Rationale for Quantitative MRI of the Human Spinal Cord and Clinical Applications

1.1.2.1

Diffusion Tensor Imaging

Diffusion imaging methods in the spinal cord are extensively described in Chapter 3 . The DTI model can be used to derive indices that quantitatively describe the directional diffusivity of extracellular water within white matter tracts. Data from animal studies have suggested that DTI-derived indices reflect underlying tissue structure. In particular, in animal models, such as experimental allergic encephalomyelitis (EAE), demyelination within white matter tracts leads to an increase in radial diffusivity (RD), while axonal loss is expected to cause a reduction in axial diffusivity (AD) (see Chapter 3.1 ). However, the situation is more complicated in human diseases, and it is likely that both demyelination and axonal loss influence both RD and AD; furthermore, changes in RD can be observed in animal models even in the absence of myelin changes.

Among the best known DTI parameters is fractional anisotropy (FA), which reflects the underlying tissue microstructure, including the coherence of white matter fibers. In addition to FA, RD, and AD, the mean diffusivity (MD) can be obtained. This parameter is very sensitive to a general change in tissue microstructure that allows water molecules to move less or more freely; for example, a reduction of the MD has been detected following acute neurological insults, but in chronic neurological disease, or where cellular necrosis leads to increased membrane permeability, a relative increase in the MD value can be seen.

Therefore, despite the difficulties in extrapolating from animal studies to human studies, spinal cord DTI-derived parameters have the potential to be used as biomarkers of both myelin and axonal integrity, and they have been demonstrated to significantly change over time after an acute injury, such as an acute demyelinating lesion.

FA, RD, AD, and MD can be measured within the spinal cord using regions of interest (ROIs), which can be drawn on the basis of the user's anatomical knowledge or can be measured within tracts, which are reconstructed using fiber-tracking (FT) algorithms. Probabilistic tractography algorithms allow the user to obtain an estimate of white matter connectivity within the spinal cord, which may be affected as a consequence of disease. Temporal changes in DTI metrics may become a useful method for monitoring disease progression or response to future neuroprotective agents in neurodegenerative diseases. The ability to visualize the major white matter tracts within the spinal cord also has potential clinical applications for preoperative surgical planning. Detailed imaging of the fiber tracts preoperatively can provide information regarding the integrity of tracts and allow the clinician to predict the potential benefit from surgery more accurately; slow-growing spinal tumors may efface tracts, leaving them relatively intact and making surgical resection less complicated, while more aggressive, invasive tumors are more likely to cause significant structural disruption to the tracts, which increases the risk of significant postoperative neurological deficits. Presurgical assessments of this type will empower clinicians and patients to proceed with surgery only when there is a favorable risk–benefit ratio.

Wheeler-Kingshott et al. reported a uniform MD along the cervical spinal cord, but found a higher FA in the middle and lower sections of the cervical cord compared with the upper cervical cord. Regional differences in DTI metrics of the cervical cord have also been reported by Mamata et al. who reported higher mean values for the apparent diffusion coefficient (ADC) and FA in the upper cervical cord (C2–C3) than in the lower level (C4–C7) in healthy volunteers. These findings suggest that regional DTI measures should be compared between patients and controls whenever possible, since averaging values of DTI measures may dilute the effect of focal pathology. For DTI studies that are discussed in this chapter, spinal level is summarized in Table 1.1.1 .

1.1.2.2

Proton Magnetic Resonance Spectroscopy

Proton magnetic resonance spectroscopy (MRS) (see Chapter 5 ) is a powerful tool that allows quantification of metabolite concentrations from human tissue in vivo. Reliable quantification of metabolites from the spinal cord using 1.5 T scanners has been limited to a few metabolites, namely N -acetylaspartate (NAA), choline (Cho), and creatine (Cr). However, over the past decade, developments in imaging acquisition and postprocessing, together with a wider availability of high-field-strength scanners, which allow increased separation of metabolite peaks, have permitted the study of metabolites with more specific relevance to the pathogenesis of neurological diseases, such as glutamate-glutamine (Glx) and myo-inositol (Ins).

NAA is synthesized by neuronal mitochondria, and it is commonly used as a marker of axonal integrity and/or metabolic dysfunction in neuroimaging studies. More recently, studies modeling NAA concentrations in the spinal cord with other markers of axonal integrity, such as cross-sectional cord area, demonstrate that mathematically derived estimates of mitochondrial function can be made from spectroscopic data. The development of such imaging biomarkers of mitochondrial function has wide implications for studying a large number of neurological diseases in which mitochondrial dysfunction is thought to be important. Although changes in NAA are not disease specific, they can be detected early in the disease course, making them a sensitive indicator of neuroaxonal injury when conventional imaging fails to detect any change.

