Cerebral Blood Flow in Nondemented Elderly Subjects With Extensive Deep White Matter Lesions on Magnetic Resonance Imaging Hiroshi Yao, MD, Takefumi Yuzuriha, MD, Kenji Fukuda, MD, Takashi Matsumoto, BS, Setsuro Ibayashi, MD, Hideyuki Uchimura, MD, and Masatoshi Fujishima, MD

Our previous study showed that deep white matter lesions (DWML) were associated with subtle cognitive decline in community-dwelling elderly people. However, even extensive (EXT)-DWML, found in 7 (4%) of 178 subjects aged 60 years or older, did not cause dementia. The purpose of the present study was to investigate brain circulation in nondemented elderly subjects with EXT-DWML. We compared cerebral blood flow in the deep white matter and frontal cortex between 5 subjects with EXT-DWML and 5 without such lesions, using a xenon-enhanced computed tomography (CT) method. Although the difference of deep white matter findings on magnetic resonance imaging (MRI) was the greatest possible (i.e., extensive v no or minimum lesions), cerebral blood flow values in anterior deep white matter and frontal cortex were 21.4 ⫾ 5.3 standard deviation (SD) mL/100 g/minute and 42.7 ⫾ 4.1, respectively, in subjects with extensive lesions, which were not significantly different from 24.3 ⫾ 4.3 and 44.0 ⫾ 7.1 in subjects without DWML. The present study suggests that EXT-DWML in nondemented elderly individuals do not necessarily indicate apparent hypoperfusion or marked cognitive decline. Key Words: Leukoaraiosis—Aging—Vascular dementia.

Widespread lesions of the deep white matter are recognized in patients with subcortical arteriosclerotic encephalopathy or Binswanger’s disease. The main clinical features of vascular dementia of the Binswanger type include a history of longstanding hypertension, gradually progressive decline in mental function, subcortical cerebral dysfunction (e.g., small stepped gait), and minor stroke. However, such extensive deep white matter lesions (EXT-

From the Center for Emotional and Behavioral Disorders, Hizen National Hospital, Saga, Japan; and the Second Department of Internal Medicine, Kyushu University, Fukuoka, Japan. Received November 7, 1999; accepted December 15, 1999. Supported in part by Grants-in-Aid for Scientific Research from Sasagawa Health Science Foundation and the Ministry of Health and Welfare in Japan. Address reprint requests to Hiroshi Yao, MD, Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0004$3.00/0 doi:10.1053/jscd.2000.7218

172

DWML) on magnetic resonance imaging (MRI) are seen in 2% to 6% of otherwise normal elderly people.1-4 Fein et al5 reported in 2 elderly female subjects that the presence of EXT-DWML for up to 7 years did not impair the cognitive, behavioral, and neurological function, suggesting that DWML do not necessarily indicate a clinically significant disease process. Our previous positron emission tomography (PET) study in patients with vascular dementia of the Binswanger type showed significantly suppressed cerebral blood flow (CBF) both in the deep white matter and cortical areas.6,7 The decreased CBF and oxygen metabolism in EXT-DWML were considered to be attributable to tissue damage, whereas abnormal cortical CBF seemed to be due to secondary hypometabolism through a remote metabolic effect (diaschisis). No such studies have been conducted in community dwelling elderly subjects without dementia. Therefore, we investigated cortical and subcortical CBF in nondemented elderly subjects with EXT-DWML and control subjects with minimum DWML.

Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 4 ( July-August), 2000: pp 172-175

CEREBRAL BLOOD FLOW IN EXTENSIVE LEUKOARAIOSIS

Subjects and Methods Between June and August 1997, we examined 178 volunteers aged 61 to 91 years, living in the rural community of Sefuri village, Saga, Japan, using MRI as previously reported.8 All subjects were living independently at home without apparent dementia. All subjects underwent a structured clinical interview, a neurological examination, tests of cognitive function including the Hasegawa Dementia Scale revised version (HDS-R),9 the MiniMental State Examination (MMSE),10 and the modified Stroop test (color interference).11 Arterial hypertension was considered present if a subject had a history of repeated high blood pressure recordings ⬎160/95 mm Hg or the subject was being treated for hypertension. The serum levels of albumin, fasting blood glucose, total cholesterol, creatinine, and hematocrit were determined in all subjects. The severity of DWML on MRI was graded according to Fazekas et al12 as follows: grade 0, absent; grade 1, punctate; grade 2, beginning confluent; and

