Inhibition of Neutral Amino Acid Transport Across the Human Blood-Brain Barrier by Phenylalanine

The delivery of large neutral amino acids (LNAAs) to brain across the blood-brain barrier (BBB) is mediated by the L-type neutral amino acid transporter present in the membranes of the brain capillary endothelial cell. In experimental animals, the L-system transporter is saturated under normal conditions, and therefore an elevation in the plasma concentration of one LNAA will reduce brain uptake of others. In this study, we used positron emission tomography (PET) to determine the effect of elevated plasma phenylalanine concentrations on the uptake of an artificial neutral amino acid, [ 11 C]-aminocyclohexanecarboxylate ([ 11 C]ACHC), in human brain. PET scans were performed on six normal male subjects after an overnight fast and again 60 min after oral administration of 100 mg/kg of phenylalanine. The plasma phenylalanine concentration increased by an average of 11-fold between the first and second scans. This increase produced a reduction in [ 11 C]ACHC uptake in all brain regions but not in scalp. The mean ± SD influx rate constant for whole brain decreased after phenylalanine ingestion from 0.036 ± 0.002 to 0.019 ± 0.004 ml/g/min. Kinetic analysis of the effect of plasma phenylalanine concentration on the rate of [ 11 C]ACHC uptake is compatible with a model of competitive inhibition so that large increases in the concentration of one LNAA in plasma will reduce the brain uptake of other LNAAs across the human BBB.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65880/1/j.1471-4159.1995.64031252.x.pd

Covariance of Kinetic Parameter Estimators Based on Time Activity Curve Reconstructions: Preliminary Study on 1D Dynamic Imaging

We provide approximate expressions for the covariance matrix of kinetic parameter estimators based on time activity curve (TAC) reconstructions when TACs are modeled as a linear combination of temporal basis functions such as B-splines. The approximations are useful tools for assessing and optimizing the basis functions for TACs and the temporal bins for data in terms of computation and efficiency. In this paper we analyze a 1D temporal problem for simplicity, and we consider a scenario where TACs are reconstructed by penalized-likelihood (PL) estimation incorporating temporal regularization, and kinetic parameters are obtained by maximum likelihood (ML) estimation. We derive approximate formulas for the covariance of the kinetic parameter estimators using 1) the mean and variance approximations for PL estimators in (Fessler, 1996) and 2) Cramer-Rao bounds. The approximations apply to list-mode data as well as bin-mode data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85981/1/Fessler193.pd

Imaging butyrylcholinesterase activity in Alzheimer's disease

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55890/1/21023_ftp.pd

Age Differences in Behavior and PET Activation Reveal Differences in Interference Resolution in Verbal Working Memory

Older adults were tested on a verbal working memory task that used the item-recognition paradigm. On some trials of this task, response-conflict was created by presenting test-items that were familiar but were not members of a current set of items stored in memory. These items required a negative response, but their familiarity biased subjects toward a positive response. Younger subjects show an interference effect on such trials, and this interference is accompanied by activation of a region of left lateral prefrontal cortex. However, there has been no evidence that the activation in this region is causally related to the interference that the subjects exhibit. In the present study, we demonstrate that older adults show more behavioral interference than younger subjects on this task, and they also show no reliable activation at the same lateral prefrontal site. This leads to the conclusion that this prefrontal site is functionally involved in mediating resolution among conflicting responses or among conflicting representations in working memory

Multivariate and Univariate Neuroimaging Biomarkers of Alzheimer's Disease

We performed univariate and multivariate discriminant analysis of FDG-PET scans to evaluate their ability to identify Alzheimer's disease (AD). FDG-PET scans came from two sources: 17 AD patients and 33 healthy elderly controls were scanned at the University of Michigan; 102 early AD patients and 20 healthy elderly controls were scanned at the Technical University of Munich, Germany. We selected a derivation sample of 20 AD patients and 20 healthy controls matched on age with the remainder divided into 5 replication samples. The sensitivity and specificity of diagnostic AD-markers and threshold criteria from the derivation sample were determined in the replication samples. Although both univariate and multivariate analyses produced markers with high classification accuracy in the derivation sample, the multivariate marker's diagnostic performance in the replication samples was superior. Further, supplementary analysis showed its performance to be unaffected by the loss of key regions. Multivariate measures of AD utilize the covariance structure of imaging data and provide complementary, clinically relevant information that may be superior to univariate measures

