REM sleep behavior disorder correlates with constipation in de novo Chinese Parkinson's disease patients.

BACKGROUND: Constipation, rapid eye movement sleep behavior disorder (RBD) and hyposmia are common prodromal symptoms of Parkinson's disease (PD), and they may represent two distinct types of disease origin, from the body or the brain. Our study aimed to compare the clinical characteristics of de novo PD patients with and without constipation and identify which prodromal symptoms were associated with constipation. METHODS: A total of 111 de novo, drug-naïve Chinese PD patients were consecutively enrolled from Jan 2017 to Sept 2021. Patients were classified into PD with and without constipation based on item 5 of the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction (SCOPA-AUT). The demographic data, motor, and non-motor symptoms were compared between the two groups. The associated factors of constipation were analyzed by the multivariate logistic regression analysis. RESULTS: In total, 44.1% (n = 49) of de novo PD patients had constipation. PD patients with constipation were older (p = 0.028), had higher proportions of Hoehn and Yahr (H-Y) stage [Formula: see text] 2 (p = 0.002), clinical possible RBD (cpRBD) (p = 0.002) and depression (p = 0.023), as well as marginal increase of hyposmia (p = 0.058) and freezing of gait (p = 0.069). After adjusting for H-Y stage and other confounding factors, cpRBD (OR = 3.508, p = 0.009), rather than hyposmia or depression, was closely related to constipation in de novo Chinese PD patients. CONCLUSIONS: RBD is closely associated with constipation in de novo Chinese PD patients. Our results support the theory that prodromal symptoms that represent the same pathological origin are closely related to each other.

Oculomotor impairments in de novo Parkinson's disease.

Objective: Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson's disease (PD). It is still elusive whether oculomotor performance is impaired or has clinical value in early PD. This study aims to explore oculomotor performance in newly diagnosed, drug-naïve PD and its correlation with clinical phenotype. Methods: Seventy-five patients with de novo PD, 75 patients with essential tremor (ET), and 46 gender-and age-matched healthy controls (HCs) were included in this cross-sectional study. All subjects underwent oculomotor test via videonystagmography. Visually guided saccade latency, saccadic accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of the horizontal axis were compared among the three groups. Patients with PD also received detailed motor and non-motor evaluation by serial scales. The association between key oculomotor parameters and clinical phenotypes were explored in PD patients. Results: Both de novo PD and ET patients showed prolonged saccadic latency and decreased saccadic accuracy relative to HCs. SPEM gain in PD was uniformly reduced at each frequency. SPEM gain at 0.4 Hz was also decreased in ET compared with HCs. However, there was no significant difference of oculomotor parameters between de novo PD and ET patients. Furthermore, prolonged saccadic latency was correlated with long disease duration, whereas decreased SPEM gain was associated with severe motor symptoms in de novo PD patients. Conclusion: Ocular movements are impaired in de novo, drug naïve PD patients; these changes could be indicators for disease progression in PD.

Plasma miR-153 and miR-223 Levels as Potential Biomarkers in Parkinson's Disease.

Background: Small molecule RNAs (miRNAs) could induce downregulation of α-synuclein (SNCA) expression by binding the 3' untranslated region of SNCA, thus playing an important role in the pathogenesis of Parkinson's disease (PD). Recent studies suggest that SNCA-related miRNAs in saliva are promising PD biomarkers. Research on those miRNAs in plasma is rare in patients with PD. Objective: To detect the plasma expression levels of three SNCA related miRNAs (miR-7, miR-153, and miR-223) in PD, and to explore their diagnostic value and associations with clinical phenotype. Methods: MiR-7, miR-153, and miR-223 levels were detected in the plasma of 75 PD patients and 73 normal controls (NCs) via real-time quantitative polymerase chain reaction. The receiver operating characteristic (ROC) curves were delineated to evaluate their diagnostic value in PD. In addition, their associations with demographic, key motor, and non-motor symptoms were explored by serial scales. Results: The expression levels of plasma miR-153 and miR-223 were significantly decreased in patients with PD relative to NCs. The area under the ROC curve separating PD from NCs was 63.1% for miR-153 and 86.2% for miR-223, respectively. The plasma miR-153 level in de novo PD was lower than that in treated patients (p = 0.006), its level increased gradually with disease duration (r = 0.358, p = 0.002) and Unified Parkinson's Disease Rating Scale Part III score (r = 0.264, p = 0.022). Plasma miR-223 level was decreased in patients with clinical possible rapid eye movement sleep behavior disorder (cpRBD) compared with those without cpRBD (p < 0.001), and its level was negatively associated with RBDSQ score (r = -0.334, p = 0.003). Multiple linear regression analysis revealed that disease duration (p = 0.049) was the independently associated factor of miR-153 level; whereas, RBDSQ (p = 0.009) was related to miR-223 level in PD. Conclusion: Plasma miR-153 and miR-223 levels could be potential biomarkers of PD.

