1Journal of Neurology, Neurosurgery, and Psychiatry 1992;55:1018-1023

Reduced regional cerebral blood flow inHuntington's disease studied by SPECT

Steen G Hasselbalch, Gunilla 0berg, Sven A S0rensen, Allan R Andersen,Gunhild Waldemar, Jes F Schmidt, Kirsten Fenger, Olaf B Paulson

AbstractRegional cerebral blood flow (rCBF) was

studied in 18 patients with Huntington'sdisease (HD) and 19 age- and sex-mat-ched controls with high resolution singlephoton emission computerised tomogra-phy (SPECT), using Tc-99m-HMPAO.Significant reductions in tracer uptakewere found in the caudate and lentiformnuclei (20 and 8%) and in the cerebralcortex, especially in the frontal and parie-tal areas (11-13%). No significant reduc-tions were found in the thalamus, mesialtemporal cortex, and occipital cortex.Fourteen patients had neuropsychologicaltesting. Relationship between rCBF andcognitive function was tested by regres-sion analysis. A linear relationship was

found between test scores of WisconsinCard Sorting Test, Picture ArrangementTest and blood flow in the caudatenucleus. Other tests of cognitive function(Block Design Test, Face andWord Recog-nition Test, Street Fragmented PicturesTest, and Similarities Test) correlated bet-ter with flow in the cortical regionsbelieved to be involved in solving thoseparticular tests. These findings indicate,that blood flow is reduced in both corticaland subcortical structures in sympto-matic HD, and that both reductions incortical and subcortical blood flow may berelated to cognitive function in HD.

(7 Neurol Neurosurg Psychiatry 1992;55: 10 18-1023)

Rigshospitalet,University StateHospital, CopenhagenDepartment ofNeurologyS G HasselbalchG ObergA R AndersenG WaldemarO B PaulsonDepartment ofAnaestheticsJ F SchmidtInstitute of MedicalGenetics, University ofCopenhagen,Copenhagen,DenmarkS A SorensenK FengerCorrespondence to:Dr Hasselbalch, Departmentof Neurology N2081,Rigshospitalet, UniversityState Hospital, Blegdamsvej9, DK 2100 0, DenmarkReceived 19 March 1991and in final revised form9 December 1991.Accepted 16 January 1992

Huntington's disease is an autosomal domi-nant inherited neurodegenerative disordercharacterised by choreatic movements, emo-

tional disturbances and dementia. Symptomsusually occur in adult life with mean age ofonset in the mid-thirties and the inevitableprogression of the disease leads to death after15-20 years.' Histologically, in the early stagesof the disease, marked neuronal loss is found inthe caudate nucleus and putamen with fewcortical changes.2 The anomalous gene hasbeen localised to the short arm of chromosome4 and preclinical determination of carrierstatus is now possible, given sufficient familyinformation.3By CT scanning the most prominent feature

in HD is atrophy of the caudate nuclei.4'6Reduction in glucose metabolism in the basalganglia is a consistent finding by positronemission tomography (PET), even in the earlystages of the disease.7-0 This reduction corre-lates to overall functional capacity, motor

symptoms,9 and cognitive function.'0 ThesePET studies have all shown normal corticalglucose metabolism. Cortical atrophy has beenfound in HD by both CT and MRI.41 Studiesof cortical regional cerebral blood flow haveshown conflicting results of both normal bloodflow"2 and reduced blood flow which corre-lated to the degree of dementia.'3 Thus ana-tomical and functional mapping of the brainconsistently show abnormalities in the basalganglia, but the question of cortical involve-ment and its implication on cognitive functionsin HD is not clear.The aim of this study was twofold: 1) to find

abnormal uptake patterns in subcortical orcortical structures by SPECT using Tc-99m-HMPAO as tracer; 2) to correlate thesefindings to performance in neuropsychologicaltests.