173

grade 3, large confluent, and we found 7 (6 women and 1 man) with grade 3 or EXT-DWML. We used the xenon computed tomography (CT) CBF methods13,14 to study CBF in the 6 female subjects with EXT-DWML as shown in Fig 1A and compared these with 6 age- and sexmatched controls. We selected controls so that the factors for leukoaraiosis (age, hypertension, lacunar infarction on MRI) were similarly distributed. One control and 1 EXTDWML data were excluded because of unstable end-tidal gas recordings and motion artifacts, respectively. Duplex scanning and color Doppler flow imaging of the extracranial carotid arteries (SSA-260A, Toshiba Medical Corporation, Tokyo, Japan) showed unilateral (n ⫽ 1) or bilateral plaques with ⬍50% stenosis (n ⫽ 6); more severe arteriosclerotic changes were not observed. All MRI scans were performed on a 1.0-tesla superconducting magnet (MAGNEX ␣, Shimadzu, Kyoto, Japan) using the spin-echo technique and fluid-attenuated inversion-recovery (FLAIR) sequences. Transverse T1-weighted

Figure 1. (A) Magnetic resonance images (FLAIR images; TR/TI/TE 5800/1700/110 msec) in nondemented female elderly subjects with EXT-DWML (cases 1-5) and control subjects (CONT) (cases 6-10). Diffuse, but heterogeneous, hyperintensities are seen in the deep white matter in cases 1-5. Hypertension was present in cases 1, 3, 4, 6, 7, 8, and 10. In case 1 (79 years old), there was a history of minor stroke with 3 lacunar infarcts on MRI. Nonspecific headache or dizziness was found in cases 2 and 5. The mean of EXT-DWML areas was 27.4 ⫾ 7.1 (range, 19.7 to 36.0) cm.2 (B) ROI. Bilateral ROI (deep white matter [1 and 2] and frontal [3 and 4] regions) were averaged to produce 2 mean CBF values for each subject. (C) CBF images in nondemented female elderly subjects with EXT-DWML (cases 1-5) and CONT subjects (cases 6-10). (D) CBF in subjects with EXT-DWML and CONT. DWM, deep white matter; CGM, cortical gray matter. Bars represent SD.

H. YAO ET AL.

174

(TR/TE 380/14 msec), T2-weighted (TR/TE 3750/110 msec), and FLAIR (TR/TI/TE 5800/1700/110 msec) images were obtained with a slice thickness of 8 mm separated by a 2-mm interscan gap. DWML were specified as high signal intensity areas on T2-weighted images, but isointense with normal brain parenchyma on T1weighted images. Brain infarcts were defined as lesions with abnormal signal in a vascular distribution and no mass effects and were defined as low signal intensity areas on T1-weighted images and high signal intensity areas on T2-weighted images with sizes greater than 5 mm. For the CBF study, each subject was placed in a supine position and her head was fixed with an inflated head holder, with her eyes open and her ears unplugged, in a dimly lit CT scanning room. Xenon CT was performed with a CT-W 400 CT scanner (Hitachi, Tokyo, Japan). The subject inhaled a mixture of 30% xenon in 30% oxygen and balance room air for 3 minutes. After obtaining the baseline CT scan, 9 CT scans were recorded at 1-minute intervals during 3 minutes of xenon gas inhalation (washin) and 6 minutes of clearance (wash-out) period. In each brain, the slice 65 mm above the orbitomeatal line was analyzed. Regions of interest (ROI) were placed bilaterally on the frontal cortical and deep white matter areas (Fig 1C), where the characteristic patterns of CBF derangement were seen in patients with Binswanger type dementia.6,7 An AZ-7000 image processing system (Anzai Corp, Tokyo, Japan) was used to calculate CBF data by monitoring end-tidal xenon gas as indices of arterial xenon concentrations, and CBF was calculated according to KetySchmidt equation by an unweighted least-squares fit routine. All values were given as mean ⫾ standard deviation (S.D.). Student’s t-test was used for continuous variables and chi-square test for categorical variables.

Results The demographic variables for EXT-DWML and CONT subjects are presented in Table 1. No major differences were shown between the 2 groups. In subjects with EXT-DWML, CBF values in anterior deep white matter and frontal cortex were 21.4 ⫾ 5.3 mL/100 g/minute and 42.7 ⫾ 4.1, respectively, which were not significantly different from 24.3 ⫾ 4.3 and 44.0 ⫾ 7.1 in control subjects (Fig 1C and D). The Hounsfield units within deep white matter ROI before xenon enhancements were lower in subjects with EXT-DWML compared with that in controls (29.0 ⫾ 2.9 v 32.9 ⫾ 1.6, P ⫽ .03), but those in frontal cortex were not different between the groups (47.3 ⫾ 3.4 v 43.4 ⫾ 2.2). CBF values in posterior deep white matter and parietotemporal cortex were also not different between the 2 groups (data not shown).

