How can Neurofilament light concentrations help in Diagnosis?

Overview

• Neurofilaments or NFL is a cytoskeletal protein which is expressed only in neurons.
• NFL is released into the cerebrospinal fluid (CSF) and blood following damage to both central and peripheral neurons.
• NFL concentrations are reported to be high in neurodegenerative conditions.
• Results from the MIND study show that NFL measures vary in neurodegenerative conditions when compared to psychiatric conditions.
• NFL measures can be taken from a blood test. This test can cost only $150AUD.
• NFL is found to be high in Huntington’s, multiple sclerosis, and Alzheimer’s disease as well.
• NFL is found in psychiatric conditions (such as in major depression) as well however, the concentration of NFL is higher in neurodegenerative conditions when compared to psychiatric conditions.
• 22% of clinicians had a change in diagnosis after NFL test.
• Behavioural frontotemporal dementia was the most frequently revised diagnosis.

In May 2022, I attended a conference in Syndey, Australia. The conference was targeted mainly for psychiatrists and neuropsychiatrists. I was able to attend this lovely conference through my company called Monarch Mental Health Group. On the first day, the conference kicked off by an invited keynote speaker. This speaker was a psychiatrist, and a professor. He was also inlvolved in the development of the DSM-III and DSM-IV. His talk primarily focused on the importance of the biopsychosocial model. This is a great model and a very important one, and it must be implemented in practice by all clinicians. However, I was not fond of the way the professor approached his talk. In order to emphasise the importance of the biopsychosocial model, he belittled other appraoches and areas that do not necessary implement this model. One example that I can recollect is the sentence: “Neuroscience is overpromised”. He further added that “Neuroscience is just cool research”. Essentially, saying that this area of study is just fancy research and does little for clinical applications. He further gave an example with Alzheimer’s disease (AD) saying that “neuroscience has been researching AD for over 40 years, and we still do not have a biomarker for it”. As a neruoscientist, I spend the whole talk just shaking my head in disbelief. I can assure you that other mental health professionals who understood and loved neuroscience were also very disappointed with some of these statements.

Interestingly, the next day there was symposium that was just dedicated to biomarkers for neurodegenerative diseases. I truly had wished that this professor had attended this symposium but unfortunately that did not happen!

In this article, I want to discuss a study that was presented in the symposium (the study is still recruiting participants at this moment). The study I want to discuss here is part of the MIND study which stands for Markers In Neuropsychiatric Disorders. Professor Dennis Velakoulis is one of their researchers, and you can click the link here to see a video featured on the ABC news, where the Professor Velakoulis talks about his research: Australian researchers discover a simple blood test could diagnose dementia years earlier – ABC News

The biomarker that the Professor Velakoulis wants us to be aware about is ‘Neurofilament light chain” or NFL. NFL is a cytoskeletal protein which is expressed only in neurons and has emerged as a promising biomarker for neurological diseases (Borro et al., 2020). NFL is released into the cerebrospinal fluid (CSF) and blood following damage to both central and peripheral neurons (Borro et al., 2020).

NFL concentrations are reported to be high in dementia. For instance, NFL concentrations in CSF were high for behavioural frontal-temporal dementia from ‘phenocopy’ non-progressors (Eratne et al., 2022). In other words, NFL was higher in frontal-dementia when compared to a condition that has similar symptoms of frontal-dementia but is not “dementia” or a neurodegenerative condition (an example of this is provided later in the article to help you understand). So, what are the advantages of NFL measures? and how can NFL meausures be used in daily practice?

This is where Dr Dhamidhu Eratne and Professor Dennis Velakoulis’ current research (the MIND study) comes into practice. Their team has shown that NFL measures vary when neurodegerative conditions are compared to psychiatric conditions. Essentially, NFL measures are high in neurodegenerative conditons when compared to psychiatric conditions. For example, NFL in plasma was not increrased in treatment-resistance schizophrenia (Eratne et al., 2021). So how is concentration of NFL measures useful in practice?

