J. Wippold M. Duchek,

Franz Janet

II, MD PhD

#{149} Mokhtar #{149} Elizabeth

Senile Dementia A Longitudinal

of atrophy

during

the

study period. However, the overlap of indexes between the patients with SDAT and the control subjects indicates that CT data cannot be used alone to predict the presence or progression

ual

of dementia

in

individ-

cases.

Index terms: Aging #{149} Brain, atrophy, 10.83. Brain,CT, 10.1211 #{149} Brain,volume, 10.1211. Dementia, 10.83

Radiology

1991;

From

179:215-219

the Mallinckrodt

Institute

of Radiolo-

gy (F.J.W., M.H.G.). the Departments of Neurology and Neurosurgery (Neurology) and Pathology (Neuropathology) (J.C.M.) and Occupational Therapy (J.M.D.), the Division of Biostatistics (E.A.G.), and the Alzheimer’s Disease Research Center (F.J.W., M.H.G., J.C.M., J.M.D., E.A.G.), Washington University School of Medicine, 510 5 Kingshighway, St Louis, MO 63110. Received August 6, 1990; revision requested September 18; revision received December 21; accepted December 26. Supported by National Institute on Aging grants AG03991 and AG05681 and National Institute of Mental

Health

grant

quests

to F.J.W.

c

RSNA,

MH31054. 1991

Address

reprint

#{149} John

C. Morris,

and Healthy CT Study’

Volumetric indexes of cerebral atrophy obtained by using computed tomography (CT) were measured longitudinally in patients with senile dementia of the Alzheimer type (SDAT) and in healthy elderly control subjects. Measurements were made three times over a 51-month period. Of the original 44 patients with SDAT, five were available for CT examination at the last time of assessment (51 months); in contrast, 41 of the original 58 control subjects were still available for study at 51 months. As a group, scans of SDAT subjects showed greater atrophy than those of control subjects in all volumetric indexes at each time of testing and demonstrated greater progression

H. Gado, MD A. Grant, PhD

re-

S

MD

Aging:

dementia of the Alzheimem (SDAT) is a disorder chanactemized by insidious onset of progressive deterioration of memory and global cognitive function (1,2). Since the introduction of computed tomography (CT) for clinical use, considerable interest has focused on whether the cerebral atrophy associated with SDAT is greaten than that associated with normal aging. It is generally accepted that cerebral atrophy, as measurcd with CT, occurs during normal aging (3-9). However, the degree and progression of additional atrophy in SDAT remain uncertain. Some investigators have reported that atrophy is strongly associated with SDAT or other dementing processes (10-20), whereas others have found only a ENILE

type

weak

association

(2i-23).

These

con-

flicting results may be due in part to differences in the use of linear versus volumetric CT measurement techniques. In a previous report, Gado et al (24) directly compared linear and volumetric measurements of a group of persons with SDAT with those of healthy control subjects and found that linear measurements showed less pronounced group differences in atrophy than did volumetric measunements. This suggests that volumetric measurement may be a more sensitive indicator of brain volume and atrophy. The purpose of this study was to compare longitudinal differences in the progression of cerebral atrophy between patients with SDAT and control subjects by using volumetric measurements.

