Thomas F. Budinger

Regional Cerebral Metabolic Alterations in Dementia of the Alzheimer Type: Positron Emission Tomography with [1818] Fluorodeoxyglucose

Alzheimer disease is the most common cause of dementia in adults. Despite recent advances in our understanding of its anatomy and chemistry, we remain largely ignorant of its pathogenesis, physiology, diagnosis, and treatment. Dynamic positron emission tomography using [18F] fluorodeoxyglucose (FDG) was performed on the Donner 280-crystal ring in 10 subjects with dementia of the Alzheimer type and six healthy age-matched controls. Ratios comparing mean counts per resolution element in frontal, temporoparietal, and entire cortex regions in brain sections 10 mm thick obtained 40–70 min following FDG injection showed relatively less FDG uptake in the temporoparietal cortex bilaterally in all the Alzheimer subjects (p < 0.01). Left-right alterations were less prominent than the anteroposterior changes. This diminished uptake was due to lowered rates of FDG use and suggests that the metabolic effects of Alzheimer disease are most concentrated in the temporoparietal cortex. Positron emission tomography is a most powerful tool for the noninvasive in vivo assessment of cerebral pathophysiology in dementia.

Convection-Enhanced Delivery of AAV Vector in Parkinsonian Monkeys; In Vivo Detection of Gene Expression and Restoration of Dopaminergic Function Using Pro-drug Approach

Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinsons disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinsons disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.

Three-dimensional reconstruction in nuclear medicine emission imaging

The study presents application of methods of ascertaining the three-dimensional distribution of isotope concentration or density in nuclear medicine, and differs from previous three-dimensional reconstruction efforts of astrophysics, electron microscopy, and X-ray radiology in that statistically poor measurements and photon attenuation are taken into account by the algorithm. The methods discussed are applicable to photon or heavy ion transmission radiography as well as emission imaging.

Emission Computer Assisted Tomography with Single-Photon and Positron Annihilation Photon Emitters

Computed transverse section emission tomography using 99mTc with the Anger camera is compared to positron annihilation coincident detection using a ring of crystals and 68Ga. The single-photon system has a line spread function (LSF) of 9 mm full width at half maximum (FWHM) at the collimator and gives a transverse section reconstruction LSF of 11 mm FWHM with 144 views. The positron ring has a LSF of 6 mm at the center with a transverse section reconstruction LSF of 7.5 mm FWHM. Correction for uniformity of detector response and accurate center of rotation determination is essential in both techniques. The signal-to-noise ratio in a reconstruction is diminished by a factor of 1.2 x (number of resolution elements)1/4 over that expected from the average number of events per resolution element. Attenuation compensation causes more noise to appear in the center than the edge for both modes and an average increase in uncertainty of 30%. The effects of attenuation result in more loss of data for positron coincidence imaging than for single-photon imaging even at energies of 80 keV. For a 20-cm cylinder imaged in transverse section, only 20% of the positron annihilation events are not scattered; however, at 140 keV, 40% of the photons are not scattered. The relative crystal efficiency gives single-photon imaging an advantage of 5. On the other hand, the solid angle advantage of positron photon coincidence imaging is about 100 for the comparisons of this paper. Taking these factors into account, we find positron-computed section imaging has a tenfold increase in sensitivity over multiple-view imaging with the scintillation camera, which gives multiple sections but requires camera or patient rotation.

Nuclear magnetic resonance (NMR) in vivo studies: known thresholds for health effects

Three sources of harmful health effects from nuclear magnetic resonance (NMR) in vivo techniques have been examined with the following conclusions: (a) Static magnetic fields. Harmful effects on humans and reproducible cellular, biochemical, or genetic effects have not yet been observed at fields less than 2 Tesla (20,000 gauss), (b) Changing magnetic fields. The threshold for effects of induced currents is above that produced from < 1 to 100 Hz sinusoidal field changes with a maximum field of 5 mT (50 gauss). Waveform, repetition rate, maximum B field, and duration of exposure are parameters requiring further study, (c) Radiofrequency (RF) heating. A practical upper level for absorbed power is 4 W/kg in medically important studies of short duration (less than 10 min). For long-term studies, 1.5 W/kg is a reasonable level in low humidity environments. The power absorbed by the subject can be estimated by measuring the RF coil Q before and after the subject is placed in the NMR instrument. Large metal objects will absorb power in proportion to the conductivity of the device or prosthesis.

