Fluorodopa uptake and glucose metabolism in early stages of corticobasal degeneration

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1 J Neurol (1999) 246: Steinkopff Verlag 1999 ORIGINAL COMMUNICATION Steven Laureys Eric Salmon Gaetan Garraux Philippe Peigneux Christian Lemaire Christian Degueldre George Franck Fluorodopa uptake and glucose metabolism in early stages of corticobasal degeneration Received: 19 January 1999 Received in revised form: 2 July 1999 Accepted: 14 July 1999 S. Laureys ( ) E. Salmon G. Garraux G. Franck Cyclotron Research Center, and Department of Neurology, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgium laureys@pet.crc.ulg.ac.be, Tel.: , Fax: P. Peigneux Cyclotron Research Center, and Department of Psychology, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgium C. Lemaire C. Degueldre Cyclotron Research Center, University of Liège, B30 Sart Tilman, B-4000 Liège, Belgium Abstract Fluorodopa (FDOPA) and fluorodeoxyglucose (FDG) PET was performed in six patients in early stages of corticobasal degeneration (CBD) and compared to Parkinson s disease (PD) patients with a similar degree of bradykinesia and rigidity and to healthy controls. Statistical parametric mapping analysis comparing CBD to controls showed metabolic decrease in premotor, primary motor, supplementary motor, primary sensory, prefrontal, and parietal associative cortices, and in caudate and thalamus contralateral to the side of clinical signs. Except for the prefrontal regions a similar metabolic pattern was observed when CBD was compared to PD. Putamen FDOPA uptake was decreased in both CBD and PD. Caudate FDOPA uptake in CBD patients was decreased contralateral to clinical signs when compared to controls, but was higher than in PD. In early stages of CBD, FDOPA and FDG PET patterns differed from those observed in PD. In CBD the asymmetry in FDOPA uptake was less pronounced than that of clinical signs or metabolic impairment. Key words Corticobasal degeneration Parkinson s disease Positron emission tomography Glucose metabolism Dopaminergic pathway Introduction Corticobasal degeneration (CBD) is an adult-onset progressive parkinsonian syndrome with cortical and basal ganglionic dysfunction. The typical clinical features include asymmetric rigidity, bradykinesia, tremor, dystonia, myoclonus, dyspraxia, and cortical sensory loss, along with gait disorder, and dementia. The first clinicopathological description of this degenerative disease dates from more than 30 years ago [21]. Since then the nomenclature for this disorder has included corticodentatonigral degeneration with neuronal achromasia, and corticonigral degeneration with achromasia or cortical-basal ganglionic degeneration. The treatment of CBD remains largely ineffective [10]. Clinical diagnosis, particularly in the early stages, is difficult, and recent clinicopathological studies show that CBD is markedly underdiagnosed [14]. Definite diagnosis requires confirmation by autopsy. Neuropathology is characterized by cortical neuronal loss and intense astrogliosis with basophylic argyrophilic and taupositive inclusions in the substantia nigra and basal ganglia and sometimes along the dentato-rubro-thalamic tracts [24]. During life, computed tomography or magnetic resonance imaging (MRI) may demonstrate nonspecific asymmetrical frontoparietal cortical atrophy [8]. Recently, positron computed tomography (PET) studies of striatal fluorodopa (FDOPA) uptake combined with the assessment of cerebral oxygen [23] or fluorodeoxyglucose (FDG) [17] metabolism provided distinctive supportive findings for diagnosis during life. The aim of the present study was to assess the striatal dopamine storage capacity and cerebral glucose metabolism in the early stages of clinically probable CBD and to compare it to that in idiopathic Parkinson s disease (PD). Analysis of FDG PET data used statistical parametric mapping (SPM96) [6].

