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Cognitive decline in Parkinson's disease (PD) is prevalent, insidious, and burdensome during the progression of the disease.We aimed to find transcriptome-wide biomarkers in blood to predict cognitive decline and identify patients at high risk with cognitive impairment in PD.We carried out joint modeling analysis to characterize transcriptome-wide longitudinal gene expression and its association with the progression of mild cognitive impairment (MCI) in PD patients. The average time-dependent area under the curves (AUCs) were used for evaluating the accuracy of the significant joint models. A cognitive survival score (CogSs) derived from joint model was leveraged to predict the occurrence of MCI. All predicting models were built in a discovery cohort with 272 patients and replicated in an independent cohort with 177 patients.We identified five longitudinal varied expression of transcripts that were significantly associated with MCI progression in patients with PD. The most significant transcript IGLC1 joint model accurately predicted the progression of MCI in PD patients in the discovery and replication cohorts (average time-dependent AUCs0.82). The CogSs derived from the optimal IGLC1 joint model had a high accuracy at early study stage in both cohorts (AUC ≥0.91).Our transcriptome-wide joint modeling analysis uncovered five blood-based transcripts related to cognitive decline in PD. The joint models will serve as a useful resource for clinicians and researchers to screen PD patients with high risk of development of cognitive impairment and pave the path for Parkinson's personalized medicine. © 2022 International Parkinson and Movement Disorder Society.

Aims This follow‐up study aimed to examine the 8‐year efficacy and safety of subthalamic nucleus (STN) deep brain stimulation (DBS) for patients with Parkinson's disease (PD) in southern China. Methods The follow‐up data of 10 patients with PD undergoing STN‐DBS were analyzed. Motor symptoms were assessed before and 1, 3, 5, and 8 years after the surgery with stimulation‐on in both off‐medication (off‐med) and on‐medication (on‐med) status using the Unified Parkinson's disease Rating Scale Part III. The quality of life was assessed using the 39‐item Parkinson's Disease Questionnaire. The sleep, cognition, and emotion were evaluated using a series of nonmotor scales. Levodopa equivalent daily dose (LEDD) and stimulation parameters were recorded at each follow‐up. Results The motor symptoms were improved by 50.9%, 37.7%, 36.7%, and 37.3% in 1, 3, 5, and 8 years, respectively, in the off‐med / stimulation‐on status compared with the baseline. The quality of life improved by 39.7% and 56.1% in 1 and 3 years, respectively, but declined to the preoperative level thereafter. The sleep, cognition, and emotion were mostly unchanged. LEDD reduced from 708.1 ± 172.5 mg to 330 ± 207.8 mg in 8 years. The stimulation parameters, including amplitude, pulse width, and frequency, were 2.77 ± 0.49 V, 71.3 ± 12.8 μs, and 121.5 ± 21 Hz, respectively, in 8 years. Conclusion Long‐term therapeutic efficacy of STN‐DBS could be achieved even with relatively low stimulation intensity and medication dosage for PD patients in southern China. Motor improvement and medication reduction were maintained through the 8‐year follow‐up, but improvement in quality of life lasted for only 3 years. No definite changes was found in nonmotor symptoms after STN‐DBS., Long‐term therapeutic efficacy of STN DBS could be achieved even with relatively low stimulation intensity and medication dosage for PD patients in southern China.

