Rapid Eye Movement Sleep Homeostatic Response: A Potential Marker for
Early Detection of Parkinson's Disease
Silu Lu1, James P Shaffery2, Yi Pang1, Lu-Tai Tien3and Lir-Wan Fan1*
1Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA
2Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA
3School of Medicine, Fu Jen Catholic University, Xinzhuang Dist, New Taipei City 24205, Taiwan
- *Corresponding Author:
- Lir-Wan Fan
Associate Professor, Department of
Division of Newborn Medicine
University of Mississippi Medical Center
Jackson, MS 39216-4505, USA
E-mail: [email protected]
Received date July 30, 2016; Accepted date August 11, 2016; Published date August 18, 2016
Citation: Lu S, Shaffery JP, Pang Y, Tien LT, Fan LW (2016) Rapid Eye Movement
Sleep Homeostatic Response: A Potential Marker for Early Detection of Parkinson’s
Disease. J Alzheimers Dis Parkinsonism 6:255. doi: 10.4172/2161-0460.1000255
Copyright: © 2016 Lu S, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Visit for more related articles at Journal of Alzheimers Disease & Parkinsonism
Parkinson’s disease (PD) is a long-term neurodegenerative disease
characterized by the presence of dopaminergic neuronal loss and
dysfunction in the substantia nigra. Motor disturbance is the symptom
most typically reported, including bradykinesia plus either limb
rigidity, resting tremor, or postural instability [1-3]. Importantly, it has
been reported that at the point when the patient meets criteria for the
principal of motor disturbance, approximately 60% of substantia nigra
neurons are lost . Non-motor symptoms have also been observed in
both PD patients as well as in related animal models, including pain,
autonomic dysfunction, depression, anxiety, olfactory dysfunction,
cognitive impairment and sleep disorders [5,6]. The presence and
severity of these non-motor symptoms as the disease progresses
exacerbate the degree of disability of PD patients. These non-motor
symptoms suggest that neurodegenerative processes in PD extends
beyond the substantia nigra and dopaminergic deficit [6-10]. It has been
noted that before PD becomes clinically significant, neurodegeneration
has been ongoing for some time. This has led to the notion of a “premotor”
phase , during which non-motor manifestations and a
variety of other abnormalities may offer key biomarkers of the disease
Among the pre-motor signs, one of the non-motor symptoms that
may appear before the onset of PD is rapid eye movement (REM) sleep
behavior disorder (RBD). This disturbance of sleep have become a main
focus as a preclinical marker of onset of PD following the intriguing
observation that changes in regulation of the sleep and wakefulness cycle
may occur years before the onset of PD motor symptoms . RBD is
a parasomnia characterized by dream-enacting behavior occurring in
REM sleep [13,14]. RBD is believed due to dysfunction of the lower
brainstem nuclei that regulate REM sleep . Aberrant motor activity
during REM sleep is the defining characteristic of RBD. REM sleep, in
healthy individuals is a state characterized by an active inhibition of
motor tone . While the reduction of the musculoskeletal tone during
REM sleep in normal individuals can be interrupted by short periods
of breakthrough motor events such as jerks or twitches, REM sleep of
those with RBD is experienced with an absence of a predominance of
motor quiescence, and is instead accompanied by extended periods of
motor activity [16,17].
It is well-known that Lewy bodies and Lewy neurites containing
aggregates of the protein α-synuclein are the classic pathologic
hallmark of PD . The role of α-synuclein in neuronal function is
not fully understood, although there is evidence that α-synuclein has
roles in synaptic membrane function, catecholamine biosynthesis
and exocytosis . Interestingly, it has been reported that more
than 50% of RBD cases develop α-synucleinopathies similar to that
what is seen in PD . Together the forgoing evidence suggests
that RBD can be considered a prodromal phase of PD and other
neurodegenerative diseases. Indeed, 2 to 13 years following detection of
RBD symptomology, 16-65% of individuals develop motor symptoms
of PD [12,21-24]. Several regions in brains may be involved in both
sleep disturbance and PD development. Pontine tegmentum is the
one neural region involved in sleep control and shown to degenerate in PD patients . There are two cholinergic nuclei in the pontine
tegmentum: the pedunculopontine nucleus (PPT) and the laterodorsal
tegmental nucleus (LDT). PPT and LDT provide the major cholinergic
innervation of rostral and caudal targets and are believed to control
much of the phenomenology of REM sleep . More importantly, it
has been found that PD patients exhibit degeneration of PPT and LDT
neurons [27,28]. Further it has also been confirmed by morphometric
analysis that around 50% of cells are loss within PPT in PD patents
. Furthermore, degeneration of locus subcoeruleus, which has been
shown via multiple brain imaging techniques, also plays an important
in atonia, as well as in motor control during REM sleep [29-33]. Further
evidence has shown that nigrocortical nigrostriatal pathways are also
changed in RBD before the onset of motor symptoms .
