Corticobasal degeneration (CBD) is an adult-onset pro-gressive parkinsonian syndrome with cortical and basalganglionic dysfunction. The typical clinical features in-clude asymmetric rigidity, bradykinesia, tremor, dystonia,myoclonus, dyspraxia, and cortical sensory loss, alongwith gait disorder, and dementia. The first clinicopatho-logical description of this degenerative disease dates frommore than 30 years ago [21]. Since then the nomenclaturefor this disorder has included corticodentatonigral degen-eration with neuronal achromasia, and corticonigral de-generation with achromasia or cortical-basal ganglionicdegeneration. The treatment of CBD remains largely inef-fective [10]. Clinical diagnosis, particularly in the earlystages, is difficult, and recent clinicopathological studiesshow that CBD is markedly underdiagnosed [14]. Defi-nite diagnosis requires confirmation by autopsy. Neu-
ropathology is characterized by cortical neuronal loss andintense astrogliosis with basophylic argyrophilic and tau-positive inclusions in the substantia nigra and basal gan-glia and sometimes along the dentato-rubro-thalamic tracts[24]. During life, computed tomography or magnetic res-onance imaging (MRI) may demonstrate nonspecificasymmetrical frontoparietal cortical atrophy [8]. Recently,positron computed tomography (PET) studies of striatalfluorodopa (FDOPA) uptake combined with the assess-ment of cerebral oxygen [23] or fluorodeoxyglucose (FDG)[17] metabolism provided distinctive supportive findingsfor diagnosis during life.
The aim of the present study was to assess the striataldopamine storage capacity and cerebral glucose metabo-lism in the early stages of clinically probable CBD and tocompare it to that in idiopathic Parkinson’s disease (PD).Analysis of FDG PET data used statistical parametricmapping (SPM96) [6].
Abstract Fluorodopa (FDOPA) andfluorodeoxyglucose (FDG) PET wasperformed in six patients in earlystages of corticobasal degeneration(CBD) and compared to Parkinson’sdisease (PD) patients with a similardegree of bradykinesia and rigidityand to healthy controls. Statisticalparametric mapping analysis com-paring CBD to controls showedmetabolic decrease in premotor, pri-mary motor, supplementary motor,primary sensory, prefrontal, and pari-etal associative cortices, and in cau-date and thalamus contralateral to theside of clinical signs. Except for theprefrontal regions a similar meta-bolic pattern was observed whenCBD was compared to PD. Putamen
FDOPA uptake was decreased inboth CBD and PD. Caudate FDOPAuptake in CBD patients was decreasedcontralateral to clinical signs whencompared to controls, but was higherthan in PD. In early stages of CBD,FDOPA and FDG PET patterns dif-fered from those observed in PD. InCBD the asymmetry in FDOPA up-take was less pronounced than thatof clinical signs or metabolic impair-ment.
Steven LaureysEric SalmonGaetan GarrauxPhilippe PeigneuxChristian LemaireChristian DegueldreGeorge Franck
Fluorodopa uptake and glucose metabolism in early stages of corticobasal degeneration
Received: 19 January 1999Received in revised form: 2 July 1999Accepted: 14 July 1999
S. Laureys (Y) · E. Salmon · G. Garraux ·G. FranckCyclotron Research Center, and Department of Neurology, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgiume-mail: [email protected], Tel.: +32-4-3663687, Fax: +32-4-3662946
P. PeigneuxCyclotron Research Center, and Department of Psychology, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgium
C. Lemaire · C. DegueldreCyclotron Research Center, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgium
Methods and materials
Positron emission tomography
PET was performed on a Siemens CTI 951 R 16/31 scanner oper-ating in two-dimensional mode. The head was aligned along acrossed laser beam, and position was checked throughout thestudy. Data were reconstructed using a Hanning filter (cutoff fre-quency, 0.5 cycle/pixel) and corrected for attenuation and back-ground activity (final in-plane image resolution, full-width half-maximum: 8.7 mm).