Autobiographical memory disturbance in depression.

It is found that overgeneral Autobiographic Memory (AM) disturbance is related to affective disorder such as depression. This article reviewed the conception and mechanism of overgeneral AM, which including Affection Regulation, Functional Avoidance, Capture & Rumination, Impaired Executive Control and the CaR-FA-X model. The relationship between depression and overgeneral AM is also reviewed, in both adult and adolescent patients, overgeneral AM is a risk factor of depressive disorder and AM deficits might be trait-like in depressive patients.

Application of the Chinese Version of the Montreal Cognitive Assessment-Basic for Assessing Mild Cognitive Impairment in Parkinson's Disease.

Mild cognitive impairment (MCI) is a common and pivotal non-motor symptom in Parkinson's disease (PD). It is necessary to use the appropriate tools to characterize the cognitive profiles and identify the subjects at risk of MCI in clinical practice. A cohort of 207 non-demented patients with PD and 52 age- and gender-matched cognitively normal controls (NCs) underwent the Chinese Version of Montreal Cognitive Assessment-Basic (MoCA-BC) evaluation. Patients with PD also received detailed motor and non-motor evaluation by serial scales. Cognitive profiles were investigated in patients with PD-MCI, relative to patients with normal cognition (PD-NC) and cognitively NCs. In addition, differences in demography, major motor and non-motor symptoms were compared between patients with PD-MCI and PD-NC. There were 70 patients with PD-MCI, occupying 33.8% of the total patients. Patients with PD-MCI had impairment in multiple cognitive domains, especially in executive function, memory and visuospatial function on MoCA-BC, relative to cognitively NCs or PD-NC. Compared with PD-NC patients, PD-MCI patients were older (p = 0.002) and had a later onset age (p = 0.007) and higher score of the Unified Parkinson's Disease Rating Scale (UPDRS) part III (p = 0.001). The positive rate of clinical possible rapid eye movement sleep behavior disorder (cpRBD) in the PD-MCI group was significantly increased relative to the PD-NC group (p = 0.003). Multivariate logistic analysis showed that older age (OR = 1.06; p = 0.012), higher score of UPDRS-III (OR = 1.03; p = 0.018) and the presence of cpRBD (OR = 2.10; p = 0.037) were independently associated factors of MCI in patients with PD. In conclusion, executive function, memory and visuospatial function are the main impaired cognitive profiles in PD-MCI via MoCA-BC. Aging, motor severity and RBD may be independently related factors of MCI in PD.

Clinical and Oculomotor Correlates With Freezing of Gait in a Chinese Cohort of Parkinson's Disease Patients.

Accumulating evidence suggests that freezing of gait (FOG) is a unique gait disturbance in Parkinson's disease (PD), and its pathophysiology is not fully elucidated. The present study aims to investigate the clinical and oculomotor associations with FOG in Chinese PD patients. From Jan 2017 to Dec 2019, a total of 210 PD patients were consecutively registered for FOG evaluation based on item-3 of the Freezing of Gait Questionnaire (FOGQ). We explored the demographic, motor, and non-motor symptom differences in FOG positive (PD+FOG, n = 45) vs. negative (PD-FOG, n = 165) group. In addition, 40 PD patients and 37 healthy controls (HC) also underwent oculomotor test via videonystagmography (VNG). Visually guided saccade (VGS) latency, saccade accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of horizontal axis were compared among PD+FOG (n = 20), PD-FOG (n = 20), and HC (n = 37). Compared with PD-FOG, PD+FOG had longer disease duration, more severe motor symptoms, lower cognitive scores, more severe depressive and autonomic impairments, as well as higher daily levodopa equivalent dosage. FOG occurred more frequently in patients with wearing-off. VNG subgroup analysis demonstrated that PD+FOG had prolonged saccade latency and decreased saccade accuracy relative to PD-FOG or HC. SPEM gain at 0.1 and 0.2 Hz was also decreased in PD+FOG compared with HC. Furthermore, prolonged saccade latency was correlated with higher FOGQ scores in PD patients. Our results verify that PD with FOG patients suffer from more severe motor and non-motor symptoms, indicating more extensive neurodegeneration. Prolonged saccade latency could be a practical oculomotor parameter both for identification and progression of FOG in PD.

RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer's disease.

