Dissertation for Medicine Doctoral degree at Sahlgrenska Academy, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Neurofilaments in neurodegenerative diseases – Focus on axonal injury cerebrospinal fluid biomarkers
Opponent: Professor Helmut Butzkueven, Department of Neuroscience, Monash University, Melbourne, Australia
Examining committee: Associate Professor Alba Corell (chair), Associate Professor Ludmilla Morozova (UmU) and Professor Filip Bergquist
The disputation is held in English
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Chairperson of the disputation: Professor Elisabet Jerlhag Holm
Nerve cells rely on internal support structures called neurofilaments to maintain their shape and function. When nerve cells are damaged, as happens in many neurological diseases, these proteins leak into the cerebrospinal fluid (CSF), the fluid surrounding the brain and spinal cord. Because of this, neurofilaments can be measured in CSF and used as indicators of nerve damage.
One neurofilament in particular, neurofilament light (NfL), is a widely studied protein in the neurodegenerative disease field, and is used as a biomarker in Alzheimer’s disease, frontotemporal dementia, multiple sclerosis, and Huntington’s disease, for example. NfL is very sensitive, but it has a drawback: it rises whenever nerve cells are damaged, regardless of whether the injury occurs in the brain or any other nerve in the body. In contrast, α-internexin is found only in the central nervous system, making it a promising marker that is more specific to brain damage.
This thesis aimed to improve our understanding of these neurofilament proteins by developing new laboratory tests and studying how they behave in disease. First, the physical form of NfL in CSF was examined. Using a newly developed test, it was shown that NfL is mainly present as small clusters of molecules rather than as single units. These clustered forms appear to be what standard NfL tests largely detect, and their structure depends on specific chemical bonds.
In the second part of this thesis, a highly sensitive test capable of detecting very small amounts of α-internexin in CSF was developed and applied to samples from patients with a range of neurological diseases. Levels of α-internexin closely followed those of NfL and were elevated in conditions such as Alzheimer’s disease, frontotemporal dementia, and multiple sclerosis.
Across these conditions, levels of α-internexin closely matched those of NfL, and both were higher in patients than in healthy individuals. In multiple sclerosis, α-internexin levels were strongly linked not only to NfL but also to signs of inflammation. In Alzheimer’s and frontotemporal dementia, α-internexin was clearly elevated, and in Alzheimer’s disease it also showed connections to well-known Alzheimer’s biomarkers. Interestingly, in frontotemporal dementia, α-internexin tracked nerve damage independently of Alzheimer-specific markers, suggesting it reflects a more general process of nerve degeneration in the brain.
Together, these findings introduce two new robust tests for quantification of neurofilament proteins and highlight the importance of understanding what forms of NfL are measured. They also point to α-internexin as a promising, brain-specific marker of nerve cell damage.