Investigating Cortical Gray Matter Demyelination in Primary Progressive Multiple Sclerosis at 7 Tesla
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Distribution of cortical lesions in PPMS
研究概览
简要总结
Progressive-onset multiple sclerosis (PPMS) occurs in about 15% of all people living with MS. PPMS remains understudied, and most disease-modifying treatments are ineffective for PPMS. To date, it is unknown why some people progress immediately from MS onset. The present study will assess the role of gray matter in PPMS by characterizing it with ultra-high field magnetic resonance imaging (MRI). While both white and gray matter are affected in relapsing MS, in PPMS tissue damage is primarily in the cortex. Cortical gray matter consists largely of neuronal cell bodies, which send electrical signals to create a functional response, such as arm or leg movement. While white matter damage slows the signal response, cortical damage inhibits the initial creation of electrical signals. There is a great need to research and develop scientific biomarkers to identify and monitor progression and repair in PPMS. In this project, 7 Tesla MRI is used to investigate the cortical gray matter in people with PPMS. 7 Tesla MRI is the safest and most detailed way to study the brain. Because the cortex is only a few millimeters thick, it has been traditionally difficult to investigate. At 7 Tesla, different layers and lesions within the cortex can be seen. In addition, this project will use myelin-sensitive MRI to determine the biological underpinnings of both cortical lesions and the 'normal appearing' cortical damage in PPMS. This will answer relevant questions about the brain's capacity for repair, the extent of demyelination and the occurrence of inherent cortical remyelination and provides an avenue for the development of novel clinical MR biomarkers tailored to PPMS.
详细描述
PURPOSE:
PPMS presents very differently from relapsing-remitting MS. Spinal cord involvement is greater and motor impairment significantly outweighs sensory symptoms. Contrast-enhancing lesions are infrequent in PPMS. Instead, gray matter atrophy and cortical demyelination occur at greater rates than in relapsing MS. Cortical involvement is prognostically relevant. MRI at standard clinical field strengths (e.g. 1.5 and 3 Tesla) has clear limitations for visualizing cortical damage. In particular, demyelination at the outer cortical layers is underestimated. Although 7 Tesla MRI is known to be superior to clinical MRI, myelin imaging has not yet been widely explored at 7 Tesla.
STUDY AIMS:
Use anatomical and quantitative MRI at 7 Tesla to identify radiologically visible and invisible features of cortical gray matter damage that contribute to physical and cognitive impairment in PPMS.
The specific project aims are
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Diagnosed with primary progressive multiple sclerosis
- •Expanded Disability Status Scale of ≤ 6.5
- •No clinical relapse within last three months
- •Have the ability to comply with all requirements of the study protocol, as determined by the investigator
排除标准
- •Pregnancy
- •Pacemaker or other implanted electronic devices
- •Claustrophobia
- •Psychiatric disorder
- •Administration of acute cortisol
- •Changes in pharmacological treatment within the last 3 months
- •Any contraindication to MRI
- •Persons who do not wish to be informed about abnormal findings as part of the investigations
- •HEALTHY CONTROLS
- •Inclusion Criteria:
- •Able bodied
- •Have the ability to comply with all requirements of the study protocol, as determined by the investigator
- •Exclusion Criteria:
- •Pregnancy
- •Under medication at the time of the experiment (with the exception of contraceptive drugs)
- •History of neurologic disease
- •Pacemaker or other implanted electronic devices
- •History of cerebral hemorrhage or brain damage
- •Claustrophobia
- •Psychiatric disorder
- •Any contraindication to MRI
- •Persons who do not wish to be informed about abnormal findings as part of the investigations
结局指标
主要结局
Distribution of cortical lesions in PPMS
时间窗: Baseline
Three different types of cortical lesions will be quantified across all cortical areas (Leuko- and Intracortical, Subpial). Their number in each area will be compared to existing data of RRMS and SPMS patients. Most patients are expected to show cortical lesions. It will be assessed which areas of the cortex are affected earliest in PPMS.
Volume of cortical lesions in PPMS
时间窗: Baseline
The volume of the different cortical lesion subtypes \[in cubic mm\] will be quantified and compared to lesion volumes in RRMS and SPMS patients. It will be assessed which type of damage, i.e. which of the three lesion types, drives motor and cognitive impairment using linear regression models. The investigators hypothesize that more extensive cortical demyelination will relate to lower/worse test scores.
Identify central veins and the presence of paramagnetic rims for cortical lesions
时间窗: Baseline
Susceptibility-sensitive imaging data will be pre-processed as described in literature and co-registered with other anatomical MRI data. It will be assessed whether the location of veins or paramagnetic rims matches areas of already identified lesions. Although central veins have gained large attention in white matter lesions as an additional diagnostic criterium, their presence and role in cortical lesions is less well understood. Paramagnetic rims of MS lesions have been identified as highly relevant predictors of active disease progression. Their prevalence in PPMS \[in %\] will be assessed and relationships to clinical, behavioural and MRI metrics will be explored in mixed effects models that account for other patients specific (age, gender, disease duration, EDSS) or lesion-specific variables (volume, lesion subtype).
Quantitative assessment of myelin density in cortical lesions, perilesional gray and white matter, and normal appearing cortex using myelin water imaging
时间窗: Baseline
On a group level, the myelin water fraction \[in %\] will be compared between cortical lesion subtypes and the normal appearing cortex. Lesions and normal appearing cortex are expected to have lower myelin density than cortical gray matter in non-neurological individuals. The variance in myelin density among lesions is expected to be high as various degrees of demyelination and remyelination may be present. Remyelination capacity of cortical lesions may be higher than in white matter lesions and thus myelin differences between cortical lesions and normal appearing cortex may be small. Myelin water fraction values will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that lower myelin densities, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.
Quantitative assessment of fractional anisotropy in cortical lesions, perilesional gray and white matter, and normal appearing cortex using diffusion tensor imaging data
时间窗: Baseline
Fractional anisotropy (FA) is a commonly used diffusion metric for the assessment of tightly packed, myelinated axons in white matter. FA and other diffusion metrics will be compared between the cortical lesion subtypes and the normal appearing cortex. On average, lower microstructural anisotropy is expected in lesions as a reflection of demyelination and partial axonal loss. FA values will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that lower FA, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.
Quantitative assessment of magnetization transfer in cortical lesions, perilesional gray and white matter, and normal appearing cortex
时间窗: Baseline
Similarly, magnetization transfer indices will be assessed between lesion subtypes, normal appearing cortex and compared to cortical gray matter in non-neurological individuals. Instead of assessing directly the relaxation times of different water environments, MT provides an indirect assessment of the interaction of mobile and bound protons. Here, the macromolecular bound pool signal fraction \[in %\] will be assessed relative to clinical and behavioural metrics in mixed effects models. The investigators hypothesize that smaller pool fractions, in addition to the volume of cortical demyelination, will relate to lower/worse test scores.
次要结局
- Number of cortical lesions in the primary sensorimotor cortex (SM1)(Baseline)
- Motor function(Baseline)
- Regional metabolite concentration of the SM1(Baseline)
- Functional MRI data for the assessment of temporal synchronization(Baseline)
- Cognitive performance and relationship to MRI measures (Exploratory)(Baseline)
- Sensory acuity(Baseline)
- Cortical lesion volume in the primary sensorimotor cortex (SM1)(Baseline)
研究者
Hartwig R. Siebner
Professor
Danish Research Centre for Magnetic Resonance