Objective: In the present study, the ABCA1 was used as a label to capture specific exosomes, the level of ABCA1-labeled exosomal microRNA-135a (miR-135a) was evaluated for the diagnosis of Alzheimer's disease (AD), especially in patients with early stages of AD. Methods: This is a preliminary research focused on the levels of ABCA1 in WBCs, RBCs, HT-22 cells, and neuron cells. The diagnostic value of ABCA1-labeled exosomal miR-135a was examined using the CSF and serum of APP/PS1 double transgenic mice, and 152 patients with SCD, 131 patients with MCI, 198 patients with DAT, and 30 control subjects. Results: The level of ABCA1 exosomes harvested from HT-22 cells and neuron culture medium was significantly higher compared to that of RBCs and WBCs ( Conclusion This study outlines a method to capture specific exosomes and detect them using immunological methods, which is more efficient for early diagnosis of AD.
ATP Binding Cassette Transporter 1/cerebrospinal fluid* ; Aged ; Aged, 80 and over ; Alzheimer Disease/cerebrospinal fluid* ; Animals ; Biomarkers/cerebrospinal fluid* ; Cell Line ; Cognitive Dysfunction/cerebrospinal fluid* ; Erythrocytes/metabolism* ; Exosomes ; Female ; Humans ; Leukocytes/metabolism* ; Male ; Mice, Transgenic ; MicroRNAs/blood* ; Neurons/metabolism*

Cerebrospinal fluid surrounds and supports the central nervous system, including the ventricles and subarachnoid spaces. Cerebrospinal fluid should be an important source of biomarkers for central nervous system diseases because it is in direct contact with the central nervous system. Many studies are reported on cerebrospinal fluid proteomics, highlighting many recent progresses. Here, we review recent advances in proteomics technology and clinical application of cerebrospinal fluid.
Biomarkers ; Cerebrospinal Fluid Proteins ; Proteome ; Proteomics

OBJECTIVE: To investigate the differentially expressed proteins in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS) at the proteomics level using tandem mass spectrometry label (TMT) technique and explore the pathogenic mechanism and related pathways of ALS. METHODS: Between November, 2017 and April, 2018, 5 patients with medulla oblongata onset ALS and 5 patients with limb onset ALS were selected from the Departments of Neurology of 928 Hospital of Army Joint Logistics Support Force of PLA and Xiangya Hospital of Central South University, with 5 patients with migraine and low intracranial pressure headache serving as the healthy controls.CSF samples were obtained from all the participants, and the differentially expressed proteins in the CSF were identified using tandem mass spectrometry (TMT) technique with bioinformatics analysis. RESULTS: A total of 1530 proteins were identified and quantified in the CSF samples.The expression of 48 proteins was up-regulated and 6 proteins were down-regulated in medulla oblongata onset ALS patients; 16 proteins were up-regulated and 19 were down-regulated in limb onset ALS patients.GO analysis showed that these proteins, which were distributed both within and outside the cells, were involved in cell physiological process, single organ process and biological regulation and had binding function, catalytic activity, and receptor activity.KEGG pathway analysis showed that the up-regulated proteins in the CSF from patients with medulla oblongata onset ALS participated in 3 pathways involving the lysosomes, metabolism, and measles.The down-regulated proteins in the CSF from patients with limb onset ALS participated in 7 pathways involving the complement and coagulation cascade, infection and herpes simplex infection, and all the pathways contained complement components. CONCLUSIONS The CSF samples of ALS patients with medullary onset and limb onset have differentially expressed proteins.The lysosomal pathway is involved in the occurrence and progression of ALS with medullary onset, and the immune responses are involved in the occurrence and progression of ALS with limb onset.
Amyotrophic Lateral Sclerosis ; Biomarkers ; Cerebrospinal Fluid ; Humans ; Proteome ; Proteomics ; Tandem Mass Spectrometry