2 1152 Methods and materials Positron emission tomography PET was performed on a Siemens CTI 951 R 16/31 scanner operating in two-dimensional mode. The head was aligned along a crossed laser beam, and position was checked throughout the study. Data were reconstructed using a Hanning filter (cutoff frequency, 0.5 cycle/pixel) and corrected for attenuation and background activity (final in-plane image resolution, full-width halfmaximum: 8.7 mm). FDOPA uptake was measured with PET to assess presynaptic functional integrity of the dopaminergic nigrostriatal system. FDOPA was synthesized as described previously [1], and radiochemical purity was more than 99%. Six patients with clinically probable corticobasal degeneration (mean age 64 ± 6 years), 15 patients with idiopathic PD (mean age 61 ± 15 years; Hoehn and Yahr stage 1.5 ± 0.8; time since onset of symptoms 1.9 ± 2.0 years), and 8 drug-free, equally sex balanced, healthy volunteers (mean age 54 ± 13 years), underwent a FDOPA PET scan. All PD patients fulfilled the United Kingdom Parkinson s Disease Society Brain Bank criteria for PD [9]. Severity of the akinetic-rigid syndrome of CBD and PD patients was comparable: mean bradykinesia and rigidity scores [16] were 5.9 ± 3.7 and 2.4 ± 3.6 in the CBD group versus 4.6 ± 3.5 and 2.9 ± 2.9 in the PD group. L-Dopa or dopa agonist drugs (when prescribed) were discontinued the night before the scan. All subjects received 100 mg carbidopa 1 h before the study and 50 mg immediately before scanning. A 20-min transmission scan was performed to allow a measured attenuation correction. Patients received 5 8 mci (30 48 nmol) FDOPA intravenously. Dynamic emission scans were collected for 94 min (frames were as follows: 4 60, 3 120, 3 180, s). On a separate occasion we performed a FDG PET scan in the six CBD patients (within 2 months of FDOPA PET), in 15 patients with PD (age 58 ± 13 years; Hoehn and Yahr stage 1.3 ± 0.6; time since 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 transmission scan was performed before the emission scanning. Acquisition started 35 min after FDG injection, and scan duration was 20 min. Informed consent was obtained by all subjects and the study was approved by the Ethics Committee of the University of Liège. Data analysis FDOPA scans were analyzed to extract time-activity data in caudate, anterior putamen, posterior putamen, and cerebellum. Circular regions of interest (ROIs) of 165 pixels were positioned on each side on the basis of tracer activity. In all cases striatal activity was visible on three adjacent planes. The activity in the lowest ventral striatum was not used in this analysis. Average values for each anatomical structure were calculated. Three ROIs were positioned on each cerebellar hemisphere, on two adjacent planes. Regional time activity curves were plotted and the data from min were analyzed using a multiple time graphic analysis approach [19]. Cerebellar tissue activity was used as a nonspecific reference input function [13]. FDG PET data were analyzed with the statistical parametric mapping (SPM) software (SPM96 version; Welcome Department of Cognitive Neurology, Institute of Neurology, London, UK) implemented in MATLAB (Mathworks, Sherborn, Mass., USA). Data from each subject were normalized into a standard stereotaxic space [25] and smoothed with a 16 mm full-width half maximum isotropic kernel. A design matrix, specified according to the general linear model, included the scans from 6 CBD patients, 15 PD patients, and 53 healthy control subjects. Global flow normalization was performed using proportional scaling. The analysis used linear contrasts to identify brain regions where glucose metabolism significantly differed between CBD and PD patients or the control group. The resulting set of voxel values for each contrast, constituting a map of the t statistics [SPM{t}], was transformed to the unit normal distribution SPM{Z} and thresholded at P < (Z = 3.09). The resulting foci were characterized in terms of peak height over the entire volume analyzed at a threshold of corrected P < 0.05 [6]. Case reports Criteria for diagnosis of CBD were insidious onset and gradual progression of an asymmetric levodopa-resistant akinetic-rigid syndrome, with or without other basal ganglia features (dystonia, tremor), associated with signs of cortical dysfunction such as cortical sensory loss or apraxia. The principal clinical signs of the six patients with CBD are summarized in Table 1. Case 1 A 58-year-old right-handed man complained from joint pain and difficulty using the right arm for 6 months. He presented a right sided hemiparesia with hyperreflexia and cortical sensory loss. There was a bradykinesia, cogwheel rigidity, and postural-action tremor of the right arm. Gait showed an enlarged basis and the right arm did not normally swing during walking. Psychometric tests showed constructional apraxia of the left hand, the right hand was useless, without major perceptual impairment. There was apraxic writing (when drawing and at block design subtest of the Wechsler Adult Intelligence Scale), attentional deficit, and impaired performance 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. Table 1 Clinical summary of patients with CBD Patients Age at time of FDOPA-PET (years) Sex M F F M M F Handedness R R R R R L Disease duration (years) 0.5 < Side of initial symptoms R R R R R R Levodopa 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 to PET studies

