Clinical Correlates of White-Matter Changes on Magnetic Resonance Imaging Scans of the Brain Thomas R. Mirsen, MD; Donald H. Lee, DM; Cindy J. Wong, MSc; J. Fernando Diaz, MD; Allan J. Fox, MD; Vladimir C. Hachinski, MD, DSc(Med); Harold Merskey, DM

\s=b\ We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko\x=req-\ araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our

subjects. (Arch Neurol. 1991 ;48:1015-1021 )

IX/Tagnetie resonance imaging (MRI) permits the identification of subtle changes in the white matter of the Accepted for publication March 28,1991. From the Departments of Clinical Neurological Sciences (Drs Mirsen, Lee, Fox, and Hachinski), Psychiatry, (Drs Diaz and Merskey), and Radiology (Drs Lee and Fox), the University of Western Ontario, London, and the Clinical Trials Resources Group, John P. Robarts Research Institute, London, Ontario (Ms Wong). Dr Mirsen is now with the

Cooper Hospital/University Medical Center of the University of Medicine and Dentistry of New Jersey/Robert Wood Johnson School of Medicine, Camden, NJ. Dr Hachinski is a career investigator

with the Heart and Stroke Foundation of Ontario. Reprint requests to Division of Neurology, Cooper Hospital/University Medical Center, 3 Cooper Plaza, Suite 320, Camden, NJ 08103 (Dr Mirsen).

brain.13 Various investigators have re¬ ported a high prevalence of white-mat¬

on T2-weighted images,12,41° especially in subjects with cerebrovas¬ cular disease.1,2,4,5,7" We distinguish be¬ tween periventricular hyperintensity (PVH) (Fig 1) and changes distant from the ventricles (Fig 2), or leuko-araiosis

ter changes

(L-A).11

SIGNIFICANCE OF L-A AND PVH

Leuko-araiosis appears infrequently on MRI scans46,12 in young subjects and

commonly4'2

with age. It may appear often'12 and may be exten¬ sive12 in Alzheimer's disease (AD).512 occurs more

However, our interpretation of the data of Erkinjuntti et al13 suggests that se¬

changes are rare. Computed tomo¬ graphic studies14 reveal an association vere

"'

between similar lucencies and AD. No link exists between L-A on MRI scans and cognitive dysfunction, whether in AD,12,13,17 among healthy control sub¬ jects,1""2" in multi-infarct dementia (MID),12 or in unselected subjects.4 This contrasts with the relationship demon¬ strated between mental decline and L-A on CT scans.21,22 Gait disturbance does relate to L-A on MRI scans of healthy subjects,1" as previously shown for CT changes.21 Leuko-araiosis ap¬ pears on MRI scans in 64%23 to 100%12,13 of subjects with MID. Its effect on this condition remains unknown. Periventricular hyperintensity is more prevalent than L-A in older8"1012 and possibly in younger"11,12 subjects. Its frequency casts doubt on its impor¬ tance. The reported percentage of pa¬ tients with AD who exhibit PVH varies from 44% to 100%.12,13,17,2:! One study23 noted PVH in 71% of patients with MID, and other studies12,13 noted PVH in 100% of patients with MID.

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The incomplete knowledge regarding these white-matter changes results in part from variations among the existing studies.'' Some rest primarily on preex¬

isting radiologie data7"10,30,41,45'47 or on pathologic findings.+ The clinical information presented may be retro¬ spective. 7"9'35,41 Given studies involve unselected

subjects1,4,7,1'1,41;

certain stud-

jes5.n.26,za jnvojve modest numbers. Some

the preva¬ lence of white-matter changes in vari¬ ous diagnostic groups; other investiga¬ tors* also delineate their extent. Most of these latter investigators12,13,17"2"23,39,40'48 address the effect of these lesions on cognition. Many reports12,13,18,2",39,4,,,4!' in¬ clude a neuropsychologic evaluation; some1723 rely on screening tools. Other studies4,7"9'2"32,43'44 primarily examine the relationship between vascular risk fac¬ and white-matter changes. tors Few6,9,20,39,41 attend to focal neurologic findings. Other studies deal with the correlation between T,25,3"31 and T22li mea¬ surements in the white matter and dementia. No study has determined with cer¬ tainty the contribution of white-matter changes seen on MRI scans to the sever¬ ity of AD or MID. Bowen et al12 stated that patients with AD exhibit more ex¬ tensive L-A than do control subjects. However, Leys et al17 found no effect of L-A or PVH on cognition in AD. Other studies28,4" examined the effect of L-A and of PVH on cognition in cohorts of subjects with diverse diagnoses. Many studies have provided instructive infor-

investigators''8'20,32,33,43 report

References

1,4-10,12,13, 17-20, 23-48.

\s=d\ References 24,

27, 28,34, 36, 37, 42, 46, 47.

\s=dd\References12, 13, 17-19, 23, 29, 39, 48.

'

Fig

1. —Periventricular

resonance

hyperintensity imaging scan.

on

a

mation, but it is difficult to control the numerous

factors that influence the

data. Previous

reports1"·21,22,38 from a large prospective study of dementia have ex¬ amined the prevalence, clinical mean¬ ing, and probable cause of white-matter lucencies on CT scans. The acquisition of an MRI scanner and the presence of a pool of patients and control subjects who were examined systematically has made possible similar analyses based on MRI findings. PATIENTS AND METHODS

The Dementia Study of the University of Western Ontario, London, which began in 1978, involves prospective clinical and radiologic examination of healthy volunteers and patients referred for the investigation of de¬ mentia. Participants in the study underwent standardized evaluation, performed from July 1985 to July 1986 by one physician (J.F.D.) and for the next 3 years by one neurologist (T.R.M.), confirmed in both cases by another neurologist (V.C.H.). Lab¬ oratory studies included a complete blood count; determinations of serum glucose, elec¬ trolyte, urea, creatinine, vitamin B12, and folate levels; a liver profile; measurements of thyroid functions (including thyroid-stimu¬ lating hormone); and VDRL testing. Sub¬ jects initially underwent CT of the head. Magnetic resonance imaging scans have been obtained since November 1986, and electro¬ encephalograms are obtained yearly. All testable subjects undergo psychometry at 6month intervals, with the Extended Scale for

proton-density magnetic

Fig

2. —Leuko-araiosis

on a

T2-weighted magnetic

resonance

imaging

scan.

Dementia (ESD),49 with a sensitivity of 89% and a specificity of 96% in the identification of

dementia.'" The physicians apply the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, criteria"1 in diagnosis and use the Ischemie Score'2 to distinguish among AD, "mixed" dementia, and MID. Our diag¬ nosis of AD has a sensitivity of 87% and a specificity of 78%.53 Magnetic resonance imaging scans were obtained with

a

1.5-T unit

(Signa,

General

Electric, Milwaukee, Wis). They were origi¬ nally obtained as follows: in the sagittal plane, with a 24-cm field of view (FOV), a repetition time (TR) of 500 milliseconds and an echo time (TE) of 20 milliseconds, taking 5-mm sections 1 mm apart. Axial cuts in¬ volved a 20- to 24-cm FOV, a TR of 2000 milliseconds and TE s of 35 and 70 millisec¬

onds, taking 5-mm sections with 2.5-mm gaps. Coronal cuts involved a 16-cm FOV, a TR of 2000 milliseconds, and TEs of 20, 40, 60, and 80 milliseconds, as well as a TR of 600 milliseconds and a TE of 20 milliseconds, tak¬ ing 3-mm sections 3 mm apart. Later, the sagittal TRs were changed to 400 milliseconds, and axial cuts were per¬ formed with a 20-cm FOV, a TR of 2500 milliseconds, and TEs of 30 and 70 millisec¬ onds, with flow compensation and 5-mm con¬

tiguous sections. The coronal cuts involved a 20-cm FOV, a TR of 500 milliseconds, and a TE of 20 milliseconds, with a 5-mm section thickness. Two neuroradiologists (A.J.F. and D.H.L.) independently analyzed the MRI scans obtained for the Dementia Study be¬ tween November 1986 and May 1988, with¬ out knowledge of clinical diagnoses, for the

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presence of L-A,

PVH, sulcal widening, ven¬ tricular dilatation, and infarction. Periven¬ tricular hyperintensity (Fig 1) refers to areas of heightened intensity at the margins ofthe lateral ventricles. We distinguish between PVH and L-A because some PVH may ap¬ pear normally,4' while L-A may represent infarction24,27,8,4f' or demyelination and glio¬ sis.24,2,42 Periventricular hyperintensity was classified as absent or present in each hemi¬ sphere separately; more elaborate classifica¬ tion proved unreliable because of discor¬ dance between observations made on coronal and axial sections. Most work has relied on axial views.* Where other cuts were tak1,5,12,19,89,41,48 assessments oi¿" severity appar¬ en, ently rested primarily on the axial cuts, al¬ though not in some instances.12,i!l We deemed small areas of hyperintensity at the frontal or occipital horns of the lateral ventricles as normal.4, Leuko-araiosis was rated in each hemisphere according to the number and se¬ verity of lesions. Absence of lesions received a grade of 0, one or two focal lesions received a grade of 1, three to five lesions received a grade of 2, and more than five lesions re¬ ceived a grade of 3; confluent lesions received a grade of 4. Whether the changes were rela¬ l

