Toxicity of cerebrospinal fluid in ALS/MND

A systematic review of existing scientific literature, performed by a team of researchers led by Dr Arpan Mehta, MRC/MND Association Lady Edith Wolfson Clinical Fellow based at the Euan MacDonald Centre, University of Edinburgh, supports the view that cerebrospinal fluid obtained from patients with ALS/MND is toxic to cells.  This finding could help to establish additional lines of research to better understand disease mechanisms in ALS/MND and potentially contribute to the development of much needed new therapeutic strategies.

What is cerebrospinal fluid?

Cerebrospinal fluid (CSF) is a clear colourless liquid that surrounds most of the brain and spinal cord. It is produced by specialised cells forming a structure known as the choroid plexus. The average human adult is believed to possess a total CSF volume of about 150 ml, all of which is renewed three to four times in a single day.

CSF plays an important role in the human body, providing buoyant support to the brain and protecting it from mechanical damage. It is also involved in the regulation of various substances, including nutrients and waste products. In fact, scientists have recently discovered an important clearance system for the brain called the ‘glymphatic system’, with the CSF circulation being central to this clearance mechanism.

What is known about cerebrospinal fluid in ALS?

Many studies have now shown that the constitution of CSF in ALS patients is abnormal. For instance, it contains higher levels of TDP-43, a toxic protein that has repeatedly been linked to the disease process in ALS. Furthermore, raised levels of different inflammatory markers have also been observed, as well as potentially elevated levels of the neurotransmitter, glutamate, which could trigger neurodegeneration – a mechanism known as excitotoxicity.

During the 1980s and 1990s, a number of studies started to evaluate the toxicity of ALS-CSF in vitro. They did this by obtaining CSF from ALS patients and controls (via lumbar puncture), and subsequently exposing cells grown in a dish to the CSF. The results turned out to be inconclusive, with some studies observing greater toxicity following exposure to ALS-CSF compared to CSF from controls, whilst other studies reported no significant difference. The last two decades, however, saw an increasing number of studies attempting to assess the toxicity of ALS-CSF. The aim of the present study was therefore to pool together the results from all previously published studies in a systematic manner.

What did the study show?

After a comprehensive search of the existing literature, the researchers found 28 studies to be eligible for analysis. These looked at the toxicity of ALS-CSF by comparing the decrease in cell count after exposing the lab-grown cells to ALS-CSF compared to CSF from controls. A subset of studies, however, also assessed whether apoptosis, commonly known as programmed cell death, could be promoted by ALS-CSF.

The researchers found that most studies reported increased toxicity following exposure to ALS-CSF, and that negative results could usually be traced back to early studies performed before 2000.

It is intriguing to find that CSF toxicity can be consistently observed across studies, irrespective of study conditions such as: CSF concentration, exposure time and the cell type involved. We believe that this is an important area for future research, given these promising findings suggesting that CSF toxicity is seen in both sporadic and familial forms of ALS” said Dr Arpan Mehta, lead author.

What are the potential implications of this finding?

It is still unclear why exactly CSF obtained from ALS patients is toxic to cells. Whilst various studies have attempted to investigate this phenomenon, there is little consensus as to what the toxic agents and underlying mechanisms are. A number of suggested explanations based on limited evidence have been proposed, including glutamate excitotoxicity, oxidative stress due to production of free radicals, as well as proteostasis – the accumulation of toxic proteins.

Nevertheless, this study, jointly funded by the MND Association and Medical Research Council, which is the first to systematically review the ALS literature for CSF toxicity, opens new avenues for ALS research, paving the way for future studies to assess the contribution of ALS-CSF in the disease process, with the ultimate aim to discover novel therapeutic targets.

Reference to the paper: Ng Kee Kwong, K.C., Gregory, J.M., Pal, S., Chandran, S. and Mehta, A.R., 2020. Cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis: a systematic review of in vitro studies. Brain Communications.

Further resources:

• Read more about Dr Arpan Mehta on the Anne Rowling Clinic’s website.
• Our previous blog about Dr Mehta’s research on Focusing on mitochondria – a potential target for early MND treatment?
• Read about how our Lady Edith Wolfson Fellowship launched Dr Arpan Mehta’s career in our previous blog post.
• Read more about our Lady Edith Wolfson Fellows on our MND Association website.
• Can a filter be used to remove toxic chemicals from spinal fluid? Read about Dr Richard Bedlack’s research on page 11 of Thumb Print – Winter 2020.