Altered immune pathways in patients of temporal lobe epilepsy with and without hippocampal sclerosis.

Over the past decades, the immune responses have been suspected of participating in the mechanisms for epilepsy. To assess the immune related pathway in temporal lobe epilepsy (TLE), we explored the altered immune pathways in TLE patients with and without hippocampal sclerosis (HS). We analyzed RNA-seq data from 3 TLE-HS and 3 TLE-nonHS patients, including identification of differentially expressed RNA, function pathway enrichment, the protein-protein interaction network and construction of ceRNA regulatory network. We illustrated the immune related landscape of molecules and pathways on human TLE-HS. Also, we identified several differential immune related genes like HSP90AA1 and SOD1 in TLE-HS patients. Further ceRNA regulatory network analysis found SOX2-OT connected to miR-671-5p and upregulated the target gene SPP1 in TLE-HS patients. Also, we identified both SOX2-OT and SPP1 were significantly upregulated in five different databases including TLE-HS patients and animal models. Our findings established the first immune related genes and possible regulatory pathways in TLE-HS patients and animal models, which provided a novel insight into disease pathogenesis in both patients and animal models. The immune related SOX2-OT/miR-671-5p/SPP1 axis may be the potential therapeutic target for TLE-HS.

An Interpretable Deep Learning Optimized Wearable Daily Detection System for Parkinson's Disease.

Walking detection in the daily life of patients with Parkinson's disease (PD) is of great significance for tracking the progress of the disease. This study aims to implement an accurate, objective, and passive detection algorithm optimized based on an interpretable deep learning architecture for the daily walking of patients with PD and to explore the most representative spatiotemporal motor features. Five inertial measurement units attached to the wrist, ankle, and waist are used to collect motion data from 100 subjects during a 10-meter walking test. The raw data of each sensor are subjected to the continuous wavelet transform to train the classification model of the constructed 6-channel convolutional neural network (CNN). The results show that the sensor located at the waist has the best classification performance with an accuracy of 98.01%±0.85% and the area under the receiver operating characteristic curve (AUC) of 0.9981±0.0017 under ten-fold cross-validation. The gradient-weighted class activation mapping shows that the feature points with greater contribution to PD were concentrated in the lower frequency band (0.5~3Hz) compared with healthy controls. The visual maps of the 3D CNN show that only three out of the six time series have a greater contribution, which is used as a basis to further optimize the model input, greatly reducing the raw data processing costs (50%) while ensuring its performance (AUC=0.9929±0.0019). To the best of our knowledge, this is the first study to consider the visual interpretation-based optimization of an intelligent classification model in the intelligent diagnosis of PD.

Mutation analysis of the ECE1 gene in late-onset Alzheimer's disease.

We recently identified a rare coding mutation (R186C) in the ECE2 gene in a late-onset AD (LOAD) family, and demonstrated ECE2 is a risk gene for AD development. ECE1 is a homologous enzyme that shares catalytic activity with ECE2. Although ECE1 has been regarded as a potential candidate gene for AD, few studies have investigated the role of ECE1 variants in patients with AD. In this study, we aimed to investigate rare variants in ECE1 in a cohort of 610 patients with LOAD (age of onset ≥65 years). The summary data of ECE1 variants from ChinaMAP database were used as controls (n = 10,588). We found four rare variants (p.R50W, p.A166=, p.R650Q, and p.P751=) in the patients with sporadic LOAD, while we identified a large number of controls carrying rare variants in ECE1. Moreover, there was no significant association between LOAD and non-synonymous rare damaging variants at the gene level. Our results suggest rare coding variants of ECE1 might not play an important role in AD risk in the Chinese population.

Age and Sex Affect Essential Tremor (ET) Plus: Clinical Heterogeneity in ET Based on the National Survey in China.

