Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

Effects of sleep fragmentation on white matter pathology in a rat model of cerebral small vessel disease.

STUDY OBJECTIVES: Mounting evidence indicated the correlation between sleep and cerebral small vessel disease (CSVD). However, little is known about the exact causality between poor sleep and white matter injury, a typical signature of CSVD, as well as the underlying mechanisms. METHODS: Spontaneously hypertensive rats (SHR) and control Wistar Kyoto rats were subjected to sleep fragmentation (SF) for 16 weeks. The effects of chronic sleep disruption on the deep white matter and cognitive performance were observed. RESULTS: SHR were validated as a rat model for CSVD. Fragmented sleep induced strain-dependent white matter abnormalities, characterized by reduced myelin integrity, impaired oligodendrocytes precursor cells (OPC) maturation and pro-inflammatory microglial polarization. Partially reversible phenotypes of OPC and microglia were observed in parallel following sleep recovery. CONCLUSIONS: Long-term SF-induced pathological effects on the deep white matter in a rat model of CSVD. The pro-inflammatory microglial activation and the block of OPC maturation may be involved in the mechanisms linking sleep to white matter injury.

Safinamide alleviates hyperalgesia via inhibiting hyperexcitability of DRG neurons in a mouse model of Parkinson's disease.

Pain is a widespread non-motor symptom that presents significant treatment challenges in patients with Parkinson's disease (PD). Safinamide, a new drug recently introduced for PD treatment, has demonstrated analgesic effects on pain in PD patients, though the underlying mechanisms remain unclear. To investigate the analgesic and anti-PD effect of safinamide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used, and rasagiline as positive control on motor symptoms. Notably, only safinamide alleviated hyperalgesia in MPTP mice. Whole-cell patch-clamp recordings of dorsal root ganglion (DRG) neurons revealed hyperexcitability in MPTP mice, which safinamide counteracted in a concentration-dependent manner. The voltage clamp further demonstrated that sodium current in DRG neurons of MPTP mice was enhanced and safinamide reduced sodium current density. RT-qPCR identified upregulated Nav1.7 and Nav1.8 transcripts (Scn9a and Scn10a) in DRG neurons of MPTP mice. Our results suggest that safinamide could relieve hyperalgesia by inhibiting DRG neuron hyperexcitability in MPTP mice.

Correlation Between Substantia Nigra Hyperechogenicity and Iron Metabolism in the Postural Instability Gait Difficulty Subtype of Parkinson's Disease.

OBJECTIVE: The correlation between substantia nigra (SN) hyperechogenicity on transcranial sonography (TCS) and serum iron metabolism parameters in patients with the postural instability gait difficulty (PIGD) subtype of Parkinson's disease (PD) was investigated so as to explore the pathological mechanism of SN hyperechogenicity. METHODS: The study enrolled 95 PIGD patients recruited by the Parkinson's Disease Specialty in the Second Affiliated Hospital of Soochow University during June 2019-2021. On the basis of the TCS results, the PIGD patients were assigned to the PD with SN hyperechogenicity (SN+) group (n = 60) and PD without SN hyperechogenicity (SN-) group (n = 35). Meanwhile, 49 sex- and age-matched healthy individuals were included in the control group. All participants underwent blood tests. Differences in the iron metabolism parameters among the three groups and the correlation between SN hyperechogenicity and serum iron metabolism parameters were analyzed. RESULTS: Serum ferritin, ceruloplasmin and transferrin levels were lower in the SN+ and SN- groups than in the control group (all p values <0.001). The serum ceruloplasmin level was lower in the SN+ group (0.23 [0.20, 0.25] g/L) than in the SN- group (0.25 [0.22, 0.29] g/L) (p = 0.001), and the proportion of patients with an abnormal ceruloplasmin level was higher in the SN+ group than in the SN- group (43.3% [26/60] vs. 14.3% [5/35], χ2 = 8.484, p = 0.004). Moreover, the SN hyperechogenicity area was negatively correlated with the serum transferrin level (r = -0.428, p < 0.001). CONCLUSION: Decreased serum ceruloplasmin levels may be associated with SN hyperechogenicity development in PIGD patients. The SN hyperechogenicity area is negatively correlated with the serum transferrin level.

