Multi-omics profiling reveals peripheral blood biomarkers of multiple sclerosis: implications for diagnosis and stratification.

Background: Multiple sclerosis (MS), a chronic autoimmune disorder marked by demyelination in the central nervous system, is exceptionally uncommon in China, and remains poorly understood in terms of its peripheral blood manifestations. Methods: We conducted a cohort study comprising 39 MS patients and 40 normal controls (NC). High-dimensional mass cytometry, protein arrays, and targeted metabolomics were utilized to profile immune subsets, proteins, and metabolites in blood. Differences in multi-omics signatures were scrutinized across varying MS subtypes. Results: Immune profiling demonstrated an elevation in various B cell subsets and monocytes, alongside a reduction in dendritic cells among MS patients. Proteomic data revealed a downregulation in neurotrophic and tissue repair proteins. Metabolomic assessment showed a noted decrease in anti-inflammatory molecules and sphingolipids. Integrated analysis identified distinct molecular patterns distinguishing MS from controls. Additionally, multi-omics differences among different MS subtypes were uncovered. Notably, hippuric acid levels was consistently lower in MS subgroups with greater disease severity. Conclusion: This study represents the pioneering exploration of multi-omics in Chinese MS patients, presenting a comprehensive view of the peripheral blood changes in MS. Our study underscores the robust capability of multi-omics assessments in identifying peripheral blood biomarkers that delineate the varied clinical presentation, and facilitates future development of biomarkers and targeted therapeutic interventions in MS.

18F-DPA714 PET/MRI as a potential imaging tool for detecting possible antibody-negative autoimmune encephalitis: a prospective study.

BACKGROUND AND OBJECTIVES: Conventional magnetic resonance imaging (MRI) used for detecting possible antibody-negative autoimmune encephalitis (AIE) often fails to meet the diagnostic requirements of this disease. Positron emission tomography (PET) with a translocator protein radioligand can help visualize microglia distribution density in inflammation-related diseases, thereby offering potentially incremental value to conventional MRI for the in vivo assessment of possible antibody-negative AIE. METHODS: In this prospective study, 15 participants diagnosed with possible antibody-negative AIE and 10 healthy controls were enrolled (ClinicalTrials.gov: NCT05293405, dated March 15, 2022). All participants underwent hybrid 18F-DPA714 PET/MRI and evaluation for modified Rankin scale (mRS) score, clinical assessment scale for AIE (CASE), and appropriate antibodies. A positive finding was defined as the intensity of 18F-DPA714 uptake that was above a threshold of mean standardized uptake value ratio (SUVR) + two standard deviations of SUVR within the corresponding brain regions of healthy controls. RESULTS: The positive detection rate of 18F-DPA714 PET for possible antibody-negative AIE was significantly higher than that of brain MRI (10/15 [67%] vs. 3/15 [20%]; P = 0.039). In addition, both the intensity and extent of 18F-DPA714 uptake were significantly associated with the CASE score (P = 0.002 and 0.001). Meanwhile, SUVR levels in the cerebellar region were significantly higher in patients with ataxia than in those without ataxia (P = 0.006). Furthermore, 18F-DPA714 uptake decreased in 5/10 [50%] patients who underwent follow-up PET/MRI, which mirrored their symptom relief. CONCLUSION: 18F-DPA714 PET demonstrated its potentially incremental value to conventional MRI for detecting possible antibody-negative AIE.

Expanding the clinical spectrum of anti-DPPX encephalitis: a multicenter retrospective study.

