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As environmental plastic waste degrades, it creates an abundance of diverse microplastic particles. Consequently, microplastics contaminate drinking water and many staple food products, meaning the oral ingestion of microplastics is an important exposure route for the human population. Microplastics have long been considered inert, however their ability to promote microbial dysbiosis as well as gut inflammation and dysfunction suggests they are more noxious than first thought. More alarmingly, there is evidence for microplastics permeating from the gut throughout the body, with adverse effects on the immune and nervous systems. Coupled with the now-accepted role of the gut-brain axis in neurodegeneration, these findings support the hypothesis that this ubiquitous environmental pollutant is contributing to the rising incidence of neurodegenerative diseases, like Alzheimer’s disease and Parkinson’s disease. This comprehensive narrative review explores the consequences of oral microplastic exposure on the gut-brain-axis by considering current evidence for gastrointestinal uptake and disruption, immune activation, translocation throughout the body, and neurological effects. As microplastics are now a permanent feature of the global environment, understanding their effects on the gut, brain, and whole body will facilitate critical further research and inform policy changes aimed at reducing any adverse consequences.

Heightened trait impulsivity in both subclinical and pathological senses is becoming increasingly recognised in Parkinson’s disease (PD). Impulsive behaviours and impulse control disorders (ICDs) are a consequence of perturbation to the rewards pathway leading individuals to conduct activities in a repetitive, excessive, and maladaptive fashion. Commonly linked to PD, heightened trait impulsivity has been found to primarily manifest in the forms of hypersexuality, pathological gambling, compulsive shopping, and binge eating, all of which may significantly impact social and financial standing. Subsequent burden to quality of life for both individuals with PD and caregivers are common. Although risk factors and indicators for ICDs in PD are currently lacking, it is recognised that the condition is often precipitated by dopamine replacement therapies, primarily dopamine agonist administration. While this nonmotor symptom is being increasingly diagnosed in PD populations, it remains relatively elusive in comparison to its motor counterparts. Through discussion of impulsivity characteristics, neuroanatomy, and neurochemistry, in addition to reviewing existing research on the potential contributing factors to impulsivity in PD, this review highlights impulsivity as a significant and detrimental PD symptom. Thus, emphasising the imperative need to establish efficacious diagnostic tools and treatments.

Abstract Neurofilament heavy (NEFH) is one of the critical proteins required for the formation of the neuronal cytoskeleton and polymorphisms in NEFH are reported as a rare cause of sporadic ALS (sALS). In the current study, a candidate tetranucleotide (TTTA) repeat variant in NEFH was selected using an in-silico short structural variant (SSV) evaluation algorithm and investigated in two cohorts of North American sALS patients, both separately and combined (Duke cohort n = 138, Coriell cohort n = 333; combined cohort n = 471), compared to a group of healthy controls from the Coriell Institute biobank (n = 496). Stratification according to site of disease onset revealed that the 9 TTTA allele was associated with reduced disease risk, specifically confined to spinal-onset sALS patients in the Duke cohort (p = 0.001). Furthermore, carriage of the 10 TTTA allele was associated with a 2.7 year later age of disease onset in the larger combined sALS cohort (p = 0.02). These results suggest that the 9 and 10 TTTA motif length may have a protective advantage for potentially lowering the risk of sALS and delaying the age of disease onset, however, these results need to be replicated in larger multicenter and multi-ethnic cohorts.

Abstract There is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials.

Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.

In Parkinson’s disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This study aimed to investigate endogenous α-synuclein expression in enteroendocrine STC-1 cells and the potential of the CARP, R18D (18-mer of D-arginine), to prevent internalisation of pre-formed α-synuclein fibrils (PFFs) in enteroendocrine cells in vitro. Through confocal microscopy, the immunoreactivity of full-length α-synuclein and the serine-129 phosphorylated form (pS129) was investigated in STC-1 (mouse enteroendocrine) cells. Thereafter, STC-1 cells were exposed to PFFs tagged with Alexa-Fluor 488 (PFF-488) for 2 and 24 h and R18D-FITC for 10 min. After confirming the uptake of both PFFs and R18D-FITC through fluorescent microscopy, STC-1 cells were pre-treated with R18D (5 or 10 μM) for 10 min prior to 2 h of PFF-488 exposure. Immunoreactivity for endogenous α-synuclein and pS129 was evident in STC-1 cells, with prominent pS129 staining along cytoplasmic processes and in perinuclear areas. STC-1 cells internalised PFFs, confirmed through co-localisation of PFF-488 and human-specific α-synuclein immunoreactivity. R18D-FITC entered STC-1 cells within 10 min and pre-treatment of STC-1 cells with R18D interfered with PFF uptake. The endogenous presence of α-synuclein in enteroendocrine cells, coupled with their rapid uptake of PFFs, demonstrates a potential for pathogenic spread of α-synuclein aggregates in the gut. R18D is a novel therapeutic approach to reduce the intercellular transmission of α-synuclein pathology.