Discussion The present study showed that EXT-DWML alone does not indicate the presence of remarkable cerebral hypoper-

Table 1. Demographic variables for nondemented female EXT-DWML and CONT subjects

Age (yr) HDS-R MMSE MST (sec) Hypertension (⫹) SBP (mm Hg) DBP (mm Hg) Diabetes mellitus Hyperlipidemia Brain infarction (⫹) Blood chemistry Hematocrit Albumin (g/L) Blood glucose (mmol/L) Cholesterol (mmol/L) Creatinine (µmol/L)

EXT-DWML

CONT

75 ⫾ 5 28 ⫾ 2 27 ⫾ 3 28 ⫾ 21 3 155 ⫾ 22 86 ⫾ 9 0 2 1

72 ⫾ 5 28 ⫾ 1 28 ⫾ 2 21 ⫾ 14 4 166 ⫾ 18 78 ⫾ 8 1 0 1

0.38 ⫾ 0.03 43 ⫾ 4 4.94 ⫾ 0.39 6.03 ⫾ 0.88 67.2 ⫾ 11.5

0.39 ⫾ 0.07 42 ⫾ 2 5.38 ⫾ 1.11 5.46 ⫾ 1.01 51.3 ⫾ 7.1

NOTE: Values are mean ⫾ SD (n ⫽ 5). Abbreviations: EXT-DWML, extensive deep white matter lesions; CONT, control; HDS-R, Hasegawa dementia rating scale revised; MMSE, mini-mental state examination; MST, modified stroop test; SBP, systolic blood pressure; DBP, diastolic blood pressure.

fusion in elderly nondemented subjects, which contrasts with reduced CBF both in deep white matter (approximately ⫺40%) and parietal, frontal, and temporal cortices in patients with vascular dementia of the Binswanger type as shown in our previous studies.6,7 Hatazawa et al15 reported decreased white matter CBF values determined with PET in asymptomatic subjects with DWML. The extent of CBF reduction (⫺14%) was not very different from our present results (⫺12%, statistically not significant). Interestingly, they failed to find a significant difference in white matter CBF between the subgroups with mild and severe DWML and speculated that the hypoperfusion of white matter may not be directly related to DWML. In contrast to the results by Hatazawa et al and our present results, somewhat remarkable reduction in white matter CBF (⫺24%) was shown in subjects with widespread leukoaraiosis; one possible explanation for this would be that 4 of 15 subjects were demented, and subjects with vascular risk factors were included.16 The frequency of total and EXT-DWML on MRI in the studies with relatively large samples (⬎100) of healthy elderly persons1-4 are 22% to 54% and 2% to 6%, respectively. These studies found a strong association of white matter lesions with advancing age rather than hypertension. DeCarli et al17 noted that elevated blood pressure was no longer a significant predictor of white matter hyperintensities when subjects with the largest lesion volumes were removed from the analysis. In their study, subjects with large white matter lesions had significantly lower global and frontal gray matter glucose utilization.

CEREBRAL BLOOD FLOW IN EXTENSIVE LEUKOARAIOSIS

Similar to these studies, DWML were not strongly related with hypertension or brain infarction on MRI in our previous study, while confluent or large DWML were frequently associated with hypertension and brain infarction.8 Although we selected subjects with maximum differences in DWML (i.e., EXT-DWML v no or minimum DWML) to show abnormal CBF specific to DWML, we found nonsignificant or only a subtle change in white matter CBF in subjects with EXT-DWML. The radiologic features of EXT-DWML in the present study were essentially identical to those of vascular dementia of the Binswanger type as shown in Fig 1A. However, the frequency and extent of hypertension were less remarkable in nondemented elderly subjects compared with those of patients with vascular dementia of the Binswanger type. Similar to reported cases,18,19 all Binswanger type patients in our experience6,7,20 had a history of hypertension with blood pressure of 178 ⫾ 36/105 ⫾ 20 mm Hg and were frequently associated with a history of minor, but symptomatic, stroke (80%) and brain infarction on MRI (100%). Without substantially severe and longstanding hypertension, which may exacerbate the process of white matter ‘‘ischemic’’ damage, EXT-DWML alone do not seem to cause apparent dementia, although DWML caused slight, but significant, decline in mental function in community-dwelling elderly subjects.8 It is also unlikely that nondemented elderly subjects with EXTDWML develop dementia in the future, because they are already fairly aged, while CBF was not reduced. Tomographic measurements of CBF are useful in evaluating the functional aspects of EXT-DWML in nondemented elderly subjects. In conclusion, the present study does not clarify whether there are 2 distinct clinical entities (i.e., nondemented elderly subjects with EXT-DWML and vascular dementia of the Binswanger type), but we showed that nondemented elderly subjects with EXT-DWML are quite different from patients with Binswanger type dementia in terms of brain circulation. Acknowledgment: The authors gratefully acknowledge Y. Kawaga for his technical assistance. We also thank August McInnis for editing the manuscript.