FDOPA uptake was measured with PET to assess presynapticfunctional integrity of the dopaminergic nigrostriatal system. FDOPAwas synthesized as described previously [1], and radiochemicalpurity was more than 99%. Six patients with clinically probablecorticobasal degeneration (mean age 64 ± 6 years), 15 patientswith idiopathic PD (mean age 61 ± 15 years; Hoehn and Yahrstage 1.5 ± 0.8; time since onset of symptoms 1.9 ± 2.0 years), and8 drug-free, equally sex balanced, healthy volunteers (mean age 54 ± 13 years), underwent a FDOPA PET scan. All PD patientsfulfilled the United Kingdom Parkinson’s Disease Society BrainBank criteria for PD [9]. Severity of the akinetic-rigid syndrome ofCBD and PD patients was comparable: mean bradykinesia andrigidity scores [16] were 5.9 ± 3.7 and 2.4 ± 3.6 in the CBD groupversus 4.6 ± 3.5 and 2.9 ± 2.9 in the PD group. L-Dopa or dopa ag-onist drugs (when prescribed) were discontinued the night beforethe scan. All subjects received 100 mg carbidopa 1 h before thestudy and 50 mg immediately before scanning. A 20-min trans-mission scan was performed to allow a measured attenuation cor-rection. Patients received 5–8 mCi (30–48 nmol) FDOPA intra-venously. Dynamic emission scans were collected for 94 min(frames were as follows: 4 × 60, 3 × 120, 3 × 180, 15 × 300 s).
On a separate occasion we performed a FDG PET scan in thesix CBD patients (within 2 months of FDOPA PET), in 15 patientswith PD (age 58 ± 13 years; Hoehn and Yahr stage 1.3 ± 0.6; timesince onset of symptoms 2.6 ± 2.1 years), and in 53 drug-free,equally sex balanced, healthy volunteers (mean age 60 ± 12 years).FDG (7 mCi) was injected intravenously. A 20-min transmissionscan was performed before the emission scanning. Acquisitionstarted 35 min after FDG injection, and scan duration was 20 min.
Informed consent was obtained by all subjects and the studywas approved by the Ethics Committee of the University of Liège.
Data analysis
FDOPA scans were analyzed to extract time-activity data in cau-date, anterior putamen, posterior putamen, and cerebellum. Circu-lar regions of interest (ROIs) of 165 pixels were positioned on eachside on the basis of tracer activity. In all cases striatal activity wasvisible on three adjacent planes. The activity in the lowest “ventralstriatum” was not used in this analysis. Average values for eachanatomical structure were calculated. Three ROIs were positionedon each cerebellar hemisphere, on two adjacent planes. Regionaltime activity curves were plotted and the data from 20–94 minwere analyzed using a multiple time graphic analysis approach[19]. Cerebellar tissue activity was used as a nonspecific referenceinput function [13].
FDG PET data were analyzed with the statistical parametricmapping (SPM) software (SPM96 version; Welcome Departmentof Cognitive Neurology, Institute of Neurology, London, UK) im-plemented in MATLAB (Mathworks, Sherborn, Mass., USA). Datafrom each subject were normalized into a standard stereotaxic space[25] and smoothed with a 16 mm full-width half maximum isotropickernel. A design matrix, specified according to the general linearmodel, included the scans from 6 CBD patients, 15 PD patients, and53 healthy control subjects. Global flow normalization was per-formed using proportional scaling. The analysis used linear contraststo identify brain regions where glucose metabolism significantly dif-
fered between CBD and PD patients or the control group. The re-sulting set of voxel values for each contrast, constituting a map ofthe t statistics [SPM{t}], was transformed to the unit normal distrib-ution SPM{Z} and thresholded at P < 0.001 (Z = 3.09). The result-ing foci were characterized in terms of peak height over the entirevolume analyzed at a threshold of corrected P < 0.05 [6].
Case reports
Criteria for diagnosis of CBD were insidious onset and gradualprogression of an asymmetric levodopa-resistant akinetic-rigidsyndrome, with or without other basal ganglia features (dystonia,tremor), associated with signs of cortical dysfunction such as cor-tical sensory loss or apraxia. The principal clinical signs of the sixpatients with CBD are summarized in Table 1.
