Study protocol of the DUtch PARkinson Cohort (DUPARC):a prospective, observational study of de novo Parkinson's disease patients for the identification and validation of biomarkers for Parkinson's disease subtypes, progression and pathophysiology

BACKGROUND: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology. METHODS/DESIGN: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included. DISCUSSION: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication. TRIAL REGISTRATION: NCT04180865; registered retrospectively, November 28th 2019

Increasing Comparability and Utility of Gut Microbiome Studies in Parkinson's Disease : A Systematic Review

Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset with atypical parkinsonism cohorts, prodromal and treatment naive de novo PD subjects, measurements of fecal microbial concentrations and multi-omics assessments are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD.Peer reviewe

Altered cholinergic innervation in De Novo Parkinson's disease with and without cognitive impairment

BACKGROUND: Altered cholinergic innervation plays a putative role in cognitive impairment in Parkinson's disease (PD) at least in advanced stages. Identification of the relationship between cognitive impairment and cholinergic innervation early in the disease will provide better insight into disease prognosis and possible early intervention. OBJECTIVE: The aim was to assess regional cholinergic innervation status in de novo patients with PD, with and without cognitive impairment. METHODS: Fifty-seven newly diagnosed, treatment-naive, PD patients (32 men, mean age 64.6 ± 8.2 years) and 10 healthy controls (5 men, mean age 54.6 ± 6.0 years) were included. All participants underwent cholinergic [18 F]fluoroethoxybenzovesamicol positron emission tomography and detailed neuropsychological assessment. PD patients were classified as either cognitively normal (PD-NC) or mild cognitive impairment (PD-MCI). Whole brain voxel-based group comparisons were performed. RESULTS: Results show bidirectional cholinergic innervation changes in PD. Both PD-NC and PD-MCI groups showed significant cortical cholinergic denervation compared to controls (P < 0.05, false discovery rate corrected), primarily in the posterior cortical regions. Higher-than-normal binding was most prominent in PD-NC in both cortical and subcortical regions, including the cerebellum, cingulate cortex, putamen, gyrus rectus, hippocampus, and amygdala. CONCLUSION: Altered cholinergic innervation is already present in de novo patients with PD. Posterior cortical cholinergic losses were present in all patients independent of cognitive status. Higher-than-normal binding in cerebellar, frontal, and subcortical regions in cognitively intact patients may reflect compensatory cholinergic upregulation in early-stage PD. Limited or failing cholinergic upregulation may play an important role in early, clinically evident cognitive impairment in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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.Peer reviewe

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.</p

Gender Differences in Cognitive Functioning in de novo Parkinson’s Disease Patients

Objective: To clarify the differences in cognitive functioning across different cognitive domains, between male and female de novo PD patients. Background: Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disorder, with cognitive dysfunction as an important non-motor symptom. Research about the cognitive functions of male versus female PD patients is scarce, inconsistent and lacking control groups. Methods: A total of 78 PD patients (67% male) and 67 healthy controls (HC; 54% male) took part in the study. Cognitive functions were assessed using a complete neuropsychological assessment battery covering all cognitive domains. The Movement Disorders Society Unified Parkinson Disease Rating Scale part III (MDS-UPDRS III) was used as a measure of motor performance. Male and female patients and HC were compared at baseline on demographic characteristics and neuropsychological performance. Results: Male patients showed higher MDS-UPDRS III scores (p = .008) and lower MoCA scores (p < .001) than their female counterparts. Female patients presented with better verbal- and visuospatial memory than male patients (p < .01), the same trend was found in HC. Female patients performed better on attention tasks (p < .0125) and tasks assessing executive functioning (p < .01) than male patients. No significant gender differences were found in the domains of language, social cognition, visuospatial functioning and processing speed, for both patients and HC. Female patients did not differ from female HC on any of the tests conducted, whereas male patients performed significantly worse than male HC on tasks of all domains. Conclusions: The results of this study add further evidence that gender can influence the clinical presentation of both motor and cognitive symptoms of de novo PD, by more severely affecting male patients. Awareness of these differences could provide insight in underlying pathological mechanisms and facilitate diagnosis and gender-specific clinical treatment

Gender Differences in Cognitive Functioning in de novo Parkinson’s Disease Patients

Objective: To clarify the differences in cognitive functioning across different cognitive domains, between male and female de novo PD patients. Background: Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disorder, with cognitive dysfunction as an important non-motor symptom. Research about the cognitive functions of male versus female PD patients is scarce, inconsistent and lacking control groups. Methods: A total of 78 PD patients (67% male) and 67 healthy controls (HC; 54% male) took part in the study. Cognitive functions were assessed using a complete neuropsychological assessment battery covering all cognitive domains. The Movement Disorders Society Unified Parkinson Disease Rating Scale part III (MDS-UPDRS III) was used as a measure of motor performance. Male and female patients and HC were compared at baseline on demographic characteristics and neuropsychological performance. Results: Male patients showed higher MDS-UPDRS III scores (p = .008) and lower MoCA scores (p < .001) than their female counterparts. Female patients presented with better verbal- and visuospatial memory than male patients (p < .01), the same trend was found in HC. Female patients performed better on attention tasks (p < .0125) and tasks assessing executive functioning (p < .01) than male patients. No significant gender differences were found in the domains of language, social cognition, visuospatial functioning and processing speed, for both patients and HC. Female patients did not differ from female HC on any of the tests conducted, whereas male patients performed significantly worse than male HC on tasks of all domains. Conclusions: The results of this study add further evidence that gender can influence the clinical presentation of both motor and cognitive symptoms of de novo PD, by more severely affecting male patients. Awareness of these differences could provide insight in underlying pathological mechanisms and facilitate diagnosis and gender-specific clinical treatment