Patients and methodsEighteen patients, 8 males and 10 females,were studied with SPECT; neuropsychologicalassessment was possible in 14 subjects (table1). All patients were admitted from the ChoreaHuntington Register at the Institute of Medi-cal Genetics, University of Copenhagen anddiagnosed on the basis of a positive familyhistory ofHD (at least one first degree relative)and typical symptoms. Median age was 46(range 28-63 year). Patients were selected toensure a broad representation of diseaseprogression from recently diagnosed patientsto severely affected patients. The median dura-tion of HD was 2 years (range 1-9 years),measured from the time of diagnosis, butsymptoms might have been present yearsbefore the diagnosis.At the time of the study, twelve patients

received no medicine, five patients receivedneuroleptics and one patient benzodiazepines.The medical therapy was not withdrawn uponentering the trial, but medication was withheldon the examination day.The study was approved by the local ethical

committee of Copenhagen and patients wereincluded after informed consent.The control group consisted of 19 subjects

(8 males, 11 females, mean age 49 (range23-71 years). The control group were admittedaccording to the protocol for a larger controlstudy.'4 Healthy subjects with no neurologicaldeficits and a normal CT scan were included.They had no significant family history ofdementia and Mini Mental State scores wereall equal to or above 27.

All patients were outpatients, examined dur-ing the course of one day. After neuropsycho-

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rCBF in Huntington's Disease

Table 1 Patients

Case Age Duration of Funct. Cortical Cognitivenumber (years) Sex HD (years) score atrophy yJnction

1 58 M 9 3 - ++2 43 F 3 5 yes3 47 F 1 2 no +4 55 F 3 5 yes5 40 M 4 4 yes + + +6 63 M 9 4 yes7 47 F 5 3 yes +++8 46 F 1 2 no + +9 47 M 2 2 no + +10 57 M 1 3 yes +11 53 M 1 4 yes12 49 F 1 2 no ++13 41 M 5 2 - ++14 36 F 1 2 no ++ +15 40 M 1 1 no +16 28 F 4 3 no ++17 45 F 2 2 yes ++18 37 F 1 2 - ++

Median 46 (41-51), values 3 (1-4) = duration, values 3 (2-3 5) = fimct score.Values are median values (95% confidence interval).* = summed neuropsychological test scores: +mild dementia: 0-10, + +moderate dementia:11-20, and + + + severe dementia: 21 - .. = could not complete the test due to advanceddementia.

logical assessment, CT scan and neurologicalexamination, functional capacity was ratedaccording to the scale proposed by Shoulson etal. 15 Thus patients were evaluated according totheir ability to pursue their jobs, handle finan-cial affairs and manage activities of daily living,and their need for care. The scale ranges fromonly minor disability (stage 1) to an advanceddisability state, where the patient usually isconfined to a home (stage 5).

Finally regional cerebral blood flow wasmeasured by SPECT. The SPECT studieswere obtained using the Tomomatic 64, arapidly rotating SPECT Instrument (Medi-matic, Hellerup, Denmark)."6 '7Three slices ofthe brain with 4 cm between slice midplane arestudied simultaneously by four detector arraysrotating close to the patient's head. Onerotation takes 20 seconds, yielding a slicethickness of 10 mm and a resolution in theimage plane of 9-10 mm (FWHM). The pos-itioning of the head is controlled by a lightpositioning system and ink marks on the skin.The tomographic images are reconstructedusing a filtered back-projection algorithm.Approximately 950 MBq 99-Tc-d,1-HMPAO(CERETEC, Amersham International, Lon-don, UK) in 10 ml saline was injected intra-venously into a cubital vein as a bolus. Duringthe injection and data acquisition, the patientswere placed in a resting supine position witheyes closed in a quiet room. The scan proce-dure was started 5 to 10 minutes after injec-tion.

