Dynamic Magnetic Resonance Imaging of Human Subarachnoid Space Using Intrathecal Gadolinium Contrast
Background:
Cerebrospinal fluid (CSF) is the liquid that fills the space around the brain and spinal cord. Researchers do not fully understand how CSF flows and drains around the brain. They want to test a tracer (gadobutrol)-a special dye injected into the CSF-to find out if it is safe to use and can help them get clearer pictures of the CSF during magnetic resonance imaging (MRI) scans of the brain.
Objective:
To test gadobutrol in the CSF during MRI scans of healthy people.
Eligibility:
Healthy volunteers aged 18 years and older. They must be screened under NIH protocol 89N0045.
Design:
Participants will check into the clinic for a 3-day stay.
They will have a lumbar puncture: An area on their lower back will be numbed. A thin needle will be inserted into the space around the spinal cord. A sample of CSF will be taken for research. Then a low dose of gadobutrol will be injected into the CSF.
Participants will have 4 or 5 MRI scans of the brain-30 minutes, 4 hours, 8 hours (this one is optional), 24 hours, and 48 hours after receiving the gadobutrol.
For the scan, they will lie on a table that slides into a cylinder. Special padding will be used to hold their head still. The MRI uses magnetic fields to create images of the inside of the body. Blood and urine samples will also be collected at each scan.
Participants will return for an additional MRI 1 week after they leave the clinic. They will have 2 follow-up phone calls 4 and 12 weeks after the start of the study.
연구 개요
상태
상태
정황
정황
개입 / 치료
개입 / 치료
상세 설명
Study Description:
In this study, we will gather safety data on and establish the technical feasibility of bypassing the blood-brain-barrier (BBB) with intrathecal (IT) gadolinium-based contrast agent (GBCA) tracer injection (0.25 ml gadobutrol at a concentration of 1.0 mmol/ml) to dynamically image the subarachnoid space (SAS) in human healthy volunteers. We will also obtain preliminary data on whether this approach will enable us to reliably visualize physiological meningeal lymphatic drainage pathways within the parasagittal dura (PSD) and connections to cerebrospinal fluid (CSF) compartments using serial contrast-enhanced magnetic resonance imaging (CE-MRI) with minimal confounding signal from tracer blood egress. In exploratory analysis, we will quantify temporal clearance kinetics and investigate distribution patterns of GBCA enhancement in the PSD, CSF spaces, and brain parenchyma in up to 12 healthy volunteers using repeated in vivo CE-MRI over 10 days. Safety/tolerability of the IT GBCA administration will be assessed descriptively over the entire 12-week study period.
Objectives:
Primary objective: To track safety/tolerability of IT GBCA administration in healthy human volunteers.
Secondary objective: To establish technical feasibility of dynamic subarachnoid-space imaging using IT GBCA administration in healthy human volunteers.
Exploratory objectives: To explore patterns of dynamic meningeal lymphatic clearance pathway interconnections in vivo under physiological conditions in human healthy volunteers, and to obtain preliminary data regarding the effect of aging on CSF dynamics and CSF-to-blood tracer clearance.
Endpoints:
Primary endpoint: Occurrence of intervention-emergent adverse events at the participant level assessed descriptively over the 12-week study period.
Secondary outcome measure: MRI detection status (yes/no) of contrast in the cerebral SAS at 24 hours.
Exploratory outcome measures: Changes in contrast-to-noise ratio (CNR) and clearance kinetics of SAS to brain parenchyma over 48h.
연구 유형
연구 유형
등록 (추정된)
등록
단계
단계
- 1단계
연락처 및 위치
연구 연락처
연구 연락처
- 이름: Daniel S Reich, M.D.
- 전화번호: (301) 496-1801
- 이메일: reichds@ninds.nih.gov
연구 연락처 백업
- 이름: Maria I Gaitan, M.D.
- 전화번호: (301) 496-1801
- 이메일: maria.gaitan@nih.gov
연구 장소
-
-
Maryland
-
Bethesda, Maryland, 미국, 20892
- National Institutes of Health Clinical Center
-
연락하다:
- Joy Osuebi
- 전화번호: Not Listed
- 이메일: joy.osuebi@nih.gov
-
연락하다:
- Maria Gaitan
- 전화번호: Not Listed
- 이메일: maria.gaitan@nih.gov
-
-
참여기준
자격 기준
자격 기준
공부할 수 있는 나이
- 성인
- 고령자
건강한 자원 봉사자를 받아들입니다
설명
- INCLUSION CRITERIA:
To be eligible to participate in this study, an individual must meet all the following criteria:
- Healthy volunteer.
- Age >= 18 years.
To explore age-related effects on tracer dynamics and clearance, 3 cohorts of participants will be recruited: 1) 18-30 years, 2) 30-55 years, and 3) >55 years; with 2 males and 2 females in each age group.
- Able to give written and oral informed consent.
- Prior evaluation under NIH protocol 89N0045.
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
- History of chronic neurological illness, or significant concurrent medical illness.
- Contraindication to 3- or 7-tesla MRI
- Hypersensitivity reactions to contrast agents.
- History of severe allergic reactions.
- Pregnancy or breastfeeding.
- Renal dysfunction or other serious comorbidities.
- Platelet count <100,000/microliter, INR > 1.5 or prolonged PT or aPTT at baseline.
- Any of the following imaging findings: Mass effect, midline shift, herniation (tonsillar, uncal, subfalcine), or Chiari malformation.
- History of seizures or seizure disorder.
- Anti-coagulation therapy.
- Unwilling to allow coded samples to be processed offsite.
- Unwilling to have coded samples and/or data saved or used in other studies.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 다른
- 할당: 무작위화되지 않음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
팔의 수
무기와 개입
참가자 그룹 / 팔참가자 그룹 / 팔 |
개입 / 치료개입 / 치료 |
|---|---|
|
실험적: Healthy Volunteer
0.25 mmol IT gadobutrol or 0.5 mmol
|
contrast agent
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연구는 무엇을 측정합니까?
주요 결과 측정
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Occurrence of intervention-emergent adverse events at the participant level assessed descriptively
기간: 12-week study period.
|
Systematic recording of adverse events is essential to determine the safety of IT gadobutrol, especially given its off-label use in healthy volunteers.
With the limited sample size of this Phase 1 study, safety assessment is appropriately based on a descriptive evaluation rather than formal hypothesis testing.
Monitoring known procedure- and contrast-related risks (e.g., post-lumbar puncture headache, nausea, dizziness) as well as any unexpected adverse events over the study and follow-up period provides the critical foundation for ethical justification and regulatory decision-making and is a prerequisite for future feasibility and efficacy-driven studies.
|
12-week study period.
|
2차 결과 측정
2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Participant-level MRI detection status (yes/no) of contrast in the cerebral SAS
기간: 24 hours
|
Technical feasibility is assessed by determining whether IT administered GBCA can be visually detected in the cerebral SAS at 24 hours under exploratory Phase 1 conditions.
As this is a pilot safety study with limited prior human data, feasibility is not used as a stopping criterion.
Instead, MRI visibility of contrast will inform adaptive dose escalation.
If no or insufficient contrast enhancement is observed in 3 to 5 participants at the initial dose level (0.25 ml), the dose may be escalated to 0.5 ml to improve detectability.
This predefined adaptation is intended to support appropriate dose selection for subsequent studies while maintaining the focus on safety.
|
24 hours
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공동 작업자 및 조사자
스폰서
스폰서
수사관
수사관
- 수석 연구원: Daniel S Reich, M.D., National Institute of Neurological Disorders and Stroke (NINDS)
간행물 및 유용한 링크
일반 간행물
- Louveau A, Herz J, Alme MN, Salvador AF, Dong MQ, Viar KE, Herod SG, Knopp J, Setliff JC, Lupi AL, Da Mesquita S, Frost EL, Gaultier A, Harris TH, Cao R, Hu S, Lukens JR, Smirnov I, Overall CC, Oliver G, Kipnis J. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018 Oct;21(10):1380-1391. doi: 10.1038/s41593-018-0227-9. Epub 2018 Sep 17.
- Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6:e29738. doi: 10.7554/eLife.29738.
- Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9. doi: 10.1084/jem.20142290. Epub 2015 Jun 15.
- Eide PK, Lashkarivand A, Hagen-Kersten AA, Gjertsen O, Nedregaard B, Sletteberg R, Lovland G, Vatnehol SAS, Pripp AH, Valnes LM, Ringstad G. Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus. Front Neurol. 2022 Apr 6;13:857328. doi: 10.3389/fneur.2022.857328. eCollection 2022.
- Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. doi: 10.1038/nature14432. Epub 2015 Jun 1.
- Eide PK, Ringstad G. Cerebrospinal fluid egress to human parasagittal dura and the impact of sleep deprivation. Brain Res. 2021 Dec 1;1772:147669. doi: 10.1016/j.brainres.2021.147669. Epub 2021 Sep 26.