_

tively superficial ("subcortical"), "deep" (within 2

mm

of the ventricular border but

separated by a strip of normal-appearing brain), or both was also noted. Ifthe radiolo¬ gists disagreed, they reviewed the appropri¬ ate film together. They agreed initially about the presence of L-A in 88% of cases, about its extent in 56% of cases, and about the site involved in 71% of cases; they agreed as to

\s=s\References6, 10, 13, 17, 18, 20, 32, 37, 40,

44, 47.

the presence of PVH in 76% of instances. These data refer to the right hemisphere; the left hemisphere yielded comparable results. Sulcal widening, scored from 0 to 5 on a severity scale, was examined in five zones on either side: sylvian and retrosylvian areas, the high and low convexities, and the perimesencephalic cistern. The mean of all the val¬ ues provided the sulcus widening score. Ventricular dilatation likewise received a score between 0 and 5. It was assessed in two parts ofthe lateral ventricles—the temporal horns and the bodies together with the fron¬ tal horns—as well as in the third and fourth ventricles.

SUBJECTS AND METHODS

We reviewed information concerning 102 subjects from the Dementia Study who un¬ derwent MRI scanning between November 1986 and August 1988. Eight subjects were

excluded because of doubt as to the presence or type of dementia. The remaining 94 sub¬ jects included 44 subjects suffering from de¬ mentia and 24 control subjects who under¬ went full investigation in the study within 2 years of MRI scanning. The remaining 26 subjects were control subjects examined be¬ fore the introduction of a standardized neuro¬ logic evaluation form. However, their ESD scores remained in the normal range (>220) when they returned for MRI scanning. We determined the prevalence of PVH and L-A, whether deep, subcortical, or both, and the severity of L-A in the various diagnostic groups (AD, mixed dementia, MID, and healthy control subjects). We assessed the relationship between PVH and age or sex among our subjects. We determined wheth¬ er the presence of PVH or of either type of L-A bore a relation to the presence of atro¬ phy, as measured by the sulcus widening score and by lateral ventricular enlarge¬ ment. Lastly, we analyzed whether PVH and either variety of L-A appeared together. In all instances, the two hemispheres were as¬ sessed separately. All analyses, except for the last, were conducted with both the inclu¬ sion and exclusion of subjects with radiologically defined infarcts. Periventricular hyper¬ intensity could not be assessed in three and L-A in two of the 94 scans because of poor

image quality.

The effects of PVH and both types of L-A the ESD score were assessed among 28 patients with AD and 39 control subjects independently. These were the persons with these diagnoses among the 81 ofthe original 94 subjects who had undergone psychomet¬ ric evaluation within 6 months of MRI scan¬ ning. The radiologie findings were judged separately in each hemisphere. To determine whether the presence of any focal neurologic finding correlated with the presence of PVH or of a type of L-A, we selected a further subset of 50 subjects. These subjects were those whose neurologic examinations were performed within 1 year of the MRI scanning. From these 50 sub¬ jects, we excluded four with MID, two with mixed dementia, and one with an uncertain diagnosis. This left 43 subjects remaining: 20 with AD, five with mixed dementia, and 18 healthy control subjects. The 43 subjects in¬ cluded those persons with mixed dementia on

according to the Ischemie Score but no evi¬ dence of cerebral infarction, as well as three AD patients and two control subjects with infarcts seen on the MRI scan. Exclusion of such persons would, by eliminating subjects with focal neurologic signs, reduce the chances of detecting an association between such signs and white-matter changes. We also kept the patients with mixed dementia in the analysis because they may have suffered from AD. Our diagnostic criteria maximize the purity of the AD group, so that some patients who prove to have AD on pathologic examination are classified clinically as hav¬ ing mixed dementia.'3 The findings assessed appear in Table 1. Some were excluded from further consider¬ ation because they occurred in less than 5% of subjects. Most were compared with radiolog¬ ie findings in the contralateral hemisphere, but some (dyspraxia, dysarthria, and primi¬ tive reflexes) were compared with findings on either side. STATISTICAL ANALYSIS

Pearson correlation coefficients and " val¬ ues were calculated as indicated between PVH or L-A and relevant variables. Fisher's Exact Test was used when cell sizes were small. The association between the severity of L-A and the presence of other characteris¬

tics, such as PVH,

was examined with Ken¬ dall's statistic. The atrophy measures and the ESD score were compared with the Stu¬ dent t test. Partial correlations were comput¬ ed to examine the prevalence of PVH in con¬ trol and AD groups while controlling for age and sex. All values are based on two-tailed tests.