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects. METHODS: Ten amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays. RESULTS: The level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age. CONCLUSIONS: Our results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.
Alzheimer Disease ; Amyloid ; Biomarkers ; Brain ; Cerebrospinal Fluid ; Enzyme-Linked Immunosorbent Assay ; Extracellular Fluid ; Humans ; Hydrocephalus ; Metabolism ; Positron-Emission Tomography

BACKGROUND AND PURPOSE: A few groups have suggested that activated cytokines and nitrosative stress are closely involved in the pathogenesis of different demyelinating disorders induced by the neuroinflammatory destruction of neurons. The purpose of this study was to elucidate the associations of cytokines and S-nitrosothiols (RSNO) with the severity of neurodegeneration during relapse in demyelinating disorders of the central nervous system. METHODS: We measured levels of interleukin-6 (IL-6), erythropoietin, RSNO, and phosphorylated neurofilament heavy chain (pNfh) in cerebrospinal fluid (CSF) samples obtained from patients with different demyelinating disorders: multiple sclerosis (MS, n=52), acute disseminated encephalomyelitis (ADEM, n=9), and neuromyelitis optica spectrum disorders (NMOSD) with aquaporin-4 immunoglobulin G (AQP4-IgG, n=12). We compared these levels with those measured in a control group (n=24). RESULTS: We found that IL-6 in CSF was elevated in NMOSD with AQP4-IgG and ADEM patients as well as in MS patients after the destruction of soluble IL-6. Erythropoietin levels were lower in MS, while RSNO levels were higher in NMOSD with AQP4-IgG and MS patients than in the control group. CSF pNfh levels were elevated in MS and ADEM patients. CONCLUSIONS: These results confirm that IL-6 is activated in different demyelinating disorders, with this elevation being more prominent in the CSF of NMOSD with AQP4-IgG and ADEM patients. Moreover, S-nitrosylation is activated in demyelinating disorders with spinal-cord injury and neurodegeneration in these patients. However, we found no correlation between these biochemical markers, and so we could not confirm whether IL-6-mediated nitric oxide production is involved in spinal-cord lesions.
Biomarkers ; Central Nervous System* ; Cerebrospinal Fluid ; Cytokines ; Demyelinating Diseases* ; Encephalomyelitis, Acute Disseminated ; Erythropoietin ; Humans ; Immunoglobulin G ; Interleukin-6* ; Intermediate Filaments ; Multiple Sclerosis ; Neuromyelitis Optica ; Neurons ; Nitric Oxide ; Recurrence ; S-Nitrosothiols*

PURPOSE: The present study investigated associations between dopamine transporter (DAT) availability and α-synuclein levels in cerebrospinal fluid, as well as synuclein gene (SNCA) transcripts, and the effect of single nucleotide polymorphism of SNCA on DAT availability in healthy subjects. MATERIALS AND METHODS: The study population comprised healthy controls who underwent 123I-FP-CIT single-photon emission computed tomography screening. Five SNCA probes were used to target the boundaries of exon 3 and exon 4 (SNCA-E3E4), transcripts with a long 3′UTR region (SNCA-3UTR-1, SNCA-3UTR-2), transcripts that skip exon 5 (SNCA-E4E6), and the rare short transcript isoforms that comprise exons 1–4 (SNCA-007). RESULTS: In total, 123 healthy subjects (male 75, female 48) were included in this study. DAT availability in the caudate nucleus (p=0.0661) and putamen (p=0.0739) tended to differ according to rs3910105 genotype. In post-hoc analysis, DAT availability in the putamen was lower in subjects of TT genotype than those of CC/CT (p=0.0317). DAT availability in the caudate nucleus also showed a trend similar to that in the putamen (p=0.0597). Subjects of CT genotype with rs3910105 showed negative correlations with DAT availability in the putamen with SNCA-E3E4 (p=0.037, rho=−0.277), and SNCA-E4E6 (p=0.042, rho=−0.270), but not those of CC/TT genotypes. CONCLUSION: This is the first study to investigate the association of rs3910105 in SNCA with DAT availability. rs3910105 had an effect on DAT availability, and the correlation between DAT availability and SNCA transcripts were significant in CT genotypes of rs3910105.
Biomarkers ; Caudate Nucleus ; Cerebrospinal Fluid ; Dopamine Plasma Membrane Transport Proteins* ; Dopamine* ; Exons ; Female ; Genotype ; Healthy Volunteers* ; Humans ; Mass Screening ; Polymorphism, Single Nucleotide ; Protein Isoforms ; Putamen ; Synucleins* ; Tomography, Emission-Computed

