Sex-Stratified Association of Regional Dopamine Transporter Binding With Disease Progression in Amyotrophic Lateral...

To clarify the clinical relevance of dopamine transporter single-photon emission computed tomography (DAT-SPECT) abnormalities in amyotrophic lateral sclerosis (ALS), with a prespecified focus on sex-stratified associations with disease progression and short-term prognosis.

Fifty-eight consecutive patients with ALS were prospectively enrolled and underwent ¹²³I-ioflupane DAT-SPECT, and DAT-SPECT data from 30 patients with essential tremor were analyzed as a reference group. We quantified the specific binding ratio (SBR) and the caudate-to-putamen binding ratio (BR-C/P) as age-adjusted Z-scores. Associations with functional decline (ΔALSFRS-R), respiratory function (forced vital capacity), neuropsychiatric measures, and a 6-month composite endpoint of death or ventilator support were examined using correlation and logistic regression analyses, with prespecified sex-stratified evaluation.

A significant sex difference in BR-C/P Z-scores prompted sex-stratified analyses. SBR Z-scores were not associated with clinical or neuropsychiatric variables in either sex. In women, lower BR-C/P Z-scores correlated with faster functional decline and were independently associated with a higher risk of death or ventilator support within 6 months (odds ratio per 1-unit increase, 0.31; 95% confidence interval, 0.12-0.83). In men, BR-C/P Z-scores correlated with forced vital capacity and respiratory decline. Exploratory voxel-based morphometry suggested limbic and striatal gray matter correlates in women with lower BR-C/P Z-scores.

Regional dopaminergic imbalance captured by BR-C/P, rather than global SBR, demonstrated sex-stratified associations with disease progression in ALS. These findings support sex-specific interpretation of dopaminergic imaging biomarkers and suggest that BR-C/P may complement clinical measures for identifying higher-risk trajectories, particularly in women. Validation in larger, longitudinal cohorts is required.