Sarcopenia is associated with non-motor symptoms in Han Chinese patients with Parkinson's Disease: a cross-sectional study.

BACKGROUND: Sarcopenia is commonly seen in the older adults and increases in incidence with age, also in Parkinson's disease (PD). Although research has indicated that the development of sarcopenia in patients with PD may be related to both motor symptoms and non-motor symptoms (NMS), the precise relationship between the two conditions remains unclear. Therefore, we aimed to investigate the incidence of sarcopenia in patients with PD and its association with NMS. METHODS: The study included 123 patients with PD and 38 age- and sex-matched healthy controls (HC). All participants were evaluated for sarcopenia using the 2019 Asian Sarcopenia Diagnostic Criteria, and patients with PD underwent standard assessments of motor symptoms and NMS. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine the association between sarcopenia and NMS in patients with PD. RESULTS: The incidence of sarcopenia was significantly higher in patients with PD than in HC (26.8% vs. 10.4%, p = 0.046). Multiple logistic regression analysis revealed that poorer sleep quality (odds ratio [OR]: 1.245; 95% confidence interval [CI]: 1.011-1.533; p = 0.040) and fatigue (OR: 1.085, 95% CI: 1.006-1.170, p = 0.034) were independently associated with sarcopenia. ROC analysis indicated that the optimal cut-off value for Pittsburgh Sleep Quality Index (PSQI) scores was 10, with 72.7% sensitivity and 74.4% specificity (area under the curve [AUC] = 0.776, 95% CI: 0.683-0.868, p < 0.001). The optimal cut-off value for Fatigue Severity Scale (FSS) scores was 39, with 87% sensitivity and 50% specificity (AUC = 0.725, 95% CI: 0.629 -0.820, p < 0.001). Joint use of FSS and PSQI scores increased the predictive value for sarcopenia(AUC = 0.804, 95% CI: 0.724-0.885, p < 0.001). CONCLUSION: Patients with PD are more susceptible to sarcopenia than healthy older adults, and fatigue and poorer sleep are positively associated with sarcopenia. Further longitudinal studies are needed to clarify the causal relationships.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

A systematic analysis of genotype-phenotype associations with PLA2G6.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) can be categorized into infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), neurodegeneration with brain iron accumulation (NBIA), and early-onset parkinsonism (EOP). OBJECTIVES: To determine the genotype-phenotype association in PLAN. METHODS: "PLA2G6" or "PARK14" or "phospholipase A2 group VI" or "iPLA2ß" were searched across MEDLINE from June 23, 1997, to March 1, 2023. A total of 391 patients were identified, and 340 patients of them were finally included in the assessment. RESULTS: The loss of function (LOF) mutation ratios were significantly different (p < 0.001), highest in INAD, followed by NBIA, aNAD, and EOP. Four ensemble scores (i.e., BayesDel, VARITY, ClinPred, and MetaRNN) were assessed to predict the deleteriousness of missense mutations and demonstrated significant differences (p < 0.001). Binary logistic regression analyses demonstrated that LOF mutations were independently associated with brain iron accumulation (p = 0.006) and ataxia (p = 0.025). CONCLUSIONS: LOF or more deleterious missense mutations are more likely to promote the development of serious phenotype of PLAN, and LOF mutations are independently associated with brain iron accumulation and ataxia.

Associations between variants in levodopa metabolic pathway genes and levodopa-induced dyskinesia in Parkinson's disease.

