Cholinergic deficiency in Parkinson's disease patients with visual hallucinations.

Visual hallucinations can increase the burden of disease for both patients with Parkinson's disease and their caregivers. Multiple neurotransmitters have been implicated in the neuropathology of visual hallucinations, which provide targets for treatment and prevention. In this study, we assessed the association between cholinergic denervation and visual hallucinations in Parkinson's disease in vivo, using PET imaging of the cholinergic system. A total of 38 patients with Parkinson's disease 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 visual hallucinations in the past month (VH+) were compared with 20 patients who had never experienced visual hallucinations in their lives (VH-). Cholinergic system integrity was assessed with PET imaging using 18F-fluoroethoxybenzovesamicol as the tracer. We assessed the differences in tracer uptake between groups by cluster-based analysis and by analysis of predefined regions of interest 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 Parkinson's disease group (n = 38) showed an extensive pattern of decreased tracer uptake throughout the brain compared with the controls (n = 10). Within the Parkinson's disease group, the VH+ group (n = 13) showed a cluster of decreased tracer uptake compared with 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 regions of interest-based analysis, in which the VH+ group showed the strongest deficits in the left inferior temporal gyrus and the left superior temporal gyrus compared with the VH- group. Visual hallucinations in Parkinson's disease 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 Parkinson's disease population.

Cholinergic changes in Lewy body disease: implications for presentation, progression and subtypes.

Cholinergic degeneration is significant in Lewy body disease, including Parkinson's disease, dementia with Lewy bodies, and isolated REM sleep behaviour disorder. Extensive research has demonstrated cholinergic alterations in the CNS of these disorders. More recently, studies have revealed cholinergic denervation in organs that receive parasympathetic denervation. This enables a comprehensive review of cholinergic changes in Lewy body disease, encompassing both central and peripheral regions, various disease stages and diagnostic categories. Across studies, brain regions affected in Lewy body dementia show equal or greater levels of cholinergic impairment compared to the brain regions affected in Lewy body disease without dementia. This observation suggests a continuum of cholinergic alterations between these disorders. Patients without dementia exhibit relative sparing of limbic regions, whereas occipital and superior temporal regions appear to be affected to a similar extent in patients with and without dementia. This implies that posterior cholinergic cell groups in the basal forebrain are affected in the early stages of Lewy body disorders, while more anterior regions are typically affected later in the disease progression. The topographical changes observed in patients affected by comorbid Alzheimer pathology may reflect a combination of changes seen in pure forms of Lewy body disease and those seen in Alzheimer's disease. This suggests that Alzheimer co-pathology is important to understand cholinergic degeneration in Lewy body disease. Thalamic cholinergic innervation is more affected in Lewy body patients with dementia compared to those without dementia, and this may contribute to the distinct clinical presentations observed in these groups. In patients with Alzheimer's disease, the thalamus is variably affected, suggesting a different sequential involvement of cholinergic cell groups in Alzheimer's disease compared to Lewy body disease. Patients with isolated REM sleep behaviour disorder demonstrate cholinergic denervation in abdominal organs that receive parasympathetic innervation from the dorsal motor nucleus of the vagus, similar to patients who experienced this sleep disorder in their prodrome. This implies that REM sleep behaviour disorder is important for understanding peripheral cholinergic changes in both prodromal and manifest phases of Lewy body disease. In conclusion, cholinergic changes in Lewy body disease carry implications for understanding phenotypes and the influence of Alzheimer co-pathology, delineating subtypes and pathological spreading routes, and for developing tailored treatments targeting the cholinergic system.

Reduced Thickness of the Retina in de novo Parkinson's Disease Shows A Distinct Pattern, Different from Glaucoma.

