piperidines and dihydrotetrabenazine

To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA).. In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) to measure the density of 123I]IBVM.. Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) and decreased [123I]IBVM binding in the thalamus (p < 0.001). Moreover, in the MSA group, striatal [11C]DTBZ binding was inversely correlated with the severity of REM atonia loss (p = 0.003). Thalamic [123I]IBVM binding, however, was not correlated to the severity of REM atonia loss.. Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

Topics: Adult; Age Distribution; Aged; Binding, Competitive; Biogenic Monoamines; Carbon Radioisotopes; Corpus Striatum; Electromyography; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Multiple System Atrophy; Piperidines; Polysomnography; Predictive Value of Tests; Reference Values; REM Sleep Behavior Disorder; Sex Distribution; Tetrabenazine; Tetrahydronaphthalenes; Thalamus; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA).. In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea-hypopnea index during sleep. SPECT with (-)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ.. Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19).. Decreased pontine cholinergic projections may contribute to OSA in MSA.

Topics: Adult; Age Distribution; Aged; Binding, Competitive; Carrier Proteins; Corpus Striatum; Female; Humans; Iodine Radioisotopes; Male; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Multiple System Atrophy; Neuropeptides; Pilot Projects; Piperidines; Pons; Receptors, Cholinergic; Reference Values; Regression Analysis; Sex Distribution; Sleep Apnea, Obstructive; Tetrabenazine; Tetrahydronaphthalenes; Thalamus; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Transport Proteins

Subjects at risk of dementia benefit from participation in mentally stimulating activities, but no prior studies have investigated similar associations in Parkinson disease (PD). The aim of this study was to investigate the relationship between times spent engaging in mentally stimulating activities and cognitive functions in PD while accounting for the degree of primary neurodegenerations. PD patients (N = 41, 33 males; age 68.5 ± 7.2; Hoehn and Yahr stage 2.6 ± 0.6) completed the Community Health Activities Model Program for Seniors questionnaire, mini-mental state examination (MMSE), and [

Topics: Aged; Aged, 80 and over; Carbon Isotopes; Cognition Disorders; Cognitive Behavioral Therapy; Female; Humans; Magnetic Resonance Imaging; Male; Mental Status and Dementia Tests; Middle Aged; Neuropsychological Tests; Parkinson Disease; Phosphinic Acids; Piperidines; Positron-Emission Tomography; Regression Analysis; Tetrabenazine

There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.. To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.. Cross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [(11)C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [(11)C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.. There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (-0.98 ± 1.01) compared to the non-diabetics (-0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).. Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.

Topics: Aged; Butyrates; Carbon Isotopes; Cognition Disorders; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Neuroimaging; Neuropsychological Tests; Parkinson Disease; Piperidines; Positron-Emission Tomography; Severity of Illness Index; Tetrabenazine

Topics: Acetylcholine; Alzheimer Disease; Brain; Carbon Radioisotopes; Carrier Proteins; Humans; Membrane Glycoproteins; Membrane Transport Proteins; Neuromuscular Depolarizing Agents; Neurons; Neuropeptides; Neurotransmitter Agents; Parkinson Disease; Piperidines; Tetrabenazine; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Biogenic Amine Transport Proteins; Vesicular Transport Proteins

A 68-kDa glycoprotein bearing the biological activity of the plasma membrane serotonin (5-hydroxytryptamine, 5-HT) transporter has been purified from human blood platelets, a classical cell model for the study of 5-HT uptake. After treatment of the whole platelet population or its plasma membrane fraction by sulfhydryl-dependent bacterial protein toxins or by digitonin, purification was reproducibly obtained by a one-step affinity chromatography using two different columns with 5-HT or 6-fluorotryptamine as ligands and elution by 5-HT or Na(+)-free buffer. The purified fraction migrated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a single band with an apparent molecular mass of 68 kDa and exhibited an apparent isoelectric point of 5.6-6.2. Two sialic acid residues were detected in the purified material. The purified glycoprotein bound the 5-HT uptake blocker [3H]paroxetine with a Kd (0.25 nM) similar to the one observed for intact human platelets. It also bound [3H] 5-HT but neither [3H]hydroxytetrabenazine nor [3H] ouabain, the respective markers of the granular monoamine transporter and of the Na+,K(+)-ATPase associated to the plasma membrane 5-HT transporter. 5-HT derivatives and 5-HT uptake inhibitors exhibited similar Ki values for 5-HT uptake and paroxetine binding in intact human platelets and in the purified glycoprotein. Under laser UV irradiation, 40% of this purified glycoprotein could be labeled by either [3H]paroxetine or [3H]cyanoimipramine. No labeling was detected with either [3H] gamma-aminobutyric acid or [3H]GBR 12783, the respective markers of gamma-aminobutyric acid and dopamine carriers. The purified 68-kDa protein is therefore likely to correspond at least to the binding domain of the 5-HT transporter located at the human platelet plasma membrane.

Topics: Biological Transport; Blood Platelets; Blood Proteins; Carrier Proteins; Cell Membrane; Chromatography, Affinity; Electrophoresis, Gel, Two-Dimensional; Electrophoresis, Polyacrylamide Gel; Humans; Ouabain; Paroxetine; Piperidines; Serotonin; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Tetrabenazine

The carrier for 5-hydroxytryptamine (5-HT) of the 5-HT storage organelles of blood platelets was characterized by [3H]dihydrotetrabenazine binding and [125I]azidoiodokentanserin photoaffinity labeling. [3H]Dihydrotetrabenazine bound with high affinity to membrane preparations from different animal species. The [3H]dihydrotetrabenazine Bmax value was about 10-fold higher in rabbit (9.4 +/- 1.3 pmol/mg protein) than in human, rat and guinea-pig preparations (Bmax values = 1.1 +/- 0.2, 1.2 +/- 0.1 and 0.52 +/- 0.06 pmol/mg protein, respectively). After rabbit platelet subcellular fractionation, [3H]dihydrotetrabenazine binding was highly enriched in the fraction corresponding to pure 5-HT organelles, whereas ligand binding was much lower in the other subcellular fractions. Conversely, [3H]paroxetine binding sites were more concentrated in the lower density fractions, with no binding to the 5-HT granules. In competition experiments, [3H]dihydrotetrabenazine binding to human platelet membranes and rabbit platelet 5-HT organelles was markedly inhibited by the benzo[a]quinolizine derivatives, tetrabenazine and Ro 4-1284, and by ketanserin. In isolated rabbit platelet 5-HT organelles, reserpine showed a relatively high IC50 (930 nM), but the presence of ATP increased its potency about 10-fold. Paroxetine, methysergide and carrier substrates had little or no effect. After photoaffinity labeling of rabbit 5-HT granules with [125I]azidoiodoketanserin, the radioactivity was incorporated into several polypeptides. The presence of Ro 4-1284, reserpine and ketanserin prevented the labeling of a polypeptide of 85 kDa. The data obtained suggest that this protein represents a component of the granular carrier which binds [3H]dihydrotetrabenazine.

Topics: Affinity Labels; Animals; Azides; Biogenic Monoamines; Blood Platelets; Blood Proteins; Cell Membrane; Guinea Pigs; Humans; In Vitro Techniques; Iodine Radioisotopes; Ketanserin; Paroxetine; Photochemistry; Piperidines; Rabbits; Rats; Receptors, Serotonin; Subcellular Fractions; Tetrabenazine