Objective: To investigate whether cholinergic basal forebrain (cBF) atrophy mediates the relationship between short-latency afferent inhibition (SAI) and cognitive performance in PD.

Background: Cognitive impairment in PD is closely associated with the degeneration of the cholinergic system, particularly the cBF. SAI is a widely used neurophysiological marker of cholinergic circuit integrity; however, its specific association with cBF atrophy and its mechanistic role in domain-specific cognitive decline remain poorly characterized.

Method: We enrolled 119 patients with PD and 32 healthy controls. SAI was assessed using transcranial magnetic stimulation. MRI provided anterior and posterior cBF subregion volumes and substantia nigra (SN) free-water mapping (a non-cholinergic control). Cognitive status was determined using the Parkinson’s Disease Cognitive Rating Scale (PD-CRS), yielding global, fronto-subcortical (FS), and posterior-cortical (PC) scores. Non-parametric bootstrap mediation analysis was used to determine if cBF atrophy mediated the SAI-cognition link.

Results: SAI was significantly impaired in patients compared with controls (group x ISI interaction: F(1,153)=4.85, p=0.03, partial eta²=0.03; post-hoc N20 ISI: p=0.01) and was significantly associated with PD-CRS total scores (beta = -0.19, p=0.01, partial r_p=0.22) and PC scores (beta = -0.44, p<0.001, partial r_p=0.45), but not with FS scores. Mediation analysis revealed that posterior cBF volume fully mediated the relationship between SAI and global cognition, accounting for 47.4% of the total effect (indirect effect: beta=-0.08, 95% CI [-0.17, -0.03]). For PC functions, the relationship was partially mediated by both posterior (23.2% mediated) and anterior (15.5% mediated) cBF volumes. No association was found between SAI and SN free-water content, confirming neuroanatomical specificity.

Conclusion: These findings validate SAI as a functional biomarker linked to cBF integrity, particularly the posterior subregion. The identified pathways delineate a structure-function mechanism by which basal forebrain atrophy links neurophysiological circuit dysfunction to cognitive impairment. This positions SAI as a promising tool for tracking cholinergic contributions to cognitive decline and potentially guiding targeted pro-cholinergic therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cholinergic-basal-forebrain-atrophy-associates-with-short-latency-afferent-inhibition-and-cognitive-impairment-in-parkinsons-disease/