3 1153 Electroencephalography (EEG) and brain magnetic resonance imaging (MRI) were normal. After PET scanning he developed buccofacial and diaphragm dyskinesias and a mild dysarthria. Case 2 A 58-year-old right-handed woman complained of difficulty in writing for 10 months. The arm became rigid, with postural and action tremor, mildly paretic, and painful. Psychometric testing was refused by the patient. EEG was normal. MRI showed moderate generalized cerebral atrophy most pronounced in the insular regions, with a left predominance. Two years after PET scanning her speech became slurred, the right leg turned awkward, and she developed paresthesia, cortical sensory loss, and stimulus-sensitive myoclonus in her right arm. Case 3 A 71-year-old right-handed woman complained of clumsiness of the 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 impaired in both hands and feet. Psychometric tests showed apraxia of both arms more pronounced on the right. Imitation of gestures (e.g., military salute) was impossible although she could recognize and name most significant gestures. Furthermore, she showed a buccolinguo-facial dyspraxia, an impaired performance on tasks sensitive to frontal lobe dysfunction, and an attentional deficit with impaired verbal short-term memory. EEG was normal, and MRI showed generalized cerebral atrophy. In the following years she developed gait instability with frequent falling, an important global bradykinesia, and dysarthric speech. The right arm became spastic and showed important action and stimulus sensitive myoclonus. Case 4 A 64-year-old right-handed man suffered from progressively increasing bradykinesia and clumsiness of the right hand for 2 years. There were spontaneous, action, and stimulus sensitive myoclonus in both arms, more frequent in the right. He had a right facial hypotonia. There was a moderate cogwheel rigidity, altered proprioception, and dysesthesia of the right hand. Frontal release signs included vivid sucking and palmomental reflexes. Psychometric tests confirmed bilateral apraxia most marked on the left, and a moderate right hemineglect. He had poor visuospatial memory and impaired performance on tasks thought to be sensitive to frontal lobe function (difficulty in planning, structuring, and synthesizing). EEG showed mild diffuse slowing most marked on the left. MRI showed generalized cerebral atrophy most marked on the left and in the frontoparietal regions; the lenticular nuclei were small. In the year following PET scanning he developed a right sided hemiparesia with hyperreflexia, Babinski s sign, invalidating bilateral apraxia, and balance disturbance. Table 2 Statistical results and localization of voxels where glucose metabolism was decreased in patients with corticobasal degeneration compared to normal controls and compared to patients with PD (coordinates are defined in the stereotaxic space of Talairach [25]) Area (Brodmann s area) x y z Z score P (corrected) Versus normal controls L premotor cortex Precentral < Middle frontal < L motor cortex, precentral < L SMA, medial frontal < L parietal cortex Inf. lobule < Sup. lobule < L sensory cortex, postcentral < L prefrontal cortex Sup. frontal Sup. frontal < Middle frontal Middle frontal L caudate nucleus L thalamus R premotor cortex Precentral < Sup. frontal < R SMA, medial frontal R parietal cortex, sup. lobule Versus PD patients L premotor cortex Precentral < Middle frontal L motor cortex, precentral < L SMA, medial frontal < L parietal cortex, inf. lobule < L sensory cortex, postcentral L caudate nucleus L thalamus

4 1154 Fig. 1 The common pattern of altered cerebral metabolism in CBD patients compared to normal controls (A) and to patients with PD (B). SPM{Z} thresholded at voxel level corrected P < 0.05, normalized to the stereotaxic space of Talairach and Tournoux [25] and projected on a normalized MRI template Case 5 A 68-year-old right-handed man suffered a akinetic-rigid syndrome for 2 years. He first complained of difficulty in writing. The right arm showed stimulus sensitive myoclonus and a cogwheel rigidity. Gait was hypokinetic with absent arm swinging and a tendency to anteropulsion. Psychometric testing revealed constructional apraxia, limited long-term memory, an attentional deficit, and impaired performance on tasks sensitive to frontal lobe dysfunction (poor word fluency and planning, and perseverations).

