A double-injection technique for in vivo measurement of dopamine D2-receptor density in monkeys with 3-(2'-[18F]fluoroethyl)spiperone and dynamic positron emission tomography

Dopamine D2-receptor density in striatum of monkey was measured with 3-(2'-[18F]fluoroethyl)spiperone (FESP) and dynamic positron emission tomography (PET), using a double-injection technique. A first bolus of high specific activity (SA) FESP (5 mCi; approximately equal to 1 Ci/mumol) was injected i.v.; 90 min later, a second bolus of lower SA FESP (5 mCi; approximately equal to 0.04 Ci/mumol) was injected. A dynamic PET study was performed to measure the kinetics of FESP in striatum over 180 min, and the metabolite-corrected concentration of FESP in plasma as a function of time was obtained from arterial blood samples. A nonlinear compartmental model that took into account the saturability of the receptor binding was used to describe the kinetics of FESP in striatum. Model parameters were estimated by regression with a constraint based on information about the equilibrium dissociation constant of the ligand-receptor binding. Dopamine D2-receptor density in striatum was estimated to be 25.9 +/- 12.7 pmol/g in seven Macaca nemestrina monkeys. The method does not require the use of cerebellum as a reference tissue region and an estimate of dopamine D2-receptor density can be obtained from a single study.     

3-(2'-[18F]fluoroethyl)spiperone: in vivo biochemical and kinetic characterization in rodents, nonhuman primates, and humans

3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50 = 1.5 nM) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1-10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 micrograms/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (approximately 90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat greater than monkey greater than human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET.     

The quantitative analysis of D2-dopamine receptors in baboon striatum in vivo with 3-N-[2'-18F]fluoroethylspiperone using positron emission tomography

We used the ligand 3-N-[2'-18F]fluoroethylspiperone (FESP), which binds to D2-dopamine receptors in the striatum, and positron emission tomography (PET) to quantify striatal D2-dopamine densities (Bmax) and binding kinetics in baboon brain in vivo. Sequential PET scans were obtained for 4 h post injection. Various similar models based on a nonlinear kinetic four-compartment model that takes into account the effect of ligand specific activity were used. We investigated the effect of exact model configuration on the reliability of Bmax and other kinetic transfer coefficients. We found that with the ligand FESP and dynamic PET studies, the estimated values of Bmax and other model parameters are sensitive to the choice of model configuration, ligand specific activity, and data analysis technique. The limitations of the reliability of parameter estimates in a complex kinetic model for receptor ligands were studied in simulation calculations. Results showed that the accuracy of estimated values of Bmax is affected by both the ligand binding properties and the injected dose of ligand. The estimated average value of kinetic model parameters was as follows: ligand-receptor dissociation constant k4 = 0.0080 min-1; the product of ligand-receptor association constant and fraction of ligand available to bind to specific receptors f2ka = 0.0052 (min nM)-1; and D2-dopamine receptor density Bmax = 37.5 pmol g-1.     

Kinetics and modeling of L-6-[18F]fluoro-dopa in human positron emission tomographic studies

Kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) in striatum and cerebellum were measured in 10 normal human subjects with positron emission tomography (PET) from 0 to 120 min after an intravenous bolus injection of the tracer. The time course of the arterial plasma concentrations of the tracer and its metabolites was also assayed biochemically. FDOPA compartmental models that are based on biochemical information were investigated for their consistency with the measured striatal and cerebellar tissue kinetics. A modeling approach was also developed for separating plasma FDOPA and metabolite time-activity curves from the measured total 18F time-activity curve in plasma. Results showed that a model consisting of three separate compartments for tissue FDOPA, tissue 6-[18F]fluorodopamine (FDA) and its metabolites, and tissue L-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) could describe adequately the striatal kinetics in humans. Based on this model, the FDOPA transport constant across the blood-brain barrier (BBB) (K1), the FDOPA decarboxylation rate constant (k3), and the turn-over rate constant of FDA and its metabolites (k4) could be estimated by model fitting to the tissue kinetics and were found for the normal subjects to be 0.031 +/- 0.006 ml/min/g (mean +/- SD), 0.041 +/- 0.015/min, and 0.004 +/- 0.002/min, respectively. About 50% of the FDOPA that crossed the BBB from plasma to striatum was decarboxylated. The decarboxylation constant with respect to plasma FDOPA (K3) was 0.015 +/- 0.003 ml/min/g. The BBB transport corresponded to a permeability-surface area product of 0.032 ml/min/g for FDOPA. For 3-OMFD, the BBB transport was 1.7 times faster. The effects of tissue heterogeneity on the FDOPA kinetics and on the estimated model parameters were also investigated. The usefulness and implications of these findings for interpretation of PET FDOPA studies are discussed.     

Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.

The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.     

3H-3-N-methylspiperone labels D2 dopamine receptors in basal ganglia and S2 serotonin receptors in cerebral cortex

Detailed studies of the properties of 3H-3-N-methylspiperone (NMSP) binding in rat and human brain homogenates were performed at 37 degrees C. In homogenates of rat striatum and frontal cortex and human caudate and frontal cortex tissues, the specific binding was found to be saturable. Rat caudate contained 33.2 pmol/gm wet-weight tissue and displayed an equilibrium dissociation constant (Kd) of 8.7 X 10(-11) M; rat frontal cortex contained 18.5 pmol/gm wet-weight tissue and displayed a Kd of 1.5 X 10(-10) M. Human caudate contained 8.96 pmol/gm wet-weight tissue and displayed a Kd of 1.1 X 10(-10) M; human frontal cortex possessed 9.8 pmol/gm wet-weight tissue and a Kd of 4.4 X 10(-10) M. Kinetic studies revealed a very rapid rate of association in all the tissues studied. The rate of dissociation was relatively slow in all 4 tissue preparations; the dissociation rate was somewhat slower in rat striatum and human caudate relative to rat and human frontal cortex. This was consistent with the somewhat higher affinity, relative to frontal cortex, displayed by 3H-NMSP in rat striatal and human caudate tissue. The pharmacological properties of the specific binding in rat striatal and human caudate tissues were very similar and indicated the presence of brain D2 dopamine receptors. In rat and human frontal cortex tissue homogenates, the pharmacological characteristics of the specific binding indicated the presence of 5-HT2 receptors.     

Neuropeptide Y-immunoreactive neurons in the striatum of cat and monkey: Morphological characteristics, intrinsic organization and co-localization with somatostatin

A detailed study of the distribution of neuropeptide Y (NPY) in the striatum of squirrel monkey (Saimiri sciureus) and cat was undertaken by means of indirect immunofluorescence and peroxidase-antiperoxidase (PAP) methods. In monkey, the NPY-immunoreactivity is homogeneously distributed along the entire extent of the caudate nucleus (CD) and putamen (PUT), while in cat marked heterogeneities are noted. In the CD of cat, the NPY-immunoreactive fibers and cell bodies are concentrated in numerous patches of various sizes, which can be readily distinguished from zones of poor NPY-immunostaining. In the CD and PUT of squirrel monkey the NPY-positive neurons are either triangular, fusiform or globular, with long and smooth dendrites branching infrequently. The numerical density of NPY-immunoreactive cell bodies is greater in the CD than in the PUT, and it increases markedly along the rostrocaudal extent of the striatum. In the rostral CD and PUT the densities are 23 cells/mm2 and 14 cells/mm2, respectively, whereas the values for caudal CD and PUT are 35 cells/mm2 and 20 cells/mm2, respectively. Quantitative measurements reveal that these NPY-immunoreactive cells belong to a single subset of striatal neurons having a maximum diameter of 19.2 +/- 0.1 micron and a cross-sectional area of 145.5 +/- 0.6 micron2 (mean +/- S.E.M.; n = 1238 CD cells and 1169 PUT cells). Furthermore, experiments combining the use of lectin-conjugated HRP as retrograde tracer with PAP immunohistochemical method demonstrate that striatal NPY-immunoreactive neurons in squirrel monkey and cat do not project outside the striatum. Finally, co-localization studies in monkey reveal that the vast majority of striatal NPY-positive neurons also contains somatostatin. These results show that the NPY-immunoreactive neurons in mammalian striatum form a subpopulation of medium-sized interneurons containing somatostatin.     

