Disease and Normal Aging

Quantitative Brain SPECT in Alzheimer's Disease and Normal Aging Keith A. Johnson, Marie F. Kijewski, J. Alex Becker, Basem Garada, Andrew Satlin and B. Leonard Holman Depart,nents

ofMedicine

(Neumlo@j@ Division) and Radiolo@,

Biigham

and Women's

Hospital;

and Haivard

Medical

Schoo4 Boston, Massachusetts; Depamnents ofNeurolo@j' and P@sychiatiyand Magnetic Resonance Imaging Center, McLean Hospital, Bebnont, Massachusetts; and the Department ofPhysics, Massachusetts Institute of Technology, Cambridge,

Massachusetts

METhODS To improvethe diagnosticutilityof brainsingle-photonemission Patients and Control Subjects computed tomography (SPECT) in Alzheimer's disease (AD), we have developed and evaluated an objective method of dif ferentialing patients and healthy elderly controls using a quanui talive image analysis protocol. HMPAO-SPECT image datasets from 29 patients with probable AD and 78 age-matched controls

were registeredto a commonanatomicframeof reference.Ac tMty levels within 120 StandardiZed cortical volumes were deter

Patients (n = 29) were referred from the McLean Hospital Memory Diagnostic Center and the Massachusetts General Hos pital Memory Disorders Unit. Each patient met research criteria

of the NationalInstitutefor NeurologicalDiseasesand Stroke! Alzheimer's Disease and RelatedDisordersAssociation (NINDS ADRDA) for the diagnosis of “probableAlzheimer's disease― (9). There were 11 males and 18 females (mean age (±s.d.)was

Table1).Patientswereexaminedby minedbyan automated procedure. Subjects were classifiedinto 73.0±7.9yr; range,55—84, normal and AD groups by quadratic discriminant analysis using two features: global average activitylevel and average normal ized activitylevelswithinthe two dustersof Standardizedvol

a neurologist, underwentCT and/orMR imaging,and had routine

hematologicandserumchemistrystudies.Thediagnosisof prob ableADwasmadewithoutknowledgeof SPECTresults.Demen umes identifiedas most stgnfficantiy differentinAD by analyals tia severitywas assessedwitha structuredmentalstatusexami of covailance.The dassificationused split-hallrej@alionto nation, the Blessed DementiaScale (BDS) (10). The BDS is ensurevalidresutts.Classificationperformancequantifiedbythe composed of two subtests: one that assesses personality change area under a binomial ROC curve fitted to the data was 0.923 ± 0.036; at a threshold likelihood ratio of , the sample sensitivity

was 91% and specificity was 86%. We concludethat quantitative

and performance

of activities of daily living, and a second that

measures memory, orientationand concentration.A score of 0 to

2 is normal,and a score of 67 indicatesmaximaldementiasever ity. Patients'

BDS scores ranged from 3 to 56 (mean ±s.d.,

SPECTaccuratelydislinguishesAD patientsfromeldedycon trols.

24.7 ±15.6). Controlsubjects(n = 78)werereferredfromtheMassachusetts

J NucIMed1993;34:2044-2048

Instituteof Technology ClinicalResearch Centerwhere each was

extensivelyexaminedmedicallyandneurologicallyas partof an ongoingstudyof normalaging.Eachsubjecthadnormalphysical and neurological examinations, and normal tests of serum chem istiy, hematology and liver and thyroid functions. In addition,

tudies demonstrating abnormal regional cerebral per fusion or metabolism in patients with Alzheimer's disease

each underwenta standardizedbattery of neuropsychologic tests

(AD) (1—8)have led to investigation

jects were extensively screened in thisway to eliminatethose with

of the accuracy of

functional images in the diagnosis of AD. Image analysis methods have relied on visual interpretationof radiotracer activity patterns or statistical analysis of activity ratios within subjectively specified regions of interest (ROl). An objective method of extractinginformationfrom functional brain image datasets would more fully exploit the available quantitative information and may lead to a more accurate diagnosis of AD. We have developed a perfusion brain SPECT image analysis method and tested it in a group of AD patients and normal control subjects.

to documentanyimpairments inspecificcognitivedomains.Sub signs of early cognitive impairment. There were 40 males and 28

females; mean age (±s.d.)was 69.6 ±8.3 yr (range 55—92 yr),

whichdidnotsignificantly differfromADpatients(t-testp > 0.06) (Table 1).

