Background Reduced presynaptic density, commonly referred to as synaptic loss, is an early and clinically relevant feature of parkinsonian disorders. The development of positron emission tomography (PET) radiotracers targeting synaptic vesicle glycoprotein 2A (SV2A) has enabled in vivo quantification of synaptic density. Objectives This systematic review examines neuroimaging methodologies and regional SV2A PET findings in Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Methods A systematic search of PubMed, Scopus, and Web of Science was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines, including studies employing validated SV2A PET radiotracers to quantify synaptic density in parkinsonian populations. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. Substantial methodological heterogeneity precluded meta-analysis; findings were synthesized narratively. Results Fourteen studies were included. In PD, the substantia nigra was the most affected region, with striatal involvement more prominent in advanced disease (>6 years duration). In PSP and CBD, synaptic loss was widespread, exceeded grey matter atrophy, and correlated with clinical severity and cognitive decline; longitudinal PSP data showed reductions of approximately 3–4% per year in frontal and caudate regions. In MSA, infratentorial involvement (cerebellum, pons, medulla) predominated, enabling diagnostic differentiation with high accuracy (AUC up to 0.99). Conclusions SV2A PET reveals disease-specific patterns of reduced presynaptic availability, consistent with synaptic loss, across parkinsonian disorders, supporting its potential as a diagnostic and monitoring biomarker. Methodological harmonization and longitudinal multicenter studies are needed to establish clinical utility.
Increasing evidence supports the existence of a distinct body-first subtype of Parkinson's disease (PD), in which the initial site of pathology is in the gut. Animal models that recapitulate the body-first subtype of PD are needed. We tested the hypothesis that non-motor features of the body-first subtype of PD are recapitulated in the paraquat and lectin (P + L) rat model of PD, a model that has previously demonstrated the pathological motor progression of this subtype of PD. Then, we tested whether oral squalamine, a gastrointestinal prokinetic that has been shown to reduce formation of pathological α-synuclein, could prevent pathology, motor, and non-motor findings. Rats (n = 93) were orally gavaged for seven days with paraquat (1 mg/kg) and lectin (0.05%) in 1% sucrose solution. A subset of rats (n = 37) were given 30 days of squalamine (20 mg/kg) in their drinking water immediately following P + L treatment. Rats were tested for parkinsonian motor deficits, gastrointestinal dysmotility, sleep abnormalities, and cognitive deficits. Rats were euthanized and their brains processed for phospho-S129-α-synuclein pathology and neurodegeneration. We show that the P + L rat model recapitulates non-motor features and pathology of gastrointestinal dysmotility and sleep abnormalities seen in the body-first subtype of PD. We show that oral squalamine prevents motor deficits, gastrointestinal dysmotility, and sleep abnormalities, and diminishes phospho-S129-α-synuclein pathology and neurodegeneration in the nigrostriatal pathway. We show that the P + L rat model recapitulates many features of the body-first subtype of PD and provides pre-clinical evidence for the use of squalamine to mitigate progression in the body-first subtype of PD.
The accumulation of aggregated alpha-synuclein (aSyn) in the brain is one of the defining pathological features in Parkinson's Disease, Parkinson's Disease with Dementia, Lewy Body Dementia, and Multiple System Atrophy. For this reason, this group of disorders is collectively known as synucleinopathies. The identification of autosomal dominant mutations in the gene encoding aSyn (SNCA) in hereditary forms of disease further supports a central role for this protein in pathogenesis. The Synuclein Workshop was held for the first time in 2025 and is intended to be organized regularly every 2 years in countries of Latin America. The purpose of this series of workshops is to bring together leading experts in the field of synucleinopathies in a part of the world that is known for a strong tradition in the field, and to enable early career researchers to engage with and learn from other renowned experts, with the overall goal of discussing and advancing research in the field. In 2025, the Synuclein Workshop took place in Villa La Angostura, a city located in the province of Neuquén, Argentina. The meeting, entitled "The Patagonia Synuclein Workshop 2025", brought together 100 scientists studying both clinical and biomolecular aspects of synucleinopathies. The meeting covered many of the open questions in the field, in a format that promoted and encouraged open and unbiased discussions between the participants, and underscored the need for additional research that, hopefully, will lead to the development of new diagnostic tools and therapeutic strategies. Here, we provide a summary of the main topics discussed in the meeting, and highlight what is the current knowledge in the field, what we still do not know, and the future directions necessary for achieving the ultimate goal of the community: to offer better options to patients, families, and care-givers.
Patient and public involvement (PPI), defined as research undertaken with people affected by a condition as partners rather than participants, is increasingly recognized as a marker of high-quality research and is now encouraged or required by many funders. Research agendas and practices need to reflect the realities of people living with Parkinson's Disease (PD) ensuring research addresses the priorities of those affected.This narrative review examines the role of PPI across the research cycle, including priority setting, commissioning, study design, delivery, dissemination, implementation, and evaluation. We provide guidance and practical examples of how meaningful PPI can be achieved in PD research. The review explains how perspectives of lived experience can improve the relevance, feasibility, accessibility, and highlight its impact on PD research. We discuss practical considerations for embedding meaningful PPI, including project governance structures, dedicated staffing, remuneration, flexibility in conduct, and how to embed the perspectives of under-served PD communities in PPI. Finally, we consider challenges and opportunities for PPI in low- and middle-income countries, where underdiagnosis, stigma, health literacy barriers, and structural inequities require culturally responsive and community-led approaches.Involving people affected by Parkinson's as equal partners in research has the potential to improve individual studies and to reshape the wider PD research agenda to be more inclusive, representative, and responsive to the priorities of those most affected.To realise this potential, we must make a collective commitment to treat PPI as a requirement, provide funding and infrastructure support for implementation, and share experiences.
Objectives People with Parkinson's disease (PD) are at increased risk of delirium. Documentation of delirium is poor, with challenges in making a diagnosis due to overlapping symptoms. This study interviewed healthcare workers about their experiences of caring for inpatients with PD and delirium to explore their perspectives. Design A qualitative study with semi-structured interviews and thematic analysis. Participants Twelve healthcare staff, comprising five doctors and seven nurses. Results Four themes emerged: environmental pressures, relationship tensions, challenges and team working. We divided findings into those relevant to all inpatients with delirium and those specific to patients with PD and delirium. Environment pressures negatively impacted on all patients with delirium, and empathy was expressed for all carers/relatives. Staff anxiety was higher caring for patients with PD and relationship tensions occurred with juxtaposition of staff delirium expertise and patient/carer lived experience of PD. PD specific challenges were PD medications and a reciprocal relationship between diagnostic overshadowing and identifying the cause of delirium. Roles of ward nursing team to identify acute changes and doctors to identify and diagnose delirium in all patients was clearly defined. Conclusions This study identified knowledge gaps and lack of confidence specific to patients with delirium and PD. We recommend clearer definition of delirium superimposed on PD, with education and training on its complexity, alongside inclusion of expert-by-experience teaching. Future study of patient and carer views will help better understand the relationship tensions and how we can improve patient care and experiences.
