Abstract Background Autoimmunity plays a key role in the pathogenesis of Alzheimer’s disease (AD); however, whether autoantibodies in peripheral blood can be used as biomarkers has not been reported. Method Serum samples were obtained from 767, 146, and 255 patients with AD, mild cognitive impairment (MCI), and other neurodegenerative diseases, respectively, and 518 healthy controls. Specific autoantibodies were measured using a custom‐made immunoassay. Multivariate support vector machine models were employed to investigate the correlation between serum autoantibody levels and disease states. Result Seven candidate AD‐specific autoantibodies were identified, and a classification model with high accuracy (area under the curve (AUC) = 0.94) was established. Importantly, these autoantibodies could distinguish AD from other neurodegenerative diseases and out‐performed amyloid and tau protein concentrations in cerebrospinal fluid in predicting cognitive decline ( P < 0.001). Conclusion AD onset and progression are associated with an unappreciated serum autoantibody response. Therefore, future studies could optimize its application as a convenient biomarker for the early detection of AD.
Objective: To investigate the clinical features and factors associated with Parkinson's disease (PD) patients with probable rapid eye movement sleep behavior disorder (PD-pRBD). Methods: A total of 2,440 patients with clinically established or clinically probable PD were divided into two groups: PD-pRBD and PD without pRBD (PD-NRBD), according to the RBD questionnaire-Hong Kong. Data collection included demographic data, basic clinical history, and motor and non-motor symptoms. Based on the onset time of pRBD and the motor symptoms in PD, PD-pRBD patients were further divided into the pRBD prior to PD (PD-prRBD) group and the pRBD posterior to PD (PD-poRBD) group. Clinical features were compared between the PD-pRBD and PD-NRBD groups, as well as the PD-prRBD and PD-poRBD groups. The associated factors of pRBD were also explored. Results: The prevalence of pRBD was 41.4% (1,010 out of the total of 2,440) in our PD cohort. Further, compared with the PD-NRBD group, the PD-pRBD group had longer disease duration and more severe motor symptoms. Moreover, the PD-pRBD group had significantly higher levodopa equivalent daily dose and a higher ratio of dyskinesia, wearing-off, and offset of the Hoehn-Yahr stage. The scores on the non-motor symptom rating scale (NMSS), cognitive impairment, Parkinson's disease sleep scale (PDSS), excessive daytime sleepiness, constipation, hyposmia, depression, and the 39-item Parkinson's disease questionnaire also appeared worse in the PD-pRBD group. Significant differences in the educational level, disease duration, disease progression, Unified Parkinson's Disease Rating Scale (UPDRS)-II, UPDRS-III, tremor, rigidity, bradykinesia, posture gait, frozen gait, levodopa equivalent daily dose, dyskinesia, wearing-off, Hoehn-Yahr stage, NMSS-6, PDSS, and communication score widely existed between the PD-prRBD and PD-poRBD groups. Late-onset PD, long disease duration, high UPDRS-I score, high NMSS-4 score, low PDSS score, constipation, and hyposmia were all identified as the risk factors for PD-pRBD. Conclusions: Compared with the PD-NRBD group, the PD-pRBD group may have more severe motor symptoms, motor complications, and non-motor symptoms as well as a substandard quality of life. Further, late-onset PD, long disease duration, high UPDRS-I score, high NMSS-4 score, low PDSS score, constipation, and hyposmia can be risk factors for RBD in PD. Differences also occurred between the PD-prRBD and PD-poRBD groups.