The connection between inflammation and neurodegeneration
disorders is well established. In our study and those of other
researchers, it has been shown that infection and/or cytokine-mediated
inflammation plays a critical role in PD, memory and other cognition
deficiencies [35-39]. We have shown that LPS exposure in neonatal age
significantly increases vulnerability of dopaminergic system to low level
of neuron toxics such as rotenone [35-37]. Also, cytokines such as IL-1β
and TNF-α have also been reported to contribute to the PD development
[36,38]. Furthermore, it has been shown that inflammatory markers are
associated with sleep disorders such as RBD. Several reports showed that
sleep-wake pattern and electrical activity of the brain has been affected
significantly, which is associated with elevated cytokine level [40-43].
Esumi et al. reported the sleep deprivation induces neurodegeneration
through upregulating several inflammatory factors including IL-6 and
TNF-α . Indeed, LPS administration changes the sleep-wake cycle
in rats, increases slow wave sleep (SWS) and decreases wakefulness, and
more importantly, LPS interferes with REM sleep [45-48]. Although
the underlying mechanisms are still poorly understood, evidence has
shown that inflammation may play an important role in the association
between RBD and PD development.
Recently, melatonin has been considered as a pharmacological
strategy for sleep disorders in PD in several clinical studies .
Melatonin plays a key role in the circadian regulation of the sleep/wake
cycle and is also a strong antioxidant which can protect against neural
damage from oxidative stress and inflammation . Dowling et al. reported that melatonin treatment produced an objective improvement
of nighttime sleep . Medeiros et al. also reported a subjective
sleep improvement (as assessed by the Pittsburgh Sleep Quality Index
[PSQI]) with a low dose of melatonin in PD patients . Several
studies indicate that melatonin may improve RBD in PD [51-54].
However, the clinical study of exogenous melatonin treatment is still
quite controversial and the underlying mechanisms are not fully clear.
It has been reported that the expression of melatonin receptors, MT1
and MT2, are down-regulated in the substantia nigra of PD patients
. The release of melatonin is decrease in PD as well [56,57]. Also,
neuronal cell death and PD symptoms have been relieved by melatonin
administration in animal models of PD induced by neurotoxins [58-
60]. As described earlier, inflammation plays an important role in
RBD in PD. Accordingly, melatonin may act as an antioxidant agent
that may improve REM sleep in PD by preventing oxidative stress
and inflammation-induced neuron damage. In conclusion, RBD is
a common pre-motor symptom in many PD patients. Early-stage
exposure to inflammatory factors may contribute to the development
of RBD, and eventually PD. Melatonin has been shown to improve
sleep quality in several sleep disorder-related diseases, including PD.
However, the possible mechanism of this improvement remains unclear.
This work was supported by a NIH grant NIH/NINDS R01NS080844, a grant
from Michael J Fox Foundation and Newborn Medicine Funds from the Department
of Pediatrics, University of Mississippi Medical Center.
- Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinicpathological study of 100 cases. J NeurolNeurosurg Psychiatry 55: 181-184.
- Spillantini MG, Goedert M (2000) The alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. Ann N Y AcadSci 920: 16-27.
- Tolosa E, Wenning G, Poewe W (2006) The diagnosis of Parkinson’s disease. Lancet Neurol 5: 75-86.
- Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: Substantianigra regional selectivity. Brain 114: 2283-2301.
- Aarsland D, Zaccai J, Brayne C (2005) A systematic review of prevalence studies of dementia in Parkinson’s disease. MovDisord 20: 1255-1263.
- Chaudhuri KR, Healy DG, Schapira AH (2006) Non-motor symptoms of Parkinson’s disease: Diagnosis and management. Lancet Neurol 5: 235-245.
- Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, et al. (2009) The PRIAMO study: A multicenter assessment of non-motor symptoms and their impact on quality of life in Parkinson’s disease. MovDisord 24: 1641-1649.
- Mollenhauer B, Trautmann E, Sixel-Doring F, Wicke T, Ebentheuer J, et al. (2013) Non-motor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 81: 1226-1234.
- Muller B, Larsen JP, Wentzel-Larsen T, Skeie GO, Tysnes OB, et al. (2011) Autonomic and sensory symptoms and signs in incident, untreated Parkinson’s disease: Frequent but mild. MovDisord 26: 65-72
- Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, et al, (2014) The onset of non-motor symptoms in Parkinson’s disease (The ONSET PD Study). MovDisord 30: 229-237.
