frontal white matter lesions and dementia in lacunar...

1143

Frontal White Matter Lesions and Dementiain Lacunar Infarction

Hitoshi Fukuda, MD, Shotai Kobayashi, MD,

Kazunori Okada, MD, and Tokugoro Tsunematsu, MD

We studied the associations of mental deterioration and blood pressure with severity andlocation of lesions in the cerebral white matter of 35 patients (27 men and eight women) aged52-84 (mean 70.9) years with multiple lacunar infarcts; 21 had no dementia and 14 weredemented. Using magnetic resonance imaging to evaluate lesion severity, we determined thatdemented patients had more severe lesions than nondemented patients; this difference wasespecially prominent for lesions in the frontal lobe (p<0.001). Score on the dementia ratingscale of Hasegawa et al was negatively correlated with severity of the lesions in the frontal lobe.Blood pressure was positively correlated with the severity of white matter lesions. We show thatseverity of lesions in the white matter, especially in the frontal lobe, is correlated with mentaldeterioration of patients with multiple lacunar infarcts. Because uncontrolled hypertension isrelated to the severity of such lesions, careful selection of antihypertensive treatment isimportant in preventing both the cerebral lesions and the associated mental deterioration.{Stroke 1990;21:1143-1149)

Extensive lesions of the cerebral white mattercause the dementia known as Binswanger'sdisease. Several investigators have reported

that hypertension is a major risk factor for suchischemic lesions.1-5 In a clinicopathologic study ofthe autopsied brains of patients with vascular demen-tia and a lacunar state, Ishii et al6 suggested that notonly the lacunae but also incomplete softening of thewhite matter, especially in the frontal lobe, wereimportant causes of the dementia.

The purpose of our study was to investigate theassociations of mental deterioration and blood pressurewith severity and location of lesions in the cerebralwhite matter of patients with multiple lacunar infarcts.

Subjects and MethodsWe retrospectively evaluated patients who were

seen in the Shimane Medical University Hospitalfrom 1987 to 1988 and diagnosed as having multiplelacunar infarcts from their clinical signs and symp-toms, laboratory data, and brain images. All patientshad a history of stroke. Computed tomography (CT)and magnetic resonance imaging (MRI) using theinversion-recovery method demonstrated multipleischemic infarcts of restricted size in the deeper parts

From the Third Division of Internal Medicine, Shimane MedicalUniversity, Izumo, Japan.

Address for correspondence: Shotai Kobayashi, The ThirdDivision of Internal Medicine, Shimane Medical University, 89-1,Enya, Izumo, Shimane, 693, Japan.

Received October 30, 1989; accepted April 19, 1990.

of the patients' brains; their neurologic deficits couldbe explained by these lacunae. We excluded patientswith obvious cortical lesions, those with acute stroke,those who had been obviously demented before theirstrokes, and those whose MRI scans were of poorquality (had motion artifacts). After exclusion, therewere 35 patients (27 men and eight women) aged52-84 (mean 70.9) years; 21 (15 men and six women,aged 54-84 [mean 69.3] years) had no dementia, andthe other 14 (12 men and two women, aged 52-84[mean 73.2] years) were demented.

Dementia was diagnosed based on the DSM-IIIR.7

Fourteen demented patients had an ischemic score ofHachinski et al8 of >10 points, and their CT andMRI scans demonstrated multiple lacunae withoutcortical lesions. All 21 demented patients were diag-nosed as having multi-infarct dementia. Yoshimuraet al9 reported that the so-called mixed-type demen-tia with pathologic features of both senile and vascu-lar dementia accounted for only 19 of the 216autopsied brains from demented persons in Japan.Moreover, those patients with mixed-type dementiahad signs of cognitive impairment before theirstrokes. Therefore, we excluded patients who hadbeen obviously demented before their strokes.

