INTRODUCTION

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Neuropsychological (1) and electrophysiological tests (2) have been used to evaluate central nervous impairment in patients with obstructive sleep apnea. Magnetic resonance spectroscopy (MRS) is a noninvasive method useful for evaluating local metabolic changes in various conditions affecting the central nervous system, including tumors (3), infarction and ischemia (4), multiple sclerosis (9), Alzheimer's disease (10), and epilepsy (11). In patients with obstructive sleep apnea, repeated apneic episodes during sleep may lead to changes in cerebral metabolism. To our knowledge, no report of results of MRS of the brain for patients with obstructive sleep apnea has been published. We performed proton MRS to examine the cerebral metabolism of patients with obstructive sleep apnea.

	METHODS

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From May 1995 to October 1996, 25 patients with obstructive sleep apnea underwent MRS in our hospital. All were diagnosed by polysomnography (12). Two patients with cerebral infarction were excluded from this study, since metabolic changes due to obstructive sleep apnea are indistinguishable from those caused by cerebral infarction. Thus, a total of 23 patients without central nervous abnormalities (19 men and 4 women, 24-75 yr; mean ± standard deviation, 48.5 ± 13.0 yr) were evaluated. These patients included five with hypertension, one with cardiac hypertrophy, one with bronchial asthma, two with nasal allergy, one who had undergone tonsillectomy, one with cervical spondylosis, and two with diabetes mellitus. We also studied 15 healthy subjects (7 men and 8 women, 15-70 yr; mean ± standard deviation, 45.7 ± 17.6 yr) as controls. To ensure that none of the subjects had central nervous abnormalities, transverse T1- and T2-weighted magnetic resonance (MR) images were obtained (slice thickness, 6-10 mm; slice gap, 0.6-1.0 mm; 11-21 slices). Patients with obstructive sleep apnea were classified into two groups based on the severity of obstructive sleep apnea as assessed by polysomnography (apnea index: AI) (13): mild obstructive sleep apnea (AI < 20) or moderate to severe obstructive sleep apnea (AI  20). The former group consisted of 11 patients (9 men and 2 women; mean age ± standard deviation, 48.3 ± 12.2 yr). The latter group consisted of 12 patients (10 men and 2 women; mean age ± standard deviation, 48.8 ± 14.1 yr).

The MR imaging and MRS were performed with a Magnetom Vision whole-body system with a standard head coil operating at 1.5 T (Siemens, Erlangen, Germany). Two-dimensional chemical shift imaging (2DCSI) (14) studies were performed using a 10 mm-slice thickness with 16 × 16 phase encoding steps over a field of view of 160 mm, resulting in a nominal voxel size of 1 cm³. A volume of interest (VOI) of 80 × 80  80 × 100 mm was selected within the field of view. 2DCSI was measured in a transverse plane at the level of the bodies of the lateral ventricles to avoid magnetic susceptibility effects due to air-tissue interfaces (e.g., skull base, paranasal sinuses) and metallic implants in teeth. We used a repetition time of 1,500 ms and an echo time of 135 ms with two signal acquisitions, resulting in a measurement time of 12 min 55 s. To achieve good static magnetic field homogeneity, we used multi-angle projection shim (15). Additionally, localized shimming of the VOI was performed for some subjects, resulting in a water-resonance line width of 5-8 Hz (full width at half height). MR studies were performed with subjects awake.

After acquisition, MRS data were processed using NUMARIS /3 software (Siemens). Free induction decay in each voxel within the VOI was obtained by two-dimensional fast Fourier transformation. In the time domain, gaussian multiplication (center, 0 ms; width, 128 ms) was used, followed by water reference processing. After fast Fourier transformation, spectral data were obtained through automatic baseline and phase correction. Peak areas for N-acetylaspartate (NAA), creatine (Cre), and choline (Cho) were calculated by fitting the spectrum to a sum of gaussian curves. The NAA /Cho, NAA /Cre, and Cho /Cre ratios were calculated from the peak areas. Results from voxels of approximately anterior half of the VOI were discarded to avoid magnetic susceptibility effects. The metabolite ratios in the voxels containing the medial aspects of the occipital and parietal lobes (7 to 10 voxels) and those containing the posterior half of the periventricular white matter (8 to 12 voxels) were averaged separately.

Lactate signal was assigned to a resonance at 1.3 ppm with a 7-Hz J-coupling. To distinguish the lactate signal from noise, the presence of lactate was defined as a peak area more than twice that of noise. Noise level was defined as the average of area calculations of 7-Hz J-coupling curve fitting at four different chemical shifts in which no metabolite peak is expected.

Analysis of variance was used to compare the metabolite ratios of the three subject groups. The Bonferroni t test was used to determine the significance of differences in metabolite ratios. The level of statistical significance was set at p < 0.05.