- Stephenson, R., Siderowf A, Stern MB (2009) Premotor Parkinson's disease: Clinical features and detection strategies. MovDisord 24 Suppl 2: S665-S670.
- Schenck CH, Bundlie SR, Mahowald MW (1996) Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 46: 388-393.
- Arnulf I (2012) REM sleep behaviour disorder: Motor manifestations and pathophysiology. MovDisord 27: 677-689.
- Boeve BF (2010) REM sleep behavior disorder: Updated review of the core features, the REM sleep behavior disorder neurodegenerative disease association, evolving concepts, controversies and future directions. Ann N Y AcadSci 1184: 15-54.
- Chase MH (2013) Motor control during sleep and wakefulness: Clarifying controversies and resolving paradoxes. Sleep Med Rev 17: 299-312.
- Iranzo A, Aparicio J (2009) A lesson from anatomy: Focal brain lesions causing REM sleep behavior disorder. Sleep Med 10: 9-12.
- Schenck CH, Mahowald MW (2002) REM sleep behavior disorder:clinical, developmental and neuroscience perspectives 16 years after its formal identification in sleep. Sleep 25: 120-138.
- Valente EM, Arena G, Torosantucci L, Gelmetti V (2012) Molecular pathways in sporadic PD. Parkinsonism RelatDisord 18 Suppl 1: S71-S73.
- Dikiy I, Eliezer D (2012) Folding and misfolding of alpha-synuclein on membranes. BiochimBiophysActa 1818: 1013-1018.
- Postuma RB, Gagnon JF, Montplaisir JY (2012) REM sleep behavior disorder: From dreams to neurodegeneration. Neurobiol Dis 46: 553-558.
- Fantini ML, Farini E, Ortelli P, Zucconi M, Manconi M, et al. (2011) Longitudinal study of cognitive function in idiopathic REM sleep behavior disorder. Sleep 34: 619-625.
- Postuma RB, Gagnon JF, Vendette M, Montplaisir JY (2009) Idiopathic REM sleep behavior disorder in the transition to degenerative disease.MovDisord 24: 2225-2232.
- Schenck CH, Bundlie SR, Mahowald MW (2003) REM behavior disorder (RBD): delayed emergence of parkinsonism and/or dementia in 65% of older men initially diagnosed with idiopathic RBD, and an analysis of the minimum and maximum tonic and/or phasic electromyographic abnormalities found during REM sleep. Sleep 26: A316.
- Tippmann-Peikert M, Olson EJ, Boeve BF, Silber MH (2006) Idiopathic REM sleep behavior disorder: A follow-up of 39 patients. Sleep 29: A272.
- Muller ML, Bohnen NI (2013) Cholinergic dysfunction in Parkinson’s disease. CurrNeurolNeurosci Rep 13: 377.
- Datta S, Maclean RR (2007) Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. NeurosciBiobehav Rev 31: 775-824.
- Hirsch EC, Graybiel AM, Duyckaerts C, Javoy-Agid F (1987) Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. ProcNatlAcadSci USA 84: 5976-5980.
- Jellinger K (1988) Thepedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J NeurolNeurosurg Psychiatry 51: 540-543.
- Arnulf I, Bonnet AM, Damier P, Bejjani BP, Seilhean D, et al. (2000) Hallucinations, REM sleep and Parkinson’s disease: A medical hypothesis. Neurology 55: 281-288.
- Boeve BF, Silber MH, Saper CB, Ferman TJ, Dickson DW, et al. (2007) Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 130: 2770-2788.
- Garcia-Lorenzo D, Longo-Dos Santos C, Ewenczyk C, Leu- Semenescu S, Gallea C, et al. (2013) Thecoeruleus/subcoeruleus complex in rapid eye movement sleep behavior disorders in Parkinson’s disease. Brain 136: 2120-2129.
- Boissard R, Gervasoni D, Schmidt MH, Barbagli B, Fort P, et al. (2002) The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: A combined microinjection and functional neuroanatomical study. Eur J Neurosci 16: 1959-1973.
- Lu J, Sherman D, Devor M, Saper CB (2006) A putative flip-flop switch for control of REM sleep. Nature 441: 589-594.
- Ellmore TM, Castriotta RJ, Hendley KL, Aalbers BM, Furr-Stimming E, et al. (2013) Altered nigrostriatal and nigrocortical functional connectivity in rapid eye movement sleep behavior disorder. Sleep 36: 1885-1892.
- Cai Z, Fan LW, Kaizaki A, Tien LT, Ma T, et al. (2013) Neonatal systemic exposure to lipopolysaccharide enhances susceptibility of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. DevNeurosci 35:155-171.