Let us have a look at the case study below:

	Patient X		Patient Y
	50M, R-handed, unemployed, 12y schooling, manual jobs		56F, R-handed, unemployed, 9y schooling, manual jobs
	10y history of schizophrenia chronic positive symptoms 1-2y progressive behavioural and personality changes Disinhibited, impulsive, executive dysfunction		10y history of schizophrenia chronic positive symptoms 1-2y progressive behavioural and personality changes Apathy, loss of empathy, executive dysfunction
	Family history: mother diagnosed with AD in her 70s		Family history: mother diagnosed with AD in her 60s
	MRI shows frontotemporal atrophy, SPECT shows frontotemporal hypoperfusion		MRI shows frontotemporal atrophy, SPECT shows frontotemporal hypoperfusion

If you are a clinician, based on the above information provided, do you diagnose both patients with schizophrenia, behavioural frontotemporal lobe dementia, or any other neurodegenerative condition?

Remember the consequences of your diagnosis. If you diagnose them with a psychiatric condition, you essentially are giving a message to the patient that their condition can be managed through appropriate medication and therapy. However, if you diagnose them with dementia, you are saying to the patient that this condition is not reversible and will progressively get worse as they get older.

Thanks to the MIND study, a simple blood test (for just $150 AUD) can help clinicians with making such descision during diagnosis. Through NFL concentrations, they were able to diagnose patient X with schizophrenia (lower NFL concentrations), and patient Y with behavioural frontotemporal lobe dementia (higher NFL concentrations). Note that the difference in concentrations were statistically significant. This correct diagnosis now benefits both patients. Patient X can receive appropriate therapy, and medications whereas with the early diagnosis of dementia in Patient Y, appropriate care, and measures can be taken to slow down the progression of dementia. Note that NFL measures can help in letting clinicians know if the condition is psychiatric or neurodegenerative, but it cannot tell clinicians what the neurodegenerative condition is. NFL is found to be high in other neurodegenerative conditions such as Huntington’s (Byrne et al., 2017), multiple sclerosis (Cai & Huang, 2018), and Alzheimer’s disease (Lewczuk et al., 2018), just to name a few.

Remember, NFL measures are present in psychiatric conditions such as in schizophrenia and major depressive disorder (Travica et al., 2022), but here we are talking about the concentration of NFL, and not about the presence of NFL. NFL is present in both but the concentration of NFL is higher in neurodegenerative condition when compared to a psychiatric condition.

Some of the early findings by the professor Dennis Velakoulis and his team are presented below:

During the presentation, the authors reported that 47/212 (22%) had a change in diagnostic category. Moreover, behavioural frontotemporal dementia was the most frequently revised diagnosis.

This research will hopefully be published soon. However, this research provides just one example which shows that neuroscience is indeed “cool” but it is not “overpromised”. Yes, the brain is far too complex for us to have all the answers, but this is what makes neuroscience interesting. We spend everyday trying to unveil its secrets. Neuroscience has made tremendous progress over the years, and we have barely even scratched the surface. I can only imagine what the future has to offer!

Citations

Cai, L., & Huang, J. (2018). Neurofilament light chain as a biological marker for multiple sclerosis: a meta-analysis study. Neuropsychiatric disease and treatment, 14, 2241.

Barro, C., Chitnis, T., & Weiner, H. L. (2020). Blood neurofilament light: a critical review of its application to neurologic disease. Annals of clinical and translational neurology, 7(12), 2508-2523.

Byrne, L. M., Rodrigues, F. B., Blennow, K., Durr, A., Leavitt, B. R., Roos, R. A., … & Wild, E. J. (2017). Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. The Lancet Neurology, 16(8), 601-609.

Eratne, D., Janelidze, S., Malpas, C. B., Loi, S., Walterfang, M., Merritt, A., … & MiND Study Group. (2021). Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives. Australian & New Zealand Journal of Psychiatry, 00048674211058684.

Eratne, D., Keem, M., Lewis, C., Kang, M., Walterfang, M., Loi, S. M., … & MiND Study Group. (2022). Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from phenocopy non-progressors. medRxiv.

Lewczuk, P., Ermann, N., Andreasson, U., Schultheis, C., Podhorna, J., Spitzer, P., … & Zetterberg, H. (2018). Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer’s disease. Alzheimer’s research & therapy, 10(1), 1-10.

Travica, N., Berk, M., & Marx, W. (2022). Neurofilament light protein as a biomarker in depression and cognitive function. Current opinion in psychiatry, 35(1), 30-37

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