RESULTS

The 94 study subjects included 30 pa¬ tients with AD, nine with mixed demen¬ tia, and four with MID, 50 control sub¬ jects, and a man suspected to have encephalitis. The controls included 23 men and 27 women (mean [SD] age, 70.1 [9.71 years), six of whom exhibited small cerebral infarcts on the MRI scan. The demented subjects included 23 men and 21 women (mean [SDÌ age, 72.2 [7.81 years). The patients with AD included 13 men and 17 women (mean [SD] age, 72.8 [6.9] years), three of whom exhibit¬ ed cerebral infarcts on the MRI scan. The subjects with mixed dementia in¬ cluded five men and four women (mean [SD] age, 70.7 [11.0] years). The pa¬ tients with MID included four men

(mean [SDÌ age, 69.9 [8.0] years).

Both PVH and L-A appeared to the extent in the two hemispheres. Data are given only for the right side, except where a difference between hemispheres requires mention. On three scans, PVH could not be inter¬ preted. Thus, it appeared in the right hemisphere in 18 (64%) of 28 patients with AD, in three of eight patients with mixed dementia, and in three of four patients with MID, as well as in 15 (30%) same

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Table 1.—Prevalence of Focal Neurologic Findings Among 43 Subjects With Recent Neurologic Examinations

Findings Dysarthria Dysphasia Dyspraxia Hemianopsia Right

% of

5 21 21 2 0

Left Facial power

Right

7 5

Left

Spastic Right

Subjects

tone

5 5

Left

Reflex abnormalities

Right

37

Left

28

Right-left confusion

5

Primitive reflexes Glabellar Suck Snout

28 14

33

Rooting

5

Palmomental

Right

40

Left Limb weakness

37

Right

7 10 5

Left Cerebellar dysfunction Abnormal gait

26 26

Sensory abnormality Extinction

Right

0 0

Left

Finger agnosia

5

Pollicomental

Right

30

Left

28

Grasp

Right

Left Labioauricular

Right Left Extensor

plantar response Right Left

of the 50 control subjects. When sub¬ jects with infarcts seen on MRI scans were excluded, the prevalence for the right hemisphere in the AD group changed from 64% to 60% and in the

controls from 30% to 31%. Whether sub¬

jects with infarcts are included or ex¬ cluded, the difference in prevalence be¬ tween the two groups is significant ( 2, P=.003 and P=.019, respectively). This remains the case after controlling for age and sex (P .006, if cases with infarcts are included; .024, if cases =

=

with infarcts are excluded). Examina¬ tion of the prevalence of PVH in the left hemisphere, while controlling for age and sex, yields parallel results (P .019, including cases with infarcts) and approaches statistical significance if cases with infarcts are excluded =

(P .066). =

Leuko-araiosis in the right hemi-

sphere occurred in 27 (93%) of 29 pa¬ tients with AD, in seven of eight pa¬ tients with mixed dementia, and in all four patients with MID, as well as in 48 (96%) ofthe 50 control subjects. Leukoaraiosis could not be read on two scans. If subjects with cerebral infarcts were excluded, the prevalences in the AD and control groups changed little—to 92% and 96%, respectively. The severity of L-A does not correlate significantly with specific diagnoses; the data shown in Table 2 include subjects with radiologic infarcts. Exclusion of these sub¬

jects produces

no

(data not shown).

well

28 (56%) of the 50 control sub¬ jects. If subjects with infarcts were ex¬ cluded, the prevalence declined to 69% in the AD group and to 53% among the controls. No significant difference emerges between groups. Subcortical L-A in the right hemi¬ sphere appeared in 25 (86%) of 29 pa¬ tients with AD, in six of eight patients with mixed dementia, and in all four patients with MID, as well as in 47 (94%) ofthe 50 control subjects. Exclusion of subjects with infarcts yielded a preva¬ lence of 85% in the AD group and of 93% in control subjects. The prevalence of subcortical L-A did not differ notably by as

diagnosis.