SUBJECTS

AND

#{149}

METHODS

cal diagnostic criteria (25). The full characteristics of the research sample have been described previously (26). The diagnosis of SDAT was made on the basis of information obtained in an extensive clinical interview and neurologic examination, which allow determination of a clinical dementia rating (CDR) for each subject (27,28). The CDR is a five-point scale describing the degree of dementia: CDR 0 = no dementia, CDR 0.5 = questionable dementia, CDR 1 = mild dementia, CDR 2 = moderate dementia, and CDR 3 = severe dementia. The reliability of the CDR has been established (29,30). All subjects underwent longitudinal assessments of clinical and psychometric performance, electroencephalographic analysis, laboratory tests, and CT examinations. The CT examinations were conducted at entry and 15, 34, and 66 months after entry into the study. Because CT scans at entry were obtained with a 7070 EM! scanner (Hayes, England) and lent themselves only to linear rather than volumetnc measurements of the cerebrospinal fluid (CSF) space (31), only the CT data from the follow-up scans will be reported in this article. The period of this CT study, therefore, is 51 months, although clinical evaluations spanned the entire 66 months. Furthermore, only scans of subjects who were either CDR 0 or CDR 1 or greater at the first follow-up examination were included in this study. At the 0-, 19-, and 51-month CT volumetric assessments, there were 51, 49, and 41 control subjects, respectively, for whom technically suitable CT scans were available for review. Attrition factors included migration from St Louis, death (three at 51 months), and refusal to participate. All control subjects remained CDR 0 throughout the 51-month period. Forty-four subjects with SDAT were classified as CDR 1 at the initial evaluation. During the study, four of the 16 subjects originally graded as CDR 0.5 pro-

Subjects Forty-four

elderly patients with mild questionable SDAT, and 58 healthy control subjects of comparable age, education, and social position were enrolled in a longitudinal study of SDAT and healthy aging using validated cliniSDAT,

16 with

Abbreviations: Rating, CSF

CDR Clinical Dementia cenebrospinal fluid, SDAT nile dementia of the Alzheimer type, 5% umetnic index of sulcal size, V% volumetric index of ventricular size, V5% volumetric dex of total CSF volume. =

=

Sevolin-

215

gressed

to CDR

scan,

1 by

performed

and

thus

plc.

Technically

the

first

follow-up

15 months

were

included

after

in the

optimal

SDAT

scans

The

composition

summarized

the

of the

in Table

SDAT

group

of dementia study with

CDR

group

In

summary,

the control group (Table

who

had

scans

testing

the for

group and 1). Scans

to CDR

1 at

CDR

The

CT

scans

NJ),

both

at all

with scanner

follow-up

of which

were

the cranial nium were scanning

cavity. obtained

collimation,

Axial scans with the

view.

Data

of

125

of the standard kVp,

stored

on

magnetic

tive volumetric of volumetric ously

described

(24).

on segmenting parenchyma “threshold”

ed by the section.

low area

operator

and

sulci)

section. The after selecting

cluded cerebral

for each

5 seconds

for

quantita-

it depended

the

CT repeated that in-

and excluded the obtaining a value for

volume within between the

the CT values

section; for

values volume

for

and sulci and alone yielded

the the

sections

selected.

the

of sulci. Similarly, the volume of the cranial cavity within the CT section was determined by selecting a threshold value that separated bone (cranium) from soft tissue. Seven

CT

of the

skull

were

excluded

artifacts.

sulci,

tions values,

and The

were the

uppermost

to avoid volumes

base

beam-hardening of the

ventricles,

cranial cavity in the seven secwere summed. From the resultant indexes

of ventricular

size (V%), sulcal size (5%), and volume (VS%) were computed

216

The sections

and

volumetric

#{149} Radiology

SDAT

.

. .

.

.

49

.

12

5

.

51

25

0 no dementia, and are numbers of patients.

CDR

1, 2, and

. .

.

.

Control

Total

.

. .

.

. .

49 3

41

.

1 1 3

.

5

mild,

Small

peripheral

focal

Table

moderate,

.

.

.

.

.

.

.

.

.

141 25 24 11

41 and

severe

201

dementia,

respec-

the

sulcal

a potential

measurements,

(small)

they

source

2

Correlations

Volumetric Size, Sulcal Volume at ar-

of Age with CT Indexes of Ventricular Size, and Total CSF 0 Months

Volumetric Indexes V%

5% VS%

Patients with SDAT* (n = 30)

Control Subjects (n 51)

.05 .20 .09

.18 .43 .37

rep-

of error.

4

Partialled

for

dementia

severity

by using

level.