Slices at the levels of 1-0, 3-6, 5 0, 6-3, and9-0 cm above the orbitomeatal (OM) planewere obtained by three data acquisitions, eachof 30 minutes, yielding approximately 3 x 106counts per slice. CT scans were performedeither on a EMI CT1010 or Siemens DR1scanner. Three patients could not be scannedby CT because of strong movement of thehead, whereas this problem was not encoun-tered by SPECT.

RatiosSince the Tc-99m-HMPAO images reflectsflow distribution and not absolute flow values,an internal ratio was used for comparison of

count values between patients and controls:Internal ratio:

Mean countrate in region of interest 100%Mean countrate in cerebellar hemisphere

A standard atlas method developed in ourlaboratory was used for placement ofregions ofinterest (ROI).'4 From a collection of consec-utive sets of standard regions based on a largecontrol material, a set was chosen for eachslice. If necessary, a region of interest wasredrawn to fit the contours of the brain, but theinterregional relations were not altered. In allcases, the caudate nucleus region was redrawnin accordance with its size and location asjudged from the CT scan. All paired CT andSPECT images were evaluated "blindly".When a ROI comprised subregions from morethan one brain slice, the mean pixel value wasestimated as a volume weighted mean of thevalues obtained from the subregions. Due tothe small size of the putamen and globuspallidus, it was necessary to combine theseregions into one, the lentiform nucleus. Lenti-form, caudate, and thalamic flow values wereobtained from the OM +5 cm slice, mesialtemporal area (including hippocampus) fromthe OM + 3-6 cm slice.

Neuropsychological testIncluded in a wider test battery were seven wellknown tests, chosen as probes of five aspects ofcongnitive functioning:1) Reasoning/problem-solving (Wisconsin

Card Sorting Test, Picture ArrangementTest).

2) Learning/recent memory (Face and WordRecognition Test).

3) language/concept formation (WAIS Simi-larities Test).

4) Spatio/constructive ability (Block DesignTest, 12 Four-blocks Tests).

5) Visual perception (Street Fragmented Pic-tures Test).A total of 120 patients with orthopaedic and

peripheral diseases, but no known cerebraldysfunction9 20 served as the reference groupfor evaluation of individual test results (seestatistics).The degree ofdementia was evaluated by the

total test score, which placed the patient in oneof three groups (slight, moderate, and severedementia). Four patients who could not com-plete the neuropsychological test programmewere evaluated by bedside cognitive tests,which in all cases confirmed the finding ofsevere dementia.

StatisticsCorrelations between disease parameters andSPECT findings were either measured by theMann-Whitney U-test (CT atrophy present ornot present) or by Spearman Rank correlation.Regions of interest ratios were tested under thenull hypothesis using the Mann-WhitneyU-test and the Bonferroni correction formultiple comparisons. After correction, aprobability of less than 0 05 was consideredsignificant.The neuropsychological test scores of each

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Hasselbalch, Oberg, Sorensen, Andersen, Waldemar, Schmidt et al

Figure 1 SPECT imagesat the level of 5 cm abovethe OM plane obtainedwith 99Tc-d,l-HMPAO.The images are scaled from0 to 132 (relative tocerebellum = 100). A:Control, 5I years oldnormal female. Note theindentation of the caudatenuclei into the lateralventricles. B: Case 16, 28year old female with HDand moderate cognitiveimpairment. Note thereduced uptake in bothcaudate nuclei. Corticaluptake is only slightlyreduced. C: Case 6, 63year old male with HDand a disease duration ofnine years, severe dementiaand diffuse cortical atrophyon CT The lateralventricles have the typical"box shape" due todegeneration of the caudatenuclei and cortical uptakeis markedly reduced.

patient were compared with the control groupas follows: deviations from expected test per-formance, based on regression analysis of the

variables of age and education for the 120reference subjects, were calculated for eachtest, as well as the statistical significance of theresulting difference score.8 19Thus the higherthe test score, the larger was the negativedeviation from expected level of perfor-mance-indicating severity of cognitivedecline.

