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PubMed1997

Butyrylcholinesterase in the life cycle of amyloid plaques.

Deposits of diffuse beta-amyloid (Abeta) may exist in the brain for many years before leading to neuritic degeneration and dementia. The factors that contribute to the putative transformation of the Abeta amyloid from a relatively inert to a pathogenic state remain unknown and may involve interactions with additional plaque constituents. Matching brain sections from 2 demented and 4 nondemented subjects were processed for the demonstration of Abeta immunoreactivity, butyrylcholinesterase (BChE) enzyme activity, and thioflavine S binding. Additional sections were processed for the concurrent demonstration of two or three of these markers. A comparative analysis of multiple cytoarchitectonic areas processed with each of these markers indicated that Abeta plaque deposits are likely to undergo three stages of maturation, ie, a "diffuse" thioflavine S-negative stage, a thioflavine S-positive (ie, compact) but nonneuritic stage, and a compact neuritic stage. A multiregional analysis showed that BChE-positive plaques were not found in cytoarchitectonic areas or cortical layers that contained only the thioflavine S-negative, diffuse type of Abeta plaques. The BChE-positive plaques were found only in areas containing thioflavine S-positive compact plaques, both neuritic and nonneuritic. Within such areas, almost all (>98%) BChE-containing plaques bound thioflavine S, and almost all (93%) thioflavine S plaques contained BChE. These results suggest that BChE becomes associated with amyloid plaques at approximately the same time that the Abeta deposit assumes a compact beta-pleated conformation. BChE may therefore participate in the transformation of Abeta from an initially benign form to an eventually malignant form associated with neuritic tissue degeneration and clinical dementia.

Aged↗
PubMed1988

Distribution of muscarinic receptor subtypes within architectonic subregions of the primate cerebral cortex.

The regional distributions of muscarinic receptor subtypes (M1 and M2) in the macaque brain were investigated by in vitro receptor autoradiography. Putative muscarinic receptor subtypes were distinguished by their differential affinities for pirenzepine and carbachol in competition with [3H]-quinuclidinyl benzilate. Autoradiographic visualization of muscarinic receptor subtypes demonstrated marked regional and laminar variations that respected architectonic boundaries. The M1 receptor subtype was widely distributed throughout most cortical areas and was most intense over the superficial layers. Almost all limbic and paralimbic regions including the amygdala, hippocampus, orbitofrontal, temporopolar, parahippocampal, cingulate, and parolfactory areas displayed peak densities of the M1 receptor subtype. The M2 receptor subtype was selectively elevated in the primary sensory areas of all five sensory modalities, including the visual (area 17, V1), auditory (A1), and somatosensory (3b, S1) koniocortices, the anterior olfactory nucleus, and the gustatory area. The primary motor area also displayed a relative peak of M2 receptor subtype labeling. In the hippocampal formation, M1, M2, and nicotine receptors were distributed differentially, with each subdivision having a specific complement of cholinergic receptor subtype. The M1 receptor subtype was prevalent in the dentate gyrus, the CA4-CA3 region, and the CA1 ammonic sector. The M2 receptor subtype was concentrated in the CA2 sector, the subiculum, the rhinal cortices, and the parasubiculum. Putative neural nicotinic receptors, tagged with L-[3H]-nicotine, were most concentrated within the presubiculum.

Animals↗
PubMed1992

Differential cholinergic innervation within functional subdivisions of the human cerebral cortex: a choline acetyltransferase study.

