Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice.

We examined presynaptic cholinergic markers and beta-secretase activity during progressive central nervous system amyloidogenesis in Tg2576 Alzheimer mice (transgenic for human amyloid precursor protein Swedish mutation; hAPPswe). At 14, 18, and 23 months of age there were no significant differences between wild-type and transgenic mice in four distinct central nervous system cholinergic indices--choline acetyltransferase and acetylcholinesterase activities, and binding to vesicular acetylcholine transporter and Na(+)-dependent high-affinity choline uptake sites. A novel enzyme-linked immunosorbent assay measuring only the secreted human beta-secretase cleavage product (APPsbetaswe) of APPswe also revealed no change with aging in Tg2576 mouse brain.

Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders.

Rationale: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders.

Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation.

Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined.

Imaging the vesicular monoamine transporter.

Quantitative measures of striatal VMAT2 binding sites appear to represent an excellent surrogate of nigrostriatal projection integrity in experimental animal models. Importantly, there does not appear to be a significant effect of dopaminergic drugs or of lesion compensatory effect on the expressed level of VMAT2 binding sites in the striatum. Highly precise and specific measures of human VMAT2 are possible with PET employing the novel tracer (+)11C-DTBZ.

Influence of diuresis on enzymuria.

Urinary excretion of renal brush border enzymes may serve as an early marker of renal injury. However, the distinction between physiological and pathological levels remains controversial, since enzymuria is affected by physiological parameters. To clarify the influence of diuresis, we investigated the urinary excretion of alanine-aminopeptidase (AAP; EC 3.

Vesicular neurotransmitter transporters in Huntington's disease: initial observations and comparison with traditional synaptic markers.

Markers of identified neuronal populations have previously suggested selective degeneration of projection neurons in Huntington's disease (HD) striatum. Interpretations are, however, limited by effects of compensatory regulation and atrophy. Studies of the vesicular monoamine transporter type-2 (VMAT2) and of the vesicular acetylcholine transporter (VAChT) in experimental animals indicate that they are robust markers of presynaptic integrity and are not subject to regulation.

Long-term outcome of patients who receive ketamine during research.

Background: To comprehend the pathophysiology of schizophrenia and to facilitate drug discovery, animal and human models of schizophrenia are necessary. Ketamine, a noncompetitive N-methyl-D-aspartate antagonist, has been used to probe glutamatergic function in normal and schizophrenic volunteers. These studies and others have provided data consistent with a putative involvement of a glutamatergic dysfunction in the pathophysiology of schizophrenia; however, these studies have also raised concerns about the distress inflicted on patients, the potential for adverse events, and the serious long-term effects that could possibly be induced by symptom-simulating action.

Risk factors for sudden intrauterine unexplained death: epidemiologic characteristics of singleton cases in Oslo, Norway, 1986-1995.

Objective: The epidemiologic characteristics of unexplained stillbirths are largely unknown or unreliable. We define sudden intrauterine unexplained death as a death that occurs antepartum and results in a stillbirth for which there is no explanation despite postmortem examinations, and we present risk factors for this type of stillbirth in singleton gestations.

Study Design: Singleton antepartum stillbirths (n = 291) and live births (n = 582) in Oslo were included and compared with national data (n = 2025 and n = 575,572, respectively).

Blood pressure control in essential hypertension and impairment of renal function with age.

Hypertension has been recognized to be an important cause for the development of end-stage renal disease (ESRD). We assessed the quality of blood pressure control in 103 patients with essential hypertension and correlated renal function and age. Patients were stratified into three subgroups by their blood pressure level under current medication.

Assessment of muscarinic receptor concentrations in aging and Alzheimer disease with [11C]NMPB and PET.

Cerebral cholinergic deficits have been described in Alzheimer disease (AD) and as a result of normal aging. At the present time, there are very limited options for the quantification of cholinergic receptors with in vivo imaging techniques such as PET. In the present study, we examined the feasibility of utilizing [11C]N-methyl-4-piperidyl benzilate (NMPB), a nonselective muscarinic receptor ligand, in the study of aging and neurodegenerative processes associated with cholinergic dysfunction.

Vesicular monoamine transporter concentrations in bipolar disorder type I, schizophrenia, and healthy subjects.

Background: Previous analyses of vesicular monoamine transporter (VMAT2) binding in euthymic bipolar disorder type I (BDI) patients have shown increases of this presynaptic marker in the thalamus and ventral midbrain. To assess the diagnostic specificity of those findings, we compared VMAT2 concentrations between euthymic BDI patients, patients diagnosed with schizophrenia (SCH), and age-matched healthy volunteers.

Methods: Binding sites for VMAT2 were quantified with (+)-alpha-[11C]DTBZ (dihydrotetrabenazine) and positron emission tomography.

Decreased striatal dopaminergic innervation in REM sleep behavior disorder.

