David Eidelberg

Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease

BACKGROUND Transplantation of human embryonic dopamine neurons into the brains of patients with Parkinsons disease has proved beneficial in open clinical trials. However, whether this intervention would be more effective than sham surgery in a controlled trial is not known. METHODS We randomly assigned 40 patients who were 34 to 75 years of age and had severe Parkinsons disease (mean duration, 14 years) to receive a transplant of nerve cells or sham surgery; all were to be followed in a double-blind manner for one year. In the transplant recipients, cultured mesencephalic tissue from four embryos was implanted into the putamen bilaterally. In the patients who received sham surgery, holes were drilled in the skull but the dura was not penetrated. The primary outcome was a subjective global rating of the change in the severity of disease, scored on a scale of -3.0 to 3.0 at one year, with negative scores indicating a worsening of symptoms and positive scores an improvement. RESULTS The mean (+/-SD) scores on the global rating scale for improvement or deterioration at one year were 0.0+/-2.1 in the transplantation group and -0.4+/-1.7 in the sham-surgery group. Among younger patients (60 years old or younger), standardized tests of Parkinsons disease revealed significant improvement in the transplantation group as compared with the sham-surgery group when patients were tested in the morning before receiving medication (P=0.01 for scores on the Unified Parkinsons Disease Rating Scale; P=0.006 for the Schwab and England score). There was no significant improvement in older patients in the transplantation group. Fiber outgrowth from the transplanted neurons was detected in 17 of the 20 patients in the transplantation group, as indicated by an increase in 18F-fluorodopa uptake on positron-emission tomography or postmortem examination. After improvement in the first year, dystonia and dyskinesias recurred in 15 percent of the patients who received transplants, even after reduction or discontinuation of the dose of levodopa. CONCLUSIONS Human embryonic dopamine-neuron transplants survive in patients with severe Parkinsons disease and result in some clinical benefit in younger but not in older patients.

Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial.

BACKGROUND Dopaminergic neuronal loss in Parkinsons disease leads to changes in the circuitry of the basal ganglia, such as decreased inhibitory GABAergic input to the subthalamic nucleus. We aimed to measure the safety, tolerability, and potential efficacy of transfer of glutamic acid decarboxylase (GAD) gene with adeno-associated virus (AAV) into the subthalamic nucleus of patients with Parkinsons disease. METHODS We did an open label, safety and tolerability trial of unilateral subthalamic viral vector (AAV-GAD) injection in 11 men and 1 woman with Parkinsons disease (mean age 58.2, SD=5.7 years). Four patients received low-dose, four medium-dose, and four high-dose AAV-GAD at New York Presbyterian Hospital. Inclusion criteria consisted of Hoehn and Yahr stage 3 or greater, motor fluctuations with substantial off time, and age 70 years or less. Patients were assessed clinically both off and on medication at baseline and after 1, 3, 6, and 12 months at North Shore Hospital. Efficacy measures included the Unified Parkinsons Disease Rating Scale (UPDRS), scales of activities of daily living (ADL), neuropsychological testing, and PET imaging with 18F-fluorodeoxyglucose. The trial is registered with the ClinicalTrials.gov registry, number NCT00195143. FINDINGS All patients who enrolled had surgery, and there were no dropouts or patients lost to follow-up. There were no adverse events related to gene therapy. Significant improvements in motor UPDRS scores (p=0.0015), predominantly on the side of the body that was contralateral to surgery, were seen 3 months after gene therapy and persisted up to 12 months. PET scans revealed a substantial reduction in thalamic metabolism that was restricted to the treated hemisphere, and a correlation between clinical motor scores and brain metabolism in the supplementary motor area. INTERPRETATION AAV-GAD gene therapy of the subthalamic nucleus is safe and well tolerated by patients with advanced Parkinsons disease, suggesting that in-vivo gene therapy in the adult brain might be safe for various neurodegenerative diseases.