The presence of PVH in

one

hemi¬

sphere bears no link, neither in control subjects nor in patients with AD, to the

presence of L-A as a whole or to the presence of subcortical L-A in the same hemisphere. Among control subjects,

however, deep white-matter changes

associated with PVH (Table 3). A similar trend exists (P =. 194) among patients with AD (Table 4). (Both Ta¬ bles 3 and 4 refer to data from the right are

hemisphere.) Control subjects with PVH display

greater lateral ventricular dilatation (1.79 ± .99 [n 141) than do those with¬ out PVH (1.03±.69 [n 31]) (P .005). =

=

=

Patients wi,th AD exhibit relatively more such dilatation than do controls, and patients with AD with PVH exhibit no more dilatation (1.93±.88 [n=15D than do those AD patients without PVH (2.00 ± .71 [n 10]). These values repre¬ sent lateral ventricular dilatation scores from the right hemisphere derived from subjects without cerebral infarcts and resemble scores from the left side. The mean sulcus widening score did not dif¬ fer significantly between the cohorts with or without PVH, either in control subjects or in patients with AD. =

Diagnosis* LA Score

Mixed Control Dementia

AD

MID

2 (4) 1 (13) 0 (0) (7) 0 (0) 1 1 (13) 3(10) 10(20) 0 (0) 2 5 (17) 12 (24) 1 (25) 0 (0) 3 8 (28) 15 (31) 1 (25) 4 11 (22) 6 (75) 2 (50) 11 (38) Total 29(100)50(100) 8(100) 4(100) *AD indicates Alzheimer's disease; MID, multi-inf¬ arct dementia. Values are number (percent). 0

2

significant change

Deep white-matter changes in the right hemisphere characterized 21 (72%) ofthe 29 patients with AD, six of eight patients with mixed dementia, and three of four patients with MID, as

Table 3.—Prevalence of Deep White-Matter Changes and Periventricular Hyperintensity (PVH) Among Control Subjects Without Infarcts Seen on MRI Scans*

Table 2.—Distribution of Leuko-araiosis (L-A) Scores by

Deep White-Matter Changes PVH

Absent

Present Totals

(P=003)

PVH Absent Present Totals

(P=194)

Absent

Present

Totals

(20) 3(12)

(20) 12(48)

10 (40)

5

5

15(60)

Totals

12(27) 12 (27)

31(69) 14 (31)

21(46)

24(54) resonance

Table 5.—ESD Score by

45(100) imaging. Val¬

Diagnosis*

ESD Score No. of

,-«-,

SD

Subjects

53.5 79.9

28

179.8

213.0

17.4

4 1 39

Diagnosis_Mean AD Mixed dementia

Changes

Present

19(42) 2 (4)

*MRI indicates magnetic ues are number (percent).

Table 4.—Prevalence of Deep White-Matter Changes and Periventricular Hyperintensity (PVH) Among Patients With AD Without Infarcts Seen on MRI Scans* Deep White-Matter

Absent

173.0t

9

Multi-infarct dementia Other Normal control

178.0

245.0

5.6 ...

*

8(32)

17(68)

25(100)

*MRI

indicates magnetic resonance imaging; AD, Alzheimer's disease. Values are number (percent).

Neither in the control group nor in the AD group was there a link between L-A or either of its subcategories (deep and subcortical) and either of the two mea¬ sures of atrophy (lateral ventricular di¬ latation and sulcus widening score). Eighty-one subjects had ESD deter¬ minations within 6 months of MRI scan¬ ning (41 men and 40 women; mean [SDÌ age, 72.6 [6.9] years). They included 39 control subjects (20 men and 19 women; mean [SD] age, 73.2 [5.8] years) and 28 patients with AD (11 men and 17 wom¬ en; mean [SD] age, 72.7 [7.0] years). The mean ESD scores for the diagnostic groups appear in Table 5. Subjects with infarcts seen on MRI scans were includ¬ ed. The mean values for the AD and control groups differed significantly, as expected. Exclusion ofthe three control subjects and two patients with AD with infarcts seen on MRI scans did not alter the results (data not shown). Comparisons ofthe effect ofthe pres¬ ence of PVH and of L-A—whether deep, subcortical, or both—on the mean ESD score failed to show any correla¬ tion within the AD or control groups. However, there existed a trend

(P=.097, right hemisphere;

=

.176,

left hemisphere) for the ESD score to be lower among subjects with PVH than among those without it if control sub¬ jects and patients with AD were ana-

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ESD indicates Extended Scale for Dementia; AD, Alzheimer's disease. tThe mean ESD scores of the AD and control groups differ significantly (P < .001) (/ test).

link was found be¬ tween any of the focal neurologic

lyzed together. No

findings assessed and PVH, L-A, or ei¬ ther subcategory of L-A. This last anal¬ ysis is based on a cohort of 17 men and 26 women, with a mean (SD) age of 67.5 (11.1) years. COMMENT Prevalence of White-Matter Changes