Abstract Background Electroencephalogram (EEG) has emerged as a non-invasive tool to detect the aberrant neuronal activity related to different stages of Alzheimer’s disease (AD). However, the effectiveness of EEG in the precise diagnosis and assessment of AD and its preclinical stage, amnestic mild cognitive impairment (MCI), has yet to be fully elucidated. In this study, we aimed to identify key EEG biomarkers that are effective in distinguishing patients at the early stage of AD and monitoring the progression of AD. Methods A total of 890 participants, including 189 patients with MCI, 330 patients with AD, 125 patients with other dementias (frontotemporal dementia, dementia with Lewy bodies, and vascular cognitive impairment), and 246 healthy controls (HC) were enrolled. Biomarkers were extracted from resting-state EEG recordings for a three-level classification of HC, MCI, and AD. The optimal EEG biomarkers were then identified based on the classification performance. Random forest regression was used to train a series of models by combining participants’ EEG biomarkers, demographic information (i.e., sex, age), CSF biomarkers, and APOE phenotype for assessing the disease progression and individual’s cognitive function. Results The identified EEG biomarkers achieved over 70% accuracy in the three-level classification of HC, MCI, and AD. Among all six groups, the most prominent effects of AD-linked neurodegeneration on EEG metrics were localized at parieto-occipital regions. In the cross-validation predictive analyses, the optimal EEG features were more effective than the CSF + APOE biomarkers in predicting the age of onset and disease course, whereas the combination of EEG + CSF + APOE measures achieved the best performance for all targets of prediction. Conclusions Our study indicates that EEG can be used as a useful screening tool for the diagnosis and disease progression evaluation of MCI and AD.
Abnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.Patients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.In the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=-0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.NIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.
Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18 F-SynVesT-1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes.Twenty-one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent 18 F-SynVesT-1-PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed.Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus-insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus-insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis.This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. 18 F-SynVesT-1-PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS.
The aim of our study was to determine the impact of Th17/Treg imbalance on the progression and malignant transformation of oral submucosal fibrosis (OSF).To assess Th17 and Treg expression, overall 52 peripheral blood samples from OSF, oral squamous cell carcinoma (OSCC) patients, and healthy donors were analyzed by flow cytometry. Thirty normal oral mucosa, 72 OSF, and 90 OSCC samples were analyzed by immunohistochemistry.In peripheral blood samples, in OSCC with OSF, Th17 and Treg expression were significantly higher than those in OSF and OSCC without OSF as confirmed by immunohistochemistry. During OSF progression, Th17 and Th17/Treg ratio showed an increasing trend, while Treg expression showed a decreasing trend. Treg expression was significantly higher in OSCC with OSF than in OSF and OSCC without OSF, whereas the Th17/Treg ratio was significantly lower in OSCC with OSF. Treg expression was significantly correlated with smoking and clinical stage. Th17/Treg ratio was significantly associated with tumor size, lymph node metastasis, and clinical stage. A low Th17/Treg ratio was significantly associated with poor prognosis.Th17/Treg ratio is a potential diagnostic indicator for OSF occurrence and malignant transformation and was an independent prognostic factor for OSCC.
Abstract Meningiomas are among the most common adult neoplasms of the central nervous system. Like several other tumor types, these intracranial tumors often harbor an immune cell infiltrate that can include substantial numbers of B cells. Characteristic details of the B cell infiltrate remain undefined. To gain a deeper understanding of both the B cell repertoire and insight into the role they play in this tumor, we characterized the immune infiltrate of resected meningiomas. Immunohistochemistry revealed a conspicuous B cell infiltrate in the microenvironment of most tumors examined. Flow cytometry of tissue homogenate showed that the infiltrate included naïve and memory B cells and differentiated plasma cells. Molecular characterization of the immunoglobulin variable regions expressed by tumor-infiltrating B cells revealed clear evidence of antigen experience, in that the cardinal features of an antigen-driven B cell response were present: significant somatic mutation, isotype switching and codon insertion/deletion. This characterization also revealed the presence of B cell clonal expansion and intraclonal variation. Testing the specificity of recombinant immunoglobulin derived from single, dissected, intra-tumoral B cells revealed that tumor antigens were recognized. These data indicate that an adaptive and specific humoral immune response exists within meningiomas, further suggesting that tumor antigens may drive B cell maturation within the tumor microenvironment.
(1) Neuronal synchronization underlies brain functioning, and it seems possible that blocking excessive synchronization in an epileptic neural network could reduce or even control seizures. (2) Local field potential coupling is a very common phenomenon during synchronization in networks. Removal of neurons or neuronal networks that are coupled can significantly alter the extracellular field potential. Interventions of coupling mediated by local field potentials could result in desynchronization of epileptic seizures. (3) The synchronized electrical activity generated by neurons is sensitive to changes in the size of the extracellular space, which affects the efficiency of field potential transmission and the threshold of cell excitability. (4) Manipulations of the field potential fluctuations could help block synchronization at seizure onset.
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