Abstract The translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

Abstract Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

Background. Gastrointestinal symptoms (GIS) in people with Parkinson’s disease (PwP) are often underreported and may remain untreated. Constipation is a common nonmotor symptom that can adversely affect health-related quality of life (QoL); however, the impact of other GIS has not been adequately investigated. Objectives. To investigate the relationship between QoL and constipation using the Bristol Stool Chart, bowel movement frequency, and a perceived constipation measure; and to explore the relationship between QoL and other GIS in an Australian PD cohort. Methods. The impact of constipation and other GIS on QoL, as measured using the PDQ-39 scale, was assessed in a cohort of 144 (89 males, 55 females) clinic-attending PwP. Constipation was assessed using the Bristol Stool Chart as well as a composite constipation measure, and the Gastrointestinal Symptom Rating Scale (GSRS) was used to rate other GIS. Covariate corrected linear regression models were utilised to determine significant associations between GIS and QoL scores. Results. Individual and combined constipation measures were significantly associated with poorer QoL (p=0.032 and p=0.002, respectively). Analysis of GSRS symptom domains showed that in addition to symptoms of gastrointestinal hypomotility, a number of other symptoms such as increased eructation and increased flatus were also associated with poorer QoL. Conclusions. The findings point to the importance of GIS as contributor to health-related QoL in PwP. A better understanding of the relationship between GIS and QoL will help facilitate the development of more effective screening and treatment programs to improve symptom management and QoL for PwP.

Background: There has been increasing recognition of the importance of the gut microbiome in Parkinson’s disease (PD), but the influence of geographic location has received little attention. The present study characterized the gut microbiota and associated changes in host metabolic pathways in an Australian cohort of people with PD (PwP).Methods: The study involved recruitment and assessment of 87 PwP from multiple Movement Disorders Clinics in Australia and 47 healthy controls. Illumina sequencing of the V3 and V4 regions of the 16S rRNA gene was used to distinguish inter-cohort differences in gut microbiota; KEGG analysis was subsequently performed to predict functional changes in host metabolic pathways.Results: The current findings identified significant differences in relative abundance and diversity of microbial operational taxonomic units (OTUs), and specific bacterial taxa between PwP and control groups. Alpha diversity was significantly reduced in PwP when compared to controls. Differences were found in two phyla (Synergistetes and Proteobacteria; both increased in PwP), and five genera (Colidextribacter, Intestinibacter, Kineothrix, Agathobaculum, and Roseburia; all decreased in PwP). Within the PD cohort, there was no association identified between microbial composition and gender, constipation or use of gastrointestinal medication. Furthermore, KEGG analysis identified 15 upregulated and 11 downregulated metabolic pathways which were predicted to be significantly altered in PwP.Conclusion: This study provides the first comprehensive characterization of the gut microbiome and predicted functional metabolic effects in a southern hemisphere PD population, further exploring the possible mechanisms whereby the gut microbiota may exert their influence on this disease, and providing evidence for the incorporation of such data in future individualized therapeutic strategies.

IntroductionCholesterol levels have been associated with age-related cognitive decline, however, such an association has not been comprehensively explored in people with Parkinson’s disease (PD). To address this uncertainty, the current cross-sectional study examined the cholesterol profile and cognitive performance in a cohort of PD patients.MethodsCognitive function was evaluated using two validated assessments (ACE-R and SCOPA-COG) in 182 people with PD from the Australian Parkinson’s Disease Registry. Total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and Triglyceride (TRG) levels were examined within this cohort. The influence of individual lipid subfractions on domain-specific cognitive performance was investigated using covariate-adjusted generalised linear models.ResultsFemales with PD exhibited significantly higher lipid subfraction levels (TC, HDL, and LDL) when compared to male counterparts. While accounting for covariates, HDL levels were strongly associated with poorer performance across multiple cognitive domains in females but not males. Conversely, TC and LDL levels were not associated with cognitive status in people with PD.ConclusionHigher serum HDL associates with poorer cognitive function in females with PD and presents a sex-specific biomarker for cognitive impairment in PD.

