Subcortical Hypoperfusion Associated With Asymptomatic White Matter Lesions on Magnetic Resonance Imaging
Background and Purpose We examined whether hemodynamic and metabolic abnormalities in the cerebral white matter, basal ganglia, and thalamus are associated with asymptomatic white matter lesions (WML) depicted on MR images.
Methods A positron emission tomographic study with H215O, C15O, and 15O2 was performed in eight normal control subjects without any WML (mean±1 SD age, 68.5±10.2 years) and in 15 asymptomatic subjects with WML (71.3±8.5 years) to measure regional cerebral blood flow (CBF), cerebral blood volume, oxygen extraction fraction (OEF), and oxygen metabolic rate.
Results In the cerebral white matter in the asymptomatic subjects with WML, significantly lower CBF (20.3±3.9 mL/100 mL per minute; P<.05) and significantly higher OEF (0.43±0.08; P<.05) were found compared with those for control subjects (23.5±2.6 mL/100 mL per minute and 0.37±0.06, respectively). The severity of WML was not related to the magnitude of hypoperfusion. In the basal ganglia, significantly lower CBF (44.9±6.9 mL/100 mL per minute; P<.01) and significantly higher OEF (0.54±0.08; P<.01) were found in the WML group than in control subjects (70.1±12.0 mL/100 mL/min and 0.39±0.03, respectively). In the thalamus, there was no significant difference in CBF and OEF between the control and WML groups.
Conclusions Hypoperfusion of the cerebral white matter and basal ganglia in asymptomatic WML subjects may be induced by the arteriosclerosis of long penetrating medullary arteries and lenticulostriate arteries but may not be directly related to the production of WML. The role of hypoperfusion in the production of WML and acceleration of its development remains to be elucidated.
White matter hyperintense lesions on MR images of long repetition time are frequently found in neurologically asymptomatic elderly people. The lesions are related especially to age, silent infarcts, and cerebrovascular risk factors.1 2 3 Earlier studies suggested that the reduction of cortical blood flow and cerebrovascular dilatory capacity was associated with asymptomatic WML.4 5 6 However, cerebral circulation and metabolism in the subcortical brain structures have not yet been extensively studied. In this study we evaluated CBF, CBV, OEF, and CMRO2 in asymptomatic subjects with WML to elucidate whether hemodynamic and metabolic failure exist in the cerebral white matter, basal ganglia, and thalamus.
Subjects and Methods
Selection of Subjects
A total of 23 subjects were recruited for the present study from a population participating in a health screening of the brain. These subjects were all neurologically and mentally normal and without history of transient ischemic attack, head trauma, meningitis, encephalopathy, or epileptic seizures. On the basis of the laboratory studies, hematologic disease, renal disease, and liver disease were excluded. All the subjects showed normal sinus rhythm at the electrocardiographic examination. In 10 subjects, the risk factors for cerebrovascular disease (hypertension, diabetes mellitus, and a history of smoking) were found as described below. All the subjects gave written informed consent, and the study was approved by the Positron Emission Tomography Clinical Research Committee of the Institution.
Evaluation of MR Images
MR imaging was performed with the use of a 0.5-T whole-body scanner (Magnex; Shimadzu Co). T1-weighted and T2-weighted transaxial images were obtained with the use of a gradient-echo pulse sequence with TR of 300 ms and TE of 9 ms and a spin-echo pulse sequence with TR of 3000 ms and TE of 90 ms. Seventeen transaxial images parallel to the bicommissural line were obtained with 5-mm center-to-center spacing. The three-dimensional MR angiographic data were obtained by a time-of-flight technique with gradient-echo imaging. The technical parameters were as follows: TR, 40 ms; TE, 8 ms; flip angle, 25°; single excitation; matrix size, 256×180; field of view, 25 cm; and slab, 64 mm. The effective slice thickness was 1 mm.
