Masafumi Fukuda

Metabolic correlates of levodopa response in Parkinson’s disease

Objective: To assess the effects of levodopa on resting-state brain metabolism in PD. Background: In previous studies the authors used [18F] fluorodeoxyglucose (FDG) and PET to quantify regional metabolic abnormalities in PD. They found that this disease is characterized reproducibly by a specific abnormal PD-related pattern (PDRP). In this study the authors used IV levodopa infusion to quantify the effects of dopamine replacement on regional metabolism and PDRP network activity. They tested the hypothesis that clinical response to dopaminergic therapy correlates with these metabolic changes. Methods: The authors used FDG/PET to measure resting-state regional brain metabolism in seven patients with PD (age, 59.4 ± 4.2 years; Hoehn and Yahr stage, 1.9 ± 0.7, mean ± SD); subjects were scanned both off levodopa and during an individually titrated constant-rate IV levodopa infusion. The authors used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. They also quantified levodopa-induced changes in PDRP expression. Metabolic changes with levodopa correlated with clinical improvement as measured by changes in Unified PD Rating Scale (UPDRS) motor scores. Results: Levodopa infusion improved UPDRS motor ratings (30.6% ± 12.0%, p < 0.002) and significantly decreased regional glucose metabolism in the left putamen, right thalamus, bilateral cerebellum, and left primary motor cortex (p < 0.001). Changes in pallidal metabolism correlated significantly with clinical improvement in UPDRS motor ratings (p < 0.01). Levodopa infusion also resulted in a significant (p = 0.01) decline in PDRP expression. The changes in PDRP activity mediated by levodopa correlated significantly with clinical improvement in UPDRS motor ratings (r = −0.78, p < 0.04). Conclusion: Levodopa reduces brain metabolism in the putamen, thalamus, and cerebellum in patients with PD. Additionally, levodopa reduces PD-related pattern activity, and the degree of network suppression correlates with clinical improvement. The response to dopaminergic therapy in Patients with PD may be determined by the modulation of cortico-striato-pallido-thalamocortical pathways.

Functional networks in motor sequence learning: abnormal topographies in Parkinson's disease.

We examined the neural circuitry underlying the explicit learning of motor sequences in normal subjects and patients with early stage Parkinsons disease (PD) using 15O‐water (H215O) positron emission tomography (PET) and network analysis. All subjects were scanned while learning motor sequences in a task emphasizing explicit learning, and during a kinematically controlled motor execution reference task. Because different brain networks are thought to subserve target acquisition and retrieval during motor sequence learning, we used separate behavioral indices to quantify these aspects of learning during the PET experiments. In the normal cohort, network analysis of the PET data revealed a significant covariance pattern associated with acquisition performance. This topography was characterized by activations in the left dorsolateral prefrontal cortex (PFdl), rostral supplementary motor area (preSMA), anterior cingulate cortex, and in the left caudate/putamen. A second independent covariance pattern was associated with retrieval performance. This topography was characterized by bilateral activations in the premotor cortex (PMC), and in the right precuneus and posterior parietal cortex. The normal learning‐related topographies failed to predict acquisition performance in PD patients and predicted retrieval performance less accurately in the controls. A separate network analysis was performed to identify discrete learning‐related topographies in the PD cohort. In PD patients, acquisition performance was associated with a covariance pattern characterized by activations in the left PFdl, ventral prefrontal, and rostral premotor regions, but not in the striatum. Retrieval performance in PD patients was associated with a covariance pattern characterized by activations in the right PFdl, and bilaterally in the PMC, posterior parietal cortex, and precuneus. These results suggest that in early stage PD sequence learning networks are associated with additional cortical activation compensating for abnormalities in basal ganglia function. Hum. Brain Mapping 12:42–60, 2001.

