Biomedical subjects

M Guttman

Publications and source records attributed to M Guttman.

At least 37 records · Page 2Linked to original sources

PubMed2001

The use of pramipexole in Parkinson's disease: are its actions D(3) mediated?

Pramipexole is a non-ergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease (PD). It has preferential affinity for the D(3) dopamine receptor, compared to previous dopamine agonists that have higher affinity for D(2) dopamine receptors. The ultimate question is whether its efficacy is linked to its action at the D(3) dopamine site or due to its binding to D(2) dopamine receptors. There is no direct experimental evidence available to answer this question. Based on a review of the pharmacological literature, it is likely that the motor benefits of pramipexole in PD patients are due to D(2) stimulation, whereas its putative effects on mood and apathy may be related to its D(3) agonist properties.

Journal Article↗

PubMed2000

Dopamine D1 receptor protein is elevated in nucleus accumbens of human, chronic methamphetamine users.

Animal data have long suggested that an adaptive upregulation of nucleus accumbens dopamine D1 receptor function might underlie part of the dependency on drugs of abuse. We measured by quantitative immunoblotting protein levels of dopamine D1 and, for comparison, D2 receptors in brain of chronic users of methamphetamine, cocaine, and heroin. As compared with the controls, brain dopamine D1 receptor concentrations were selectively increased (by 44%) in the nucleus accumbens of the methamphetamine users, whereas a trend was observed in this brain area for reduced protein levels of the dopamine D2 receptor in all three drug groups (-25 to -37%; P < 0.05 for heroin group only). Our data support the hypothesis that aspects of the drug-dependent state in human methamphetamine users might be related to increased dopamine D1 receptor function in limbic brain.

Adult↗

PubMed2000

Dopa-responsive dystonia due to a large deletion in the GTP cyclohydrolase I gene.

Although it is assumed that most patients with autosomal dominant dopa-responsive dystonia (DRD) have a GTP cyclohydrolase I dysfunction, conventional genomic DNA sequencing of the gene (GCH1) coding for this enzyme fails to reveal any mutations in about 40% of DRD patients, which makes molecular genetic diagnosis difficult. We found a large heterozygous GCH1 deletion, which cannot be detected by the usual genomic DNA sequence analysis, in a three-generation DRD family and conclude that a large genomic deletion in GCH1 may account for some "mutation-negative" patients with dominantly inherited DRD.

Adult↗

PubMed2000

Regional distribution of cocaine in postmortem brain of chronic human cocaine users.

We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.

Adult↗

PubMed1999

Parkinson's disease management: towards a new paradigm.

Over the past decade, management of Parkinson's disease has changed significantly due to the expansion of medical and surgical treatment modalities. Neurologists now have the ability (and the challenge) of choosing from multiple medications to devise an individual management strategy for each patient depending on his/her clinical symptoms and needs. Several different surgical therapies are also available. The topics covered in this supplement have highlighted the new options that are now available, as well as the treatments that have been in clinical usage. This review attempts to synthesize the information that is currently available in an attempt to help clinical neurologists make the appropriate choice for their patients.

Catechol O-Methyltransferase Inhibitors↗

PubMed1999

Brain choline acetyltransferase activity in chronic, human users of cocaine, methamphetamine, and heroin.

Cognitive impairment has been reported in some chronic users of psychostimulants, raising the possibility that long-term drug exposure might damage brain neuronal systems, including the cholinergic system, which are responsible for normal cognition. We measured the activity of choline acetyltransferase (ChAT), the marker enzyme for cholinergic neurones, in autopsied brain of chronic users of cocaine, methamphetamine, and, for comparison, heroin. As compared with the controls, mean ChAT levels were normal in all cortical and subcortical brain areas examined. However, the two of 12 methamphetamine users, who had the highest brain/blood drug levels at autopsy, had a severe (up to 94%) depletion of ChAT activity in cerebral cortex, striatum, and thalamus. Based on the subjects examined in the present study, our neurochemical data suggest that brain cholinergic neurone damage is unlikely to be a typical feature of chronic use of cocaine, methamphetamine, or heroin, but that exposure to very high doses of methamphetamine could impair, at least acutely, cognitive function requiring a normal nucleus basalis cholinergic neuronal system. Reduced brain ChAT might be explained in part by a hyperthermia-related mechanism as low ChAT levels have also been observed in brain of some patients with neuroleptic drug-associated hyperthermia. Studies of cognitive and brain cholinergic status in high dose users of MA are warranted.

