Snapshot: What is Cerebrospinal Fluid (CSF)?

Public transit may not be the first thing that comes to mind when we think about the brain, but it’s a great way to understand how all the parts of the central nervous system work together. Nutrients, hormones, and other important molecules (the passengers) need to get on and off at different stations to do their work. They might first stop at the large internal chambers within the brain, called ventricles. From the ventricles, they can get to the central canal in the spinal cord, as well as the subarachnoid space. The subarachnoid space is a space between two membranes that surround the brain and spinal cord. It provides a stable structure for a network of veins and arteries.

The passengers are shuttled from station to station by the cerebrospinal fluid (CSF), a clear, colourless fluid that provides the central nervous system with necessary nutrients and hormones while carrying away waste products. CSF also cushions the brain and spinal cord by circulating between layers of tissues surrounding them. The whole public transit system is enclosed: the subarachnoid space and the ventricles are connected to the central canal in the spinal cord, forming a single reservoir for CSF.

Cerebrospinal fluid written in colorful letters under a Stethoscope on wooden background
Photo used under license by Sohel Parvez Haque/Shutterstock.com.

CSF is made by the choroid plexus, a collection of tiny blood vessels called capillaries. Capillaries filter the blood and secrete it into the ventricles. When the pressure of CSF is less than the pressure in the capillaries, CSF flows out and into the ventricles. When the pressure of CSF is greater than that of the bloodstream, the extra fluid is absorbed from the subarachnoid space and into sinuses (large areas filled with blood), where it can flow into the surrounding veins. The blood supply in the central nervous system tightly regulates the movement of molecules or cells between the blood and brain. This blood-brain barrier is crucial for protecting the brain from toxins and pathogens. Dysfunction of this specific system contributes to the development of neurological diseases.

Anatomical labeled scheme with human head and inside of skull, including superior sigittal sinus, ventricles, arachnoid Villi and spinal cord central canal.
Structure of the ventricles and central canal components that contribute to the public transit system. Photo used under license by VectorMine/Shutterstock.com.

Why is CSF Important for Neurodegenerative Diseases?

In neurodegenerative diseases like Spinocerebellar Ataxias, CSF contains molecules that can be used as biomarkers. Biomarkers are disease-specific proteins that change in concentration depending on disease stages. Biomarkers provide information on disease progression, with or without the impact of therapeutics. They are also crucial for understanding how disease processes work and assist in developing treatments.

The development of intrathecal injections, injecting into the central canal for distribution to the central nervous system (for example, spinal anesthesia), has been monumental for administering drugs in neurodegenerative diseases. In other words, not only can the public transit system of the central nervous system be investigated to see what passengers are associated with the disease, but it can be used to deliver “medicine passengers” to the place where the disease occurs.

If you would like to learn more about Cerebrospinal Fluid, take a look at these resources by MedlinePlus and WebMD.

Snapshot written by Kaitlyn Neuman and edited by Dr. Tamara Maiuri.

Elongating expansions in HD and SCA1

Written by Dr. Marija Cvetanovic  Edited by Dr. Larissa Nitschke

Expanded CAG repeats are the cause of Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Longer inherited CAG expansions correlate with the earlier disease onset and worse symptoms. We know from past research that these expansions are unstable and become longer from one generation to the next.

This study by Mouro Pinto and colleagues shows that repeat expansions also keep getting longer throughout life in patients affected with HD and SCA1 in many cells, including brain, muscle, and liver cells.

Expansion of CAG repeats in different human genes cause several neurodegenerative diseases. This includes Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). These long CAG repeats in disease genes tend to be unstable in the sperm and egg cells. This instability in sperm and egg cells can result in either longer repeat tracts (expansions) or shorter ones (contractions) in the children of affected patients. Unfortunately, CAG repeats more often expand than shrink. This results in a worse disease in the affected children, with earlier onset and more severe symptoms than their parents.

However, repeat instability and expansion of repeats are not confined to the sperm and egg cells. It can occur in many cells in a patient’s body. This ongoing expansion that occurs in other body cells is called somatic expansion.

Abstract background of DNA sequence
Long CAG repeats in disease genes can be unstable and expand. Photo used under license by Enzozo/Shutterstock.com.

As affected patients age, the ongoing somatic expansion, especially in the brain, may accelerate the onset of neuronal dysfunction and loss of neurons and. This may worsen the disease progression. This has been previously shown in mouse models and patients with HD. However, those studies examined expansion in only a few brain regions and tissues outside the brain (called peripheral tissues).

In this study lead by Dr. Vanessa C. Wheeler, the authors systematically examined repeat instability in 26 different regions of the brain, post-mortem cerebrospinal fluid (CSF) and nine peripheral tissues, including testis and ovaries from seven patients with HD and one patient with SCA1.

Continue reading “Elongating expansions in HD and SCA1”

Snapshot: What is Neurofilament light protein (NfL)?

Nerve cells (aka neurons) are unique cells in that they have long, and thin extensions called axons which form connections with and talk to other neurons. This particular shape of neurons determines how quickly they can get their messages to other cells. You can think of the axons in the brain like the wires connecting all the components of a dense electrical network.

