Biomedical subjects
Publications and source records attributed to D Eidelberg.
Eleven patients suffering from Parkinson's disease were followed for up to 4 years after unilateral pallidotomy. We observed persistent contralateral improvement and unexpected ipsilateral improvement of motor symptoms. In addition, there was a protracted relief of contralateral dyskinesias and maintenance of relatively stable levodopa dosage.
We assessed the utility of preoperative clinical assessment and functional brain imaging with 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) in predicting the clinical outcome of stereotaxic pallidotomy for the treatment of advanced Parkinson's disease (PD). Twenty-two PD patients undergoing posteroventral pallidotomy were assessed preoperatively with the Core Assessment Program for Intracerebral Transplantation (CAPIT) ratings measured on and off levodopa; quantitative FDG/PET was also performed before surgery. Preoperative clinical and metabolic measurements were correlated with changes in off-state CAPIT ratings determined 3 months after surgery. Clinical outcome following pallidotomy was also correlated with intraoperative measures of spontaneous pallidal single-unit activity as well as postoperative MRI measurements of lesion volume and location. We found that unilateral pallidotomy resulted in variable clinical improvement in off-state CAPIT scores for the contralateral limbs (mean change 30.9 +/- 15.5%). Postoperative MRI revealed that pallidotomy lesions were comparable in location and volume across the patients. Clinical outcome following surgery correlated significantly with preoperative measures of CAPIT score change with levodopa administration (r = 0.60, p < 0.005) and with preoperative FDG/PET measurements of lentiform glucose metabolism (r = 0.71, p < 0.0005). Operative outcome did not correlate with intraoperative measures of spontaneous pallidal neuronal firing rate. We conclude that preoperative measurements of lentiform glucose metabolism and levodopa responsiveness may be useful indicators of motor improvement following pallidotomy. Both preoperative quantitative measures, either singly or in combination, may be helpful in selecting optimal candidates for surgery.
Stereotaxic ventral pallidotomy has been employed in the symptomatic treatment of patients with advanced Parkinson's disease (PD). To understand the pathophysiology of clinical outcome following this procedure, we studied 10 PD patients (5 men and 5 women; mean age 60.0 +/- 6.1 years; mean Hoehn and Yahr stage 3.8 +/- 1.0) with quantitative 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). All patients were scanned preoperatively; 8 of 10 patients were rescanned 6 to 8 months following surgery. Clinical performance was assessed off medications before and after surgery using standardized timed motor tasks. We found that preoperative lentiform metabolism correlated significantly with improvement in contralateral motor tasks at 1 week, 3 months, and 6 months following unilateral pallidotomy (p<0.03). Postoperatively, significant metabolic increases were noted in the primary motor cortex, lateral premotor cortex, and dorsolateral prefrontal cortex (p<0.01) of the hemisphere that underwent surgery. Improvement in contralateral limb motor performance correlated significantly with surgical declines in thalamic metabolism (p<0.01) and increases in lateral frontal metabolism (p<0.05). Principal components analysis disclosed a significant covariance pattern characterized by postoperative declines in ipsilateral lentiform and thalamic metabolism associated with bilateral increase in supplementary motor control metabolism. Subject scores for this pattern correlated significantly with improvements in both contralateral and ipsilateral limb performance (p<0.005). These results suggest that pallidotomy reduced the preoperative overaction of the inhibitory pallidothalamic projection. Clinical improvement may be associated with modulations in regional brain metabolism occurring remote from the lesion site.
A procedure for the routine preparation of [18F]FP-CIT has been developed. Purification of the final product was achieved by preparative HPLC using phenethyl column without decomposition or epimerization. [18F] labeled-N-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl) nortropane was prepared and PET imaging was performed on human subjects. A high uptake into striatal regions was observed. HPLC plasma analysis using [18F]FP-CIT indicated the presence of only one metabolite. By directly comparing the behavior of these three radiotracers ([18F]DOPA, [123I]FP-CIT, and [18F]FP-CIT) in the same subjects, we can enhance our understanding of the dopaminergic system as well as the relative potential of these techniques in a clinical research setting.