Age Differences in the Frontal Lateralization of Verbal and Spatial Working Memory Revealed by PET

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline

Assessment of the biodistribution of an [ 18 F]FDG‐loaded perfluorocarbon double emulsion using dynamic micro‐PET in rats

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97497/1/cmmi1532.pd

In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease

To map presynaptic cholinergic terminal densities in normal aging (n = 36), Alzheimer's disease (AD) (n = 22), and Parkinson's disease (PD) (n = 15), we performed single-photon emission computed tomography using [ 123 I]iodoben-zovesamicol (IBVM), an in vivo marker of the vesicular acetylcholine transporter. We used coregistered positron emission tomography with [ 18 F]fluorodexyglucose for metabolic assessment and coregistered magnetic resonance imaging for atrophy assessment. In controls (age, 22–91 years), cortical IBVM binding declined only 3.7% per decade. In AD, cortical binding correlated inversely with dementia severity. In mild dementia, binding differed according to age of onset, but metabolism did not. With an onset age of less than 65 years, binding was reduced severely throughout the entire cerebral cortex and hippocapus (about 30%), but with an onset age of 65 years or more, binding reductions were restricted to temporal cortex and hippocampus. In PD without dementia, binding was reduced only in parietal and occipital cortex, but demented PD subjects had extensive cortical binding decreases similar to early-onset AD. We conclude that cholinergic neuron integrity can be monitored in living AD and PD patients, and that it is not so devastated in vivo as suggested by postmortem choline acetylransferase activity (50–80%).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50361/1/410400309_ftp.pd

Regional vesicular acetylcholine transporter distribution in human brain: A [18F]fluoroethoxybenzovesamicol positron emission tomography study

Prior efforts to image cholinergic projections in human brain in vivo had significant technical limitations. We used the vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) and positron emission tomography to determine the regional distribution of VAChT binding sites in normal human brain. We studied 29 subjects (mean age 47 [range 20–81] years; 18 men; 11 women). [18F]FEOBV binding was highest in striatum, intermediate in the amygdala, hippocampal formation, thalamus, rostral brainstem, some cerebellar regions, and lower in other regions. Neocortical [18F]FEOBV binding was inhomogeneous with relatively high binding in insula, BA24, BA25, BA27, BA28, BA34, BA35, pericentral cortex, and lowest in BA17–19. Thalamic [18F]FEOBV binding was inhomogeneous with greatest binding in the lateral geniculate nuclei and relatively high binding in medial and posterior thalamus. Cerebellar cortical [18F]FEOBV binding was high in vermis and flocculus, and lower in the lateral cortices. Brainstem [18F]FEOBV binding was most prominent at the mesopontine junction, likely associated with the pedunculopontine–laterodorsal tegmental complex. Significant [18F]FEOBV binding was present throughout the brainstem. Some regions, including the striatum, primary sensorimotor cortex, and anterior cingulate cortex exhibited age‐related decreases in [18F]FEOBV binding. These results are consistent with prior studies of cholinergic projections in other species and prior postmortem human studies. There is a distinctive pattern of human neocortical VChAT expression. The patterns of thalamic and cerebellar cortical cholinergic terminal distribution are likely unique to humans. Normal aging is associated with regionally specific reductions in [18F]FEOBV binding in some cortical regions and the striatum.Using [18F]FEOBV PET, we describe the distribution of cholinergic terminals in human brain. The distribution of cholinergic terminals is similar to that found in other mammals with some distinctive features in cortex, thalamus, and cerebellum. There are regionally specific age‐related changes in cholinergic terminal density.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/1/cne24541.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146604/2/cne24541_am.pd