Correlation between neuropsychological testscores and regional flow values was tested byregression analysis with flow values as pre-dictors and test score in each test as out-come.As our preliminary analyses, using linear

regression, showed that caudate flow was thebest single predictor ofsome test performancesand cortical flow variables were the bestpredictors of other test performances, we hadto discriminate between two possible situa-tions: a) test performance has the generallyexpected association with cortical blood flow,and the preliminary finding of correlationbetween caudate flow and test performancesimply reflects the inter-regional correlationbetween regional blood flows-in combinationwith the fact that the caudate nucleus is the keytarget of the HD disease process, or b) thepreliminary finding is genuine in the sense thattest performance degrades because of reducedsubcortical rather than cortical blood flow. Tothis end, the cortical region(s) most likely to beinvolved in solving a particular test was des-ignated and used in a two-step regression, thecaudate flow value being introduced into theregression equation in the second step. When-ever the second step did not add significantlyto predictive power (R2, as judged by theappropriate t statistic), there was no reason toabandon the simple hypothesis (a) in favour ofidea (b).

ResultsThe two subgroups of HD patients with(n = 8) and without (n = 7) cortical atrophy,showed no differences in caudate flow or meancortical flow (Mann-Whitney U-test). Dura-tion of HD, and functional score were notcorrelated with flow in the caudate nuclei orwith mean cortical flow (Spearman rank cor-relation).

Region of interest flow valuesReduction in Tc-99m-HMPAO uptake wasfound in both subcortical and cortical ROIs inthe HD group compared with the controls (fig1). As expected, significant reduction wasfound in the caudate nuclei (20%), smaller,but still statistically significant, reduction wasfound in lentiform nuclei (8%) (table 2). Thereduction found in the thalamus did not reachstatistical significance, and uptake in the mesialtemporal region was comparable in the twogroups. In all cortical regions, except in occipi-tal cortex, statistically significant reductions intracer uptake were found, especially in dorso-lateral frontal and parietal regions (11 and13%). The parietal cortex showed the highestvariability among the cortical flow values. Thetotal cortical flow value comprised a volume

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Table 2 Region of Interest Ratios

n HD Control p Significance

N Caud 18 77 (71-81) 96 (91-99) < 0-00001N Lent 18 94 (90-98) 102 (99-108) <0-001Thalam 18 95 (91-98) 104 (97-108) NSMesTmp 16 83 (79-85) 85 (83-88) NSV Front 16 89 (86-91) 96 (91-99) <0 03D Front 17 84 (79-87) 95 (91-99) <0-001SupTmp 18 94 (92-97) 101 (98-106) <0-03Pariet 17 84 (80-90) 97 (96-101) <0-002Occip 18 101 (96-105) 101 (99-110) NSTot Cort 15 91 (88-95) 97 (95-102) <0 03

Median values (95% confidence interval) of flow ratios ((count rate in region of interest/countrate in cerebellar hemisphere) *100) in HD and control group.N Caud = Caudate Nucleus, N Lent = Lentiform Nucleus (Globus Pallidus and Putamen),Thal = Thalamus, V Front = Ventral Frontal Cortex, D Front = Dorsolateral FrontalCortex, Ms Temp = Mesial Temporal Cortex, Sup Tmp = Superor Temporal Cortex, Paret= Parietal Cortex, Occip = Occipital Cortex, Tot Cot = All Cortical ROIs.

weighted mean value of all cortical regionsexamined and was reduced by 6% in the HDgroup.

