Principal component analysis of PiB distribution in Parkinson and Alzheimer diseases.

OBJECTIVE: To use principal component analyses (PCA) of Pittsburgh compound B (PiB) PET imaging to determine whether the pattern of in vivo ß-amyloid (Aß) in Parkinson disease (PD) with cognitive impairment is similar to the pattern found in symptomatic Alzheimer disease (AD). METHODS: PiB PET scans were obtained from participants with PD with cognitive impairment (n = 53), participants with symptomatic AD (n = 35), and age-matched controls (n = 67). All were assessed using the Clinical Dementia Rating and APOE genotype was determined in 137 participants. PCA was used to (1) determine the PiB binding pattern in AD, (2) determine a possible unique PD pattern, and (3) directly compare the PiB binding patterns in PD and AD groups. RESULTS: The first 2 principal components (PC1 and PC2) significantly separated the AD and control participants (p < 0.001). Participants with PD with cognitive impairment also were significantly different from participants with symptomatic AD on both components (p < 0.001). However, there was no difference between PD and controls on either component. Even those participants with PD with elevated mean cortical binding potentials were significantly different from participants with AD on both components. CONCLUSION: Using PCA, we demonstrated that participants with PD with cognitive impairment do not exhibit the same PiB binding pattern as participants with AD. These data suggest that Aß deposition may play a different pathophysiologic role in the cognitive impairment of PD compared to that in AD.

Metabolic control of resting hemispheric cerebral blood flow is oxidative, not glycolytic.

Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO(2)) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO(2), CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO(2) was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO(2): arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO(2) and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.

Platelet mitochondrial complex I and I+III activities do not correlate with cerebral mitochondrial oxidative metabolism.

Assays of mitochondrial electron transport system (ETS) activity in circulating blood platelets have been used to investigate the cause of neurodegenerative diseases. However, the correspondence between platelet ETS function and cerebral mitochondrial metabolism is not well characterized. To assess the validity of using platelet ETS activity to infer cerebral mitochondrial metabolism, we measured platelet ETS activity (complex I and complex I+III), cerebral metabolic rate of oxygen (CMRO(2)), and the CMRO(2)/cerebral metabolic rate for glucose ratio in 40 subjects: 7 with never-medicated Parkinson's disease, 13 with genetically proved Huntington's disease, and 20 normal controls. We found no correlation between in vivo measures of cerebral mitochondrial oxidative metabolism and ex vivo assays of platelet complex I and complex I+III activity performed on blood collected immediately before cerebral metabolism studies. We saw no evidence of a threshold effect when comparing platelet complex I and complex I+III activity with cerebral oxidative metabolism across a 4- to 10-fold range of platelet ETS activity. On the basis of these data, we conclude that measures of mitochondrial complex I and I+III activity in platelets within the ranges we have studied do not correlate with oxidative function of cerebral mitochondria.

Dynamic susceptibility contrast MRI with localized arterial input functions.

Compared to gold-standard measurements of cerebral perfusion with positron emission tomography using H(2)[(15)O] tracers, measurements with dynamic susceptibility contrast MR are more accessible, less expensive, and less invasive. However, existing methods for analyzing and interpreting data from dynamic susceptibility contrast MR have characteristic disadvantages that include sensitivity to incorrectly modeled delay and dispersion in a single, global arterial input function. We describe a model of tissue microcirculation derived from tracer kinetics that estimates for each voxel a unique, localized arterial input function. Parameters of the model were estimated using Bayesian probability theory and Markov-chain Monte Carlo, circumventing difficulties arising from numerical deconvolution. Applying the new method to imaging studies from a cohort of 14 patients with chronic, atherosclerotic, occlusive disease showed strong correlations between perfusion measured by dynamic susceptibility contrast MR with localized arterial input function and perfusion measured by quantitative positron emission tomography with H(2)[(15)O]. Regression to positron emission tomography measurements enabled conversion of dynamic susceptibility contrast MR to a physiologic scale. Regression analysis for localized arterial input function gave estimates of a scaling factor for quantitation that described perfusion accurately in patients with substantial variability in hemodynamic impairment.