The new term essential tremor (ET) plus was proposed in the 2018 tremor consensus criteria. The National Survey of Essential Tremor Plus in China, a large multicenter registry study, aimed to evaluate the clinical features of pure ET and ET plus and explore possible factors related to ET plus. All patients with ET underwent neurological examination and neuropsychological assessment at 17 clinical sites. The diagnosis was made according to the 2018 consensus criteria. Clinicodemographic characteristics were analyzed. A total of 1160 patients were included, including 546 patients with pure ET and 614 patients with ET plus. The proportion of females was significantly higher in the ET plus than that in the pure ET (P = 0.001). The age at onset (AAO) of pure ET showed a bimodal distribution, with peaks in the 2nd and 5th decades. However, the AAO of the ET plus group demonstrated a skewed distribution, with a single peak in the 6th decade. Female sex (OR=1.645, P<0.001), older age (OR=1.023, P<0.001), lower educational level (OR=0.934, P<0.001), head tremor (OR=1.457, P<0.001), and higher the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS)-II scores (OR=1.134, P<0.001) were significantly associated with ET plus. Old age and female sex may contribute to ET plus development. Pure ET showed a bimodal distribution for AAO, whereas ET plus showed a unimodal distribution. It remains unclear whether pure ET and ET plus are merely different stages of a single disease or represent distinct disease entities.

An Auxiliary Diagnostic System for Parkinson's Disease Based on Wearable Sensors and Genetic Algorithm Optimized Random Forest.

Parkinson's disease (PD) is a neurodegenerative disorder characterized mainly by motor-related impairment, an accurate, quantitative, and objective diagnosis is an effective way to slow the disease deterioration process. In this paper, a user-friendly auxiliary diagnostic system for PD is constructed based on the upper limb movement conditions of 100 subjects consisting of 50 PD patients and 50 healthy subjects. This system includes wearable sensors that collect upper limb movement data, host computer for data processing and classification, and graphic user interface (GUI). The genetic algorithm optimized random forest classifier is introduced to classify PD and normal states based on the selected optimal features, and the 50 trials leave-one-out cross-validation is used to evaluate the performance of the classifier, with the highest accuracy of 94.4%. The classification accuracy among different upper limb movement tasks and with the different number of sensors are compared, results show that the task with only alternation hand movement also has satisfactory classification accuracy, and sensors on both wrists performance better than one sensor on a single wrist. The utility of the proposed system is illustrated by neurologists with a deployed GUI during the clinical inquiry, opening the possibility for a wide range of applications in the auxiliary diagnosis of PD.

Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia and is characterized by the deposition of extracellular aggregates of amyloid-ß (Aß), the formation of intraneuronal tau neurofibrillary tangles and microglial activation-mediated neuroinflammation. One of the key molecules involved in microglial activation is galectin-3 (Gal-3). In recent years, extensive studies have dissected the mechanisms by which Gal-3 modulates microglial activation, impacting Aß deposition, in both animal models and human studies. In this review article, we focus on the emerging role of Gal-3 in biology and pathobiology, including its origin, its functions in regulating microglial activation and neuroinflammation, and its emergence as a biomarker in AD and other neurodegenerative diseases. These aspects are important to elucidate the involvement of Gal-3 in AD pathogenesis and may provide novel insights into the use of Gal-3 for AD diagnosis and therapy.

Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with Parkinson's disease.