Adult↗

PubMed1999

Decreased brain protein levels of cytochrome oxidase subunits in Alzheimer's disease and in hereditary spinocerebellar ataxia disorders: a nonspecific change?

Controversy exists as to the clinical importance, cause, and disease specificity of the cytochrome oxidase (CO) activity reduction observed in some patients with Alzheimer's disease (AD). Although it is assumed that the enzyme is present in normal amount in AD, no direct measurements of specific CO protein subunits have been conducted. We measured protein levels of CO subunits encoded by mitochondrial (COX I, COX II) and nuclear (COX IV, COX VIc) DNA in autopsied brain of patients with AD whom we previously reported had decreased cerebral cortical CO activity. To assess disease specificity, groups of patients with spinocerebellar ataxia type I and Friedreich's ataxia were also included. As compared with the controls, mean protein concentrations of all four CO subunits were significantly decreased (-19 to -47%) in temporal and parietal cortices in the AD group but were not significantly reduced (-12 to -17%) in occipital cortex. The magnitude of the reduction in protein levels of the CO subunits encoded by mitochondrial DNA (-42 to -47%) generally exceeded that encoded by nuclear DNA (-19 to -43%). In the spinocerebellar ataxia disorders, COX I and COX II levels were significantly decreased in cerebellar cortex (-22 to -32%) but were normal or close to normal in cerebral cortex, an area relatively unaffected by neurodegeneration. We conclude that protein levels of mitochondrial- and nuclear-encoded CO subunits are moderately reduced in degenerating but not in relatively spared brain areas in AD and that the decrease is not specific to this disorder. The simplest explanation for our findings is that CO is decreased in human brain disorders as a secondary event in brain areas having reduced neuronal activity or neuronal/synaptic elements consequent to the primary neurodegenerative process.

Aged↗

PubMed1998

Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.

BACKGROUND: Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons. OBJECTIVE: To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders. PATIENTS AND METHODS: Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients with Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. RESULTS: Brain GAPDH activity was normal in all groups with the exception of a slight but statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%). CONCLUSION: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.

Adolescent↗

PubMed1998

Effect of catechol-O-methyltransferase inhibition on brain uptake of [18F]fluorodopa: implications for compartmental modelling and clinical usefulness.

The efficacy of levo-DOPA in the treatment of Parkinson's disease is potentiated by blockade of its peripheral metabolism with inhibitors of catechol-O-methyltransferase (COMT). Some COMT inhibitors may act entirely in the periphery (nitecapone, OR-462), while others may also have some activity in brain (entacapone, OR-611). We used positron emission tomography (PET) to test the effects of these two COMT inhibitors on the plasma kinetics and brain metabolism of the levo-DOPA analog 6-[18F]fluoro-L-dopa (FDOPA) in cynomolgus monkeys, employing a compartmental model for the assay of DOPA decarboxylase activity in living brain. Four monkeys each underwent two PET scans in the baseline condition, one PET scan after treatment with OR-462 (15 mg/kg, i.v.), and one PET scan after treatment with OR-611 (15 mg/kg, i.v.). Pharmacokinetic analysis of FDOPA metabolism in plasma indicated that these compounds blocked peripheral COMT activity by 80% for at least 60 minutes. Both COMT inhibitors increased the net availability of FDOPA in circulation, and increased the ratio of the radioactivity concentrations in striatum and occipital cortex, suggesting that [18F]fluorodopamine synthesis in striatum was potentiated. However, OR-611 treatment reduced the unidirectional (K1D) and net (Ki) blood-brain clearances of FDOPA, and also inhibited the rate of decarboxylation (k3D) of FDOPA in striatum. These observations suggest that high doses of OR-611 may partially antagonize the cerebral utilization of levo-DOPA. We used the present data to test the sensitivity of the compartmental model to the physiological constraint that the blood-brain permeabilities of the O-methylated plasma metabolite and FDOPA have a fixed ratio. In the groups with COMT inhibition, the estimates of k3D were insensitive to the magnitude of the permeability ratio. In the control group, the estimate of k3D increased by 40% as the magnitude of the constrained permeability ratio increased in the range of published estimates.

Animals↗

PubMed1998

Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia.

We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.

Adolescent↗

PubMed1997

Immune complexes bound to the primate erythrocyte complement receptor (CR1) via anti-CR1 mAbs are cleared simultaneously with loss of CR1 in a concerted reaction in a rhesus monkey model.

