Cholinergic denervation is present in patients with PD even in the absence of dementia. Although the traditional view of the cholinergic system is that of a diffuse neuromodulator system, more recent data point to a deterministic role of regional cholinergic functions.  It is unclear whether cholinergic effects on cognition in PD are driven by diffuse vs. regional specific brain changes.

A total of 87 individuals with PD (67 males/20 females; age: 67.9±7.6 yrs.; modified Hoehn & Yahr stage: 1-4 (median 2.5); duration of disease: 5.8 ± 6.0 yrs.) underwent neuropsychological assessment and [¹⁸F]-FEOBV vesicular acetylcholine transporter brain PET imaging to quantify cholinergic innervation. Principal component analysis of the cholinergic brain PET data was used to identify cholinergic sub-components.

The data-driven PET analysis identified 6 higher loading factors. Correlational analysis of these sub-components with the cognitive test battery identified the third factor as having the most robust correlations with different cognitive domains, including memory, attention and executive functions (P< 0.001). More limited correlations were seen not only with the other factors but also with diffuse cholinergic brain activity. The topography of the third component includes the bilateral insula, fronto-temporal opercula, anterior and mid cingulum and thalamus that are also key hub of the cingulo-opercular task control (COTC) network.

Findings support a deterministic function of the cholinergic system. Cholinergic denervation of key hubs of the COTC network has robust correlation with cognitive impairment in PD across several cognitive domains, including memory, attention and executive functions. Cholinergic denervation of the COTC may represent a shared network sub-serving these domains. Findings may auger novel network-targeted therapeutic approaches to treat cognitive impairment in PD.