Multiple system atrophy (MSA) is an adult-onset, progressive neurodegenerative disorder. Patients with MSA show various phenotypes during the course of their illness, including parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs. Patients with MSA sometimes present with isolated autonomic failure or motor symptoms/signs. The median duration from onset to the concomitant appearance of motor and autonomic symptoms is approximately 2 years but can range up to 14 years. As the presence of both motor and autonomic symptoms is essential for the current diagnostic criteria, early diagnosis is difficult when patients present with isolated autonomic failure or motor symptoms/signs. In contrast, patients with MSA may show severe autonomic failure and die before the presentation of motor symptoms/signs, which are currently required for the diagnosis of MSA. Recent studies have also revealed that patients with MSA may show nonsupporting features of MSA such as dementia, hallucinations, and vertical gaze palsy. To establish early diagnostic criteria and clinically definitive categorization for the successful development of disease-modifying therapy or symptomatic interventions for MSA, research should focus on the isolated phase and atypical symptoms to develop specific clinical, imaging, and fluid biomarkers that satisfy the requirements for objectivity, for semi- or quantitative measurements, and for uncomplicated, worldwide availability. Several novel techniques, such as automated compartmentalization of the brain into multiple parcels for the quantification of gray and white matter volumes on an individual basis and the visualization of α-synuclein and other candidate serum and cerebrospinal fluid biomarkers, may be promising for the early and clinically definitive diagnosis of MSA.
Biomarkers ; Brain ; Cerebellar Ataxia ; Cerebrospinal Fluid ; Dementia ; Diagnosis ; Early Diagnosis ; Hallucinations ; Humans ; Multiple System Atrophy ; Neurodegenerative Diseases ; Paralysis ; Parkinsonian Disorders ; Phenotype ; White Matter

A lumbar puncture can be used to measure the concentrations of drugs and/or pharmacodynamic biomarkers during clinical trials of central nervous system drugs. We report a case of a post lumbar puncture headache (PLPH) in a first-in-human study, which was reported as a serious adverse event. A 20-year-old man received 200 mg of the investigational product (IP) for 7 days and underwent a lumbar puncture for cerebrospinal fluid sampling before IP administration (Day 1, pre-dose) and after 7 days and multiple IP administrations (Day 7, 1 hour post-dose). After discharge on Day 8, the subject complained of headache, nausea, vomiting, neck stiffness, and numbness of the extremities. The symptoms occurred when he got up and disappeared after he remained in the supine position for several minutes. Five days later, he visited the neurology clinic of the main hospital. The neurologist recommended hospitalization for further evaluation and symptom management, and the subject was then admitted to the hospital. There were no abnormal findings in vital signs, laboratory results, or brain-computed tomography. His symptoms disappeared during the hospitalization period. It was important to distinguish whether the headache was IP-related or lumbar puncture-related. Therefore, knowledge of clinical characteristics and differential diagnosis of PLPH is paramount. Furthermore, if severe PLPH occurs, a consultation with a neurologist and imaging studies should be considered for a differential diagnosis of PLPH.
Biomarkers ; Central Nervous System Agents ; Cerebrospinal Fluid ; Diagnosis, Differential ; Extremities ; Headache* ; Hospitalization ; Humans ; Hypesthesia ; Nausea ; Neck ; Neurology ; Spinal Puncture* ; Supine Position ; Vital Signs ; Vomiting ; Young Adult