REM sleep behavior disorder (RBD) is a possible herald of neurodegenerative disorders with parkinsonism. The authors determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic RBD and 19 age-appropriate controls. In subjects with RBD, there were significant reductions in striatal [11C]dihydrotetrabenazine binding, particularly in the posterior putamen.

Synthesis, (18)F-labeling, and biological evaluation of piperidyl and pyrrolidyl benzilates as in vivo ligands for muscarinic acetylcholine receptors.

A series of 31 compounds based on the piperidyl or pyrrolidyl benzilate scaffold were prepared from methyl benzilate and 4-piperidinol, (R)-(+)-3-piperidinol, or (R)-(+)-3-pyrrolidinol. Amine substituents included alkyl and aralkyl groups. In vitro K(i) values ranged from 0.

In vivo measurement of the vesicular monoamine transporter in schizophrenia.

Given evidence for excessive striatal dopamine activity in schizophrenia, we sought to test the hypothesis that dopaminergic innervation in the striatum is abnormally elevated, and a secondary hypothesis that age-related loss is accelerated. Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [11C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2). DTBZ binding reflects principally dopaminergic projections in the striatum and appears in animal models, over treatment periods as long as two weeks, not to be regulated by antipsychotic drugs.

High vesicular monoamine transporter binding in asymptomatic bipolar I disorder: sex differences and cognitive correlates.

Objective: It has been hypothesized that anomalies in monoaminergic function underlie some of the manifestations of bipolar disorder. In this study the authors examined the possibility that trait-related abnormalities in the concentration of monoaminergic synaptic terminals may be present in patients with asymptomatic bipolar disorder type I.

Method: The concentration of a stable presynaptic marker, the vesicular monoamine transporter protein (VMAT2), was quantified with (+)[(11)C]dihydrotetrabenazine (DTBZ) and positron emission tomography.

Radiotracers and analytical approaches in positron and single-photon emission tomography.

Important advances in PET and SPECT imaging of neurochemistry have permitted direct investigation of neurologic diseases and syndromes, including many associated with seizures and epilepsy. Insights into issues of development and evolution of epileptogenic changes, mechanisms of seizure propagation, and mechanisms underlying therapeutic interventions will be increasingly gained from direct clinical study, rather than from experimental animal models, with the increasing application of this imaging technology.

Limited donepezil inhibition of acetylcholinesterase measured with positron emission tomography in living Alzheimer cerebral cortex.

Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr).

The anesthetic and recovery profile of two doses (60 and 80 mg) of plain mepivacaine for ambulatory spinal anesthesia.

Unlabelled: Reports of transient neurological symptoms with the use of subarachnoid lidocaine has generated interest in alternate local anesthetics of intermediate duration, such as mepivacaine. This prospective randomized, double-blinded, dose-response study examined the anesthetic and recovery profiles of 60- and 80-mg doses of preservative-free plain mepivacaine for ambulatory spinal anesthesia. Sixty patients undergoing ambulatory anterior cruciate ligament repair of the knee under spinal anesthesia were randomized into two groups; Group 1 (29 patients) received 4 mL of 1.

Neuroimaging in neurotoxicology.

The development of imaging technology over the past 25 years has had a profound impact on the clinical practices of a number of medical disciplines. In this article, the author reviews the various neuroimaging modalities and the neurologic processes that they can address.

Decreased striatal monoaminergic terminals in Huntington disease.

Objective: To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD).

Background: Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup.

Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes.

We have reported that inhibition of protein kinase C blocks the Ca(2+)-independent reverse transport of dopamine mediated by amphetamine. In this study we investigated whether activation of protein kinase C by 12-O-tetradecanoyl phorbol-13-acetate (TPA) would mediate dopamine release through the plasmalemmal dopamine transporter. TPA, at 250 nM, increased the release of dopamine from rat striatal slices and synaptosomes while the inactive phorbol ester, 4alpha-phorbol, was ineffective.

Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [11C]dihydrotetrabenazine.

Previous studies have demonstrated the utility of [11C]dihydrotetrabenazine ([11C]DTBZ) as a ligand for in vivo imaging of the vesicular monoamine transporter system. The (+)-isomer has a high affinity (approximately 1 nmol/L) for the vesicular monoamine transporter (VMAT2) binding site, whereas the (-)-isomer has an extremely low affinity (approximately 2 micromol/L). Efforts to model dynamic (+)-[11C]DTBZ data demonstrate the difficulty in separating the specific binding component from the free plus nonspecific component of the total positron emission tomography (PET) measure.

Infants of depressed mothers exhibit atypical frontal electrical brain activity during interactions with mother and with a familiar, nondepressed adult.

Previous studies have shown that infants of depressed mothers exhibit atypical frontal brain electrical activity when they are interacting with their mothers. Whereas typically developing infants exhibit greater left versus right frontal brain activity, infants of depressed mothers have been found to exhibit reduced relative left frontal activity. The left frontal brain region has been associated with the expression of positive emotions.