ALS neurochemical marker could lead to new treatments

Researchers from the University of Alberta have made a significant discovery related to amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. They have identified a neurochemical marker linked to the loss of motor function and breakdown in communication between the primary motor cortex and the rest of the brain in ALS patients.

The study, titled “Motor cortex functional connectivity is associated with underlying neurochemistry in ALS,” was published in the Journal of Neurology, Neurosurgery & Psychiatry.

In ALS, as motor neurons deteriorate, the primary motor cortex loses its ability to communicate with muscles, leading to muscle stiffness and weakness. Eventually, this communication breakdown affects muscles essential for survival.

Previous studies have shown that the drug riluzole can improve patients’ life expectancy. Interestingly, the use of riluzole is associated with increased levels of N-acetylaspartate (NAA), a neurochemical linked to healthy neurons. Notably, this same neurochemical has been identified by Sanjay Kalra and his team as a potential ALS marker.

Now, the researchers are intrigued to find out whether improving neurochemistry through medication might enhance functional connectivity in ALS patients. They are also interested in determining whether the increased NAA levels observed with riluzole usage are correlated with improved survival.

Avyarthana Dey, a Ph.D. student involved in the study, hopes to uncover the extent to which riluzole affects patient survival, as the drug has shown to increase survival by an average of three to six months, without a clear understanding of its mechanism. The findings of their research could potentially offer new insights into evaluating treatments to improve brain function in ALS patients.

Identifying the marker

Dr. Sanjay Kalra is a prominent neurologist and professor in the Division of Neurology, holding the Henri M. Toupin Chair in Neurological Sciences. He is a key member of the Neuroscience and Mental Health Institute and serves as the director of two crucial initiatives, the Comprehensive Analysis Platform to Understand, Remedy, and Eliminate ALS (CAPTURE ALS) and the Canadian ALS Neuroimaging Consortium (CALSNIC). These initiatives played a vital role in the latest study.

The researchers analyzed data from five Canadian university hospitals within CALSNIC, namely the University of Alberta, University of Calgary, McGill University, University of Toronto, and University of British Columbia.

The study involved 52 patients with ALS and 52 healthy controls. ALS patients exhibited reduced foot tapping frequency and various other symptoms, such as overly responsive tendon reflexes, spasticity, and the Babinski sign.

Using functional MRI scans and other tests, the researchers aimed to understand the communication breakdown between the primary motor cortex and the rest of the brain in ALS patients. They hypothesized that issues with the structure or neurochemistry of the upper motor neurons in the brain might be causing this breakdown. These upper motor neurons, which extend from the brain to the spinal cord, connect with lower motor neurons, which, in turn, communicate with muscles.

As motor function and the communication between the primary motor cortex and the rest of the brain declined in ALS patients, the levels of N-acetylaspartate (NAA) in the motor cortex (where the upper motor neurons originate) also decreased. While structural deterioration of the white matter was observed, it did not directly correlate with the communication deterioration.

The researchers suggest that the abnormality in NAA occurs before any visible structural changes, indicating its potential as an early marker for ALS-related neurodegeneration.

A step toward a definitive test

One of the major challenges in ALS research is the variability of symptoms among patients, which can often mimic other diseases like stroke or neuropathy. As a result, the current process involves ruling out other conditions to arrive at an ALS diagnosis.

While a decrease in N-acetylaspartate (NAA) in upper motor neurons could potentially serve as a definitive test for ALS in the future, currently, clinicians are not equipped with the necessary imaging techniques for such a diagnosis. Brain imaging is primarily used as a research tool at this stage.

Having a definitive test for ALS could lead to earlier diagnoses, enabling patients to receive treatment and support sooner. Early diagnosis would also allow for enrollment in clinical trials and the initiation of therapies, which have been shown to be more effective when started early, slowing down the disease’s progression and prolonging life expectancy.

Even if the diagnosis remains terminal, an earlier identification can provide patients with some peace of mind. It helps reduce the anxiety, stress, and panic experienced by patients and their caregivers when facing rapid loss of function without a clear diagnosis.

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