The diastolic, systolic, and mean arterial bloodpressures of each patient were the mean of 10 serialmeasurements obtained several months before MRI.We compared age and blood pressure in the twogroups using Student's t test and the incidence of risk

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1144 Stroke Vol 21, No 8, August 1990

FIGURE 1. Top left: Tl-weighted magnetic resonance image; top right: long spin-echo image; bottom left: inversion-recoveryimage; and bottom right: schema of axial slice, all at level of basal ganglia. Severity of lesions in white matter was measured onTl-weighted image in regions 1 and 2 shown in schema.

factors for cerebrovascular disease as documented inthe patients' records using the x1 t e s t -

The MRI studies were performed using an MRT-15 unit (Toshiba, Tokyo, Japan) with a 0.15-T mag-net at Shimane Institute of Health Science. Brainimages were obtained approximately parallel to the

orbitomeatal line in the transverse plane. AbsoluteTl-weighted images were obtained by taking inver-sion-recovery (repetition time [TR] 2,000 msec; echotime [TE] 40 msec; inversion time 400 msec) andspin-echo (TR 1,600 msec; TE 40 msec) scans at thesame time (Figures 1 and 2). We evaluated severity of



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Fukuda et al White Matter Lesions and Dementia 1145

FIGURE 2. Top left: Tl-weighted magnetic resonance image; top right: long spin-echo image; bottom left: inversion-recoveryimage; and bottom right: schema of axial slice, all at level of body of lateral ventricle. Severity of lesions in white matter wasmeasured on Tl-weighted image in regions 3-8 shown in schema.

the white matter lesions on Tl-weighted images asdistance from the nearest margin of the lateralventricle to the point at which the Tl valueexceeded 400 msec on a television monitor; distancewas measured using commercially available soft-ware for the MRI unit. In this study, the Tl value of

normal white matter was <300 msec. The area inwhich the Tl value exceeds 400 msec is nearly equalto the area of hyperintensity shown by the T2-weighted method. This area shows not only thelacuna but also the so-called periventricular hyper-intensity.



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We measured severity of the white matter lesionsin eight regions: the right and left frontal lobe on anaxial slice at the level of the basal ganglia (Figure 1)and the right and left anterior (frontal), middle(frontoparietal), and posterior (parieto-occipital)portions on an axial slice at the level of the body ofthe lateral ventricle (Figure 2). It was difficult tomeasure severity of the white matter lesions in pos-terior areas on an axial slice at the level of the basalganglia because white matter in those areas wasnarrow, especially when brain atrophy was severe,and contamination of the white matter with thecortex and the subarachnoid space could not beexcluded. We compared severity between groups foreach region individually and for the sum of all eightregions using Student's t test. We investigated therelations of the sum of severities with diastolic,systolic, and mean arterial blood pressures for all 35patients and for each group separately using linearregression analysis.

We studied interrater reliability of the severitymeasure using MRI scans from 10 of the 35 patientsanalyzed by three observers. We evaluated interrateragreement using Pearsons' correlation coefficients.

Using the dementia rating scale of Hasegawa et al,10

we evaluated the mental abilities of 26 of the 35patients, 12 (nine men and three women) withoutdementia and the 14 (12 men and two women) whowere demented. This dementia rating scale is a usefulbedside method of scoring cognitive impairment andconsists of five subtests to measure orientation, gen-eral information, calculation, memory recall, andmemorization. The maximum score is 32.5 points, withlow scores reflecting more cognitive impairment. Weinvestigated the relations of severity and location ofthe white matter lesions with score on the dementiarating scale for the 26 patients using linear regressionanalysis. Data are presented as mean±SD. Statisticalsignificance was tested using Student's t distributionwith a probability value of 0.05.

ResultsTable 1 shows the clinical characteristics of the two

groups. There were no significant differences in age,blood pressure, or the incidence of risk factors forcerebrovascular disease between groups.

In the comparison of lesion severity as measured bythree observers, high levels of interrater agreementwere obtained. Correlations ranged from 0.9320( / J<0.001) to 0.9978 (/><0.001) and averaged 0.9760.

Severity of the white matter lesions in each regionfor the two groups is shown in Figure 3. White matterlesions in the demented patients were significantlymore severe than those in the nondemented patientsin all regions, especially in the frontal lobe aroundthe anterior horns of the lateral ventricles. The sumof severities of the white matter lesions for all eightregions was also higher in the demented group thanin the nondemented group (100±25 and 47±25 mm,respectively; p<0.001).