The distribution of cholinergic fibers in the human brain was investigated with choline acetyltransferase immunocytochemistry in 35 cytoarchitectonic subdivisions of the cerebral cortex. All cortical areas and all cell layers contained cholinergic axons. These fibers displayed numerous varicosities and, on occasion, complex preterminal profiles arranged in the form of dense clusters. The density of cholinergic axons tended to be higher in the more superficial layers of the cerebral cortex. Several distinct patterns of lamination were identified. There were also major differences in the overall density of cholinergic axons from one cytoarchitectonic area to another. The cholinergic innervation of primary sensory, unimodal, and heteromodal association areas was lighter than that of paralimbic and limbic areas. Within unimodal association areas, the density of cholinergic axons and varicosities was significantly lower in the upstream (parasensory) sectors than in the downstream sectors. Within paralimbic regions, the non-isocortical sectors had a higher density of cholinergic innervation than the isocortical sectors. The highest density of cholinergic axons was encountered in core limbic structures such as the hippocampus and amygdala. These observations show that the cholinergic innervation of the human cerebral cortex displays regional variations that closely follow the organization of information processing systems.

Adult↗
PubMed1992

Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus.

The anatomical organization of cholinergic markers such as acetylcholinesterase, choline acetyltransferase, and nerve growth factor receptors was investigated in the basal ganglia of the human brain. The distribution of choline acetyltransferase-immunoreactive axons and varicosities and their relationship to regional perikarya showed that the caudate, putamen, nucleus accumbens, olfactory tubercle, globus pallidus, substantia nigra, red nucleus, and subthalamic nucleus of the human brain receive widespread cholinergic innervation. Components of the striatum (i.e., the putamen, caudate, olfactory tubercle, and nucleus accumbens) displayed the highest density of cholinergic varicosities. The next highest density of cholinergic innervation was detected in the red nucleus and subthalamic nucleus. The level of cholinergic innervation was of intermediate density in the globus pallidus and the ventral tegmental area and low in the pars compacta of the substantia nigra. Immunoreactivity for nerve growth factor receptors (NGFr) was confined to the cholinergic neurons of the basal forebrain and their processes. Axonal immunoreactivity for NGFr was therefore used as a marker for cholinergic projections originating from the basal forebrain (Woolf et al., '89: Neuroscience 30:143-152). Although the vast majority of striatal cholinergic innervation was NGFr-negative and, therefore, intrinsic, the striatum also contained NGFr-positive axons, indicating the existence of an additional cholinergic input from the basal forebrain. This basal forebrain cholinergic innervation was more pronounced in the putamen than in the caudate. The distribution of NGFr-positive axons suggested that the basal forebrain may also project to the globus pallidus but probably not to the subthalamic nucleus, substantia nigra, or red nucleus. The great majority of cholinergic innervation to these latter three structures and to parts of the globus pallidus appeared to come from cholinergic neurons outside the basal forebrain, most of which are probably located in the upper brainstem. These observations indicate that cholinergic neurotransmission originating from multiple sources is likely to play an important role in the diverse motor and behavioral affiliations that have been attributed to the human basal ganglia.

Acetylcholinesterase↗
PubMed1993

Cholinergic innervation of the amygdaloid complex in the human brain and its alterations in old age and Alzheimer's disease.

The cholinergic innervation of the human amygdaloid complex was studied immunohistochemically with a choline acetyltransferase (ChAT) antibody in eight brains: five control and three with Alzheimer's disease (AD). All amygdaloid nuclei displayed ChAT-immunopositive axons and varicosities. The density of these axons reached levels that were higher than in any other part of the forebrain except for the striatum. The highest level of ChAT-immunopositive profiles was seen in the basolateral nucleus and the second highest in the lateral part of the central nucleus. The basomedial, accessory basal, and cortical nuclei, the amygdalohippocampal and cortico-amygdaloid transition areas, as well as the anterior amygdaloid area, showed a moderate density of ChAT-positive varicosities and fibers. The lateral nucleus displayed a relatively low density of cholinergic innervation, and there were only rare ChAT-positive fibers in the medial nucleus. Although the level of cholinergic innervation in the lateral nucleus was relatively lower than in many of the other amygdaloid nuclei, it was approximately equivalent to that of entorhinal cortex, a region that receives one of the heaviest cholinergic inputs in the cerebral cortex. The distribution of the cholinergic fibers as studied by ChAT immunohistochemistry was nearly identical to that observed with AChE histochemistry. Quantitative densitometry in control specimens showed that there was no decline of amygdaloid cholinergic input when middle-aged subjects were compared with senescent subjects. In AD there was a severe and regionally selective depletion of this innervation in the amygdaloid complex. The cortical, accessory basal, and lateral nuclei displayed the most severe loss of ChAT-positive profiles, whereas the basolateral, and especially the central, nuclei displayed relatively little change. There was no consistent relationship between the loss of cholinergic fibers and the density of amyloid plaques and neurofibrillary tangles in amygdaloid nuclei.