MR images were reviewed independently by two neuroradiologists (E.S. and J.H.). In each subject, the location, appearance, number, and size of hyperintense lesions on each T2-weighted MR image were evaluated. Eight of the 23 subjects (6 men and 2 women) showed neither WML nor basal ganglia lesions on T2-weighted MR images. They were defined as a control group. Their ages ranged from 49 to 82 years (mean±1 SD, 68.5±10.2 years). These eight subjects were neither hypertensive nor diabetic. Two male subjects had a history of cigarette smoking for more than 10 years.
In the other 15 subjects (11 men and 4 women), punctate or patchy WML were found in the subcortical and/or deep supratentorial white matter with various other lesions. These subjects were defined as the WML group. The severity of punctate or patchy WML was graded as follows: mild, focal WML limited to one region of the brain; moderate, multiple WML extending beyond one region; and severe, confluent WML forming multiple patches. Their ages ranged from 50 to 82 years (mean±1 SD, 71.3±8.5 years). Of these 15 subjects, two were hypertensive under medication. Two subjects were diagnosed as having diabetes mellitus and were treated by diet. Two subjects had both hypertension medicated orally and diabetes treated by diet. Five subjects were cigarette smokers with more than a 10-year history. Patient profiles are summarized in Table 1⇓.
PET images were acquired with a whole-body four-ring, seven-slice positron tomograph (Headtome IV, Shimadzu Co). The CBF, CMRO2, and CBV were measured by administering H215O,7 and by delivering inhaled 15O28 and C15O,9 respectively. All the PET images were obtained parallel to the bicommissural line. The detailed procedures for setting the scan slice and the quantification of physiological parameters were previously described elsewhere.10
The arterial partial pressures of O2 and CO2, hematocrit, and pH were measured in a blood gas tension analyzer (IL-1303, Instrumental Laboratory). The arterial hemoglobin concentration was measured with a hemoglobin analyzer (MLK-1100, NIHON KODEN Ltd). There was no significant difference between the mean values of these physiological parameters in the control subjects and those in the subjects with WML. Systemic arterial blood pressure and heart rate were monitored with a 2300 Finapress blood pressure monitor (Omeda) during the study.
The functional data were transferred to a conventional Unix work station system (TITAN 750, Kubota Computer). A fully automatic multimodality image registration algorithm11 was applied to the MR and PET images in each subject. The circular regions of interest, each with a 16-mm diameter, were manually placed in the caudate nucleus, lentiform nucleus, thalamus, corona radiata, and centrum semiovale on the MR images. The PET measures were read by the use of predetermined regions of interest on MR images superimposed on the PET images. The measures for basal ganglia were defined as an average of the values for the caudate nucleus and lentiform nucleus. The values for cerebral white matter were calculated by averaging the values for corona radiata and centrum semiovale. In each subject, the mean measures were obtained by averaging the values for both hemispheres. The Wilcoxon-Mann-Whitney test for small sample size was used for the statistical analysis.
Table 2⇓ summarizes the mean values of CBF, CBV, OEF, and CMRO2 in the cerebral white matter, basal ganglia, and thalamus for the control subjects and asymptomatic subjects with WML. In the cerebral white matter in the latter group, the mean CBF was significantly decreased (P<.05), and the mean OEF was significantly increased (P<.05) compared with the control value. The mean CMRO2 was not significantly different from the control value. The cerebral white matter CBF for the subgroups of mild (n=6), moderate (n=4), and severe WML (n=5) was 18.9±3.0, 21.8±1.4, and 21.0±5.4 mL/100 mL per minute, respectively. There was no significant difference among the subgroups.
In the basal ganglia, the CBF for the asymptomatic WML group was significantly decreased compared with that in the control subjects (P<.01), the OEF was significantly increased (P<.01), and the CMRO2 value was not significantly different. In the thalamus, no significant differences from the control values in these measures were found in the asymptomatic WML group.
The Figure⇓ demonstrates the T2-weighted images (left), CBF (center), and CMRO2 (right) images at the level of the basal ganglia for a control subject (top row) and an asymptomatic subject with WML (bottom row).