INTRODUCTION: Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson's disease (PD). Several genes in the levodopa metabolic pathway, such as COMT, DRDx and MAO-B, were reported associated with LID. However, there has been no systematic analyses between common variants in levodopa metabolic pathway genes and LID in a large sample of the Chinese population. METHODS: Through the whole exome sequencing (WES) and target region sequencing, we aimed to explore the potential associations between common single nucleotide polymorphisms (SNPs) in the levodopa metabolic pathway and LID in Chinese PD individuals. Five hundred and two PD individuals were enrolled in our study, among them, 348 individuals underwent WES, and 154 individuals underwent target region sequencing. We acquired the genetic profile of 11 genes including COMT, DDC, DRD1-5, SLC6A3, TH and MAO-A/B. We established a stepwise strategy to filter SNPs, which finally included 34 SNPs in our analyses. And we used a two-stage study, with discovery (348 individuals with WES) and the replication (all 502 individuals) to confirm our findings. RESULTS: Among the 502 PD individuals, 104 (20.7%) were diagnosed with LID. In the discovery stage, we found that COMT rs6269, DRD2 rs6275 and DRD2 rs1076560 were associated with LID. In the replication stage, associations between the three above-mentioned SNPs and LID were still present in all 502 individuals. CONCLUSION: We demonstrated that in the Chinese population, COMT rs6269, DRD2 rs6275 and rs1076560 were significantly associated with LID. And rs6275 was reported associated with LID for the first time.

Circadian disruption and sleep disorders in neurodegeneration.

Disruptions of circadian rhythms and sleep cycles are common among neurodegenerative diseases and can occur at multiple levels. Accumulating evidence reveals a bidirectional relationship between disruptions of circadian rhythms and sleep cycles and neurodegenerative diseases. Circadian disruption and sleep disorders aggravate neurodegeneration and neurodegenerative diseases can in turn disrupt circadian rhythms and sleep. Importantly, circadian disruption and various sleep disorders can increase the risk of neurodegenerative diseases. Thus, harnessing the circadian biology findings from preclinical and translational research in neurodegenerative diseases is of importance for reducing risk of neurodegeneration and improving symptoms and quality of life of individuals with neurodegenerative disorders via approaches that normalize circadian in the context of precision medicine. In this review, we discuss the implications of circadian disruption and sleep disorders in neurodegenerative diseases by summarizing evidence from both human and animal studies, focusing on the bidirectional links of sleep and circadian rhythms with prevalent forms of neurodegeneration. These findings provide valuable insights into the pathogenesis of neurodegenerative diseases and suggest a promising role of circadian-based interventions.

Quantitative Transcranial Sonography Evaluation of Substantia Nigra Hyperechogenicity Is Useful for Predicting Levodopa-Induced Dyskinesia in Parkinson Disease.

Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson disease (PD). Abnormal substantia nigra hyperechogenicity (SN+), detected by transcranial sonography (TCS), plays an important role in the differential diagnosis of PD. The purpose of this study was to investigate the predictive performance of quantitative SN+ evaluations for LID. Five hundred sixty-two individuals were included in our analysis, and 198 individuals were followed up. These individuals were divided into two groups at baseline: the PD with LID (PD+LID) group and the PD without LID (PD-LID) group. The association between total hyperechogenic area of the SN on both sides (SNT) and LID was analyzed by binary logistic analysis. A binary logistic regression model including SNT was applied to establish a model for discriminating LID. At baseline, 105 (18.7%) individuals were diagnosed with LID. The PD+LID group had a longer disease duration, shorter education duration, higher levodopa equivalent doses, greater disease severity and larger SNT. A model combining clinical features and SNT was further established with better efficiency (area under the receiver operating characteristic curve = 0.839). One hundred ninety-eight individuals were followed up; individuals with a larger SNT and a higher predicted probability were more likely to develop LID in our follow-up. Our study determined that quantitative TCS evaluation of SN echogenicity is useful in predicting LID in PD.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.

Inflammation is one of the pathogenic processes in Parkinson's disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg-1·d-1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1ß in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1ß, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100-400 µM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 µM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 µmol/L) and palosetron (10 µmol/L), but not 5-HT3 receptor agonist m-CPBG (30 µmol/L) and SR 57,727 (10 µmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 µmol/L) and eptapirone (10 µmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 µmol/L) and p-MPPI (10 µmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Association Between Asymmetry of Substantia Nigra Hyperechogenicity and Clinical Characteristics in Different Parkinson Disease Subtypes: A 5-Year Follow-up Study.

