Protoplasmic and fibrous astrocytes, illustration
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Groundbreaking research could pave the way for a future diagnostic for Amyotrophic lateral sclerosis (ALS). Researchers at Hiroshima University found that muscle biopsies tested for phosphorylated transactive response DNA-binding protein 43 (pTDP-43)–positive axons in intramuscular nerve bundles distinguish ALS patients.

Their paper was published last month in JAMA Neurology.

“It is difficult to diagnose ALS in its early stages because there is not a known biomarker,” said researcher Hirofumi Maruyama, a professor at the Graduate School of Biomedical and Health Sciences at Hiroshima University in Japan.

“Muscle is possible to biopsy, and transactive response DNA-binding protein 43 (TDP-43) accumulates in the peripheral nerves inside muscle. TDP-43 is a protein that plays a key role on motor neurons, and accumulation of TDP-43 may be a biomarker for early diagnosis of ALS,” he added.

ALS is a progressive disease of the nervous system that affects motor neurons. The disease causes these neurons, which affect movement, to deteriorate and eventually die. Over time, they lose the ability to send messages to the muscles in the body, affecting voluntary muscle movements. There have been recent advances in treating ALS, but current treatments can only slow disease progression.

There is currently no single test that can confirm the disease, although degeneration of neuromuscular junctions and axons is considered an important aspect of it, Doctors look for neurological symptoms such as muscle weakness and upper and lower motor neuron symptoms. They will also do diagnostic tests to rule out other conditions like cervical spondylosis. A diagnostic test that could confirm ALS would help people get a diagnosis earlier and start treatment as soon as possible.

Multiple genetic mutations have been linked to the condition, including variants in the gene for TDP-43.  However, a mechanism including the role of TDP-43 in axons, in ALS, has not been well explained.

This study was based on previous research in mice that had revealed a crucial function of TDP-43 in axons, the part of the neuron that sends signals to other neurons. This is important for ALS, because axonal degeneration causes the lower motor neuron problems that can be a symptom of the disease. Researchers hypothesized that TDP-43 accumulation in muscular nerve bundles could be an early predictor of ALS.

To test this theory, researchers first examined the muscle tissue of 10 individuals who had confirmed cases of ALS at the time of their death and 12 who did not. All 10 ALS patients had TDP-43 accumulations in their intramuscular nerve bundles, while 12 non-ALS controls had none.

Next, researchers targeted 114 patients who underwent a muscle biopsy and did not have a family history of ALS or another muscle or neuromuscular diagnosis. Of these, 71 had evidence of intramuscular nerve bundles and 43 did not. Among the 71 patients, axonal TDP-43 accumulations in their nerve bundles were confirmed in 33. These 33 patients with axonal TDP-43 accumulations were all later diagnosed with ALS. Among the 43 patients without nerve bundles, three were later diagnosed with ALS.

“Results of this dual case-control and cohort study suggest that axonal TDP-43 accumulations may be characteristic for patients with ALS, and consequently may be a novel diagnostic biomarker for ALS,” said Maruyama. “Early diagnosis enables patients to initiate prompt treatment. We aim to prevent the progression of ALS and will continue research into developing new medication.”

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