Distribution of the histamine H(2) receptor in monkey brain and its mRNA localization in monkey and human brain

The distribution of histamine H(2) receptor mRNA was determined by in situ hybridization histochemistry in human and monkey brain. In the case of monkey brain, we combined this technique with receptor ligand autoradiography to compare the distribution of mRNA and receptor binding sites. [(125)I]Iodoaminopotentidine ([(125)I]-APT), a reversible, high specific activity antagonist with high affinity and selectivity for the H(2) receptor, was used for receptor autoradiography. Radiolabeled oligonucleotides derived from the human mRNA sequence encoding this receptor were used as hybridization probes. The highest density of the H(2) receptor mRNA in human and monkey brain was found in caudate and putamen nuclei and external layers of cerebral cortex. Moderate levels were seen in the hippocampal formation and lower densities in the dentate nucleus of cerebellum. Areas such as globus pallidus, amygdaloid complex, cerebellar cortex, and substantia nigra were devoid of hybridization signal. The distribution of H(2) receptor mRNA in monkey brain is generally in good agreement with that of the corresponding binding sites: prominent in caudate, putamen, accumbens nuclei, and cortical areas. The hippocampus showed lower densities of receptors and low levels were detected in the globus pallidus pars lateralis. No binding sites were seen in amygdaloid complex and substantia nigra. The distribution of histaminergic innervation is in good correlation with the areas of high density for H(2) receptors: caudate, putamen, and external layers of cerebral cortex in monkey and human brain. The presence of mRNA in caudate and putamen nuclei, together with its absence from substantia nigra, suggests that the H(2) receptors found in the striatum are synthesized by intrinsic cells and not by nigral dopaminergic cells. These striatal H(2) receptors may be located on short circuit striatal interneurons or somatodendritically on striatal projection neurons which project to the globus pallidus pars lateralis. In conclusion, the present results, which constitute, to our knowledge, the first report of the regional distribution of mRNA encoding H(2) receptors detected by in situ hybridization, define the sites of synthesis of H(2) receptors and are the basis for future, more detailed studies that should result in a better understanding of H(2) receptor function.     

Measuring the in vivo binding parameters of [18F]-fallypride in monkeys using a PET multiple-injection protocol.

The goal of this work was to quantify the in vivo transport and binding parameters of [F-18]fallypride and the D2/D3 receptor density (B'max) in both the striatal (putamen, caudate, ventral striatum) and extrastriatal regions (thalamus, amygdala, cerebellum, temporal and frontal cortices) of the rhesus monkey brain. Multiple-injection PET experimental protocols with injections of radiolabeled and unlabeled doses of fallypride were used to estimate the K1, k2, kon/VR, koff and B'max kinetic parameters. The experimental design was chosen using the D-optimal criterion to maximize the precision of the estimated binding parameters for the various brain regions. There was a significant range in B'max for the putamen (27 pmol/mL), caudate (23 pmol/mL), ventral striatum (14 pmol/mL), thalamus (1.8 pmol/mL) and amygdala (0.9 pmol/mL). Significant receptor binding was also found in the cortical regions. Knowledge of these in vivo rate constants serves as a necessary step in using [F-18]fallypride PET to measure D2/D3 receptor density and drug occupancy in clinical research applications. We believe the precise parameter estimates derived from these complicated experimental protocols are necessary for proper application of drug occupancy and clinical research studies with [F-18]fallypride, which often rely on the validity of assumptions regarding the model parameters.     

Adenosine A2A agonist CGS 21680 decreases the affinity of dopamine D2 receptors for dopamine in human striatum.

Adenosine A2A receptors (A2AR) and dopamine D2 receptors (D2R) are highly concentrated in the striatum, where they are co-localized and exert reciprocal antagonistic interactions. It has been suggested that the A2R/D2R interactions might provide a therapeutic approach for basal ganglia disorders, such as Parkinson's disease, and schizophrenia. In the present work evidence is presented for the existence of an A2AR/D2R interaction in human brain by using quantitative autoradi- ography. The areas analyzed were the dorsal caudate nucleus and putamen. Parallel studies were performed in rat striatal sections. The A2AR agonist CGS 21680 was found to significantly increase IC50 values of competitive inhibition curves of the D2R/D3R antagonist [125I]iodosulpiride vs dopamine both in rat striatal and human striatal brain sections.     

The centre médian and parafascicular thalamic nuclei project respectively to the sensorimotor and associative-limbic striatal territories in the squirrel monkey.

The striatal projections of the centre médian (CM) and parafascicular (Pf) thalamic nuclei were examined in the squirrel monkey (Saimiri sciureus) by using the lectin wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) as an anterograde tracer. CM was found to project massively to the putamen, where terminal fields appeared principally in the form of oblique bands, and more diffusely to the dorsolateral border of the caudate nucleus. Striatal inputs from Pf were found more rostrally, especially in the ventromedial portion of the putamen, the entire ventromedial half of the caudate nucleus, and the ventral striatum including the nucleus accumbens and the olfactory tubercle. Pf terminal fields in the rostral striatum often displayed a patchy organization. Both CM and Pf projections were found to terminate in the matrix compartment of the striatum as defined by acetylcholinesterase staining. These results suggest that CM is more specifically involved in sensorimotor and Pf in associative and limbic aspects of basal ganglia function in primates.     