Blind identification of evoked human brain activity with independent component analysis of optical data.

Diffuse optical tomography (DOT) methods observe hemodynamics in the brain by measuring light transmission through the scalp, skull, and brain. Thus, separating signals due to heart pulsations, breathing movements, and systemic blood flow fluctuations from the desired brain functional responses is critical to the fidelity of the derived maps. Herein, we applied independent component analysis (ICA) to temporal signals obtained from a high-density DOT system used for functional mapping of the visual cortex. DOT measurements were taken over the occipital cortex of human adult subjects while they viewed stimuli designed to activate two spatially distinct areas of the visual cortex. ICA was able to extract clean functional hemodynamic signals and separate brain activity sources from hemodynamic fluctuations related to heart and breathing without knowledge of the stimulus paradigm. Furthermore, independent components were found defining distinct functional responses to each stimulus type. Images generated from single ICA components were comparable, with regard to spatial extent and resolution, to images from block averaging (with knowledge of the block stimulus paradigm). Both images and estimated time-series signals demonstrated that ICA was superior to principal component analysis in extracting the true event-evoked response signals. Our results suggest that ICA can extract the time courses and the corresponding spatial extent of functional responses in DOT imaging.

Cerebral mitochondrial metabolism in early Parkinson's disease.

Abnormal cerebral energy metabolism owing to dysfunction of mitochondrial electron transport has been implicated in the pathogenesis of Parkinson's disease (PD). However, in vivo data of mitochondrial dysfunction have been inconsistent. We directly investigated mitochondrial oxidative metabolism in vivo in 12 patients with early, never-medicated PD and 12 age-matched normal controls by combined measurements of the cerebral metabolic rate of oxygen (CMRO(2)) and the cerebral metabolic rate of glucose (CMRglc) with positron emission tomography. The primary analysis showed a statistically significant 24% increase in bihemispheric CMRO(2) and no change in CMRO(2)/CMRglc. These findings are inconsistent with a defect in mitochondrial oxidative phosphorylation owing to reduced activity of the mitochondrial electron transport system (ETS). Because PD symptoms were already manifest, deficient energy production owing to a reduced activity of the mitochondrial ETS cannot be a primary mechanism of neuronal death in early PD. Alternatively, this general increase in CMRO(2) could be due not to an increased metabolic demand but to an uncoupling of ATP production from oxidation in the terminal stage of oxidative phosphorylation. Whether this is the case in early PD and whether it is important in the pathogenesis of PD will require further study.

Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans.

Positron emission tomography measurements of dopaminergic D2-like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The positron emission tomography (PET) radioligand [18F](N-methyl)benperidol ([18F]NMB) has high affinity and selectivity for D2-like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate the use of a graphical method utilizing a reference tissue region for [18F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (P<.0001 by repeated-measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward, thereby simplifying these measurements.

Precision, signal-to-noise ratio, and dose optimization of magnitude and phase arterial input functions in dynamic susceptibility contrast MRI.

PURPOSE: To determine optimal conditions for precise measurement of arterial input function (AIFs) in dynamic susceptibility contrast (DSC) perfusion MRI. MATERIALS AND METHODS: Magnitude-based (DeltaR(2)*) and phase-based (Deltaphi) AIFs were numerically simulated for several doses and baseline MRI noise levels [SNR(I(0))]. Random noise (1000 realizations) was added to real/imaginary MRI signals (derived from an internal carotid AIF), and AIF signal, noise, and signal-to-noise ratio (SNR) were determined. The optimal dose was defined as the dose that maximizes mean AIF SNR over the first-pass (SNR(mean)), rather than SNR at the AIF peak (SNR(peak)) because, compared to SNR(peak), doses predicted by SNR(mean) reduced the AIF-induced variability in cerebral blood flow (CBF) by 24% to 40%. RESULTS: The AIF SNR is most influenced by choice of AIF signal, then optimal dosing, each with little penalty. Compared to DeltaR(2)*, Deltaphi signal has 4 to 80 times the SNR over all doses and time points, and approximately 10-fold SNR(mean) at respective optimal doses. Optimal doses induce 85% to 90% signal drop for the DeltaR(2)* method, and 70% to 75% for Deltaphi, with two-fold dose errors causing approximately 1.7-fold loss in SNR(mean). Increases in SNR(I(0)) proportionally increase AIF SNR, but at a cost. CONCLUSION: AIF SNR is affected most by signal type, then dosing, and lastly, SNR(I(0)).