Objective: Anti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a rare autoimmune encephalitis, and clinical and experimental information regarding this disease is limited. We conducted this study to comprehensively describe the clinical characteristics, ancillary test results, neuroimaging results, and treatment response in a group of Chinese patients with anti-DPPX encephalitis for better understanding this disease. Methods: We recruited 14 patients who tested positive for anti-DPPX antibodies in the serum and/or cerebrospinal fluid from 11 medical centers between March 2021 and June 2023. This retrospective study evaluated data on symptoms, autoantibody test, auxiliary examinations, treatments, and outcomes. Results: The average age at diagnosis was 45.93 ± 4.62 years (range: 11-72 years), and 9 of the 14 patients were males. The main symptoms included cognitive impairment (50.0%, 7/14), central nervous system hyperexcitability (42.9%, 6/14), gastrointestinal dysfunction (35.7%, 5/14), and psychiatric disorders (35.7%, 5/14). Notably, we discovered specific findings on 18F-fluorodeoxyglucose positron-emission tomography (PET)/magnetic resonance imaging in two patients. Co-existing autoantibodies were identified in two patients. Parainfection was identified in four patients. One patient had other autoimmune diseases, and one had tumor. Eleven patients received immunotherapy and most patients improved at discharge. Surprisingly, three male patients but no female patients relapsed during the 6 months of follow-up. Conclusion: The development and outcome of anti-DPPX encephalitis are variable. Male patients were predominant in our cohort. The most common symptoms were the classical triad of prodromal gastrointestinal dysfunction, cognitive and mental disorders, and central nervous system hyperexcitability. Infections, immune dysregulation, and tumors may be important etiologies. Long-term monitoring of disease development should be done in male patients. Overall, our results highlight novel clinical characteristics of anti-DPPX encephalitis.

Microglial Activation Imaging Using 18F-DPA-714 PET/MRI for Detecting Autoimmune Encephalitis.

Background Translocator protein (TSPO) PET has been used to visualize microglial activation in neuroinflammation and is a potential imaging tool for detecting autoimmune encephalitis (AIE). Purpose To compare the detection rate between TSPO radioligand fluorine 18 (18F) DPA-714 PET and conventional MRI and assess the relationship between 18F-DPA-714 uptake and clinical features in participants with AIE. Materials and Methods Healthy volunteers and patients with AIE were enrolled in this prospective study between December 2021 and April 2023. All participants underwent hybrid brain 18F-DPA-714 PET/MRI and antibody testing. Modified Rankin scale scoring and AIE-related symptoms were assessed in participants with AIE. Positive findings were defined as intensity of 18F-DPA-714 uptake above a threshold of the mean standardized uptake value ratio (SUVR) plus 2 SD inside the corresponding brain regions of healthy controls. The McNemar test was used to compare the positive detection rate between the two imaging modalities; the independent samples t test was used to compare continuous variables; and correlation with Bonferroni correction was used to assess the relationship between 18F-DPA-714 uptake and clinical features. Results A total of 25 participants with AIE (mean age, 39.24 years ± 19.03 [SD]) and 10 healthy controls (mean age, 28.70 years ± 5.14) were included. The positive detection rate of AIE was 72% (18 of 25) using 18F-DPA-714 PET compared to 44% (11 of 25) using conventional MRI, but the difference was not statistically significant (P = .065). Participants experiencing seizures exhibited significantly higher mean SUVR in the entire cortical region than those without seizures (1.23 ± 0.21 vs 1.15 ± 0.18; P = .003). Of the 13 participants with AIE who underwent follow-up PET/MRI, 11 (85%) demonstrated reduced uptake of 18F-DPA-714 accompanied by relief of symptoms after immunosuppressive treatment. Conclusion 18F-DPA-714 PET has potential value in supplementing MRI for AIE detection. Clinical trial registration no. NCT05293405 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Zaharchuk in this issue.

Circulating proteomic biomarkers for diagnosing sporadic amyotrophic lateral sclerosis: a cross-sectional study.