This case report is the first to describe the detection of antibodies against inositol 1,4,5-trisphosphate receptor 1 (ITPR1, I3PR) in a patient diagnosed with autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. ITPR1 is known as one of the Purkinje cell antibodies present in autoimmune cerebellar ataxia (ACA). Here, we described the association between autoimmune GFAP astrocytopathy and autoimmune cerebellar disease (ACD).Demographic features, clinical characteristics, cerebrospinal fluid (CSF) parameters and neuroimaging findings were collected from this patient. Specifically, antibodies against GFAP and other proteins associated with neurological disorders were measured by immunofluorescence staining in both serum and CSF samples.A 52-year-old woman was diagnosed with autoimmune inflammatory meningoencephalitis. She presented with cognitive dysfunction, psychiatric/behavioral abnormalities and serious insomnia with subacute onset. Brain magnetic resonance imaging (MRI) showed bilateral hyperintensity in the semioval centers on axial images and perivascular linear enhancement oriented radially to the ventricles on sagittal images. GFAP-IgG, oligoclonal bands (OBs), N-methyl-D-aspartate receptor (NMDAR)-IgG and ITPR1-IgG co-existed in her CSF. She responded well to immunoglobulin and steroid treatments.Here, we describe the case of a patient with autoimmune GFAP astrocytopathy whose CSF was positive for ITPR1-IgG; however, she did not show typical ataxia manifestations or cerebellar lesions on her MRI scan. This suggests that ITPR1-IgG is not pathogenic, and the positivity of this antibody in CSF is probably associated with the presence of autoimmune inflammation.

Introduction Propofol is a general anesthetic option for deep brain stimulation (DBS) of the subthalamic nucleus (STN) of patients with Parkinson's disease (PD). However, its effects on STN activity and neuropsychological outcomes are controversial. The optimal propofol anesthesia for asleep DBS is unknown. This study investigated the safety and effectiveness of an optimized propofol anesthesia regimen in asleep DBS. Methods This retrospective study enrolled 68 PD patients undergoing bilateral STN-DBS surgery. All patients received local scalp anesthesia, with (asleep group, n = 35) or without (awake group, n = 33) propofol-remifentanil general anesthesia by target-controlled infusion under electroencephalogram monitoring. The primary outcome was subthalamic neuronal spiking characterization during microelectrode recording. The secondary outcomes were clinical outcomes including motor, cognition, mind, sleep, and quality of life at 6 months. Results Significantly increased delta and theta power were obtained under propofol anesthesia (awake vs. asleep group, mean ± standard deviation; delta: 31.97 ± 9.87 vs. 39.77 ± 10.56, p

Background Limb girdle muscular dystrophy type 2Y (LGMD2Y) is a rare subgroup of limb girdle muscular dystrophy featuring limb-girdle weakness, tendon contracture and cardiac involvement. It is caused by the mutation of TOR1AIP1, which encodes nuclear membrane protein LAP1 (lamina-associated polypeptide 1) and comprises heterogeneous phenotypes. The present study reported a patient with a novel homozygous TOR1AIP1 mutation that presented with selective muscle weakness, which further expanded the phenotype of LGMD2Y- and TOR1AIP1-associated nuclear envelopathies. Case presentation A 40-year-old male presented with Achilles tendon contracture and muscle weakness that bothered him from 8 years old. While the strength of his distal and proximal upper limbs was severely impaired, the function of his lower limbs was relatively spared. Muscle pathology showed dystrophic features, and electron microscopy showed ultrastructural abnormalities of disrupted muscle nuclei envelopes. Whole-exome sequencing showed a frameshift mutation in TOR1AIP1 (c.98dupC). Conclusion We reported a novel mild phenotype of LGMD2Y with relatively selective distal upper limb weakness and joint contracture and revealed the heterogeneity of LGDM2Y and the role of the LAP1 isoform by literature review.

Background White matter hyperintensities (WMHs) in the cholinergic pathways are associated with cognitive impairment in Parkinson's disease (PD). This study aimed to investigate the role of WMHs within the cholinergic pathways in cognitive performance following bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with PD. Methods 38 patients with PD who underwent bilateral STN DBS were assessed using the Cholinergic Pathways Hyperintensities Scale (CHIPS) with magnetic resonance imaging before surgery. Their cognitive statuses were evaluated pre-surgically and 6 months, 1 year, and 2 years post operation. The correlations between the CHIPS score and cognitive performance were analyzed. The differences in cognitive performance before and after the surgery between the high-CHIPS and low-CHIPS groups were also compared. Results The CHIPS score in patients with PD negatively correlated with the general cognition assessed using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) both at baseline and after DBS. No correlation was found between the CHIPS score and the change of MMSE and MoCA scores after DBS. No significant difference was observed in the change in cognitive performance after the surgery between the high and low-CHIPS groups. Conclusion The severity of cholinergic WMHs was correlated with the cognition in patients with PD both before and after the STN DBS. However, it does not correlate with the cognitive change in patients with PD after bilateral STN-DBS.