Background: Parkinson's disease (PD) patients experience visual symptoms and retinal degeneration. Studies using optical coherence tomography (OCT) have shown reduced thickness of the retina in PD, also a key characteristic of glaucoma. Objective: To identify the presence and pattern of retinal changes in de novo, treatment-naive PD patients compared to healthy controls (HC) and early primary open angle glaucoma (POAG) patients. Methods: Macular OCT data (10×10 mm) were collected from HC, PD, and early POAG patients, at the University Medical Center Groningen. Bayesian informative hypotheses statistical analyses were carried out comparing HC, PD-, and POAG patients, within each retinal cell layer. Results: In total 100 HC, 121 PD, and 78 POAG patients were included. We showed significant reduced thickness of the inner plexiform layer and retinal pigment epithelium in PD compared to HC. POAG patients presented with a significantly thinner retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, outer plexiform layer, and outer photoreceptor and subretinal virtual space compared to PD. Only the outer segment layer and retinal pigment epithelium were significantly thinner in PD compared to POAG. Conclusions: De novo PD patients show reduced thickness of the retina compared to HC, especially of the inner plexiform layer, which differs significantly from POAG, showing a more extensive and widespread pattern of reduced thickness across layers. OCT is a useful tool to detect retinal changes in de novo PD, but its specificity versus other neurodegenerative disorders has to be established.

Short-latency afferent inhibition as a biomarker of cholinergic degeneration compared to PET imaging in Parkinson's disease.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cholinergic innervation topography in GBA-associated de novo Parkinson's disease patients.

The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.

Cholinergic centro-cingulate network in Parkinson disease and normal aging.

Decreased cholinergic binding within the recently identified centro-cingulate brain network robustly has been shown to robustly correlate with the severity of cognitive impairment in Parkinson disease (PD). This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing "effector" regions for fine movement control intercalated with interlinked "inter-effector" regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.

Impaired facial emotion recognition in relation to social behaviours in de novo Parkinson's disease.

Facial emotion recognition (FER) is a crucial component of social cognition and is essential in social-interpersonal behaviour regulation. Although FER impairment is well-established in advanced PD, data about FER at the time of diagnosis and its relationship with social behavioural problems in daily life are lacking. The aim was to examine FER at the time of PD diagnosis compared to a matched healthy control (HC) group and to associate FER with indices of social behavioural problems. In total, 142 de novo, treatment-naïve PD patients and 142 HC were included. FER was assessed by the Ekman 60 faces test (EFT). Behavioural problems in PD patients were assessed using the Dysexecutive Questionnaire (DEX-self and DEX-proxy) and the Apathy Evaluation Scale (AES-self). PD patients had significantly lower EFT-total scores (p = .001) compared to HC, with worse recognition of Disgust (p = .001) and Sadness (p = .016). Correlational analyses yielded significant correlations between AES-self and both EFT-total (rs = .28) and Fear (rs = .22). Significant negative correlations were found between DEX-proxy and both EFT-total (rs = -.28) and Anger (rs = -.26). Analyses of DEX-subscales showed that proxy ratings were significantly higher than patient-ratings for the Social Conventions subscale (p = .047). This DEX-proxy subscale had the strongest correlation with EFT-total (rs = -.29). Results show that de novo PD patients already show impaired FER compared to HC. In addition, lower FER is linked to self-reported apathy and proxy-reported social-behavioural problems, especially concerning social conventions. These findings validate the importance of the inclusion of social cognition measures in the neuropsychological assessment even in early PD.

Identification of cholinergic centro-cingulate topography as main contributor to cognitive functioning in Parkinson's disease: Results from a data-driven approach.

