piperidines and Multiple-System-Atrophy

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

Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.

Topics: alpha-Synuclein; Animals; Cerebral Cortex; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Lewy Body Disease; Mice; Mice, Transgenic; Multiple System Atrophy; Neurons; Parkinson Disease; Piperidines; Protein Aggregation, Pathological; Protein Folding; Pyrazines; Pyrimidines; Retina

We report anesthetic management of a 61-year-old man with multiple system atrophy undergoing adrenal grand tumor surgery. Before surgery, he was sufficiently hydrated and an elastic bandage had been applied to the legs. After epidural catheterization for the postoperative analgesia, general anesthesia was induced with midazolam 7 mg and remifentanil 0.25 microg x kg(-1) x min(-1) and his trachea was intubated. During surgery, general anesthesia was maintained with sevoflurane and remifentanil 0.12-0.25 microg x kg(-1) x min(-1). Hemodynamics was almost stable although transient hypotension occurred during surgery because of bleeding and partial clamping of the inferior vena cava. After surgery, he emerged from anesthesia and tracheal tube was removed uneventfully. However, on the first postoperative day, hypotension and respiratory failure occurred. Noradrenaline infusion was needed to treat hypotension due to vasodilation and reintubation was performed. After several days, hypotension and respiratory failure improved and he was discharged from ICU.

Topics: Adrenal Gland Neoplasms; Anesthesia, General; Humans; Male; Middle Aged; Multiple System Atrophy; Norepinephrine; Piperidines; Postoperative Care; Remifentanil

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

Topics: Acetylcholinesterase; Adult; Aged; Brain; Carbon Radioisotopes; Cerebellar Cortex; Cerebral Cortex; Female; Humans; Image Processing, Computer-Assisted; Machado-Joseph Disease; Magnetic Resonance Imaging; Male; Middle Aged; Multiple System Atrophy; Neurologic Examination; Piperidines; Positron-Emission Tomography; Propionates; Spinocerebellar Ataxias; Spinocerebellar Degenerations; Thalamus