The centre me´dian and parafascicular thalamic nuclei project respectively to the sensorimotor and associative-limbic striatal territories in the squirrel monkey

The striatal projections of the centre me´dian (CM) and parafascicular (Pf) thalamic nuclei were examined in the squirrel monkey (Saimiri sciureus) by using the lectin wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) as an anterograde tracer. CM was found to project massively to the putamen, where terminal fields appeared principally in the form of oblique bands, and more diffusely to the dorsolateral border of the caudate nucleus. Striatal inputs from Pf were found more rostrally, especially in the ventromedial portion of the putamen, the entire ventromedial half of the caudate nucleus, and the ventral striatum including the nucleus accumbens and the olfactory tubercle. Pf terminal fields in the rostral striatum often displayed a patchy organization. Both CM and Pf projections were found to terminate in the matrix compartment of the striatum as defined by acetylcholinesterase staining. These results suggest that CM is more specifically involved in sensorimotor and Pf in associative and limbic aspects of basal ganglia function in primates.     

Positron emission tomography with (18F)methylspiperone demonstrates D2 dopamine receptor binding differences of clozapine and haloperidol

Summary Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (¹⁸F)fluorodeoxyglucose (FDG) and (¹⁸F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D₂ dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D₂ dopamine receptor affinities of clozapine and haloperidol.     

Cortical inputs to m2-immunoreactive striatal interneurons in rat and monkey

Previous anatomical studies have been unsuccessful in demonstrating significant cortical inputs to cholinergic and somatostatinergic striatal interneurons in rats. On the other hand, electrophysiological studies have shown that cortical stimulation induces monosynaptic EPSPs in cholinergic interneurons. It has been proposed that the negative anatomical findings might have been the result of incomplete labeling of distal dendrites. In the present study, we reinvestigated this issue using m2 muscarinic receptor antibodies as a selective marker for cholinergic and somatostatinergic interneurons in the striatum. This was combined with injections of either the anterograde tracer biotinylated dextran amine (BDA) in the monkey prefrontal cortex or aspiration lesion of the sensorimotor cortex in rats. The results showed that, in both species, a small percentage (1-2%) of cortical terminals make asymmetric synaptic contacts with m2-immunoreactive interneurons in the striatum. Interestingly, the majority of these synapses are onto small dendritic spines or spine-like appendages, as opposed to dendritic shafts and/or cell bodies. Thus, m2-containing striatal interneurons do receive direct cortical inputs and can, therefore, integrate and modulate cortical information flow through the striatum. Although the density of cortical terminals in contact with individual striatal interneurons is likely to be relatively low compared to the massive cortical input to projection neurons, both cholinergic and somatostatinergic interneurons display intrinsic properties that allow even small and distal inputs to influence their overall state of neuronal activity.     

Long-term methamphetamine-induced decreases of [(11)C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey

The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatment on methamphetamine (METH)-induced striatal dopamine system deficits in the vervet monkey were characterized with [(11)C]WIN 35,428 (WIN)-positron emission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine terminal integrity. In two subjects, GDNF (200 microg/40 microl) was injected into the caudate and putamen unilaterally vs. saline contralaterally. After 1-2 weeks, + and -GDNF striatal WIN-PET binding values were equivalent as calculated by multiple time graphic analysis, suggestive of an absence of unilateral DAT up-regulation. Three other subjects (n = 3) received GDNF injections into the caudate and putamen unilaterally and one week later, were administered METH HCl (2 x 2 mg/kg; i.m., 24 hours apart; a neurotoxic dosage for this species). At 1 week post-METH, WIN-PET studies showed that mean WIN binding was decreased by 72% in the +GDNF and by 92% in the -GDNF striatum relative to pre-drug assessment values. Thus, GDNF pretreatment reduced the extent of METH-induced decreases in WIN binding. Subsequent WIN-PET studies (1.5-9-month range) showed a protracted recovery of WIN binding in each striatum, indicative of long-term but partially reversible METH neurotoxicity. Further, at each time point, WIN binding remained relatively higher in the +GDNF vs. -GDNF striatum. These results provide further evidence that the adult non-human primate brain remains responsive to exogenously administered GDNF and that this pharmacotherapy approach can counteract aspects of neurotoxic actions associated with methamphetamine.     

Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics.