Our study focused on three aspects to determine whether bilateral substantia nigra hyperechogenicity (SN+) is asymmetrical, whether the asymmetry of SN+ is related to the clinical features and whether there is variation in SN+ asymmetry during the progression of Parkinson disease (PD). This follow-up study included 234 patients with PD, who were divided into tremor PD (TD, n = 67) and non-tremor PD (NTD, n = 167) groups based on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. All participants underwent transcranial sonography (TCS) and clinical assessment. In both the TD and NTD groups, the initial SN+ was larger than the non-initial SN+. The initial SN+ was associated with Hoehn and Yahr (H&Y) stage, PD duration and initial UPDRS III, and the SN+ asymmetry index was associated with motor asymmetry index in the TD group. In the NTD group, the initial SN+ was associated only with initial UPDRS III. After a 5-year follow-up, the area of SN+ on both sides was gradually inclining to symmetry in the NTD group. Our study determined that SN+ asymmetry could reflect asymmetrical characteristics of PD. Furthermore, we inferred that the dynamic change in SN+ asymmetry might reflect a dynamic change in motor asymmetry in the NTD group.

G2019S LRRK2 Mutation Enhances MPP+-Induced Inflammation of Human Induced Pluripotent Stem Cells-Differentiated Dopaminergic Neurons.

Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to mimic human diseases of related cell types, but it is unclear whether they can successfully mimic age-related diseases such as Parkinson's disease (PD). We generated iPSCs lines from three patients with familial PD associated with the G2019S mutation in the LRRK2 gene and one age-matched healthy individual (control). During long-term culture, dopaminergic (DA) neurons differentiated from iPSCs of G2019S LRRK2 PD patients exhibited morphological changes, including a reduced number of neurites and neurite arborization, which were not evident in DA neurons differentiated from control iPSCs. To mimic PD pathology in vitro, we used 1-methyl-4-phenylpyridium (MPP+) to damage DA neurons and found that DA neurons differentiated from patients with G2019S LRRK2 mutation significantly reduced the survival rate and increased apoptosis compared with the controls. We also found that the mRNA level of inflammatory factors [interleukin (IL)-1ß, tumor necrosis factor-α, cyclooxygenase-2, IL-6, and inducible NO synthase] with G2019S LRRK2 mutation were higher than control group after exposure to MPP+. Our study provides an in vitro model based on iPSCs that captures the patients' genetic complexity and investigates the pathogenesis of familial PD cases in a disease-associated cell type.

Cognitive Performance is Associated with Altered Cerebral Hemodynamics Assessed by Transcranial Ultrasound in Parkinson's Disease.

Purpose: Cognitive impairment (CI) is a common but debilitating non-motor symptom in Parkinson's disease (PD). Although cerebrovascular functions are related to cognitive performance in healthy individuals, such a relation in PD remains elusive. This study aims to assess the association between cerebrovascular function and cognitive performance in PD individuals. Patients and Methods: Two-hundred-and-one PD individuals were retrospectively included. They were subsequently divided into two groups: PD with normal cognition (PD-NC) and PD with CI (PD-CI). Cerebral hemodynamic characteristics of the middle cerebral arteries were assessed by transcranial ultrasound. The association between scores in each cognitive domain and cerebral hemodynamic parameters was further analyzed using regression analyses. Additionally, a binary logistic regression model with backward stepwise procedure was applied to build the model for discriminating CI in PD individuals. An independent dataset of additional 46 PD individuals was used further. Results: The PD-CI group showed a relatively lower end-diastolic blood flow velocity (EDV, p < 0.05) and a higher resistive index (RI, p < 0.05) compared to the PD-NC group. RI showed significant associations with the memory item score of Montreal Cognitive Assessment (p < 0.05). A model combining clinical and hemodynamic variables was established with optimal efficiency (area under the curve, AUC = 0.651). Further replication of the model in an independent dataset yielded a great consistency (AUC = 0.704). Conclusion: In our study, cerebrovascular functions were significantly associated with the cognitive performance in PD individuals, especially with the memory task. The established model was effective in identifying CI in PD individuals, which might be a potentially useful tool to screen the cognitive decline in PD individuals at an early stage of the disease. Further studies with larger sample sizes in different populations are warranted.