Abstract Poly-arginine peptide-18 (R18) has recently emerged as a highly effective neuroprotective agent in experimental stroke models, and is particularly efficacious in protecting cortical neurons against glutamic acid excitotoxicity. While we have previously demonstrated that R18 can reduce excitotoxicity-induced neuronal calcium influx, other molecular events associated with R18 neuroprotection are yet to investigated. Therefore, in this study we were particularly interested in protein expression changes in R18 treated neurons subjected to excitotoxicity. Proteomic analysis was used to compare protein expression patterns in primary cortical neuronal cultures subjected to: (i) R18-treatment alone (R18); (ii) glutamic acid excitotoxic injury (Glut); (iii) R18-treatment and glutamic acid injury (R18 + Glut); (iv) no treatment (Cont). Whole cell lysates were harvested 24 h post-injury and subjected to quantitative proteomic analysis (iTRAQ), coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and subsequent bioinformatic analysis of differentially expressed proteins (DEPs). Relative to control cultures, R18, Glut, and R18 + Glut treatment resulted in the detection of 5, 95 and 14 DEPs respectively. Compared to Glut alone, R18 + Glut revealed 98 DEPs, including 73 proteins whose expression was also altered by treatment with Glut and/or R18 alone, as well as 25 other uniquely regulated proteins. R18 treatment reversed the up- or down-regulation of all 73 Glut-associated DEPs, which included proteins involved in mitochondrial integrity, ATP generation, mRNA processing and protein translation. Analysis of protein-protein interactions of the 73 DEPs showed they were primarily associated with mitochondrial respiration, proteasome activity and protein synthesis, transmembrane trafficking, axonal growth and neuronal differentiation, and carbohydrate metabolism. Identified protein pathways associated with proteostasis and energy metabolism, and with pathways involved in neurodegeneration. Collectively, the findings indicate that R18 neuroprotection following excitotoxicity is associated with preservation of neuronal protein profiles, and differential protein expression that assists in maintaining mitochondrial function and energy production, protein homeostasis, and membrane trafficking. Graphical abstract

Stroke is the second leading cause of death globally and represents a major cause of devastating long-term disability. Despite sustained efforts to develop clinically effective neuroprotective therapies, presently there is no clinically available neuroprotective agent for stroke. As a central mediator of neurodamaging events in stroke, mitochondria are recognised as a critical neuroprotective target, and as such, provide a focus for developing mitochondrial-targeted therapeutics. In recent years, cationic arginine-rich peptides (CARPs) have been identified as a novel class of neuroprotective agent with several demonstrated mechanisms of action, including their ability to target mitochondria and exert positive effects on the organelle. This review provides an overview on neuronal mitochondrial dysfunction in ischaemic stroke pathophysiology and highlights the potential beneficial effects of CARPs on mitochondria in the ischaemic brain following stroke.

Background/Objective: The current study aimed to determine whether previously identified candidate polymorphisms were associated with match performance in sub-elite Australian Rules Football (ARF) players. Methods: The genotypes of thirty players were analysed along with 3x1-kilometre time trial results, ARF-specific skill assessments (handball and kicking), and match performance (direct game involvements) per minute (DGIs/min) to investigate if there was a relationship between any of the variables. Results: Results support previous findings that aerobic time trials are a significant predictor of DGIs/min in sub-elite ARF players. Significant associations were found for genotypes ADRB2 CC (p = .001), PPARGC1A AA (p = .001), PPARGC1A AG (p

ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

Since the first case of the novel coronavirus emerged in late 2019 (COVID-19), it quickly spread beyond China, with reported cases in nearly all countries and territories. As these unprecedented times have resulted in significant social and economic disruption, educational institutions have been forced to implement alternative teaching and learning approaches, including a total transition to online learning. Given the dependence of undergraduate science units and degrees on practical and laboratory activities, students and academics are faced with significant hurdles regarding delivery, learning, and assessment. Therefore, this article considers the impact of COVID-19 and the approaches being utilized to facilitate undergraduate science learning during the evolving pandemic.

