Faculty Bibliography

OBJECTIVE: A multivariate analysis of baseline brain metabolism was used to investigate the relationships among pathophysiological mechanisms responsible for cognitive dysfunction and dysphoria in nondemented patients with Parkinson's disease. METHOD: Using [(18)F]fluorodeoxyglucose positron emission tomography and neuropsychological tests, the authors studied 15 nondemented patients who had Parkinson's disease without major depression (DSM-III-R). Their mean age was 59.2 years (SD=9.2), the mean rating of Parkinson's disease stage (Hoehn and Yahr scale) was 3.3 (SD=0.9), and all had Mini-Mental State Examination scores of 24 or higher. To identify specific regional patterns of brain metabolism associated with abnormal cognitive and mood functioning, the data were analyzed by using brain-behavior partial least squares. This multivariate voxel-based analysis allowed detection of significant topographic patterns of metabolic activity and quantification of the extent to which each topographic pattern correlated with scores on mnemonic, visuospatial, and dysphoric tests. RESULTS: Two significant, independent topographic patterns were identified. Pattern 1 included parieto-occipito-temporal and medial temporal brain regions, and pattern 2 included the lateral frontal and anterior limbic cortex. Patterns 1 and 2 exhibited a double dissociation in their behavioral correlates: pattern 1 correlated with both visuospatial and mnemonic functioning but not with dysphoria; pattern 2 correlated with dysphoria but not with the cognitive measures. CONCLUSIONS: The authors used the independence of topographic patterns and the size of correlations between topographic patterns and behavior to infer relationships among the pathophysiological processes responsible for the correlations. The finding that mildly abnormal mnemonic and visuospatial functioning correlated with the same topographic pattern suggests that a common pathophysiology underlies this marker of cognition in Parkinson's disease. By contrast, the independence of the two topographic patterns supports the notion that different mechanisms underlie cognitive and dysphoric symptoms in nondemented patients with 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

The identification of discrete patterns of altered functional brain circuitry in preclinical Huntington's disease (HD) gene carriers is important to understanding the pathophysiology of this disorder and could be useful as a biologic disease marker. The purpose of this study was to use PET imaging of regional cerebral glucose metabolism to identify abnormal networks of brain regions that are specifically related to the preclinical phase of HD. METHODS: Eighteen presymptomatic HD gene carriers, 13 early-stage HD patients, and 8 age-matched gene-negative relatives were scanned using PET with [(18)F]FDG to quantify regional glucose utilization. A network modeling strategy was applied to the FDG PET data to identify disease-related regional metabolic covariance patterns in the preclinical HD cohort. The outcome measures were the region weights defining the metabolic topography of the HD gene carriers and the subject scores quantifying the expression of the pattern in individual subjects. RESULTS: Network analysis of the presymptomatic carriers and the gene-negative control subjects revealed a significant metabolic covariance pattern characterized by caudate and putamenal hypometabolism but also included mediotemporal metabolic reductions as well as relative metabolic increases in the occipital cortex. Subject scores for this pattern were abnormally elevated in the preclinical group compared with those of the control group (P < 0.005) and in the early symptomatic group compared with those of the presymptomatic group (P < 0.005). CONCLUSION: These findings show that FDG PET with network analysis can be used to identify specific patterns of abnormal brain function in preclinical HD. The presence of discrete patterns of metabolic abnormality in preclinical HD carriers may provide a useful means of quantifying the rate of disease progression during the earliest phases of this illness

Background: In vivo imaging of the dopamine transporter (DAT) with SPELT is a quantitative biomarker for PD onset and severity. Objective: To use a multicenter study to evaluate the diagnostic accuracy of DOPASCAN and SPELT in patients with PD, progressive supranuclear palsy (PSP), and essential tremor (ET), and in healthy controls (HC). Methods: Ninety-six individuals with known clinical diagnosis were imaged with DOPASCAN at five sites with different multidetector SPELT systems. Both masked visual interpretation and region of interest (ROI) analysis were performed at each site and at a core analysis center. Results: Visual interpretation of the images by an expert panel demonstrated a sensitivity of 0.98 and specificity of 0.83 comparing parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) controls. Quantitative analysis of putamen and caudate DOPASCAN uptake for each region in the PD or PSP groups was significantly reduced compared to the ET or HC groups. Comparison of parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals demonstrated a reduction of 76% in mean putamen and 48% in mean caudate DOPASCAN uptake. Conclusions: DOPASCAN and SPELT imaging reliably and effectively distinguish between subjects with Parkinson's syndrome (PD + PSP) and without Parkinson's syndrome (HC + ET). This is the first multicenter assessment of dopamine transporter imaging demonstrating that this tool may be used widely to assess dopaminergic degeneration in patients with parkinsonism

Background: In vivo imaging of the dopamine transporter (DAT) with SPECT is a quantitative biomarker for PD onset and severity. Objective: To use a multicenter study to evaluate the diagnostic accuracy of DOPASCAN and SPECT in patients with PD, progressive supranuclear palsy (PSP), and essential tremor (ET), and in healthy controls (HC. Methods: Ninety-six individuals with known clinical diagnosis were imaged with DOPASCAN at five sites with different multidetector SPECT systems. Both masked visual interpretation and region of interest (ROI) analysis were performed at each site and at a core analysis center. Results: Visual interpretation of the images by an expert panel demonstrated a sensitivity of 0.98 and specificity of 0.83 comparing parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) controls. Quantitative analysis of putamen and caudate DOPASCAN uptake for each region in the PD or PSP groups was significantly reduced compared to the ET or HC groups. Comparison of parkinsonian (PD + PSP) versus nonparkinsonian (ET + HC) individuals demonstrated a reduction of 76% in mean putamen and 48% in mean caudate DOPASCAN uptake. Conclusions: DOPASCAN and SPECT imaging reliably and effectively distinguish between subjects with Parkinson's syndrome (PD + PSP) and without Parkinson's syndrome (RC + ET). This is the first multicenter assessment of dopamine transporter imaging demonstrating that this tool may be used widely to assess dopaminergic degeneration in patients with parkinsonism