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| Key brain structures affected by Lewy bodies, Lewy neuritis, and neuronal loss n Parkinson's disease (highlighted in red box): SN, substantia nigra; DRN, dorsal raphe nuclei; vlPAG, ventrolateral periaqueductal gray; LDT, laterodorsal tegmental nucleus; PPN, pedunculopontine nucleus; LC, locus coeruleus; SLD, sublaterodorsal nucleus; MCRF, magnocellular reticular formation. REMS onset occurs when a certain balance is reached between REMS-on and off neurons as well as inhibitory and excitatory pathways within the different brain structures. Damage and degeneration to these brain structures and their relationships lead to RBD. (Adapted and published under the Creative Commons Attribution-Share Alike 3.0 Unported license).
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Sleep is an indispensable normal physiology of the human body fundamental for healthy functioning. It has been observed that Parkinson’s disease (PD) not only exhibits motor symptoms, but also non-motor symptoms such as metabolic irregularities, altered olfaction, cardiovascular dysfunction, gastrointestinal complications and especially sleep disor...
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This sleep disorder is reflected as the changes in the electrical activities and chemical activities in the brain that can be observed by capturing the brain signals and the images. In this research, Short Time-frequency analysis of Power Spectrum Density (STFAPSD) approach applied on Electroencephalogram (EEG) Signals for prediction of RBD sleep d...
In Parkinson's disease (PD), abnormal movements consisting of hypokinetic and hyperkinetic manifestations commonly lead to nocturnal distress and sleep impairment, which significantly impact quality of life. In PD patients, these nocturnal disturbances can reflect disease-related complications (e.g., nocturnal akinesia), primary sleep disorders (e....
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra and subsequent motor symptoms, but various non-motor symptoms (NMS) often precede motor symptoms. Recently, NMS have attracted much attention as a clue for identifying patients in a prodromal stage of PD, which is an excellent point at which to adm...
Citations
... Interestingly, we observed the presence of pSer129 in the brainstem including the Laterodorsal tegmental nucleus (LDTg) and the Pedunculopontine nucleus (PPN, Fig. S11L) and the ventral dorsal raphe (DR, Fig. S11M) (24,25). This Confirm previous observations in PD patients (26,27), where increased accumulation of alpha-synuclein in the LDTg and the DR correlated with sleep disorders and depressive-like phenotypes (28,29). ...
Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (aSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of aSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of aSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of aSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between aSynucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.
... 2 Sleep disorders in PD patients are commonly observed as daytime sleepiness, nocturnal insomnia, sleep fragmentation, and rapid eye movement sleep behavior disorder (RBD). [3][4][5] Therefore, comprehensive circadian rhythm monitoring is crucial for early disease diagnosis and personalized treatment. ...
Aims
Sleep disturbance is a prevalent nonmotor symptom of Parkinson's disease (PD), however, assessing sleep conditions is always time‐consuming and labor‐intensive. In this study, we performed an automatic sleep–wake state classification and early diagnosis of PD by analyzing the electrocorticography (ECoG) and electromyogram (EMG) signals of both normal and PD rats.
Methods
The study utilized ECoG power, EMG amplitude, and corticomuscular coherence values extracted from normal and PD rats to construct sleep–wake scoring models based on the support vector machine algorithm. Subsequently, we incorporated feature values that could act as diagnostic markers for PD and then retrained the models, which could encompass the identification of vigilance states and the diagnosis of PD.
Results
Features extracted from occipital ECoG signals were more suitable for constructing sleep–wake scoring models than those from frontal ECoG (average Cohen's kappa: 0.73 vs. 0.71). Additionally, after retraining, the new models demonstrated increased sensitivity to PD and accurately determined the sleep–wake states of rats (average Cohen's kappa: 0.79).
Conclusion
This study accomplished the precise detection of substantia nigra lesions and the monitoring of sleep–wake states. The integration of circadian rhythm monitoring and disease state assessment has the potential to improve the efficacy of therapeutic strategies considerably.