SPECTAcqulsftlon SPECI' images were acquiredusing a dedicated brain imaging

instrument(ASPECT,DigitalScintigraphics,Inc., Waltham,MA) equipped with a stationary annular Nal crystal and a rotating collimator system (12). The measured system resolution in air using capillaryline sources was 8.2 mm at the center and 7.3 mm at 9 cm from the center for @Tc (12). Images were acquired20 mm after intravenous injection of 20.0 mCi (±1.0mCi) of

ReceivedMar.11, 1993;revisionacceptedJuty 19, 1993. For correspondenceand repdnts cont@ Keih A Johnson, MD,Dept. of

Radiology, Brigh@n andWomen's Hospital, Boston, MA02115.

2044

@‘@Tc

HMPAO (Ceretec, AmershamLtd., Amersham, UK), with pa tientssupine,at rest,witheyes open,in a darkenedroom.Total acquisition time was 20 or 30 mm. Two pulse-height analyzer

The Journalof NudearMedicine• Vol.34 • No. 11 • November1993

@

TABLE I DemographicData for Alzheimer'sDisease PatientSand NormalControlSubjects SexAge AD

ellipse, and O@ = 2n(i/N) is the polar angle of the point i measured counterclockwise relative to the horizontal line passing through

(yr)

(M:F)

73.O±7.r

11:18

24.7±

(55-8@ 69.6±8.3@

4038

(3-5@ n.a.

15.6

(n= 29) Controls

(n = 78)

(55@

Valuesare mean±s.d. (range);n.e.indicatesnotapplicable. @

algorithmas itinteractivelygenerateda detailedcontourbasedon pixelintensityandits derivative.A contourconsistedof a set of points{(r1,Os)'= 0, N — 1}whereNis thenumberofpointsinthe contour,r1is thedistanceof pointi fromthecenterof theguiding

Dementia Scale.

*Mean age not significantlydlfferentfrom ADgroup by Student's t-test (p > 0.06).

@ windows were employed with one set at 140 ±14 keV and one set to acquire scatter information at 119 ±7 keV. These two datasets

werestoredas separatearrayscontrolledby an arrayprocessor. After acquisitionwas complete, collimator!ciystalnormaliza tions were performedon each dataset.The scattercorrection method(13),whichis standardon the ASPEC1',was applied.The projections were prefilteredusing a Butterworthfilter (cutoff = 0.175 cycles per pixel; power factor = 10). Sixty-four slices were

the centerof the ellipse. Individualsurfacecontouringaccom plishedcross-sectional(i.e., x-y plane)scaling,compensatingfor differencesin brainsize betweensubjects.Contoursin the four higher slices were automaticallygenerated using the parameters and contours of previous slices. Contours were edited as neces sai)r to define the brain surface in cases where background activ ity was relatively high.

The contourin each slice was then used to definethe outer marginof a circumferential regioncenteredovercorticalactivity in each slice. The circumferential region for each slice was defined

to be theimageareaboundedby thecontours{(r1,Os), = 0, N — 1}and{(0.8r1, Of),i = 0, N — 1}.Thisareawasdividedinto24parts (“macrovoxels―), such that macrovoxel n consisted of image

pixels in the portion of the circumferential region defined by

2@n(n/24) 0 < 2ii((n + 1)124),where n = 0, 23. Thus, the inner margin of the region was concentric with the outer contour and

locatedcloser to the center by a factorof 08 alongany radius. A total of 120macrovoxels(24 x 5 averagedslices)were identified in each SPECT dataset. Statistical

Ana@yses.

We

used

analysis

of

covariance

reconstructed in a 128 x 128matrix with each pixel measuring (ANCOVA)(16)to assess the significanceof changesin patterns 1.67 x 1.67 mm, and attenuationcorrected (14). of regionalactivitybetweendiseaseandcontrolgroups,control lingfor variationin counts in a referencevolume.This technique Quantitative Analysis Data were obtained using a supervised,

that yielded

automated procedure

@“@‘Fc-HMPAO activity levels (mean counts per

voxel) in corticalregions.Thisprocedurecomprisedthreesteps. Standard Oñentation. Each three-dimensional

dataset was dis

playedsimultaneouslyin transaxial,sagittalandcoronalplanes and each plane was rotated to conform to a standard orientation,

is designed to eliminate “global― effects which cause between subjects differences in brain tracer uptake. It was proposed by

Friston et al. (17) and appliedto PET data on a voxel-by-voxel basis.Theanalysisis basedon themodel: Y=@0+@,X+@2Z+@XZ+error.