Case 1
A 58-year-old right-handed man complained from joint pain anddifficulty using the right arm for 6 months. He presented a rightsided hemiparesia with hyperreflexia and cortical sensory loss.There was a bradykinesia, cogwheel rigidity, and postural-actiontremor of the right arm. Gait showed an enlarged basis and the rightarm did not normally swing during walking. Psychometric testsshowed constructional apraxia of the left hand, the right hand wasuseless, without major perceptual impairment. There was apraxicwriting (when drawing and at block design subtest of the WechslerAdult Intelligence Scale), attentional deficit, and impaired perfor-mance on tests thought to be sensitive to frontal lobe dysfunction(graphic perseverations, difficulty in planning, poor word fluency).The patient had frontal release signs, and aggressive behavior.
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Table 1 Clinical summary of patients with CBD
Patients
1 2 3 4 5 6
Age at time of FDOPA-PET 58 58 71 64 68 68(years)
Sex M F F M M FHandedness R R R R R LDisease duration (years) 0.5 < 1 1 2 2 1.5Side of initial symptoms R R R R R RLevodopa resistance + + + + + +Akinesia, rigidity + + + + + +Postural instability, falls (+) – (+) (+) – +Myoclonus (+) (+) + + + (+)Tremor (postural, action) + + + – – –Cortical sensory loss + (+) + – + –Apraxic signs + + + + + +Alien limb – – – – – –Dementia – – – – – –Frontal dysfunction + – + + + +Supranuclear gaze palsy – – + – (+) +Hyperreflexia + – (+) – + +Primitive reflexes + – – + – +Babinski’s sign – – (+) (+) – +Dysarthria (+) + (+) + (+) (+)
+, Present; –, absent; (+), signs that have developed subsequent toPET studies
Electroencephalography (EEG) and brain magnetic resonance imag-ing (MRI) were normal. After PET scanning he developed bucco-facial and diaphragm dyskinesias and a mild dysarthria.
Case 2
A 58-year-old right-handed woman complained of difficulty inwriting for 10 months. The arm became rigid, with postural andaction tremor, mildly paretic, and painful. Psychometric testingwas refused by the patient. EEG was normal. MRI showed moder-ate generalized cerebral atrophy most pronounced in the insular re-gions, with a left predominance. Two years after PET scanning herspeech became slurred, the right leg turned awkward, and she de-veloped paresthesia, cortical sensory loss, and stimulus-sensitivemyoclonus in her right arm.
Case 3
A 71-year-old right-handed woman complained of clumsiness ofthe right arm for 1 year. She had limited upgaze eye movements,dystonia of the right hand, postural-action tremor of the right arm,and cogwheel rigidity in the left arm. Proprioception was impairedin both hands and feet. Psychometric tests showed apraxia of botharms more pronounced on the right. Imitation of gestures (e.g.,military salute) was impossible although she could recognize andname most significant gestures. Furthermore, she showed a buc-
colinguo-facial dyspraxia, an impaired performance on tasks sensi-tive to frontal lobe dysfunction, and an attentional deficit with im-paired verbal short-term memory. EEG was normal, and MRIshowed generalized cerebral atrophy. In the following years shedeveloped gait instability with frequent falling, an important globalbradykinesia, and dysarthric speech. The right arm became spasticand showed important action and stimulus sensitive myoclonus.
Case 4
A 64-year-old right-handed man suffered from progressively in-creasing bradykinesia and clumsiness of the right hand for 2 years.There were spontaneous, action, and stimulus sensitive myoclonusin both arms, more frequent in the right. He had a right facial hy-potonia. There was a moderate cogwheel rigidity, altered proprio-ception, and dysesthesia of the right hand. Frontal release signs in-cluded vivid sucking and palmomental reflexes. Psychometrictests confirmed bilateral apraxia most marked on the left, and amoderate right hemineglect. He had poor visuospatial memory andimpaired performance on tasks thought to be sensitive to frontallobe function (difficulty in planning, structuring, and synthesiz-ing). EEG showed mild diffuse slowing most marked on the left.MRI showed generalized cerebral atrophy most marked on the leftand in the frontoparietal regions; the lenticular nuclei were small.In the year following PET scanning he developed a right sidedhemiparesia with hyperreflexia, Babinski’s sign, invalidating bilat-eral apraxia, and balance disturbance.