Research is increasingly focusing on gut inflammation as a contributor to Parkinson's disease (PD). Such gut inflammation is proposed to arise from a complex interaction between various genetic, environmental, and lifestyle factors, however these factors are under-characterized. This study investigated the association between PD and single-nucleotide polymorphisms (SNPs) in genes responsible for binding of bacterial metabolites and intestinal homeostasis, which have been implicated in intestinal infections or inflammatory bowel disease. A case-control analysis was performed utilizing the following cohorts: (i) patients from the Australian Parkinson's Disease Registry (APDR) (n = 212); (ii) a Caucasian subset of the Parkinson's Progression Markers Initiative (PPMI) cohort (n = 376); (iii) a combined control group (n = 404). The following SNPs were analyzed: PGLYRP2 rs892145, PGLYRP4 rs10888557, TLR1 rs4833095, TLR2 rs3804099, TLR4 rs7873784, CD14 rs2569190, MUC1 rs4072037, MUC2 rs11825977, CLDN2 rs12008279 and rs12014762, and CLDN4 rs8629. PD risk was significantly associated with PGLYRP4 rs10888557 genotype in both cohorts. PGLYRP2 rs892145 and TLR1 rs4833095 were also associated with disease risk in the APDR cohort, and TLR2 rs3804099 and MUC2 rs11825977 genotypes in the PPMI cohort. Interactive risk effects between PGLYRP2/PGLYRP4 and PGLYRP4/TLR2 were evident in the APDR and PPMI cohorts, respectively. In the APDR cohort, the PGLYRP4 GC genotype was significantly associated with age of symptom onset, independently of gender, toxin exposure or smoking status. This study demonstrates that genetic variation in the bacterial receptor PGLYRP4 may modulate risk and age-of-onset in idiopathic PD, while variants in PGLYRP2, TLR1/2, and MUC2 may also influence PD risk. Overall, this study provides evidence to support the role of dysregulated host-microbiome signaling and gut inflammation in PD, and further investigation of these SNPs and proteins may help identify people at risk of developing PD or increase understanding of early disease mechanisms.

Mild traumatic brain injury (mTBI) causes structural, cellular and biochemical alterations which are difficult to detect in the brain and may persist chronically following single or repeated injury. Lipids are abundant in the brain and readily cross the blood-brain barrier, suggesting that lipidomic analysis of blood samples may provide valuable insight into the neuropathological state. This study used liquid chromatography-mass spectrometry (LC-MS) to examine plasma lipid concentrations at 11 days following sham (no injury), one (1×) or two (2×) mTBI in rats. Eighteen lipid species were identified that distinguished between sham, 1× and 2× mTBI. Three distinct patterns were found: (1) lipids that were altered significantly in concentration after either 1× or 2× F mTBI: cholesterol ester CE (14:0) (increased), phosphoserine PS (14:0/18:2) and hexosylceramide HCER (d18:0/26:0) (decreased), phosphoinositol PI(16:0/18:2) (increased with 1×, decreased with 2× mTBI); (2) lipids that were altered in response to 1× mTBI only: free fatty acid FFA (18:3 and 20:3) (increased); (3) lipids that were altered in response to 2× mTBI only: HCER (22:0), phosphoethanolamine PE (P-18:1/20:4 and P-18:0/20:1) (increased), lysophosphatidylethanolamine LPE (20:1), phosphocholine PC (20:0/22:4), PI (18:1/18:2 and 20:0/18:2) (decreased). These findings suggest that increasing numbers of mTBI induce a range of changes dependent upon the lipid species, which likely reflect a balance of damage and reparative responses.

Background. Heightened impulsivity has been reported in a subset of people with Parkinson’s disease (PwP) and is considered a risk factor for the development of impulse control disorders (ICDs). However, at present, there are no recognised biochemical markers of heightened impulsivity. Objectives. To determine if ceruloplasmin, a serum marker involved in the regulation of iron and copper homeostasis, is associated with trait impulsivity in PwP. Methods. The study measured serum ceruloplasmin and impulsivity using the Barratt Impulsiveness Scale (BIS-11) in an Australian cohort of 214 PwP. Multivariate general linear models (GLMs) were used to identify whether higher serum ceruloplasmin levels (>75th percentile) were significantly predictive of BIS-11 scores. Results. Serum ceruloplasmin was higher in females with PD (p