TABLE 1. Clinical Characteristics of Demented and Non-demented Patients With Multiple Lacunar Infarcts

Characteristic

Age (yr)Blood pressure

(mm Hg)DiastolicSystolicMean arterial

Risk factorHypertension

Diabetes mellitusHypercholesterolemiaAngina pectoris

and/or oldmyocardialinfarct

Atrial fibrillation

None known

Nondemented

Mean±SD No.

69.3±7.8

84±12140+26103 ±16

1836

403

Group

Demented

Mean±SD No.

73.2±9.4

84±16140±27103 ±20

1132

420

Hypercholesterolemia, total cholesterol concentration of >200mg/dl.

The correlations between severity of the whitematter lesions in all eight regions and score on thedementia rating scale for 26 patients appear in Table2. Severity was significantly correlated with score inthe anterior half of the brain, namely, the frontallobe. The correlation was strongest in the frontallobe around the anterior horns (Figure 4).

Diastolic, systolic, and mean arterial blood pres-sures in all 35 patients and in each group individuallywere significantly correlated with the sum of severi-ties of the white matter lesions (Table 3). Diastolic

25 "

20-

15"

10"

0 J

n n n n

r1- O

X tn n

O -L

-L JL U Ut

1 2 3 4 5 6 7 8R E G I O N N U M B E R

FIGURE 3. Mean±SD severity of white matter lesions(SWML) in nondemented (o, n=21) and demented (*,n=14) patients in eight regions. 1, 2: right (R), left (L) frontallobe; 3,4: R, L anterior portion; 5, 6: R, L middle portion; 7,8: R, L posterior portion. *ft p<0.007, 0.07, and 0.025,respectively, different between groups by Student's t test.



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TABLE 2. Correlation Coefficients and Probabilities for Severity of White Matter Lesions and Score on DementiaRating Scale for 26 Patients

Region

Anterior horns

12

Body of lateral ventricle

345678

Total

Location

R frontal lobe anterior

L frontal lobe

R anterior

L anterior

R middle

L middle

R posterior

L posterior

r

-0.701

-0.790

-0.621

-0.538

-0.626

-0.363

-0.189

-0.273

-0.682

P

< 0.001

< 0.001

<0.001

<0.005

<0.001

NSNSNS

<0.001

R, right; L, left; NS, not significant.

blood pressure was most strongly correlated withseverity of the white matter lesions (Figure 5).

DiscussionSeveral investigators have suggested an association

between dementia and extensive lesions in the whitematter of patients with multiple lacunar infarcts.6'11-13

Positive relations of white matter lesions to a history ofstroke2-14 and to atherosclerogenic risk factors such ashypertension1"5 and diabetes mellitus1 have beenreported. The area surrounding the anterior horns is acommon site for the lacunae.615

We studied the association of mental deteriorationand blood pressure with severity and location ofwhite matter lesions in patients with multiple lacunarinfarcts. Demented patients had more severe whitematter lesions than nondemented patients, with thedifference between groups especially marked in thefrontal lobe. Score on the dementia rating scale ofHasegawa et al10 was negatively correlated with the

2 0 -

15 -

10

H D R S ( p o i n t s )

FIGURE 4. Scatter plot of correlation between severity ofwhite matter lesions around left anterior horn of lateralventricle (SWML) and score on dementia rating scale ofHasegawa et al'° (HDRS) for 12 nondemented (o) and 14demented (•) patients. Maximum score on HDRS is 32.5points. r= -0.790, p<0.001.

severity of white matter lesions in the frontal lobe,especially in the area surrounding the anterior horns.

Ishii et al6 described a clinicopathologic study of 30autopsied brains of patients with vascular dementiaand a lacunar state and suggested that not only thelacunae but also incomplete softening of the whitematter, especially in the frontal lobe, were importantcauses of the dementia. Kameyama11 studied 700autopsied brains and reported that persons withfrontal cerebrovascular lesions, especially multipleinfarcts in the bilateral white matter of the frontallobe, cingulate gyrus, and anterior part of the corpuscallosum, had a higher incidence of dementia. Ourfindings agree with these previous reports.

In a study of multi-infarct dementia using oxygen-15 positron emission tomography, Ujike et al16

reported that decreases in cerebral blood flow andmetabolism were most prominent in the frontal lobe.We suggest that their results correspond with apredominant lesion in the white matter of the frontallobe in persons with multi-infarct dementia.

