Background: The role of the gut‐brain axis has been recently highlighted as a major contributor to Parkinson's disease (PD) physiopathology, with numerous studies investigating bidirectional transmission of pathological protein aggregates, such as α‐synuclein (αSyn). However, the extent and the characteristics of pathology in the enteric nervous system have not been fully investigated.Objective: We characterized αSyn alterations and glial responses in duodenum biopsies of patients with PD by employing topography‐specific sampling and conformation‐specific αSyn antibodies.Methods: We examined 18 patients with advanced PD who underwent Duodopa percutaneous endoscopic gastrostomy and jejunal tube procedure, 4 untreated patients with early PD (disease duration <5 years), and 18 age‐ and ‐sex‐matched healthy control subjects undergoing routine diagnostic endoscopy. A mean of four duodenal wall biopsies were sampled from each patient. Immunohistochemistry was performed for anti‐aggregated αSyn (5G4) and glial fibrillary acidic protein antibodies. Morphometrical semiquantitative analysis was performed to characterize αSyn‐5G4⁺ and glial fibrillary acidic protein–positive density and size.Results: Immunoreactivity for aggregated α‐Syn was identified in all patients with PD (early and advanced) compared with controls. αSyn‐5G4⁺ colocalized with neuronal marker β‐III‐tubulin. Evaluation of enteric glial cells demonstrated an increased size and density when compared with controls, suggesting reactive gliosis.Conclusions: We found evidence of synuclein pathology and gliosis in the duodenum of patients with PD, including early de novo cases. Future studies are required to evaluate how early in the disease process duodenal pathology occurs and its possible contribution to levodopa effect in chronic patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Monoclonal gammopathy and peripheral neuropathy are common diseases of elderly patients, and almost 10% of patients with neuropathy of unknown cause have paraprotein. However, growing evidence suggests that several hematological malignancies synthesize and release monoclonal proteins that damage the peripheral nervous system through different mechanisms. The spectrum of the disease varies from mild to rapidly progressive symptoms, sometimes affecting not only sensory nerve fibers, but also motor and autonomic fibers. Therefore, a multidisciplinary approach, mainly between hematologists and neurologists, is recommended in order to establish the correct diagnosis of monoclonal gammopathy of neurological significance and to tailor therapy based on specific genetic mutations. In this review, we summarize the spectrum of monoclonal gammopathies of neurological significance, their distinctive clinical and neurophysiological phenotypes, the most relevant pathophysiological events and new therapeutic approaches.

The complexity of neurodegenerative disorders necessitates an integrative approach that incorporates morphological, functional, and molecular biomarkers. The advent of highly sensitive single-molecule array (Simoa®) assays has significantly enhanced the accuracy of blood-based biomarker quantification, including glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181). This study evaluates the diagnostic utility of these biomarkers in neurodegenerative diseases. We analyzed data from 279 individuals from the PADUA-CESNE cohort: 120 with Parkinson's disease (PD), 88 with Alzheimer's disease (AD), 16 with frontotemporal dementia (FTD), 11 with multiple system atrophy (MSA), 14 with progressive supranuclear palsy (PSP), and 30 cognitively unimpaired controls. NfL levels were significantly lower in PD and AD compared to atypical parkinsonisms and FTD, effectively distinguishing MSA and PSP from controls. NfL also negatively correlated with Montreal Cognitive Assessment (MoCA) scores in AD and PD, indicating its association with cognitive decline. Elevated GFAP levels were observed in both PD and AD and inversely correlated with global cognition. Combining GFAP and p-tau181 improved AD differentiation from PD and other parkinsonian disorders, while the integration of all three biomarkers facilitated the distinction between AD and FTD. Notably, lower NfL levels (<20 ng/L) in conjunction with elevated p-tau181 were indicative of AD, whereas NfL levels below 40 ng/L were suggestive of PD. In conclusion, NfL serves as a sensitive indicator of neurodegeneration, albeit with limited specificity. However, by establishing biomarker concentration thresholds and integrating complementary biomarkers, blood-based assays may enhance the differential diagnosis of neurodegenerative diseases, providing valuable clinical insights.

In this study, we compared the value of pathological alpha‐synuclein (αSyn) seed amplification assay (SAA) in gastric and duodenal biopsies with skin biopsies in Parkinson disease (PD) patients with different disease duration. The accuracy of αSyn SAA was 87.7% in skin, 67.4% in duodenum, and 80.0% in gastric biopsies, with significantly higher sensitivity in advanced PD (skin: 81.8%; gastric: 88.9%; duodenal 58.8%). Misfolded αSyn was detected with higher sensitivity in advanced PD across all matrices, likely reflecting the progression of αSyn pathology. The seeding activity was lower in the duodenal than in the gastric wall, indicating differences in αSyn burden.