Aged↗
PubMed2005

Dementia in Parkinson's disease: a post-mortem study in a population of brain donors.

OBJECTIVE: To identify factors associated with dementia in a cohort of Parkinson's disease (PD) brain donors and determine whether its presence may influence the clinical phenotype of the disease. METHODS: We included 67 consecutive patients with a clinical and pathological diagnosis of PD, who while alive, consented to donate their brains to the University of Miami Brain Endowment Bank(TM). Dementia and psychiatric complications of PD were diagnosed according to established criteria. Case histories were abstracted and reviewed and comparisons between PD patients with (PD-D, n = 34) and without (PD, n = 33) dementia were made. RESULTS: Age at death, age at disease onset and disease duration did not differ significantly between PD-D and PD patients. Other symptoms were similar in both groups. Visual hallucinations and bilateral symptoms at diagnosis were significantly higher in PD-D patients. No association between dementia and overall survival duration was found. Although the frequency of depression and psychosis was higher in the PD patients with dementia no statistical significance was reached. The overall lifetime prevalence of dementia in our group was 50.7%. CONCLUSIONS: Visual hallucinations and bilateral symptoms were associated with dementia in our cohort of PD brain donors. No association between dementia and survival duration was found. Understanding the influence of dementia on the clinical phenotype of the disease and predicting its development is essential for the successful management of PD.

Age of Onset↗
PubMed2006

Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin.

DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM(-1) and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0, 1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.

Animals↗
PubMed1990

Pargyline-sensitive selective accumulation of a radiolabeled MPTP analog in the primate cerebral cortex and basal ganglia.

The distribution of radioiodinated N-methyl-4-(4-hydroxy-3-iodobenzyl)-1,2,3,6-tetrahydropyridine (MHTP), an analog of the reportedly nontoxic N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, (4-homo-MPTP), has been studied in the primate. [123I]MHTP-derived radioactivity exhibited a progressive accumulation and prolonged retention within the primate eye. Following iv injection, [123I]MHTP rapidly accumulated within the primate brain and was subsequently oxidized to a radiolabeled metabolite. The half-life of [123I]MHTP-derived radioactivity within the primate brain was 50 min. The highest concentrations of radioactivity were found in the caudate-putamen and the frontal, temporal and cingulate cortices; the substantia nigra and inferior olivary nucleus were labeled with medium intensity. Very low concentrations of radiolabel were detected in the cerebellum and white matter. Selective accumulation of [125I]MHTP-derived radioactivity within these structures was blocked by pretreatment with pargyline, suggesting that monoamine oxidase B is involved in the bioactivation of radioiodinated MHTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Sigma receptors are associated with cortical limbic areas in the primate brain.