All patients gave written informed consent for participation in the MR study.

	RESULTS

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An MR spectrum for a 36-yr-old patient with obstructive sleep apnea is shown in Figure 1. The spectrum was selected from the cerebral cortex shown in the positioning images. Figure 2 is an MR spectrum selected from the cerebral white matter for the same patient.

View larger version (94K): [in this window] [in a new window]   Figure 1.   Magnetic resonance spectrum selected from cerebral cortex of a patient with obstructive sleep apnea. The chemical-shift axis is displayed in parts per million. NAA = N-acetylaspartate; Cre = creatine; Cho = choline.

View larger version (110K): [in this window] [in a new window]   Figure 2.   Magnetic resonance spectrum selected from cerebral white matter of a patient with obstructive sleep apnea.

The metabolite ratios for the two patient groups and the control group are shown in Table 1. A statistically significant intergroup difference was found for the NAA/Cho ratio for cerebral white matter (p < 0.005). Significant differences in the NAA/Cho ratio for the white matter were found between the patients with moderate to severe obstructive sleep apnea and the healthy subjects, as well as between the patients with moderate to severe obstructive sleep apnea and those with mild obstructive sleep apnea (p < 0.01, each case). However, no significant difference in this ratio was found between patients with mild obstructive sleep apnea and healthy subjects. No significant intergroup difference was found in the three metabolite ratios for cerebral cortex.

None of the subjects exhibited an obvious lactate signal in brain tissue.

	DISCUSSION

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There was a significant decrease in the NAA/Cho ratio in the periventricular white matter in patients with moderate to severe obstructive sleep apnea. Although NAA is believed to be solely of neuronal and axonal origin, its primary function remains uncertain (16, 17). A decrease in NAA resonance has been observed in various conditions associated with neuronal loss and/or axonal injury (3, 9). Cho resonance is believed to originate mainly from phosphorylated cholines (17). Changes in membrane metabolism and glial cell reaction may cause increased Cho resonance (7). Although the NAA/ Cho ratio indicates relative changes of the two metabolites in concentration and/or relaxation time, it is widely used as a marker for cerebral metabolism (3, 8, 10, 11). We observed modest decreases in the NAA /Cre ratio and modest increases in the Cho/Cre ratio in the white matter of patients with moderate to severe obstructive sleep apnea, but found no statistically significant difference between the subject groups for either of the two metabolite ratios. The NAA /Cho ratio is considered a sensitive, though not at all specific, marker for cerebral metabolic changes in patients with obstructive sleep apnea. Our findings indicate that changes in cerebral metabolism occur in normal-appearing brain tissue in patients with moderate to severe obstructive sleep apnea, though the metabolic change observed is smaller than those in other pathological conditions associated with abnormal appearances on MR imaging (3, 9). The decreased NAA/Cho ratio suggested the presence of cerebral damage, probably caused by repeated apneic episodes. Hypertension, a frequent concomitant of obstructive sleep apnea (18), as well as hypoxia, may have contributed to these metabolic changes. It is uncertain which was most responsible for the changes.

No significant difference was found among the groups in NAA /Cho ratios for cerebral cortex. van der Grond and colleagues (8) reported a decrease in the NAA /Cho ratio of noninfarcted brain tissue in patients with occlusion or stenosis of the internal carotid artery. In their study, metabolic changes indicated cerebral damage, probably caused by hypoperfusion. The centrum semiovale, the so called border zone, was selected for examination in their study. The border zone area is located in the most distal part of the territory of perfusion by the main cerebral arteries and is the first area to suffer ischemic damage (19). Hypercapnia causes an increase in cerebral blood volume and cerebral blood flow (20), but in the border zone area, this hemodynamic adjustment may not be sufficient to compensate for decrease in oxyhemoglobin saturation during apnea. These anatomical and hemodynamic features may be the reason why only the NAA /Cho ratio of the cerebral white matter exhibited a significant decrease in patients with moderate to severe obstructive sleep apnea.

The lactate signal is found in regions of infarct or hypoperfusion (4). Anaerobic glycolysis and/or infiltrating macrophages are considered sources of lactate (4). In our study, none of the subjects exhibited an obvious lactate signal. Patients with cerebral infarction were excluded from this study. Thus, there was no evidence of severe hypoperfusion and /or hypoxia causing anaerobic glycolysis in the subjects while awake.

In this study, a static change in cerebral metabolism was demonstrated in patients with moderate to severe obstructive sleep apnea. Follow-up studies will be needed to determine whether this metabolic change reverses with therapy. MRS studies during sleep are needed to determine whether sleep apneic episodes cause hypoxic changes (e.g., changes in lactate production and in pH) in the brain. Determination of the relative contributions of hypoxia and hypertension to the metabolic change observed in this study will be the aim of future investigations.