Altered spontaneous brain activity is associated with cognitive impairment in patients with Kallmann syndrome

This study aimed to investigate alterations in spontaneous brain activity in Kallmann syndrome (KS) and their associations with cognitive impairment and genetic mutations. We prospectively enrolled 100 patients with KS and 100 matched healthy controls. All participants underwent brain MRI and neuropsychological assessment targeting global cognition (Montreal-Cognitive-Assessment, MoCA), executive function (Stroop-Color-and-Word-Test, SCWT), cognitive flexibility (Trail-Making-Test), and working memory (Digit-Span-Test, DST; Visual-Reproduction, VR). Regional brain activity was quantified using the amplitude of low-frequency fluctuation (ALFF) metric. We further conducted brain-cognition correlations, genetic association analysis with whole-exome sequencing, and extrapolated neuroimaging-transcription-association analysis. Compared to the controls, patients with KS exhibited significant cognitive deficits across most domains, with 36% reached the clinical cutoff for cognitive impairment. Patients showed increased ALFF predominantly in the fronto-insular executive network and salience network, but decreased ALFF in the cerebellum and left angular gyrus (cluster-level GRF-corrected-p < 0.05). The increased ALFF in fronto-insular regions was positively correlated with MoCA (r = 0.215, FDR-p = 0.037) and SCWT-B (r = 0.253, FDR-p = 0.026), while the reduced ALFF in the left angular gyrus was negatively correlated with VR and DST-forward (r=-0.270, FDR-p = 0.011; r=-0.280, FDR-p = 0.011, respectively). Exploratory genetic analysis revealed that a higher cumulative mutation burden was associated with lower ALFF in cerebellum and angular gyrus, while ANOS1 and PROKR2 mutations mapped to distinct network alterations. Furthermore, the spatial pattern of ALFF alterations was significantly associated with extrapolated gene expression profiles enriched for neurodevelopment and cell migration. This study found a genetically related trade-off between compensatory executive hyperactivation and dysfunctional brain activity with suppression as a potential neuroimaging biomarker for cognitive impairment risk in patients with KS.