Persisting Transglutaminase 6 Antibodies in Neurological Gluten-Related Disorders.

OBJECTIVE

Gluten-related autoimmunity can cause neurological disease, although the best way to diagnose and monitor such patients is unclear. Serological testing for antibodies against transglutaminase 6 (TG6) has been proposed; however, this is not widely available in clinical practice. Using longitudinal data from patients attending a specialist neurological center with routine TG6 testing, this observational study explores how antibody history relates to brain atrophy, cognition, and quality of life.

METHODS

Serological records of patients with gluten-related neurological disease were collected alongside clinical brain magnetic resonance imaging. Patients were recruited to undertake questionnaires that assessed/included chronic symptom severity, the hospital anxiety and depression scale, the SF-12, and the Biagi scale for gluten-free diet adherence. Volunteers were offered the cerebellar cognitive affective syndrome scale for cognitive testing. Primary analyses focused on patients with ≥5 years of serology (n = 462), and related TG6 history to available clinical outcomes (primary analysis range 89-104).

RESULTS

Patients with a previous positive immunoglobulin A (IgA) TG6 result reported greater depression, symptom severity, and poorer physical functioning. IgA TG6 antibody exposure was correlated with regional brain atrophy (age-corrected). Greater self-reported gluten-free diet adherence significantly predicted a recent negative IgA TG6 test. Subgroup analyses replicated multiple findings in patients with and without celiac disease.

INTERPRETATION: TG6 testing can identify patients at risk of accelerated brain atrophy, poorer physical functioning, and worsened mental health. IgA TG6 should be used as a diagnostic and monitoring test for patients with relevant neurological presentations, while achieving negative serology with a strict gluten-free diet should be the goal. ANN NEUROL 2026;99:274-282.