- Ringstad G, Eide PK. Safety of Intrathecal Gadolinium-based Contrast Agents and Benefit versus Risk. Radiology. 2021 Apr;299(1):E223-E224. doi: 10.1148/radiol.2021203351. Epub 2021 Feb 16. No abstract available.
- Patel M, Atyani A, Salameh JP, McInnes M, Chakraborty S. Safety of Intrathecal Administration of Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology. 2020 Oct;297(1):75-83. doi: 10.1148/radiol.2020191373. Epub 2020 Jul 28.
- Halvorsen M, Edeklev CS, Fraser-Green J, Lovland G, Vatnehol SAS, Gjertsen O, Nedregaard B, Sletteberg R, Ringstad G, Eide PK. Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols. Neuroradiology. 2021 Jan;63(1):51-61. doi: 10.1007/s00234-020-02519-4. Epub 2020 Aug 15.
- Edeklev CS, Halvorsen M, Lovland G, Vatnehol SAS, Gjertsen O, Nedregaard B, Sletteberg R, Ringstad G, Eide PK. Intrathecal Use of Gadobutrol for Glymphatic MR Imaging: Prospective Safety Study of 100 Patients. AJNR Am J Neuroradiol. 2019 Aug;40(8):1257-1264. doi: 10.3174/ajnr.A6136. Epub 2019 Jul 18.
- Eide PK, Lashkarivand A, Pripp A, Valnes LM, Hovd MH, Ringstad G, Blennow K, Zetterberg H. Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders. Nat Commun. 2023 Apr 12;14(1):2084. doi: 10.1038/s41467-023-37685-5.
- Okar SV, Dieckhaus H, Beck ES, Gaitan MI, Norato G, Pham DL, Absinta M, Cortese IC, Fletcher A, Jacobson S, Nair G, Reich DS. Highly Sensitive 3-Tesla Real Inversion Recovery MRI Detects Leptomeningeal Contrast Enhancement in Chronic Active Multiple Sclerosis. Invest Radiol. 2024 Mar 1;59(3):243-251. doi: 10.1097/RLI.0000000000001011.
- Zhou Y, Cai J, Zhang W, Gong X, Yan S, Zhang K, Luo Z, Sun J, Jiang Q, Lou M. Impairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human. Ann Neurol. 2020 Mar;87(3):357-369. doi: 10.1002/ana.25670. Epub 2020 Jan 30.
- Okar SV, Fagiani F, Absinta M, Reich DS. Imaging of brain barrier inflammation and brain fluid drainage in human neurological diseases. Cell Mol Life Sci. 2024 Jan 12;81(1):31. doi: 10.1007/s00018-023-05073-3.
- Ringstad G, Eide PK. Cerebrospinal fluid tracer efflux to parasagittal dura in humans. Nat Commun. 2020 Jan 17;11(1):354. doi: 10.1038/s41467-019-14195-x.
- Eide PK, Pripp AH, Ringstad G, Valnes LM. Impaired glymphatic function in idiopathic intracranial hypertension. Brain Commun. 2021 Mar 21;3(2):fcab043. doi: 10.1093/braincomms/fcab043. eCollection 2021.
- Eide PK, Mariussen E, Uggerud H, Pripp AH, Lashkarivand A, Hassel B, Christensen H, Hovd MH, Ringstad G. Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood. JCI Insight. 2021 May 10;6(9):e147063. doi: 10.1172/jci.insight.147063.
- Smyth LCD, Xu D, Okar SV, Dykstra T, Rustenhoven J, Papadopoulos Z, Bhasiin K, Kim MW, Drieu A, Mamuladze T, Blackburn S, Gu X, Gaitan MI, Nair G, Storck SE, Du S, White MA, Bayguinov P, Smirnov I, Dikranian K, Reich DS, Kipnis J. Identification of direct connections between the dura and the brain. Nature. 2024 Mar;627(8002):165-173. doi: 10.1038/s41586-023-06993-7. Epub 2024 Feb 7.
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
연구 시작
기본 완료 (추정된)
기본 완료
연구 완료 (추정된)
연구 완료
연구 등록 날짜
최초 제출
최초 제출
QC 기준을 충족하는 최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
처음 게시됨
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
마지막 업데이트 게시됨
QC 기준을 충족하는 마지막 업데이트 제출
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
기타 연구 ID 번호
- 10002744
- 002744-N
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
IPD 공유 기간
IPD 공유 액세스 기준
IPD 공유 지원 정보 유형
- CSR
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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