Enhancing the interactions between study participants, clinicians, and investigators is imperative for advancing Parkinson's disease (PD) research. The Canadian Open Parkinson Network (C-OPN) stands as a nationwide endeavor, connecting the PD community with ten accredited universities and movement disorders research centers spanning, at the time of this analysis, British Columbia, Alberta, Ontario, and Quebec.

For decades the greatest goal of Parkinson's disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible.

The recent development of new methods to detect misfolded α-synuclein (αSyn) aggregates in biofluids and tissue biopsies in the earliest Parkinson's disease (PD) phases is dramatically challenging the biological definition of PD. The αSyn seed amplification methods in cerebrospinal fluid (CSF) showed high sensitivity and specificity for early diagnosis of PD and Lewy bodies disorders. Several studies in isolated REM sleep behavior disorders and other at-risk populations also demonstrated a high prevalence of CSF αSyn positivity and its potential value in predicting the phenoconversion to clinically manifested diseases. Growing evidence exists for αSyn aggregates in olfactory mucosa, skin, and other tissues in subjects with PD or at-risk subjects. DOPA decarboxylase and numerous other candidates have been additionally proposed for either diagnostic or prognostic purposes in earliest PD phases. The newly described αSyn detection in blood, through its quantification in neuronally-derived exosome vesicles, represents a technical challenge that could open a new scenario for the biological diagnosis of PD. Despite this growing evidence in the field, most of method of αSyn detection and markers still need to be validated in ongoing longitudinal studies through an accurate assessment of different prodromal disease subtypes and scenarios before being definitively implemented in clinical settings.

Parkinson's disease (PD) unfolds with pathological processes and neurodegeneration well before the emergence of noticeable motor symptoms, providing a window for early identification. The extended prodromal phase allows the use of risk stratification measures and prodromal markers to pinpoint individuals likely to develop PD. Importantly, a growing body of evidence emphasizes the heterogeneity within prodromal and clinically diagnosed PD. The disease likely comprises distinct subtypes exhibiting diverse clinical manifestations, pathophysiological mechanisms, and patterns of α-synuclein progression in the central and peripheral nervous systems. There is a pressing need to refine the definition and early identification of these prodromal subtypes. This requires a comprehensive strategy that integrates genetic, pathological, imaging, and multi-omics markers, alongside careful observation of subtle motor and non-motor symptoms. Such multi-dimensional classification of early PD subtypes will improve our understanding of underlying disease pathophysiology, improve predictions of clinical endpoints, progression trajectory and medication response, contribute to drug discovery and personalized medicine by identifying subtype-specific disease mechanisms, and facilitate drug trials by reducing confounding effects of heterogeneity. Here we explore different subtyping methodologies in prodromal and clinical PD, focusing on clinical, imaging, genetic and molecular subtyping approaches. We also emphasize the need for refined, theoretical a priori disease models. These will be prerequisite to understanding the biological underpinnings of biological subtypes, which have been defined by large scale data-driven approaches and multi-omics fingerprints.

DATATOP was a study of early Parkinson's disease (PD) conducted in the 1980 s, before mandatory folic acid fortification in the United States. Our analysis of its baseline serum samples revealed a geometric mean vitamin B12 of 369 pg/mL and homocysteine (tHcy) of 9.5μmol/l. We also found that low B12 predicted greater worsening of ambulatory capacity (AC) and elevated tHcy (>15μmol/L) predicted greater declines in cognitive function.

Eye tracking assessments in the laboratory have previously highlighted clear differences in eye movements between Parkinson's disease (PD) and healthy aging. However, laboratory-based eye movement tasks are artificial and limit the ecological validity of observed results. Eye movement tasks utilizing more naturalistic scenarios may provide more accurate insight into cognitive function but research in this area is limited.

Increasing evidence suggests a potential role for infectious pathogens in the etiology of synucleinopathies, a group of age-related neurodegenerative disorders including Parkinson's disease (PD), multiple system atrophy and dementia with Lewy bodies. In this review, we discuss the link between infections and synucleinopathies from a historical perspective, present emerging evidence that supports this link, and address current research challenges with a focus on neuroinflammation. Infectious pathogens can elicit a neuroinflammatory response and modulate genetic risk in PD and related synucleinopathies. The mechanisms of how infections might be linked with synucleinopathies as well as the overlap between the immune cellular pathways affected by virulent pathogens and disease-related genetic risk factors are discussed. Here, an important role for α-synuclein in the immune response against infections is emerging. Critical methodological and knowledge gaps are addressed, and we provide new future perspectives on how to address these gaps. Understanding how infections and neuroinflammation influence synucleinopathies will be essential for the development of early diagnostic tools and novel therapies.

Our language affects patients' perceptions of therapies. In Parkinson's disease, emergent response fluctuations and dyskinesias typically trigger conversations around commencing an "Advanced Therapy" which carries notions of Advanced Disease. The patient, resolute in their commitment to fighting the disease, is misled. Chasing reassurance that their disease has not yet progressed considerably; they may therefore resist a potentially life-changing therapy. Instead, we should offer a "Smart Therapy". This term more accurately and positively describes therapies on offer that stabilize response fluctuations and improve quality of life, without a focus on the negative connotations of progression to more advanced disease.

 Inflammation and immune dysregulation have been linked to the pathogenesis and progression of Parkinson's disease (PD), and represent an attractive target for therapeutic intervention, given the potential for repurposing of existing anti-inflammatory and immunomodulatory agents. Despite the fact that initial studies of drugs with secondary anti-inflammatory effects did not yield positive results, agents specifically targeting immune and inflammatory pathways may hold more promise. This article will briefly review the evidence base for targeting the immune system and neuroinflammation in PD, and discuss in detail the recently completed and currently active trials of primary anti-inflammatory/immunomodulatory drugs in PD.

Stigma is a relevant aspect of Parkinson's disease (PD). Specific stigma tools are needed to address the complex construct of stigma in PD comprehensively.

Parkinson's disease (PD) is a disabling neurodegenerative movement disorder. Most PD patients are looked after by caregivers who are close to them regardless of their relationship. Caregivers may experience a notable impact on their mental health as they dedicate a significant amount of time to the patient while observing the progression of the disease.

Digital self-management tools including mobile apps and wearables can enhance personalized care in Parkinson's disease, and incorporating patient and clinician feedback into their evaluation can empower users and nurture patient-clinician relationships, necessitating a review to assess the state of the art and refine their use.

Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited.

Whether body weight changes are associated with Parkinson's disease (PD) mortality remains uncertain.

 Family studies have linked several rare genetic variants to hereditary forms of Parkinson's disease (PD). In addition to these monogenic forms, many PD cases are associated with genetic risk factors. Asymptomatic individuals carrying pathogenic variants linked to PD are at risk of developing the disease later in life, thereby providing a unique opportunity for the detection of the earliest pathophysiological and later clinical changes and, importantly, also of protective and compensatory features and mechanisms. However, the rarity of monogenic PD-causing variants is a major challenge of this approach. In this review, we discuss recent advances in the search for biomarkers in the prodromal/earliest phase of genetically linked PD.

The association of lung function with the risk of developing prodromal and clinical-diagnosed Parkinson's disease (PD) and with the risk of mortality among individuals with PD remains unknown.

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has emerged as a potent treatment for alleviating motor symptoms in Parkinson's disease (PD). Despite its effectiveness, the impact of high frequency STN-DBS on cerebellar oscillations remains unclear, posing an intriguing challenge for neural modulation. Given the direct and indirect connections between the STN and cerebellum, we investigated whether STN-DBS affects cerebellar oscillations.