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CLUE is a prospective study to assess structural and functional changes of the brain, spinal cord, and optic nerve, as well as the inflammatory environment in patients with neuroinflammatory and demyelinating diseases. Participants will receive magnetic resonance (MR) techniques including DIR, DKI, QSM, Rs-fMRI, conventional sequences (T1WI/T2WI/FLAIR), and the MR metabolic SPICE sequence, and will be followed up for one year using 3T MRI. In addition, participants will receive a one-time baseline examination including T1WI, T2WI, FLAIR, and SWI sequences on 7T MRI, as well as PET-MRI.
The study is an observational study of multi-model imaging to determine structural and functional changes of the brain, spinal cord and optic nerve as well as the inflammatory environment inflammatory environment in patients with neuroinflammatory and demyelination disease. Brain, spinal cord and optic nerve involvement are common in neuroinflammatory and demyelination disease including clinical isolated syndrome (CIS), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody - associated disorders (MOGAD). The pathophysiology in neuroinflammatory disease involves the intensive autoimmune inflammatory response, resulting in demyelination and neuroaxonal injury and loss. Some cerebrospinal fluid (CSF) biomarkers have been reported to indicate the pathology and reflect disease activity, especially during the acute stage. However, they couldn't directly reflect the macroscopic and microscopic neuroaxonal change in the brain and spinal cord, which seem to be important determinants of long-term severe disability in chronic neuroinflammatory disease.
Finally, new MRI techniques are the most reliable and non-invasive method to assess the structure and function of brain and spinal cord, plus to monitor disease activity in clinical practice. Double inversion recovery (DIR) imaging allows better detection of cortical and white matter lesion, which has highlighted the role in MS. Diffusion kurtosis imaging (DKI) which has been proposed to characterize the deviation of water diffusion in neural tissues from Gaussian diffusion, is promising to provide information of demyelination and subsequent inflammatory processes in brain or spinal cord. Quantitative susceptibility mapping (QSM) has enabled MRI of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM better depicts spatial susceptibility patterns in MS lesions compared to phase-based imaging. Besides, resting-state functional imaging(Rs-fMRI) has the potential to map the intrinsic functional brain networks and to detect early functional brain changes in neuroinflammatory disease. Metabolic SPICE sequence enables simultaneous mapping of multiple brain metabolites such as Glx, tNAA, and Cho, offering complementary information on neuronal injury and neuroinflammation. 7T MRI provides ultra-high-field imaging with superior signal-to-noise ratio, allowing visualization of subtle cortical lesions, central veins within plaques, and microbleeds not discernible at lower field strengths. PET-MRI integrates molecular imaging using radiotracers like TSPO ligands to quantify microglial activation and neuroinflammation, while coregistered MRI provides anatomical localization of corresponding lesions. In addition, our 3T MRI protocol includes other immune-mediated diseases such as autoimmune encephalitis (AE) and primary angiitis of the central nervous system (PACNS), as well as healthy controls, to further explore differences between diseases and between patients and healthy individuals.
This study will be a prospective cohort study of patients with neuroinflammatory and demyelination disease. Subjects will undertake MR scans at the acute stage and required follow-up visits after 3 month, 6 months, and 1 year. The MR scans are necessary at each visit.
This study does not limit treatment methods. Patients commonly use high-dose intravenous steroid therapy (HD-S) during the acute stage. The HD-S treatment course referred to intravenous administration of 1 g of glucocorticoid daily for 3 consecutive days and continuous dose 240 mg reduction for 60mg oral administration. Immunomodulatory therapies are necessary for the remission stage. The treatment methods include: Azathioprine (start at 50 mg per day, add 50 mg per week to 2 mg/kg*d); Mycophenolate Mofetil (The initial dose was 0.25g bid, add 0.5g per week to 0.75g bid); and Rituximab (500 mg on the 1st day, the 15th day, then 500mg per half year).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| NMOSD | Patients with neuromyelitis optica spectrum disorders |
| |
| Multiple sclerosis(MS) | Patients with multiple sclerosis |
| |
| MOGAD | Patients with myelin oligodendrocyte glycoprotein antibody-associated disease |
| |
| Healthy controls (HC) | Healthy people without any neuroinflammation disease | ||
| PACNS | primary angiitis of the central nervous system |
| |
| AE | autoimmune encephalitis |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intravenous steroid | Drug | This study does not limit treatment methods. During the acute stage, patients commonly receive high-dose intravenous methylprednisolone (1g daily for 3-5 days). For severe or refractory cases, plasma exchange (PLEX) or intravenous immunoglobulin (IVIG) may be added. For PACNS, cyclophosphamide is added to steroids as standard induction. During remission, immunomodulatory or immunosuppressive therapies vary by disease: for MS, DMTs such as ocrelizumab or natalizumab; for NMOSD, rituximab (500mg on day 1 and 15, then every 6 months), eculizumab, or satralizumab; for MOGAD, azathioprine, mycophenolate mofetil, or rituximab but only for relapsing patients; for PACNS, azathioprine or mycophenolate mofetil for 12-18 months after cyclophosphamide; for AE, rituximab or cyclophosphamide for refractory cases, with maintenance only for relapsing forms. |
