or metastatic brain lesions. Candidates had to be older than 18 years, with a Karnofsky Performance Status score of 50 or greater, life expectancy of 2 months or more, and no contraindication for MR imaging (eg, cardiac pacemaker, metal implants, claustrophobia). All participants signed a consent form approved by the institutional review board. No patient was undergoing chemotherapy or surgery.

Eight patients (four women, four men; median age, 55 years; age range, 39–70 years) were recruited. All subjects had lung cancer (non–small cell lung cancer [n = 5], small-cell lung cancer [n = 3]) and received whole-brain radiation therapy either as palliative or prophylactic treatment. The doses and number of fractions were recorded. The patients with small-cell lung cancer received prophylactic cranial irradiation at 3,000 cGy to the whole brain, by using opposed lateral fields in 15 fractions at 200 cGy each. The patients with non–small cell lung cancer received palliative whole-brain radiation therapy for brain metastases, and their doses ranged from 3,500 cGy in 14 fractions to 3,750 cGy in 15 fractions, by using opposed lateral fields. Six of these patients also agreed to undergo the Mini-Mental Status Examination (MMSE) for correlation with the whole-brain NAA. The Folstein MMSE is a validated tool to evaluate a patient’s cognitive state, including orientation, concentration, and memory. Of a maximum score of 30 points, a score lower than 24 is indicative of dementia (17).

Proton MR Spectroscopic Sequence, Instrumentation, and NAA Quantification
Whole-brain NAA was the proton MR spectroscopic tool of choice for the assessment of whole-brain radiation therapy injury for two main reasons: First, it is insensitive to serial misregistration of the common, small (<100 cm3), localized spectroscopic volumes of interest. Second, since we examined the absolute amount of NAA of the entire contents of the skull, this method is immune to edema, which can mislead quantification when local swelling causes transient reduction in regional metabolite concentrations to be misinterpreted as temporary or permanent losses (15). This method exploits the fivefold difference in the longitudinal T1 relaxation times between the skull’s lipids and NAA signals. It alternates between (a) fully thermal (NAA and lipids) acquisitions and (b) NAA-nulled (lipids only) acquisitions after a nonselective inversion-recovery sequence. Subtraction of signals from these two sets of acquisitions leads to almost total destructive interference of the intense lipids signals, leaving behind only the sought NAA.

A simple proton MR spectroscopic sequence to acquire the whole-brain NAA signal was demonstrated recently, both theoretically and in vivo in a cohort of five healthy women 40–47 years old (15). Statistical error analysis in that cohort showed that the intrapersonal whole-brain NAA variations in healthy persons during a short period (weeks) are small (<5%).

The present study was conducted by using the same sequence in a 1.5-T full-body clinical imager with its standard circularly polarized head coil (Magnetom 63SP; Siemens, Erlangen, Germany). After the patients were positioned in the magnet, an automatic field-shim procedure yielded a consistent 9.0 Hz ± 1.0 (SD) full width at half maximum waterline from the whole head (18). This was followed by the whole-brain NAA acquisition, with 2,048 complex points at 0.5 msec per point. At a repetition time of 10 seconds to ensure thermal equilibrium, and with 16 signals acquired and averaged, the proton MR spectroscopic cycle took 160 seconds or approximately 2.5 minutes. To improve the precision, five such back-to-back cycles were used. Overall, the procedure took approximately 20 minutes.

A baseline whole-brain NAA study was performed in all patients before radiation therapy. The average time between the baseline whole-brain NAA measurements obtained before whole-brain radiation therapy and those obtained after whole-brain radiation therapy was 29 days (range, 20–46 days).

After the subjects underwent proton MR spectroscopy, an absolute quantification reference, a 3-L sphere containing 130 mmol/L of sodium chloride and 5 mmol/L of NAA in water, was placed at approximately the same position as the head. It was shimmed to a similar waterline width and subjected to the same protocol. Subject and phantom NAA spectral peak areas, SV and SP, respectively, were integrated. The whole-brain NAA was obtained in a manner similar to that used by Soher et al (19): Whole-brain NAA = ([SV · VV180°]/[SP · VV180°]) · 15 mmol, where VV180° and VV180° are the voltages into 50{Omega} of radio-frequency power required for nonselective 1-msec 180° inversion pulses, which gauge the receiver sensitivity. Since the acquisition is neither T1 nor T2 weighted and both the phantom and head samples had similar radio-frequency and static magnetic field distributions, no corrections for any of these parameters were necessary (15).