Putative sigma receptors are a current target for antipsychotic drug development. Novel antipsychotic agents which possess selective and high affinity for sigma binding sites may serve as an alternative to the principal neuroleptic drugs currently in clinical use which mediate extrapyramidal side effects and dyskinesias through their blockade of dopamine receptors. We have used in vitro autoradiography to localize putative sigma receptors labelled with (+)-[3H]-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine [(+)-[3H]-3-PPP] in the brain of the rhesus macaque. The binding characteristics of (+)-[3H]-3-PPP in the primate brain were comparable to those previously described in the rodent. Saturation analysis demonstrated a single class of sites in cerebellar and hippocampal membranes with a Kd value of 28 nM. Sigma receptors labeled with (+)-[3H]-3-PPP in the primate brain displayed the appropriate rank order of potency and stereoselectivity in competition binding assays. Haloperidol displaced (+)-[3H]-3-PPP binding in the low nanomolar range, and the (+) isomer of pentazocine was 50-fold more potent than (-) pentazocine. Computerized densitometric analysis of the autoradiograms demonstrated a striking enrichment of sigma binding sites over the paralimbic belt cortices, including the orbitofrontal, cingulate, insular, parahippocampal, and temporopolar gyri. Peak densities of sigma receptors were seen over the medial and central nuclei of the amygdala and were widely distributed within the hippocampal formation. Sigma binding sites densities were elevated over the suprachiasmatic and supraoptic nuclei of the hypothalamus. Moderate sigma receptor densities were observed over the ventromedial sectors of the caudate and the putamen. Sigma receptors were also elevated over autonomic relay nuclei of the brainstem, including the nucleus of the solitary tract and the dorsal motor nucleus of the vagus. The distribution of sigma receptors in the primate brain suggests that the paralimbic belt cortices, amygdala, hippocampus, hypothalamus, and autonomic relay nuclei of the brainstem may be interrelated by a topographic chemical linkage. The autoradiographic visualization of sigma receptor distributions in the primate brain provides further support for a role of sigma receptor mechanisms in the functions of the limbic system.

Animals↗
PubMed1993

Distinct kinetic binding properties of N-[3H]-methylscopolamine afford differential labeling and localization of M1, M2, and M3 muscarinic receptor subtypes in primate brain.

Three classes of muscarinic receptors in mammalian brain have been postulated on the basis of equilibrium and kinetic binding data. However, equilibrium binding assays alone have not permitted a clear demonstration of the localization of putative M1, M2, and M3 receptor subtypes in the brain because of the overlapping affinities of virtually all muscarinic antagonists. In the present study, the conditions for selective occupancy of the M1, M2, and M3 receptor subtypes in the brain of the rhesus monkey were based on the distinct kinetic and equilibrium binding properties of N-[3H]-methylscopolamine (NMS) at cloned m1-m4 muscarinic receptor subtypes expressed in A9L transfected cells. Quantitative autoradiography of the M1, M2, and M3 muscarinic receptor subtypes in the primate brain was performed according to the following strategy. The M1 (m1) receptor subtype was labeled directly with a non-saturating concentration of [3H]-pirenzepine. The M2 (m2) subtype was labeled by incubations consisting of short, two minute pulses of [3H]-NMS after a preincubation with 0.3 microM pirenzepine to occlude m1, m3, and m4 sites. Selective occupancy of the M3 (m3) receptor (subtype) was achieved by pre-incubation with 0.5 nM unlabeled NMS to partially occlude the m1, m2, and m4 sites, equilibrium with 0.5 nM [3H]-NMS, followed by a 60 minute tracer dissociation in the presence of 1 microM atropine. In vitro autoradiography demonstrated that the M1 receptor subtype was confined to forebrain structures. M1 receptors were prevalent throughout the cerebral cortical mantle, amygdala, hippocampus, and the striatum. Low to background levels of the M1 receptor subtype were measured over the thalamus, hypothalamus, and brainstem. The M2 subtype was widely distributed with elevated densities of binding sites seen over all primary sensory cortical areas, and within discrete thalamic, hypothalamic, and brainstem nuclei. The distribution of the M3 receptor subtype was largely coincident with the pattern of the M1 sites labeled by non-saturating concentrations of [3H]-pirenzepine with some notable exceptions. Within the cerebral cortical mantle, the M3 receptor exhibited an elevated gradient over the orbitofrontal gyrus and the temporal lobe. Within the striatum, the M3 subtype was elevated over the anterior and dorsal part of the caudate nucleus, while the M1 receptors were most prevalent over the ventromedial sector. Selective labeling of M3 receptors was seen over the medial division of the globus pallidus and within the substantia nigra pars reticulata. In contrast to the pattern of the M1 receptor subtype, M3 receptors were prevalent also over midline nuclei of the hypothalamus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Mapping dopamine transporters in the human brain with novel selective cocaine analog [125I]RTI-121.