Eq.1

defined as follows: maximal right-leftsymmetiy of petrous bone

Forourapplication,thedependentvariableY is themeanactivity withina particularmacrovoxeland the independentvariableX is abouty; the frontalandoccipitalpolesdefinedthe sagittalplane the meanactivitywithinthe referencevolume.Forthisstudyof activity voids defined the transaxial plane by rotating the dataset

by rotations about x; and maximal symmetry ofthe caudate heads

AD patients, the reference volume consisted of the two posterior

definedthe coronal plane by rotations about z. This procedure macrovoxels in the four lowest slices which fall within the medial minimized differences in anatomic orientation between subjects. occipitallobe.Z is a dummyvariablewhichtakes the values0 and The reorientedthree-dimensional datasetswere transferredto a 1 for the two subject groups. Valid application of ANCOVA DECstation

5000t200 (Digital Equipment Corp., Maynard, MA)

forfurtherprocessing. Tm,&sa@alReference Slice Selection@ To standardize the range

of slices alongthez-axisto be averagedandanalyzed,we identi fled the 1.67-mmslice which contained the most superiorportion of the thalami. This served as the “seed― slice. To identify the seed slice, uniformscalingofgray-scale values was appliedto the

entire64-slicedataset.The topmosttransaxialslice in whichac

requires that @,is 0, i.e., the group data can be represented by parallel regression lines. Parallelism was established for each mac

rovoxelby a large-samplez-test of a hypothesisthat the regres sion coefficientsfor lines fittedseparatelyto the datafor each grouparedifferent(16).Giventhattheassumptionof parallelism is valid,thedatacanbe fittedto the reducedmodel: Y=@0+@1X+@2Z+ermr.

Eq.2

tivity from the thalami was at 90% or greater of the maximum Identification of “Macmvoxels―@ The seed slice was averaged

Thechangeinregionalactivitythatcanbe attributedto diseaseis representedby fl2,i.e., theverticaldistancebetweenthe regres

with the two slices above and the two slices below to provide

sion lines for the normalandAD groups. The null hypothesis that

activityin the whole brain was definedas the seed slice. meanslice 0. Two adjacent meanslices were calculated from above

and two from below meanslice 0, yielding five meanslices, each

@2 equals zero was tested for each macrovoxel

using a partial F

test (16). The ANCOVA yielded a group of macrovoxels that

with a thicknessof 1.67mm x 5 = 8.35 mm,whichis approxi differed significantly between the two groups (see Results). This information guidedselectionof thefeaturesusedina discriminant mately equal to the FWHM resolution of the ASPECF system. Contours delineating the brain surface in meanslices —2,— 1,0, analysis, and revealed for each macrovoxelthe relationshipbe 1 and2 weregeneratedby a semi-automated edgedetectionalgo

rithm implementedon the DECstation(15). An ellipseapproxi mating the brain surface in slice —2was used as a guide by the

SPECTin ,6Jzheimer's Disease• Johnsonat al.

tween macrovoxel activity and average occipital activity for use in normalization. Discriminant analysis(18) is a method ofclassifying individuals

2045

into groups based on the values of features derived from the

images.Weusedthreefeatures:meancorticalactivity(withinthe 120 macrovoxels) and regional activity, normalized to occipital activity using ANCOVA slopes, within two clusters of macrovox

@

els identifiedby ANCOVA as most significantlydifferentbetween the normal and AD groups. The macrovoxel activity values

were normalizedfor subjectoccipitalactivitylevel O@ by A@ @

@

+

@, (O@—Os), where 0,, is an arbitrary standard occipital

activity level and is the slope of the regressionlines fitted by ANCOVAfor macrovoxeli. Quadraticrather than linearanalysis was usedbecausedatafor the two groupscouldnot be charac terizedby a commoncovariancematrix(p < 0.001).For each

regions). The likelihood ratios (of belonging to the AD rather than the normal group) for individual subjects are plotted in Figure 2. A likelihood ratio of 1 implies equal

probability of belonging to either group. The sample sen sitivity for these data (using resubstitution) was 94% and specificity was 86% (Fig. 2). The area under the binormal ROC curve fitted to data generated by the discriminant analysis using the more robust crossvalidation

technique

was 0.923 ±0.036. At a threshold likelihood ratio of 1, the sample sensitivity

was 91% and specificity

was 86% which

is expected for new patients being imaged in our clinic.

subject, the analysis yielded a likelihood ratio that the subject

belongedto theAD ratherthanthenormalgroup.BinormalROC curves were fitted (19) to data generatedby varying the criterion for assignment to the AD rather than the normal group, i.e., by