Analysis

were

nested

within

the

SDAT

group,

be-

the (yen-

particular

same procedure was a region of interest

ventricular the difference

Control

8

thus accounting for any correlations secondary to repeated measures on subjects.

(voxels)

value determined of the CSF spaces within

. .

Data were analyzed with SAS software (SAS Institute, Cary, NC) (32). To assess the changes in volumetric indexes longitudinally, a split-plot analysis of variance was conducted by using all available scans. There were three class variables: group, with two levels (control subjects and patients with SDAT); time, with three levels (0, 19, and 51 months followup); and subjects, with 89 levels (81 subjects with available scans at 0 months and eight additional subjects with available scans at 19 months). In the model, subjects

independent

of pixels

the ventricles sulci, thus

ventricles ventricles

mAs, of

The method has been previ-

Briefly,

number

the threshold (or volume)

tricles

Data

areas of attenuation into and CSF by means of a CT attenuation value select-

The

51 Months

interval

reconThe reconon film

disk

evaluations. assessment

45

was

for a single section. Data were structed on a 256 X 256 matrix. structed images were recorded and

resent

cra-

field

time

of Follow-up

with

25-cm2

acquisition

30

Note.-CDR tively. Values

from

2 or SoIselin,

equipped

and

Total

. .

.

eas of low attenuation, such as lacunar infarctions, were excluded from the ventricular regions of interest. Because they could not, however, reliably be excluded

volumetric assessCSF spaces and

parameters

8-mm

51

.

measurements.

in

visits

a Somatom (Siemens,

software that allowed ment of the intracranial

.

16 11 3

group.

dim-

Measurements

were obtained matom DRH

.

(standard

were

mean age follow-up deviation

5.06), compared with 72.9 years deviation = 4.68) in the control

Volumetric

SDAT

ages of the cranial volume. These volumetric indexes were used as indexes of cerebral atrophy. Subjects with large areas of periventricular white-matter attenuation were cxcluded from this study because of potential contamination of ventricular volume

0.5 at 0

19 months

mated from this study. The the SDAT group at the first scan was 72.6 years (standard

Months

51

from

60 from the SDAT from two subjects

from

and

0, 19,

obtained

periods-141

progressed

months

were

at

l9Months Control

SDAT

0 1 2 3

because

throughout unavailability

201

three

Groups

is

within

largely

Control

and

OMonths

CT scanning (eg, at 51 months, 17 subjects were institutionalized, nine had died, and several had left the St Louis area). for the

of SDAT

avail-

1. Attrition

progression subsequent

1

Composition

with respective-

study

occurred

sam-

were

able for 30, 25, and five patients SDAT at 0, 19, and 51 months, ly.

Table

entry,

total CSF as percent-

RESULTS The correlations three volumetric atrophy (V%, 5%, months are shown cause there was a tion between age

of age and the indexes of cerebral and VS%) at 0 in Table 2. Bemoderate correlaand stage of dementia severity as measured by the CDR (r -.36), the CDR was partialbed out of this portion of the analysis. Although the correlations are moderate, age is significantly cormebated with 5% (P < .002) and VS% (P < .007) in the control group. The oldem the control subjects, the greater the S% and VS% were. Age was not significantly correlated with the measures of cerebral atrophy in the SDAT group, perhaps because the atrophy caused by the disease is greater

than the atrophy that occurs during normal aging. The SDAT group had significantly greater volumetric indexes than the control group on all three measures: V%, F(1, 87) = 22.67; S%, F(1, 87) 32.43; and VS%, F(1, 87) 51.7. All were significant at P < .0001. There was also a significant group-by-time interaction for all three measures: V%, F(2, 108) = 29.14, P < .0001; S%, F(2, 108) = 13.73, P < .0001; VS%, F(2, 108) = 32.76, P < .0001. Only V% changed over time in the control subjects: F(2, 108) = 12.88, P < .0001. A comparison of the means in the control group showed that a slight increase occurred between 19 and 51 months (P < .0007). All three measures increased significantly in the SDAT group over time: V%, F(2, 108) = 58.98, P < .0001; S%, F(2, 108) 13.61, P < .0001; VS%, F(2, 108) 46.92, P < .0001. V% increased significantly between 0 and 19 months (P < .0001) and between 19 and 51 months (P < .01). Both S% and VS% increased significantly from 0 to 19 months but remained stable between 19 and 51 months (Table 3). The box plots of each of the volumetric indexes over time are shown in the Figure. The plots for the controb subjects show a fairly stable course, while the plots for the SDAT group show more variability and an increase over time. Some overlap cxApril

