Anatomical distribution of Fyn kinase in the human brain in Parkinson's disease.

INTRODUCTION: Fyn kinase is an Src family kinase (SFK) widely expressed in many tissues, including the CNS. Recently, Fyn kinase activation has been associated with pathological mechanisms underlying neurodegenerative diseases and, as such, the role of Fyn dysfunction is under investigation. In particular, Fyn is implicated as a major upstream regulator of neuroinflammation in Parkinson's Disease (PD). Chronic neuroinflammation has been observed not just in the substantia nigra (SN), but also in several key regions of the brain, with disruption associated with symptoms presentation in PD. This study aimed to characterise the anatomical distribution of Fyn in key brain regions affected in PD, namely the prefrontal cortex, hippocampus, striatum and SN. METHODS: Fresh and fixed post-mortem PD brain samples (n = 10) were collected and compared with neurologically healthy age-matched controls (n = 7) to assess markers of Fyn activity and neuroinflammation. RESULTS: Increased Fyn phosphorylation was observed in SN and striatum of post-mortem samples from PD patients compared with controls. No such increase was observed in the prefrontal cortex or hippocampus. In contrast with previous findings, no increase in microglial activation or astrocyte reactivity was observed in PD brains across regions. CONCLUSION: Taken together, these results indicate that Fyn dysfunction may be involved in the pathological processes observed in PD; however, this appears to be independent of inflammatory mechanisms. Further investigations are required to elucidate if increased Fyn activity is a potential cause or consequence of pathological processing in PD.

Development and Co-design of NeuroOrb: A Novel "Serious Gaming" System Targeting Cognitive Impairment in Parkinson's Disease.

Whilst Parkinson's disease (PD) is typically thought of as a motor disease, a significant number of individuals also experience cognitive impairment (CI), ranging from mild-CI to dementia. One technique that may prove effective in delaying the onset of CI in PD is cognitive training (CT); however, evidence to date is variable. This may be due to the implementation of CT in this population, with the motor impairments of PD potentially hampering the ability to use standard equipment, such as pen-and-paper or a computer mouse. This may, in turn, promote negative attitudes toward the CT paradigm, which may correlate with poorer outcomes. Consequently, optimizing a system for the delivery of CT in the PD population may improve the accessibility of and engagement with the CT paradigm, subsequently leading to better outcomes. To achieve this, the NeuroOrb Gaming System was designed, coupling a novel accessible controller, specifically developed for use with people with motor impairments, with a "Serious Games" software suite, custom-designed to target the cognitive domains typically affected in PD. The aim of the current study was to evaluate the usability of the NeuroOrb through a reiterative co-design process, in order to optimize the system for future use in clinical trials of CT in individuals with PD. Individuals with PD (n = 13; mean age = 68.15 years; mean disease duration = 8 years) were recruited from the community and participated in three co-design loops. After implementation of key stakeholder feedback to make significant modifications to the system, system usability was improved and participant attitudes toward the NeuroOrb were very positive. Taken together, this provides rationale for moving forward with a future clinical trial investigating the utility of the NeuroOrb as a tool to deliver CT in PD.

Optimizing Cognitive Training for the Treatment of Cognitive Dysfunction in Parkinson's Disease: Current Limitations and Future Directions.

Cognitive dysfunction, primarily involving impairments in executive function, visuospatial function and memory, is one of the most common non-motor symptoms of Parkinson's disease (PD). Currently, the only pharmacological treatments available for the treatment of cognitive dysfunction in PD provide variable benefit, making the search for potential non-pharmacological therapies to improve cognitive function of significant interest. One such therapeutic strategy may be cognitive training (CT), which involves the repetition of standardized tasks with the aim of improving specific aspects of cognition. Several studies have examined the effects of CT in individuals with PD and have shown benefits in a variety of cognitive domains, but the widespread use of CT in these individuals may be limited by motor impairments and other concerns in study design. Here, we discuss the current state of the literature on the use of CT for PD and propose recommendations for future implementation. We also explore the potential use of more recent integrative, adaptive and assistive technologies, such as virtual reality, which may optimize the delivery of CT in PD.

Fyn Kinase Activity and Its Role in Neurodegenerative Disease Pathology: a Potential Universal Target?

Fyn is a non-receptor tyrosine kinase belonging to the Src family of kinases (SFKs) which has been implicated in several integral functions throughout the central nervous system (CNS), including myelination and synaptic transmission. More recently, Fyn dysfunction has been associated with pathological processes observed in neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Neurodegenerative diseases are amongst the leading cause of death and disability worldwide and, due to the ageing population, prevalence is predicted to rise in the coming years. Symptoms across neurodegenerative diseases are both debilitating and degenerative in nature and, concerningly, there are currently no disease-modifying therapies to prevent their progression. As such, it is important to identify potential new therapeutic targets. This review will outline the role of Fyn in normal/homeostatic processes, as well as degenerative/pathological mechanisms associated with neurodegenerative diseases, such as demyelination, pathological protein aggregation, neuroinflammation and cognitive dysfunction.