The novel cocaine analog RTI-121 [3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid isopropyl ester] was evaluated as a probe for the in vitro labeling and localization of the dopamine transporter in the human brain. Saturation binding experiments conducted in sucrose-phosphate buffer (10 mM sodium phosphate, pH 7.4, 0.32 M sucrose) revealed high- and low-affinity binding components with affinity values (KD) of 0.25 +/- 0.04 and 4.9 +/- 1.6 nM (mean +/- SE) and densities (Bmax) of 56.8 +/- 13.8 and 147.7 +/- 23.4 pmol/g tissue, respectively. In contrast, when saturation binding experiments were performed in phosphate-buffered saline (10 mM Na2HPO4, 1.8 mM KH2PO4, 136 mM NaCl, 2.8 mM KCl, 10 mM NaI, pH 7.4), a 9-fold decrease in the density of the low-affinity component was noted, suggesting that the low-affinity RTI-121 binding site is associated with the region of the transporter involved in the ionic dependence of substrate recognition and/or uptake. The rank order of potency for inhibition of [125I]RTI-121 binding to human caudate membranes demonstrates that the radioligand selectively labels the dopamine transporter (GBR 12909 > RTI-121 > mazindol > nomifensine > (-) cocaine > desipramine > citalopram). Autoradiographic mapping of [125I]RTI-121 revealed very high densities of cocaine recognition sites over areas known to be rich in dopaminergic innervation, including the caudate, putamen, and nucleus accumbens. Moderate densities were also observed over the substantia nigra and the ventral tegmental area. Low-to-background labeling of [125]RTI-121 was seen throughout the cerebral cortex, amygdaloid nuclei, globus pallidus, and thalamus. In comparison with the autoradiographic distribution of the cocaine analogs [3H]WIN 35,428 (or CFT) and [125I]RTI-55 (or beta-CIT), the labeling pattern for [125I]RTI-121 was more restricted. These studies demonstrate that [125I]RTI-121 labels dopamine-rich brain regions with greater selectivity than other currently available cocaine analogs, which makes it a potentially superior imaging probe for mapping the dopamine transporter in the human brain.

Adult↗
PubMed1999

Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson's disease.

The vesicular monoamine transporter (VMAT2) has been suggested to be an excellent marker of presynaptic dopaminergic nerve terminals in the striatum of Parkinson's disease patients based on its high level of expression and insensitivity to drugs used to treat the disease. Previous in vivo imaging and postmortem binding studies have detected a loss in striatal VMAT2 binding in Parkinson's diseased (PD) brain; however, these techniques have poor spatial resolution and may suffer from nonspecific binding of some ligands. In this study, we use novel polyclonal antibodies to distinct regions of human VMAT2 to quantify and localize the protein. Western blot analysis demonstrated marked reductions in VMAT2 immunoreactivity in putamen, caudate, and nucleus accumbens of PD brain compared to control cases. Immunohistochemistry revealed VMAT2 immunoreactive fibers and puncta that were dense throughout the striatum of control brains, but which were drastically reduced in putamen of PD brains. In PD brains the caudate showed a significant degree of sparing along the border of the lateral ventricle and the nucleus accumbens was relatively preserved. The distribution of VMAT2 in striatum and its loss in PD paralleled that of the dopamine transporter (DAT), a phenotypic marker of dopamine neurons. Thus, immunochemical analysis of VMAT2 protein provides novel and sensitive means for localizing and quantifying VMAT2 protein and nigrostriatal dopamine terminals in PD. Furthermore, the relative expression of VMAT2 compared to that of DAT may predict the differential vulnerability of dopamine neurons in PD.

Animals↗
PubMed1996

Pharmacological screen for activities of 12-hydroxyibogamine: a primary metabolite of the indole alkaloid ibogaine.

The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and is O-demethylated to 12-hydroxyibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [3H]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine's ability to alter drug-seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits.

Binding Sites↗