Faculty Bibliography

Early-stage nondemented Parkinson's disease (PD(es)) patients can learn short but not long sequences as well as controls. We have previously shown that to achieve normal performance, PD(es) patients activated the same right-sided cortical regions as controls plus the homologous left sided cortex and bilateral cerebellum. In this study, we evaluated two related hypotheses to explain the behavioral abnormalities and the increased bilateral brain activation observed in the PD(es) group. Hypothesis 1 proposed that PD(es) patients recruit regions from a normal bilateral network specialized for sequence learning that healthy controls would activate if performing difficult tasks. Thus, PD(es) patients can learn short sequences as well as controls. Hypothesis 2 proposed that information processing within the network in the PD(es) group is impaired. Thus, PD(es) patients cannot learn as difficult a sequence as controls. To test hypothesis 1, we increased task difficulty and statistical power in the control group and showed that the control and the PD(es) groups activated the same regions. To test hypothesis 2, we analyzed the equal performance data using two partial least squares (PLS) multivariate analyses. The task-PLS analysis showed that to perform equally with controls, the PD(es) group expressed the normal bilateral network more than the control group. The behavior-PLS analysis showed that the correlation between learning performance and regional activation was significantly different between the groups. We conclude that PD(es) patients have near normal learning if task difficulty is moderate because they can recruit additional regions from a normal bilateral network specialized for sequence learning. However, when a difficult task would normally require bilateral activation, PD(es) patients fail to learn because information processing within the network is impaired. Hum. Brain Mapp. 20:246-258, 2003

In a previous H(2) (15)O/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 Parkinson's 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

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 H(2)(15)O 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

BACKGROUND: Although the pathophysiology remains unknown, most nondemented patients with PD have difficulty with frontal tasks, including trial-and-error sequence learning. If given time, they can perform cognitive tasks of moderate difficulty as well as controls. However, it is not known how brain function is altered during this time period to preserve higher cortical function in the face of PD pathology. METHOD: To evaluate this phenomenon, the authors matched sequence learning between PD and control subjects for the last 30 seconds of a PET scan. Learning during the initial 50 seconds of PET was unconstrained. RESULTS: Learning indices were equivalent between groups during the last 30 seconds of the scan, whereas rates of acquisition, correct movements, and forgetting differed in the first 30 seconds. In normal controls sequence learning was associated with activations in the right prefrontal, premotor, parietal, rostral supplementary motor area, and precuneus regions. To achieve equal performance, the PD group activated greater volume within these same regions, and also their left sided cortical homologs and the lateral cerebellum bilaterally. CONCLUSIONS: Mildly affected patients with PD demonstrated only modest impairment of learning during the first 30 seconds of the task and performed equivalently with controls thereafter. However, the mechanism by which they achieved equiperformance involved considerable changes in brain function. The PD group had to activate four times as much neural tissue as the controls, including recruiting brain from homologous cortical regions and bilateral lateral cerebellum

Positron emission tomography (PET) and network analysis have been used to identify a reproducible pattern of regional metabolic covariation that is associated with idiopathic Parkinson's 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

Persistent dyskinesias in the absence of or with only minimal amounts of dopaminergic medication have been reported after dopamine cell implantation for Parkinson's disease. In this study, we used [(18)F]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

We used (15)O-labeled water and positron emission tomography to assess the effect of deep brain stimulation of the internal globus pallidus on motor sequence learning in Parkinson's disease. Seven right-handed patients were scanned on and off stimulation while they were performing a motor sequence learning task and a kinematically matched motor execution reference task. The scans were performed after a 12-hour medication washout. Stimulation parameters were adjusted for maximal motor improvement; experimental task parameters were held constant across stimulation conditions. Internal globus pallidus stimulation improved motor ratings by 37% (p < 0.01). During the sequence learning task, stimulation improved performance as measured by several correct anticipatory movements (p < 0.01) and by verbal report (p < 0.001). Concurrent positron emission tomography imaging during learning demonstrated significant (p < 0.01) increases in brain activation with stimulation in the left dorsolateral prefrontal cortex, bilaterally in premotor cortex, and in posterior parietal and occipital association areas. Stimulation did not affect the activity of these regions during the performance of the motor execution reference task. These findings suggest that internal globus pallidus deep brain stimulation can enhance the activity of prefrontal cortico-striato-pallidothalamic loops and related transcortical pathways. Improved sequence learning with stimulation may be directly related to these functional changes

PURPOSE OF REVIEW: In this article we have set out to critically review recent advances in the basic and clinical understanding of Huntington's disease, with specific emphasis on those findings that are most relevant to the planning, design, and conduct of future clinical trials for this devastating disorder. RECENT FINDINGS: The exact mechanisms underlying neuronal death in Huntington's disease remain unknown. Over the past 10 years, the leading models of neurodegeneration in the disease have involved mitochondrial dysfunction and subsequent excitotoxic injury, oxidative stress, and apoptosis. Recent studies have lent support to these models, but additional theories involving abnormalities of protein metabolism and transcriptional dysregulation have emerged as well. As progress is made toward clarifying the pathophysiological mechanisms leading to Huntington's disease, and new therapies are proposed, investigators have begun to develop improved outcome measures for potential use in future clinical trials aimed at slowing the progression of the disorder. SUMMARY: Recent advances in the understanding of the molecular biology and pathophysiology of Huntington's disease have suggested new therapeutic strategies aimed at slowing progression or forestalling onset of this neurodegenerative disease. In preparation for future clinical trials, clinical studies have begun to provide more quantitative measures of disease onset and progression. This progress in both the basic science and clinical realms raises real hope for effective therapies in the near future

BACKGROUND: Clinical improvement with levodopa therapy for PD is associated with specific regional changes in cerebral glucose metabolism. However, it is unknown how these effects of treatment in the resting state relate to alterations in brain function that occur during movement. In this study, the authors used PET to assess the effects of levodopa on motor activation responses and determined how these changes related to on-line recordings of movement speed and accuracy. METHODS: Seven right-handed PD patients were scanned with H(2)15O/PET while performing a predictable paced sequence of reaching movements and while observing the same screen displays and tones. PET studies were performed during 'on' and 'off' states with an individually titrated constant rate levodopa infusion; movements were kinematically controlled across treatment conditions. RESULTS: Levodopa improved 'off' state UPDRS motor ratings (34%; p < 0.006) and movement time (18%; p = 0.001). Spatial errors worsened during levodopa infusion (24%; p = 0.02). Concurrent regional cerebral blood flow (rCBF) recordings revealed significant enhancement of motor activation responses in the posterior putamen bilaterally (p < 0.001), left ventral thalamus (p < 0.002), and pons (p < 0.005). Movement time improvement with treatment correlated with rCBF increases in the left globus pallidus and left ventral thalamus (p < 0.01). By contrast, the increase in spatial errors correlated with rCBF increases in the cerebellar vermis (p < 0.01). CONCLUSION: These results suggest that levodopa infusion may improve aspects of motor performance while worsening others. Different components of the motor cortico-striato-pallido-thalamo-cortical loop and related pathways may underlie motor improvement and adverse motoric effects of levodopa therapy for PD