What question did this study set out to answer?

Investigate alterations in spontaneous brain activity in Kallmann syndrome and their relationship with cognitive impairment and genetic mutations.

April 17, 2026Open Access

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

YFYan FuTongji Hospital XWX.Y. WangCentral South University FWF. WuCentral South University

Key Points

Investigate alterations in spontaneous brain activity in Kallmann syndrome and their relationship with cognitive impairment and genetic mutations.
Enrolled 100 patients with Kallmann syndrome and 100 matched healthy controls
Conducted MRI scans and neuropsychological assessments including MoCA, SCWT, and other tests
Calculated regional brain activity using ALFF metric
Performed genetic sequencing and biological correlations
Patients with Kallmann syndrome showed significant cognitive deficits, with 36% meeting the cutoff for cognitive impairment.
Increased ALFF in fronto-insular and salience networks, decreased ALFF in cerebellum and left angular gyrus.
Positive correlations found between increased ALFF in fronto-insular regions and cognitive scores.
Exploratory genetic analysis revealed links between mutation burden and decreased ALFF.

Abstract

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.

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