1991

Table Mean

3

Volumetric

Indexes

for Control

and SDAT

Subjects

at

No. of Subjects

V%

51 30

5.7 (2.8) 9.7 (4.3)

Control SDAT Note-Numbers

51 Months

Follow-up

19 Months

5%

in parentheses

and

0, 19,

0 Months

VS%

7.2(2.9) 1 1.2(3.4)

12.9(4.7) 20.9(4.8)

are standard

deviations.

51 Months

No. of Subjects

V%

S%

49 25

5.7 (2.6) 11.8 (5.7)

6.6(2.6) 12.4 (3.2)

See text for discussion

of the significant

interaction

N

__

-r

t

T

I

I

>
20.5), 82% of the subjects had SDAT; only 18% were control subjects. Furthemmore, no systematic association with the severity of SDAT was cvident across the middle and higher mange of VS% values. That is, subjects from each CDR category were in both the middle and higher mange of the distribution.

L

DISCUSSION

z

40

N C’) 5-

U

00

20

U>

LU

-:--.4-

C

IL-

1-

-1-4-

I

-J

11

0

l

-‘-

I

-‘-

‘

I

I

--

______________________

>

This study was conducted to assess the longitudinal differences in cenebra! atrophy between SDAT and healthy aging. The results cleanly indicate large differences in ventricular size, sulcal size, and total CSF volume between patients with SDAT and healthy control subjects over a 51-month period. Scans of the SDAT group showed greater atrophy compared with those of healthy control

subjects use

40

E 0

I[

II

I

I

percentile,

time.

horizontal

(included yond

over

1

1

0

19

the

in data

indexes

Upper

I

1

line

within

interquartile

Vertical

of box box

lines

179

Number

#{149}

outside

‘

“

‘

IY

,)

1

I

OF FOLLOW-UP size

(V%),

75th

percentile, small

sulcal horizontal

of boxes

size

(S%),

lower extend

and

margin lines

and

to nearest

total

CSF

of box dots

point

=

vol-

25th outliers

not be-

range.

ists between the distributions for control and demented subjects. For example, in the distribution of VS% at 0 months, 98% of subjects with VS% values between 4.5 and 14.5

Volume

median,

I

O

51

of ventricular

margin

analysis).

#{149}

I

MONTHS (VS%)

-

T

I

of volumetric

-

L

T

0

plots

#{149} _____

_____

20

1

at the

of volumetric

first

evaluation

were control subjects. Only one subject with SDAT had a VS% within this mange. Greater overlap between SDAT and control subjects occurred in the middle of the distribution

with

measurements.

Cerebra! atrophy in patients SDAT was more pronounced examination. Gado et al (31)

I

>z.

ume

by SDAT

14.5-20.5);

LU

Box

S%

6.3 (2.7) 12.4(3.9)

for time

(VS%,

V%

were control patients with

40

D

41 5

12.3(4.2) 24.2(5.6)

SDAT

Control

No. of Subjects

VS%

with at each also

found greater atrophy in subjects with mild SDAT at entry into their study by using linear measurements. Therefore, some degree of cerebral atrophy already has occurred at an early stage of SDAT. Our results demonstrate that the amount of atmophy in SDAT increased over time. Except for the slight increase in V%, the volumetric indexes of cerebral atrophy were fairly stable for the cognitively normal control subjects during the 51-month study. These findings are in agreement with those from the recently reported longitudinal study of deLcon et a! (17), in which 50 patients with SDAT and 45 control subjects were followed up for 3 years. Similar results were found in earlier longitudinal studies performed with much smaller samples (18,19). the