Functional correlates of pallidal stimulation for Parkinson's disease

We measured regional cerebral blood flow with H215O and positron emission tomography (PET) scanning at rest and during a motor task to study the mechanism of motor improvement induced by deep brain stimulation of the internal globus pallidus in Parkinsons disease. Six right‐handed patients with Parkinsons disease were scanned while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed ON and OFF stimulation in a medication‐free state. Internal globus pallidus deep brain stimulation improved off‐state United Parkinsons Disease Rating Scale motor ratings (37%, p < 0.002) and reduced timing errors (movement onset time, 55%, p < 0.01) as well as spatial errors (10%, p < 0.02). Concurrent regional cerebral blood flow recordings revealed a significant enhancement of motor activation responses in the left sensorimotor cortex (Brodmann area [BA] 4), bilaterally in the supplementary motor area (BA 6), and in the right anterior cingulate cortex (BA 24/32). Significant correlations were evident between the improvement in motor performance and the regional cerebral blood flow changes mediated by stimulation. With internal globus pallidus deep brain stimulation, improved movement initiation correlated with regional cerebral blood flow increases in the left sensorimotor cortex and ventrolateral thalamus and in the contralateral cerebellum. By contrast, improved spatial accuracy correlated with regional cerebral blood flow increases in both cerebellar hemispheres and in the left sensorimotor cortex. These results suggest that internal globus pallidus deep brain stimulation may selectively improve different aspects of motor performance. Multiple, overlapping neural pathways may be modulated by this intervention. Ann Neurol 2001:49:155–164

Patients with temporal lobe epilepsy show an increase in brain-derived neurotrophic factor protein and its correlation with neuropeptide Y

Model studies on animal seizures have proposed potential involvement of the neurotrophins, BDNF and NGF, in human epilepsy. However, their biological significance in this disease itself remains to be evaluated. Here we demonstrate that patients with intractable temporal lobe epilepsy show a marked increase in protein levels of BDNF (2.6-fold, p<0.01) but not other neurotrophins. Moreover, the specific BDNF increase was significantly correlated with contents of neuropeptide Y. Thus, these results indicate the activity-dependent expression of BDNF in human subjects and its potential contribution to the pathophysiology of human epilepsy via neuropeptide Y.

Metabolic changes following subthalamotomy for advanced Parkinson's disease.

We studied 6 advanced‐stage Parkinsons disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinsons disease‐related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinsons disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinsons disease‐related metabolic brain networks, suggesting a widespread modulation of motor circuitry.

Effects of levodopa on motor sequence learning in Parkinson’s disease

Background: Dopaminergic therapy with levodopa improves motor function in PD patients, but the effects of levodopa on cognition in PD remain uncertain. Objective: To use H215O and PET to assess the effect of levodopa infusion on motor sequence learning in PD. Methods: Seven right-handed PD patients were scanned “on” and “off” levodopa while performing a sequence learning task. The changes in learning performance and regional brain activation that occurred during this intervention were assessed. Results: During PET imaging, levodopa infusion reduced learning performance as measured by subject report (p < 0.05). This behavioral change was accompanied by enhanced activation during treatment in the right premotor cortex and a decline in the ipsilateral occipital association area (p < 0.01). Levodopa-induced changes in learning-related activation responses in the occipital association cortex correlated with changes in learning indexes (p < 0.01). Conclusions: Levodopa treatment appears to have subtle detrimental effects on cognitive function in nondemented PD patients. These effects may be mediated through an impairment in brain activation in occipital association cortex.

Tc-99m ethylene cysteinate dimer SPECT in the differential diagnosis of parkinsonism

Positron emission tomography (PET) and network analysis have been used to identify a reproducible pattern of regional metabolic covariation that is associated with idiopathic Parkinsons disease (PD). The activity of this PD‐related pattern can be quantified in individual subjects and used to discriminate PD patients from atypical parkinsonians. Because PET is not commonly available, we sought to determine whether similar discrimination could be achieved using more routine single photon emission computed tomography (SPECT) perfusion methods. Twenty‐three subjects with PD (age, 63 ± 9 years), 22 subjects with multiple system atrophy (MSA; age, 64 ± 7 years), and 20 age‐matched healthy controls (age, 62 ± 13 years) underwent SPECT imaging of regional cerebral perfusion with Tc‐99m ethylene cysteinate dimer (ECD). Using network analysis, we determined whether a PD‐related pattern existed in the SPECT data, and whether its expression discriminated PD from MSA patients. Additionally, we compared the accuracy of group discrimination achieved by this pattern with that of the PET‐derived PD‐related pattern applied to the SPECT data. Network analysis of the SPECT data identified a significant pattern characterized by relative increases in cerebellar, lentiform, and thalamic perfusion covarying with decrements in the frontal operculum and in the medial temporal cortex. Subject scores for this pattern discriminated PD patients from controls (P < 0.01) and from MSA patients (P < 0.03). Subject scores for the PET‐derived PD‐related pattern computed in the individual SPECT scans more accurately distinguished PD patients from controls (P < 0.005) and from MSA patients (P = 0.0002). A significant PD‐related covariance pattern can be identified in SPECT perfusion data. Moreover, the disease related pattern identified previously with PET can be applied to individual SPECT perfusion scans to provide group discrimination between PD patients, healthy controls, and individuals with MSA. Because of significant individual subject overlap between groups, however, the clinical utility of this method in the differential diagnosis of Parkinsonism remains uncertain.

