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Biomedical subjects

K A Frey

Publications and source records attributed to K A Frey.

At least 19 recordsLinked to original sources
PubMed2004

Cannabis improves night vision: a case study of dark adaptometry and scotopic sensitivity in kif smokers of the Rif mountains of northern Morocco.

Previous reports have documented an improvement in night vision among Jamaican fishermen after ingestion of a crude tincture of herbal cannabis, while two members of this group noted that Moroccan fishermen and mountain dwellers observe an analogous improvement after smoking kif, sifted Cannabis sativa mixed with tobacco (Nicotiana rustica). Field-testing of night vision has become possible with a portable device, the LKC Technologies Scotopic Sensitivity Tester-1 (SST-1). This study examines the results of double-blinded graduated THC administration 0-20 mg (as Marinol) versus placebo in one subject on measures of dark adaptometry and scotopic sensitivity. Analogous field studies were performed in Morocco with the SST-1 in three subjects before and after smoking kif. In both test situations, improvements in night vision measures were noted after THC or cannabis. It is believed that this effect is dose-dependent and cannabinoid-mediated at the retinal level. Further testing may assess possible clinical application of these results in retinitis pigmentosa or other conditions.

Adult↗
PubMed2003

Increased ventral striatal monoaminergic innervation in Tourette syndrome.

BACKGROUND: Excessive striatal dopaminergic innervation is suggested to underlie Tourette syndrome (TS). Prior imaging and postmortem studies yield conflicting data. METHODS: The authors used PET with the type 2 vesicular monoamine transporter ligand [(11)C]dihydrotetrabenazine (DTBZ) to quantify striatal monoaminergic innervation in patients with TS (n = 19) and control subjects (n = 27). Compartmental modeling was used to determine blood to brain ligand transport (K(1)) and tissue to plasma distribution volume (a measure of ligand binding) during continuous infusion of DTBZ. TS data were compared with control data using predefined regions of interest and on a voxel by voxel basis. RESULTS: There were no significant differences in ligand binding or ligand transport between patients with TS and control subjects in the dorsal striatum. With voxel by voxel analysis, there was increased DTBZ binding in the right ventral striatum. CONCLUSIONS: Previously reported differences between patients with TS and control subjects in dorsal striatal dopamine terminal markers may reflect medication-induced regulation of terminal marker expression or be the result of intrinsic differences in striatal dopaminergic synaptic function. Increased right ventral striatal DTBZ binding suggests that abnormal ventral striatal dopaminergic innervation may underlie tics.

Adolescent↗
PubMed2003

Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease.

A major goal of research in Parkinson's disease (PD) has been the development of treatments to slow the progressive degeneration of the nigrostriatal dopaminergic system and to reduce the functional decline of patients. Because of the uncertainty in the ability of the clinical evaluation to reflect the status of the nigrostriatal dopaminergic system once dopaminergic therapy has commenced, investigators in PD have sought to develop alternative measures of disease. One approach, which has been extensively explored, is neuroimaging with radiotracers that interact with processes central to dopaminergic neurotransmission in the nigrostriatal dopaminergic axons-conversion of levodopa to dopamine through aromatic amino acid decarboxylase (AADC), [(18)F]fluorodopa PET, storage of dopamine in synaptic vesicles via the vesicular monoamine transporter 2 (VMAT2), (+)-[(11)C]dihydrotetrabenazine PET, and reuptake of dopamine into axons via the dopamine transporter (DAT), [(123)I]beta-CIT SPECT, and a number of other PET and SPECT ligands. During the 54(th) Annual Meeting of the American Academy of Neurology, a group of investigators active in the fields of biomakers, neuroimaging, and neuroprotection met to review the three techniques mentioned above. Prior to the meeting, the participants developed consensus on a set of 10 criteria for a neuroimaging technique to be considered adequate as a biomarker for progression of PD and levels at which the available data for each technique indicate that the criterion was met. The criteria and each of the three imaging techniques mentioned above were reviewed, and the results of that meeting are presented.

Animals↗
PubMed2001

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. We measured dopamine and acetylcholine vesicular transporters to characterize the selectivity of degeneration in HD striatum. Brains were obtained at autopsy from four HD patients and five controls. Autoradiography was used to quantify radioligand binding to VMAT2, VAChT, the dopamine plasmalemmal transporter (DAT), benzodiazepine (BZ) binding sites, and D2-type dopamine receptors. The activity of choline acetyltransferase (ChAT) was determined as an additional marker of cholinergic neurons. Autoradiograms were analyzed by video-assisted densitometry and assessment of atrophy was made from regional structural areas in the coronal projection. Striatal VMAT2, DAT, and VAChT concentrations were unchanged or increased, while D2 and BZ binding and ChAT activity were decreased in HD. After atrophy correction, all striatal binding sites were decreased. However, the decrease in ChAT activity was 3-fold greater than that of VAChT binding. In addition to degeneration of striatal projection neurons, there are losses of extrinsic nigrostriatal projections and of striatal cholinergic interneurons in HD on the basis of vesicular transporter measures. There is also markedly reduced expression of ChAT by surviving cholinergic striatal interneurons.