Our data show that enlargement CSF spaces in SDAT occurs

Radiology

of in

#{149} 217

both

the

ventricles

and

cerebral

indicating

a process of mixed and cortical atrophy. Previous tigators have maintained that

sulci, central invesyen-

tricular enlargement was a better indicator of the presence of SDAT (16). However, their studies relied primarily

on

linear

measurements.

Because

of the geometric complexity of the cerebral sulci, linear measures of a few sulci underrcpnesent differences in their overall volume. Gado et a! (24) compared linear and volumetric measurements of the same subjects and found that volumetric measurements provided better distinction between patients with SDAT and control subjects. DeLeon et a! (17) maintamed that the linear method is as accurate as the volumetric method and easier to use in CT analysis, but they

did

not

measure

the

sulci.

A po-

tential source of error in our study was the inclusion of small peripheral white-matter

areas

of low

attenua-

tion, such as lacunar infarctions, into the sulcal measurement. This was minimized by excluding all individuals with large areas of low attenuation in the white matter from the study

population.

Beam-hardening

artifacts were avoided by eliminating from consideration the uppermost CT sections. Given the limitations sulcal measurements, results were evaluated

as indexes

en than nations. Although

the phy

of atrophy

as absolute

mean

volume

there

values

between

were

the

of math-

differences

SDAT

in

of atro-

and

control

groups, considerable overlap existed between individual patients with SDAT and control subjects. Thus, it was not possible to predict the presence on absence of SDAT for a given case solely on the basis of CT findings.

Although

the

extreme

values

of

the VS% distribution corresponded well with the presence on absence of SDAT, the middle range of VS% distribution was problematic. On the basis of magnetic resonance (MR) imaging volume measurements of the hippocampus,

Scab

et a! (33)

suggested

that detectable hippocampal atrophy occurs early in SDAT and may be more indicative of the presence of the disease than measurements of ventricular size, sulcal size, or brain atrophy.

Dementia severity by the CDR did not highly with CT volumetric (r ranged from .02 to .27).

suned

with mean ing

ence 218

the overlap between indexes of atrophy, suggests

that

neither

non the severity #{149} Radiology

as meacorrelate measures Combined

groups

subjects months

can

differ

still and

problems longitudinal

between

those

of conducting studies

extended in SDAT popula-

in SDAT.

The

control

MR the fact CSF

bone

is not

visualized

Investigators

have

already

demented

phy

progressively

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

1 1.

during

Except

U

Adams RD. Victor M. Principles of neurology. 4th ed. New York: McGraw-Hill, 1989; 923-932. Berg L, Morris JC. Aging and dementia. In: Pearlman AL, Collins RC, eds. Neurobiology of disease. New York: Oxford University Press, 1990; 299-322. Roberts MA, Caird Fl, Grossart KW, Steyen JL. Computerized tomography in the diagnosis of cerebral atrophy. J Neurol Neurosung Psychiatry 1976; 39:909-915. Hahn FJY. Rim K. Frontal ventricular dimensions on normal computed tomography. AJR 1976; 126:593-596. Barron SA, Jacobs L, Kinkel WR. Changes in size of normal lateral ventricles during aging determined by computerized tomography. Neurology 1976; 26:1011-1013. Gyldensted C. Measurements of the nonma! ventricular system and hemispheric sulci of 100 adults with computed tomography. Neuroradiology 1977; 14:183-192. Haug G. Age and sex dependence of the size of normal ventricles on computed tomognaphy. Neunoradiology 1977; 14:201204. Jacoby RJ, Levy R, Dawson JM. Computed tomography in the elderly. I. The normal population. Br J Psychiatry 1980; 136:249-255. Yamaura H, Ito M, Kubota K, Matsuzawa T. Brain atrophy during aging: a quantitative study with computed tomography. Gerontol 1980; 35:492-498. Huckman MS. Fox J, Topel J. The validity of criteria for the evaluation of cerebral atrophy by computed tomography. Radiology 1975; 116:85-92. Roberts MA, Caird Fl. Computenised tomography and intellectual impairment in

the elderly. J Neurol try 1976; 39:986-989. 12.