BACKGROUND AND PURPOSE: The cerebrospinal fluid (CSF) biomarkers play an important supportive role as diagnostic and predictive indicators of Alzheimer's disease (AD). About 30% of controls in old age show abnormal values of CSF biomarkers and display a higher risk for AD compared with those showing normal values. The cut-off values are determined by their diagnostic accuracy. However, the current cut-off values may be less accurate, because controls include high-risk groups of AD. We sought to develop models of patients with AD, who are homogenous for CSF biomarkers. METHODS: We included participants who had CSF biomarker data in the Alzheimer's Disease Neuroimaging Initiative database. We investigated the factors related to CSF biomarkers in patients with AD using linear mixed models. Using the factors, we developed models corresponding to CSF biomarkers to classify patients with mild cognitive impairment (MCI) into high risk and low risk and analyzed the conversion from MCI to AD using the Cox proportional hazards model. RESULTS: APOE ε4 status and age were significantly related to CSF Aβ1-42. CSF t-tau, APOE ε2 status and sex were significant factors. The CSF p-tau181 was associated with age and frequency of diagnosis. Accordingly, we modeled the three CSF biomarkers of AD. In MCI without APOE ε4, our models were better predictors of conversion. CONCLUSIONS: We can interpret CSF biomarkers based on the models derived from the data obtained from patients with AD.
Alzheimer Disease* ; Apolipoproteins E ; Biomarkers ; Cerebrospinal Fluid ; Diagnosis ; Humans ; Methods* ; Mild Cognitive Impairment* ; Neuroimaging ; Proportional Hazards Models ; Reference Values

Objective To explore the diffusion pattern of tumor markers (TM) from serum to cerebrospinal fluid (CSF) via the blood-brain barrier in patients with elevated serum tumor markers (TM).Methods Inpatients receiving lumbar puncture during hospitalization in our center from January 1, 2013 to December 31, 2015 were divided into study group (n=181) and control group (n=251). The study group consisted of patients with elevated serum TMs but without malignant central nervous system diseases. The control group consisted of patients with normal serum TM levels and without malignant diseases. TMs measured in the study group included elevated serum alpha-fetoprotein (AFP) (n=0), carcinoembryonic antigen (CEA) (n=26), carcinomic antigen(CA)125 (n=39), CA15- 3 (n=3),CA19- 9 (n=19), CA724 (n=47), CYFRA21- 1 (n=49), and SCC (n=17).Levels of TMs in the CSF of study group was compared with that of control group.Results Median CEA (U=0.00,P=0.00),CA19- 9 (U=0.00,P=0.00),CA15- 3 (U=0.00,P=0.04),SCC (U=0.00,P=0.00),CA125 (U=0.00,P=0.00),CA72- 4 (U=3.00,P=0.00)),and CYFRA21- 1 (U=0.00,P=0.00) in CSF were significantly lower than the corresponding serum TM levels in the study group.There was no significant difference between study group and control group for the CSF level of CEA (U=3091.00,P=0.18),CA19- 9 (U=1897.00,P=0.14), CA15- 3 (U=373.50,P=0.91)and SCC (U=1925.50,P=0.76). CSF CA125 (U=2188.00,P=0.00) and CA724 (U=1279.00,P=0.00) levels in the study group were lower than those in control group. CSF level of CYFRA21- 1 (U=1826.50,P=0.00) in study group was higher than that in control group;however, it was still lower than the upper limit of reference value. Conclusion In patients with elevated serum CEA, CA19- 9, CA15- 3, SCC, CA125, and CA72- 4 levels, transblood-brain-barrier diffusion of TMs from serum to CSF is highly unlikely.
Biomarkers, Tumor ; cerebrospinal fluid ; CA-125 Antigen ; cerebrospinal fluid ; CA-19-9 Antigen ; cerebrospinal fluid ; Carcinoembryonic Antigen ; cerebrospinal fluid ; Case-Control Studies ; Central Nervous System Neoplasms ; cerebrospinal fluid ; diagnosis ; Humans ; Mucin-1 ; cerebrospinal fluid ; Reference Values