Science News: Ratio of Urinary N-terminal Titin Fragment to Urinary Creatinine is a Novel Biomarker for Amyotrophic Lateral Sclerosis

Submitted by: Pritikanta Paul, MD
Edited by: Sarah Chen, MD
 
Yamada S, Hashizume A, Hijikata Y, et al. Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2021 Oct;92(10):1072-1079. doi: 10.1136/jnnp-2020-324615. PMID: 33737450

Summary: Sensitive and specific disease biomarkers for amyotrophic lateral sclerosis (ALS) are lacking. There has been ongoing research in the past several years looking for them. Titin is a giant myofibrillar protein in skeletal muscle. Elevated levels of urinary N-terminal fragment of titin has been reported in degenerative conditions, such as Duchene muscular dystrophy (DMD). This study looked at the validity and reliability of urinary N-terminal titin fragment as a biomarker in ALS.
 
Consecutive newly diagnosed ALS patients (revised El Escorial criteria - definite, possible, and probable) between ages 40 and 80 (n=70) were analyzed along with age-matched and sex-matched healthy controls (n=43) without neurological diseases. Urine levels of N-terminal titin fragment were measured and standardized according to urinary creatinine content. Blood levels of other biomarkers including neurofilament light chain (NfL), creatine kinase (CK), and creatinine (Cr) were also measured. Clinical measurements included ALSFRS-R score, pulmonary function tested via spirometry.
 
ALS patients had significantly decreased appendicular lean soft tissue (ALST) mass compared to controls as well as increased serum CK levels and reduced serum Cr levels. Ratio of urinary levels of titin N-terminal fragment and urinary Cr was significantly increased in patients with ALS as compared to healthy controls. After adjusting for ALST mass, the ratio remained higher in ALS patients. Ratio of urinary titin/Cr levels were more elevated in the patients with ALS with lower limb onset. Additionally, ratio of urinary titin/Cr to serum CK was significantly increased in patients with ALS compared to healthy controls.
 
The authors studied if urinary titin N- terminal fragment would reflect ALS disease severity and they found that urinary titin/Cr levels were strongly correlated with total score and segmental scores (upper limb, trunk and lower limb) of ALSFRS-R. Similar findings were noted with quantitative respiratory measures. They also found urinary levels of titin/Cr reflected disease progression (assessed over six months). Finally, statistical analysis also showed low urinary titin/Cr level group had longer median survival compared to high urinary titin/Cr group and therefore, the baseline level of urinary titin/Cr level can serve as a prognostic marker.
 
Comments: Your personal comments on the article: This study clearly shows potential utilization of urinary titin/Creatinine as a potential biomarker in ALS patients with evidence of correlation with disease, disease severity, and survival. Compared to other biomarkers, the urinary titin/Cr level is convenient to get samples, does not require special equipment, and is non-invasive.
 
However, urinary titin fragments are the products of muscle degeneration, thus could have false positive in non-ALS disorders such as cardiomyopathy DMD, or even strenuous physical activities. Despite some limitations, including short follow-up and failure to enroll patient with advanced stage of disease, this study introduced a novel biomarker for ALS that needs to be validated by larger studies in the future.
 
Article of similar interest: Lu CH, Macdonald-Wallis C, Gray E, et al. Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015 Jun 2;84(22):2247-57.