... Sleep in MCI-Park mice also was more fragmented, which manifested as increased numbers of wake and NREM sleep bouts, decreased REM sleep bouts, more state shifts, and a decreased median NREM bout duration. These patterns may approximate the insomnia experienced by PD patients, characterized by difficulty falling asleep, staying asleep, and consolidating sleep without interruption [2][3][4][5][6][7][8] . The temporal distribution of sleep was also altered in MCI-Park mice, with decreases in the proportion of NREM sleep and total sleep occurring during the light phase, or "right" time of day for these nocturnal animals. ...
Disrupted sleep has a profound adverse impact on lives of Parkinson’s disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD – the MCI-Park mouse – was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities resemble those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.
... Our results show that mild motor impairments, characterized by a dissociation of explorative horizontal locomotion in open field (impaired) and motor coordination on the rotarod (intact), are detectable already at very early stages, even one week after a single low dose of striatal 6-OHDA injection. PD leads to severe motor symptoms: tremor, rigidity, bradykinesia and postural instability 54-57 as well as nonmotor symptoms including depression and altered motivation, autonomic dysfunction such as constipation and bladder dysfunction, sleep disturbances, anosmia and cognitive deficit [58][59][60][61] . The key component of PD pathogenesis is the degeneration of DAergic neurons of the SNc, resulting in the deafferentation of the striatum 7,62 . ...
Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice. Abbreviations PD Parkinson's disease 6-OHDA 6-Hydroxy-dopamine DA Dopamine DAergic Dopaminergic SNc Substantia nigra pars compacta TH Tyrosine-hydroxylase TH + Tyrosine-hydroxylase immunopositive LD Low dose OPEN
... [47][48][49][50][51] Indeed, as the brain networks generating sleep oscillations are the same networks engaged in cognitive processes, analysis of sleep may also allow prediction of impaired cognition. [52][53][54] Questions regarding the specific brain structural abnormalities that might influence sleep patterns and quality, [55][56][57] the extent to which good sleep quality can compensate for neuropathology, 58 and the compensatory role of healthy brain structure in the presence of sleep pathology 59 are actively being investigated. Notably, certain studies suggest that individuals with resilient brain structures may exhibit better sleep quality even in the presence of sleep disorders or disruption. ...
Study Objectives
To use relatively noisy routinely collected clinical data (brain magnetic resonance imaging (MRI) data, clinical polysomnography (PSG) recordings, and neuropsychological testing), to investigate hypothesis-driven and data-driven relationships between brain physiology, structure, and cognition.
Methods
We analyzed data from patients with clinical PSG, brain MRI, and neuropsychological evaluations. SynthSeg, a neural network-based tool, provided high-quality segmentations despite noise. A-priori hypotheses explored associations between brain function (measured by PSG) and brain structure (measured by MRI). Associations with cognitive scores and dementia status were studied. An exploratory data-driven approach investigated age-structure-physiology-cognition links.
Results
623 patients with sleep PSG and brain MRI data were included in this study; 160 with cognitive evaluations. 342 subjects (55%) were female, and age interquartile range was 52 to 69 years. 36 individuals were diagnosed with dementia, 71 with mild cognitive impairment (MCI), and 326 with major depression. 115 individuals were evaluated for insomnia and 138 subjects had an apnea-hypopnea index (AHI) equal to or greater than 15. Total PSG delta power correlated positively with frontal lobe/thalamic volumes, and sleep spindle density with thalamic volume. REM duration and amygdala volume were positively associated with cognition. Patients with dementia showed significant differences in five brain structure volumes. REM duration, spindle, and slow oscillation features had strong associations with cognition and brain structure volumes. PSG and MRI features in combination predicted chronological age (R2 =0.67) and cognition (R2 =0.40).
Conclusions
Routine clinical data holds extended value in understanding and even clinically using brain-sleep-cognition relationships.