- Fan LW, Tien LT, Lin RC, Simpson KL, Rhodes PG, et al. (2011) Neonatal exposure to lipopolysaccharide enhances vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Neurobiol Dis 44: 304-316.
- Fan LW, Tien LT, Zheng B, Pang Y, Lin RC, et al. (2011) Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity. Brain BehavImmun 25: 286-297.
- Lan KM, Tien LT, Pang Y, Bhatt AJ, Fan LW (2015) IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats. ToxicolLett 234: 30-39.
- Pang Y, Tien LT, Zhu H, Shen J, Wright CF, et al. (2015) Interleukin-1 receptor antagonist reduces neonatal lipopolysaccharide-induced long-lasting neurobehavioral deficits and dopaminergic neuronal injury in adult rats. Int J MolSci 16: 8635-8654.
- Lorton D, Lubahn CL, Estus C, Millar BA, Carter JL, et al. (2006) Bidirectional communication between the brain and the immune system: Implications for physiological sleep and disorders with disrupted sleep. Neuroimmunomodulation 13: 357-374.
- Opp MR (2005) Cytokines and sleep. Sleep Med Rev 9: 355-364.
- Opp MR, Born J, Irwin MR (2007) Psychoneuroimmunology: Sleep and immune system. Ader R (Ed), Academic Press, San Diego pp: 579-618.
- Shandra AA, Godlevsky LS, Vastyanov RS, Oleinik AA, Konovalenko VL, et al. (2002) The role of TNF-alpha in amygdala kindled rats. Neurosci Res 42: 147-153.
- Esumi LA, Palma BD, Gomes VL, Tufik S, Hipolide DC (2011) Inflammatory markers are associated with inhibitory avoidance memory deficit induced by sleep deprivation in rats.Behav Brain Res 221: 7-12.
- Kapas L, Hansen MK, Chang HY, Krueger JM (1998) Vagotomy attenuates but does not prevent the somnogenic and febrile effects of lipopolysaccharide in rats. Am J Physiol 274: R406-R411.
- Krueger JM, Kubillus S, Shoham S, Davenne D (1986) Enhancement of slow wave sleep by endotoxin and lipid A. Am J Physiol 251: R591-R597.
- Schiffelholz T, Lancel M (2001) Sleep changes induced by lipopolysaccharide in the rat is influenced by age. Am J PhysiolRegulIntegr Comp Physiol 280: 398-403.
- Belaid H, Adrien J, Karachi C, Hirsch EC, François C (2015) Effect of melatonin on sleep disorders in a monkey model of Parkinson's disease. Sleep Med 16: 1245-1251.
- Dowling HA, Mastick J, Colling E, Carter JH, Singer CM (2005) Aminoff MJ, Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med 6: 459-466.
- Medeiros CAM, de Bruin PFC, Lopes LA, Magalhaes MC, Seabra ML, et al. (2007) Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. J Neurol 254: 459-464.
- Gutierrez-Valdez AL, Anaya-Martinez V, Ordonez-Librado JL, García-Ruiz R, Torres-Esquivel C, et al. (2012) Effect of chronic l-dopa or melatonin treatments after dopamine deafferentation in rats: Dyskinesia, motor performance and cytological analysis. ISRN Neurol 2012: 360379.
- Naskar A, Manivasagam T, Chakraborty J, Singh R, Thomas B, et al. (2013) Melatonin synergizes with low doses of l-dopa to improve dendritic spine density in the mouse striatum in experimental Parkinsonism. J Pineal Res 55: 304-312
- Patki G, Lau YS (2011) Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson’s disease. PharmacolBiochemBehav 99: 704-711.
- Zaitone SA, Hammad LN, Farag NE (2013) Antioxidant potential of melatonin enhances the response to l-dopa in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-parkinsonian mice. Pharmacol Rep 65: 1213-1226.
- Adi N, Mash DC, Ali Y, Singer C, Shehadeh L, et al. (2010) Melatonin MT1 and MT2 receptor expression in Parkinson’s disease. Med SciMonit 16: BR 61-67.
- Breen DP, Vuono R, Nawarathna U, Fisher K, Shneerson JM, et al. (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 71: 589-595.
- Videnovic A, Noble C, Reid KJ, Peng J, Turek FW, et al. (2014) Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 71: 463-469.
- Absi E, Ayala A, Machado A, Parrado J (2000) Protective effect of melatonin against the 1-methyl-4 phenylpyridinium-induced inhibition of complex I of the mitochondrial respiratory chain. J Pineal Res 29: 40-47.
- Antolin I, Mayo JC, Sainz RM, del BríoMde L, Herrera F, et al. (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943: 163-173.
- Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: A role for mitochondrial complex I activity. FASEB J 15: 164-170.