Peripheral blood inflammatory cytokines are associated with rapid eye movement sleep behavior disorder in Parkinson's disease.

OBJECTIVE: Previous studies have shown the essential role of inflammation in rapid eye movement (REM) sleep behavior disorder (RBD). However, the association of RBD in Parkinson's disease (PD) with peripheral blood inflammatory cytokines is still unknown. We investigated the relationship between inflammatory cytokines and the clinical characteristics of PD patients with RBD. METHODS: A total of 153 PD patients and 36 healthy controls were included in this study, and blood plasma was collected. PD patients were classified as PD with RBD (PD-RBD, n = 60) and PD without RBD (PD-nRBD, n = 93). Inflammatory factor levels were compared among the control, PD-RBD, and PD-nRBD groups. RESULTS: The PD-RBD group had significantly higher C-reactive protein (CRP) levels (P < 0.001), monocytes (P = 0.003), and neutrophil-to-lymphocyte ratio (NLR) (P < 0.001), whereas this group has lower lymphocytes levels (P < 0.001) and lymphocyte-to-monocyte ratio (LMR) (P < 0.001) than the PD-nRBD group. Univariate and multivariate logistic regression analysis indicated that LMR (P < 0.0001 odds ratio [OR] = 0.424) was a protective factor, whereas CRP (P < 0.001 OR = 2.326) was a risk factor for the PD-RBD group. PD-RBD patients had lower Montreal Cognitive Assessment (Beijing version) (MoCA) (P < 0.001) and Mini-Mental State Examination (MMSE) (P = 0.039) scores than PD-nRBD patients. CONCLUSIONS: Significant differences were found in inflammation levels between PD-RBD and PD-nRBD, suggesting that inflammatory factors are associated with the pathogenesis of RBD in PD patients. Thus, CRP and LMR levels may serve as biomarkers and predict the prognosis of PD patients with RBD.

Fiber selectivity of peripheral neuropathy in patients with Parkinson's disease.

OBJECTIVE: To determine the function of each type of peripheral nerve fiber and investigate the possible role of levodopa (LD) in peripheral neuropathy (PN) in Parkinson's disease (PD) patients. METHODS: We enrolled 60 patients with idiopathic PD. All PD patients were divided into three groups: levodopa exposure >3 years (LELD), levodopa exposure ≤3 years (SELD) and de novo patients with PD (NOLD). The current perception threshold (CPT), which was measured by Neurometer at 2000, 250 and 5 Hz, the level of homocysteine, Vitamin B12 and folic acid in plasma, were compared with those of sex- and age-matched healthy controls (HCs). RESULTS: Current perception threshold was higher at 250 Hz (p < .05) and 5 Hz (p < .05) in the LELD group than the NOLD, SELD, and control group. CPT was lower at 5 Hz in the NOLD than in the HCs group (p < .05). The CPT of the more affected side of PD patients was positively correlated with H-Y stage at 5 Hz current stimulation (r = .42, p = .01). Multivariate logistic regression analysis showed that elevated homocysteine levels were the risk factor of sensory nerve injury in PD patients (p < .01). Serum homocysteine levels were positively correlated with levodopa (LD) daily dose, LD equivalent daily dose, and LD cumulative lifetime dose (p < .05). CONCLUSIONS: Peripheral neuropathy in PD patients can occur in the early stage of PD exhibiting as hyperesthesia and is fiber selectivity, especially for Aδ and C nerve fibers. PN in PD patients is related to PD itself and long-term LD exposure. Elevated plasma homocysteine is a risk factor for PN in PD patients.

