Visual hallucinations (VH) can increase the burden of disease for both patients with Parkinson’s disease (PD) and their caregivers. Multiple neurotransmitters have been implicated in the neuropathology of VH, which provide targets for treatment and prevention. In this study, we assessed the association between cholinergic denervation and VH in PD in vivo, using PET imaging of the cholinergic system. A total of 38 PD patients participated in this study. A group of 10 healthy subjects, matched for age, sex and education, was included for comparison. None of the participants used cholinergic drugs. Thirteen patients who had experienced VH in the past month (VH+) were compared to 20 patients who had never experienced VH in their lives (VH-). Cholinergic system integrity was assessed with PET imaging using [¹⁸F]fluoroethoxybenzovesamicol ([¹⁸F]FEOBV) as the tracer. We assessed the differences in tracer uptake between groups by cluster-based analysis and by analysis of predefined regions of interest (ROIs) consisting of the ventral visual stream, the dorsal attentional network, the ventral attentional network and the lateral geniculate nucleus and mediodorsal nucleus of the thalamus. The PD group (n=38) showed an extensive pattern of decreased tracer uptake throughout the brain, compared to the controls (n=10). Within the PD group, the VH+ group (n=13) showed a cluster of decreased tracer uptake compared to the VH- group (n=20), which covered most of the left ventral visual stream and extended towards superior temporal areas. These results were mirrored in the ROI-based analysis, where the VH+ group showed the strongest deficits in the left inferior temporal gyrus and the left superior temporal gyrus, compared to the VH- group. VH in PD are associated with a marked cholinergic deficiency in the left ventral visual stream and the left superior temporal lobe, in addition to an extensive global cholinergic denervation in the general PD population.

Cognitive impairment is considered to be one of the key features of Parkinson's disease (PD), ultimately resulting in PD‐related dementia in approximately 80% of patients over the course of the disease. Several distinct cognitive syndromes of PD have been suggested, driven by different neurotransmitter deficiencies and thus requiring different treatment regimes. In this study, we aimed to identify characteristic brain covariance patterns that reveal how cholinergic denervation is related to PD and to cognitive impairment, focusing on four domains, including attention, executive functioning, memory, and visuospatial cognition. We applied scaled sub‐profile model principal component analysis to reveal cholinergic‐specific disease‐related and cognition‐related covariance patterns using [¹⁸F]fluoroethoxybenzovesamicol PET imaging. Stepwise logistic regression was applied to predict disease state (PD vs. healthy control). Linear regression models were applied to predict cognitive functioning within the PD group, for each cognitive domain separately. We assessed the performance of the identified patterns with leave‐one‐out cross validation and performed bootstrapping to assess pattern stability. We included 34 PD patients with various levels of cognitive dysfunction and 10 healthy controls, with similar age, sex, and educational level. The disease‐related cholinergic pattern was strongly discriminative (AUC 0.91), and was most prominent in posterior brain regions, with lower tracer uptake in patients compared to controls. We found largely overlapping cholinergic‐specific patterns across cognitive domains, with positive correlations between tracer uptake in the opercular cortex, left dorsolateral prefrontal cortex and posterior cingulate gyrus, among other regions, and attention, executive, and visuospatial functioning. Cross validation showed significant correlations between predicted and measured cognition scores, with the exception of memory. We identified a robust structural covariance pattern for the assessment of cholinergic dysfunction related to PD, as well as overlapping cholinergic patterns related to attentional, executive‐ and visuospatial impairment in PD patients.

Short-latency afferent inhibition (SAI) is a relatively cheap and non-invasive method that has been proposed as a cholinergic marker in Parkinson's disease (PD). We aim to verify the clinical feasibility of SAI as a cholinergic marker in PD using positron emission tomography (PET) with the tracer (2R,3R)-5-(2-[¹⁸F]fluoroethoxy)benzovesamicol ([¹⁸F]FEOBV) as a reference. We examined relations between SAI and [¹⁸F]FEOBV PET using linear regression analysis, with the primary motor cortex (M1) as primary region of interest. Additionally, we examined relations of both measures with clinical features. 30 PD patients with varying degrees of cognitive dysfunction and 10 healthy controls (HC) were included in the analysis. SAI was not related to tracer uptake in M1 in the PD group (p = .291) or the HC group (p = .206). We could not replicate the previously published relations between SAI and cholinergic symptoms, such as cognition, psychotic experiences and olfactory function. SAI was not related to [¹⁸F]FEOBV imaging parameters, nor to clinical measures of cholinergic dysfunction. Therefore, SAI may not be feasible as a clinically applied cholinergic marker in PD.