13.

14.

15.

subjects.

increased

study.

References

demon-

In conclusion, our results demonstrate greater cerebra! atrophy in SDAT than in healthy aging. This increased atrophy was apparent in patients with mild SDAT, and the atro-

of the

Acknowledgments: We thank Leonard Berg, MD. for critical review of this material and Beverly McDonald for manuscript preparation.

with

strated the utility of MR imaging in SDAT (33,38). Validation studies of MR imaging-based volume measurements have also been published (39). One of the major disadvantages of MR imaging is the lengthy time needed to complete the image. This is particularly critical when studying and

period.

group,

imaging. The identification of high cerebral sulci without antifrom the skull should improve volume determinations.

51 months

for minimal increase in V%, the volumetric indexes of atrophy observed in healthy, aging control subjects were fairly stable during the same

available for CT at 51 those who were not. The

however, only diminished from 58 at entry to 41 at 51 months, permitting reasonable estimation of CT features of atrophy in healthy aging oven this period. In the future, MR imaging undoubtedly will be the modality of choice in volumetric studies of the brain. Compared with CT, MR imaging offers superior tissue contrast and multiplanar display. These featunes facilitate analysis of specific structures such as the hippocampus of the temporal lobe, which is a site of selective atrophy in SDAT (36,37). Cortical

the

SDAT

tions are well recognized (34,35). Attnition due to severe debility or death reduces the study population between the times of follow-up. Themefore, the data from the five SDAT patients who were scanned at 51 months may actually underrepresent the deterioration in the original SDAT group. For this study, the small sample size at 51 months limits conclusions about the long-term CT

elderly

in

this findthe pres-

of SDAT

nificantly

changes

determi-

of indexes

be inferred from CT measures. Attrition was notable in the SDAT subjects during the study. The numben of SDAT subjects with technically optimal CT scans diminished from 30 at the first follow-up examination (0 months) to only five at the last foblow-up (51 months). At the time of the first follow-up scan, these five subjects did not differ significantly from the 25 SDAT subjects who were not scanned at 51 months. Subject age, duration of dementia, quantitative measures of cognitive impairment, and CT measures did not sig-

16.

17.

Neurosung

Psychia-

Gonzalez CF. Lantieni RL, Nathan RJ. The CT scan appearance of the brain in the normal elderly population: a correlative study. Neuronadiology 1978; 16:120122. deLeon MJ, Ferris SH, Blau I, et al. Comelations between computenised tomographic changes and behavioural deficits in senile dementia (letter). Lancet 1979; 2:859860. Jacoby RJ, Levy R. Computed tomography in the elderly. II. Senile dementia: diagnosis and functional impairment. Br Psychiatry 1980; 136:256-269. deLeon MJ, Ferris SH, George AE, Reisberg B, Kricheff II, Genshon S. Computed tomography evaluations of brain-behavior relationships in senile dementia of the Alzheimer’s type. Neurobiol Aging 1980; 1:69-79. Bninkman SD, Samwar M, Levin HS, Monmis HH III. Quantitative indexes of computed tomography in dementia and nonmal aging. Radiology 1981; 138:89-92. deLeon MJ, George AE, Reisberg B, et al. Alzheimer’s disease: longitudinal CT studies of ventricular change. AJNR 1989;

April

1991

18.

19.

20.

21.

22.

23.

24.