JOURNAL/nrgr/04.03/01300535-202408000-00039/figure1/v/2023-12-16T180322Z/r/image-tiff Biomarkers are required for the early detection, prognosis prediction, and monitoring of amyotrophic lateral sclerosis, a progressive disease. Proteomics is an unbiased and quantitative method that can be used to detect neurochemical signatures to aid in the identification of candidate biomarkers. In this study, we used a label-free quantitative proteomics approach to screen for substantially differentially regulated proteins in ten patients with sporadic amyotrophic lateral sclerosis compared with five healthy controls. Substantial upregulation of serum proteins related to multiple functional clusters was observed in patients with sporadic amyotrophic lateral sclerosis. Potential biomarkers were selected based on functionality and expression specificity. To validate the proteomics profiles, blood samples from an additional cohort comprising 100 patients with sporadic amyotrophic lateral sclerosis and 100 healthy controls were subjected to enzyme-linked immunosorbent assay. Eight substantially upregulated serum proteins in patients with sporadic amyotrophic lateral sclerosis were selected, of which the cathelicidin-related antimicrobial peptide demonstrated the best discriminative ability between patients with sporadic amyotrophic lateral sclerosis and healthy controls (area under the curve [AUC] = 0.713, P < 0.0001). To further enhance diagnostic accuracy, a multi-protein combined discriminant algorithm was developed incorporating five proteins (hemoglobin beta, cathelicidin-related antimicrobial peptide, talin-1, zyxin, and translationally-controlled tumor protein). The algorithm achieved an AUC of 0.811 and a P-value of < 0.0001, resulting in 79% sensitivity and 71% specificity for the diagnosis of sporadic amyotrophic lateral sclerosis. Subsequently, the ability of candidate biomarkers to discriminate between early-stage amyotrophic lateral sclerosis patients and controls, as well as patients with different disease severities, was examined. A two-protein panel comprising talin-1 and translationally-controlled tumor protein effectively distinguished early-stage amyotrophic lateral sclerosis patients from controls (AUC = 0.766, P < 0.0001). Moreover, the expression of three proteins (FK506 binding protein 1A, cathelicidin-related antimicrobial peptide, and hemoglobin beta-1) was found to increase with disease progression. The proteomic signatures developed in this study may help facilitate early diagnosis and monitor the progression of sporadic amyotrophic lateral sclerosis when used in combination with current clinical-based parameters.

Anti-IgLON5 disease: a novel topic beyond neuroimmunology.

Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.

Characteristics of cerebral blood flow in an Eastern sample of multiple sclerosis patients: A potential quantitative imaging marker associated with disease severity.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is rare in China. At present, there are no widespread quantitative imaging markers associated with disease severity in MS. Despite several previous studies reporting cerebral blood flow (CBF) changes in MS, no consensus has been reached. In this study, we enrolled 30 Eastern MS patients to investigate CBF changes in different brain regions using the arterial spin labeling technique and their relationship with disease severity. The average CBF in MS patients were higher than those in health controls in various brain regions except cerebellum. The results indicated that MS patients with strongly increased CBF showed worse disease severity, including higher Expanded Disability Status Scale (EDSS) scores and serum neurofilament light chain (sNfL) values than those with mildly increased CBF in the parietal lobes, temporal lobes, basal ganglia, and damaged white matter (DWM). From another perspective, MS patients with worse disease severity (higher EDSS score and sNfL values, longer disease duration) showed increased CBF in parietal lobes, temporal lobes, basal ganglia, normal-appearing white matter (NAWM), and DWM. Correlation analysis showed that there was a strong association among CBF, EDSS score and sNfL. MS patients with strongly increased CBF in various brain regions had more ratio in relapsing phase than patients with mildly increased CBF. And relapsing patients showed significantly higher CBF in some regions (temporal lobes, left basal ganglia, right NAWM) compared to remitting patients. In addition, MS patients with cognitive impairment had higher CBF than those without cognitive impairment in the right parietal lobe and NAWM. However, there were no significant differences in CBF between MS patients with and without other neurologic dysfunctions (e.g., motor impairment, visual disturbance, sensory dysfunction). These findings expand our understanding of CBF in MS and imply that CBF could be a potential quantitative imaging marker associated with disease severity.

Anti-NF155/NF186 IgG4 Antibody Positive Autoimmune Nodopathy.

Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) seropositive for autoantibodies against nodal and paranodal proteins display distinct clinical presentations. In the latest study, CIDP with autoantibodies against paranodal proteins was defined as autoimmune nodopathy (AN). We herein present a case of 39-year-old male with anti- neurofascin (NF) 155 and NF186 IgG4 antibody with gait disturbance and tremor, who was followed up for 4 months and demonstrated clinical improvements after apparently effective rituximab therapy. In addition, a literature review was conducted to investigate the clinical characteristics of anti-NF155/NF186-positive AN.

Paraneoplastic Amyotrophic Lateral Sclerosis: Case Series and Literature Review.

Paraneoplastic amyotrophic lateral sclerosis (ALS) is a rare and special type of ALS. The pathogenesis, clinical presentation, treatment and prognosis remain poorly understood. We herein presented three cases of paraneoplastic ALS. In case 1, we first reported an ALS patient with the positive serum antibodies against both Sry-like high mobility group box 1 (SOX1) and glutamic acid decarboxylase 65 (GAD65). However, immunotherapy did not improve his neurological symptoms. We also reported two ALS patients with renal clear cell carcinoma and chronic myelogenous leukemia. No positive paraneoplastic antibodies were detected in either the serum or the cerebrospinal fluid of the two patients, and their clinical symptoms progressed slowly after tumor treatment. The three cases enriched the existing case pool of this rare disorder. In addition, we have comprehensively reviewed the literature of paraneoplastic ALS. The clinical features, treatment effect and prognosis were summarized to broaden our understanding of paraneoplastic ALS.