Adult↗
PubMed2001

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. Based on prior data describing the accuracy of various kinetic methods, we examined the concentration of muscarinic receptors with [11C]NMPB and PET using two- and three-compartment kinetic models. Eighteen healthy subjects and six patients diagnosed with probable AD were studied. Pixel-by-pixel two-compartment model fits showed acceptable precision in the study of normal aging, with comparable results to those obtained with a more complex and less precise three-compartment model. Normal aging was associated with a reduction in muscarinic receptor binding in neocortical regions and thalamus. In AD patients, the three-compartment model appeared capable of dissociating changes in tracer transport from changes in receptor binding, but suffered from statistical uncertainty, requiring normalization to a reference region, and therefore limiting its potential use in the study of neurodegenerative processes. After normalization, no regional changes in muscarinic receptor concentrations were observed in AD.

Adult↗
PubMed2001

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. Fifteen euthymic BDI and 12 SCH patients and 15 group-matched healthy controls were studied. [11C]DTBZ tracer transport and binding potentials were examined in the thalamus and ventral midbrain with factorial analyses of variance and post hoc Tukey's honestly significantly different tests. RESULTS: Analysis of variance detected diagnosis effects in binding potentials in both brain regions. Binding of VMAT2 in the thalamus was higher in BDI patients than in control subjects and SCH patients. Conversely, ventral brainstem binding was nearly identical between BDI and SCH patients and were higher than in the control group. CONCLUSIONS: The patterns of regional VMAT2 expression, and by extension, the concentration of monoaminergic synaptic terminals, differ between BDI, SCH, and a control group. These findings may relate to both similarities and differences in the presentation or clinical course of these syndromes and require further examination.

Adult↗
PubMed2001

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. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

Aged↗
PubMed2001

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. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. OBJECTIVES: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. METHODS: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. RESULTS: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. CONCLUSIONS: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors.

Animals↗
PubMed2001

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. This methodology appears particularly suited to the objective measure of PD severity and of its progression. Such measures will be indispensable in the search for disease-modifying effects of PD therapy.

Animals↗
PubMed2000

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 0.05 nM to >100 nM. (R)-N-(2-Fluoroethyl)-3-piperidyl benzilate (3-FEPB, 22, K(i) = 12.1 nM) and N-(2-fluoroethyl)-4-piperidyl benzilate (4-FEPB, 8, K(i) = 1. 83 nM) were selected for radiolabeling with fluorine-18. Using alkylation with 2-[(18)F]fluoroethyl triflate, 3-[(18)F]FEPB (42) and 4-[(18)F]FEPB (43) were produced in 7-9% radiochemical yield and >97% radiochemical purity. For in vivo studies, retention was moderate in mouse brain for 42; however, blocking with scopolamine showed that uptake was not muscarinic cholinergic receptor-mediated. Conversely, 43 exhibited high, receptor-mediated retention in mouse brain, with significant clearance after 1 h. These results suggest that 43 could have applications as an in vivo probe for measuring endogenous acetylcholine levels.

Acetylcholine↗
PubMed2000

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.

Aged↗
PubMed2000

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. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. METHODS: Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. RESULTS: The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.

Adult↗
PubMed2000

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. The TPA-mediated dopamine release was independent of extracellular calcium and was blocked by a selective protein kinase C inhibitor, Ro31-8220. The dopamine transporter antagonists, cocaine and GBR 12935 blocked the TPA-mediated dopamine release. In addition, cocaine blocked TPA-mediated phosphorylation of the plasmalemmal dopamine transporter. These results suggest that activation of protein kinase C results in reverse transport of dopamine through the plasmalemmal dopamine transporter and the phosphorylated substrate could be the dopamine transporter.

Animals↗
PubMed2000

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.

Brain↗
PubMed2000

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. Using an equilibrium analysis, we obtained measurements of the binding potential (BP) of [11C]DTBZ, as well as a transport (K(1)) measure, corresponding to regional cerebral blood flow. BP in the striatum showed no difference between the patient and control groups, and no differential effect of age. We did not find evidence supporting the hypothesis that excessive dopamine activity in schizophrenia could be explained by increased density of striatal dopamine terminals.

Adolescent↗
PubMed2000

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. Sixteen asymptomatic patients with bipolar I disorder who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. Correlational analyses were conducted to examine the relationship between regional VMAT2 binding, cognitive function, and clinical variables. RESULTS: VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than that in the comparison subjects. VMAT2 concentrations in these regions correlated with performance on measures of frontal, executive function. In addition, sex differences in VMAT2 binding were detected in the thalamus of the bipolar patients; the male patients had higher binding than the women. No sex differences in binding were observed in the healthy comparison group. CONCLUSIONS: These initial results suggest that higher than normal VMAT2 expression and, by extension, concentration of monoaminergic synaptic terminals, may represent a trait-related abnormality in patients with bipolar I disorder and that male and female patients show different patterns. Also, VMAT2 concentrations may be associated with some of the cognitive deficits encountered in euthymic bipolar disorder.

Adult↗
PubMed2000

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). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition.

Acetylcholinesterase↗