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Table 2 Statistical results andlocalization of voxels whereglucose metabolism was de-creased in patients with corti-cobasal degeneration comparedto normal controls and com-pared to patients with PD (co-ordinates are defined in thestereotaxic space of Talairach[25])
Area (Brodmann’s area) x y z Z score P (corrected)
A 68-year-old right-handed man suffered a akinetic-rigid syn-drome for 2 years. He first complained of difficulty in writing. Theright arm showed stimulus sensitive myoclonus and a cogwheel
rigidity. Gait was hypokinetic with absent arm swinging and a ten-dency to anteropulsion. Psychometric testing revealed construc-tional apraxia, limited long-term memory, an attentional deficit,and impaired performance on tasks sensitive to frontal lobe dys-function (poor word fluency and planning, and perseverations).
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Fig.1 The common pattern ofaltered cerebral metabolism inCBD patients compared to nor-mal controls (A) and to pa-tients with PD (B). SPM{Z}thresholded at voxel level cor-rected P < 0.05, normalized tothe stereotaxic space of Ta-lairach and Tournoux [25] andprojected on a normalized MRItemplate
EEG and brain MRI were normal. In the 2 years following PETscanning, his speech became moderately dysathric, the downwardgaze limited and the right arm progressively apraxic.
Case 6
A 68-year-old left-handed woman reported frequent falls for 1.5years. She had a facial hypomimia, an upward gaze palsy, a righthemiparesis, and a bilateral hyperreflexia with Babinski’s sign.Gait was hypokinetic with absent arm swinging and a tendency toretropulsion. The left arm showed a cogwheel rigidity. Frontal re-lease signs included vivid sucking and palmomental reflexes. Psy-chometric testing showed apraxia of both arms more prominent onthe left, poor verbal short memory and poor performance on taskssensitive to frontal lobe dysfunction (poor word fluency and plan-
ning). EEG and brain MRI were normal. After PET scanning herwriting and dressing became progressively impossible due to lefthand apraxia. She developed buccolingual dyskinesias, majordysarthria, and spontaneous myoclonus in the right arm.
Results
Table 2 and Fig.1 show the results of SPM analysis iden-tifying brain regions where glucose metabolism was sig-nificantly lower in CBD patients than in healthy controls.Metabolic impairment was markedly asymmetrical in ourCBD patients with predominant right-sided clinical signs.Regional decreases involved the left premotor, primarymotor, supplementary motor, primary sensory, prefrontal,and parietal associative cortices. Metabolic impairmentwas bilateral in premotor cortex, supplementary motor area(SMA), and inferior parietal lobule. Subcortical decreasesin glucose consumption were observed in the left caudateand thalamus. Table 2 and Fig.1 also show the results of
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Fig.2 Adjusted glucose metabolism (mg/100 g per minute) in themost significant voxel of the left premotor cortex (A), left inferiorparietal lobule (B), left caudate nucleus (C) and left thalamus (D)in corticobasal degeneration (CBD), Parkinson’s disease (PD), andhealthy volunteers (control). For CBD patient’s numbers see text
the SPM analysis comparing CBD patients with PD pa-tients. CBD glucose metabolism was lower in left premo-tor, primary motor, supplementary motor, primary sensory,parietal associative cortices, left caudate, and thalamusthan in PD patients. Figure 2 depicts the individual andmean adjusted glucose metabolism in left premotor cortex(panel A), parietal cortex (panel B), left caudate nucleus(panel C), and left thalamus (panel D) in the three popula-tions.