Purpose: This study is to investigate the relationship between thyroid function and Parkinson's disease (PD).Materials and Methods: Totally 77 PD patients were included, who were divided into tremor-dominant-type (TDT), akinetic-rigid-type (ART) and mixed-type (MXT) subgroups. Parkinsonism severity and stage was assessed by modified H-Y stage. Thyroid-stimulating hormone (TSH), fT3 and fT4 levels were detected to analyze thyroid function. Parameters of thyroid homeostasis, including thyroid's secretory capacity (SPINA-GT), the total deiodinase activity (SPINA-GD) and Jostel's TSH index and the thyrotroph thyroid hormone sensitivity index (TTSI), were calculated and compared.Results: Thyroid hormone levels in PD patients were lower than normal controls. Patients with TDT/MXT had significantly higher fT4 level than those with ART. TSH levels were 1.73 ± 0.93 and 2.06 ± 1.04 ulU/ml for patients with TDT/MXT and ART, respectively. The patients in the TDT/MXT group had significantly lower SPINA-GD while significantly higher SPINA-GT than ART group. The fT3 level was significantly higher in early group than advanced group. TSH index in the early group was significantly higher than the advanced group. The fT4 level was negatively correlated with UPDRS motor score. Univariate and multivariable logistic regression analysis indicated that fT4 was positively correlated with PD motor subtype, which disappeared after adjusting for confounding factors. The fT3 level was negatively correlated with PD disease severity, even after adjusting for confounding factors. In female PD patients, fT4 level in TDT/MXT group was significantly higher than ART group. Male PD patients had higher fT4 levels in early patients than advanced patients. Percentage of patients exhibiting ART was decreased significantly in higher fT4 level subgroups. With the increase of TSH index and TTSI, the proportion of advanced PD patients gradually decreased. The proportion of PD patients with TDT/MXT motor subtype gradually increased with the quartiles of SPINA-GT.Conclusion: Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with PD.

Astragalus polysaccharide exerts anti-Parkinson via activating the PI3K/AKT/mTOR pathway to increase cellular autophagy level in vitro.

Astragalus polysaccharide (APS) is a bioactive macromolecule, which has been used to alleviate the development of Parkinson's disease (PD), while its mechanism is still unresolved. As is generally accepted that autophagy has an important link with PD, thus it is reasonable to hypothesize that APS was involved in autophagy pathway for the presence of anti-PD. To verify this hypothesis, PD model was induced by 100 µM 6-hydroxydopamine (6-HODA) in PC12 cells and then treated with different concentration of APS. Results showed that APS could increase cell viability and the level of autophagy, improve the formation of autophagosome, promote the conversion of LC3-I to LC3-II, showing APS could improve autophagy level. Moreover, APS could down-regulate the expression of pAKT and pmTOR, and up-regulate the expression of PTEN. While these proteins are involved in PI3K/AKT/mTOR pathway, we then knocked down (KD) endogenous PI3K protein (the PI3K/AKT/mTOR pathway receptor protein) in PC12 cells. Results showed that these events regulated by APS were reversed in PI3K KD cells, shown that APS activated autophagy through PI3K/AKT/mTOR pathway for treating PD. Altogether, APS has the role of increasing autophagy, and this event was responsible for inhibiting PI3K protein to activate PI3K/AKT/mTOR pathway.

Identification of Alzheimer's disease-associated rare coding variants in the ECE2 gene.

Accumulation of amyloid ß protein (Aß) due to increased generation and/or impaired degradation plays an important role in Alzheimer's disease (AD) pathogenesis. In this report, we describe the identification of rare coding mutations in the endothelin-converting enzyme 2 (ECE2) gene in 1 late-onset AD family, and additional case-control cohort analysis indicates ECE2 variants associated with the risk of developing AD. The 2 mutations (R186C and F751S) located in the peptidase domain in the ECE2 protein were found to severely impair the enzymatic activity of ECE2 in Aß degradation. We further evaluated the effect of the R186C mutation in mutant APP-knockin mice. Overexpression of wild-type ECE2 in the hippocampus reduced amyloid load and plaque formation, and improved learning and memory deficits in the AD model mice. However, the effect was abolished by the R186C mutation in ECE2. Taken together, the results demonstrated that ECE2 peptidase mutations contribute to AD pathogenesis by impairing Aß degradation, and overexpression of ECE2 alleviates AD phenotypes. This study indicates that ECE2 is a risk gene for AD development and pharmacological activation of ECE2 could be a promising strategy for AD treatment.

Mutation screening of the PRRT2 gene for benign epilepsy with centrotemporal spikes in Chinese mainland population.

