Neuroimaging Advances in Amyotrophic Lateral Sclerosis

Structural Imaging in Amyotrophic Lateral Sclerosis

According to the revised El-Escorial criteria, evidence of upper and lower motor neuron development is needed for the diagnosis of ALS. However, there is no in vivo marker available for involvement of the upper motor neurons, and involvement of the lower motor neurons often masks upper motor neuron involvement. There is a pronounced delay between the onset of symptoms and diagnosis. Neuroimaging in ALS is mostly used to exclude other pathologies to increase the probability for the diagnosis of ALS rather than to provide definite evidence. Positive evidence may only be subtle and unspecific, although there are some signs in neuroimaging data with positive predictive value.1 for clinical diagnosis.

Criteria based on these findings are used

One of the most widely used structural imaging techniques in the clinical diagnosis of ALS is MRI, which provides high-contrast images of anatomical structures.2

controls). Evidence of changes in various cortical and subcortical regions in patients with ALS has been provided using this technique.3–5

DTI and DTI-based fibre tracking (FT) are unique ways to learn more about human neuroanatomy, especially white matter, in vivo.6

In ALS,

DTI has the potential to non-invasively visualise the involvement of the upper motor neurons. It has the greatest diagnostic potential in ALS and the number of DTI studies has increased markedly over the last few years. DTI is based on the concept of diffusion of molecules according to Brownian motion. Diffusion-weighted MRI (DWI) can be used to determine diffusion within tissue in the human body. Membranes, tracts and other constraints in human tissue reduce free (isotropic) diffusion of molecules. Molecular diffusion is reduced perpendicularly to those barriers and, accordingly, aligns along those barriers. This anisotropy can be measured with DTI. Fractional anisotropy (FA) is a parameter of the disruption of diffusion within tracts of the human body.7

DTI is highly sensitive to the loss of directed Voxel- and tensor-based morphometry

MRI (VBM and TBM) enables quantitative measures of grey- and white-matter volume loss. Diffusion-weighted MRI (DTI) is mostly used for the detection of white-matter pathology. MRS complements MRI by providing information about the histological properties of tissue. Arterial spin labelling (ASL) MRI measures regional brain perfusion and complements the field of connectivity and therefore structural conditions in the brain. Other structural imaging methods such as X-ray radiography and computed tomography (CT), which are based on the fact that different tissues absorb different amount of X-rays depending on their density, have lost their importance in ALS diagnostics and are mostly used in emergency diagnostics.

MRI is based on the fact that atoms with uneven nucleus numbers have a magnetic moment. In living organisms this fact can best be exploited using hydrogen. A patient is placed inside a constant magnetic field and the nuclear spins of hydrogen atoms (for example) are aligned. Radiofrequency pulses (gradients) are used to alter the energetic states of the hydrogen atoms. When the gradients are turned off, the atoms revert to their original energetic state and the spare energy is radiated. Different types of tissue have different ratios of hydrogen and, accordingly, radiate different amounts of energy. T1- and T2-weighted MRI can be best used to assess anatomical structures of brain structure and the cervical spine. Artefacts of bone structures are not a problem, unlike in CT. MRI of the cervical spine is one of the most prominent and significant techniques to rule out, for example, lesions of the myelon in cervical myelopathy or polyradicular lesions. Vascular lesions such as those seen in cerebral microangiopathy in aged people can present signs that resemble ALS. However, great experience is needed to distinguish between artefacts and positive results. Furthermore, MRI has no predictive value for histological properties of tissue. Some further limitations concern the implementation of MRI. No metal is allowed inside the MRI scanner and therefore pacemakers and surgical clips are a contraindication. Claustrophobic patients have difficulties spending half an hour inside an MRI scanner. Open systems have been developed but they have lower field strength and lower resolution, leading to longer scanning times and an increase in the time needed to take measurements.

TBM and VBM can be used to determine volumes of tissues in MR images. Differences in the volume of grey and white matter in the brain can be analysed between groups (e.g. between patients and

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fibre tracts such as those in the pyramidal tract. Accordingly, it allows quantitative measurement of white matter loss of cortical and cervical motor neurons in ALS. The first evidence of reduced FA in ALS patients compared with healthy controls emerged as early as the 1990s.8

In

regions-of-interest (ROI) analysis, there was evidence that FA reduction correlated with disease severity and clinical affection of the upper motor neuron. This was most prominent for ALS patients with bulbar onset. Further evidence for FA reduction was also given for other parts of the pyramidal tract. However, these ROI-based analyses were highly dependent on intra- and inter-rater variance of ROI placement. Semi-automated techniques have since been developed.9 Recent advances in DTI analysis have led to evidence of affection of the upper motor neurons in ALS before clinical onset of the disease, and therefore this technique might serve as an early clinical marker for the disease in motor and extramotor areas such as the frontal, temporal and occipital areas.10–12

Currently, there are high constraints

in using DTI for detecting FA changes in the cervical myelon. The limited spatial resolution and vulnerability for movement artefacts of echo planar imaging (EPI) sequences, which are usually used for DTI measurements, necessitate thorough implementation of acquisition, planning and study design as well as high patient compliance.

There is evidence supporting MRS as a helpful technique for monitoring disease progression.13,14

Based on measurements of the

nuclear properties of a substrate, metabolites can be detected in the brain; for example, cortical N-acetyl-aspartate (NAA) can be measured non-invasively using MRS. Reduced NAA levels in the cortical motor areas of ALS patients have been shown to correlate with the severity of the disease. Furthermore, cortical NAA has been associated with reduced survival time and might therefore have potential as a biomarker for ALS.15

Proton MRS has been suggested as

MRS has been applied clinically in medical treatment trials.16 ASL perfusion has similarly been suggested to be a useful tool for monitoring disease progression in ALS.17

a useful tool for reflecting the characteristic changes of metabolites in ALS.14

Functional Imaging in Neuroscience Neuroscience aims to explore the functional state of the brain as well as the capacity of the adult brain to functionally compensate for a progressive loss of neurons. Non-invasive functional neuroimaging techniques that can effectively map brain functions have now been available for almost 80 years. Since different techniques have different shortcomings, the development and implementation of new

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