The underlying genetic and molecular mechanisms that drive amyotrophic lateral sclerosis (ALS) remain poorly understood. Structural variants within the genome can play a significant role in neurodegenerative disease risk, such as the repeat expansion in C9orf72 and the tri-nucleotide repeat in ATXN2, both of which are associated with familial and sporadic ALS. Many such structural variants reside in uncharacterized regions of the human genome, and have been under studied. Therefore, characterization of structural variants located in and around genes associated with ALS could provide insight into disease pathogenesis, and lead to the discovery of highly informative genetic tools for stratification in clinical trials. Such genomic variants may provide a deeper understanding of how gene expression can affect disease etiology, disease severity and trajectory, patient response to treatment, and may hold the key to understanding the genetics of sporadic ALS. This article outlines the current understanding of amyotrophic lateral sclerosis genetics and how structural variations may underpin some of the missing heritability of this disease.

ABSTRACT: Background: Despite extensive studies, there are still no clinically available neuroprotective treatments for traumatic brain injury. Objectives: In previous studies we demonstrated beneficial treatment effects of polyarginine peptides R18 (18-mer of arginine; 300 nmol/kg) and R18D (18-mer of D-arginine; 1000 nmol/kg) in a rat model of impact-acceleration closed-head injury. Methods: We examined the efficacy of R18D when intravenously administered at a low (100 nmol/kg) and high (1000 nmol/kg) dose, 30 minutes after a closed-head injury in male Sprague-Dawley rats. Results: At postinjury day 3, treatment with R18D at the high dose significantly reduced axonal injury (P = 0.044), whereas the low-dose treatment of R18D showed a trend for reduced axonal injury. Following assessment in the Barnes maze, both doses of R18D treatment appeared to improve learning and memory recovery compared with vehicle treatment at postinjury days 1 and 3, albeit not to a statistically significant level. Rotarod assessment of vestibulomotor recovery did not differ between R18D and the vehicle treatment groups. Conclusions: R18D modestly decreased axonal injury only at the highest dose used but had no significant effect on functional recovery. These findings warrant further studies with additional doses to better understand peptide pharmacodynamics and provide information to guide optimal dosing.

Abstract We examined the neuroprotective efficacy of the poly-arginine peptide R18 and its D-enantiomer R18D in a perinatal hypoxic-ischaemic (HI) model in P7 Sprague-Dawley rats. R18 and R18D peptides were administered intraperitoneally at doses of 30, 100, 300 or 1000 nmol/kg immediately after HI (8% O2/92%N2 for 2.5 h). The previously characterised neuroprotective JNKI-1-TATD peptide at a dose of 1000 nmol/kg was used as a control. Infarct volume and behavioural outcomes were measured 48 h after HI. For the R18 and R18D doses examined, total infarct volume was reduced by 25.93% to 43.80% (P = 0.038 to

Glioblastoma (GBM) are lethal primary brain tumours whose pathogenesis is aided, at least partly, via a pro-tumorigenic microenvironment. This study investigated whether microglia, a cell component of the GBM microenvironment, mediates pro-tumorigenic properties via the action of cyclophilin A (CypA), a potent secretable chemokine and cytoprotectant that signals via the cell surface receptor, CD147. To this end, intracellular and secreted CypA expression was assessed in human primary microglia and BV2 microglial cells treated with the endotoxin, lipopolysaccharide (LPS) and the oxidative stress inducer, LY83583. We report that human primary microglia and BV2 microglia both express CypA and CD147, and that BV2 microglial cells secrete CypA in response to pro-inflammatory and oxidative stimuli. We also demonstrate for the first time that recombinant CypA (rCypA; 1nM–1000nM) dose-dependently increased wound healing and reduced basal cell death in BV2 microglial cells. To determine the cell–signalling pathways involved, we probed microglial cell lysates for changes in ERK1/2 and AKT phosphorylation, IκB degradation, and IL-6 secretion using Western blot and ELISA analysis. In summary, BV2 microglial cells secrete CypA in response to inflammatory and oxidative stress, and that rCypA increases cell viability and chemotaxis. Our findings suggest that rCypA is a pro-survival chemokine for microglia that may influence the GBM tumour microenvironment.