Proline-rich transmembrane protein 2 gene (PRRT2) mutations are reported to cause common paroxysmal neurological disorders and show a remarkable pleiotropy. Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common epilepsy syndrome in childhood. It is placed among the idiopathic localization related epilepsies. Recently, it was reported that a girl with a PRRT2 mutation c.649_650insC developed infantile focal epilepsy with bilateral spikes which resembled the rolandic spikes. Hereby we performed a comprehensive genetic mutation screening of PRRT2 gene in a cohort of 53 sporadic BECTS patients. None of the 53 sporadic BECTS patients and other 250 controls carried mutations including c.649_650insC in PRRT2. Our data indicated that the PRRT2 mutations might most likely not be associated with BECTS in Chinese mainland population.

Prediction of orthostatic hypotension in multiple system atrophy and Parkinson disease.

Orthostatic hypotension (OH) is common in multiple system atrophy (MSA) and Parkinson disease (PD), generally assessed through a lying-to-standing orthostatic test. However, standing blood pressure may not be available due to orthostatic intolerance or immobilization for such patients. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were successively measured in supine, sitting, and standing positions in patients with MSA and PD. Receiver operating characteristic analysis was used to evaluate diagnostic performance of the drops of sitting SBP or DBP. OH and severe OH were respectively regarded as "gold standard". The drops of SBP in standing position were associated with increased disease severity for MSA and correlated with age for PD. In MSA group, drops in sitting SBP ≥ 14 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH, and drops in sitting SBP ≥ 18 mmHg or DBP ≥ 8 mmHg for severe OH. In PD group, drops in sitting SBP ≥ 10 mmHg or DBP ≥ 6 mmHg had highest validity for prediction of OH. The lying-to-sitting orthostatic test is an alternative method for detection of OH in MSA and PD, especially when standing BP could not be validly measured due to various reasons.

[1H-proton magnetic resonance spectroscopy in patients with multiple system atrophy and cognitive dysfunction].

OBJECTIVE: To detect metabolic changes of bilateral frontal lobe in patients with multiple system atrophy (MSA) and cognitive dysfunction by 1H-proton magnetic resonance spectroscopy (1H-MRS).
 METHODS: N-acetylaspartate (NAA)/creatine(Cr), choline (Cho)/Cr, myoinositol (mI)/Cr in three sides of frontal lobe were detected by 1H-MRS in 48 healthy controls, 23 patients with MSA and cognitive dysfunction and 19 patients with MSA but without cognitive dysfunction.
 RESULTS: NAA/Cr of bilateral frontal lobes in patients with MSA and cognitive dysfunction was significantly decreased compared with MSA patients without cognitive dysfunction and healthy controls (P<0.05). mI/Cr of right frontal lobes was significantly increased in patients with MSA and cognitive dysfunction compared with healthy controls (P<0.05). There was a negative correlation between NAA/Cr of bilateral frontal lobes and duration while a positive correlation between NAA/Cr of bilateral frontal lobes and MoCA score in patients with MSA and cognitive dysfunction.
 CONCLUSION: There is a decrease in NAA/Cr and an increase in mI/Cr in frontal lobes in patients with MSA and cognitive dysfunction, which may be associated with cognitive dysfunction in MSA patients.

High Serum GFAP Levels in SCA3/MJD May Not Correlate with Disease Progression.

Spinocerebellar ataxia type 3(SCA3), also known as Machado-Joseph disease (MJD), is the most frequent subtype of autosomal dominant inherited spinocerebellar ataxias, which caused by the expansion of CAG repeats in the ATXN3 gene. The number of CAG repeats of the abnormal allele determines the rate of disease progression in patients with SCA3/MJD. Markers to assess the clinical severity, to predict the course of illness and to monitor the efficacy of therapeutic measures, can be clinical, biological, and radiological. Here, we aimed to explore whether the serum glial fibrillary acidic protein (GFAP) may act as a biomarker in SCA3/MJD patients and to evaluate the correlation between some markers with the number of CAG repeats in SCA3/MJD patients. We showed that the serum levels of GFAP were significantly higher in SCA3/MJD patients than in controls. There was a strong positive correlation between the age-adjusted GFAP levels with the number of CAG repeats. Age-adjusted International Cooperative Ataxia Rating Scale (ICARS) scores and Scale for the Assessment and Rating of Ataxia (SARA) scores correlated with the number of CAG repeats. Raw scores and disease duration-adjusted GFAP levels, ICARS scores, and SARA scores were not correlated with the number of CAG repeats. Our results reveal novel evidence for the role of the triplet expansion in SCA3/MJD-associated neuronal damage.