Blinded positron emission tomography study of dopamine cell implantation for Parkinson's disease

We assessed nigrostriatal dopaminergic function in Parkinsons disease (PD) patients undergoing a double‐blind, placebo‐controlled surgical trial of embryonic dopamine cell implantation. Forty PD patients underwent positron emission tomography (PET) imaging with [18F]fluorodopa (FDOPA) prior to randomization to transplantation or placebo surgery. The 39 surviving patients were rescanned 1 year following surgery. Images were quantified by investigators blinded to treatment status and clinical outcome. Following unblinding, we determined the effects of treatment status and age on the interval changes in FDOPA/PET signal. Blinded observers detected a significant increase in FDOPA uptake in the putamen of the group receiving implants compared to the placebo surgery patients (40.3%). Increases in putamen FDOPA uptake were similar in both younger (age ≤60 years) and older (age >60 years) transplant recipients. Significant decrements in putamen uptake were evident in younger placebo‐operated patients (–6.5% ) but not in their older counterparts. Correlations between the PET changes and clinical outcome were significant only in the younger patient subgroup (r = 0.58). The findings suggest that patient age does not influence graft viability or development in the first postoperative year. However, host age may influence the time course of the downstream functional changes that are needed for clinical benefit to occur.

Thalamic stimulation for parkinsonian tremor: correlation between regional cerebral blood flow and physiological tremor characteristics

We used (15)O-labeled water (H(2)(15)O) positron emission tomography (PET) to study eight Parkinsons disease (PD) patients with unilateral ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS) for severe tremor. Triaxial accelerometry (TRIAX) was used during imaging to obtain on-line measures of tremor characteristics. Regional cerebral blood flow (rCBF) scans together with TRIAX recordings were collected in three stimulation conditions (OFF, MID, and ON, corresponding, respectively, to 0%, 50%, and 100% reductions in mean accelerometry signal). Statistical Parametric Mapping (SPM99) revealed significant rCBF reductions during stimulation in the ipsilateral sensorimotor cortex (SMC) and the contralateral cerebellum, as well as concurrent increases in the ipsilateral ventral thalamus (P < 0.05, corrected). Covariate analysis of rCBF with physiological tremor characteristics revealed that tremor acceleration correlated positively with changes in the SMC and supplementary motor cortex ipsilaterally (P < 0.05, uncorrected), and negatively with changes in the ipsilateral cuneus (P < 0.05, corrected). After removing tremor acceleration effects, changes in tremor frequency correlated negatively with changes in the contralateral dentate nucleus and pons (P < 0.05, uncorrected). Our results suggest that Vim DBS for PD tremor modulates the activity of cerebello-thalamo-cortical pathways. Specific tremor characteristics relate to activity in different nodes of this system.

Learning networks in health and Parkinson's disease: Reproducibility and treatment effects

In a previous H215O/PET study of motor sequence learning, we used principal components analysis (PCA) of region of interest (ROI) data to identify performance‐related activation patterns in normal subjects and patients with Parkinsons disease (PD). In the present study, we determined whether these patterns predicted learning performance in subsequent normal and untreated PD cohorts. Using a voxel‐based PCA approach, we correlated the changes in network activity that occurred during antiparkinsonian treatment and their relationship to learning performance. We found that the previously identified ROI‐based patterns correlated with learning performance in the prospective normal (P < 0.01) and untreated PD (P < 0.05) cohorts. Voxel analysis revealed that target retrieval was related to a network characterized by bilateral activation of the dorsolateral prefrontal, premotor and anterior cingulate cortex, the precuneus, and the occipital association areas as well as the right ventral prefrontal and inferior parietal regions. Target acquisition was associated with a different network involving activation of the caudate, putamen, and right dentate nucleus, as well as the left ventral prefrontal and inferior parietal areas. Antiparkinsonian therapy gave rise to changes in retrieval performance that correlated with network modulation (P < 0.01). Increases in network activation and learning performance occurred with internal pallidal deep brain stimulation (GPi DBS); decrements in these measures were present with levodopa. Our findings suggest that network analysis of activation data can provide stable descriptors of learning performance. Network quantification can provide an objective means of assessing the effects of therapy on cognitive functioning in neurodegenerative disorders. Hum. Brain Mapping 11:197–211, 2003.