Visual hallucinations are a major problem for many patients with Parkinson’s disease. A recent study published in the journal Brain The results of a study reveal that these hallucinations are associated with a marked impairment of cholinergic activity in certain brain regions, including the left ventral visual stream and the left superior temporal lobe. This research highlights the importance of cholinergic denervation in visual hallucinations, providing new insights into the underlying mechanisms and potential therapeutic options.
Parkinson’s disease is commonly associated with motor symptoms, but non-motor symptoms such as visual hallucinations are also common and can have a serious impact on quality of life. Approximately 25% of patients with Parkinson’s disease experience visual hallucinations, which can become more common in later stages of the disease. These hallucinations often involve seeing people or animals that are not present, adding to the complexity and burden of the disease.
Traditional beliefs associated visual hallucinations with the side effects of dopaminergic treatments. However, recent studies suggest that dopaminergic stimulation alone does not fully explain these symptoms. Instead, researchers have suggested that deficiencies in the cholinergic system, which involves the neurotransmitter acetylcholine, may play a key role. This study aimed to examine the alive cholinergic activity in patients with Parkinson’s disease, specifically comparing those with and without visual hallucinations, to better understand the neurochemical underpinnings of these symptoms.
“Visual hallucinations are an often underestimated problem in Parkinson’s disease. Very often, they are considered as part of the complications of long-term dopaminergic treatment, and not as a result of an underlying pathology. With this study, we wanted to evaluate whether the presence of visual hallucinations in Parkinson’s disease is associated with cholinergic denervation and, if so, which specific brain areas are involved,” explains study author Emile d’Angremont, postdoctoral researcher at the University Medical Center Amsterdam.
The research team studied 38 patients with Parkinson’s disease and 10 healthy controls. All participants underwent positron emission tomography (PET) scans using a tracer called (18F)FEOBV, which binds to the vesicular acetylcholine transporter, allowing visualization of cholinergic activity in the brain. In addition, participants underwent T1-weighted MRI scans and standardized assessments of psychotic symptoms and cognition.
Participants were divided into three groups: 13 patients who had visual hallucinations in the previous month (VH+ group), 20 patients who had never had visual hallucinations (VH- group), and five patients who had hallucinations but not in the previous month (excluded from the main analysis).
The study found significant differences in cholinergic activity between Parkinson’s disease patients and healthy controls, as well as between patients with and without visual hallucinations.
Patients with Parkinson’s disease showed a generalized reduction in cholinergic activity compared with healthy controls. This reduction was most pronounced in the occipital lobe but extended to the parietal, temporal, and frontal lobes.
Patients with visual hallucinations had significantly lower cholinergic activity in the left precuneus, left lingual gyrus, left fusiform gyrus, left inferior temporal gyrus, left middle and superior temporal gyri, and left supramarginal gyrus compared with those without hallucinations.
These results support the Perceptual Attention Deficit (PAD) model, which suggests that visual hallucinations in Parkinson’s disease result from impaired visual perception and attention to objects, exacerbated by cholinergic hypoactivity. The results remained significant even after adjusting for cognitive scores, indicating that the observed cholinergic impairments were specifically related to the presence of visual hallucinations rather than to general cognitive decline.
“It is likely that visual hallucinations in Parkinson’s disease are at least partly caused by cholinergic denervation, particularly in the ventral visual pathway and in some brain areas related to attention,” d’Angremont told PsyPost. “These findings provide the neurochemical basis for the treatment of visual hallucinations by cholinesterase inhibitors.”
Interestingly, the differences were observed primarily in the left hemisphere of the brain. Previous studies have shown mixed results regarding hemispheric involvement in psychotic symptoms, with some suggesting left hemisphere dominance and others suggesting right hemisphere or bilateral involvement.
“We found that the differences in cholinergic tracer uptake between patients with and without hallucinations were particularly marked in the left hemisphere,” d’Angremont said. “This was not expected, and we also don’t know how to interpret this result.”
This study, although very informative, has some limitations, including a small sample size that may limit the generalizability of the results and potential confounding due to the more advanced stage of the disease in the hallucination group. Future research could validate these findings in larger and more diverse populations, consider the role of visual acuity, and explore treatments targeting cholinergic deficiencies, such as cholinesterase inhibitors, to manage visual hallucinations in Parkinson’s disease.
“My long-term goal for this line of research is to personalize care for Parkinson’s disease,” d’Angremont explained. “In the future, we hope to be able to use a cholinergic biomarker, such as the PET tracer used in this study, to identify patients who will benefit from cholinesterase inhibitor therapy.”
The study, titled “Cholinergic deficiency in Parkinson’s disease patients with visual hallucinations,” was authored by Emile d’Angremont, Sygrid van der Zee, Sofie Slingerland, Anne C. Slomp, Erik F.J. de Vries, Teus van Laar, and Iris E. Sommer.