The uptake of FDOPA into caudate and putamen ispresented in Table 3. A two-way analysis of variancecomparing controls, PD and CBD patients for anteriorversus posterior ROI placement on the putamen showedno significant interaction (F2,26 = 0.51, P = 0.6). Thereforein further analyses Ki of anterior and posterior putamenwere averaged to one value. A three-way analysis of vari-ance with condition (control, PD, and CBD) as between-subjects variable, and Ki values in caudate vs. putamenand side (contralateral vs. ipsilateral to clinical symp-toms) as within-subject variables gave an overall signifi-cance level of 0.0001. Post hoc region-by-region compar-ison using Tukey’s honest significant difference testyielded the P values displayed in Table 3 (results wereconsidered significant at P < 0.05). FDOPA uptake wasdecreased in CBD caudate contralateral to initial clinicalsigns when compared to control subjects, but values weresignificantly higher than those in PD. Putamen FDOPAuptake was lower in both CBD and PD than controls, witha predominance on the side contralateral to clinical signs.However, asymmetry in FDOPA uptake was variable inCBD, and two patients had symmetrical decreases.
Discussion
The diagnosis of CBD was based on clinical findings. Atpresent there are no validated, universally accepted crite-ria for the diagnosis of CBD, and neuropathology remainsthe gold standard. The clinical features and evolution ofthe presented cases were distinct from other movementdisorders. They all followed a chronic progressive courseand were asymmetric at onset. All showed higher corticaldysfunction: apraxic signs (all cases) or cortical sensoryloss (four cases). None had developed an alien limb. Allcases showed an asymmetric rigid/akinetic syndrome re-sistant to levodopa. Five had spontaneous or reflex focalmyoclonus. Two had dystonic limb posturing. Supranu-clear gaze palsy was observed in three cases. None showedsevere autonomic disturbances. Except for patient no. 6,all CBD patients were right-handed, and all showed aright-sided lateralization of clinical symptoms. Formalpsychometric assessment was obtained in five cases. Allpatients showed deficits on tasks thought to reflect frontallobe dysfunction, but none was clearly demented.
Compared to normal controls our CBD patients showeda markedly asymmetrical pattern of cortical and subcorti-cal hypometabolism. Premotor cortex, parietal associationareas, and posterior part of medial area 6 including SMAwas bilaterally impaired yet with a clear left sided pre-dominance. Regions of purely left sided metabolic im-pairment included the left primary motor and primary sen-sory cortex, prefrontal cortex, caudate, and thalamus. Thisleft-sided asymmetry in cortical and subcortical metabolicimpairment is in agreement with the asymmetric right-sided clinical signs manifested in each individual case.Previous studies have reported asymmetric metabolic dys-
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Table 3 FDOPA uptake values in CBD patients (n = 6) compared to controls (n = 8) and compared to PD patients (n = 15)
P vs. controls < 0.05 NS < 0.001 < 0.05 NS < 0.005P vs. PD < 0.05 NS NS NS < 0.05 NS
Values are influx constants (Ki 10–2 min–1) for FDOPA uptake intothe regions listed, using multiple-time graphic analysis methodwith cerebellar cortex as reference to input function. Data from the6 patients with suspected CBD are compared to 8 controls (4 women, 4 men, mean age 54 ± 13 years) and to 15 patients with
idiopathic PD (mean age 58 ± 13 years). For each patient the sidecontralateral to the first and most severely affected limb is consid-ered the “affected” striatal side; t test P values are corrected ac-cording to Bonferroni for multiple comparisons
functioning in paracentral, posterior frontal, and inferiorparietal cortices [2, 4]. Necropsy studies have shown ex-tensive and regionally selective neuronal loss (gliosis andachromatic or pale neuronal inclusions) in these corticalareas, accompanied by ipsilateral thalamic cell loss andgliosis, presumed secondary to cortical deafferentation [22].The observed metabolic impairment in frontal premotor,motor, and parietal areas together with an altered nigros-triatal pathway integrity makes it difficult to draw a pre-cise correlation between particular patient’s motor find-ings and the anatomical site of their pathology.