Statistics
Paired-sample Student t tests were used to determine whether there was a change in MMSE or in the total or calculated average daily whole-brain NAA after whole-brain radiation therapy. Patients receiving prophylactic cranial irradiation and therapeutic radiation therapy were compared in terms of total and average changes in whole-brain NAA via independent-sample unequal variance t tests. All tests were two-tailed and conducted at the 5% significance level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Whole-Brain NAA
The baseline whole-brain NAA (in millimoles) before radiation therapy and its percentage of change at the time of the measurement (in days) after radiation therapy are summarized in the Table and shown graphically in the Figure (part A). The corresponding MMSE scores are also shown (maximum achievable = 30). Average whole-brain NAA before radiation therapy was 9.40 mmol ± 3.02 and reduced to 8.49 mmol ± 3.71 after radiation therapy. The average whole-brain NAA decline, -0.91 mmol per person, was statistically significant (P = .042).


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  		Treatment Details for the Study Participants and Their Whole-Brain NAA and MMSE Results before and Immediately after Radiation Therapy

 


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  		Figure 1. A, Connectivity plot tracks the changes in the amount of NAA per individual patient over the temporal spacing between the whole-brain NAA measurement points at baseline ({circ}) and after radiation therapy ({bullet}). B, Box plots show first, second (median), and third quartiles of the data, with whiskers showing the minimum and maximum data points. Changes in whole-brain NAA in millimoles per person from before to after radiation therapy are summarized in the eight cancer patients (WBRT patients) and during a similar period in five healthy subjects studied previously (15) and shown here for comparison. Note that, for control subjects, the median change in whole-brain NAA is 0.0 mmol during 3-4 weeks, represented by the upper dashed horizontal line. For patients receiving approximately 3,500-cGy whole-brain radiation therapy during a similarly short time, the median change is statistically significant: -0.88 mmol, as represented by the lower dashed horizontal line.

 
Since the elapsed time between measurements before and after radiation therapy varied from 3 to 4 weeks among patients, the daily change in whole-brain NAA was also examined. Its average decline (Figure, A) was also statistically significant: -0.033 mmol per day per person (P = .05).

For comparison, a box plot (Figure, B) shows the change in millimoles in whole-brain NAA in the patients versus that in the five 40–47-year-old healthy women (previously studied and reported on [15]) during a similar time span. While there were no observable changes in the whole-brain NAA (median value, ~0) in the control subjects, the median value of the patients’ whole-brain NAA changes was -0.88 mmol.

The decline in whole-brain NAA from the baseline measurement to that obtained after radiation therapy was -1.21 mmol per person ± 0.56 for patients receiving prophylactic cranial irradiation and -0.72 mmol per person ± 1.26 for those receiving therapeutic radiation therapy. This corresponds to an average daily whole-brain NAA decline of -0.041 mmol per person ± 0.026 for patients receiving prophylactic cranial irradiation and -0.033 mmol per person ± 0.055 for those receiving therapeutic radiation therapy, which are not significantly different (P > .24).

MMSE Scores
Of the six patients with MMSE data, only two exhibited a change from the baseline to after radiation therapy (Table). Specifically, expressed as a percentage of the baseline score before radiation therapy, the 39-year-old woman exhibited a 10% decline in MMSE, whereas the 55-year-old woman exhibited a 4% increase. Overall, with an average change of less than 1% per person, there was no demonstrable change in MMSE scores in this group (t = -0.6, P = .58). On the basis of the SD of 1.37 observed for the change in MMSE score, the study had 95% power at the two-sided 5% significance level to depict a change in MMSE of 2.6 units, which corresponded to an average change of approximately 9% per person relative to the median MMSE score of 29 before radiation therapy. Consequently, we are 95% confident that the MMSE score can be expected to change by an average of less than 9% after radiation therapy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
Despite the relatively small group size (n = 8), the changes in whole-brain NAA demonstrate a statistically significant decline of -0.91 mmol (~10%) per person, with an average rate of -0.033 mmol per day per person. By contrast, the whole-brain NAA fluctuation in a follow-up of healthy subjects was previously shown to be only ±3% during a similar period (Figure, B) (15,16). Note that the two groups of subjects in the Figure (part B), control subjects and patients treated with whole-brain radiation therapy, are completely distinct (ie, whole-brain NAA appears to be sensitive to quantify neuronal cell losses secondary to radiation therapy). Compared with the significant changes in whole-brain NAA, no corresponding demonstrable changes occurred in the MMSE scores (average change, <1% per patient). The fact that whole-brain NAA decline was detectable even when MMSE scores were unchanged suggests that the former technique is more sensitive to radiation therapy losses than the latter is. However, the clinical implications of either test are not yet known.

Partial NAA concentration recoveries have been reported, both after whole-brain radiation therapy (20) and in acute multiple sclerosis plaques (21), by using localized proton MR spectroscopy. However, it is possible that regional volume changes (eg, from edema) caused the NAA concentration to appear to decline and then to recover, which reflects volume rather than absolute changes. Similarly, the use of metabolite ratios instead of absolute values (20) could confound the interpretation as to which metabolite actually contributed to the observed ratio change.