The interaction between the gut microbiota and alpha-synuclein (αSyn) aggregation in Parkinson’s disease (PD) is receiving increasing attention. The objective of this study was to investigate gut microbiota, and effects of an inflammatory lipopolysaccharide (LPS) trigger in a human αSyn over-expressing mouse model of PD (Thy1-αSyn). Stool samples from patients with confirmed PD and Thy1-αSyn mice were analyzed using 16S ribosomal RNA sequencing. Compared to healthy controls, the relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients. In mice, the abundance of Gammaproteobacteria was negligible in both Thy1-αSyn and wild-type (WT) animals, while Verrucomicrobiae were reduced in Thy1-αSyn mice. The effect of LPS on intestinal barrier function was investigated in vitro using intestinal epithelial (IEC-6) cells, and in vivo via administration of LPS in drinking water to Thy1-αSyn mice. Acute exposure to LPS in vitro resulted in a reduction and altered distribution of the tight junction markers ZO-1 and e-Cadherin around the cell membrane in IEC-6 cells, as shown by immunohistochemistry. LPS administration in Thy1-αSyn mice resulted in the emergence of early motor manifestations at 10 weeks, compared to untreated mice who were still asymptomatic at this age. This study reaffirms that an altered microbiome exists in patients with PD, and supports the notion of a proinflammatory gut microbiome environment as a trigger for PD pathogenesis.

Background. Studies attempting to elucidate an association between homocysteine and symptom progression in Parkinson’s disease (PD) have had largely discrepant findings. This study aimed to investigate elevated serum homocysteine levels and symptom progression in a cohort of PD patients. Methods. Serum homocysteine, folate, and vitamin B12 levels were measured in 205 people with PD and 78 age-matched healthy controls. People with Parkinson’s disease underwent a battery of clinical assessments to evaluate symptom severity, including motor (MDS-UPDRS) and cognitive (ACE-R) assessments. Multivariate generalised linear models were created, controlling for confounding variables, and were used to determine whether serum markers are associated with various symptom outcome measures. Results. People with Parkinson’s disease displayed significantly elevated homocysteine levels (p

Introduction. Patients with Parkinson’s disease (PD) commonly experience cognitive deficits and some also develop impulse control disorders (ICDs); however, the relationship between impulsivity and cognitive dysfunction remains unclear. This study investigated whether trait impulsivity associates with mild cognitive impairment (MCI), or is altered in a PD patient cohort with MCI. Methods. A total of 302 patients with idiopathic PD were recruited sequentially from three Australian Movement Disorder clinics. Based on cognitive scores, participants were divided into two groups, one defined as having mild cognitive impairment (PD-MCI; n = 113) and the other with normal cognitive function (PD-C; n = 189). Trait impulsivity was evaluated using the Barrett Impulsiveness Scale 11 (BIS-11). Total impulsivity scores, as well as subscale scores, were compared between PD-C and PD-MCI groups. Results. The PD-MCI cohort had significantly lower scores in all cognitive domains, and mirrored expected clinical differences in medication, motor symptoms, and disease duration, when compared to the PD-C cohort. Self-reported impulsivity was not significantly different between groups, nor was there a difference within first-order subscale scores: attention p=0.137, cognitive instability p=0.787, self-control p=0.503, cognitive complexity p=0.157, motor impulsivity p=0.559, or perseverance p=0.734 between the PD-MCI and PD-C groups. Conclusions. These findings suggest that impulsive traits and behaviors are independent of changes in cognitive state and are not altered in PD patients with mild cognitive impairment.

Genetic variants in the angiotensin-converting enzyme (ACE) (rs4343), alpha-actinin-3 (ACTN3) (rs1815739), adrenoceptor-beta-1 (ADRB1) (rs1801253), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) (rs8192678) genes have previously been associated with elite athletic performance. This study assessed the influence of polymorphisms in these candidate genes towards endurance test performance in 46 players from a single Australian Football League (AFL) team. Each player provided saliva buccal swab samples for DNA analysis and genotyping and were required to perform two independent two-kilometre running time-trials, six weeks apart. Linear mixed models were created to account for repeated measures over time and to determine whether player genotypes are associated with overall performance in the two-kilometre time-trial. The results showed that the ADRB1 Arg389Gly CC (p = 0.034) and PPARGC1A Gly482Ser GG (p = 0.031) genotypes were significantly associated with a faster two-kilometre time-trial. This is the first study to link genetic polymorphism to an assessment of endurance performance in Australian Football and provides justification for further exploratory or confirmatory studies.