There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its 'vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (DeltaBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D(2)/D(3) tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for DeltaBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D(2)/D(3) tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.     

Efferent connections of the centromedian and parafascicular thalamic nuclei in the squirrel monkey: a PHA-L study of subcortical projections.

The subcortical projections of the centromedian (CM) and the parafascicular (Pf) thalamic nuclei were examined in the squirrel monkey (Saimiri sciureus) by using the lectin Phaseolus vulgaris-leucoagglutinin (PHA-L) as an anterograde tracer. Both CM and Pf project massively to the striatum where they arborize in a complementary fashion. On the one hand, CM innervates most of the putamen caudal to the anterior commissure, a dorsolateral rim of the putamen rostral to the anterior commissure, discrete areas of the head of the caudate nucleus close to the internal capsule, and a lateral sector of the body of the caudate nucleus. On the other hand, Pf provides a heavy input to the head, body, and tail of the caudate nucleus, and to the rostral putamen, excluding the areas innervated by CM. In addition, Pf projects more discretely to the nucleus accumbens and the olfactory tubercle. Therefore, the projections from both CM and Pf cover the entire striatum, with those from CM arborizing into the "sensorimotor" striatal territory and the ones from Pf innervating the "associative-limbic" striatal territory. Furthermore, CM and Pf project to extrastriatal subcortical structures, such as the globus pallidus, the subthalamic nucleus, and the substantia nigra, where they also terminate in a complementary fashion. Topographically and cytologically, Pf is closely related to the subparafascicular nucleus (sPf). The Pf-sPf complex projects to the hypothalamus, the substantia innominata, the peripeduncular nucleus, and the amygdala. It also gives rise to descending efferents arborizing in various brainstem structures, including the inferior olivary complex. Additional studies with retrograde double-labeling methods show that distinct cell groups within CM project to the motor cortex and the striatum. Likewise, separate neuronal populations within the CM-Pf-sPf complex give rise to striatal and brainstem projections, the former arising from CM and Pf and the latter mainly from sPf. The complementary nature of CM and Pf projections to the striatum and other basal ganglia components suggests that this thalamic complex participates in a highly ordered manner in the parallel processing of the information that flows through the basal ganglia.     

The occurrence of large acetylcholinesterase-containing neurons in human neostriatum as disclosed in normal and Alzheimer-diseased brains

The human neostriatum was found to contain large neurons (maximum diameter: 30–40 μm) that stain intensely for acetylcholinesterase (AChE). These neurons are few in number, representing less than 5% of the total striatal neuronal population, and appear uniformly scattered throughout the caudate nucleus and putamen. They are morphologically similar to the AChE-containing neurons disclosed in the striatum of rat, cat and monkey after AChE inhibitor (DFP) pretreatment. In Alzheimer-diseased brains the number, morphological characteristics, and staining intensity of the striatal AChE neurons were found to be unaltered despite a marked loss of AChE cells in the adjoining nucleus basalis. These findings suggest that large intrinsic cholinergic neurons exist in human neostriatum and that these elements, in contrast to those of nucleus basalis, are not affected in Alzheimer's disease.     

Striatal size,glucose metabolic rate,and verbal learning in normal aging

The striatum has recently been implicated as an area that may mediate age-associated cognitive decline because of diminution of volume and functional activity. We used 18F-fluorodeoxyglucose (FDG) with positron emission tomography (PET) and high-resolution magnetic resonance imaging (MRI) to examine the effects of age on striatal glucose metabolic rate and size in 70 healthy, normal subjects. During the FDG tracer uptake period, subjects performed a serial verbal learning task, based on the California Verbal Learning Test. PET images were co-registered to the MR images. The interrelations among striatal glucose metabolic rate, size, and performance on the verbal learning task were examined with repeated-measures analysis of variance and correlational analysis. As age increased, relative glucose metabolic rate (GMR) increased in the putamen and decreased in the caudate. Female subjects had lower relative GMR than male subjects in the caudate, but equal in the putamen. Striatal size remained relatively constant across the lifespan in men but was lower in women aged 50-70 than in men. While there were significant associations between striatal activity and performance on the uptake task, these findings were mostly accounted for by age. The findings are consistent with our earlier report on the same cohort that demonstrated an age-related shift from anterior to posterior cortical metabolism, as the putamen receives primarily posterior cortical input and the caudate receives relatively more anterior cortical input. Findings of significant involvement of striatal functioning in verbal learning are most likely accounted for by age and suggest an age-related shift from anterior to posterior circuitry in the human telencephalon.