In this study, we measured the total amount of NAA in the whole brain, which is immune to volume changes. This also allowed us to make the proton MR spectroscopic protocol as efficient as possible because there was no need for an additional 15 minutes of high-spatial-resolution MR imaging to obtain the brain volumes nor was time spent performing MR spectroscopic localization. However, two trade-offs were made: First, since the whole-brain NAA was not normalized for brain volume, the subjects were not comparable with each other, but were only their own controls. Second, since the entire head yielded a single whole-brain NAA value, possible regional differences in whole-brain radiation therapy damage were undetectable.

Radiation therapy may be one cause among multifactorial causes for potential injury to the central nervous system. These include infections, metabolic defects, smoking, psychological stress, chemotherapy, surgery, tumor progression and/or metastases, subclinical disease, and/or paraneoplastic syndromes (22–28). The operative hypothesis in this study was that the effect of radiation therapy could be isolated from the rest of these risk factors by the close temporal proximity, 3–4 weeks apart, of the measurements obtained before and after whole-brain radiation therapy. None of the patients developed any signs or symptoms of disease progression while receiving whole-brain radiation therapy during this short period. Since none of the participating patients was undergoing chemotherapy or surgery, all other injury mechanisms were assumed to be too slow to have a measurable deleterious effect during this time.

MMSE is a relatively coarse measurement with inherent limitations. Although the Folstein MMSE has been validated to measure cognitive decline in the context of dementia, its applicability in patients receiving radiation therapy has not been established (17,29–33). Since many of the neurocognitive effects previously studied relate to whole-brain radiation therapy in children with acute lymphoblastic leukemia, some investigators have suggested that neurocognitive sequelae of brain radiation therapy may be underestimated in long-term survivors (34,35).

Choucair et al (36), in a prospective study of 126 patients who received radiation therapy for malignant astrocytomas, found a substantial correlation between lower Karnofsky Performance Status scores and lower average MMSE scores. However, in that study, the change in MMSE was not analyzed over time. In contrast, Taylor et al (37), in a prospective study of 701 patients with high-grade glioma treated with brain radiation and chemotherapy, reported no significant increase in the percentage of patients whose MMSE score decreased during 2 years. However, these authors point out that more subtle changes in memory, personality, or intelligence could not be assessed by means of such a simple, predominantly verbally based, tool. On the other hand, more comprehensive neuropsychological testing is relatively expensive, time-consuming, and often difficult for patients receiving brain radiation therapy to endure.

The confounding issues encountered with neuropsychological test results underscore another potential advantage of whole-brain NAA: The effect of radiation therapy, in terms of neuronal cell loss, is quantified instrumentally early after the damaging event. In this study, the average change in whole-brain NAA was a significant -0.91 mmol from baseline to after radiation therapy just 3–4 weeks later, as shown in the Table and Figure (part A). Nevertheless, additional prospective trials to assess the long-term effects of radiation therapy on both regional and whole-brain NAA are clearly necessary.

The implications of this study are interesting. The controversy regarding prophylactic cranial irradiation in small-cell lung cancer is a timely example. Although results of a recent meta-analysis (1) have demonstrated a significant benefit to prophylactic cranial irradiation not only in terms of local control, but also survival, the main argument against it remains the concern of neurotoxicity. This is further complicated by data suggesting that higher doses may be more effective. Whole-brain NAA may provide an objective assessment, with relatively short follow-up, of the benefit of dose escalation versus the risk for increased neurotoxicity. The significance of such a noninvasive tool is amplified in light of recent suggestions that prophylactic cranial irradiation also be used in non–small cell lung cancer, dramatically increasing the population affected by the debate. A sensitive quantitative technique will be critical in assessing the benefit-to-risk ratio of this strategy, as well as other applications of brain radiation therapy, such as for primary brain tumors (29,38–41), prophylaxis in leukemia and lymphoma (42), and metastases (43).


   ACKNOWLEDGMENTS
 
The authors acknowledge the help of the study’s patient coordinator, Patricia Martin, RN, and the secretarial assistance of Louise Marcewicz.


   FOOTNOTES
 
Abbreviations: MMSE = Mini-Mental Status Examination, NAA = N-acetylaspartate

Author contributions: Guarantor of integrity of entire study, O.G.; study concepts, B.M., O.G.; study design, B.M., B.S.Y.L., O.G.; literature research, B.M., B.S.Y.L., O.G.; clinical studies, B.M., N.N., B.L.F., B.S.Y.L., O.G.; experimental studies, B.S.Y.L., J.S.B., O.G.; data acquisition, B.S.Y.L., B.L.F., N.N., O.G.; data analysis/interpretation, B.M., B.S.Y.L., J.S.B., O.G.; statistical analysis, J.S.B.; manuscript preparation, B.M., B.S.Y.L., O.G.; manuscript definition of intellectual content, all authors; manuscript editing, B.M., B.S.Y.L., N.N., B.L.F.; manuscript revision/review, B.M., N.N., B.L.F., O.G.; manuscript final version approval, B.M., O.G.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

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