Objective: The phenotype of patients with Parkinson's disease carrying GBA1 variants (GBA‐PD) suggest similarities to symptomatology associated with early cholinergic system degeneration. Therefore, this study aims to investigate the clinical features and the cholinergic innervation pattern in patients with early GBA‐PD versus those without the GBA1 mutation (non‐GBA‐PD).Methods: A total of 46 GBA‐PD and 104 non‐GBA‐PD subjects were included. Clinical assessments included motor and non‐motor evaluation, as well as a comprehensive neuropsychological examination. Cholinergic system integrity was assessed using ¹⁸F‐Fluoroethoxybenzovesamicol (¹⁸F‐FEOBV) positron emission tomography (PET) to investigate the differences between GBA‐PD and non‐GBA‐PD. Given the higher prevalence of females in GBA‐PD, analyses were repeated when stratified by sex. Additionally, we examined the association between cognitive domains and whole‐brain cholinergic binding in both groups. Exploratory analyses examined clinical and ¹⁸F‐FEOBV binding differences among GBA1 variants.Results: GBA‐PD patients exhibited a higher burden of non‐motor symptoms and lower cognitive performance on executive functions and attention. We observed a more pronounced cholinergic denervation in GBA‐PD, compared to non‐GBA‐PD, primarily in the anterior, central, and limbic regions. However, the distribution of cholinergic loss and its association with attention and executive dysfunction was comparable between GBA‐PD and non‐GBA‐PD. In addition, the clinical presentation and cholinergic binding differed significantly between sexes.Interpretation: These results suggest an important role of early cholinergic denervation in GBA‐PD patients, which is related to more severe cognitive dysfunction. ANN NEUROL 2025;98:398–409

Background: Limited treatment options with a rapid onset of action are available to treat off episodes in Parkinson’s disease (PD) patients. Therefore, the development of rapid onset formulations, for instance with levodopa, is warranted, which was the reason to investigate an inhalable formulation of levodopa. Objectives: The primary objective was to determine the duration until maximum effect is reached of inhaled levodopa on the improvement of motor function of PD patients. The secondary objective was to compare the time until maximal effect and the maximal effect of inhaled levodopa versus oral levodopa. Design: Open-label randomized two-way one-period crossover trial. Methods: Nine PD patients in the ‘off state’ received one dose of inhaled levodopa (90 mg) from Cyclops® and one dose of levodopa orodispersible tablet (100 mg) on two consecutive days in a randomized order. A timed tapping test, Timed Up and Go test (TUG test) and Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) III score were performed pre-dose and on set time points up to 90 min post-dose as measure for motor function. In addition, blood samples were taken for a pharmacokinetic evaluation ( T_max, C_max and area under the concentration time curve (AUC) 0–3 h). Results: The maximal effect of inhaled levodopa was reached at 30 min (tapping test), at 75 min (TUG test) and at 60 min (UPDRS III). The positive effect on the UPDRS was statistically significant within 20 min after inhalation. After oral administration, C_max and AUC 0–3 h were found to be significant higher ( p = 0.028 and p = 0.028, respectively) than after pulmonary administration. T_max was achieved significantly ( p = 0.028) faster after inhalation. The motor function examinations showed a similar maximum clinical improvement after pulmonary and oral administration and although not significant, inhaled levodopa results in a shorter median duration to maximum clinical effect for the TUG and timed finger-tapping test compared with oral administration (TUG: inhalation 55.0 and oral 67.5 min, timed finger-tapping test: inhalation 35.0 and oral 57.5 min). After the levodopa inhalation, there were no adverse events observed and no significant differences found in long-function parameters. Conclusion: Inhaled levodopa from Cyclops^® shows promising data as a rescue therapy for PD patients with off episodes, not responsive to the current oral therapies. Trial registration: The study protocol was approved by the local ethics board ‘Regionale toetsingscommissie patiëntgebonden onderzoek’ (RTPO) in Leeuwarden, The Netherlands (approval number RTPO1019). The study was registered in in the Dutch trial register (LTR) with identification number NL6876. From 5 March 2024 on, the research data on onderzoekmetmensen.nl are known as ‘Overview of Medical Research in the Netherlands’ (OMON). This means the use of the name LTR has thus been dropped. Now, it is registered in the OMON with the same identification number (NL6876, Effectiveness of inhaled levodopa in PD | Research with human participants (onderzoekmetmensen.nl)). All patients provided written informed consent.