Neuropsychological test scoresThe test results are shown in fig 2. A high testscore corresponds to a poor performance in thetest (see statistics). The most sensitive test wasthe WAIS Picture Arrangement which showeda significant impairment in all patients but one.Least affected was the test of visual synthesis(Street Fragmented Pictures Test), where only4 patients had significantly high scores. TheBlock Design Test showed a considerablevariability. Seven patients scored within thenormal range in this test, whereas severalsubjects had marked difficulties amounting toconstructional apraxia in one patient (case 7).All but one subject had significantly highscores in at least two tests; case 15 showedclearly subnormal performance only in ThePicture Arrangement Test.Four patients could not complete the tests

due to severe dementia. These four patients

Neuropsychological Test Scores

40

30

20

10

-10WCS Pict Ar Rec Mem Simil Block D Street

* a abnormal/total 1 95 % Cl -e Median

Figure 2 Neuropsychological test scores. Values are deviations from expected performance(0), a high score corresponds to a poor performance (see statistics). Lines indicate medianvalues, bars 95% confidence intervals. The ratio on the number ofpatients, who hadabnormal scores to the total ofpatients tested is shown.WCS = Wisconsin Card Sorting Test, Pict Ar = Picture Arrangement Test, Rec Mem =

Face and Word Recognition Test, Simil = WAIS Similarities Test, Block D = BlockDesign Tests, Stret = Street Fragmented Picture Test.

were not included in the regression analysis ofrelationship between test results and regions ofinterest flow values since individual test resultscould not be obtained.

Results of the regression analysis are shownin table 3. By adding the caudate nucleus tothe regression equation, the linear relationshipimproved significantly between the test resultsofWisconsin Card Sorting Test and ROI flowvalues (R2 increased from a non significantvalue of 27-2% to 61-0%), and betweenPicture Arrangement Test and ROI flow values(R2 increased from 37-8 to 61-2%). Thisindicates a significant linear relationship bet-ween caudate flow values and test scores inthese two tests with poor test performancecorresponding to low flow values in the cau-

date nucleus and hence points to the caudateregion as the primary source of the perform-ance reduction (hypothesis (b) of the methodssection). An insignificant (t between 1-23 and- 0-32) increase in an already significant R2was found after adding caudate nucleus to theregression equation between flow values andtest results of Recognition MemoryTest, Sim-ilarities Test, Block Design Test, and StreetFragmented Pictures Test, indicating that thereis no reason to view the caudate region as theprimary source of performance reduction inthe context of these four tests (note that theSimilarities Test is also only slightly signifi-cantly associated with cortical flow).

DiscussionThe main findings in this study are reductionsin regional cerebral blood flow in both subcor-tical and cortical structures in symptomaticHD patients.The lack of correlation between disease

parameters such as duration ofHD, functionalscore, and cortical atrophy with SPECT find-ings is probably due to the small numbersbeing studied, but might also reflect thevariable progression of the disease.

Since the SPECT-HMPAO method meas-

ures internal ratios, a suitable reference regionis required, that is, a region that is easilydefined and not affected by the disease studied.In diseases affecting both cortical and subcor-tical structures, any kind of cortical referenceregion diminishes the difference between HDpatients and controls, since abnormalities arefound in both the region of interest and thereference region. Although the occipital cortexseems less affected in HD than other corticalareas, this region is difficult to define exactlyon a SPECT image. The cerebellum, however,is easily depicted. A loss of Purkinje cells andneural depletion have been found in thecerebellum in HD,2' but there seems to be no

substantial loss of cerebellar neurons.2' In 14of the HD patients we measured rCBF withthe Xe'33 inhalaton technique. Since this

technique yields image resolution of onlyapproximately 2 cm we considered it unsuit-able for a region of interest analysis, and dataare therefore not shown. The absolute flow,mean (SD), in the cerebellar hemispheres was,however, measured and was comparable in the

*9/14 13/14 9114 9/14 7/14 4/14

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Table 3 Relationship between neuropsychological test results and regional cerebral bloodflow

b t-ratio p(b) R2 p(F)

Wisconsin Card Sorting TestCortical region(s)V Front - 1 190 - 1-37 0-202D Front -0-243 -0-51 0-619 27-2 0-204

Cortical region(s) and n caudatusV Front 0-314 0-36 0-724D Front 0-727 1-44 0-184N Caud -2-420 -2-79 0-021 61-0 0-031

