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An altered immune response has been identified as a pathophysiological factor in Parkinson's disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls and that are associated with long-term disease severity in PD patients. Immune response-derived proteins in blood plasma were measured using Proximity Extension Technology by OLINK in a cohort of PD patients (N = 66) and age-matched healthy controls (N = 52). In a selection of 30 PD patients, we evaluated changes in protein levels 7-10 years after the baseline and assessed correlations with motor and cognitive assessments. Data from the Parkinson's Disease Biomarkers Program (PDBP) cohort and the Parkinson's Progression Markers Initiative (PPMI) cohort were used for independent validation. PD patients showed an altered immune response compared to controls based on a panel of four proteins (IL-12B, OPG, CXCL11, and CSF-1). The expression levels of five inflammation-associated proteins (CCL23, CCL25, TNFRSF9, TGF-alpha, and VEGFA) increased over time in PD and were partially associated with more severe motor and cognitive symptoms at follow-up. Increased CCL23 levels were associated with cognitive decline and the APOE4 genotype. Our findings provide further evidence for an altered immune response in PD that is associated with disease severity in PD over a long period of time.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.

Background: Increased neurofilament levels in biofluids are commonly used as a proxy for neurodegeneration in several neurodegenerative disorders. In this study, we aimed to investigate the distribution of neurofilaments in the cerebral cortex of Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) donors, and its association with pathology load and MRI measures of atrophy and diffusivity., Methods: Using a within-subject post-mortem MRI-pathology approach, we included 9 PD, 12 PDD/DLB and 18 age-matched control donors. Cortical thickness and mean diffusivity (MD) metrics were extracted respectively from 3DT1 and DTI at 3T in-situ MRI. After autopsy, pathological hallmarks (pSer129-αSyn, p-tau and amyloid-β load) together with neurofilament light-chain (NfL) and phosphorylated-neurofilament medium- and heavy-chain (p-NfM/H) immunoreactivity were quantified in seven cortical regions, and studied in detail with confocal-laser scanning microscopy. The correlations between MRI and pathological measures were studied using linear mixed models., Results: Compared to controls, p-NfM/H immunoreactivity was increased in all cortical regions in PD and PDD/DLB, whereas NfL immunoreactivity was increased in the parahippocampal and entorhinal cortex in PDD/DLB. NfL-positive neurons showed degenerative morphological features and axonal fragmentation. The increased p-NfM/H correlated with p-tau load, and NfL correlated with pSer129-αSyn but more strongly with p-tau load in PDD/DLB. Lastly, neurofilament immunoreactivity correlated with cortical thinning in PD and with increased cortical MD in PDD/DLB., Conclusions: Taken together, increased neurofilament immunoreactivity suggests underlying axonal injury and neurofilament accumulation in morphologically altered neurons with increased pathological burden. Importantly, we demonstrate that such neurofilament markers at least partly explain MRI measures that are associated with the neurodegenerative process., (© 2023. The Author(s).)

The clinical diagnosis in patients with parkinsonian disorders can be challenging, and a definite diagnosis requires neuropathological confirmation. The aim of this study was to examine whether a clinical diagnosis of Parkinson's disease (PD) and atypical parkinsonian disorders predict the presence of Lewy pathology (LP) and concomitant neuropathological lesions.We included 293 donors with a history of parkinsonism without dementia at disease onset, collected by the Netherlands Brain Bank (NBB) from 1989 to 2015. We retrospectively categorized donors according the International Parkinson and Movement Disorder Society clinical diagnostic criteria for PD (MDS-PD criteria) as 'not PD', 'probable PD' or 'established PD'. We compared the final clinical diagnosis to presence of neuropathological lesions as defined by BrainNet Europe and National Institute on Aging - Alzheimer's Association guidelines.LP was present in 150 out of 176 donors (85%) with a clinical diagnosis of PD, in 8 out of 101 donors (8%) with atypical parkinsonian disorders and in 4 out of 16 donors (25%) without a definite clinical diagnosis. Independent from age at death, stages of amyloid-β, but not neurofibrillary tau or neuritic plaques, were higher in donors with LP compared to other types of pathology (p = 0.009). The MDS-PD criteria at a certainty level of 'probable PD' predicted presence of LP with a diagnostic accuracy of 89.3%. Among donors with LP, 'established PD' donors showed similar Braak α-synuclein stages and stages of amyloid-β, neurofibrillary tau and neuritic plaques compared to 'not PD' or 'probable PD' donors.In conclusion, both a clinical diagnosis of PD as well as MDS-PD criteria accurately predicted presence of LP in NBB donors. LP was associated with more widespread amyloid-β pathology, suggesting a link between amyloid-β accumulation and LP formation.

