Marta Campagnolo

The complexity of α-synucleinopathies, namely Parkinson’s disease (PD) and multiple system atrophy (MSA), calls for the adoption a multimodal approach integrating biological, morphological, and functional data. Phosphorylated α-synuclein (α-syn) detection in bodily fluids and tissues such as the skin helps provide biological characterization of the disease, but specific and accessible biomarkers are not available yet. The aim of this study was to define the role of Optical Coherence Tomography (OCT, a minimally invasive retinal imaging technique) patterns as possible biomarkers in the early stages of α-synucleinopathies, also supporting the differential diagnosis. Thirty-five (23 PD, 12 MSA), clinically, biologically and genetically characterized patients included in the PADUA-CESNE (Centro Studi per la Neurodegenerazione) cohort underwent OCT. A significant atrophy in the inferior, superior and temporal regions of the Retinal Nerve Fiber Layer (RNFL) and in the inner nuclear layer (INL) were observed in PD compared to controls, differently from MSA. Hyperreflective foci (HRF) counts were elevated across all retinal layers in all patients with PD exhibiting significantly higher numbers, suggesting microglial activation and greater retinal damage. Further research regarding OCT patterns in PD and MSA may consolidate the role of specific features, such as INL abnormalities and different HRF counts, in supporting the diagnosis and differential diagnosis in α-synucleinopathies. In light of the availability of potentially disease-modifying therapies, studies should focus on newly diagnosed patients, also undergoing thorough clinical, biological and genetic characterization.

Background: Mutations in progranulin (GRN) are associated with frontotemporal dementia, although a Parkinson disease (PD) phenotype is uncommon, especially in young patients.Cases: We report three subjects from the PADUA‐CESNE cohort, meeting diagnostic criteria for PD, with onset under age 55. All had good response to dopaminergic therapy, abnormal dopamine transporter single‐photon emission computed tomography striatal uptake and a disease course consistent with PD, without clear atypical features, behavioral, or cognitive deficits. Genetic testing (next‐generation sequencing [NGS] panel) revealed three different variants in GRN gene. Skin biopsy immunohistochemistry analysis showed phosphorylated α‐synuclein deposition in two and was negative in one subject.Conclusions: Our findings expand the phenotypic spectrum of GRN mutations, showing that patients can present with clinical manifestations of PD, including phosphorylated synuclein pathology in the skin, with a relatively young age of onset. Our observations support the use of broad‐spectrum NGS panels to properly guide patients in counseling and accurately allocate them to disease‐modifying therapies.

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.

In Parkinson’s disease, neuroinflammation is a double-edged sword; when inflammation occurs it can have harmful effects, despite its important role in battling infections and healing tissue. Once triggered by microglia, astrocytes acquire a reactive state and shift from supporting the survival of neurons to causing their destruction. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson’s disease. Protein aggregates and PAR2 expression were analyzed using Thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson’s patients, treated or untreated with 1-PPA. A significant decrease in amyloid aggregates was observed after 1-PPA treatment in all patients. A parallel decrease in PAR2 expression, which was higher in sporadic Parkinson’s patients, was also observed both at the transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease in IL-1β, IL-6, and TNF-α, together with a decreased expression of PAR2. In conclusion, 1-PPA determines the reduction in neuroglia inflammation and amyloid aggregates formation, suggesting that the pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

In Parkinson's disease, neuroinflammation is a complex defense mechanism. Activated microglia and Proteinase-activated receptor-2 (PAR2) are key points in the regulation of neuroinflammation. 1-Piperidin Propionic Acid (1-PPA) has been recently described as a novel inhibitor of PAR2. The aim of our study was to evaluate the effect of 1-PPA in neuroinflammation and microglial activation in Parkinson's disease. Protein aggregates and PAR2 expression were analyzed by thioflavin S assay and immunofluorescence in cultured human fibroblasts from Parkinson's patients, treated or not with 1-PPA. A significant decrease of amyloid aggregates and expression of PAR2 were observed after 1-PPA treatment in all patients. A parallel decrease of PAR2 expression, that was higher in sporadic Parkinson’s patients, was also observed both at transcriptional and protein level. In addition, in mouse LPS-activated microglia, the inflammatory profile was significantly downregulated after 1-PPA treatment, with a remarkable decrease of IL-1, IL-6 and TNF-togheter with PAR2 decreased expression.In conclusion, 1-PPA determines reduced neuroglia inflammation and amyloid aggregates formation, suggesting that pharmacological inhibition of PAR2 could be proposed as a novel strategy to control neuroinflammation.

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 + 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.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.