10:371-376. Luxenbeng JS, Haxby JV, Creasey H, Sundaram M, Rapoport SI. Rate of ventriculan enlargement in dementia of the Alzheimer type correlates with the rate of neuropsychological deterioration. Neurology 1987; 37:1135-1 140. Brinkman SD, Largen JW. Changes in brain ventricular size with repeated CAT scans in suspected Alzheimer’s disease. Am J Psychiatry 1984; 141:81-83. George AE, deLeon MJ, Rosenbloom 5, et al. Ventricular volume and cognitive deficit: a computed tomographic study. Radiology 1983; 149:493-498. Earnest MP, Heaton RK, Wilkinson WE, Manke WF. Cortical atrophy, ventricular enlargement, and intellectual impairment in the aged. Neurology 1979; 29:11381143. Kaszniak AW, Gamron DC, Fox JH, Bergen D, Huckman M. Cerebral atrophy, EEG slowing, age, education, and cognitive functioning in suspected dementia. Neurology 1979; 29:1273-1279. Hughes CP, Gado M. Computed tomognaphy and aging of the brain. Radiology 1981; 139:391-396. Gado M, Hughes CP, Danziger W, Chi D, Jost G, Berg L. Volumetric measurements of cerebrospinal fluid spaces in demented subjects and controls. Radiology 1982;

25.

26.

27.

28.

29.

1988; 30.

McCulla

MM,

31.

32.

Coats

179

#{149} Number

1

M, VanFleet

E, Morris

JC.

Reliability

TF.

NMR measurements of hippocampal atnophy in Alzheimer’s disease. Magn Reson Med 1988; 8:200-208. Zimmen AW, Calkins E, Hadley E, Ostfeld AM, Kaye JM, Kaye D. Conduction of nesearch in geriatric populations. Ann In-

tern Med 1985; 103:276-283. 35.

36.

Botwinick J, Storandt M, Berg L, Boland S. Senile dementia of the Alzheimer type: subject attrition and testability in research. Arch Neunol 1988; 45:493-496. Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal

formation. 37.

Ball

Science

MJ, Fisman

new definition

N, Du-

of

clinical nurse specialists in the staging of dementia. Arch Neurol 1989; 46:12101211. Gado M, Hughes CP, Danzigen W, Chi D. Aging, dementia, and brain atrophy: a longitudinal computed tomognaphic study. AJNR 1983; 4:699-702. SAS Institute, Inc. SAS/STAT guide for personal computers. 6th ed. Cary, NC: SAS Institute, 1987. Scab JP, Jagust WJ, Wong STS, Roos MS.

Reed BR, Budinger

Volume

34.

38.

45:31-32.

chek J, Grant

33.

144:535-538.

Morris JC, McKeel DW Jr. Fulling K, Tonack RM, Berg L. Validation of clinical diagnostic criteria for Alzheimer’s disease. Ann Neurol 1988; 24:17-22. Berg L, Hughes CP, Coben LA, Danziger WL, Martin RL, Knesevich J. Mild senile dementia of the Alzheimer type: research diagnostic criteria, recruitment and description of a study population. J Neurol Neurosurg Psychiatry 1982; 45:962-968. Hughes CP, Berg L, Danziger W, Cohen LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry 1982; 40:566-572. Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24:637-639. Burke WJ, Miller JP, Rubin EH, et al. The reliability of the Washington University Clinical Dementia Rating. Arch Neurol

V. et al.

of Alzheimer’s

disease:

A

a

hippocampal dementia. Lancet 1985; 1:1416. Bowen BC, Barker WW, Loewenstein DA, Sheldon J, Duara R. MR signal abnormalities in memory disorder and dementia.

AJNR 39.

1984; 225:1168-1170.

M, Hachinski

1990; 11:283-290.

Jack CR Jn, Bentley MD, Twomey CK, Zinmeister AR. MR imaging-based volume measurements of the hippocampal formation and anterior temporal lobe: validation studies. Radiology 1990; 176:205-209.

Quantitative

Radiology

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