White-matter changes appear in 59% to 74%1!U9'U of healthy aged subjects and in 80% of

healthy middle-aged

volun¬

teers.2" The prevalence of PVH on MRI scans likewise varies greatly. Bowen et al12 identified PVH in 89% of 36 healthy

subjects with

a mean age of 70 years. Kertesz et al·5 found PVH "rims" in 98% of their 58 control subjects older than 50 years. Zimmerman et alKI found PVH in 90% of studies with otherwise normal findings involving 63 subjects older than 30 years. The prevalence of PVH increases with age, but we find PVH in only 30% of our relatively old controls (mean age, 70 years). This may mean that changes that we denote as "deep" L-A are identified as PVH by other in¬ vestigators. Also, we do not designate as PVH small triangular hyperintensi¬ ties at the tips of the lateral ventricles, as other investigators may have done. The prevalence of clinically silent changes in the white matter distant

from the ventricles was reported to in¬ crease sixfold with age in one report12 and fourfold in another report,4" during a span of approximately 30 years; other investigators6,29,39 have reported a simi¬ lar trend. We found L-A in a similarly high percentage (96%) of control sub¬ jects. The higher prevalence of L-A and lower prevalence of PVH in our subjects compared with those of Bowen et al12 suggests that they classify as PVH some changes that we consider to be L-A. White-Matter Changes and Cognitive Function

Leuko-araiosis,

as seen on

CT scans,

appears in 30%14 to 33%1:' of patients with AD and in 10%15 to 16%14 of similar¬ ly aged control subjects. Other investi¬

gators1"

concur,

finding relatively

ex¬

tensive lucencies in patients with AD. Kobari et al43 observed L-A in 22% of young control subjects and in 62% of patients with AD, which is in agreement with findings of pathologic examina¬ tion.'*4 In contrast, Fazekas et al33 found white-matter changes in 16% of controls and 13% of patients with AD. The pres¬ ence of L-A correlates with decreased cognition21 and may relate to psychomo¬ tor retardation"·' in healthy persons. Cognitive decline accompanies L-A in early AD.22 Other studies14,56,57 do not confirm this last observation, but our * previous findings support it strongly. A weak relationship at best exists be¬ tween the severity of dementia in AD and white-matter T,2' and T,26 values on MRI. Other investigators3" have ob¬ served no association between T, values and cognitive decline in AD. Karlik et al·'9 have suggested, based on only a few patients, that there is prolongation of T, in hippocampal white matter in AD. Our findings regarding PVH estab¬ lish the firmest link to date between AD and any type of change in white matter on

MRI, although our neuropsychologic was not especially extensive.

testing

We found PVH twice as often in pa¬ tients with AD compared with similarly aged control subjects (64% vs 30%), sup¬ porting the suggestion of Fazekas et al,5 based on a smaller study, that PVH may accompany AD. Bowen et al12 did not observe a difference in the prevalence of PVH between patients with AD and control subjects, although PVH was more widespread in the former group. Leys et al," in a study based on few subjects, found a trend in this direction. Information regarding L-A is less clear. It appears equally frequently in patients with AD and in control subjects (93% vs 96%) in our study group, as suggested by other authors.6'6'" Kobari et al23 noted a tendency for L-A to ap-

pear more often, and' to a greater de¬ gree, in patients with AD than in control subjects. Bowen et al12 found a trend toward a higher prevalence of L-A in patients with AD compared with age-

matched controls and a significantly greater severity of L-A in the former group. Their AD group included sub¬ jects with isolated memory disorders who did not meet criteria for dementia. These subjects displayed degrees of L-A and PVH comparable with those seen in AD. The increased involvement by PVH and L-A in that report may not, therefore, be specific for AD. Other investigators18,19 have stated that both L-A and mental decline in healthy aged subjects relate only to age rather than to one another. Rao et al,2" in a study involving middle-aged sub¬ jects, reached similar conclusions. They stated the number and size range of L-A change in each subject, not an overall degree of white-matter involvement. Junque et al39 found that L-A in subjects who are prone to cerebrovascular dis¬ ease correlates with slowing of complex mental processing. Leys et al," in a study involving few subjects, reported no effect of PVH or L-A on mental function in AD. Cogni¬ tive impairment, as measured by the ESD, tends to correlate with the pres¬ ence of PVH when patients with AD and control subjects are considered togeth¬ er, although not, as also noted by Bowen et al,12 if the two groups are considered separately. The connection between PVH or L-A and mental impairment may bear further scrutiny, using either larger cohorts or using subjects with MID, who have more diffuse L-A. MID

White-matter lucencies

reportedly

appear on CT scans in 52% to 97%43"56'57 of patients with MID. These reports do not clearly differentiate L-A from PVH.