... Studies using animal models of PD showed that circadian disruption could exacerbate neurodegeneration and motor symptoms 4 . However, it remains elusive whether circadian disturbances causally drive neurodegeneration or are caused by neurodegeneration, partly because PD pathology includes dysfunction of the brain regions regulating sleep, resulting in disrupted sleep-wake cycles 5 . Dissecting mechanistic links between circadian clock disruption and neurodegeneration-two intertwined and potentially synergistic processes-is critical for developing reliable diagnostic tools and treatment strategies for PD. ...
Sleep and circadian rhythm disruptions are frequent comorbidities of Parkinson’s disease (PD), a disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, the causal role of circadian clocks in the degenerative process remains uncertain. We demonstrated here that circadian clocks regulate the rhythmicity and magnitude of the vulnerability of DA neurons to oxidative stress in male Drosophila. Circadian pacemaker neurons are presynaptic to a subset of DA neurons and rhythmically modulate their susceptibility to degeneration. The arrhythmic period (per) gene null mutation exacerbates the age-dependent loss of DA neurons and, in combination with brief oxidative stress, causes premature animal death. These findings suggest that circadian clock disruption promotes dopaminergic neurodegeneration.
... However, other pathways, such as noradrenergic, cholinergic, and serotonergic, can also explain the broad clinical spectrum of the disease. 1,2 The latter is the one that better explains the presence of sleep disorders, considering that from 74% to 98% of the individuals with PD are affected by sleep disorders, such as nocturnal akinesia, rapid eye movement (REM) sleep behavior disorder, restless legs syndrome, excessive daytime sleepiness, obstructive sleep apnea, nocturia, and hallucinations. 3,4 Pharmacological treatment is the approach most frequently used to manage the disease's motor symptoms, and dopaminergic agents are the most efficient 3,4 ; however, it is little efficient to manage non-motor symptoms, which are often refractory to pharmacological treatments. ...
Objective Sleep disorders are disabling and highly prevalent comorbidities in Parkinson's disease (PD). This study's objective was to verify the effectiveness of neurofunctional physiotherapy in sleep quality, objectively and subjectively assessing it among individuals with PD.
Methods A sample of individuals with PD was assessed before and after 32 physiotherapy sessions and three months later (follow-up). The following instruments were used: Pittsburgh Sleep Quality Index (PSQI); Epworth Sleepiness Scale (ESS); Parkinson's Disease Sleep Scale (PDSS), and actigraphy.
Results Nineteen individuals aged 67.37 years old ( ± 8.03) on average were included. No differences were found in any of the variables measured by the actigraphy or the ESS. Improvement was found from pre- to post-intervention in terms of nocturnal movements (p = 0.04; d = 0.46) and total score (p = 0.03; d = 0.53) obtained on the PDSS. Improvement was also found in the PDSS sleep onset/maintenance domain (p = 0.001; d = 0.75) between pre-intervention and follow-up. The participants' total score obtained in the PSQI improved from pre- to post-intervention (p = 0.03; d = 0.44). Significant differences were found in nighttime sleep (p = 0.02; d = 0.51) and nocturnal movements (p = 0.02; d = 0.55), and in the PDSS total score (p = 0.04; d = 0.63) between pre- and post-intervention when only the poor sleepers subgroup (n = 13) was considered, while improvements were found in sleep onset/maintenance (p = 0.003; d = 0.91) between pre-intervention and follow-up.
Discussion Neurofunctional physiotherapy was ineffective in improving objective parameters of sleep but was effective in improving the perception of sleep quality subjectively assessed among individuals with PD, especially those who perceived themselves to be poor sleepers.
... These findings support the idea that multifactorial causes underpin insomnia in PD, including the degeneration of sleep regulatory centers, comorbidity, and the detrimental effect of antiparkinsonian medications [98e100]. Particularly, insomnia seems to occur when wake structures (i.e., locus coeruleus and other arousal structures) fail to deactivate during the transition from wake to sleep [101]. Therefore, the dysregulation of the "sleep-wakefulness switch" resulting from both dopaminergic replacement therapy and degenerative processes, leads to an altered release of neurotransmitters by these structures, which in turn promote arousal and, consequently, insomnia. ...
