Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease

Department of Neurology, University of Michigan, Ann Arbor, USA.
Annals of Neurology (Impact Factor: 9.98). 04/2012; 71(4):560-8. DOI: 10.1002/ana.22691
Source: PubMed


Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD), but its relationship to the varied neurotransmitter deficits of PD and prognostic significance remain incompletely understood. RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia.
Eighty subjects with PD without dementia (age, 64.6 ± 7.0 years; range, 50-82 years; 60 males, 20 females; mean Montreal Cognitive Assessment Test [MoCA] score, 26.2 ± 2.1; range 21-30) underwent clinical assessment, neuropsychological testing, and [(11)C]methylpiperidyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 positron emission tomography (PET) imaging. (11)C3-Amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) serotonin transporter PET imaging was performed in a subset of 35 subjects. The presence of RBD symptoms was determined using the Mayo Sleep Questionnaire.
Twenty-seven of 80 subjects (33.8%) indicated a history of RBD symptoms. Subjects with and without RBD symptoms showed no significant differences in age, motor disease duration, MoCA, Unified Parkinson Disease Rating Scale motor scores, or striatal DTBZ binding. Subjects with RBD symptoms, in comparison to those without, exhibited decreased neocortical, limbic cortical, and thalamic cholinergic innervation (0.0213 ± 0.0018 vs 0.0236 ± 0.0022, t = 4.55, p < 0.0001; 0.0388 ± 0.0029 vs 0.0423 ± 0.0058, t = 2.85, p = 0.0056; 0.0388 ± 0.0025 vs 0.0427 ± 0.0042, t = 4.49, p < 0.0001, respectively). Brainstem and striatal DASB binding showed no significant differences between groups.
The presence of RBD symptoms in PD is associated with relative neocortical, limbic cortical, and thalamic cholinergic denervation although not with differential serotoninergic or nigrostriatal dopaminergic denervation. The presence of RBD symptoms may signal cholinergic system degeneration.