BACKGROUND: Exosomes are lipid-bilayer enclosed nano-sized vesicles that transfer functional cellular proteins, mRNA and miRNAs. Mesenchymal stem cells (MSCs) derived exosomes have been demonstrated to prevent memory deficits in the animal model of Alzheimer's disease (AD). However, the intravenously injected exosomes could be abundantly tracked in other organs except for the targeted regions in the brain. Here, we proposed the use of central nervous system-specific rabies viral glycoprotein (RVG) peptide to target intravenously-infused exosomes derived from MSCs (MSC-Exo) to the brain of transgenic APP/PS1 mice. MSC-Exo were conjugated with RVG through a DOPE-NHS linker. RESULTS: RVG-tagged MSC-Exo exhibited improved targeting to the cortex and hippocampus after being administered intravenously. Compared with the group administered MSC-Exo, in the group administered RVG-conjugated MSC-Exo (MSC-RVG-Exo) plaque deposition and Aß levels were sharply decreased and activation of astrocytes was obviously reduced. The brain targeted exosomes derived from MSCs was better than unmodified exosomes to improve cognitive function in APP/PS1 mice according to Morris water maze test. Additionally, although MSC-Exo injected intravenously reduced the expression of pro-inflammatory mediators TNF-α, IL-ß, and IL-6, but the changes of anti-inflammatory factors IL-10 and IL-13 were not obvious. However, administration of MSC-RVG-Exo significantly reduced the levels of TNF-α, IL-ß, and IL-6 while significantly raised the levels of IL-10, IL-4 and IL-13. CONCLUSIONS: Taken together, our results demonstrated a novel method for increasing delivery of exosomes for treatment of AD. By targeting exosomes to the cortex and hippocampus of AD mouse, there was a significant improvement in learning and memory capabilities with reduced plaque deposition and Aß levels, and normalized levels of inflammatory cytokines.

Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aß levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1ß); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aß levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1ß, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Validation of 5-item and 2-item questionnaires in Chinese version of Dizziness Handicap Inventory for screening objective benign paroxysmal positional vertigo.

As possible candidate screening instruments for benign paroxysmal positional vertigo (BPPV), studies to validate the Dizziness Handicap Inventory (DHI) sub-scale (5-item and 2-item) and total scores are rare in China. From May 2014 to December 2014, 108(55 with and 53 without BPPV) patients complaining of episodic vertigo in the past week from a vertigo outpatient clinic were enrolled for DHI evaluation, as well as demographic and other clinical data. Objective BPPV was subsequently determined by positional evoking maneuvers under the record of optical Frenzel glasses. Cronbach's coefficient α was used to evaluate the reliability of psychometric scales. The validity of DHI total, 5-item and 2-item questionnaires to screen for BPPV was assessed by receiver operating characteristic (ROC) curves. It revealed that the DHI 5-item questionnaire had good internal consistency (Cronbach's coefficient α = 0.72). Area under the curve of total DHI, 5-item and 2-item scores for discriminating BPPV from those without was 0.678 (95 % CI 0.578-0.778), 0.873(95 % CI 0.807-0.940) and 0.895(95 % CI 0.836-0.953), respectively. It revealed 74.5 % sensitivity and 88.7 % specificity in separating BPPV and those without, with a cutoff value of 12 in the 5-item questionnaire. The corresponding rate of sensitivity and specificity was 78.2 and 88.7 %, respectively, with a cutoff value of 6 in 2-item questionnaire. The present study indicated that both 5-item and 2-item questionnaires in the Chinese version of DHI may be more valid than DHI total score for screening objective BPPV and merit further application in clinical practice in China.

[Long term depression of the recurrent inhibition of monosynaptic spinal reflexes after sciatic nerve crush in adult rats].

Sciatic nerve injury is a common disease of peripheral nerve in clinic. After nerve injury, there are many dysfunctions in motoneurons and muscles following regeneration. Previous studies mostly investigated the aspects related to the injured nerve, and the effect on the recurrent inhibition (RI) pathway of spine following regeneration was not fully understood. Following reinnervation after temporary sciatic nerve crush, the functional alteration of RI was studied. In adult rats, RI between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes (MSRs) elicited from the cut dorsal roots and recorded from either the LG-S or MG nerves by antidromic stimulation of the synergist muscle nerve. The following results were obtained. (1) The RI of MSRs in rats was almost lost (<5 weeks) after sciatic nerve crush. Although the RI partially recovered following reinnervation (6 weeks), it remained permanently depressed (up to 14 weeks). (2) Sciatic nerve crush on one side did not affect the contralateral RI. (3) Sciatic nerve crush did not induce any motoneuron loss revealed by immunohistochemistry. Peripheral nerve temporary disconnection causes long term alterations in RI pathway which make up motoneuron's function enhance for the alteration of muscle power and suggests that peripheral nerve injury induces long term plastic changes in the spinal motoneuron circuitry.