5 1155 Fig.2 Adjusted glucose metabolism (mg/100 g per minute) in the most significant voxel of the left premotor cortex (A), left inferior parietal lobule (B), left caudate nucleus (C) and left thalamus (D) in corticobasal degeneration (CBD), Parkinson s disease (PD), and healthy volunteers (control). For CBD patient s numbers see text EEG and brain MRI were normal. In the 2 years following PET scanning, his speech became moderately dysathric, the downward gaze limited and the right arm progressively apraxic. Case 6 A 68-year-old left-handed woman reported frequent falls for 1.5 years. She had a facial hypomimia, an upward gaze palsy, a right hemiparesis, and a bilateral hyperreflexia with Babinski s sign. Gait was hypokinetic with absent arm swinging and a tendency to retropulsion. The left arm showed a cogwheel rigidity. Frontal release signs included vivid sucking and palmomental reflexes. Psychometric testing showed apraxia of both arms more prominent on the left, poor verbal short memory and poor performance on tasks sensitive to frontal lobe dysfunction (poor word fluency and planning). EEG and brain MRI were normal. After PET scanning her writing and dressing became progressively impossible due to left hand apraxia. She developed buccolingual dyskinesias, major dysarthria, and spontaneous myoclonus in the right arm. Results Table 2 and Fig. 1 show the results of SPM analysis identifying brain regions where glucose metabolism was significantly lower in CBD patients than in healthy controls. Metabolic impairment was markedly asymmetrical in our CBD patients with predominant right-sided clinical signs. Regional decreases involved the left premotor, primary motor, supplementary motor, primary sensory, prefrontal, and parietal associative cortices. Metabolic impairment was bilateral in premotor cortex, supplementary motor area (SMA), and inferior parietal lobule. Subcortical decreases in glucose consumption were observed in the left caudate and thalamus. Table 2 and Fig. 1 also show the results of

6 1156 Table 3 FDOPA uptake values in CBD patients (n = 6) compared to controls (n = 8) and compared to PD patients (n = 15) Caudate Putamen Mean, caudate Mean, putamen Side of onset Other side Side of onset Other side Controls 0.92 ± ± 0.08 PD patients 0.64 ± ± ± ± ± ± 0.12 No No No No No No Mean 0.79 ± ± ± ± ± ± 0.15 P vs. controls < 0.05 NS < < 0.05 NS < P vs. PD < 0.05 NS NS NS < 0.05 NS Values are influx constants (K i 10 2 min 1 ) for FDOPA uptake into the regions listed, using multiple-time graphic analysis method with cerebellar cortex as reference to input function. Data from the 6 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 side contralateral to the first and most severely affected limb is considered the affected striatal side; t test P values are corrected according to Bonferroni for multiple comparisons the SPM analysis comparing CBD patients with PD patients. CBD glucose metabolism was lower in left premotor, primary motor, supplementary motor, primary sensory, parietal associative cortices, left caudate, and thalamus than in PD patients. Figure 2 depicts the individual and mean 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 populations. The uptake of FDOPA into caudate and putamen is presented in Table 3. A two-way analysis of variance comparing controls, PD and CBD patients for anterior versus posterior ROI placement on the putamen showed no significant interaction (F 2,26 = 0.51, P = 0.6). Therefore in further analyses K i of anterior and posterior putamen were averaged to one value. A three-way analysis of variance with condition (control, PD, and CBD) as betweensubjects variable, and K i values in caudate vs. putamen and side (contralateral vs. ipsilateral to clinical symptoms) as within-subject variables gave an overall significance level of Post hoc region-by-region comparison using Tukey s honest significant difference test yielded the P values displayed in Table 3 (results were considered significant at P < 0.05). FDOPA uptake was decreased in CBD caudate contralateral to initial clinical signs when compared to control subjects, but values were significantly higher than