10 0—.

8 0 -

60_

4 0 -

2 0 -

0

d i a s t o l i c b l o o d p r e s s u r e ( n H g )FIGURE 5. Scatter plot of correlation between sum of sever-

ities of white matter lesions (SWML) and diastolic bloodpressure in 21 nondemented patients. r=0.711, p<0.001.



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TABLE 3. Correlation Coefficients and Probabilities for Sum of Severities of White Matter Lesions and Blood Pressure

Group

Nondemented(n = 21)

Demented(n-14)

Total(JV=35)

Blood pressure (mm Hg)DiastolicSystolicMean arterial

r0.7110.5280.634

P<0.001<0.025<0.005

r0.6600.6070.634

P<0.025< 0.025< 0.025

r0.4670.3900.437

P< 0.005<0.01<0.025

What does elongation of the Tl values reflect?MRI-pathologic studies using the T2-weighted methodshow that white matter lesions on MRI correspond tosuch conditions as etat crible,17 demyelination,18-19 andlacunae or gliosis.19-20 Although we used Tl values, thearea in which the Tl value exceeds 400 msec is nearlyequal to the high-intensity area shown by the T2-weighted method. Therefore, we consider the whitematter lesions in our study to be ischemic lesions,especially lacunae and areas of incomplete softening.

The positive correlation between blood pressureand severity of white matter lesions suggests thatuncontrolled hypertension accelerates the progres-sion of white matter lesions. An association betweenhypertension and white matter lesions has beenreported.1-5 Hypertension is a major risk factor forlacunae.15 The cases of subcortical arterioscleroticencephalopathy reported by Olszewski4 were attrib-uted to hypertensive vasculopathy of small arteriesand arterioles in the white matter. Ishizaki3 reportedthat multiple small infarcts around the basal ganglia(etat lacunaire) may be associated with subcorticalarteriosclerotic encephalopathy in the brains ofelderly patients with a history of hypertension. Mul-tiple lacunae and incomplete softening may enlargemore easily in those patients with multiple lacunarinfarcts and uncontrolled hypertension. Ischemiclesions elongate both the Tl and T2 values on MRI.Extensive frontal white matter lesions are closelyrelated to mental deterioration.

Although a difference between demented and non-demented patients in the severity of white matterlesions was prominent in our study, mean arterialblood pressure did not differ significantly betweengroups. We speculate that there are differences in thehistory of hypertension such as severity, duration,therapy, and episodes of transient hypotension. How-ever, these factors cannot be accurately determinedin a retrospective study. More detailed prospectivestudies are necessary to investigate this possibility.

Our study shows that severity of white matterlesions, especially in the frontal lobe, is correlatedwith mental deterioration in patients with multiplelacunar infarcts. Because uncontrolled hypertensionis related to the severity of white matter lesions,selection of appropriate antihypertensive therapy isimportant in preventing both white matter lesionsand mental deterioration.

To what level must we reduce blood pressure in ahypertensive patient to prevent white matter lesions?

This question is very difficult to answer, especiallyduring the later stages of uncontrolled hypertensionwhen vasculopathy may already be severe. Duringthis stage, overreduction of blood pressure may leadto ischemic brain lesions. Autoregulation of thecerebral circulation also changes in hypertensivepatients. The lower limit of cerebrovascular autoreg-ulation is higher among persons with hypertensionthan among those who are normotensive, and theextent of the change varies among patients.21-22

Therefore, optimal blood pressure, which not onlymaintains sufficient cerebral blood flow but alsoprevents the formation of hypertensive vasculopathy,may also differ in each case.

AcknowledgmentsWe acknowledge the technical contributions of

Akira Besho, Shimane Institute of Health Science.Thanks are also due to Dr. Shuhei Yamaguchi, Dr.Hiromi Koide, Dr. Nobuo Suyama, and Dr. HirokazuBokura for much help.