Compared to PD patients those with CBD showed asignificant decrease in metabolism in left-sided cortical(left premotor, primary motor, parietal, primary sensory,and SMA) and subcortical (caudate and thalamus) struc-tures. This pattern is similar to the comparison betweenCBD patients and controls, with the exception of the pre-frontal area that seems to be affected in both CBD andPD. Previous studies in nondemented PD patients early intheir disease showed small but significant decreases infrontal blood flow and metabolism [5, 20, 26]. It shouldbe noted that cortical atrophy may affect FDG PET mea-surements due to partial volume effects. Generalized cere-bral atrophy was observed in patients 2, 3, and 4, withleft-sided focal changes in patients 2 and 4. The left-sidedfrontoparietal atrophy in patient 4 could confound the ob-served inferior frontal metabolic impairment in this pa-tient. In patient 3 a generalized atrophy was noted whilemetabolic impairment was confined to the left paracentral,parietal and frontal regions. Moreover, half of our CBDpatients (nos. 1, 5, and 6) had normal MRI results, includ-ing patient 5 in whom cortical metabolic impairment wasfound most prominent of all cases. Given the high degreeof significance of our results, we believe that both func-tional impairment and cerebral atrophy account for theobserved reduction in metabolic function in the CBDgroup analysis. On an individual basis, there seems to bean overlap in cerebral metabolism between CBD patients(e.g., patient 2) and some normal controls and PD pa-tients. This overlap is most pronounced in subcorticalstructures (caudate and thalamus).
FDOPA influx constants (Ki min–1 values) are consid-ered to reflect uptake and decarboxylation of FDOPA into18F-dopamine and its metabolites by the nigrostriatalnerve terminals. Given tyrosine hydroxylase as rate-limit-ing enzyme, it is related not to the endogenous dopaminesynthesis but to the rate of exogenous dopa metabolism[19]. Thus uptake rate of FDOPA represents the numberof functional nigrostriatal dopaminergic neurons at thepresynaptic site of the striatum [12]. The accumulation ofFDOPA was distributed symmetrically in the caudate nu-cleus and the putamen of the normal control subjects. Inpatients with PD we observed a mean reduction to 47% ofnormal uptake into the putamen and to 25% into the cau-date. These results are within the range of previous pub-lished data [3, 13, 18]. In our CBD patients we found amean reduction to 33% of normal uptake into the puta-
men, while uptake into the caudate was relatively pre-served (mean reduction to 11% of normal). Pathologicalfindings report basophylic argyrophilic and tau-positiveinclusions in the substantia nigra with variable involve-ment of the striatum and pallidum [7, 24]. FDOPA-PETstudies by Sawle et al. [23] and Nagasawa et al. [17] havereported almost as great a reduction in caudate than inputamen uptake in their CBD patients. However, the dis-ease duration of their cases was considerably longer thanfor our patients. Lang [11] reported a CBD patient in theearly stage where FDOPA uptake was found “essentiallynormal.” We did not find a significant difference in puta-men FDOPA uptake between CBD and PD patients, butcaudate uptake was higher in our early stage CBD pa-tients. Eidelberg et al. [4] described a CBD patient withreduced striatal FDOPA uptake but without quantitativedifference with their PD patients. In the pathologicalprocess of PD Lewy body degeneration targets the ventro-lateral area of the substantia nigra (pars compacta), whichprojects mainly to the posterior putamen [15]. The rela-tively preserved caudate FDOPA uptake is thought to re-flect the selectivity of nigral cell loss in PD, and this isprobably true in CBD as well. We measured FDOPA up-take in anterior and posterior putamen but did not find asignificant interaction between groups (CBD, PD, andcontrols) or putamen ROI placement. If the defect of thestriatal dopaminergic system was purely presynaptic, aclinical response to L-dopa therapy would be expected. Aconcomitant loss of postsynaptic receptors or the coexis-tence of cortical deficits (premotor and SMA cortex)could explain the observed therapeutic failure. In all CBDpatients mean FDOPA uptake in putamen was lower thanin controls. This decrease was sometimes more importantcontralateral to the clinically most severely affected side,but in patients 3 and 5 there was no asymmetry. In patient6 FDOPA uptake was also impaired in the caudate nucleuscontralateral to clinical side, while in the other cases thisdecrease was less important.