A 65-year-old man with no past history of violent or criminal behavior abruptly strangled his wife after she scratched his face during a domestic argument. He appeared emotionally blunted and lacked insight into the motivations for his violent actions. The presence of left-sided cerebral dysfunction was initially suggested by subtly decreased dexterity of his dominant right hand. A magnetic resonance image (MRI) revealed a large arachnoid cyst centered in his left Sylvian fissure that effaced ventral frontal, anterior temporal and insular cortical gyri. The left middle cerebral artery was displaced relative to an earlier study, providing indirect evidence that the cyst had enlarged during his adult life. Neuropsychological testing indicated generally intact cognitive abilities except for mild impairment on tests of prospective memory and executive functions. He was found to have intermittently decreased EEG amplitude in the left fronto-temporal region. Positron emission tomography (PET) revealed significantly reduced resting glucose metabolism in the left frontal and temporal lobes. He was also found to have pathological diminution of autonomic responses to affectively charged visual stimuli, a phenomenon previously reported in patients with ventromedial frontal lobe injury and acquired disturbances of social conduct. In light of these findings, we suggest that his violent behavior represents stimulus-bound aggression, triggered by a novel physical threat and unchecked by learned social restraints owing to the presence of ventral prefrontal dysfunction.
Normal aging is associated with the degeneration of specific neural systems. We used [18F] fluorodeoxyglucose (FDG)/positron emission tomography (PET) and a statistical model of regional covariation to explore the metabolic topography of this process. We calculated global and regional metabolic rates for glucose (GMR and rCMRglc) in two groups of normal subjects studied independently on different tomographs: Group 1--130 normal subjects (62 men and 68 women; range 21-90 years); Group 2--20 normal subjects (10 men and 10 women; range 24-78 years). In each of the two groups, the Scaled Subprofile Model (SSM) was applied to rCMRglc data to identify specific age-related profiles. The validity of these profiles as aging markers was assessed by correlating the associated subject scores with chronological age in both normal populations. SSM analysis disclosed two significant topographic profiles associated with aging. The first topographic profile, extracted in an analysis of group 1 normals, was characterized by relative frontal hypometabolism associated with covariate metabolic increases in the parietooccipital association areas, basal ganglia, mid-brain, and cerebellum. Subject scores for this profile correlated significantly with age in both normal groups (R2 = 0.48 and 0.33, p < 0.0001 for groups 1 and 2, respectively). Because of clinical similarities between normal motoric aging and parkinsonism, we explored the possibility of shared elements in the metabolic topography of both processes. We performed a combined group SSM analysis of the 20 group 2 normals and 22 age-matched Parkinson's disease patients, and identified another aging-related topographic profile. This profile was characterized by relative basal ganglia hypermetabolism associated with covariate decreases in frontal premotor cortex. Subject scores for this profile also correlated significantly with age in both normal groups (group 1: R2 = 0.30, p < 0.00001; group 2: R2 = 0.59, p < 0.01). Healthy aging is associated with reproducible topographic covariation profiles associated with specific neural systems. FDG/PET may provide a useful metabolic marker of the normal aging process.
Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.
Some cases of familial amyotrophic lateral sclerosis (FALS) are associated with copper/zinc superoxide dismutase (Cu/Zn-SOD) mutations, which are implicated in the death of motor neurons. Because Cu/Zn-SOD is present in high amounts in nigrostriatal dopaminergic neurons, we considered the possibility that FALS may be associated with subclinical nigrostriatal dopaminergic dysfunction. We used [18F]fluorodopa (FDOPA) and PET to study 14 FALS patients (50 +/- 11 years [mean +/- SD]): seven with (FALS-1) and seven without (FALS-0) Cu/Zn-SOD mutations. Fourteen age-matched normal volunteers (48 +/- 18 years) served as controls. Striato-occipital ratios (SORs) for the caudate and the putamen were calculated. Five of the 14 FALS patients had reduced striatal FDOPA uptake in the caudate nucleus, putamen, or both. Mean caudate SOR did not differ among FALS-1, FALS-0, and control subjects. Mean putamen SOR was significantly abnormal in FALS-0 but not in FALS-1 patients. These findings indicate that subclinical nigrostriatal dopaminergic dysfunction is present in some FALS patients and that FDOPA/PET abnormalities are more likely to be associated with FALS-0 status. This suggests that SOD mutations are less cytotoxic to dopaminergic than to motor neurons.