Patterns of regional brain activation associated with different forms of motor learning

To examine the variations in regional cerebral blood flow during execution and learning of reaching movements, we employed a family of kinematically and dynamically controlled motor tasks in which cognitive, mnemonic and executive features of performance were differentiated and characterized quantitatively. During 15O-labeled water positron emission tomography (PET) scans, twelve right-handed subjects moved their dominant hand on a digitizing tablet from a central location to equidistant targets displayed with a cursor on a computer screen in synchrony with a tone. In the preceding week, all subjects practiced three motor tasks: 1) movements to a predictable sequence of targets; 2) learning of new visuomotor transformations in which screen cursor motion was rotated by 30 degrees -60 degrees; 3) learning new target sequences by trial and error, by using previously acquired routines in a task placing heavy load on spatial working memory. The control condition was observing screen and audio displays. Subtraction images were analyzed with Statistical Parametric Mapping to identify significant brain activation foci. Execution of predictable sequences was characterized by a modest decrease in movement time and spatial error. The underlying pattern of activation involved primary motor and sensory areas, cerebellum, basal ganglia. Adaptation to a rotated reference frame, a form of procedural learning, was associated with decrease in the imposed directional bias. This task was associated with activation in the right posterior parietal cortex. New sequences were learned explicitly. Significant activation was found in dorsolateral prefrontal and anterior cingulate cortices. In this study, we have introduced a series of flexible motor tasks with similar kinematic characteristics and different spatial attributes. These tasks can be used to assess specific aspects of motor learning with imaging in health and disease.

FDG PET in the differential diagnosis of parkinsonian disorders

The differential diagnosis of parkinsonian disorders can be challenging, especially early in the disease course. PET imaging with [(18)F]-fluorodeoxyglucose (FDG) has been used to identify characteristic patterns of regional glucose metabolism in patient cohorts with idiopathic Parkinsons disease (PD), as well as variant forms of parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBGD). In this study, we assessed the utility of FDG PET in the differential diagnosis of individual patients with clinical parkinsonism. 135 parkinsonian patients were referred for FDG PET to determine whether their diagnosis could be made accurately based upon their scans. Imaging-based diagnosis was obtained by visual assessment of the individual scans and also by computer-assisted interpretation. The results were compared with 2-year follow-up clinical assessments made by independent movement disorders specialists who were blinded to the original PET findings. We found that blinded computer assessment agreed with clinical diagnosis in 92.4% of all subjects (97.7% early PD, 91.6% late PD, 96% MSA, 85% PSP, 90.1% CBGD, 86.5% healthy control subjects). Concordance of visual inspection with clinical diagnosis was achieved in 85.4% of the patients scanned (88.4% early PD, 97.2% late PD, 76% MSA, 60% PSP, 90.9% CBGD, 90.9% healthy control subjects). This study demonstrates that FDG PET performed at the time of initial referral for parkinsonism accurately predicted the clinical diagnosis of individual patients made at subsequent follow-up. Computer-assisted methodologies may be particularly helpful in situations where experienced readers of FDG PET images are not readily available.

Dyskinesia after fetal cell transplantation for parkinsonism: A PET study

Persistent dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after dopamine cell implantation for Parkinsons disease. In this study, we used [18F]fluorodopa (FDOPA) and positron emission tomography to determine whether this complication resulted from specific alterations in dopamine function after transplantation. Caudate and putamen FDOPA uptake values in these patients (DYS+, n = 5) were compared with those obtained in a cohort of age‐ and disease duration‐matched transplant recipients who did not develop this complication (DYS−, n = 12). PET signal for both groups was compared at baseline and at 12 and 24 months after transplantation. We found that putamen FDOPA uptake was significantly increased (p < 0.005) in DYS+ transplant recipients. These increases were predominantly localized to two zones within the left putamen. In addition to the posterodorsal zone in which a prominent reduction in FDOPA uptake was present at baseline, the DYS+ group also displayed a relative increase ventrally, in which preoperative dopaminergic input was relatively preserved. Postoperative FDOPA uptake did not reach supranormal values over the 24‐month follow‐up period. These findings suggest that unbalanced increases in dopaminergic function can complicate the outcome of neuronal transplantation for parkinsonism.

Metabolic brain networks associated with cognitive function in Parkinson's disease.

The motor manifestations of Parkinsons disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated (p<0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance (p<0.005), visuospatial function (p<0.01), and perceptual motor speed (p<0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test-retest reliability (intraclass correlation coefficient, ICC=0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.

Cerebellothalamocortical connectivity regulates penetrance in dystonia.