In the circulation of primates, C3b-opsonized immune complexes (IC) bound to erythrocyte (E) CR1 are taken to the liver and spleen where IC are removed and destroyed without lysis or sequestration of E. Individuals with diseases associated with IC processing often have decreased E CR1 levels, and in previous primate animal models of IC disease, E CR1 was shown to be reduced, but the relationship between IC processing and CR1 loss remained to be clarified. We have developed a simple model to study this question. In naive (nonimmunized) rhesus monkeys, E-bound mouse anti-CR1 mAbs (1500 IgG/E) are not rapidly cleared from the circulation. Infusion of monkey anti-mouse IgG leads to rapid indirect binding of this second antibody to E CR1. Subsequently, in what appears to be a concerted reaction, CR1-bound nascent IC are rapidly cleared from the circulation and CR1 is removed from E at the same rate. Clearance of bound IC and loss of CR1 were both independently followed by RIA. Imaging studies localized the cleared anti-CR1 mAbs to the liver. Western blots indicated that the loss of CR1 was not due to a conformational change, and E CR1 levels returned to normal in 2-3 weeks, suggesting that the return was associated with synthesis of new E. Our findings suggest that the key step in the clearance mechanism requires recognition (possibly by Fc receptors) of IC-like material associated with E CR1, and this leads to loss of CR1 and uptake of the CR1-IC substrate by liver phagocytic cells.

Animals↗

PubMed1997

Striatal dopamine nerve terminal markers but not nigral cellularity are reduced in spinocerebellar ataxia type 1.

We previously reported markedly reduced (-76%) dopamine (DA) levels in the putamen of seven patients with spinocerebellar ataxia type 1 (SCA1) who had no evidence of nigral cell loss or parkinsonism. To determine whether the DA reduction was accompanied by loss of DA nerve terminals, we measured levels of the DA transporter ([3H]WIN, 35,428 binding; DA transporter protein) and the vesicular monoamine transporter ([3H]DTBZ binding) in the putamen of these patients. As compared with the controls (n = 14), mean putamen concentrations of [3H]WIN 35,428 binding (-45%), dopamine transporter protein (-61%), and [3H]DTBZ binding (-48%) were significantly reduced in this SCA1 subgroup. We conclude that the degeneration in nigrostriatal DA neurons begins at the nerve ending in SCA1.

Adult↗

PubMed1997

[11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson's disease: implications for the symptomatic threshold.

To estimate the threshold of nigrostriatal dysfunction required for symptomatic Parkinson's disease (PD), we employed [11C]RTI-32 and PET to study the dopamine transporter in striatal subdivisions of 11 L-dopa-naive patients with very early parkinsonism. As compared with the controls (N = 10), the PD group had on the side contralateral to the maximal clinical symptoms, significantly reduced binding in the posterior putamen (-56%) and anterior putamen (-28%), with the reduction in caudate (-12%) not significantly different. To the extent that dopamine transporter binding accurately reflects the number of nigrostriatal dopamine nerve terminals, these findings suggest that the clinical threshold for PD in the middle-age human is approximately 50% loss of dopaminergic innervation to the posterior putamen. Our data also suggest that damage to the putamen component of the striatum is sufficient for the clinical expression of PD.

Adult↗

PubMed1997

Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson's disease. International Pramipexole-Bromocriptine Study Group.

Pramipexole is a new, selective, nonergoline dopamine agonist that acts on D2 and preferentially on D3 dopamine receptors. Phase II and III clinical trials have shown this drug to be useful in treating both early and advanced Parkinson's disease (PD) patients. A double-blind, randomized, multicenter study was performed to compare the safety, tolerance, and efficacy of pramipexole versus placebo in patients with advanced PD with motor fluctuations. A bromocriptine treatment group was included to enable comparisons between bromocriptine and placebo groups, but the study was not powered to show statistical differences between the active treatment groups. The study included 247 patients with "wearing off." Patients were Hoehn and Yahr stages II to IV during "on" times. The trial included three phases: dose escalation, 6 months' maintenance, and dose reduction. The primary end points were the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III. Up to 4.5 mg per day of pramipexole and 30 mg per day of bromocriptine were used. The results of the study showed that the UPDRS part II improved by 26.7% for pramipexole (p = 0.0002) and 14% for bromocriptine (p = 0.02) versus 4.8% for placebo. The UPDRS part III showed improvements of 34% for pramipexole (p = 0.0006) and 23.8% for bromocriptine (p = 0.01) versus 5.7% for placebo. There were no major differences in safety data. In the active treatment groups there were more reports of dyskinesia and nausea compared with placebo. In regard to comparison of the Global Clinical Assessment of Efficacy between active treatment groups, there was a trend to significance (p = 0.056) in favor of pramipexole. We conclude that pramipexole-treated patients with advanced PD improved significantly more than placebo for both primary end points.