Background: Degeneration of the cholinergic system plays an important role in cognitive impairment in Parkinson's disease (PD). Positron emission tomography (PET) imaging using the presynaptic vesicular acetylcholine transporter (VAChT) tracer [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) allows for regional assessment of cholinergic innervation. The purpose of this study was to perform a data-driven analysis to identify co-varying cholinergic regions and to evaluate the relationship of these with cognitive functioning in PD. Materials and methods: A total of 87 non-demented PD patients (77% male, mean age 67.9 ± 7.6 years, disease duration 5.8 ± 4.6 years) and 27 healthy control (HC) subjects underwent [18F]FEOBV brain PET imaging and neuropsychological assessment. A volume-of-interest based factor analysis was performed for both groups to identify cholinergic principal components (PCs). Results: Seven main PCs were identified for the PD group: (1) bilateral posterior cortex, (2) bilateral subcortical, (3) bilateral centro-cingulate, (4) bilateral frontal, (5) right-sided fronto-temporal, (6) cerebellum, and (7) predominantly left sided temporal regions. A complementary principal component analysis (PCA) analysis in the control group showed substantially different cholinergic covarying patterns. A multivariate linear regression analyses demonstrated PC3, PC5, and PC7, together with motor impairment score, as significant predictors for cognitive functioning in PD. PC3 showed most robust correlations with cognitive functioning (p < 0.001). Conclusion: A data-driven approach identified covarying regions in the bilateral peri-central and cingulum cortex as a key determinant of cognitive impairment in PD. Cholinergic vulnerability of the centro-cingulate network appears to be disease-specific for PD rather than being age-related. The cholinergic system may be an important contributor to regional and large scale neural networks involved in cognitive functioning.

Fecal microbiome alterations in treatment-naive de novo Parkinson's disease.

Gut microbiota alterations in Parkinson's disease (PD) have been found in several studies and are suggested to contribute to the pathogenesis of PD. However, previous results could not be adequately adjusted for a potential confounding effect of PD medication and disease duration, as almost all PD participants were already using dopaminergic medication and were included several years after diagnosis. Here, the gut microbiome composition of treatment-naive de novo PD subjects was assessed compared to healthy controls (HC) in two large independent case-control cohorts (n = 136 and 56 PD, n = 85 and 87 HC), using 16S-sequencing of fecal samples. Relevant variables such as technical batches, diet and constipation were assessed for their potential effects. Overall gut microbiome composition differed between PD and HC in both cohorts, suggesting gut microbiome alterations are already present in de novo PD subjects at the time of diagnosis, without the possible confounding effect of dopaminergic medication. Although no differentially abundant taxon could be replicated in both cohorts, multiple short chain fatty acids (SCFA) producing taxa were decreased in PD in both cohorts. In particular, several taxa belonging to the family Lachnospiraceae were decreased in abundance. Fewer taxonomic differences were found compared to previous studies, indicating smaller effect sizes in de novo PD.

Cerebral topography of vesicular cholinergic transporter changes in neurologically intact adults: A [18F]FEOBV PET study.

Acetylcholine plays a major role in brain cognitive and motor functions with regional cholinergic terminal loss common in several neurodegenerative disorders. We describe age-related declines of regional cholinergic neuron terminal density in vivo using the positron emission tomography (PET) ligand [18F](-)5-Fluoroethoxybenzovesamicol ([18F] FEOBV), a vesamicol analogue selectively binding to the vesicular acetylcholine transporter (VAChT). A total of 42 subjects without clinical evidence of neurologic disease (mean 50.55 [range 20-80] years, 24 Male/18 Female) underwent [18F]FEOBV brain PET imaging. We used SPM based voxel-wise statistical analysis to perform whole brain voxel-based parametric analysis (family-wise error corrected, FWE) and to also extract the most significant clusters of regions correlating with aging with gender as nuisance variable. Age-related VAChT binding reductions were found in primary sensorimotor cortex, visual cortex, caudate nucleus, anterior to mid-cingulum, bilateral insula, para-hippocampus, hippocampus, anterior temporal lobes/amygdala, dorsomedial thalamus, metathalamus, and cerebellum (gender and FWE-corrected, P < 0.05). These findings show a specific topographic pattern of regional vulnerability of cholinergic nerve terminals across multiple cholinergic systems accompanying aging.