The

prevalence of L-A, based on our interpretation of the data, is between

20% and 30%.S6'5' Small studies involving MRI'29 sug¬ gest that both PVH and L-A are espe¬ cially extensive in MID. White-matter changes appear on MRI scans in eight of

II4" and in all of 2913 patients with MID, much more often than in AD13 or in healthy subjects.4" Periventricular hy¬ perintensity most frequently occurs among controls but is most extensive in MID.23 Other authors12 have reported PVH universally in MID and AD alike, with greater severity in MID. Leukoaraiosis manifests in nine of 1423 and in all of 1212 patients with MID. It appears in four of nine23 and in roughly two thirds of8712 patients with AD. The MID group exhibits more advanced changes.

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Further investigations have assessed whether white-matter changes produce vascular dementia. Hershey et al37 found PVH in 88% of patients with MID, a prevalence close to that seen in cognitively "borderline" (63%) and men¬ tally intact (61%) stroke patients. Their patients with MID exhibited L-A four times as often (25% vs 6%) as did the mentally intact stroke subjects, but this

finding was not statistically significant. A study of patients with lacunar infarc¬ tion48 revealed markedly more whitematter changes in demented subjects compared with "borderline" and cogni¬ tively unimpaired subjects. It remained

unclear whether dementia related to L-A specifically or to lacunar infarction. Loeb et al,60 in contrast, found L-A more frequently among nondemented subjects with multiple strokes com¬ pared with patients with MID but did not examine its extent. Bowen et al12 observed PVH and L-A alike in all sub¬ jects with memory complaints and Isch¬ emie Scores in the MID range. Both changes were markedly more severe in this group than in other cohorts. Their presence did not influence the MiniMental Status Score. To summarize the above, we found PVH in 75% of our patients with MID, in 38% of our patients with mixed de¬ mentia, and in 64% of our patients with AD. It occurred surprisingly infre¬ quently in the mixed dementia group. The rather low prevalence in our MID and AD groups reflects our stringent criteria for PVH. The prevalence of L-A hovered near 90% in all of our diagnostic categories. Its severity did not differ significantly among the various groups. We found L-A in AD more often than in the roughly two thirds12 or four tenths',23 of cases reported elsewhere. The low prevalence may stem from the exclusion of subjects with vascular risk factors.17 In another instance, the au¬ thors12 may, in comparison with our data, have underestimated L-A to the benefit of PVH. We found, as did Bowen et al,12 an association between L-A and MID. A demonstration that L-A contributes to intellectual decline in MID must await a large series of patients, with allowance made for the effect of stroke. Focal Neurologic Signs and MRI White-Matter Changes

In the present report, we examined the relationship between focal signs on neurologic examination and MRI whitematter changes. Other such work, with two exceptions,1"39 has focused on CT

findings.

In a case-control study, Masdeu et al61 identified an association between the

severity of white-matter hypodensity and a history of falls. Rezek et al16 ob¬ served

a

trend for motor abnormalities

(abnormal tone, gait,

or

reflexes) to oc¬

in patients with AD with L-A than in those without L-A (11%). No such relationship emerged among healthy control sub¬ jects. George et al14 found gait distur¬ bances substantially more often (45%) among demented subjects with L-A than among those without L-A (20%). Gait impairment was rare among elder¬ ly healthy subjects, regardless of the presence of L-A. George et al did not screen for other neurologic abnormali¬ ties. Steingart et al21,22 observed, among both nondemented and demented sub¬ jects, that limb weakness and abnormal plantar responses correlated signifi¬ cantly with L-A. In healthy subjects,21 gait difficulty and the rooting and palmomental reflexes also were related to L-A. Previous studies have linked L-A, as seen on MRI scans, with gait impair¬ ment18 and with primitive reflexes. Both groups of investigators 18,:W screened only for certain focal neurolog¬ ic signs. In one report,18 the subjects were neurologically intact, which may explain why other correlations did not emerge. In the other study,39 the pres¬ ence of diverse cerebral insults may have masked an effect of L-A on focal deficits. In patients with AD and in control subjects alike, we found that neither PVH nor L-A bears any relationship to focal neurologic signs. The absence of a correlation between L-A and either cog¬ nitive decline or focal findings supports the view24 that L-A is a normal change in the aging brain. It clearly can reflect infarction,27,28,42,46 however. Periventricular hyperintensity is as¬ sociated with AD and, in control sub¬ jects, with cerebral atrophy. A de¬ crease in brain tissue may leave more free water to be resorbed at the ventric¬ ular border, yielding an increase in PVH.1" Alternatively, PVH may result from increased transependymal seep¬ age of ventricular fluid as a result of decreased brain hydrostatic pressure secondary to atrophy. No pathologic change, except increased water con¬ cur more