Objective measurement of walking speed and gait deficits are an important clinical tool in chronic illness management. We previously reported in Parkinson’s disease that different types of gait tests can now be implemented and administered in the clinic or at home using Ambulosono smartphone-sensor technology, whereby movement sensing protocols can be standardized under voice instruction. However, a common challenge that remains for such wearable sensor systems is how meaningful data can be extracted from seemingly “noisy” raw sensor data, and do so with a high level of accuracy and efficiency. Here, we describe a novel pattern recognition algorithm for the automated detection of gait-cycle breakdown and freezing episodes. Ambulosono-gait-cycle-breakdown-and-freezing-detection (Free-D) integrates a nonlinear m-dimensional phase-space data extraction method with machine learning and Monte Carlo analysis for model building and pattern generalization. We first trained Free-D using a small number of data samples obtained from thirty participants during freezing of gait tests. We then tested the accuracy of Free-D via Monte Carlo cross-validation. We found Free-D to be remarkably effective at detecting gait-cycle breakdown, with mode error rates of 0% and mean error rates

Astrocytes, which have various important functions, have previously been associated with Parkinsons disease (PD), particularly in 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of PD. MPP+ is the toxic metabolite of MPTP and is generated by the enzymatic activity of monoamine oxidase B, which is predominantly located in astrocytes. MPP+ acts as a mitochondrial complex I inhibitor. Autophagy is an evolutionarily conserved self-digestion pathway in eukaryotic cells, which occurs in response to various types of stress, including starvation and oxidative stress. Lithium treatment has previously been shown to induce autophagy in astrocytes by inhibiting the enzyme inositol monophosphatase, which may aid in the treatment of neurodegenerative diseases, including Huntington's disease, in which the toxic protein is an autophagy substrate. Therefore, using western blotting and MTT assay, the present study aimed to investigate the protective effects of lithium-induced autophagy against astrocyte injury caused by MPP+ treatment, as well as the potential underlying mechanisms. The results of the present study suggested that lithium was able to induce autophagy in astrocytes treated with MPP+, and this likely occurred via activation of the phosphoinositide 3-kinase/AKT pathway.

Supplemental Digital Content is available in the text, The authors aimed to determine whether early changes in fibrinogen were associated with the efficacy of intravenous thrombolysis at 24 hours after alteplase infusion. The authors retrospectively reviewed a consecutive series of 56 patients with acute ischemic stroke treated with alteplase in the clinical database. The fibrinogen levels were monitored at the first and fourth hours after alteplase infusion. Additionally, the National Institutes of Health Stroke Scale (NIHSS) scores were recorded to define the short-term efficacy of intravenous thrombolysis before and 24 hours after alteplase infusion. The patients were distributed into amelioration, deterioration, and inefficiency groups according the short-term efficacy of intravenous thrombolysis. One-way ANOVA and post hoc analysis were used to compare the differences in the clinical characteristics among these groups. The relationships among changes in the fibrinogen levels, other potential risk factors, and NIHSS scores were examined using logistic regression analysis. Fifty-two patients (mean age, 65.71 ± 11.04 years; male, 57.7%) were finally enrolled in the study. The median NIHSS of these patients was 11 (range, 2–23), and the mean time from symptom onset to thrombolysis was 187.17 ± 67.53 minutes. The frequency of hypertension in the deterioration group was significantly higher than that in the inefficiency group (P = .01). Changes in the fibrinogen level were more significant in the amelioration group than in the other groups (P