Recent studies have highlighted that a novel class of neuroprotective peptide, known as cationic arginine-rich peptides (CARPs), have intrinsic neuroprotective properties and are particularly effective anti-excitotoxic agents. As such, the present study investigated the mechanisms underlying the anti-excitotoxic properties of CARPs, using poly-arginine-18 (R18; 18-mer of arginine) as a representative peptide. Cortical neuronal cultures subjected to glutamic acid excitotoxicity were used to assess the effects of R18 on ionotropic glutamate receptor (iGluR)-mediated intracellular calcium influx, and its ability to reduce neuronal injury from raised intracellular calcium levels after inhibition of endoplasmic reticulum calcium uptake by thapsigargin. The results indicate that R18 significantly reduces calcium influx by suppressing iGluR overactivation, and results in preservation of mitochondrial membrane potential (ΔΨm) and ATP production, and reduced ROS generation. R18 also protected cortical neurons against thapsigargin-induced neurotoxicity, which indicates that the peptide helps maintain neuronal survival when intracellular calcium levels are elevated. Taken together, these findings provide important insight into the mechanisms of action of R18, supporting its potential application as a neuroprotective therapeutic for acute and chronic neurological disorders.

Background. Impulsive behaviour has become increasingly recognised as a neuropsychiatric complication of Parkinson’s disease (PD). Thought to be a product of compromised cognitive control, the spectrum of impulsive behaviours in PD ranges from cognitive disinhibition to impulse control disorders (ICDs). Objective. At present, there are no indicators for trait impulsivity in PD. The objective of the current study was to identify demographic and clinical predictors of susceptibility to trait impulsivity in a cohort of PD patients. Methods. The current study assessed impulsivity using the Barratt Impulsiveness Scale 11 (BIS-11) in a cohort of 87 PD patients. General linear models (GLMs) were used to identify clinical and demographic variables predictive of heightened BIS-11 second-order attentional and nonplanning subscale scores. Results. Male gender, no history of smoking, postsecondary education, and heightened disease severity were predictive of increased BIS-11 attentional scores (p

Perinatal hypoxic-ischemic encephalopathy (HIE) is the leading cause of mortality and morbidity in neonates, with survivors suffering significant neurological sequelae including cerebral palsy, epilepsy, intellectual disability and autism spectrum disorders. While hypothermia is used clinically to reduce neurological injury following HIE, it is only used for term infants (>36 weeks gestation) in tertiary hospitals and improves outcomes in only 30% of patients. For these reasons, a more effective and easily administrable pharmacological therapeutic agent, that can be used in combination with hypothermia or alone when hypothermia cannot be applied, is urgently needed to treat pre-term (≤36 weeks gestation) and term infants suffering HIE. Several recent studies have demonstrated that cationic arginine-rich peptides (CARPs), which include many cell-penetrating peptides [CPPs; e.g., transactivator of transcription (TAT) and poly-arginine-9 (R9; 9-mer of arginine)], possess intrinsic neuroprotective properties. For example, we have demonstrated that poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer (R18D) are neuroprotective in vitro following neuronal excitotoxicity, and in vivo following perinatal hypoxia-ischemia (HI). In this paper, we review studies that have used CARPs and other peptides, including putative neuroprotective peptides fused to TAT, in animal models of perinatal HIE. We critically evaluate the evidence that supports our hypothesis that CARP neuroprotection is mediated by peptide arginine content and positive charge and that CARPs represent a novel potential therapeutic for HIE.

In elite sporting codes, the identification and promotion of future athletes into specialised talent pathways is heavily reliant upon objective physical, technical, and tactical characteristics, in addition to subjective coach assessments. Despite the availability of a plethora of assessments, the dependence on subjective forms of identification remain commonplace in most sporting codes. More recently, genetic markers, including several single nucleotide polymorphisms (SNPs), have been correlated with enhanced aerobic capacity, strength, and an overall increase in athletic ability. In this review, we discuss the effects of a number of candidate genes on athletic performance, across single-skilled and multifaceted sporting codes, and propose additional markers for the identification of motor skill acquisition and learning. While displaying some inconsistencies, both the ACE and ACTN3 polymorphisms appear to be more prevalent in strength and endurance sporting teams, and have been found to correlate to physical assessments. More recently, a number of polymorphisms reportedly correlating to athlete performance have gained attention, however inconsistent research design and varying sports make it difficult to ascertain the relevance to the wider sporting population. In elucidating the role of genetic markers in athleticism, existing talent identification protocols may significantly improve—and ultimately enable—targeted resourcing in junior talent pathways.