Picture Arrangement TestCortical region(s)V Front - 0-533 - 0-93 0 373D Front -0 473 - 1-52 0-160 37-8 0 093

Cortical region(s) and n caudatusV Front 0-357 0 59 0 573D Front 0 101 0-28 0-783N Caud - 1-430 - 2-33 0 045 61-2 0 030

Face and Word Recognition TestCortical region(s)MesTmp -0 907 -3-54 0-004 51-0 0 004

Cortical region(s) and n caudatusMes Tmp - 0 733 - 2-54 0-027N Caud -0-378 - 1-23 0-246 56-9 0 010

Similarities TestCortical region(s)SupTmp -0-728 - 1-76 0-104 20-5 0-104

Cortical region(s) and n caudatusSup Temp - 0 407 - 0-64 0 543N Caud -0-486 -0-68 0-510 23-7 0-225

Block Designs TestCortical region(s)

Pariet - 0-727 - 3 39 0-006 51-1 0-006Cortical region(s) and n caudutus

Pariet - 0-519 - 0-64 0 543N Caud -0-520 -0-68 0-510 56 0 0-016

Street Fragmented Pictures TestCortical region(s)

Occip - 1-006 - 2-32 0-039 31-0 0 039Cortical region(s) and n caudutusOccip - 0-856 - 1-32 0-21N Caud -0-244 -0-32 0 754 31 7 0 123

The cortical region(s) which were believed to be involved in solving a particular test wereanalysed by multiple (single) regression analysis with neuropsychological test results asoutcome and rCBF as predictors. Then rBCF in caudate nucleus was included as anadditional predictor (see statistics). The four patients who could not complete theneuropsychological tests were excluded from this analysis. Shown are b = regressioncoefficient (negative value indicate correlation between poor test performance and low flowvalues), t-ratio = blstandard error of b, p(b) = probability of b = 0 (t-test), R2 = %of variability explained by the regression measured by analysis of variance, andp(F) = probability of no linear relationship for the multiple (single) regression equation(F-test). In cases of single regression analysis p(b) = p(F). VFront = Ventral FrontalCortex, D Front = Dorsolateral Frontal Cortex, N Caud = Nucleus Caudatus, MesTemp = Mesial Temporal Cortex, Sup Tmp = Superior Temporal Cortex,Pariet = Parietal Cortex, occip = occipital cortex.

two groups [(0 59 (013) ml/g/min in the HDgroup, 0-58 (0 12) ml/g/min in the controlgroup)]. The cerebellum therefore seemed tobe a suitable reference region, but one mustinterpret the results with the knowledge thatboth the choice of reference region and itsplacement influence all internal ratios.The reduction in flow in the subcortical and

cortical structures is statistically significant,when looking at the HD group as a whole, buta considerable overlap is found between thecontrol group and the HD group. In this study,the most pronounced reductions in corticalflow were found in the dorsal parts of theneocortex. Weinberger et al,52 using the 133Xe-inhalation technique, found reductions in cor-tical flow in HD patients, but corrected themfor expiratory pCO2, which elevated the flowvalues. This correction is always controversial,

and with a similar method, Tanahashi'3 foundsignificant flow reductions in mean hemis-pheric flow of aproximately 15%, most pro-nounced in the frontotemporal and parietalregions. We confirm these findings by Tanaha-shi, in terms of relative activity. Measuringglucose metabolism with PET in HD patients,Kuhl et al, Hayden et al, and Young et al79found a much more profound reduction incaudate metabolism of approximately 50 to60%, compared with 20% flow reductionfound in this study. We used a standard atlasROI approach, which might increase flowvalues, because regions can be redrawn toavoid incorporating large sulci or ventricles inthe ROI. In contrast to ROIs of fixed shape(that is, circles or boxes) our approach does, tosome extent, eliminate the effect of partialvolume, which is particularly important to takeinto account when measuring blood flow inneurodegenerative diseases. Apart from dif-ferences in methods, differences in patientmaterial could explain the discrepancybetween this study and the PET studies, sinceeight of our patients had a disease duration ofless than one year. The SPECT method, asmentioned earlier, measures internal ratios,and the problem of reference region might alsohave had an influence on the results. Theactivity distribution images can be correctedfor early backdiffusion of the tracer by themethod proposed by Lassen et al.22 In ourstudy, this approach would further decreasethe flow in caudate nuclei by approximately8% to a total decrease of 28%.