Background: Subthalamic nucleus deep brain stimulation (STN DBS) is effective against advanced Parkinson′s disease (PD), allowing dramatic improvement of Parkinsonism, in addition to a significant reduction in medication. Here we aimed to investigate the long-term effect of STN DBS in Chinese PD patients, which has not been thoroughly studied in China. Methods: Ten PD patients were assessed before DBS and followed up 1, 3, and 5 years later using Unified Parkinson′s Disease Rating Scale Part III (UPDRS III), Parkinson′s Disease Questionnatire-39, Parkinson′s Disease Sleep Scale-Chinese Version, Mini-mental State Examination, Montreal Cognitive Assessment, Hamilton Anxiety Scale and Hamilton Depression Scale. Stimulation parameters and drug dosages were recorded at each follow-up. Data were analyzed using the ANOVA for repeated measures. Results: In the "off" state (off medication), DBS improved UPDRS III scores by 35.87% in 5 years, compared with preoperative baseline (P < 0.001). In the "on" state (on medication), motor scores at 5 years were similar to the results of preoperative levodopa challenge test. The quality of life is improved by 58.18% (P < 0.001) from baseline to 3 years and gradually declined afterward. Sleep, cognition, and emotion were mostly unchanged. Levodopa equivalent daily dose was reduced from 660.4 ± 210.1 mg at baseline to 310.6 ± 158.4 mg at 5 years (by 52.96%, P < 0.001). The average pulse width, frequency and amplitude at 5 years were 75.0 ± 18.21 μs, 138.5 ± 19.34 Hz, and 2.68 ± 0.43 V, respectively. Conclusions: STN DBS is an effective intervention for PD, although associated with a slightly diminished efficacy after 5 years. Compared with other studies, patients in our study required lower voltage and medication for satisfactory symptom control.

SummaryAims Neuroinflammation contributed to the pathogenesis of multiple system atrophy (MSA). We aimed to detect the correlation between inflammatory mediators, such as Klotho (Klt), vitamin D (25(OH)D) and homocysteine (Hcy), and disease severity among MSA patients. Methods A total of 53 MSA patients, 65 PD patients, and 62 normal subjects were recruited in our cross-sectional study. Serum Klotho (Klt), vitamin D (25(OH)D), and homocysteine (Hcy) levels were measured. Several scales were undertaken to assess the motor/nonmotor function and cognitive impairment of MSA. Results Decreased Serum Klt and 25(OH)D levels and increased Hcy levels were found in patients with MSA, compared with healthy controls. These results were more pronounced in male patients. The three biomarkers also displayed differences between MSA and PD subgroups based on genders. Interestingly, Klt, 25(OH)D and Hcy levels associated with cognition impairment, motor dysfunction, mood/cardiovascular disorder among MSA patients. In addition, the combination of Klt, 25(OH)D and Hcy had a better diagnostic ability for distinguishing MSA patients from healthy subjects, as well as distinguishing male MSA patients from male PD patients. Conclusion This study suggested that Klt, 25(OH)D and Hcy levels could be a potential predictor for MSA severity evaluation.

Background Meta-analyses and cohort studies have shown blood trace mineral concentration may be associated with incidence risk of lung cancer. However, there is no comprehensive study to investigate causal relationship between blood trace mineral and lung cancer. The purpose of this study is to inspect the causal effect of blood trace mineral concentration on lung cancer with Mendelian randomization (MR) method. Methods With a two‐sample MR approach, we analyzed the summary data of zinc, selenium, copper from the Queensland Institute of Medical Research(QIMR, 2603 individuals) and The Avon Longitudinal Study of Parents and Children (ALSPAC, 10115 individuals), data of calcium from discovery cohorts(39400 individuals) and replication cohorts(21875 individuals), data of iron from Genetics of Iron Status Consortium(23986 individuals), data of lung cancer patients from Consortium and International Lung Cancer Consortium (ILCCO, 11 348 lung cancer cases and 15 861 controls) to assess the possible causal relationship of blood trace mineral concentration on the risk of lung cancer. Results Our results indicated that genetically predicted higher blood copper level has a positive association with lung cancer, each per-unit increase in copper is associated with a 14% increase in the risk of lung cancer (odds ratio [OR]: 1.14, 95% CI = 1.01‐1.29; P = 0.04). Additionally, blood calcium, zinc, selenium, iron were not causal factors for lung cancer. Conclusions Genetically higher blood copper is positively associated with risk of lung cancer, and more work is needed to examine the potential mechanism. Legal entity responsible for the study The authors. Funding National Key RD Science and Technology Program of Guangdong (Grant No. 2017B020227001, 2016A020215084); Science and Technology Program of Guangzhou (Grant No. 201607020031, 201400000001-2); Chinese National Natural Science Foundation project (Grant No. 81772476, 81572659,81602011); Pearl River Nova Program of Guangzhou (Grant No. 201610010048); National Natural Science Funds for Young Scholars of China (Grant No. 81502355). Disclosure All authors have declared no conflicts of interest.

