ALS is not just a disease of the primary motor area of the brain.

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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 26 months after diagnosis. It usually affects older adults and is characterized by progressive weakness in the muscles of the limbs and difficulty speaking and swallowing.

Also and to differentiate this disease from other diseases with similar symptoms, for over a century ALS has been defined as a disease of the higher motor neurons. However, this definition is artificial in that for most of these 100 years it has been impossible to directly verify the state of upper motor neurons in patients.

The very great diversity of symptoms has led "theoretical" doctors to introduce new pathologies (PLS, PMA, MMA, PLS, PBP) which seem very far from clinical reality.

Finger and foot tapping scores have long been used as a surrogate for upper motor neuronal dysfunction in ALS studies. Myography studies are also very subjective.

Moreover, a minority of scientists do not share this point of view and prefer a hypothesis called "dying backward" where the disease begins either in a muscle or at the muscle / lower motor neuron junction, which is found in the peripheral nervous system. .

For the past fifteen years, scientists have recognized that frontotemporal dementia (FTD) is present in about 10% of patients at the time of diagnosis, with up to 50% of patients showing cognitive and behavioral deficits on detailed neuropsychometric tests. Frontotemporal dementia also has molecular characteristics similar to the majority of cases of ALS.

Fortunately, more and more doctors and scientists are using medical imaging to examine patients with neurodegenerative diseases. Functional MRI studies have demonstrated reduced cortical activity in the prefrontal cortices during voluntary movement tasks in patients with ALS. This indicates that the classic definition of ALS, as only a disease of the higher motor neurons, is wrong. Obviously the new imaging techniques are not well received by classical neurologists. enter image description here

Motor weakness associated with volitional tasks in ALS is associated with failures and compensations in larger networks and not with isolated dysfunctions in the primary motor area where the body of higher motor neurons is located.

However previous functional MRI studies were limited by small sample sizes (n <20) and the majority of studies either examined gray matter only with T1-weighted images, or white matter with diffusion tensor imaging ( DTI). So far, only four studies have included more than 20 ALS patients with a multimodal MRI protocol to study progressive whole brain changes, although none have included more than 35 ALS patients. Two of these studies demonstrated progressive changes in the corticospinal tract and found no change in gray matter after 6 to 8 months (Cardenas-Blanco et al., 2016; de Albuquerque et al., 2017). In contrast, generalized gray matter degeneration was reported with limited white matter involvement in the other two studies (Bede and Hardiman, 2018; Menke et al., 2014). More comprehensive analyzes were therefore necessary.

Texture analysis is a computer image processing technique that quantifies the variations and relationships between the intensities of voxels in an image, variations that are difficult to detect by qualitative visual inspection and may not be detectable by the methods. common image analysis

Two-dimensional (2D) texture analysis methods have been widely used in other neurological conditions such as brain tumors, stroke, epilepsy, and multiple sclerosis to detect and classify lesions. Scientists have developed an analysis of the texture characteristics of the whole brain (Maani, Yang & Kalra, 2015).

With this technique, the authors of a new article have shown that the autocorrelation calculated from T1-weighted images is altered in ALS compared to controls in the regions of the motor cortex, the frontal lobe. , temporal lobe and posterior limb internal capsule (PLIC).

A comprehensive assessment of progressive brain degeneration in ALS is essential to further understanding the pathophysiology of the disease. As such, the main objectives of this new study were (1) to examine brain changes in patients with ALS over an 8-month period with texture analysis of T1-weighted images, and (2) to assess whether the gradual changes are different between patients at slow and rapid evolution.

The study design included whole brain and region of interest (ROI) based approaches to study changes in texture. The authors hypothesized that

  • (1) texture alterations in T1-weighted images are present in gray and white matter and associated with the known pathology and clinical alteration of ALS;
  • (2) progressive brain degeneration is evident as texture alterations over time;
  • (3) gradual brain changes in rapidly progressing patients are more important than changes in slowly progressing patients.

To test their hypotheses, they conducted the study in a large multicenter cohort of 256 participants (119 controls and 137 patients with ALS). The mean age of the ALS patients was higher than that of the controls (p = 0.02) and there were proportionally more men than women in the ALS group than in the control group.

In the whole-brain group comparison, patients with ALS had reduced autocorrelation compared to controls in bilateral pre-central gyri, subcortical white matter, left supplemental motor area, left upper and middle frontal gyri, bilateral frontal white matter, bilateral insular cortex and bilateral temporal white matter.

Compared to controls, the slowly progressing ALS group had alterations in autocorrelation in bilateral precentral gyri, left middle frontal gyrus, bilateral frontal white matter, left insular cortex, and bilateral pyramidal tracts. In contrast, the rapidly progressing ALS group had fewer regions of altered autocorrelation in the frontal cortex, but greater involvement of bilateral pyramidal tracts, temporal white matter, and parahippocampal regions.

Conclusion: In this study, the authors set out to investigate progressive brain degeneration in ALS with texture analysis of T1-weighted images in a large multicenter cohort. they first showed that the texture abnormalities in the gray and white matter at the start were spatially congruent with the brain pathology of ALS.

It is important to note that textural alterations in the pyramidal tract have also been shown to be highly specific for clinical dysfunction of the upper motor neurons. This contrasted with the ALSFRS-R and finger and foot tapping scores which showed diffuse associations with gray and white matter structures. In addition, longitudinal analyzes revealed that the progression of gray matter was characterized by the spread of the pathology to the frontotemporal regions.

They observed progressive changes in the pyramidal tracts after only 4.5 months. This is a new and important observation because clinical dysfunction of the upper motor neurons did not progress during this period. Finally, they showed that progressive brain degeneration in ALS was based on the rate of disease progression at baseline. Taken together, these results also strongly suggest that texture analysis of T1-weighted images is a sensitive marker for longitudinal mapping of disease-related brain degeneration in ALS.

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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