NAA concentrations can be expressed as absolute values, or more commonly as ratios with Cr or Cho. The Cr signal, which is a composite peak of creatine and phosphocreatine, is a better reference signal as levels are thought to be quite constant in the nervous system. In neurological disease, however, changes in the resonance intensity of both Cr and Cho have been suggested; for example, changes in Cho are thought to reflect increases in the steady-state levels of membrane phospholipids released during myelin breakdown, as is seen in active demyelinating disease.

Lactate is produced as a by-product when cells within the nervous system respire under anaerobic conditions. Elevations in brain lactate have been detected using MRS in cerebral ischemia, brain tumors, and mitochondrial disease. Although it is thought that lactate may be a relevant marker in spinal cord pathology, it is likely to be produced in much smaller concentrations, making its detection in healthy subjects difficult, if not impossible.

As with DTI, it is possible that the spinal cord level is an important methodological consideration with MRS experiments. A small study by Edden et al. found a nonsignificant variation in metabolite concentrations between the upper cervical cord and the medulla. Additional work is needed to evaluate whether metabolite concentrations differ between cervical, thoracic, and lumbar segments of the spinal cord.

1.1.2.3

Magnetization Transfer Imaging

Magnetization transfer imaging (see Chapter 3.4 ) is based on the interaction between hydrogen protons bound to macromolecules, such as those associated with lipids and lipoproteins, and the free protons normally imaged by MRI. MTR, obtained by magnetization transfer imaging, can be used as an indirect marker of demyelination and possibly axonal loss. In patients with MS, high-resolution magnetization transfer measurements from the spinal cord have demonstrated that it is possible to assess tissue damage, including demyelination (and possibly axonal loss) of specific spinal pathways, with good accuracy. However, in neurodegenerative diseases other than MS, the use of magnetization transfer imaging has largely been confined to studies of brain changes, and very few studies have focused on the spinal cord. Brain MTR has been incorporated as an exploratory endpoint to assess treatment efficacy in large multicenter trials, and similar studies of spinal cord disease are still awaited. Relevant studies of spinal cord disease that have used MTR will be discussed in this chapter.

1.1.3.1

Multiple Sclerosis

MS is an inflammatory disorder of the central nervous system characterized by inflammation, demyelination, incomplete remyelination, axonal loss, and gliosis. Clinically evident signs and symptoms then develop that reflect impaired salutatory conduction at affected sites. At disease onset, MS can present either with a relapsing, remitting clinical course or with progressive accumulation of neurological symptoms and disability. The lifetime risk is thought to be approximately 1 in 400, making MS the commonest cause of progressive neurological disability affecting young people.

MS is characterized by the recurrent formation of multifocal plaques in both white matter and gray matter. The white matter plaques are readily visible on T2-weighted and proton density (PD)-weighted MRI, and imaging of these lesions at the onset of the first clinical symptoms predicts conversion to clinically definite MS with good accuracy. Imaging of white matter lesions has subsequently been incorporated into the diagnostic criteria for MS since 2001.

The availability of good histopathological data on MS plaques and their visibility on PD and T2 imaging have made them a convenient marker of disease progression, but lesion frequency and volumes do not always explain the degree of clinical disability in patients. qMRI research has therefore tried to fill this gap to improve our understanding of the mechanisms causing disability in MS.

As the most visually evident imaging abnormality in MS, focal T2 lesions might be expected to be the predominant substrate of disability. but spinal cord lesion load does not correlate well with disability, even when disability is determined by using a clinical measure such as the expanded disability severity score (EDSS), which is heavily weighted toward spinal cord functions, such as ambulation. In fact, spinal cord T2 lesions are often clinically silent. Asymptomatic spinal cord lesions have been reported in about 50% of patients with clinically isolated syndromes (CIS) and early MS.

This clinico-radiological paradox might partly be explained by difficulties in accurately quantifying neurological dysfunction, but it is more likely to be explained by the lack of sensitivity and specificity of conventional MRI techniques for detecting microscopic histopathological change. Axonal loss, which is the principal substrate for disability in MS, occurs largely independently of T2-weighted lesions. New quantitative MRI techniques, which are more sensitive to change in underlying tissue microstructure and metabolism within the spinal cord, show much better correlation with disability and can more accurately discriminate between patients with similar T2 lesion loads on the basis of disability.

We will now review studies that used volumetric imaging, MRS, DTI, and MTR of the spinal cord in patients with MS.