References1. Kertesz A, Black SE, Tokar G, Benke T, Carr T, Nicholson L:

Periventricular and subcortical hyperintensities on magneticresonance imaging: 'Rims, caps, and unidentified brightobjects.'/4rc/i Neurol 1988;45:404-408

2. Awad IA, Spetzler RF, Hodak JA, Awad CA, Carey R:Incidental subcortical lesions identified on magnetic reso-nance imaging in the elderly: I. Correlation with age andcerebrovascular risk factors. Stroke 1986;17:1084-1089

3. Ishizaki T: Coexistence of etat lacunaire and subcorticalarteriosclerotic encephalopathy in old age. Rinsho Shinkeigaku1975;15:618-624

4. Olszewski J: Subcortical arteriosclerotic encephalopathy:Review of the literature on the so-called Binswanger's diseaseand presentation of two cases. World Neurol 1962;3:359-375

5. McQuinn BA, O'Leary DH: White matter lucencies on com-puted tomography, subacute arteriosclerotic encephalopathy(Binswanger's disease), and blood pressure. Stroke 1987;18:900-905

6. Ishii N, Nishihara Y, Imamura T: Why do frontal lobesymptoms predominate in vascular dementia with lacunes?Neurology 1986;36:340-345

7. American Psychiatric Association: Diagnostic and StatisticalManual of Mental Disorders, ed 3. Washington, DC, AmericanPsychiatric Association, 1987, pp 103-109

8. Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllisterVL, Marshall J, Russell RWR, Symon L: Cerebral blood flowin dementia. Arch Neurol 1975;32:632-637

9. Yoshimura M, Tomonaga M: Mixed type of dementia: Itsclinico-pathological aspects. Shinkei Kenkyu Shinpo (Tokyo)1985;29:641-654



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10. Hasegawa K, Inoue K, Moriya K: An investigation of dementiarating scale for the elderly. Seishin Igaku (Tokyo) 1974;16:965-969

11. Kameyama M: Vascular lesions in the frontal association fieldand dementia. Seishin Igaku (Tokyo) 1973;15:357-366

12. Goto K, Ishii N, Fukasawa H: Diffuse white-matter disease inthe geriatric population: A clinical, neuropathological, and CTstudy. Radiology 1981;141:687-695

13. Erkinjuntti T, Ketonen L, Sulkava R, Sipponen J, VuorialhoM, Iivanainen M: Do white matter changes on MRI and CTdifferentiate vascular dementia from Alzheimer's disease? /Neurol Neurvsurg Psychiatry 1987;50:37-42

14. Inzitari D, Diaz F, Fox A, Hachinski VC, Steingart A, Lau C,Donald A, Wade J, Mulic H, Merskey H: Vascular risk factorsand leuko-araiosis. Arch Neurol 1987;44;42-47

15. Fisher CM: Lacunes: Small, deep cerebral infarcts. Neurology1965;15:774-784

16. Ujike T, Terashi A, Soeda T, Kitamura S, Kato T, Iio M:Cerebral blood flow and metabolism in multi-infarct dementia.No To Shinkei 1985;37:905-912

17. Awad IA, Johnson PC, Spetzler RF, Hodak JA: Incidentalsubcortical lesions identified on magnetic resonance imaging

in the elderly: II. Postmortem pathological correlations. Stroke1986;17:1090-1097

18. Kirkpatrick JB, Hayman LA: White-matter lesions in MRimaging of clinically healthy brains of elderly subjects: Possiblepathologic basis. Radiology 1987;162:509-511

19. Braffman BH, Zimmerman RA, Trojanowski JQ, GonatasNK, Hickey WF, Schlaepfer WW: Brain MR: Pathologiccorrelation with gross and histopathology. 2. Hyperintensewhite-matter foci in the elderly. AW? 1988;151:559-566

20. Marshall VG, Bradley WG Jr, Marshall CE, Bhoopat T,Rhodes RH: Deep white matter infarction: Correlation of MRimaging and histopathologic findings. Radiology 1988;167:517-522

21. Strandgaard S, Olesen J, Skinhoj E, Lassen NA: Autoregu-lation of brain circulation in severe arterial hypertension. BrMed J 1973;l:507-510

22. Strandgaard S: Autoregulation of cerebral circulation inhypertension. Ada Neurol Scand 1978;57(suppl 66):l-82

KEY WORDS • dementia • hypertension • lacunar infarction



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H Fukuda, S Kobayashi, K Okada and T TsunematsuFrontal white matter lesions and dementia in lacunar infarction.

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright © 1990 American Heart Association, Inc. All rights reserved.

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