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UNLABELLED: PET has been used to quantify striatal 6-[18F]fluoro-L-dopa (FDOPA) uptake as a measure of presynaptic dopaminergic function. It has been suggested that the estimation of dopa-decarboxylation (DDC) rate, kD3, using a compartmental approach to dynamic FDOPA/PET data, can provide a better objective marker of parkinsonism. This modeling process, however, requires many assumptions to estimate DDC activity with acceptable errors. METHODS: We combined FDOPA 3-O-methyl-fluorodopa PET studies on three normal subjects and five Parkinson's disease patients. RESULTS: The contradicted modeling assumptions are: (a) the rate constants across the blood-brain barrier, KD1 and kD2, for 3OMFD and FDOPA were in similar range (ratio approximately equal to 1) and thus not equal to assumed values of KM1/KD1 of 2.3 derived from rat studies and applied to human FDOPA studies and (b) the KD1/kD2 ratio for frontal cortex was not equal to that for the striatum (0.70 +/- 0.15 versus 1.07 +/- 0.3; p < 0.002). Discriminant analyses indicate that simple estimates like the striatum-to-occipital ratio, or the graphically derived unidirectional transport rate constant (KiFD) separate normals from Parkinson's disease patients at least as accurately as estimates of striatal DDC activity (kD3). CONCLUSION: Measurements of striatal DDC activity with dynamic FDOPA/PET and compartmental modeling may be based on incorrect assumptions. Even though such complex models yield microparameters that may be applicable to certain clinical research demands, they may produce misleading results in other experimental settings.
UNLABELLED: We performed dynamic PET studies with fluorodopa (FDOPA) in 9 normal volunteers and 16 patients with Parkinson's disease to investigate the applicability of dopa decarboxylase (DDC) activity measurements as useful markers of the parkinsonian disease process. METHODS: From the 3-O-methyl-FDOPA (3OMFD)/PET studies, we obtained mean population values of the kinetic rate constants for 3OMFD (K1M = 0.0400 and k2M = 0.0420). We applied these values to calculate striatal DDC activity using the FDOPA compartmental model. We estimated k3D in this group using dynamic FDOPA-PET and population mean K1M and k2M values. We then applied the mean population K1M and k2M values to estimate k3D(pop) to a new group (6 normal volunteers and 11 patients) studied only with dynamic FDOPA-PET. In all FDOPA/PET studies, we calculated striatal uptake rate constants (KiFD) using a graphical method and also measured the striato-occipital ratio (SOR). RESULTS: Although DDC activity has been postulated as a precise indicator of presynaptic nigrostriatal dopaminergic function, KiFD and SOR provided better between-group discrimination than did estimates of striatal DDC activity. KiFD and k3D(pop) both correlated significantly with quantitative disease severity ratings, with a similar degree of accuracy (r = 0.69 and 0.63 for k3D(pop) and KiFD, respectively; p < 0.01). CONCLUSION: Although estimated striatal DDC activity correlates with clinical disability, this measure is comparably less effective for early diagnosis. We conclude that a simple estimate such as striatal KiFD is superior to k3D measurements for most clinical and research applications.
UNLABELLED: SPECT imaging of the dopamine transporter is now an alternative to PET in the quantification of nigrostriatal dopaminergic function. We compared [123I] beta CIT-FP/SPECT and [18F]FDOPA/PET in the assessment of nigrostriatal dopaminergic function in Parkinson's disease (PD) and normal aging. METHODS: We studied 12 mildly affected PD patients (mean age: 61.0 +/- 13.2 yr; H&Y Stage I-II) with both [123I] beta CIT-FP and [18F]FDOPA. Fifteen normal volunteers (mean age: 45.5 +/- 22.1 yr) served as controls for both tracers. We measured the striato-occipital ratio (SOR) for both tracers at approximately 100 min postinjection. RESULTS: We found a highly significant correlation between SOR measures obtained for both tracers (r = 0.79, p < 0.0001). In normal volunteers a significant age-related decline in striatal uptake was noted with [123I] beta CIT-FP (r = -0.56, p < 0.04) but not with [18F]FDOPA. SOR values for both tracers discriminated PD patients from controls with comparable accuracy (F[1,25] = 52.1 and 53.0, p < 0.0001 for [123I] beta CIT-FP and [18F]FDOPA, respectively). UPDRS motor ratings correlated with SOR values obtained by both imaging techniques (r = -0.69 and -0.60, p < 0.04 for [123I] beta CIT-FP and [18F]FDOPA, respectively). CONCLUSION: These results indicate that [123I] beta CIT-FP/SPECT can provide quantitative descriptors of presynaptic dopaminergic function comparable to those obtained with [18F]FDOPA/PET.
UNLABELLED: PET, in conjunction with 18F-fluorodopa (FDOPA), has become the standard technique to assess basal ganglia degeneration in patients with movement disorders. Based on published dosimetry data, the injected dose of FDOPA is limited to 111 Mbq (3 mCi) because of exposure to the bladder wall, which is the critical organ for such studies. These dosimetry studies are based on mathematical models for the bladder radioactivity accumulation and clearance when the subjects were asked to void approximately 2 hr after the intravenous injection of FDOPA. In this study, we improved the radiation dose estimate to the bladder wall using dynamic PET to image the bladder during the uptake phase as well as before and after voiding. METHODS: The subjects were tested on a new protocol. They were hydrated preinjection and given a first bladder void break at 40 min postinjection and a second void at the end of study at 120 min. RESULTS: The MIRD model, applied to the data collected from 10 adults of both sexes, yielded an average absorbed dose of 0.15 +/- 0.08 mGy/MBq (0.57 +/- 0.28 rad/mCi). CONCLUSION: This absorbed dose is significantly lower than previous estimates and allows for FDOPA injections up to 333 Mbq (9 mCi).