Hybrid 18F-florbetapir PET/MRI for assessing myelin recovery in GFAP-A patients.

Glial fibrillary acidic protein astrocytopathy (GFAP-A) is a rare autoimmune disease of the central nervous system that was newly reported in 2016. Previous studies have speculated that the pathological mechanism and clinical outcome of GFAP-A lie in the demyelination of the central nervous system, but due to the limitations of MR, this conclusion has not been further confirmed from the perspective of neuroimaging. A non-invasive, quantitative measurement of demyelination would be clinically valuable, given its critical role in mediating GFAP-A. Here, we report a case in which we use 18F-florbetapir positron emission tomography-magnetic resonance imaging (PET/MRI) to evaluate myelin recovery with follow-up in the patient with GFAP-A. Our patient displayed a decreased uptake of PET tracer 18F-florbetapir in the brain lesions and lower distribution volume ratio in the damaged white matter lesions compared to the normal-appearing white matter, indicating significant intracranial demyelination. After treatment, the 18F-florbetapir PET/MRI examination showed a significant increase in the uptake of 18F-florbetapir in the brain lesions, along with a reduced Expanded Disability Status Scale score. Although only a small number of patients have been validated, this case first reported 18F-florbetapir PET/MRI could quantitatively and non-invasively assess the myelin recovery in GFAP-A patients, which may lead to improvements in the early diagnosis and long-term prognosis.

Immune Checkpoint Inhibitor Associated Autoimmune Encephalitis, Rare and Novel Topic of Neuroimmunology: A Case Report and Review of the Literature.

Immune checkpoint inhibitors (ICIs) are being used in patients with various advanced malignancies, and patient outcomes have improved considerably. Although ICIs can effectively treat tumors, 30-60% of patients experience immune-related adverse events (irAEs). Autoimmune encephalitis (AE) is a rare irAE that has become a novel topic in neuroimmunology and has received increasing attention in recent years. Herein, we report a rare case of GAD65-antibody-associated AE after metastatic small cell lung cancer treatment with pembrolizumab. The patient received IVIg therapy for AE and continuous pembrolizumab therapy without suspension of tumor treatment. At 1 year follow-up, both the patient's AE symptoms and tumors were stable. We consider that the treatment of ICI-associated AE should be more individualized with prudent decision-making and should balance the tumor progression and AE treatment. In addition, we have also comprehensively reviewed the literature of ICI-associated AE, and summarized the clinical features, treatment, and prognosis of AE caused by ICI, thus broadening our understanding of the neurological complications caused by ICI.

A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

18F-florbetapir PET/MRI for quantitatively monitoring myelin loss and recovery in patients with multiple sclerosis: A longitudinal study.

BACKGROUND: Amyloid positron emission tomography (PET) can measure in-vivo demyelination in patients with multiple sclerosis (MS). However, the value of 18F-labeled amyloid PET tracer, 18F-florbetapir in the longitudinal study for monitoring myelin loss and recovery has not been confirmed. METHODS: From March 2019 to September 2020, twenty-three patients with MS and nine healthy controls (HCs) underwent a hybrid PET/MRI at baseline and expanded disability status scale (EDSS) assessment, and eight of 23 patients further underwent follow-up PET/MRI. The distribution volume ratio (DVR) and standard uptake value ratio (SUVR) of 18F-florbetapir in damaged white matter (DWM) and normal-appearance white matter (NAWM) were obtained from dynamic and static PET acquisition. Diffusion tensor imaging-derived parameters were also calculated. Data were expressed as mean ± standard deviation with 99% confidence interval (99%CI). FINDING: The mean DVR (1.08 ± 0.12, 99%CI [1.02 ~ 1.14]) but not the mean SUVR of DWM lesions was lower than that of NAWM in patients with MS (1.25 ± 0.10, 99%CI [1.20 ~ 1.31]) and HCs (1.29 ± 0.08, 99%CI [1.23 ~ 1.36]). A trend toward lower mean fractional anisotropy (374.95 ± 45.30 vs. 419.07 ± 4.83) and higher mean radial diffusivity (0.45 ± 0.05 vs. 0.40 ± 0.01) of NAWM in patients with MS than those in HCs was found. DVR decreased in DWM lesions with higher MD (rho = -0.261, 99%CI [-0.362 ~ -0.144]), higher AD (rho = -0.200, 99%CI [-0.318 ~ -0.070]) and higher RD (rho = -0.198, 99%CI [-0.313 ~ -0.075]). Patients' EDSS scores were reduced (B = 0.04, 99%CI [-0.005 ~ 0.084]) with decreased index of global demyelination in the longitudinal study. INTERPRETATION: Our exploratory study suggests that dynamic 18F-florbetapir PET/MRI may be a very promising tool for quantitatively monitoring myelin loss and recovery in patients with MS. FUNDING: Shanghai Pujiang Program, Shanghai Municipal Key Clinical Specialty, Shanghai Shuguang Plan Project, Shanghai Health and Family Planning Commission Research Project, Clinical Research Plan of SHDC, French-Chinese program "Xu Guangqi".

