Finding TDP-43 Clumps in Muscle Biopsies May Speed Diagnosis

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Doing a muscle biopsy to look for abnormal clumps of the TDP-43 protein in the nerve fibers of muscle tissue may be useful for the early detection of amyotrophic lateral sclerosis (ALS), according to a single-center study from Japan.

“It is difficult to diagnose ALS in its early stages because there is not a known biomarker,” Hirofumi Maruyama, MD, PhD, said in a press release. Maruyama is the study’s senior author and a professor at Hiroshima University’s Graduate School of Biomedical and Health Sciences, in Japan.

“Muscle is possible to biopsy, and transactive response DNA-binding protein 43 (TDP-43) accumulates in the peripheral nerves inside muscle,” Maruyama added.

Since the buildup of TDP-43 aggregates has been implicated in ALS-associated neurodegeneration, these findings suggest that TDP-43 accumulation in the nerves inside muscle “may be a biomarker for early diagnosis of ALS,” Maruyama said.

The study, “TDP-43 Accumulation Within Intramuscular Nerve Bundles of Patients With Amyotrophic Lateral Sclerosis,” was published in JAMA Neurology.

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Scientists Shed Light on ‘Critical’ Impact of TDP-43 Protein in ALS

ALS is caused by the progressive death of upper motor neurons — nerve cells that carry voluntary movement signals from the brain to the spinal cord — and lower motor neurons, which send these signals from the spinal cord to muscles.

Motor neuron degeneration in ALS is associated with the toxic buildup and clumping of certain proteins, such as TDP-43, in their nerve fibers, or axons.

While this has been well-demonstrated in motor neurons of the brain and spinal cord, this type of analysis can’t be performed in a live person; as such, this biomarker has not been useful for diagnosing ALS.

Interestingly, a previous study reported TDP-43 clumps in the axons of muscle biopsies from three people diagnosed with clinically definite or probable ALS, suggesting that TDP-43 aggregates in muscle may be used as a diagnostic marker of the disease.

To assess whether this was true in a larger patient population, a team of researchers in Japan analyzed post-mortem muscle tissue samples from 10 people (eight men and two women) with confirmed ALS, and 12 people (10 men and two women) without the disease.

The mean age at time of death was 76.1 years for ALS patients and 71.3 years for those without the disease (the control group).

Scientists detected TDP-43 aggregates in muscle nerve bundles on all 10 ALS patients, but in none on those without the disease. About half of the evaluated muscle nerve fibers in each ALS patient had detectable TDP-43 clumps.

The team then analyzed data from 114 people (76 men and 38 women, mean age 62.3 years) who had undergone muscle biopsy for diagnostic purposes at a single institution in Japan from 2004 to 2019.

Neither had a family history of ALS or other neuromuscular diseases, nor carried ALS-associated mutations.

Among these participants, 71 (62.3%) had detectable nerve bundles in their muscle biopsies, and 33 of them were positive for TDP-43 aggregates, which were found in more than half of muscle axons. All 33 individuals went on to be diagnosed with ALS, as did three of the 43 people without nerve bundles from their muscle biopsy.

Of the 38 participants whose biopsies contained nerve bundles but no TDP-43 clumps, all were diagnosed subsequently with neuromuscular or neurodegenerative diseases other than ALS.

Overall, the findings suggest that TDP-43 accumulation in muscle axons “may be characteristic for patients with ALS, and as a result, may be a novel diagnostic biomarker for ALS,” the researchers wrote.

Notably, TDP-43 clumps were detected not only in patients with symptoms of both upper and lower motor neuron damage — a common ALS diagnostic criterium — “but also in approximately 20% of patients with only LMN [lower motor neuron] symptoms,” the team wrote.

As such, TDP-43 aggregates in muscle nerves were evident before the individuals met current clinical criteria for an ALS diagnosis, suggesting that these clumps may serve as a useful biomarker for early detection of ALS, which could allow for beginning treatments sooner to slow its progression.

“Early diagnosis enables patients to initiate prompt treatment,” Maruyama said. “We aim to prevent the progression of ALS and will continue research into developing new medication.”

More research is needed to validate the findings of this study and “to clarify the utility of this potential diagnostic test for ALS,” the researchers wrote.