Deficits in cognitive functioning are a common yet poorly understood symptom in Parkinson's disease (PD). Recent studies have highlighted the importance of (dynamic) interactions between resting-state networks for cognition, which remains understudied in PD. We investigated how altered (dynamic) functional interactions between brain networks relate to cognitive dysfunction in PD patients. In this fMRI study, 50 PD patients (mean age 65.5 years ± 6.27) on dopaminergic medication were studied cross-sectionally, and of this cohort 31 PD patients were studied longitudinally. MRI imaging and neuropsychological testing was performed at two time points, with a follow-up duration of approximately three years. Functional connectivity within and between seven resting-state networks was calculated (both statically and dynamically) and correlated with four neuropsychological test scores; a combined score of (four) executive tasks, a motor perseveration, memory, and category fluency task. Cognitive dysfunction was determined based on a longitudinal sample of age-matched healthy controls (n = 13). PD patients showed dysfunction on six out of seven cognitive tasks when compared to healthy controls. Severity of executive dysfunction was correlated with higher static and lower dynamic functional connectivity between deep gray matter regions and the frontoparietal network (DGM-FPN). Over time, declining executive function was related to increasing static DGM-FPN connectivity, together with changes of connectivity involving the dorsal attention network (amongst others with the ventral attention network). Static functional connectivity between the ventral and dorsal attention network correlated with motor perseveration. Our findings demonstrate that in PD patients, dysfunctional communication between (i) subcortical, fronto-parietal and attention networks mostly underlies worsening of executive functioning, (ii) attention networks are involved in motor perseveration., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The insula is a central brain hub involved in cognition and affected in Parkinson's disease (PD). The aim of this study was to assess functional connectivity (FC) and betweenness centrality (BC) of insular sub-regions and their relationship with cognitive impairment in PD., Methods: Whole-brain 3D-T1, resting-state functional MRI and a battery of cognitive tests (CAMCOG) were included for 53 PD patients and 15 controls. The insular cortex was segmented into ventral (vAI) and dorsal (dAI) anterior and posterior sub-regions. Connectivity between insular sub-regions and resting-state networks was assessed and related to cognition; BC was used to further explore nodes associated with cognition., Results: Cognitive performance was significantly lower in PD patients compared to controls (p < 0.01) and was associated with FC of the dAI with default mode network (DMN) (adjusted R 2  = 0.37, p < 0.001). In controls, cognitive performance was positively related to FC of the dAI with the fronto-parietal network (FPN) only (adjusted R 2  = 0.5, p = 0.003). Regionally, FC of the dAI with the anterior cingulate cortex (ACC) was significantly reduced in PD (F(1,65) = 11, p = 0.002) and correlated with CAMCOG (r = 0.4, p = 0.001). DMN and FPN showed increased BC in PD which correlated with cognition and reduced connectivity of dAI with the ACC (r s  = -0.33, p = 0.014 and r s  = -0.44, p = 0.001 respectively)., Conclusions: These results highlight the relevance of the insula in cognitive dysfunction in PD. Disconnection of the dAI with ACC was related to altered centrality in the DMN and FPN only in patients. Disturbance in this network triad appears to be particularly relevant for cognitive impairment in PD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose To gain more insight into the pathophysiological mechanisms of visual hallucinations (VHs) in patients with Parkinson disease (PD) by analyzing whole-brain resting-state functional connectivity in PD patients with VH (hereafter, referred to as PD + VH patients) and without VH (hereafter, referred to as PD - VH patients) and control participants. Materials and Methods For this retrospective study, 15 PD + VH patients, 40 PD - VH patients, and 15 control participants from a prospective cohort study were included, which was approved by the local ethics board and written informed consent was obtained from all participants. Functional connectivity was calculated between 47 regions of interests, of which whole-brain and region-specific means were compared by using a general linear model with false discovery rate control for multiple comparisons. Results Whole-brain mean functional connectivity was significantly lower in PD patients compared with control participants, with regional decreases involving paracentral and occipital regions in both PD + VH and PD - VH patients (mean whole-brain functional connectivity in PD + VH vs PD - VH, 0.12 ± 0.01 [standard deviation] vs 0.14 ± 0.03, respectively; control participants, 0.15 ± 0.04; P < .05, corrected). In PD + VH patients, nine additional frontal, temporal, occipital, and striatal regions showed decreased functional connectivity compared with control participants (mean of these nine regions in PD + VH, PD - VH, and control participants: 0.12 ± 0.02, 0.14 ± 0.03, and 0.16 ± 0.04, respectively; P < .05, corrected). Resting-state functional connectivity was unrelated to motor performance (r = 0.182; P = .184) and related to cognitive deficits such as attention and perception (ρ, -0.555 and -0.558, respectively; P < .05). Conclusion The findings show a PD-related effect on resting-state functional connectivity of posterior and paracentral brain regions, whereas the presence of VH is associated with a more global loss of connectivity, related to attention and perception. These findings suggest that the pathophysiological mechanisms of VH in PD may include a global loss of network efficiency, which could drive disturbed attentional and visual processing. © RSNA, 2017 Online supplemental material is available for this article.

Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson's disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD - VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD - VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients.

There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) that plays a role in a variety of clinical symptoms, including visual hallucinations (VH). The aim of this study was to assess cholinergic neuronal loss and PD and Alzheimer disease pathology in the pedunculopontine nucleus pars compacta (PPNc) of PD and DLB patients with VH. Postmortem brainstem tissue samples of 9 clinically diagnosed and pathologically confirmed PD patients with VH, 9 DLB patients with VH, and 9 age- and sex-matched nondemented controls were obtained from the Netherlands Brain Bank. Using a morphometric approach, we estimated the density of cholinergic neurons in the PPNc and determined the local load of α-synuclein-immunoreactive Lewy pathology, neurofibrillary tangles, and β-amyloid plaques. Cholinergic cell density in the PPNc was significantly lower in PD compared with DLB patients with VH (-39%, p < 0.001) and controls (-41%, p < 0.001). Alpha-synuclein load was higher in PD, whereas β-amyloid plaque pathology was more pronounced in DLB patients. The mean cell density in DLB patients was not significantly reduced compared with that in controls. These results may indicate different patterns of degeneration of cholinergic output structures in PD and DLB.

Background: Visual hallucinations (VH) in Parkinson's disease (PD) are associated with PD dementia and have been related to cognitive impairments in non-demented PD patients. Reports on the specific cognitive domains affected are conflicting. The aim of the present study was to investigate the presence of specific cognitive impairments in non-demented PD patients with VH, compared to those without VH., Methods: We compared the clinical characteristics and neuropsychological test scores of 31 non-demented PD patients with VH with those of 31 PD patients without VH that were carefully matched for sex, age, disease duration and educational level. Several non-motor symptoms, including depression, anxiety and sleep disturbances, were also taken into account, as these may influence cognitive performance., Results: The PD with VH group performed significantly worse on the Trail Making Test part A (p = 0.01) and the Rey Auditory Verbal Learning Test, immediate recall (p = 0.01). In addition, PD patients with VH were more anxious, more depressed and reported more sleep disturbances. Verbal learning scores were not associated with levels of anxiety, depression or sleep disruption, whereas worse Trail Making Test A performance was associated with concomitant sleep disturbances., Conclusions: In non-demented PD patients, the presence of VH is associated with a cognitive profile characterized by impairments in verbal learning and probably attention. Since these cognitive functions are believed to be non-dopaminergic mediated functions, the present results support the hypothesis that multiple neurotransmitter systems, other than dopamine, contribute to the pathophysiology of VH in PD., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is characterized by a gradual accumulation of neuropathology that may begin many years before a clinical diagnosis can be made using currently accepted criteria. Here, we first review the prevalence of α-synuclein neuropathology in elderly and discuss its clinical relevance in Parkinson patients. Subsequently, the results of a retrospective study focussing on the distribution of neuropathology in Parkinson patients with a tremor-dominant (TD), non-tremordominant (NTD) or rapid disease progression (RDP) subtype are presented. The study population recruited by the Netherlands Brain bank consisted of 149 non-neurological donors, 26 donors with incidental Lewy body disease (iLBD) and 111 Parkinson patients. In total, 89% of these cases could be classified in accordance with the Braak staging when taking into account the severity of α-synuclein pathology and adding an amygdala-predominant category of synucleinopathy. The pathological progression seemed to be non-linear. Interestingly, a strong correlation between neuronal loss and α-synuclein pathology was observed in the substantia nigra in Braak stages 3-6 (P < 0.01). However, there was no correlation between Hoehn & Yahr and Braak stages. Neuropathological progression may, however, vary between subtypes as cortical Lewy body load and Braak stages were higher in patients with NTD compared to TD and Alzheimer pathology was more prevalent in RDP patients. Recognition of clinical subtypes in neuropathological studies is essential to identify selective vulnerability to protein accumulation that may determine the clinical phenotype in PD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)