Alzheimer's disease: Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization

We performed dynamic positron emission tomographic studies with [18F]fluorodeoxyglucose in 17 subjects with presumed Alzheimers disease (AD) and 7 healthy aged subjects. Glucose metabolism was depressed by 27% in temporal-parietal cortex of the AD group, as compared to healthy aged controls. This focal impairment in temporal-parietal glucose use was found in all AD subjects. In addition, the AD group showed a striking lateral asymmetry of cortical metabolism not favoring either hemisphere, which has not been previously reported. Relationships between these focal changes and behavioral features of the illness were demonstrated. These results have important implications for the diagnosis and perhaps the etiology of Alzheimers disease.

An attenuated projector-backprojector for iterative SPECT reconstruction

A new ray-driven projector-backprojector which can easily be adapted for hardware implementation is described and simulated in software. The projector-backprojector discretely models the attenuated Radon transform of a source distributed within an attenuating medium as line integrals of discrete pixels, obtained using the standard sampling technique of averaging the emission source or attenuation distribution over small square regions. Attenuation factors are calculated for each pixel during the projection and backprojection operations instead of using precalculated values. The calculation of the factors requires a specification of the attenuation distribution, estimated either from an assumed constant distribution and an approximate body outline or from transmission measurements. The distribution of attenuation coefficients is stored in memory for efficient access during the projection and backprojection operations. The reconstruction of the source distribution is obtained by using a conjugate gradient or SIRT type iterative algorithm which requires one projection and one backprojection operation for each iteration.

Differentiation of Cerebral Radiation Necrosis from Tumor Recurrence by [18f]fdg and 82rb Positron Emission Tomography

Nine radiation-treated brain tumor patients were studied by positron emission tomography (PET) in an attempt to differentiate tumor recurrence from radiation necrosis. Rubidium-82 was used to define the region of absent or disturbed blood–brain barrier and [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) was used to evaluate the metabolic state of the brain. By comparing glucose utilization in the pathologic region with utilization in the adjacent tissue, a diagnosis of recurrent tumor (increased [18F]FDG accumulation) or necrosis (decreased FDG accumulation) was made. In the seven patients who underwent surgery the PET diagnosis was confirmed by histologic examination of resected tissue. The two patients who did not undergo surgery have had a clinical course consistent with the PET diagnosis of necrosis. Dynamic 82Rb imaging showed that the rate of 82Rb accumulation was greater in tumor than in normal brain. However, this finding alone did not differentiate tumor from necrosis, as some necrotic tissue also showed high rates of 82Rb accumulation, and washout kinetics were similarly nonspecific. The differentiation of radiation necrosis from tumor recurrence is reliably achieved by [18F]FDG PET examination and is aided by information obtained from a 82Rb PET study done immediately prior to the [18F]FDG injection.

Diminished Glucose Transport in Alzheimer's Disease: Dynamic PET Studies

Dynamic positron emission tomography with [18F]fluorodeoxyglucose was used in six patients with Alzheimers disease (AD) and seven healthy age-matched control subjects to estimate the kinetic parameters K1*, k2*, and k3* that describe glucose transport and phosphorylation. A high-resolution tomograph was used to acquire brain uptake data in one tomographic plane, and a radial artery catheter connected to a plastic scintillator was used to acquire arterial input data. A nonlinear iterative least-squares fitting procedure that included terms for the vascular fraction and time delay to the peripheral sampling site was used to fit a three-compartment model to the brain data. Regions studied included frontal, temporal, occipital, and the entire cortex and subcortical white matter. The values obtained for the individual rate constants and regional CMRglc (rCMRglc; calculated using regional values of the rate constants) were higher than those reported previously. A significant (p < 0.05) decrease was found in K1* in frontal and temporal cortex in the AD patients compared with the controls, with values of 0.157 and 0.161 ml/g/min in frontal and temporal cortex, respectively, of controls and 0.127 and 0.126 ml/ g/min in frontal and temporal cortex of the AD patients. rCMRglc was also significantly (p < 0.02) lower in the AD patients than controls in all cortical brain regions. Lower values of k3* were found in all brain regions in the AD patients, although these were not statistically significant. These findings provide evidence of an in vivo abnormality of forward glucose transport in AD. This transport defect, however, is probably not the cause of the diminution in glucose metabolism that has been widely found in AD patients, since a diminution of this magnitude should not lower intracerebral glucose content enough to alter rCMRglc.

Longitudinal studies of regional cerebral metabolism in Alzheimer's disease

Measurement of cerebral glucose metabolism in six patients with Alzheimers disease using positron emission tomography demonstrated that hypometabolism remained relatively more severe in parietal cortex than in frontal cortex over time. Lateral metabolic asymmetries were preserved in less severely involved brain regions, but were less stable in parietal cortex.