The present study revealed that asymptomatic WML was associated with hypoperfusion in the cerebral white matter and basal ganglia but not in the thalamus. The oxygen metabolism was not significantly affected in these structures.
We speculated on several mechanisms responsible for the hypoperfusion in the cerebral white matter. We observed that the CMRO2 in the cerebral white matter was not significantly altered in the WML group. Therefore, this hypoperfusion may not be induced by the metabolic inactivation of the white matter. In the WML subjects, we did not find steno-occlusive arterial disease of the internal carotid artery and main trunks of cerebral arteries on MR angiography. This suggested that the hypoperfusion was not due to steno-occlusive disease of the carotid arteries and major cerebral arteries.
The cerebral white matter is supplied by long penetrating medullary arteries and partly by lenticulostriate arteries. Furuta et al12 found that the sclerotic changes of the medullary artery advanced with age and correlated well with the presence of ischemic white matter changes in 110 autopsied brains from nonneuropsychiatric subjects. The histopathological studies in asymptomatic subjects with WML revealed that punctate or patchy MR lesions were often associated with a variety of arteriosclerotic changes in arterioles and ischemic damage of the brain parenchyma.13 14 15 16 17 These pathological studies indicated that the cerebral white matter hypoperfusion associated with asymptomatic WML would probably be due to subclinical sclerosis of medullary arteries and arterioles.
It is noteworthy that the basal ganglia CBF was reduced in the asymptomatic WML group. We tentatively subdivided the asymptomatic WML subjects into two subgroups with and without basal ganglia lesions depicted on MR images. There was no significant difference in the mean basal ganglia CBF, OEF, and CMRO2 between the two subgroups. Our results suggested that arteriosclerosis of perforating arteries may coexist with that of medullary arteries and may induce hypoperfusion in its territory regardless of the presence of basal ganglia lesions on MR imaging.
The blood flow in the thalamus was not significantly altered in the asymptomatic subjects with WML. This structure is supplied by thalamoperforating arteries that primarily belong to the vertebrobasilar system. Since the cerebral white matter is supplied by medullary arteries and lenticulostriate arteries, the presence of the WML in the cerebral white matter may be independent of thalamic blood flow. Collateral channels of lenticulostriate arteries are rare,18 but thalamoperforating arteries have rich collaterals to each other.19 The different collateral potential may contribute to the CBF difference between the basal ganglia and thalamus in the subjects with WML.
It is still unclear whether hypoperfusion of the cerebral white matter is a primary cause of the production of WML. When decreased CBF is directly related to WML, the more severe hypoperfusion may result in the greater production of WML. We preliminarily analyzed the relationship between the magnitude of hypoperfusion and the severity of WML. However, we failed to find a significant difference in the cerebral white matter CBF between the subgroups with mild and severe WML. In addition, there was no asymmetrical CBF even though the WML was predominantly located in the unilateral hemisphere. These observations suggested that the hypoperfusion of cerebral white matter may not be directly related to the production of WML. The role of hypoperfusion in the production of WML and acceleration of its development remains to be elucidated.
Selected Abbreviations and Acronyms
|CBF||=||cerebral blood flow|
|CBV||=||cerebral blood volume|
|CMRO2||=||oxygen metabolic rate|
|OEF||=||oxygen extraction fraction|
|PET||=||positron emission tomography|
|WML||=||white matter hyperintense lesions|
This study was supported by grants-in-aid for asymptomatic cerebrovascular disease from 1994 to 1996 and a grant-in-aid for longevity science in 1997 from the Ministry of Health and Welfare, Japan. We are grateful to Dr Y. Ono of the Department of Internal Medicine, Dr. N. Yasui and A. Suzuki of the Department of Neurosurgery, Drs Y. Hirata and K. Nagata of the Department of Neurology, Dr Y. Yoshida of the Department of Pathology, Dr I. Kanno of the Department of Radiology and Nuclear Medicine, and Dr K. Uemura, Director, Akita Research Institute of Brain and Blood Vessels. Dr Y. Miura of the Department of Radiology and Nuclear Medicine is acknowledged for statistical analysis of the data. Dr B. Ardekani of Akita Laboratory, Japan Science and Technology Corporation is acknowledged for technical assistance in image registration.