Sleep disorders (SDs) are common non-motor symptoms of Parkinson's disease (PD) with wide variability in their prevalence rates. The etiology of SDs in PD is multifactorial because the degenerative processes underlying the disease and their interaction with drugs and clinical features may promote REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS) and insomnia. Therefore, we designed a meta-analytic study to provide a reliable estimate of the prevalence and associated clinical and neuropsychiatric aspects of SDs in PD. A systematic literature search was performed up to February 2022. Pooled RBD prevalence was 46%, and its occurrence was associated with older age, lower education, longer disease duration, higher levodopa equivalent daily dose (LEDD), worse motor and autonomic manifestations, poorer quality of life and autonomy, and more severe neuropsychiatric symptoms. The pooled prevalence of EDS was 35% and was associated with older age, longer disease duration, worse motor and autonomic symptoms, higher LEDD, reduced autonomy, and more severe neuropsychiatric symptoms. Insomnia was reported in 44% of PD patients and was related to longer disease duration, higher LEDD, and more severe depression. SDs are associated with a more severe PD clinical phenotype; further studies should explore the pathophysiological mechanisms underlying SDs and develop targeted therapeutic strategies.
... A range of non-motor symptoms, some of which arise prodromal to clinical onset of disease [129,130], are strong correlates of PD including autonomic dysfunction [131][132][133][134], neuropsychiatric symptoms [135][136][137][138], dementia [139,140], sensory symptoms [141,142] including loss of olfaction (which commonly predates motor symptoms ) [143] and sleep and circadian rhythm dysfunction [144][145][146]. In the following section we will summarize the sleep and circadian phenotypes in PDfor a more in-depth analysis of this see these recent reviews [3,144,[147][148][149]. ...
The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson’s disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson’s disease. However, it is important that models accurately encompass important facets of the disease to allow for comprehensive mechanistic understanding and translational significance. Circadian rhythm and sleep issues are tightly correlated to Parkinson’s disease, and often arise prior to the presentation of typical motor deficits. It is essential that models used to understand Parkinson’s disease reflect these dysfunctions in circadian rhythms and sleep, both to facilitate investigations into mechanistic interplay between sleep and disease, and to assist in the development of circadian rhythm-facing therapeutic treatments. This review describes the extent to which various genetically- and neurotoxically-induced murine models of Parkinson’s reflect the sleep and circadian abnormalities of Parkinson’s disease observed in the clinic.
... This finding is consistent with the state of permanent EDS reported by parkinsonian patients. The onset of an increasingly early morning nap is reminiscent of a delayed phase syndrome, which is also reported in patients with PD 59 . Dopamine depletion could also induce disturbances of the circadian rhythm, which is mediated by a regulatory mechanism called process C 60 . ...
Parkinsonian patients often experience sleep/wake disturbances, which may appear at an early stage of the disease; however, these disturbances have not been fully described. To better understand the evolution of these disturbances with respect to disease progression, we aimed to characterize these clinical signs in a progressive nonhuman primate model of Parkinson's disease. Three adult macaques (Macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of sleep/wake behavior via long-term neurophysiological recordings and underwent a modified multiple sleep latency test. Experiments were first performed in a healthy state and then during the progressive induction of a parkinsonian syndrome by intramuscular injections of low doses of MPTP. We observed an early onset of significant sleep/wake disturbances (i.e., before the appearance of motor symptoms). These disturbances resulted in (i) a disorganization of nighttime sleep with reduced deep sleep quality and (ii) an excessive daytime sleepiness characterized by sleep episodes occurring more rapidly in the morning and spreading through the middle of the day. The present study suggests that nighttime and daytime sleep/wake disturbances may appear early in the disease and should be considered in the development of biomarkers in further studies.