DISCUSSION

Quantitative methods for evaluating functional neuroim aging in the aged population are essential because changes threshold likelihood ratios. Ckt@aiflcation performance of the in the normally agingbrainoverlap those seen in neurode methodwas quantifiedby the area under the curve (20).To avoid generative disease. We developed a quantitativemethod in bias introducedby resubstitution,i.e., testing a classification which radiolabeled tracer activity in cortical regions was method by classifyingthe same subjects used to establish the sampled from a standardized brain volume. Our method method, we used a crossvalidation (split-halfreplication)proce calculatingtrue-positiveand false-positiverates for a number of

durewhereby each half of the subjectswas classffiedon the basis

represents

a departure

from ROl-based

methods and has

of meanvectors and covariancematricescalculatedfrom the the following features: (1) Global effects were controlled otherhalf. with an ANCOVA normalizationprocedure, adaptedfrom Friston et al. (17), which permitted the isolation of regional

RESULTS

group differences. (2) A large number ofvoxels was exam ined in each brain, without the use of anatomically sped fled, operator-dependent ROl placement. (3) The AN COVA resulted in selection of a cluster of macrovoxels

Normalized @Tc-HMPAOuptake was significantly re duced (ANCOVA p < 0.001) in AD patients compared to normal control subjects in 43!112 macrovoxels (Fig. 1). Significantly reduced HMPAO uptake was found in left (18 which were used in a discriminant analysis to classify each macrovoxels) and right (15 macrovoxels) temporoparietal, case into AD or normal groups. We validated this proce and left (4 macrovoxels) and right (6 macrovoxels) frontal dure using split-half replication, and evaluated perfor regions. These resultswere not corrected for multiplecom mance using ROC techniques (20). (4) Our method com parisons, however, < 1 significant macrovoxel would be pensated for differences in underlying brain volume expected by chance at p = 0.001. Moreover, the clustering between normals and AD patients by measuring activity in of significantly differentmacrovoxels makes it even more volumes defined by surface contours. Artifactually re unlikely that the results are due to chance. Because each duced perfusion due to brain atrophy was therefore less macrovoxel is composed of a large number of image voxels likely to be a factor in diagnostic accuracy. We recognize, (—500),spatial correlation in noise between adjacent mac

however,

rovoxels is negligible (21,22). Because of the much greater than expected number of highly significantly different mac rovoxels and the clustering, we conclude that these mac rovoxels represent locations of change in brain perfusion due to AD. The parallelism assumption required for ANCOVA was rejected at the p = 0.001 level for only three macrovoxels. At the p = OO1level, the assumption was rejected for 20

and volume correction would be necessaiy to fully evalu ate this issue. Our method successfully distinguished eld erly normal subjects from patients with the clinical diagno sinof probableAD; 25 of29 (86%)AD patients and 71 of 78

macrovoxels,

however, only two of these were among

those found significantly different at the p = 0.001 level. From these results we conclude that the ANCOVA model is appropriate

for quantifying

changes

in brain activity

pat

tems due to AD. The quadraticdiscriminantanalysis used three features: global average activity and average normalized

activity

within two clusters of macrovoxels identified by ANCOVA. The two clusters corresponded to the contigu ous groups (11 left and 5 rightparietal)of macrovoxels that were the most significantly different (Fig. 1, dark blue

2046

that structuraVfunctional

image superposition

(91%) normal control subjectswere correctly classified.

The accuracy of SPECF or PET in AD has been re ported (7;23—25)in studies comparing visual image pat terns or ROI measurements with clinical diagnosis estab lished by strictly applying NIH criteria for “probable AD― (9). Accuracy of the NIH criteria evaluated at autopsy is

reported to be approximately 80%—85% (26), but this level of accuracy was obtained in patients who were carefully screened in a research setting, followed over time, and required to be clinically uncomplicated (24,27,28). In the early stages of illness, patients may not yet satisfy these criteria and the diagnostic error rate has been estimated to be 30% (29). The reported accuracy of functional imaging for AD defined by NIH criteria has varied widely and depended on

The Journalof NuclearMedicine• Vol.34 • No. 11 • November1993

A@

.

@DQ

cal

tool

for

evaluating

image abnormality

@

the

presence,

extent

and

course

of

dementia, as well as response to putative therapies. The anatomic distribution of perfusion defects is characteristic of underlying symptomatology (33,36) and the severity of parallels the severity of cognitive im

pairments (4,6,7,35,36). While our method successfully separated AD patients from control subjects, we cannot exclude the possibility that the features responsible for discriminating power were features of dementia, and not specifically ofAD. The development of this type of method sets the stage for further studies of the heterogeneity of AD

9EØ

c@e

(36,37), as well as coexisting conditions such as parkinson

ism and cerebrovasculardisease. levals from a patientwfth AD. At left regions used Inthe discriminant

functions(darkblue)and regionswithsignificantly reducedperfusion REFERENCES (p < 0.001, dark blue or green) are shown superimposed on images

fromthesamepatientasat right.

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Normal Controls

FiGURE2.

AD patients

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The Journalof NudearMedicine• Vol.34 • No. 11 • November1993