Parkinson's disease CA2-CA3 hippocampal atrophy is accompanied by increased cholinergic innervation in patients with normal cognition but not in patients with mild cognitive impairment

Abstract

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson's disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory process have been further studied here, using MRI volumetry and morphometry coupled with molecular imaging using the PET radiotracer [¹⁸F]-Fluoroethoxybenzovesamicol ([¹⁸F]-FEOBV). Following a thorough screening procedure, 18 participants were selected and evenly distributed in three groups, including cognitively normal PD patients (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and healthy volunteers (HV). Participants underwent a detailed neuropsychological assessment, structural MRI, and PET imaging with [¹⁸F]-FEOBV. Basal forebrain Ch1-Ch2 volumes were measured using stereotaxic mapping. Hippocampal subfields were automatically defined using the MAGeT-Brain segmentation algorithm. Cholinergic innervation density was quantified using [¹⁸F]-FEOBV uptake. Compared with HV, both PD-CN and PD-MCI displayed significantly reduced volumes in CA2-CA3 bilaterally. We found no other hippocampal subfield nor Ch1-Ch2 volume differences between the three groups. PET imaging revealed higher [¹⁸F]-FEOBV uptake in CA2-CA3 of the PD-CN compared with HV or PD-MCI. A positive correlation was observed between cognitive performances and [¹⁸F]-FEOBV uptake in the right CA2-CA3 subfield. Reduced volume, together with increased [¹⁸F]-FEOBV uptake, were observed specifically in the CA2-CA3 hippocampal subfields. However, while the volume change was observed in both PD-CN and PD-MCI, increased [¹⁸F]-FEOBV uptake was present only in the PD-CN group. This suggests that a cholinergic compensatory process takes place in the atrophied CA2-CA3 hippocampal subfields and might underlie normal cognition in PD.

Keywords: Acetylcholine, Cognition; Compensation, FEOBV, Hippocampus; PET; Parkinson; Volumetry.