The single nucleotide polymorphism Rs12817488 is associated with Parkinson's disease in the Chinese population.

A recent meta-analysis of datasets from five of the published Parkinson's disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population.

SNP rs11931074 of the SNCA gene may not be associated with multiple system atrophy in Chinese population.

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by poorly levodopa-responsive parkinsonism, cerebellar ataxia, and autonomic dysfunction. Pathogenic mechanisms remain obscure, but the neuropathological hallmark is the presence of α-synuclein-positive glial cytoplasmic inclusions. Previous studies suggested that a single nucleotide polymorphism (SNP), rs11931074, in the α-synuclein gene, SNCA, had highly significant association with an increased risk of the development of MSA in the Caucasian subjects. In contrast, a Korean study failed to identify an association with disease risk. METHODS: To study the effect of rs11931074 on MSA risk in a Chinese population, we conducted a case-control study and genotyped SNP rs11931074 by Sanger sequencing in 96 Chinese patients with MSA and 120 healthy controls. Moreover, we performed a meta-analysis on the topic. RESULTS: There was no statistical difference in genotypes or allele frequencies of SNP rs11931074 between MSA and control groups in our cohort. The results of meta-analysis showed that the risk allele T of rs11931074 was associated with MSA (pooled odds ratio = 1.26, 95% confidence interval = 1.07-1.49, P = 0.006). CONCLUSIONS: Despite a positive result of the meta-analysis, the significant difference in frequency of allele T of rs11931074 between Asian and Caucasian subjects indicates that population heterogeneity at rs11931074 may exist.

Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.

APOE ε2 allele may decrease the age at onset in patients with spinocerebellar ataxia type 3 or Machado-Joseph disease from the Chinese Han population.

Polymorphism of the apolipoprotein E (APOE) gene has been defined as a modifying factor for age at onset (AO) in neurodegenerative disorders. The AO of spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3 or MJD) is inversely correlated with expanded CAG repeat lengths in the ATXN3 gene; however, AO is only partially explained by the expanded CAG repeats. We performed a case-control study to explore whether APOE genotypes play a role in AO of SCA3 or MJD from the Chinese Han population. The APOE genotypes were analyzed in an independent cohort of 155 patients with SCA3 or MJD and 191 controls both from Mainland China. Our study demonstrated that SCA3 or MJD patients experienced an earlier onset if they were carriers of APOE ε2 allele, which decreased the AO by nearly 4 years. This study may also reconfirm the effect of the APOE gene on SCA3 or MJD patients from different races and indicated that certain APOE alleles might be genetic modifiers for AO in SCA3 or MJD.

Increase of the plasma α-synuclein levels in patients with multiple system atrophy.

Multiple system atrophy, a sporadic neurodegenerative disease, is characterized by the presence of high numbers of glial cytoplasmic inclusions mainly formed by α-synuclein protein, which is encoded by the SNCA gene. To date, however, few studies have investigated the plasma α-synuclein levels in patients with multiple system atrophy. We studied plasma α-synuclein concentrations by using an enzyme-linked immunosorbent assay in 74 patients with multiple system atrophy and 90 healthy controls. The plasma α-synuclein levels were significantly elevated in patients who had multiple system atrophy compared with the control group (P = 0.000). In a subgroup of 48 patients who had probable multiple system atrophy, there was a weakly negative correlation between plasma α-synuclein levels and subscores on Unified Multiple System Atrophy Rating Scale item VI (r(s) = -0.307; P = 0.034). Plasma α-synuclein levels were elevated in patients with multiple system atrophy, and these levels may be decreased with the development of disease.