those in PD. Putamen FDOPA uptake was lower in both CBD and PD than controls, with a predominance on the side contralateral to clinical signs. However, asymmetry in FDOPA uptake was variable in CBD, and two patients had symmetrical decreases. Discussion The diagnosis of CBD was based on clinical findings. At present there are no validated, universally accepted criteria for the diagnosis of CBD, and neuropathology remains the gold standard. The clinical features and evolution of the presented cases were distinct from other movement disorders. They all followed a chronic progressive course and were asymmetric at onset. All showed higher cortical dysfunction: apraxic signs (all cases) or cortical sensory loss (four cases). None had developed an alien limb. All cases showed an asymmetric rigid/akinetic syndrome resistant to levodopa. Five had spontaneous or reflex focal myoclonus. Two had dystonic limb posturing. Supranuclear gaze palsy was observed in three cases. None showed severe autonomic disturbances. Except for patient no. 6, all CBD patients were right-handed, and all showed a right-sided lateralization of clinical symptoms. Formal psychometric assessment was obtained in five cases. All patients showed deficits on tasks thought to reflect frontal lobe dysfunction, but none was clearly demented. Compared to normal controls our CBD patients showed a markedly asymmetrical pattern of cortical and subcortical hypometabolism. Premotor cortex, parietal association areas, and posterior part of medial area 6 including SMA was bilaterally impaired yet with a clear left sided predominance. Regions of purely left sided metabolic impairment included the left primary motor and primary sensory cortex, prefrontal cortex, caudate, and thalamus. This left-sided asymmetry in cortical and subcortical metabolic impairment is in agreement with the asymmetric rightsided clinical signs manifested in each individual case. Previous studies have reported asymmetric metabolic dys-

7 1157 functioning in paracentral, posterior frontal, and inferior parietal cortices [2, 4]. Necropsy studies have shown extensive and regionally selective neuronal loss (gliosis and achromatic or pale neuronal inclusions) in these cortical areas, accompanied by ipsilateral thalamic cell loss and gliosis, presumed secondary to cortical deafferentation [22]. The observed metabolic impairment in frontal premotor, motor, and parietal areas together with an altered nigrostriatal pathway integrity makes it difficult to draw a precise correlation between particular patient s motor findings and the anatomical site of their pathology. Compared to PD patients those with CBD showed a significant decrease in metabolism in left-sided cortical (left premotor, primary motor, parietal, primary sensory, and SMA) and subcortical (caudate and thalamus) structures. This pattern is similar to the comparison between CBD patients and controls, with the exception of the prefrontal area that seems to be affected in both CBD and PD. Previous studies in nondemented PD patients early in their disease showed small but significant decreases in frontal blood flow and metabolism [5, 20, 26]. It should be noted that cortical atrophy may affect FDG PET measurements due to partial volume effects. Generalized cerebral atrophy was observed in patients 2, 3, and 4, with left-sided focal changes in patients 2 and 4. The left-sided frontoparietal atrophy in patient 4 could confound the observed inferior frontal metabolic impairment in this patient. In patient 3 a generalized atrophy was noted while metabolic impairment was confined to the left paracentral, parietal and frontal regions. Moreover, half of our CBD patients (nos. 1, 5, and 6) had normal MRI results, including patient 5 in whom cortical metabolic impairment was found most prominent of all cases. Given the high degree of significance of our results, we believe that both functional impairment and cerebral atrophy account for the observed reduction in metabolic function in the CBD group analysis. On an individual basis, there seems to be an overlap in cerebral metabolism between CBD patients (e.g., patient 2) and some normal controls