ABSTRACT Objective 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. Methods Fifty‐eight consecutive patients with ALS were prospectively enrolled and underwent 123 I‐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. Results 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. Interpretation 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.
Kawazoe et al. (Thu,) studied this question.