Reprint request to Jun Hatazawa, MD, PhD, Department of Radiology and Nuclear Medicine, Akita Research Institute of Brain and Blood Vessels, 6-10 Senshu-Kubota Machi, Akita 010, Japan.
- Received February 24, 1997.
- Revision received July 2, 1997.
- Accepted July 2, 1997.
- Copyright © 1997 by American Heart Association
Awad IA, Spetzler RF, Hodak JA, Awad CA, Carely R. Incidental subcortical lesions identified on magnetic resonance imaging in the elderly, I: correlation with age and cerebrovascular risk factors. Stroke. 1986;17:1084-1089.
Lechner H, Schmidt R, Bertha G, Justich E, Offenbecher H, Schneider G. Nuclear magnetic resonance imaging white matter lesions and risk factors for stroke in normal individuals. Stroke. 1988;19:263-265.
Ylikoski A, Erkinjuntti T, Raininko R, Sarna S, Sulkava R, Tilvis R. White matter hyperintensities on MRI in the neurologically nondiseased elderly: analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke. 1995;26:1171-1177.
Meguro K, Hatazawa J, Yamaguchi T, Itoh M, Matsuzawa T, Ono S, Miyazawa H, Hishinuma T, Yanai K, Sekita Y, Yamada K. Cerebral circulation and oxygen metabolism associated with subcortical periventricular hyperintensity as shown by magnetic resonance imaging. Ann Neurol. 1990;28:378-383.
Kobayashi S, Okada K, Yamashita K. Incidence of silent lacunar lesion in normal adults and its relation to cerebral blood flow and risk factors. Stroke. 1991;22:1379-1383.
Isaka Y, Okamoto M, Ashida K, Imaizumi M. Decreased cerebrovascular dilatory capacity in subjects with asymptomatic periventricular hyperintensities. Stroke. 1994;25:375-381.
Herscovitch P, Markham J, Raichle ME. Brain blood flow measured with intravenous H215O, I: theory and error analysis. J Nucl Med. 1983;24:782-789.
Raichle ME, Martin WRW, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with intravenous H215O, II: implementation and validation. J Nucl Med. 1983;24:790-798.
Mintun MA, Raichle ME, Martin WRW, Herscovitch P. Brain oxygen utilization measured with O-15 radiotracers and positron emission tomography. J Nucl Med. 1984;25:177-187.
Hatazawa J, Fujita H, Kanno I, Satoh T, Iida H, Miura S, Murakami M, Okudera T, Inugami A, Ogawa T, Shimosegawa E, Kyo Noguchi, Shohji Y, Uemura K. Regional cerebral blood flow, blood volume, oxygen extraction fraction, and oxygen utilization rate in normal volunteers measured by the autoradiographic technique and the single breath inhalation method. Ann Nucl Med. 1995;9:15-21.
Furuta A, Ishii N, Nishihara Y, Horie A. Medullary arteries in aging and dementia. Stroke. 1991;22:442-446.
Awad IA, Johnson P, Spetzler RF, Hodak JA. Incidental subcortical lesions identified on magnetic resonance imaging in the elderly, II: postmortem pathological correlations. Stroke. 1986;17:1090-1097.
Braffman BH, Zimmerman RA, Trojanowski JQ, Gonatas NK, Hickey WF, Schaepfer WW. Brain MR: pathologic correlation with gross and histology, II: hyperintense white-matter foci in the elderly. AJNR Am J Neuroradiol. 1988;9:629-636.
Fazekas F, Kleinert R, Offenbacher H, Payer F, Schmidt R, Kleinert G, Radner H, Lechner H. The morphologic correlate of incidental punctate white matter hyperintensities on MR images. AJNR Am J Neuroradiol.. 1990;12:915-921.