and PD patients. This overlap is most pronounced in subcortical structures (caudate and thalamus). FDOPA influx constants (K i min 1 values) are considered to reflect uptake and decarboxylation of FDOPA into 18 F-dopamine and its metabolites by the nigrostriatal nerve terminals. Given tyrosine hydroxylase as rate-limiting enzyme, it is related not to the endogenous dopamine synthesis but to the rate of exogenous dopa metabolism [19]. Thus uptake rate of FDOPA represents the number of functional nigrostriatal dopaminergic neurons at the presynaptic site of the striatum [12]. The accumulation of FDOPA was distributed symmetrically in the caudate nucleus and the putamen of the normal control subjects. In patients with PD we observed a mean reduction to 47% of normal uptake into the putamen and to 25% into the caudate. These results are within the range of previous published data [3, 13, 18]. In our CBD patients we found a mean reduction to 33% of normal uptake into the putamen, while uptake into the caudate was relatively preserved (mean reduction to 11% of normal). Pathological findings report basophylic argyrophilic and tau-positive inclusions in the substantia nigra with variable involvement of the striatum and pallidum [7, 24]. FDOPA-PET studies by Sawle et al. [23] and Nagasawa et al. [17] have reported almost as great a reduction in caudate than in putamen uptake in their CBD patients. However, the disease duration of their cases was considerably longer than for our patients. Lang [11] reported a CBD patient in the early stage where FDOPA uptake was found essentially normal. We did not find a significant difference in putamen FDOPA uptake between CBD and PD patients, but caudate uptake was higher in our early stage CBD patients. Eidelberg et al. [4] described a CBD patient with reduced striatal FDOPA uptake but without quantitative difference with their PD patients. In the pathological process of PD Lewy body degeneration targets the ventrolateral area of the substantia nigra (pars compacta), which projects mainly to the posterior putamen [15]. The relatively preserved caudate FDOPA uptake is thought to reflect the selectivity of nigral cell loss in PD, and this is probably true in CBD as well. We measured FDOPA uptake in anterior and posterior putamen but did not find a significant interaction between groups (CBD, PD, and controls) or putamen ROI placement. If the defect of the striatal dopaminergic system was purely presynaptic, a clinical response to L-dopa therapy would be expected. A concomitant loss of postsynaptic receptors or the coexistence of cortical deficits (premotor and SMA cortex) could explain the observed therapeutic failure. In all CBD patients mean FDOPA uptake in putamen was lower than in controls. This decrease was sometimes more important contralateral to the clinically most severely affected side, but in patients 3 and 5 there was no asymmetry. In patient 6 FDOPA uptake was also impaired in the caudate nucleus contralateral to clinical side, while in the other cases this decrease was less important. In conclusion, FDOPA uptake and cerebral glucose metabolism in patients with CBD in the early stage of their disease differed from those in healthy control subjects and in patients with PD. Striatal FDOPA uptake in our six CBD patients was not always asymmetrical, as were their clinical and metabolic findings. Cerebral metabolic impairment was clearly asymmetrical and targeted both cortical (primary and secondary motor cortex, primary sensory cortex, parietal association areas, and prefrontal cortex) and subcortical (caudate and thalamus) structures. In CBD patients the clinical signs appeared to be related to a dysfunction of corticosubcortical loops more than to loss of nigrostriatal dopaminergic pathway integrity. Acknowledgements This study was supported by the Fonds National pour la Recherche Scientifique, the Fondation Médicale Reine Elisabeth, and by the Interuniversity Pole of Attraction P4/22, Belgian State, Prime Minister s Office, Federal Office for Scientific, Technical and Cultural Affairs. G.G. is researcher at FNRS.

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