Generalized EEG Slowing Across Phasic REM Sleep, Not Subjective RBD Severity, Predicts Neurodegeneration in Idiopathic RBD.

Purpose: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is the prodromal marker of α-synuclein degeneration with markedly high predictive value. We aim to evaluate the value of electroencephalography (EEG) data during rapid eye movement (REM) sleep and subjective RBD severity in predicting the conversion to neurodegenerative diseases in iRBD patients. Methods: At the baseline, iRBD patients underwent clinical assessment and video-polysomnography (PSG). Relative spectral power for nine frequency bands during phasic and tonic REM sleep in three regions of interest, slow-to-fast ratios, clinical and PSG variables were estimated and compared between iRBD patients who converted to neurodegenerative diseases (iRBD-C) and iRBD patients who remained disease-free (iRBD-NC). Receiver operating characteristic (ROC) curves evaluated the predictive performance of slow-to-fast ratios, and subjective RBD severity as assessed with RBD Questionnaire-Hong Kong. Results: Twenty-two (33.8%) patients eventually developed neurodegenerative diseases. The iRBD-C group showed shorter total sleep time (p < 0.001), lower stage 2 sleep percentage (p = 0.044), more periodic leg-movement-related arousal index (p = 0.004), increased tonic chin electromyelographic activity (p = 0.040) and higher REM density in the third REM episode (p = 0.034) than the iRBD-NC group. EEG spectral power analyses revealed that iRBD phenoconverters showed significantly higher delta and lower alpha power, especially in central and occipital regions during the phasic REM state compared to the iRBD-NC group. Significantly higher slow-to-fast ratios were observed in a more generalized way during the phasic state in the iRBD-C group compared to the iRBD-NC group. ROC analyses of the slowing ratio in occipital areas during phasic REM sleep yielded an area under the curve of 0.749 (p = 0.001), while no significant predictive value of subjective RBD severity was observed. Conclusion: Our study shows that EEG slowing, especially in a more generalized manner during the phasic period, may be a promising marker in predicting phenoconversion in iRBD, rather than subjective RBD severity.

REM sleep without atonia and vestibular-evoked myogenic potentials: clinical brainstem dysfunction in early-stage Parkinson's disease and isolated REM sleep behavior disorder.

OBJECTIVE: To determine whether the onset of rapid eye movement (REM) sleep behavior disorder (RBD) is associated with changes in brainstem neuronal pathway dysfunction as reflected by vestibular-evoked myogenic potentials (VEMPs) and to evaluate associations between VEMPs and REM sleep without atonia (RSWA) in patients with early-stage Parkinson's disease (PD) and isolated RBD (iRBD). METHODS: Eighty-two early-stage PD patients, 40 iRBD patients, and 41 healthy control individuals underwent one-night video-polysomnography (vPSG) and VEMPs examination. We compared cervical (cVEMP), ocular (oVEMP), and masseter (mVEMP) VEMP parameters among PD with RBD (PD + RBD), PD without RBD (PD-RBD), iRBD, and control groups and analyzed correlations between VEMPs and RSWA in PD and iRBD groups. RESULTS: The PD + RBD group showed delays in bilateral cVEMP (Lp13, Ln23, Rn23: all p < 0.05) and oVEMP (Ln10, Rn10, Rp15: all p < 0.05) peak latencies compared with the PD-RBD group. Total cVEMP scores were higher in the PD + RBD group than in the iRBD group (p = 0.033). In PD patients, phasic RSWA was correlated with total cVEMP scores (p = 0.003), and tonic RSWA was correlated with left oVEMP scores (p = 0.013). CONCLUSIONS: Brainstem neurophysiology as evidenced by altered VEMPs in patients with PD and iRBD could reflect disease evolvement. Moreover, VEMPs alterations may vary depending on the presence of RBD in PD patients. The associations between altered RSWA and VEMP parameters highlight the meaningfulness of detecting brainstem dysfunction in early-stage PD.