Adult↗

PubMed1996

Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal paralytic disorder of unknown cause. Recent evidence implicated the role of free radicals in the death of motor neurons in this disease. To investigate this hypothesis further, we measured the activity of the main free radical scavenging enzymes copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase in postmortem brain samples from 9 patients with sporadic amyotrophic lateral sclerosis and from 9 control subjects. We examined samples from the precentral gyrus of the cerebral cortex, a region affected in amyotrophic lateral sclerosis, and from the cerebellar cortex, a region not affected. The two groups did not differ in age or postmortem delay. In the precentral gyrus from amyotrophic lateral sclerosis samples, glutathione peroxidase activity as measured by spectrophotometric assay (13.8 +/- 2.6 nmol/min/mg protein [mean +/- standard error of mean]) was reduced significantly compared to the activity in the precentral gyrus from control samples (22.7 +/- 0.5 nmol/min/mg protein). In contrast, glutathione peroxidase activity was not significantly altered in the cerebellar cortex from amyotrophic lateral sclerosis patients compared to controls. Copper/zinc superoxide dismutase, manganese superoxide dismutase (corrected or not corrected for citrate synthase), and catalase were not significantly altered in the precentral gyrus or cerebellar cortex in the patient samples. This study indicated that glutathione peroxidase activity is reduced in a brain region affected in amyotrophic lateral sclerosis, thus suggesting that free radicals may be implicated in the pathogenesis of the disease.

Amyotrophic Lateral Sclerosis↗

PubMed1996

Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease.

To determine the extent that different dopamine (DA) neuronal markers provide similar estimates of striatal (caudate and putamen) DA nerve terminal loss in idiopathic Parkinson's disease (PD), we compared, in postmortem striatum of 12 patients with PD and 10 matched controls, levels of five different DA neuronal markers. These markers included DA itself, three different estimates of the density of the DA transporter (DAT) ([3H])GBR 12,935 and [3H]WIN 35,428 binding; DAT protein immunoreactivity), and one estimate of the vesicular monoamine transporter (VMAT2; [3H]DTBZ binding). Striatal levels of all examined DA markers in PD were significantly intercorrelated. However, the magnitude of loss relative to controls was unequal (DAT protein = DA > [3H]WIN 35,428 > [3H]DTBZ > [3H]GBR 12, 935), with the differences more marked in the severely affected putamen. The less severe reduction of binding of the DAT/VMAT2 radioligands relative to DA and DAT protein could be explained by differential regulation/degeneration of different DA nerve terminal components or lack of specificity of the radioligands for the DA neuron. These postmortem data may help in interpretation of in vivo neuroimaging studies in PD in which only one radioligand is routinely employed.

Aged↗

PubMed1995

Regional striatal DOPA transport and decarboxylase activity in Parkinson's disease.

METHODS: We measured blood-brain barrier transport and decarboxylation of 6-[18F]fluoro-L-DOPA (FDOPA) using PET in patients with Parkinson's disease (n = 7, 57 +/- 7 yr) and age-matched control subjects (n = 7, 60 +/- 6 yr). To visually present regional changes of FDOPA uptake in Parkinson's disease, we introduced maps of FDOPA uptake relative to occipital cortex, averaged across control subjects and Parkinson's disease patients in an MRI-based stereotaxic coordinate space. RESULTS: There was no significant changes in the blood-to-brain transport of FDOPA (KD1) in Parkinson's disease. The KD1 values of the head of caudate were lower than those of putamen in both normal subjects and Parkinson's disease patients. In Parkinson's disease, the activity of L-DOPA decarboxylase (DDC) was differentially reduced in subdivisions of striatum. The residual DDC activity was 63% of the control value in the head of caudate nucleus, 54% in the anterior putamen and 39% in the posterior putamen. The DDC activity in frontal and occipital cortices remained unchanged by the disease. Subtraction of averaged FDOPA uptake maps (control minus Parkinson's disease) visualized a spatial pattern of pathological changes in FDOPA uptake common to Parkinson's disease patients. CONCLUSION: The striatal blood-to-brain transport of FDOPA remained unchanged while the DDC activity was differentially reduced within the striatum in Parkinson's disease. We found the FDOPA uptake maps useful in identifying altered patterns of FDOPA metabolism common in Parkinson's disease.

Biological Transport↗

PubMed1994

The baby chase.

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Ambulatory Care Facilities↗