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    • "Interestingly, sleep disordered-breathing, which may contribute to daytime somnolence, was not found to be associated with caudal brainstem changes in a PET study of patients with Parkinson's disease (Lelieveld et al., 2012). A recent imaging study has suggested that cholinergic denervation in cortical, thalamic and limbic structures, rather than dopaminergic or serotonergic denervation, is associated with the occurrence of rapid eye movement sleep behaviour disorder (Kotagal et al., 2012). In line with these findings, we did not find any association between raphe serotonin transporter availability and rapid eye movement sleep behaviour disorder. "
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    ABSTRACT: Post-mortem and neuroimaging studies suggest that the serotonergic system, which originates from the brainstem raphe nuclei, is disrupted in Parkinson's disease. This could contribute to the occurrence of non-motor symptoms and tremor, which are only partially explained by dopamine loss. However, the level of involvement of the serotonergic raphe nuclei in early Parkinson's disease is still debated. (123)I-FP-CIT single photon emission computed tomography is a marker of dopamine and serotonin transporter availability. While (123)I-FP-CIT binds primarily to dopamine transporters in the striatum, its binding in the brainstem raphe nuclei reflects serotonin transporter availability. We interrogated baseline single photon emission computed tomography scans of subjects recruited by the Parkinson's Progression Markers Initiative to determine: (i) the integrity of the brainstem raphe nuclei in early Parkinson's disease; and (ii) whether raphe serotonin transporter levels correlate with severity of tremor and symptoms of fatigue, depression, and sleep disturbance. Three hundred and forty-five patients with early drug-naïve Parkinson's disease, 185 healthy controls, and 56 subjects with possible Parkinson's disease without evidence of dopaminergic deficit were included. In the Parkinson's disease cohort, 37 patients had a tremulous, 106 patients had a pure akinetic-rigid, and 202 had a mixed phenotype. Patients with Parkinson's disease had significantly lower serotonin transporter availability in the brainstem raphe nuclei compared to controls (P < 0.01) and subjects without evidence of dopaminergic deficit (P < 0.05). However, only 13% of patients with Parkinson's disease individually had reduced signals. Raphe serotonin transporter availability over the entire Parkinson's disease cohort were associated with rest tremor amplitude (β = -0.106, P < 0.05), rest tremor constancy (β = -0.109, P < 0.05), and index of rest tremor severity (β = -0.104, P < 0.05). The tremulous Parkinson's disease subgroup had significantly lower raphe serotonin transporter availability but less severe striatal dopaminergic deficits compared to akinetic-rigid patients with no resting tremor (P < 0.05). In tremulous patients, raphe serotonin transporter availability was also associated with rest tremor constancy (β = -0.380, P < 0.05) and index of rest tremor severity (β = -0.322, P < 0.05). There was no association between raphe serotonin transporter availability and fatigue, depression, excessive daytime sleepiness, or rapid eye movement sleep behaviour disorder in early Parkinson's disease. We conclude that the raphe nuclei are affected in a subgroup of early drug-naïve Parkinson's disease patients and that reduced raphe serotonin transporter availability is associated with the severity of resting tremor but not non-motor symptoms. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 07/2015; DOI:10.1093/brain/awv215 · 9.20 Impact Factor
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    • " the selective loss of PPT cholinergic neurons ( Kotagal et al . , 2012 ) , and the degeneration of about 50% of PPT cholinergic neurons has been reported ( Bohnen and Albin , 2011 ) . Cortical and thalamic subcorti - cal cholinergic denervation , due to the degeneration of PPT cholinergic neurons , has been related to REM behav - ioral disorder ( Kotagal et al . , 2012 ) , gait and balance impairment , including falls , in patients with Parkinson ' s disease ( Bohnen and Albin , 2011 ) . In addition , recent studies in rat models of functionally distinct cholinergic neuropathology provided evidence that only broad thalamo - cortical cholinergic neuronal denervation induced the severe and topographical"
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    ABSTRACT: Objectives We hypothesized that the impact of distinct anesthetic regimens could be differently expressed during anesthesia and on post-anesthesia sleep in the neurodegenerative diseases. Therefore, we followed the impact of ketamine/diazepam and pentobarbital anesthesia in a rat model of the severe Parkinson’s disease cholinergic neuropathology on the electroencephalographic (EEG) microstructure and respiratory pattern during anesthesia, and on the post-anesthesia sleep. Methods We performed the experiments on adult, male, spontaneously breathing Wistar rats chronically instrumented for sleep recording. The bilateral pedunculopontine tegmental nucleus (PPT) lesion was done by ibotenic acid microinfusion. Following postoperative recovery, we recorded sleep for 6 h, induced anesthesia 24 h later using ketamine/diazepam or pentobarbital, and repeated sleep recordings sessions 48 h and 6 days later. During 20 min of each anesthesia we recorded both the EEG and respiratory movements. For sleep and EEG analysis, Fourier analysis was applied on 6 h recordings, and each 10 s epoch was differentiated as a state of wakefulness (Wake), non-rapid eye movement (NREM) or rapid eye movement (REM). Additionally, the group probability density distributions of all EEG frequency band relative amplitudes were calculated for each state, with particular attention during anesthesia. For respiratory pattern analysis we used Monotone Signal Segments Analysis. The PPT lesion was identified through nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry. Results and Conclusions Our data show that the ketamine/diazepam anesthetic regimen in the PPT lesioned rats induces more alterations in the EEG microstructure and respiratory pattern than does the pentobarbital anesthesia. In addition, the equal time required to establish an anesthetized state, and the long-term effect on post-anesthesia sleep in the PPT lesioned vs. control rats suggest this anesthetic regimen as potentially more beneficial both for anesthesia induction and for post-anesthesia sleep in the surgical procedures of the elderly, and Parkinson’s, and Alzheimer’s patients.
    Neuroscience 07/2015; 304:1-13. DOI:10.1016/j.neuroscience.2015.07.020 · 3.36 Impact Factor
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    • "With respect to the brain cholinergic system , AD involves loss of cholinergic neurons in the basal forebrain (Dringenberg, 2000; Kotagal et al., 2012b), whereas PD involves selective loss of cholinergic neurons in the PPT (Bohnen et al., 2009; Bohnen and Albin, 2011; Kotagal et al., 2012a,b). The cortical and thalamic subcortical cholinergic denervations, because of the degeneration of PPT cholinergic neurons, are related to gait and balance impairment (Bohnen et al., 2009; Bohnen and Albin, 2011) and REM behavioral disorder in PD (Kotagal et al., 2012a). "
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    ABSTRACT: Alzheimer's disease (AD) involves selective loss of basal forebrain cholinergic neurons, particularly in the nucleus basalis (NB). Similarly, Parkinson's disease (PD) might involve the selective loss of pedunculopontine tegmental nucleus (PPT) cholinergic neurons. Therefore, lesions of these functionally distinct cholinergic centers in rats might serve as models of AD and PD cholinergic neuropathologies. Our previous articles described dissimilar sleep/wake-state disorders in rat models of AD and PD cholinergic neuropathologies. This study further examines astroglial and microglial responses as underlying pathologies in these distinct sleep disorders. Unilateral lesions of the NB or the PPT were induced with rats under ketamine/diazepam anesthesia (50 mg/kg i.p.) by using stereotaxically guided microinfusion of the excitotoxin ibotenic acid (IBO). Twenty-one days after the lesion, loss of cholinergic neurons was quantified by nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry, and the astroglial and microglial responses were quantified by glia fibrillary acidic protein/OX42 immunohistochemistry. This study demonstrates, for the first time, the anatomofunctionally related astroglial response following unilateral excitotoxic PPT cholinergic neuronal lesion. Whereas IBO NB and PPT lesions similarly enhanced local astroglial and microglial responses, astrogliosis in the PPT was followed by a remote astrogliosis within the ipslilateral NB. Conversely, there was no microglial response within the NB after PPT lesions. Our results reveal the rostrorostral PPT-NB astrogliosis after denervation of cholinergic neurons in the PPT. This hierarchically and anatomofunctionally guided PPT-NB astrogliosis emerged following cholinergic neuronal loss greater than 17% throughout the overall rostrocaudal PPT dimension. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 02/2015; 93(2). DOI:10.1002/jnr.23483 · 2.59 Impact Factor
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