| Measure | Description | Time Frame |
|---|---|---|
| The brain structural change over time between the baseline MRI and the follow-up MRIs | To describe changes of lesions, grey matter and white matter in patients with neuroinflammatory and demyelination disease measured by DIR and QSM. The primary endpoint is the change over time between the baseline MRI and the follow-up MRIs, of the lesions and brain volumes. | On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| The spinal cord change over time between the baseline MRI and the follow-up MRIs. | To describe changes of lesions and integrity of fiber bundle in spinal cord in neuroinflammatory and demyelination disease patients measured by DKI. The primary endpoint is the change over time between the baseline MRI and the follow-up MRIs, of structural change in spinal cord. | On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| The functional change over time between the baseline MRI and the follow-up MRIs. | To describe brain functional changes in patients with neuroinflammatory and demyelination disease measured by resting-state functional imaging. The primary endpoint is the functional change over time between the baseline MRI and the follow-up MRIs | On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| Measure | Description | Time Frame |
|---|---|---|
| Change from Baseline Expanded Disability Status Scale （EDSS）/ Functional Systems （FS） | admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later.] The Kurtzke Expanded Disability Status Scale (EDSS) was developed to measure the disability status of subjects with multiple sclerosis. It allows an objective quantification of the level of functioning that could be widely and reproducibly used by researchers and health care providers. The EDSS provides a total score on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to Multiple sclerosis (MS). In addition, it also provides eight subscale measurements called Functional System (FS) scores. |
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Inclusion Criteria:
Exclusion Criteria:
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To reflect the daily practices, this study includes all patients with neuroinflammatory and demyelination disease at the beginning of the study.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yaou Liu, PhD | Contact | +86 1059975396 | yaouliu80@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Yaou Liu, PhD | Beijing Tiantan Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Tiantan Hospital | Recruiting | Beijing | Beijing Municipality | 100053 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33469828 | Derived | Xu Y, Ren Y, Li X, Xu W, Wang X, Duan Y, Liu Y, Zhang X, Tian DC. Persistently Gadolinium-Enhancing Lesion Is a Predictor of Poor Prognosis in NMOSD Attack: a Clinical Trial. Neurotherapeutics. 2021 Apr;18(2):868-877. doi: 10.1007/s13311-020-00973-9. Epub 2021 Jan 19. |
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Clinical and MR data can be shared.
Within 5 years after the end of the trial.
Neurologist and radiologist who submitting an application to Prof. Liu.
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| ID | Term |
|---|---|
| D009471 | Neuromyelitis Optica |
| D009103 | Multiple Sclerosis |
| D000098542 | Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease |
| ID | Term |
|---|---|
| D009188 | Myelitis, Transverse |
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D001379 | Azathioprine |
| D009173 | Mycophenolic Acid |
| D000069283 | Rituximab |
| D000069442 | Natalizumab |
| D003520 | Cyclophosphamide |
| ID | Term |
|---|---|
| D013872 | Thionucleosides |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D015122 | Mercaptopurine |
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|
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| On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| Timed 25-foot Walk | Timed 25-foot walking trials will be assessed on admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later. The Timed 25-Foot Walk test is a quantitative measure of lower extremity function. If required, the subject may use an appropriate assistive device to walk as quickly as he/she can from one end to the other end of a clearly marked, unobstructed, 25-foot course. Timing will begin when any part of the subject's foot crosses the tape. Timing will end when any part of the subject's foot crosses the finish line (identified by a taped mark on the floor). Time will be recorded in seconds. The task is immediately administered again (a maximum five-minute rest period is allowed between trials) by having the subject walk back the same distance. The average of the two values will be recorded. | On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| Mean change in visual acuity as assessed by Sloan 2.5% low contrast visual acuity chart. | admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later.] Low Contrast Visual Acuity: Low-contrast Sloan letter charts are readily available and provide a practical, quantitative, and standardized assessment of visual function. Each chart consists of rows of black letters (decreasing in size from top to bottom) on a white background. For this trial, 2.5% low contrast visual acuity will be measured on days 1 and 5 during the steroid phase and completion after the plasma exchange phase. Charts will be read at a 2.5-meter distance by trained examiners in the hospital room with constant lighting. | On admission to the hospital on day 1, on discharge 180 days later and on follow up 360 days later |
| D009902 | Optic Neuritis |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
| D003711 | Demyelinating Diseases |
| D005128 | Eye Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D061067 | Antibodies, Monoclonal, Humanized |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |