Novel SLC18A2 Variant in Infantile Dystonia-Parkinsonism Type 2.

Infantile dystonia-parkinsonism type 2 (PKDYS2) is a rare inherited autosomal recessive movement disorder with onset in infancy. The disease is associated with a mutation in the solute carrier family 18 member A2 gene (SLC18A2). There are reports of trials with dopaminergic drugs and the condition of patients given levodopa almost always worsens and dopamine agonists give varying degrees of benefit to some. Here, we report a PKDYS2 patient with a new variant in the SLC18A2 gene who underwent multiple trials of pharmacotherapy. The abnormalities in development and neurological examination of the case were first noted at the age of 2 months, and after a series of treatment attempts (e.g., with antiepileptics) and diagnostic procedures, the diagnosis of PKDYS2 was determined when whole exome sequencing (WES) at age 6, revealed a homozygous pathologic variant NM_003054.4:c.1107dup, p.(Val370Serfs∗91) in the SLC18A2 gene. The patient then received treatment with multiple dopaminergic drugs (e.g., levodopa, pramipexole, and methylphenidate). The patient with PKDYS2 harbored a new variant in SLC18A2. The phenotype of the patient resembles that of some previously reported patients with PKDYS2. The patient received minor benefits from certain dopaminergic drugs, such as pramipexole, but side effects led to the discontinuation of tested medications.

Seasonal variation in D2/3 dopamine receptor availability in the human brain.

PURPOSE: Brain functional and physiological plasticity is essential to combat dynamic environmental challenges. The rhythmic dopamine signaling pathway, which regulates emotion, reward and learning, shows seasonal patterns with higher capacity of dopamine synthesis and lower number of dopamine transporters during dark seasons. However, seasonal variation of the dopamine receptor signaling remains to be characterized. METHODS: Based on a historical database of healthy human brain [11C]raclopride PET scans (n = 291, 224 males and 67 females), we investigated the seasonal patterns of D2/3 dopamine receptor signaling. Daylength at the time of scanning was used as a predictor for brain regional non-displaceable binding of the radiotracer, while controlling for age and sex. RESULTS: Daylength was negatively correlated with availability of D2/3 dopamine receptors in the striatum. The largest effect was found in the left caudate, and based on the primary sample, every 4.26 h (i.e., one standard deviation) increase of daylength was associated with a mean 2.8% drop (95% CI -0.042 to -0.014) of the receptor availability. CONCLUSIONS: Seasonally varying D2/3 receptor signaling may also underlie the seasonality of mood, feeding, and motivational processes. Our finding suggests that in future studies of brain dopamine signaling, especially in high-latitude regions, the effect of seasonality should be considered.

Dietary Caffeine and Brain Dopaminergic Function in Parkinson Disease.

OBJECTIVE: This study was undertaken to investigate the effects of dietary caffeine intake on striatal dopamine function and clinical symptoms in Parkinson disease in a cross-sectional and longitudinal setting. METHODS: One hundred sixty-three early Parkinson disease patients and 40 healthy controls were investigated with [123I]FP-CIT single photon emission computed tomography, and striatal dopamine transporter binding was evaluated in association with the level of daily coffee consumption and clinical measures. After a median interval of 6.1 years, 44 patients with various caffeine consumption levels underwent clinical and imaging reexamination including blood caffeine metabolite profiling. RESULTS: Unmedicated early Parkinson disease patients with high coffee consumption had 8.3 to 15.4% lower dopamine transporter binding in all studied striatal regions than low consumers, after accounting for age, sex, and motor symptom severity. Higher caffeine consumption was further associated with a progressive decline in striatal binding over time. No significant effects of caffeine on motor function were observed. Blood analyses demonstrated a positive correlation between caffeine metabolites after recent caffeine intake and dopamine transporter binding in the ipsilateral putamen. INTERPRETATION: Chronic caffeine intake prompts compensatory and cumulative dopamine transporter downregulation, consistent with caffeine's reported risk reduction in Parkinson disease. However, this decline does not manifest in symptom changes. Transiently increased dopamine transporter binding after recent caffeine intake has implications for dopaminergic imaging guidelines. ANN NEUROL 2024.

Alterations in type 2 dopamine receptors across neuropsychiatric conditions: A large-scale PET cohort.

PURPOSE: Aberrant dopaminergic function is linked with motor, psychotic, and affective symptoms, but studies have typically compared a single patient group with healthy controls. METHODS: Here, we investigated the variation in striatal (caudate nucleus, nucleus accumbens, and putamen) and thalamic type 2 dopamine receptor (D2R) availability using [11C]raclopride positron emission tomography (PET) data from a large sample of 437 humans including healthy controls, and subjects with Parkinson's disease (PD), antipsychotic-naïve schizophrenia, severe violent behavior, pathological gambling, depression, and overweight. We analyzed regional group differences in D2R availability. We also analyzed the interregional correlation in D2R availability within each group. RESULTS: Subjects with PD showed the clearest decline in D2R availability. Overall, the groups showed high interregional correlation in D2R availability, while this pattern was weaker in violent offenders. Subjects with schizophrenia, pathological gambling, depression, or overweight did not show clear changes in either the regional receptor availability or the interregional correlation. CONCLUSION: We conclude that the dopaminergic changes in neuropsychiatric conditions might not only affect the overall receptor availability but also how coupled regions are across people. The region-specific receptor availability more profoundly links to the motor symptoms, while the between-region coupling might be disrupted in violence.

Case-Fatality Rate in Parkinson's Disease: A Nationwide Registry Study.

BACKGROUND: Patients with Parkinson's disease (PD) may have an increased risk of mortality, but robust estimates are lacking. OBJECTIVE: To compare mortality rates nationally between patients with PD and controls. METHODS: The case-fatality rates of Finnish PD patients diagnosed in 2004-2018 (n = 23,688; 57% male, mean age at diagnosis = 71 years) and randomly selected sex- and age-matched control subjects (n = 94,752) were compared using data from national registries. The median follow-up duration was 5.8 years (max 17 years). RESULTS: The case-fatality rate in patients with PD was higher than that in matched controls (HR 2.29; 95% CI 2.24-2.33; P < 0.0001). Excess fatality among PD patients was already present at 1 year from diagnosis and then plateaued at 29% at 12 years after diagnosis. The long-term relative hazard of death in PD patients vs. matched controls did not differ based on sex. Patients with early-onset PD (age at diagnosis <50 years old) had the highest relative hazard of death (HR 3.36) compared to matched control subjects, and the relative hazard decreased with higher age at diagnosis. The seven-year excess risk of death decreased during the study period, especially in men. In patients with PD, male sex, increasing age, and increasing comorbidity burden were associated with an increased risk of death. CONCLUSIONS: An increased risk of death among PD patients was evident from early on. The increase in risk was greatest among young-onset patients. The excess risk in early PD declined during the study period, particularly in men. The reasons for this are unknown.

GPi-DBS-induced brain metabolic activation in cervical dystonia.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia. METHODS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR<0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen. CONCLUSIONS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.

Early cortical atrophy is related to depression in patients with neuropathologically confirmed Parkinson's disease.

OBJECTIVE: Depression is a common comorbidity in Parkinson's disease (PD) and other synucleinopathies. In non-PD geriatric patients, cortical atrophy has previously been connected to depression. Here, we investigated cortical atrophy and vascular white matter hyperintensities (WMHs) in autopsy-confirmed parkinsonism patients with the focus on clinical depression. METHODS: The sample consisted of 50 patients with a postmortem confirmed neuropathological diagnosis (30 Parkinson's disease [PD], 10 progressive supranuclear palsy [PSP] and 10 multiple system atrophy [MSA]). Each patient had been scanned with brain computerized tomography (CT) antemortem (median motor symptom duration at scanning = 3.0 years), and 19 patients were scanned again after a mean interval of 2.7 years. Medial temporal atrophy (MTA), global cortical atrophy (GCA) and WMHs were evaluated computationally from CT scans using an image quantification tool based on convolutional neural networks. Depression and other clinical parameters were recorded from patient files. RESULTS: Depression was associated with increased MTA after controlling for diagnosis, age, symptom duration, and cognition (p = 0.006). A similar finding was observed with GCA (p = 0.017) but not with WMH (p = 0.47). In PD patients alone, the result was confirmed for MTA (p = 0.021) with the same covariates. In the longitudinal analysis, GCA change per year was more severe in depressed patients than in nondepressed patients (p = 0.029). CONCLUSIONS: Early medial temporal and global cortical atrophy, as detected with automated analysis of CT-images using convolutional neural networks, is associated with clinical depression in parkinsonism patients. Global cortical atrophy seems to progress faster in depressed patients.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Abnormal frontostriatal connectivity and serotonin function in gambling disorder: A preliminary exploratory study.

Background: The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities. Methods: Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (18F-FDOPA), opioid (11C-carfentanil) and serotonin (11C-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches. Results: Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (PFWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC 11C-MADAM binding (p = 0.03) but not in 18F-FDOPA uptake or 11C-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex 11C-MADAM binding (PFWE <0.05). Right NAcc 11C-MADAM binding potential correlated with attentional impulsivity in individuals with gambling disorder (r = -0.73, p = 0.005). Discussion: Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify potential treatment targets for gambling disorder.

Dopamine transporter binding in the brain is linked to irritable bowel syndrome in Parkinson's disease.

BACKGROUND: Gastrointestinal symptoms are common in Parkinson's disease (PD), but their neurophysiological correlates are not well understood. We recently reported that functional gastrointestinal symptoms were not associated with asymmetry per se but might be associated with lower left striatal dopamine transporter (DAT) binding. The purpose of this study was to further investigate if specific gastrointestinal symptoms associate with monoamine transporter changes in specific striatal or extrastriatal areas. METHODS: Ninety PD patients, who underwent DAT ¹2 3 I-FP-CIT SPECT imaging, were assessed using the MDS-Unified Parkinson's Disease Rating Scale part III, Rome III, and Wexner constipation score. DAT binding was calculated from striatal subregions using region-to-occipital cortex ratio. Voxel-wise analysis was used to assess the relationship between gastrointestinal symptoms and striatal DAT and extrastriatal serotonin transporter (SERT) binding. RESULTS: Irritable bowel syndrome (IBS) criteria were fulfilled in 17 patients and were linked to higher ¹2 3 I-FP-CIT binding in the right posterior putamen and adjacent areas as compared to patients without IBS. No other significant associations between gastrointestinal symptoms and DAT or SERT binding were found. CONCLUSIONS: These findings suggest that PD patients with IBS may have higher DAT binding in the right hemisphere. This finding implicates alterations of brain neurotransmitter physiology in the gastrointestinal symptoms of PD patients.

Feasibility and patient acceptability of a commercially available wearable and a smart phone application in identification of motor states in parkinson's disease.

In the quantification of symptoms of Parkinson's disease (PD), healthcare professional assessments, patient reported outcomes (PRO), and medical device grade wearables are currently used. Recently, also commercially available smartphones and wearable devices have been actively researched in the detection of PD symptoms. The continuous, longitudinal, and automated detection of motor and especially non-motor symptoms with these devices is still a challenge that requires more research. The data collected from everyday life can be noisy and frequently contains artefacts, and novel detection methods and algorithms are therefore needed. 42 PD patients and 23 control subjects were monitored with Garmin Vivosmart 4 wearable device and asked to fill a symptom and medication diary with a mobile application, at home, for about four weeks. Subsequent analyses are based on continuous accelerometer data from the device. Accelerometer data from the Levodopa Response Study (MJFFd) were reanalyzed, with symptoms quantified with linear spectral models trained on expert evaluations present in the data. Variational autoencoders (VAE) were trained on both our study accelerometer data and on MJFFd to detect movement states (e.g., walking, standing). A total of 7590 self-reported symptoms were recorded during the study. 88.9% (32/36) of PD patients, 80.0% (4/5) of DBS PD patients and 95.5% (21/22) of control subjects reported that using the wearable device was very easy or easy. Recording a symptom at the time of the event was assessed as very easy or easy by 70.1% (29/41) of subjects with PD. Aggregated spectrograms of the collected accelerometer data show relative attenuation of low (<5Hz) frequencies in patients. Similar spectral patterns also separate symptom periods from immediately adjacent non-symptomatic periods. Discriminative power of linear models to separate symptoms from adjacent periods is weak, but aggregates show partial separability of patients vs. controls. The analysis reveals differential symptom detectability across movement tasks, motivating the third part of the study. VAEs trained on either dataset produced embedding from which movement states in MJFFd could be predicted. A VAE model was able to detect the movement states. Thus, a pre-detection of these states with a VAE from accelerometer data with good S/N ratio, and subsequent quantification of PD symptoms is a feasible strategy. The usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients. Finally, the usability of the data collection method is important to enable the collection of self-reported symptom data by PD patients.

Budget-Based Classification of Parkinson's Disease From Resting State EEG.

Early detection is vital for future neuroprotective treatments of Parkinson's disease (PD). Resting state electroencephalographic (EEG) recording has shown potential as a cost-effective means to aid in detection of neurological disorders such as PD. In this study, we investigated how the number and placement of electrodes affects classifying PD patients and healthy controls using machine learning based on EEG sample entropy. We used a custom budget-based search algorithm for selecting optimized sets of channels for classification, and iterated over variable channel budgets to investigate changes in classification performance. Our data consisted of 60-channel EEG collected at three different recording sites, each of which included observations collected both eyes open (total N = 178) and eyes closed (total N = 131). Our results with the data recorded eyes open demonstrated reasonable classification performance (ACC = .76; AUC = .76) with only 5 channels placed far away from each other, the selected regions including right-frontal, left-temporal and midline-occipital sites. Comparison to randomly selected subsets of channels indicated improved classifier performance only with relatively small channel-budgets. The results with the data recorded eyes closed demonstrated consistently worse classification performance (when compared to eyes open data), and classifier performance improved more steadily as a function of number of channels. In summary, our results suggest that a small subset of electrodes of an EEG recording can suffice for detecting PD with a classification performance on par with a full set of electrodes. Furthermore our results demonstrate that separately collected EEG data sets can be used for pooled machine learning based PD detection with reasonable classification performance.

A severe neurodegenerative disease with Lewy bodies and a mutation in the glucocerebrosidase gene.

Several heterozygous variants of the glucocerebrosidase gene (GBA1) have been reported to increase the risk of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1-associated PD has been reported to be more severe than idiopathic PD, and more deleterious variants are associated with more severe clinical phenotypes. We report a family with a heterozygous p.Pro454Leu variant in GBA1. The variant was associated with a severe and rapidly progressive neurodegenerative disease with Lewy bodies that were clinically and pathologically diverse. Pathogenicity prediction algorithms and evolutionary analyses suggested that p.Pro454Leu is deleterious.

Clinical spectrum and genotype-phenotype associations in Finnish patients with Wilson's disease.

Genotype-phenotype correlation data covering all ages of Wilson's disease onset in Caucasian patients are limited. We therefore analyzed genotype-phenotype correlations in a retrospective cohort of Finnish patients. Six homozygous (HoZ) and 11 compound heterozygous (CoHZ) patients were included. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis (p > 0.30 for all) between HoZ and CoHZ patients, but HoZ patients had an earlier age of diagnosis (median 6.7 versus 34.5; p = 0.003). Severe liver affliction was almost exclusively associated with the p.H1069Q variant. Patients with p.H1069Q had a later mean age of diagnosis (30.2 ± 11.6 vs. 8.7 ± 4.9 years; p < 0.001) compared to those without. There were no differences in the presence/absence of hepatic, neurological, psychiatric or any symptoms at diagnosis between p.H1069Q-positive and p.H1069Q-negative patients (p > 0.54 for all). These results suggest that population-specific factors may partly explain the high clinical variability of Wilson's disease.

Floating door sign does not differentiate Parkinson's disease from essential tremor.

Diagnostic usefulness of the floating door sign was tested in 144 PD patients, 41 essential tremor patients and 38 controls. There were no differences in the presence of floating door sign between PD and ET patients. The sign does not seem to be a reliable differential diagnostic tool.

Regulators of proteostasis are translationally repressed in fibroblasts from patients with sporadic and LRRK2-G2019S Parkinson's disease.

Deficits in protein synthesis are associated with Parkinson's disease (PD). However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S PD, the most common monogenic form. Here we used bio-orthogonal non-canonical amino acid tagging for global analysis of newly translated proteins in fibroblasts from sporadic and LRKK2-G2019S patients. Quantitative proteomic analysis revealed that several nascent proteins were reduced in PD samples compared to healthy without any significant change in mRNA levels. Using targeted proteomics, we validated which of these proteins remained dysregulated at the static proteome level and found that regulators of endo-lysosomal sorting, mRNA processing and components of the translation machinery remained low. These proteins included autophagy-related protein 9A (ATG9A) and translational stability regulator YTH N6-ethyladenosine RNA binding protein 3 (YTHDF3). Notably, 77% of the affected proteins in sporadic patients were also repressed in LRRK2-G2019S patients (False discovery rate (FDR) < 0.05) in both sporadic and LRRK2-G2019S samples. This analysis of nascent proteomes from PD patient skin cells reveals that regulators of proteostasis are repressed in both sporadic and LRRK2-G2019S PD.

Cross-Cultural Differences in Patient Perceptions of Dyskinesia in Parkinson's Disease.

BACKGROUND: The prevalence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) varies among geographical regions. Cultural differences in patient-based perceptions of LID have not been studied. OBJECTIVE: We compared patient and clinician evaluations of LID severity across multiple cultures in patients with PD. METHODS: The data set included the Unified Dyskinesia Rating (UDysRS) scores from 16 language translation programs (3566 patients). We defined the Perception Severity Index (PSI) as the ratio between normalized patient-based subjective ratings (UDysRS Part 1B) and normalized clinician examination (Parts 3 and 4) scores (Part 1B/Parts 3 + 4) and compared the PSI across languages. RESULTS: The mean PSI for the Chinese language (2.16) was higher than those of all other languages, whereas the ratio for the Korean language (0.73) was lower than those for Japanese, German, Turkish, Greek, Polish, and Finnish languages (corrected P values <0.05). CONCLUSIONS: Culture, as represented by language, affects the subjective perception of LID and needs to be considered in multinational clinical PD trials on dyskinesia. © 2023 International Parkinson and Movement Disorder Society.

Serotonergic and dopaminergic control of impulsivity in gambling disorder.

Gambling disorder (GD) is major public health issue. The disorder is often characterized by elevated impulsivity with evidence from analogous substance use disorders underlining prominent roles of brain monoamines in addiction susceptibility and outcome. Critically, GD allows the study of addiction mechanisms without the confounder of the effects of chronic substances. Here, we assessed the roles of striatal dopamine transporter binding and extrastriatal serotonin transporter binding in GD as a function of impulsivity using [123 I]FP-CIT SPECT imaging in 20 older adults with GD (DSM-5 criteria; mean age 64 years) and 40 non-GD age- and sex-matched controls. We focused on GD in older individuals because there are prominent age-related changes in neurotransmitter function and because there are no reported neuroimaging studies of GD in older adults. Volume-of-interest-based and voxelwise analyses were performed. GD patients scored clearly higher on impulsivity and had higher tracer binding in the ventromedial prefrontal cortex than controls (p < 0.001), likely reflecting serotonin transporter activity. The binding in the medial prefrontal cortex positively correlated with impulsivity over the whole sample (r = 0.62, p < 0.001) as well as separately in GD patients (r = 0.46, p = 0.04) and controls (r = 0.52, p < 0.001). Striatal tracer binding, reflecting dopamine transporter activity was also positively correlated with impulsivity but showed no group differences. These findings highlight the role of prefrontal serotonergic function in GD and impulsivity. They identify cerebral coordinates of a potential target for neuromodulation for both GD and high impulsivity, a core phenotypic dimensional cognitive marker in addictions.

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.