Relationship between neuropsychological test scoresand flow valuesFlow in the caudate nuclei seemed to berelated to the test scores of the Wisconsin CardSortingTest and the Picture ArrangementTest.Although these two tests require frontal-typeabstract reasoning, and flow was clearly sub-normal in frontal cortical regions, the corticalflow values were less related to the test scoresof these tests. Although rCBF is a crudemeasure of neuronal function, these findingsmight support the hypothesis that the frontaldysfunction found in HD is due to degenera-tion of the caudate nuclei and not directlyrelated to some intrinsic malfunction of thefrontal cortex. This hypothesis is also sup-ported by CT studies, in which caudateatrophy correlated to functional status5 and tocognitive impairment,6 and by PET studies, inwhich caudate metabolism correlated to overallfunctional capacity and cognitive function, andputamen metabolism to motor symptoms.9 1OHowever, a counter hypothesis could be thatany intrinsic malfunction of the frontal (andfunctionally related) cortex is better reflectedby caudate than cortical flow values becausethe former have a closer correlation with thedisease stage and/or have less error ofmeasure-ment. This hypothesis is, however, not sup-ported by our findings with the other fourneuropsychological tests. There we found thattest scores (possibly apart from SimilaritiesTest) were significantly related to cortical flowvalues and only indirectly to caudate flow

1 022

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rCBF in Huntington's Disease

values. It is tempting to hypothesise that thecognitive dysfunction in HD stems from bothsubcortical and cortical degeneration.To evaluate the four severely demented

patients who could not complete the neuropsy-chological tests, we assigned a total test scoreof 40 (above the rest of the group) for thesepatients, ranked test scores and flow values,and tested the validation of the regressionanalysis once more. This gave essentially thesame results, although the correlation betweentest results and rCBF became stronger. As anexample, R2 for the regression analysisbetween Wisconsin Card Sorting Test scoresand frontal cortical flow values improved from27-2 to 36-6%. By including caudate flowvalues into this regression analysis, R2increased from 61-0 to 72-5%. This indicatesthat our conclusion regarding the regressionanalysis is not altered by including the severelydemented patients.

It may be an overinterpretation of our datato claim that "frontal" functions are thosemost affected by lesions in the caudate nuclei,although this is the pattern we observed. Also,in three patients with severe cortical flowreduction and diffuse cortical atrophy, clearconstructional apraxia, aphasia and typical"frontal" behaviour was found (cases 4, 6, and7). In a recent study, Kuwert et al23 reportedthat both cortical and caudate glucose metabo-lism correlated to overall cognitive perform-ance in severely affected HD patients, whichagrees with the findings of this study. Thuswhatever might be the cause and extent of thisdegeneration of cortex, it might eventuallyreach a stage where it contributes significantlyto the cognitive dysfunction found in HD.

This study was supported by grants from The LundbeckFoundation, The Danish Medical Research Council, TheWachenhausen Foundation, and The Folmer and IngeborgLuttichau Foundation. We thank Dr J0rgen Hilden, Institute ofMedical Genetics, University of Copenhagen, for valuablediscussion and Gerda Thomson for expert technical assis-tance.

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doi: 10.1136/jnnp.55.11.1018 1992 55: 1018-1023J Neurol Neurosurg Psychiatry

 S G Hasselbalch, G Oberg, S A Sørensen, et al. Huntington's disease studied by SPECT.Reduced regional cerebral blood flow in

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