In conclusion, FDOPA uptake and cerebral glucosemetabolism in patients with CBD in the early stage oftheir disease differed from those in healthy control sub-jects and in patients with PD. Striatal FDOPA uptake inour six CBD patients was not always asymmetrical, as weretheir clinical and metabolic findings. Cerebral metabolicimpairment was clearly asymmetrical and targeted bothcortical (primary and secondary motor cortex, primarysensory cortex, parietal association areas, and prefrontalcortex) and subcortical (caudate and thalamus) structures.In CBD patients the clinical signs appeared to be relatedto a dysfunction of corticosubcortical loops more than toloss of nigrostriatal dopaminergic pathway integrity.
Acknowledgements This study was supported by the Fonds Na-tional pour la Recherche Scientifique, the Fondation MédicaleReine Elisabeth, and by the Interuniversity Pole of AttractionP4/22, Belgian State, Prime Minister’s Office, Federal Office forScientific, Technical and Cultural Affairs. G.G. is researcher atFNRS.
8.Hauser RA, Murtaugh FR, Akhter K,Gold M, Olanow CW (1996) Magneticresonance imaging of corticobasal de-generation. J Neuroimaging 6 :222–226
9.Hughes AJ, Daniel SE, Kilford L, LeesAJ (1992) Accuracy of clinical diagno-sis of idiopathic Parkinson’s disease: aclinico-pathological study of 100 cases.J Neurol Neurosurg Psychiatry 55 :181–184
10.Kompoliti K, Goetz CG, Boeve BF,Maraganore DM, Ahlskog JE, MarsdenCD, Bhatia KP, Greene PE, Przed-borski S, Seal EC, Burns RS, HauserRA, Gauger LL, Factor SA, Molho ES,Riley DE (1998) Clinical presentationand pharmacological therapy in corti-cobasal degeneration. Arch Neurol 55 :957–961
13.Leenders KL, Salmon EP, Tyrrell P,Perani D, Brooks DJ, Sager H, JonesT, Marsden CD, Frackowiak RS(1990) The nigrostriatal dopaminergicsystem assessed in vivo by positronemission tomography in healthy volun-teer subjects and patients with Parkin-son’s disease. Arch Neurol 47 :1290–1298
14.Litvan I, Agid Y, Goetz C, Jankovic J,Wenning GK, Brandel JP, Lai EC,Verny M, Ray-Chaudhuri K, McKeeA, Jellinger K, Pearce RK, Bartko JJ(1997) Accuracy of the clinical diagno-sis of corticobasal degeneration: a clin-icopathologic study. Neurology 48 :119–125
15.Ma SY, Rinne JO, Collan Y, Roytta M,Rinne UK (1996) A quantitative mor-phometrical study of neuron degenera-tion in the substantia nigra in Parkin-son’s disease. J Neurol Sci 140 :40–45
16.Marsden CD, Parkes JD, Rees JE(1973) A year’s comparison of treat-ment of patients with parkinson’s dis-ease with levodopa combined with car-bidopa versus treatment with levodopaalone. Lancet 2 :1459–1462
17.Nagasawa H, Tanji H, Nomura H,Saito H, Itoyama Y, Kimura I, Tuji S,Fujiwara T, Iwata R, Itoh M, Ido T(1996) PET study of cerebral glucosemetabolism and fluorodopa uptake inpatients with corticobasal degeneration.J Neurol Sci 139 :210–217
18.Otsuka M, Ichiya Y, Hosokawa S,Kuwabara Y, Tahara T, Fukumura T,Kato M, Masuda K, Goto I (1991) Sri-atal blood flow, glucose metabolismand 18F-Dopa uptake: difference inParkinson’s disease and atypical Par-kinsonism. J Neurol Neurosurg Psychi-atry 54 :898–904
25.Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the humanbrain. Thieme, Stuttgart
26.Wolfson LI, Leenders KL, Brown LL,et al (1985) Alterations of regionalcerebral blood flow and oxygen metab-olism in Parkinson’s disease. Neurol-ogy 35 :1399–1405
