Pesticides and the Microbiome-Gut-Brain Axis: Convergent Pathways in the Pathogenesis of Parkinson's Disease.

The increasing global burden of Parkinson's disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.

Dermal Real-Time Quaking-Induced Conversion Is a Sensitive Marker to Confirm Isolated Rapid Eye Movement Sleep Behavior Disorder as an Early α-Synucleinopathy.

BACKGROUND: Skin biopsy is a potential tool for the premortem confirmation of an α-synucleinopathy. OBJECTIVE: The aim was to assess the aggregation assay real-time quaking-induced conversion (RT-QuIC) of skin biopsy lysates to confirm isolated rapid eye movement sleep behavior disorder (iRBD) as an α-synucleinopathy. METHODS: Skin biopsies of patients with iRBD, Parkinson's disease (PD), and controls were analyzed using RT-QuIC and immunohistochemical detection of phospho-α-synuclein. RESULTS: α-Synuclein aggregation was detected in 97.4% of iRBD patients (78.4% of iRBD biopsies), 87.2% of PD patients (70% of PD biopsies), and 13% of controls (7.9% of control biopsies), with a higher seeding activity in iRBD compared to PD. RT-QuIC was more sensitive but less specific than immunohistochemistry. CONCLUSIONS: Dermal RT-QuIC is a sensitive method to detect α-synuclein aggregation in iRBD, and high seeding activity may indicate a strong involvement of dermal nerve fibers in these patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Expression Profiling of Rectal Biopsies Suggests Altered Enteric Neuropathological Traits in Parkinson's Disease Patients.

Still little is known about the nature of the gastrointestinal pathological alterations occurring in Parkinson's disease (PD). Here, we used multiplexed mRNA profiling to measure the expression of a panel of 770 genes related to neuropathological processes in deep submucosal rectal biopsies of PD patients and healthy controls. Altered enteric neuropathological traits based on the expression of 22 genes related to neuroglial and mitochondrial functions, vesicle trafficking and inflammation was observed in 9 out of 12 PD patients in comparison to healthy controls. These results provide new evidences that intestinal neuropathological alterations may occur in a large proportion of PD patients.

Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.

OBJECTIVE: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). METHODS: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD. RESULTS: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old). CONCLUSIONS: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.