Dystonia is a brain disorder characterized by sustained involuntary muscle contractions. It is typically inherited as an autosomal dominant trait with incomplete penetrance. While lacking clear degenerative neuropathology, primary dystonia is thought to involve microstructural and functional changes in neuronal circuitry. In the current study, we used magnetic resonance diffusion tensor imaging and probabilistic tractography to identify the specific circuit abnormalities that underlie clinical penetrance in carriers of genetic mutations for this disorder. This approach revealed reduced integrity of cerebellothalamocortical fiber tracts, likely developmental in origin, in both manifesting and clinically nonmanifesting dystonia mutation carriers. In these subjects, reductions in cerebellothalamic connectivity correlated with increased motor activation responses, consistent with loss of inhibition at the cortical level. Nonmanifesting mutation carriers were distinguished by an additional area of fiber tract disruption situated distally along the thalamocortical segment of the pathway, in tandem with the proximal cerebellar outflow abnormality. In individual gene carriers, clinical penetrance was determined by the difference in connectivity measured at these two sites. Overall, these findings point to a novel mechanism to explain differences in clinical expression in carriers of genes for brain disease.

Metabolic brain networks in neurodegenerative disorders: a functional imaging approach.

Network analysis of functional brain imaging data is an innovative approach to study circuit abnormalities in neurodegenerative diseases. In Parkinsons disease, spatial covariance analysis of resting-state metabolic images has identified specific regional patterns associated with motor and cognitive symptoms. With functional imaging, these metabolic networks have recently been used to measure system-related progression and to evaluate novel treatment strategies. Network analysis is also being used to characterize specific functional biomarkers for Huntingtons disease and Alzheimers disease. These networks have been particularly helpful in uncovering compensatory mechanisms in genetically at-risk individuals. Ongoing developments in network applications are likely to enhance the role of functional imaging in the investigation of neurodegenerative disorders.

Impaired sequence learning in carriers of the DYT1 dystonia mutation

Previous positron emission tomography (PET) studies have shown that nonmanifesting carriers of the DYT1 dystonia mutation express an abnormal pattern of resting glucose metabolism. To determine whether motor behavior is impaired in these subjects, we compared movement and sequence learning in 12 clinically unaffected DYT1 carriers with 12 age‐matched controls. Regional differences in brain function during task performance were assessed with simultaneous H215O/PET. We found that motor performance was similar in the DYT1 and control groups, with no significant differences in movement time and spatial accuracy measured during each of the tasks. In contrast, sequence learning was reduced in gene carriers relative to controls (p < 0.01). PET imaging during motor execution showed increased activation in gene carriers (p < 0.001, uncorrected) in the left premotor cortex and right supplementary motor area, with concomitant reduction in the posterior medial cerebellum. During sequence learning, activation responses in DYT1 carriers were increased in the left ventral prefrontal cortex, and lateral cerebellum. These findings suggest that abnormalities in motor behavior and brain function exist in clinically nonmanifesting DYT1 carriers. Although localized increases in neural activity may enable normal movement execution in these subjects, this mechanism may not compensate for their defect in sequence learning. Ann Neurol 2003;54:102–109

Abnormal Metabolic Network Activity in Parkinson'S Disease: Test—Retest Reproducibility

Parkinsons disease (PD) is associated with an abnormal pattern of regional brain function. The expression of this PD-related covariance pattern (PDRP) has been used to assess disease progression and the response to treatment. In this study, we validated the PDRP network as a measure of parkinsonism by prospectively computing its expression (PDRP scores) in 15O-water (H215O) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans from PD patients and healthy volunteers. The reliability of this measure was also assessed within subjects using a test—retest design in mildly affected and advanced PD patients scanned at baseline and during treatment with levodopa or deep brain stimulation (DBS). We found that PDRP expression was significantly elevated in PD patients (P<0.001) relative to controls in a prospective analysis of brain scans obtained with either H215O or FDG PET. A significant correlation (R2=0.61; P<0.001) was evident between PDRP scores computed from H215O and FDG images in PD subjects scanned with both tracers. Test—retest reproducibility was very high (intraclass correlation coefficient (ICC)>0.92) for PDRP scores measured both within PET session and between sessions separated by up to 2 months. This high reproducibility was observed in both early stage and advanced PD patients scanned at baseline and during treatment. The within-subject variability of this measure was less than 10% for both unmedicated and treated conditions. These findings suggest that the PDRP network is a reproducible and stable descriptor of regional functional abnormalities in parkinsonism. The quantification of PDRP expression in PD patients can serve as a potential biomarker in PET intervention studies for this disorder.