FoxP3- Tr1 Cell in Generalized Myasthenia Gravis and Its Relationship With the Anti-AChR Antibody and Immunomodulatory Cytokines.

Introduction: The changes in the number and function of regulatory T cells (Tregs) are thought to play important roles in the pathogenesis of generalized myasthenia gravis (gMG). Previous studies have suggested the decrease of FoxP3+ Treg cells in the MG development. However, there is no study on the pathophysiological mechanism of FoxP3-Treg, especially Tr1 cells, in gMG patients. Therefore, this study was conducted to reveal the effect of Tr1 cells to the pathophysiology of gMG. Methods: Thirteen patients with gMG and twelve healthy volunteers were enrolled in this study. The titer of anti-AChR Ab was measured by ELISA. The separated PBMCs were labeled for CD4, CD25, CD49b, LAG3 and FoxP3. The CD4+ T cell count, FoxP3+ Treg to CD4+ T cell ratio and Tr1 cell to CD4+ T cell ratio were measured by flow cytometry. Based on the FoxP3+ Treg and Tr1 cell to CD4+ T cell ratios, the patients' Tr1 cell to FoxP3+ Treg ratios were calculated. The IL-6, IL-7, IL-10, TGF-ß and IFN-γ concentration in the serum of MG patients and normal controls (NCs) were measured via ELISA. Results: We found a significantly positive correlation between the Tr1 cell/CD4+ T cell ratio and the anti-AChR Ab (r = 0.6889 ± 0.4414, p = 0.0401). Although there were no significant differences in the relationship between FoxP3+ Treg cells and anti-AChR Ab, a positive correlation between the Tr1 cell/FoxP3+ Treg cell ratio and the anti-AChR Ab (r = 0.7110 ± 0.4227, p = 0.0318) was observed. In addition, the Tr1 cell/CD4+ T cell ratio but not the proportion of FoxP3+ Tregs was positively correlated with IL-10 (p = 0.048). These results suggested that in the process of the immunomodulatory effect of Tr1 cells in patients with gMG, IL-10 and other cytokines may be involved, but the specific mechanism needs further study. Conclusion: This is the first study of the immunoregulatory mechanism of Tr1 cells in gMG. We conducted this study to elucidate the significance of Tr1 cells in the pathogenesis of MG. We believe that in patients with gMG, Tr1 cells may play an immunomodulatory role in counteracting AChR-related autoimmune responses. In this process, IL-10 and other immunomodulatory cytokines may be involved.

Anti-Ma encephalitis masquerading as Wernicke encephalopathy.

BACKGROUND: Anti-Ma encephalitis is a disease usually associated with testicular cancer in young male patients. Anti-Ma encephalitis presented as Wernicke encephalopathy-like symptoms and with gastric cancer is rare. Here, we report a case of anti-Ma encephalitis with gastric cancer in an elderly patient, which has been misdiagnosed of Wernicke encephalopathy. CASE REPORT: A 71-year old male with a history of alcohol abuse was admitted to the hospital because of progressive dizziness, diplopia and anorexia lasted for 1 month. He was initially diagnosed as Wernicke encephalopathy. However, this patient failed in the treatment of VitB1. The blood and cerebrospinal fluid examination found the presence of anti-Ma1/2 antibodies. 18F-FDG PET-MR showed symmetrical hypermetabolic changes on the bilateral hypothalamus, basal ganglion and brainstem, as well as gastric neoplasms with liver metastasis. The patient was finally diagnosed with anti-Ma encephalitis. CONCLUSION: Anti-Ma encephalitis should be suspected in patient with Wernicke encephalopathy-like symptoms but failed VitB1 treatment.