Selective defect of in vivo glycolysis in early Huntington's disease striatum.

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntington's disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO(2)/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO(2)/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 +/- 1.6 vs. 5.1 +/- 0.9, P = 0.04). CMRO(2) was not different from controls (126 +/- 37 vs. 134 +/- 31 micromol 100 g(-1) min(-1), P = 0.49), whereas CMRglc was decreased (21.6 +/- 6.1 vs. 26.4 +/- 4.6 micromol 100 g(-1) min(-1), P = 0.01). Striatal volume was decreased as well (13.9 +/- 3.5 vs. 17.6 +/- 2.0 ml, P = 0.001). Increased striatal CMRO(2)/CMRglc with unchanged CMRO(2) is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.

Intravenous levodopa administration in humans based on a two-compartment kinetic model.

Levodopa, when combined with a decarboxylase inhibitor, essentially delivers dopamine directly to the brain, with no net effect on brain blood vessels. For future neuroimaging studies of Parkinson disease and Tourette syndrome, we sought to rapidly produce a biologically relevant levodopa concentration in plasma and then maintain that concentration long enough to assess motor, cognitive, emotional, and neuroimaging responses, while minimizing side effects in levodopa-naive individuals. Based on available pharmacokinetic data and a two-compartment model, we designed a decreasing-exponential-rate infusion to meet these goals. This report gives results of double-blind levodopa and placebo infusions in six healthy subjects. Mean plasma levodopa concentrations were within 3% of their 1200 ng/mL target at 20 and 40 min into the infusion, and within 20% between approximately 12 and 90 min. Levodopa significantly reduced serum prolactin and raised serum growth hormone concentrations. Volunteers had no significant side effects.

Arterial input functions for dynamic susceptibility contrast MRI: requirements and signal options.

Cerebral perfusion imaging using dynamic susceptibility contrast (DSC) has been the subject of considerable research and shows promise for basic science and clinical use. In DSC, the MRI signals in brain tissue and feeding arteries are monitored dynamically in response to a bolus injection of paramagnetic agents, such as gadolinium (Gd) chelates. DSC has the potential to allow quantitative imaging of parameters such as cerebral blood flow (CBF) with a high signal-to-noise ratio (SNR) in a short scan time; however, quantitation depends critically on accurate and precise measurement of the arterial input function (AIF). We discuss many requirements and factors that make it difficult to measure the AIF. The AIF signal should be linear with respect to Gd concentration, convertible to the same concentration scale as the tissue signal, and independent of hematocrit. Complicated relationships between signal and concentration can violate these requirements. The additional requirements of a high SNR and high spatial/temporal resolution are technically challenging. AIF measurements can also be affected by signal saturation and aliasing, as well as dispersion/delay between the AIF sampling site and the tissue. We present new in vivo preliminary results for magnitude-based (DeltaR2*) and phase-based (Deltaphi) AIF measurements that show a linearity advantage of phase, and a disparity in the scaling of Deltaphi AIFs, DeltaR2* AIFs, and DeltaR2* tissue curves. Finally, we discuss issues related to the choice of AIF signal for quantitative perfusion imaging.

Numerical evaluation of Hankel transforms for oscillating functions.

Six methods for the numerical calculation of zero-order Hankel transforms of oscillating functions were evaluated. One method based on Filon quadrature philosophy, two published projection-slice methods, and a third projection-slice method based on a new approach to computation of the Abel transform were implemented; alternative versions of two of the projection-slice methods were derived for more accurate approximations in the projection step. These six algorithms were tested with an oscillating sweep signal and with the calculation of a three-dimensional diffraction-limited point-spread function of a fluorescence microscope. We found that the Filon quadrature method is highly accurate but also computationally demanding. The projection-slice methods, in particular the new one that we derived, offer an excellent compromise between accuracy and computational efficiency.