Sex dependent atrophy of hypothalamus across ALS subtypes: A quantitative volumetric MRI study

Amyotrophic lateral sclerosis (ALS) is frequently associated with metabolic alterations, in which the hypothalamus plays a central regulatory role. This study aimed to radiologically quantify hypothalamic atrophy using brain magnetic resonance imaging (MRI) across different ALS phenotypes, including primary lateral sclerosis (PLS), lower motor neuron disease (LMND), progressive bulbar palsy (PBP), and flail limb syndrome (FLS), as well as in presymptomatic genetic mutation carriers, with a particular focus on sex-dependent differences. Compared with healthy controls, significant hypothalamic atrophy was observed in all ALS phenotypes except PBP, although conclusions regarding PBP are limited by the small sample size. Sex-specific analyses revealed more pronounced hypothalamic atrophy in male ALS patients compared with females. In contrast, female PLS patients exhibited greater hypothalamic volume loss than their male counterparts, indicating phenotype-dependent sex differences that may hold clinical relevance for individualized therapeutic approaches. The underlying mechanisms driving these differences remain unclear and warrant further investigation. Presymptomatic mutation carriers demonstrated hypothalamic volumes intermediate between healthy controls and symptomatic ALS patients, supporting the concept that hypothalamic involvement precedes the onset of motor symptoms. This effect was particularly evident in male carriers, suggesting that early hypothalamic atrophy may contribute to sex-specific disease vulnerability and could serve as a potential radiological marker for earlier diagnosis. In summary, hypothalamic atrophy is present early in the ALS disease course and shows significant sex-related variation. However, despite clinical heterogeneity among ALS phenotypes, hypothalamic involvement appears to reflect a shared pathophysiological process related to metabolic dysregulation rather than phenotype-specific mechanisms.