Effectiveness of Combined Immunoglobulin and Glucocorticoid Treatments in a Patient With Stiff Limb Syndrome: Case Report and Review of the Literature.

Stiff limb syndrome (SLS) is a rare autoimmune-related central nervous system disorder, resulting in stiffness and spasms of limbs since onset with rare involvement of the truncal muscles. However, SLS patients will gain notable effects by appropriate therapy focusing on symptomatic treatment and immunotherapy. We reported on a 55-year-old female who showed typical painful spasms in both lower limbs and abduction of the right eyeball that partially responded to low-dose diazepam and had high-titer anti-glutamic acid decarboxylase (anti-GAD) antibody. Electromyography (EMG) only showed continuous motor unit activity (CMUA) in the anterior tibialis and right triceps. Eventually, our patient was diagnosed with SLS and treated with intravenous immunoglobulin (IVIG) and glucocorticoid combined simultaneously. She obtained notable effects. We also review and summarize the current literature on clinical characteristics, coexisting disease, treatment, and outcome of 40 patients with SLS. We hope that this report will provide a basis for further understanding of SLS and promote the formation of more advanced diagnosis and treatment processes.

Multiple genetic factors affecting the pharmacokinetic and pharmacodynamic processes of tacrolimus in Chinese myasthenia gravis patients.

PURPOSE: Tacrolimus is a novel effective immunosuppressant for myasthenia gravis (MG) patients. However, the narrow therapeutic window, and high inter- and intrapatient variation in bioavailability largely limited its clinical application. This article intended to find the SNPs influencing clinical outcome and discover the possible mechanisms. METHODS: Based on the tagSNPs genotyped by Improved Multiple Ligase Detection Reaction, Plink 1.07 was used to find the SNPs having close interaction to tacrolimus serum concentration, QMG score changes or even reasonable drug dose. Then we searched several databases to predict the possible miRNA binding rs15524 sequence. Based on the prediction, dual-luciferase reporter assay and miRNA transfection were used to discover the mechanism of how SNP rs15524 controls tacrolimus serum concentration through influencing CYP3A5 expression. RESULTS: In this article, we found multiple SNPs on CYP3A4, CYP3A5, FKBP1A, NFATC2 genes were predicted closely related to tacrolimus serum concentration, therapeutic effect which reflected by QMG score changes or even reasonable drug dose. After in silico miRNA selection, possible relationship between hsa-miR-500a and rs15524 was found. With the help of dual-luciferase reporter assay, wild-type rs15524 (T allele) was found having a stronger binding affinity for hsa-miR-500a. Higher expression of CYP3A5 may also led by lower hsa-miR-500a level. CONCLUSIONS: SNP rs15524 may control CYP3A5 expression by affecting the binding affinity between CYP3A5 3'UTR and hsa-miR-500a. Wild type (T allele) 3'UTR of CYP3A5 has stronger binding affinity to hsa-miR-500a and cause lower CYP3A5 expression and higher tacrolimus serum concentration.

Anti-dipeptidyl-peptidase-like protein 6 encephalitis, a rare cause of reversible rapid progressive dementia and insomnia.

Anti-dipeptidyl-peptidase-like protein 6 (DPPX) encephalitis is a rare type of autoimmune encephalitis. We present a case of a 72-year-old male with anti-DPPX encephalitis who developed rapidly progressive cognitive decline, psychiatric and sleep problems, severe abdominal pain and diarrhea. Antibodies against DPPX were positive both in serum and cerebrospinal fluid. 18F-FDG PET-MR imaging indicated hypometabolism in the bilateral temporal lobes and thalamus. No related tumors were found, and the patient responded to immunotherapy without relapse at the 3-year follow-up. The present case enriches the understanding of the clinical, imaging manifestations and prognosis of anti-DPPX encephalitis.