175

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

References 1. Boone KB, Miller BL, Lesser IM, et al. Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect. Arch Neurol 1992;49:549-554. 2. Schmidt R, Fazekas F, Offenbacher H, et al. Neuropsychologic correlates of MRI white matter hyperintensities: A study of 150 normal volunteers. Neurology 1993;43:24902494. 3. Ylikoski A, Erkinjuntti T, Raininko R, et al. White matter hyperintensities on MRI in the neurologically nondis-

18. 19. 20.

eased elderly. Analysis of cohorts of consecutive subjects aged 55 to 85 years living at home. Stroke 1995;26:11711177. Schmidt R, Hayn M, Fazekas F, et al. Magnetic resonance imaging white matter hyperintensities in clinically normal elderly individuals. Correlations with plasma concentrations of naturally occurring antioxidants. Stroke 1996; 27:2043-2047. Fein G, Van Dyke C, Davenport L, et al. Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration. Arch Gen Psychiatry 1990;47:220-223. Yao H, Sadoshima S, Kuwabara Y, et al. Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type. Stroke 1990;21:16941699. Yao H, Sadoshima S, Ibayashi S, et al. Leukoaraiosis and dementia in hypertensive patients. Stroke 1992;23:16731677. Yao H, Yuzuriha T, Koga H, et al. Decreased plasma tryptophan associated with deep white matter lesions in elderly subjects. J Neurol Neurosurg Psychiatry 1999;66: 100-103. Katoh S, Simogaki H, Onodera A, et al. Development of the revised version of Hasegawa’s dementia scale (HDS-R) [in Japanese]. Jpn J Geriatr Psychiatry 1991;2:1339-1347. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-Mental State’’: A practical method for grading the cognitive state of patients for clinician. J Psychiatr Res 1975;12:189-198. MacLeod CM. Half a century of research on the Stroop effect: An integrative review. Psychol Bull 1991;109:163203. Fazekas F, Niderkorn K, Schmidt R, et al. White matter signal abnormalities in normal individuals: Correlation with carotid ultrasonography, cerebral blood flow measurements, and cerebrovascular risk factors. Stroke 1988; 19:1285-1288. Gur D, Yonas H, Good WF. Local cerebral blood flow by xenon-enhanced CT: Current status, potential improvements, and future directions. Cerebrovasc Brain Metab Rev 1989;1:68-86. Meyer JS, Shinohara T, Imai A, et al. Imaging local cerebral blood flow by Xenon-enhanced computed tomography—Technical optimization procedures. Neuroradiology 1988;30:283-292. Hatazawa J, Shimosegawa E, Satoh T, et al. Subcortical hypoperfusion associated with asymptomatic white matter lesions on magnetic resonance imaging. Stroke 1997; 28:1944-1947. Turc J-D, Chollet F, Berry I, et al. Cerebral blood flow, cerebral blood flow reactivity to acetazolamide, and cerebral blood volume in patients with leukoaraiosis. Cerebrovasc Dis 1994;4:287-293. DeCarli C, Murphy DGM, Tranh M, et al. The effects of white matter hyperintensity volume on brain structure, cognitive performance, and cerebral metabolism of glucose in 51 healthy adults. Neurology 1995;45:2077-2084. Babikian V, Ropper AH. Binswanger’s disease: A review. Stroke 1987;18:2-12. Fisher CM. Binswanger’s encephalopathy: A review. J Neurol 1989;236:65-79. Yao H, Ibayashi S, Fukuda K, et al. Silent cerebrovascular disease and vascular dementia of the Binswanger type in patients with headache, dizziness or vertigo. Jpn J Stroke 1995;17:101-108.

Cerebral blood flow in nondemented elderly subjects with extensive deep white matter lesions on magnetic resonance imaging.

Our previous study showed that deep white matter lesions (DWML) were associated with subtle cognitive decline in community-dwelling elderly people. Ho...
209KB Sizes 0 Downloads 0 Views