Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA

Objective: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). Methods: 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. Results: 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). Conclusion: Decreased pontine cholinergic projections may contribute to OSA in MSA.

[1]  A. Beaudet,et al.  Distribution of acetylcholine and catecholamine neurons in the cat brainstem: A choline acetyltransferase and tyrosine hydroxylase immunohistochemical study , 1987, The Journal of comparative neurology.

[2]  C. Cavada,et al.  A population of cholinergic neurons is present in the macaque monkey thalamus , 1998, The European journal of neuroscience.

[3]  F. Munschauer,et al.  Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomie failure , 1990, Neurology.

[4]  G. Plazzi,et al.  REM sleep behavior disorders in multiple system atrophy , 1997, Neurology.

[5]  H. Fibiger,et al.  Basal forebrain and mesopontine tegmental projections to the reticular thalamic nucleus: an axonal collateralization and immunohistochemical study in the rat , 1989, Brain Research.

[6]  M. Xi,et al.  Changes in electrophysiological properties of cat hypoglossal motoneurons during carbachol-induced motor inhibition , 2000, Brain Research.

[7]  H. Fibiger,et al.  Single cholinergic mesopontine tegmental neurons project to both the pontine reticular formation and the thalamus in the rat , 1990, Neuroscience.

[8]  J. Remmers,et al.  Premotor input to hypoglossal motoneurons from Kölliker-Fuse neurons in decerebrate cats. , 1999, Respiration physiology.

[9]  J. Remmers,et al.  Pathogenesis of upper airway occlusion during sleep. , 1978, Journal of applied physiology: respiratory, environmental and exercise physiology.

[10]  J. Harcourt,et al.  Abductor vocal fold palsy in the Shy-Drager syndrome presenting with snoring and sleep apnoea , 1996, Journal of Laryngology and Otology.

[11]  K. Spyer,et al.  Intracellular analysis of respiratory-modulated hypoglossal motoneurons in the cat , 1988, Neuroscience.

[12]  Remmers Je,et al.  Pathogenesis of upper airway occlusion during sleep , 1978 .

[13]  S. Gilman,et al.  Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging , 1996, Annals of neurology.

[14]  D E Kuhl,et al.  Equilibrium versus Compartmental Analysis for Assessment of the Vesicular Monoamine Transporter Using (+)-α-[11C]Dihydrotetrabenazine (DTBZ) and Positron Emission Tomography , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[15]  A. Levey,et al.  Choline acetyltransferase immunoreactivity in the rat thalamus , 1987, The Journal of comparative neurology.

[16]  J. Parisi,et al.  Depletion of mesopontine cholinergic and sparing of raphe neurons in multiple system atrophy , 2002, Neurology.

[17]  P. Shiromani,et al.  Pontine cholinergic neurons simultaneously innervate two thalamic targets , 1990, Brain Research.

[18]  R. M. Harper,et al.  The human tongue during sleep: Electromyographic activity of the genioglossus muscle , 1976, Experimental Neurology.

[19]  M. Cassell,et al.  Glycine receptor (gephyrin) immunoreactivity is present on cholinergic neurons in the dorsal vagal complex , 1999, Neuroscience.

[20]  S. Olusi,et al.  Relations of Serum Interleukin 18 Levels to Serum Lipid and Glucose Concentrations in an Apparently Healthy Adult Population , 2003, Hormone Research in Paediatrics.

[21]  K. Semba,et al.  Dual projections of single cholinergic and aminergic brainstem neurons to the thalamus and basal forebrain in the rat , 1993, Brain Research.

[22]  R. Spreafico,et al.  Branching projections from mesopontine nuclei to the nucleus reticularis and related thalamic nuclei: A double labelling study in the rat , 1993, The Journal of comparative neurology.

[23]  C. Saper,et al.  Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[24]  E. Wolpert.  A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. , 1969 .

[25]  D. Kuhl,et al.  Synthesis of the 123I- and 125I-labeled cholinergic nerve marker (-)-5-iodobenzovesamicol. , 1993, Nuclear medicine and biology.

[26]  M. Xi,et al.  Hypoglossal motoneurons are postsynaptically inhibited during carbachol-induced rapid eye movement sleep , 1999, Neuroscience.

[27]  H. Konno,et al.  Decrease of substance P in the parabrachial nucleus of multiple system atrophy , 2001, Autonomic Neuroscience.

[28]  I Litvan,et al.  Consensus statement on the diagnosis of multiple system atrophy , 1998, Journal of the Neurological Sciences.

[29]  B. K. Hartman,et al.  Characterization of the extent of pontomesencephalic cholinergic neurons' projections to the thalamus: comparison with projections to midbrain dopaminergic groups , 1999, Neuroscience.

[30]  D. Rye.  Contributions of the pedunculopontine region to normal and altered REM sleep. , 1997, Sleep.

[31]  C. Saper,et al.  Medullary and spinal efferents of the pedunculopontine tegmental nucleus and adjacent mesopontine tegmentum in the rat , 1988, The Journal of comparative neurology.

[32]  L. Brown.  Abductor vocal fold palsy in the Shy-Drager syndrome presenting with snoring and sleep apnoea , 1997, The Journal of Laryngology & Otology.

[33]  J. C. Hwang,et al.  Characterization of respiratory-modulated activities of hypoglossal motoneurons. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[34]  D E Kuhl,et al.  In vivo mapping of cholinergic neurons in the human brain using SPECT and IBVM. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[35]  H. Moldofsky,et al.  Abnormal respiratory pattern generation during sleep in patients with autonomic dysfunction. , 1983, The American review of respiratory disease.

[36]  Sudhansu Chokroverty,et al.  Sleep, Breathing, and Neurological Disorders , 1994 .

[37]  J. Parisi,et al.  Depletion of cholinergic neurons of the medullary arcuate nucleus in multiple system atrophy , 2001, Autonomic Neuroscience.

[38]  S. Minoshima,et al.  In vivo mapping of cholinergic terminals in normal aging, Alzheimer's disease, and Parkinson's disease , 1996, Annals of neurology.

[39]  G. Rogers,et al.  Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogues of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol). , 1989, Journal of medicinal chemistry.

[40]  R. Inoue,et al.  Inhibitory NANC neurotransmission in choledocho-duodenal junction of rabbits--a possible role of PACAP. , 1998, Journal of the autonomic nervous system.

[41]  R. Chervin,et al.  REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA , 2003, Neurology.

[42]  C. Guilleminault,et al.  The impact of autonomic nervous system dysfunction on breathing during sleep. , 1981, Sleep.

[43]  M J Hensley,et al.  Activation of upper airway muscles before onset of inspiration in normal humans. , 1980, Journal of applied physiology: respiratory, environmental and exercise physiology.

[44]  J. Hodder.  Shy Drager syndrome. , 1997, Axone.

[45]  S. Horiguchi,et al.  Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[46]  P. Martinelli,et al.  Changes in systemic arterial pressure during sleep in Shy-Drager syndrome. , 1981, Sleep.

[47]  R. Lydic,et al.  Pontine cholinergic reticular mechanisms cause state-dependent changes in the discharge of parabrachial neurons. , 1994, American Journal of Physiology.