NfL stands for Neurofilament light protein (Not to be confused with the national football league!). Neurofilaments are proteins found in our neurons. They are important for helping these cells hold their structure and size. We know this is important for their ability to send messages to other neurons. NfL is the smallest unit of three types of neurofilaments (light, medium and heavy). There is a lot of NfL found in the axons of neurons.

A large neuron with long interconected axons
A cortical neuron stained green with antibody to NfL. Image courtesy of GerryShaw on Wikimedia.

How do you measure NfL levels?

Like other proteins, NfL levels can be measured in fluids using tools known as immunoassays. These tools make use of antibodies generated by the immune systems to capture and count the protein of interest. It has been possible to measure NfL in cerebrospinal fluid (CSF) – the clear fluid that surrounds the brain and has lots of brain proteins – since 2005. In recent years, immunoassay technology has improved significantly, permitting the quantification of proteins previously too low in concentration to detect. One of these technologies is Single Molecule Array (Simoa) and has made it possible to measure NfL reliably in blood.

Why is NfL used as a biomarker?

Biomarkers are biological characteristics that can be measured and that tell us about a particular biological or disease process or response to a therapy. They can be used to make drug development more efficient. NfL is released into CSF after brain injury and also in many neurodegenerative diseases. This makes it a biomarker of neuronal injury. The problem with CSF is that it requires a safe but relatively invasive medical procedure called a lumbar puncture or spinal tap to collect. It would be a lot easier for both patients and doctors if we could get the same information from a blood test. Being able to quantify NfL – a brain protein – in blood, and more importantly, that it reflected what was happening in the brain was very exciting for many diseases.

In neurodegenerative diseases with effective disease modifying therapies (such as Multiple Sclerosis and Spinal Muscular Atrophy), a lowering of NfL reflects the clinical benefit in response to these therapies. In another genetic neurodegenerative disease caused by a CAG expansion, Huntington’s disease, NfL increase has been shown to be the earliest detectable change in asymptomatic gene carriers who are very far from their predicted age of disease onset. Many results like these suggest that NfL could help monitor disease even before symptoms appear, decide when to start therapies, and tell us if a drug is improving the health of neurons.

What NfL research is being done in ataxia research?

So what about ataxias? You will be pleased to know that Ataxia researchers have also jumped on the NfL band wagon. We previously wrote an article on two independently published studies in SCA3 which showed in many patients that NfL levels increased as Ataxia severity got worse, they were correlated with a measure of clinical severity (SARA) and increased with the level of brain loss (atrophy). One of the studies showed NfL levels increased with a higher number of CAG repeats in someone’s SCA3 mutation. There is also work using mouse models of SCA3 to understand this biomarker further. Two studies have now shown that NfL is also increased in Friedreich’s ataxia. With more research, NfL could potentially be used to design better clinical trials for ataxias and to monitor disease.

If you would like to learn more about NfL, take a look at this article by NeurologyLive.

Snapshot written by Dr. Lauren Byrne and edited by Dr. Gülin Öz.

A promising biomarker to track disease progression in SCA3

Written by Dr. Ambika Tewari Edited by Dr. Gulin Oz

Neurofilament light chain could provide a reliable readout of how far an SCA3 patient’s disease has progressed

How often have you heard that the most effective way to treat a disorder is early intervention? In reality, “early” is not possible for many disorders because patients receive a diagnosis only after the appearance of symptoms. But what if there was a way we could tell that a patient will develop a disease – even before they have any symptoms? Thankfully, that’s exactly what researchers in the field of biomarkers are trying to do. Biomarkers are biological indicators that are not only present in patients before the manifestation of symptoms, but can also be used to measure disease progression. In the SCA field, there have been a recent series of articles that have shed light on a promising biomarker for SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is the most common dominantly-inherited ataxia. It is caused by an expansion of CAG repeats (a small segment of DNA that codes for the amino acid glutamine) in the ATXN3 gene. An important feature of SCA3, as well as in other spinocerebellar ataxias, is the progressive development of symptoms. Symptoms usually occur across decades, and can be divided into three major phases: asymptomatic, preclinical, and symptomatic. In the asymptomatic phase, there is no evidence of clinical symptoms (even though the patient has had the SCA-causing mutation since birth). In the preclinical stage, patients show unspecified neurological symptoms such as muscle cramps and/or mild movement abnormalities. By the symptomatic (i.e., clinical) stage, patients have significant difficulty walking.

A Spinal Cord Motor Neuron sample stained purple.
Neurofilament light chain (NfL) is an important building block of neurons. But when neurons are damaged, NfL is released. Image of a spinal cord motor neuron courtesy of Berkshire Community College.

Currently in SCA research, disease progression is measured using the Scale for the Assessment and Rating of Ataxia (SARA). A score of 3 or more on the SARA differentiates clinical and preclinical groups. Structural and functional brain imaging methods (such as MRI) also track the progressive nature of the disease, like the SARA, but give us a visual picture of changes in the brain. Together, these methods have provided the SCA community with important insights into the clinical spectrum of each specific disease and its rate of progression. And, with the exciting progress we have recently made in the realm of SCA3 therapeutics, a biomarker that is cost-effective and easy to measure (like in a blood test) could provide a convenient way to assess how effective a potential treatment is.

Continue reading “A promising biomarker to track disease progression in SCA3”

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart