SP # 6: Quantifying Demyelination and Axonal Loss with Diffusion MRI

Quantifying Demyelination and Axonal loss with Diffusion MRI

Significance:

Demyelination and axonal loss are common pathological features found in multiple sclerosis (MS), Alzheimer’s disease (AD) and in other diseases of the central nervous system [1-12]. While there is currently no treatment to reverse damage to axons, demyelination has been shown to be a reversible process [13,14]. Quantitative, noninvasive biomarkers for both demyelination and axonal loss would improve accuracy of diagnosis and be essential tools for monitoring treatment response and providing effective patient management.

We recently introduced a white matter (WM) model (Figure 1) that allows a direct physical interpretation of the non-Gaussian diffusion signal as measured with diffusional kurtosis imaging (DKI)[15,16]. Analysis with this model yields specific WM microstructural integrity metrics such as intra- and extra-axonal diffusivities, axonal water fraction (AWF) and tortuosity (α) of the extra-axonal space[17]. Our modeling suggests that α correlates strongly with the thickness of the myelin sheath, and AWF correlates strongly with the axonal density. We have confirmed these findings both analytically and numerically. In addition, we have demonstrated that measurements of AWF and α in MS and AD patients are consistent with their expected pathology.

Aims:

The main goals of this study are histological validation of the predictions of our model, and preliminary evaluation of the utility of AWF and α in monitoring disease progression and recovery.  We will determine the relationship between the tortuosity and AWF using in vivo DKI in an animal model. We will also determine the longitudinal changes in tortuosity and AWF during cuprizone intoxication and recovery.

Approach:

Acute and chronic cuprizone intoxication will be induced in C57BL/6 mice by a 6-week and 12-week cuprizone diet, respectively. Acute intoxication leads to demyelination without significant axonal los [18], while chronic intoxication leads to demyelination with significant axonal loss [19]. DKI will be conducted on both control and cuprizone intoxicated mice, followed by histopathological study. Myelin thickness will be measured on electron microscopy images; axonal density will be measured with SMI-31 staining. To observe the longitudinal changes of α and AWF, DKI then will be monitored every 2 weeks over the course of a 6-week recovery period with a normal control diet following cuprizone intoxication. 

BTRC Resources Utilized:

TR&D#1: Interaction with the BTRC will advance our study aims beyond their original scope in a number of ways.  Currently, we use a conventional 2D DW-GRASE sequence with an in-plane resolution of 120 x 120 µm2, which restricts our analysis to the genu and splenium of the corpus callosum (CC). Alternatively, decreasing the voxel size to an in-plane resolution of 50 x 50 µm2 would reduce bias associated with partial voluming, and would allow testing our analysis in more WM regions, e.g. the body of CC, fimbria, fornix, etc.  Combining a DW radial pulse sequence with compressed sensing image reconstruction, using techniques developed in TR&D 1, could compensate for the corresponding increase in acquisition time and loss in SNR, and potentially enable a much broader validation of the proposed biomarkers.  Early pilot studies in humans will also be pursued.

TR&D #2: We will also benefit from a dedicated multi-channel transmit-receive surface coil array for mouse imaging which will be developed by the BTRC’s RF engineering group. 

TR&D #3: Access to PET technology and novel tracer and biomarker development is another important part of this project. Since the original submission, we have received funding from the Alzheimer’s Disease foundation for preliminary methodological work on WM involvement in preclinical AD using MR-PET.  In future, we will use the (currently operational) animal microPET/CT scanner at NYUSOM with tracers including the myelin imaging agent [11C] CIC_ENREF_19 [20] and the tau imaging agent [18F]-T808 [21],  for cross-validation of our MR-based WM integrity measures

Principal Investigator: 

Sponsors

Latest Updates

10/31/2017 - 11:54
10/31/2017 - 11:37

Philanthropic Support

We gratefully acknowledge generous support for radiology research at NYU Langone Medical Center from:
 
• The Big George Foundation
• Raymond and Beverly Sackler
• Bernard and Irene Schwartz

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