Patients with stroke suffer from nutrition impairments and often rely on enteral nutrition (EN), which is associated with respiratory complications such as regurgitation and aspiration.To evaluate the incidence of regurgitation and aspiration in patients with severe stroke infused with different volumes of EN.A randomized controlled trial was conducted on 210 patients with severe stroke undergoing EN therapy. Patients were randomly assigned into two groups. Subjects in the treatment group received EN with an initial rate defined according to the total volume and the infusion rate was adjusted based on gastric residual volume (GRV) assessed every 4 hours. Subjects of the control group received EN without monitoring the GRV and reached the target infusion volume within 72 hours. The incidence of reflux and aspiration was recorded.The incidences of regurgitation and aspiration were significantly lower in treatment group (6.3% and 7.9%, respectively) than control group (18.8% and 17.5%, respectively). In the treatment group, 1 patient developed regurgitation while 2 developed aspiration when EN was 500 mL. When EN increased to 1000 mL, 2 patients developed regurgitation and 2 developed aspiration, and 5 patients developed regurgitation and 6 had aspiration when EN was 1500 mL. There was no significant difference in the risk of reflux and aspiration when total volume of EN increased from 500 to 1500 mL.During EN therapy for patients with stroke, using feeding pump with a continuous infusion for 20 hours and adjusting infusion rate based on GRV could reduce the incidence of respiratory complications.背景：脑卒中患者容易伴发营养不良，通常依靠肠内营养（EN）来维持。但 肠内营养也存在反流和误吸等呼吸系统方面的并发症。目的：探讨重症脑卒中 患者在不同EN 输注总量之间反流及误吸风险的差异。方法：选择重症脑卒中 患者210 例进行随机对照研究，患者随机分为2 组：治疗组患者初始速度根据 EN 总量调节，输注过程中通过每4 小时测定胃残留量（GRV）的情况进行调 速。对照组患者不监测GRV，在72 小时内缓慢增速至EN 目标量。比较两组 患者反流和误吸的风险。结果：治疗组患者反流和误吸的发生率分别为6.3% 和7.9%显著低于对照组的18.8% 和17.5%。在治疗组中，500 mL 输注时有1 例患者发生反流和2 例患者发生误吸；当输注量增至1000 mL 时，2 例患者发 生反流，2 例患者发生误吸；1500 mL 输注时，5 例患者发生反流，6 例患者发 生误吸。EN 输注总量从500 mL 增至1500 mL 时，并未显著增加反流和误吸的 风险。结论：脑卒中患者EN 治疗过程中，采用以营养泵持续20 小时匀速输 注，初始速度按总量调节，输注过程中通过监测GRV 调整速度可显著减少呼 吸系统的并发症。.

Deep brain stimulation of the subthalamic nucleus is recognized as the most effective treatment for moderate and advanced Parkinson's disease. Programming of the stimulation parameters is important for maintaining the efficacy of deep brain stimulation. Voltage is considered to be the most effective programming parameter. The present study is a retrospective analysis of six patients with Parkinson's disease (four men and two women, aged 37-65 years), who underwent bilateral deep brain stimulation of the subthalamic nucleus at the First Affiliated Hospital of Sun Yat-sen University, China, and who subsequently adjusted only the stimulation voltage. We evaluated motor symptom severity using the Unified Parkinson's Disease Rating Scale Part III, symptom progression using the Hoehn and Yahr scale, and the levodopa equivalent daily dose, before surgery and 1 and 2 years after surgery. The 2-year follow-up results show that rigidity and tremor improved, and clinical symptoms were reduced, while pulse width was maintained at 60 μs and frequency at 130 Hz. Voltage adjustment alone is particularly suitable for patients who cannot tolerate multiparameter program adjustment. Levodopa equivalent daily dose was markedly reduced 1 and 2 years after surgery compared with baseline. Our results confirm that rigidity, tremor and bradykinesia can be best alleviated by voltage adjustment. The trial was registered at ClinicalTrials.gov (identifier: NCT01934881).