frequently (67%)

tent, accompanies PVH,34,36,47 although

investigators24,2" dispute this. Periventricular hyperintensity in AD does not correlate with atrophy. Pa¬ tients with AD exhibit more lateral ven¬ tricular dilatation than do normal sub¬ jects with PVH. Its degree does not vary with the presence of PVH. As PVH is more common in AD than in normal subjects (64% vs 30%), its pres¬ ence favors the former diagnosis. some

Among subjects without PVH, the presence of atrophy should suggest AD, although there is considerable overlap in the degree of atrophy exhibited by healthy subjects and patients with AD.

Thus, either the presence of PVH or of

atrophy without PVH may help to iden¬ tify AD, while the absence of both enti¬ ties may indicate normality. In control subjects, PVH accompa¬ nies deep white-matter changes; a simi¬ lar trend exists among patients with

AD. The association of the two entities may reflect either a common pathogene¬ sis, as they differ little in location, or difficulty in distinguishing between the two. Among control subjects, deep white-matter changes appear in the ab¬ sence of PVH considerably more often than the converse (27% vs 4%; Table 3). This implies that deep white-matter changes herald the development of PVH in control subjects. Among pa¬ tients with AD, similarly, deep whitematter changes without PVH appear slightly more often than does PVH without deep changes (20% vs 12%; Ta¬ ble 4). This may be explained in two ways: PVH and deep white-matter changes coexist, but neither produces the other; alternatively, the develop¬ ment of the latter may precede the ap¬ pearance of the former, with this effect submerged in AD by a high prevalence of PVH from another cause. The genesis of PVH in AD is unclear. White-matter changes seen on CT scans have been related to the presence of hypertension and of infarcts seen on CT scans15 in a population of demented sub¬ jects. Rezek et al16 found significantly elevated systolic blood pressures among patients with AD who exhibited white-matter changes compared with other patients with AD; some investiga¬ tors62 have observed the opposite trend. The absence of marked arteriolar changes in the white matter of

some,16,54,r'3 though not all,14 patients with AD who exhibit white-matter lucencies has focused attention on other factors: cerebral amyloid angiopathy38,64 and even hypotension.54 The former in¬ volves meningeal vessels remote from the ventricle and likely produces L-A, not PVH. Increased water content or tissue loss in the white matter may gen¬ erate PVH via the mechanisms postu¬ lated earlier. Increased water content appears in the white matter of patients with AD on autopsy.54,63 One group25,31 reported an increased Tt value in the white matter of patients with AD rela¬ tive to controls, but another group3" did not. The presence or absence of PVH may help to diagnose or exclude AD, even though the cause of PVH itself remains uncertain.

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Leuko-araiosis, as identified by MRI, embraces common and subtle changes of unclear cause. On microscopic exami¬ nation,24'27'28,42'45"47 some L-A represents areas of infarction, gliosis, or demyelin¬ ation. It may also reflect other entities (état crible, cysts, ventricular diverticulae, or venous angiomas) that spare the brain parenchyma and should not compromise neurologic function. Although severe L-A can produce de¬ mentia,65 its heterogeneity and often limited extent render assessment of its effects difficult. Prospective investiga¬ tion involving more subjects and de¬ tailed neuropsychologic, neuroradiologic, and neurologic evaluations will resolve the issue. The effect of L-A may be more evident when it is more severe, as in MID; with MID, however, one must contend with the confounding ef¬ fects of stroke. Leuko-araiosis may con¬ stitute a risk factor or marker for the development ofmental decline, even if it produces no incapacity itself. Appropri¬ ate observation over time will yield the answer. Lastly, proper ascertainment of coexisting conditions will identify the of L-A and guide future causes treatment. This work was supported by program grant 21 and grant MA 9125 entitled "Neuroimaging of Or¬ ganic Dementia" from the Medical Research Coun¬ cil of Canada, Ottawa, which funded the MRI scan¬ ning, and by grants 66062889-44 and 66063768 from the National Health Research and Development Program, Department of Health and Welfare, Ottawa. We thank all the members of the University of Western Ontario Dementia Study Group, especial¬ ly Kim Wands, for their support and encourage¬ ment. We also thank Dalice Sim, PhD, for making available the resources of the Robarts Research Institute, and Lance Bailey for designing the database.

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