Understanding Neurodegeneration as the Core Driver of Disability in Multiple Sclerosis

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• MS Neurodegeneration Discovery
• Axonal Loss Evidence
• Gray Matter Damage
• Inflammation-Neurodegeneration Link
• Clinical Implications & Prognosis
• Full Transcript

MS Neurodegeneration Discovery

Dr. Paul Matthews, MD, describes a fundamental shift in understanding multiple sclerosis. Historically, MS was classified primarily as an autoimmune demyelinating disease. Dr. Matthews and his colleagues spearheaded research that revealed its strong neurodegenerative component. This work was a re-discovery of early 20th-century pathological evidence that had been overshadowed.

The paradigm shift began with observations made between 1990 and 1995. Dr. Doug Arnold in Montreal and Dr. Matthews' team noted two critical, unexpected findings that challenged the established view of MS.

Axonal Loss Evidence

Key evidence for neurodegeneration in MS came from measuring a specific brain chemical. Dr. Paul Matthews, MD, explains they found substantial losses of N-acetyl-aspartate (NAA). This chemical is found largely, or only, within nerve cells. The loss was detected in both the white matter and gray matter of the brain in MS patients.

Concurrently, researchers recognized a significant loss of brain volume, or brain atrophy. This shrinking of the brain provided macroscopic evidence of the widespread neuronal damage occurring. Dr. Bruce Trapp later published landmark pathology studies showing how inflammation within MS lesions directly causes axonal damage and loss.

Gray Matter Damage

Neurodegeneration in MS extends far beyond the classic white matter lesions. Dr. Paul Matthews, MD, highlights crucial work by Dr. Jeroen Geurts and others. Their research demonstrated that nerve cells are lost in the gray matter of the brain. This includes critical subcortical structures like the thalamus and the neocortex.

This widespread axonal loss in white matter and nerve cell death in gray matter creates a comprehensive picture of brain degeneration. The disease process damages both the long axons that transmit signals and the nerve cell bodies themselves.

Inflammation-Neurodegeneration Link

The inflammatory process is the primary instigator of neurodegeneration in multiple sclerosis. Dr. Matthews clarifies that an MS lesion forms first through inflammatory activity. This is followed by chronic inflammatory processes and other factors that drive progressive neurodegeneration over time.

Dr. Anton Titov, MD, facilitates this discussion on the direct damage to nerve cells. Inflammation is not separate from neurodegeneration; it is the mechanism that causes it. This link is fundamental to understanding MS disease progression and developing effective treatments.

Clinical Implications & Prognosis

Recognizing MS as a neurodegenerative disease has profound implications for patient prognosis. Dr. Paul Matthews, MD, explains that the number of inflammatory lesions on an MRI scan only approximates disability. The degree of irreversible axon and nerve cell loss provides critical independent information about a patient's future.

Dr. Paul Matthews, MD, states that this neurodegeneration is the proximate substrate of disability progression. Therefore, clinicians must look beyond T2 inflammatory lesions on MRI. Assessing brain volume loss is essential for understanding the primary cause of disability in most MS patients and forming an accurate long-term prognosis.

Full Transcript

Dr. Anton Titov, MD: Neurodegeneration in multiple sclerosis. Let's start with this major theme of your research. Multiple sclerosis is generally described as a primary autoimmune disease. But you and your colleagues showed paradigm-shifting evidence. You showed that multiple sclerosis is a neurodegenerative disease. You showed that multiple sclerosis is accompanied by significant axonal and neuronal loss.

Dr. Anton Titov, MD: What is the significance of your discoveries about axonal and neuronal loss in multiple sclerosis? What are the implications of loss of neurons and axons for treatment and prognosis in multiple sclerosis patients?

Dr. Paul Matthews, MD: Thanks! First, many patients contributed to this discovery. In fact, it was a re-discovery. The evidence for loss of axons and even nerve cell loss is well-documented. It is present in the pathology literature from the early 20th century. But the demyelinating aspects of the inflammatory disease were emphasized.

This is really what entered the textbooks and became the dominant theme in the 1960s and thereafter. Dr. Doug Arnold in Montreal and we noted that there were two peculiar findings. We discovered it around 1990 to 1995.

First, we found evidence for loss of a chemical, N-acetyl-aspartate. It is found largely or only in nerve cells in patients with multiple sclerosis. There were really substantial losses. This was unexpected. This was found both in the white matter and in the gray matter of the brain.

In addition, we recognized that there was a significant loss of brain volume. It was associated with severe losses of neurons. We also noted shrinking of the brain.

Dr. Bruce Trapp of Cleveland Clinic published a landmark New England Journal of Medicine multiple sclerosis research paper. He followed up on our discoveries with very elegant neuropathological clinical trials. They showed how the inflammatory process within individual white matter lesions of multiple sclerosis gives rise to loss of axons. Axons are damaged in conjunction with demyelination.

Then Dr. Bruce Trapp and our group provided pathology-based evidence for more widespread damage in multiple sclerosis. That included damage to the gray matter of the brain.

My colleagues and I, and Bruce Trapp and his colleagues, and an increasing number of other groups, particularly Dr. Jeroen Geurts at the Free University of Amsterdam, published a series of important research articles. They nicely highlighted how nerve cells are lost in gray matter. Nerve cells die particularly in subcortical structures, such as the thalamus and the neocortex.

Dr. Anton Titov, MD: There is widespread axonal loss in the white matter of the brain. Together this is creating a picture of brain degeneration. Inflammation is accompanied by a direct damage to nerve cells. Multiple sclerosis damages both axons and the nerve cell bodies.

This is associated with the progression over time. A multiple sclerosis lesion is formed first. Then there is a chronic inflammatory processes and possibly other factors. All that leads to a progression of neurodegeneration.

Dr. Anton Titov, MD: Why is this important to the person with Multiple Sclerosis? We have come to recognize the relationship between the number and the distribution of inflammatory lesions in the brain. These are the hyper-intense lesions that we see on the MRI T2-weighted scan.

This relationship is only approximately correlated with the degree of disability in multiple sclerosis. It only approximately correlates with the rate of multiple sclerosis progression over time. Additional independent information is added. It includes data about the degree of nerve cell body and axon loss in multiple sclerosis.

Indeed, we believe that the irreversible axon and nerve cell loss is the proximate substrate of disability progression in the multiple sclerosis disease.

Dr. Paul Matthews, MD: Thus, we are looking at the T2 inflammatory lesions on MRI of patients with multiple sclerosis. We are looking at a primary cause of the neurodegeneration. We look at the neurodegeneration. We are looking at the primary cause of the disability in most patients with multiple sclerosis.