Background: Leucine-rich repeat kinase 2 (LRRK2) S1647T has been identified as a risk variant for Parkinson’s disease (PD) in Han Chinese. Methods: To replicate the association of LRRK2 S1647T with risk of PD, we conducted a case–control study of this variant involving 406 PD subjects and 412 controls from southern mainland China. Results: The results showed that the frequency of A allele was higher in patients with PD (OR = 1.238, 95% CI: 1.015–1.510, P = 0.035) compared to controls. In a multivariate logistic regression analysis with the disease group (patients with PD vs. controls) as the dependent variable and genotype as an independent factor adjusting for the effect of age and gender, the homozygous S1647T genotype (AA) was associated with an increased risk of PD (OR = 1.815, 95% CI:1.270–2.594, P = 0.001). The pooled analysis of present data and the data from the previous work demonstrated that the frequency of A allele was higher in patients with PD (OR = 1.2, 95% CI: 1.09–1.32, P

Background Cognitive impairments have been reported to be common in Parkinson’s disease (PD) without dementia, which occur not only in the late stages of PD, but also in the early and middle stages. Until now, no reports on the profile of cognitive impairment in Chinese non-demented PD population have been published yet. Different ethnic groups should be assessed to improve evaluation of cognitive impairment in clinical practice. The aims of this study are to estimate the frequencies and profile of cognitive impairments and to explore the risk factors of cognitive impairments in Han Chinese non-demented PD patients at early and middle stages. Methods Eighty non-demented PD patients in early and middle stages and 86 healthy controls were invited to participate in this study. Neuropsychological batteries testing executive function, visuospatial function, memory and attention were evaluated. Cognitive impairments were defined as impaired performance in at least one cognitive domain. Results Neuropsychological batteries detected 30 cases with executive dysfunction, 27 cases with memory impairment, eight cases with visuospatial dysfunction and seven cases with attention impairment. As many as 48 cases (60%) of PD patients presented cognitive impairment. Logistic regression analysis indicated that education level and Hoehn & Yahr stage were associated with cognitive impairment in PD. Conclusions Cognitive impairment is common in the early and middle stages of PD without dementia; executive function is the most common domain impaired in a Chinese PD population. Cognitive impairment might be predicted by lower education level and higher Hoehn and Yahr stage.

Objective To study the relationship between sleep disturbances and symptoms in patients with Parkinson’s disease (PD). Methods The Parkinson’s Disease Sleep Scale-Chinese Version (PDSS-CV) was used to evaluate the sleep disturbances of PD patients in a cross sectional study. The Unified Parkinson’s Disease Rating Scale (UPDRS) parts II-IV, and the Hoehn & Yahr (H&Y) stage were used to determine the level of motor function in PD and the severity of PD. The Spearman correlation and a multiple regression analysis were used to identify the relationship between sleep disturbances and symptoms of PD. The quantities derived from the UPDRS and the H&Y stage and disease duration were compared between groups of patients either with or without sleep disturbances identified by the PDSS. This study was conducted from December 2011 to March 2012 at the First Affiliated Hospital of Sun Yat-sen University, in Guangzhou. Results A total of 136 PD patients were included in this study. The overall total PDSS score in PD patients was 107.58 ± 23.35 points (range: 30–146). There were significant differences in the disease duration, the H&Y stage, and the UPDRS section subscores between groups of patients either with or without sleep disturbances (Kruskal-Wallis Test, p