Visual hallucinations (VH) are common in Parkinson’s disease and predict faster cognitive decline, higher mortality, and earlier institutionalization. Rather than dopaminergic therapy alone, convergent evidence implicates central cholinergic degeneration—especially in the nucleus basalis of Meynert (NBM) and pedunculopontine nucleus. Post-mortem studies show α-synuclein pathology with cholinergic loss. Acetylcholinesterase/vesicular acetylcholine transporter PET demonstrates posterior cortical and thalamic denervation. Receptor imaging reveals altered M1/M4 and nicotinic binding. Structural/functional MRI link VH to occipitoparietal, thalamic, hippocampal, and lateral geniculate nucleus-centered networks with abnormal default mode network–visual coupling and weak attentional engagement. Electrophysiology (reduced short-latency afferent inhibition, theta↑/gamma↓) supports a hypocholinergic state that biases top-down predictions over noisy sensory input.
Clinically, cholinesterase inhibitors can attenuate psychosis, with greatest benefit likely in biomarker-selected patients. Receptor-specific approaches (eg, M1/M4 positive allosteric modulators, selective nicotinic agents) and NBM deep brain stimulation are emerging options to restore network balance. A cholinergic-centered model reconciles competing theories and supports personalized strategies that combine cholinomimetics, receptor modulation, and neuromodulation. Key next steps are testing whether early cholinergic targeting can delay psychosis onset and slow cognitive decline.
Reference: Ignatavicius A, Matar E, Lewis SJG. Visual hallucinations in Parkinson’s disease: spotlight on central cholinergic dysfunction. Brain. 2025;148(2):376-393. doi: 10.1093/brain/awae289.
Link: https://academic.oup.com/brain/article/148/2/376/7754318