We used [18F]fluorodeoxyglucose with positron emission tomography to explore the functional basis of lid opening apraxia (LOA). We studied four patients with LOA without associated pyramidal or extrapyramidal motor dysfunction (mean age 65.5 +/- 4.7 years). We compared measures of glucose metabolism with those calculated for 10 age-matched normal volunteers (mean age 60.6 +/- 11.4). All four patients demonstrated significant metabolic reductions (> 2 SD) in the medial frontal lobe: bilaterally in two, unilaterally in two. Significant abnormal unilateral metabolic reductions in the left basal ganglia were evident in two patients. These findings suggest that medial frontal lobe hypometabolism is associated with LOA. Abnormal striatofrontal interactions may be involved in the pathogenesis of this condition.
Our ongoing study of ventral pallidotomy for the control of Parkinson's disease in selected patients has provided the opportunity to explore the topographical and somatotopic organization of the human globus pallidus. Utilizing microelectrode techniques we have obtained recordings which were correlated with data from MPTP-parkinsonian primates. In addition, we performed pre- and post-operative FDG/PET scans in these patients. Our studies reveal similarities between the MPTP-parkinsonian primate model and human Parkinson's disease in terms of physiologic recordings and responses. However, we have encountered significant differences between dominant and non-dominant hemisphere representations, particularly for the hand, in the human. In addition, our PET studies confirmed, as in previous parkinsonian primate models, glucose hypermetabolism in the lenticular area of Parkinson's disease patients. This hypermetabolism is dramatically altered by creation of a lesion in the globus pallidus medialis. This is demonstrated by follow-up PET scans which reveal not only a decrease in metabolism of the operated lenticular region, but also in the frontal cortical projections. These combined observations of the cellular activity in the globus pallidus and the observed changes in PET metabolism support the selection of the pallidum for lesioning and control of Parkinson's disease, and offer insight into the underlying physiology of this disorder. The above physiological and PET data will be clinically correlated with our ongoing series of 35+ patients.
We used [18F]fluorodeoxyglucose (FDG) and PET with a statistical model of regional metabolic covariation to study brain topographic organization in idiopathic torsion dystonia (ITD). We studied 11 patients with predominantly right-sided ITD and 11 age-matched controls, and measured global, regional cerebral and normalized metabolic rates for glucose (GMR, rCMRGlc, rCMRGlc/GMR). The Scaled Subprofile Model was applied to the combined rCMRGlc dataset to identify topographic covariance profiles associated with ITD. We found that global and regional metabolic rates were normal in ITD. The SSM analysis of the combined groups of ITD patients and normals revealed a significant topographic profile characterized by relative bilateral increases in the metabolic activity of the lateral frontal and paracentral cortices, associated with relative covariate hypermetabolism of the contralateral lentiform nucleus, pons and midbrain. Subject scores for this profile correlated significantly with Fahn-Marsden disease severity ratings (r = 0.67, P < 0.02). In contrast to parkinsonism, lentiform and thalamic metabolism were dissociated in dystonia. We conclude that ITD is characterized by relative metabolic overactivity of the lentiform nucleus and premotor cortices. The presence of lentiform thalamic metabolic dissociation suggests that in this disorder hyperkinetic movements may arise through excessive activity of the direct putameno-pallidal inhibitory pathway.
A 55 year old man with bilateral internal carotid and unilateral vertebral artery occlusions presented subacutely with profound behavioural and cognitive changes featuring frontal lobe deficits. Neuropsychological testing showed severe cognitive impairment compatible with dementia. Anatomical imaging showed only a small right superior frontal infarction. Cerebral blood flow was severely reduced, with profound hypofrontality and limited hypercapnic reactivity, and cerebral metabolism was reduced primarily in the medial frontal lobes. After right sided extracranial to intracranial cerebral bypass surgery, both flow and metabolism improved, as did behavioural and neuropsychological deficits. Perfusion insufficiency from bilateral carotid occlusions, with secondarily reduced metabolism in the frontal zones bilaterally, may be an unusual cause of a reversible frontal dementia syndrome.