Trait Impulsivity as a Feature of Parkinson's Disease Treatment and Progression.

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.

Mind over Microplastics: Exploring Microplastic-Induced Gut Disruption and Gut-Brain-Axis Consequences.

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.

The Poly-Arginine Peptide R18D Interferes with the Internalisation of α-Synuclein Pre-Formed Fibrils in STC-1 Enteroendocrine Cells.

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.

Corrigendum to "Microglia are both a source and target of extracellular cyclophilin A" [Heliyon 5(9) August 2019 e02390].

[This corrects the article DOI: 10.1016/j.heliyon.2019.e02390.].

Lower gut dysbiosis and mortality in acute critical illness: a systematic review and meta-analysis.

BACKGROUND: The human gastrointestinal tract harbours a complex multi-kingdom community known as the microbiome. Dysbiosis refers to its disruption and is reportedly extreme in acute critical illness yet its clinical implications are unresolved. The review systematically evaluates the association between gut dysbiosis and clinical outcomes of patients early in critical illness. METHODS: Following PRISMA guidelines, a prospectively registered search was undertaken of MEDLINE and Cochrane databases for observational studies undertaking metagenomic sequencing of the lower gastrointestinal tract of critically ill adults and children within 72 h of admission. Eligible studies reported an alpha diversity metric and one or more of the primary outcome, in-hospital mortality, or secondary clinical outcomes. After aggregate data were requested, meta-analysis was performed for four studies with in-hospital mortality stratified to high or low Shannon index. RESULTS: The search identified 26 studies for systematic review and 4 had suitable data for meta-analysis. No effect of alpha diversity was seen on in-hospital mortality after binary transformation of Shannon index (odds ratio 0.52, CI 0.12-4.98, I2 = 0.64) however certainty of evidence is low. Pathogen dominance and commensal depletion were each more frequently associated with in-hospital mortality, adverse clinical and ecological sequelae, particularly overabundance of Enterococcus. CONCLUSIONS: There is a paucity of large, rigorous observational studies in this population. Globally, alpha diversity was dynamically reduced in early ICU admission in adults and children and was not associated with in-hospital mortality. The abundance of taxa such as Enterococcus spp. appears to offer greater predictive capacity for important clinical and ecological outcomes.

Quality of life implications for elevated trait impulsivity in people with Parkinson's disease.

BACKGROUND: Several non-motor features of Parkinson's disease (PD) are known to adversely affect patient health-related quality of life (HRQL). However, the specific impact of neuropsychiatric complications, such as impulsive behaviour, is yet to be elucidated. OBJECTIVES: The present cross-sectional, observational study aimed to investigate the effects of heightened trait impulsivity on HRQL in individuals with PD. METHODS: A total of 322 people with idiopathic PD were sequentially recruited from Movement Disorder clinics across Australia. Trait impulsivity in patients was determined by Barratt's Impulsiveness Scale Version 11 (BIS-11), and grouped into tertiles (low, medium, and high). Patient HRQL was determined by the 39-item Parkinson's Disease Questionnaire (PDQ-39), complemented by the Cambridge Behavioural Inventory-Revised (CBI-R) indicating caregivers' perception of patient HRQL. RESULTS: When total BIS-11 scores were grouped into tertiles, patient perceived and caregiver-perceived HRQL were 1.7-fold (p < .001) and 2.2-fold (p < .001) worse in the high BIS-11 group when compared to patients in the low group. Univariate analysis revealed significant associations between second-order attentional (p < .001) and non-planning (p < .001) impulsivity domains with PDQ-39 scores. When controlling for confounding demographic and clinical variables, a multivariate linear regression model revealed second-order attentional impulsivity was independently predictive of poor patient perceived HRQL (p < .001). CONCLUSION: These findings suggest that increasing trait impulsivity is significantly associated with patient perceived HRQL in PD. Improved knowledge and recognition of subclinical impulsivity may guide clinicians' treatment and reduce disease burden for patients experiencing PD symptoms.

The role of the microbiota-gut-brain axis in long-term neurodegenerative processes following traumatic brain injury.

Traumatic brain injury (TBI) can be a devastating and debilitating disease to endure. Due to improvements in clinical practice, declining mortality rates have led to research into the long-term consequences of TBI. For example, the incidence and severity of TBI have been associated with an increased susceptibility of developing neurodegenerative disorders, such as Parkinson's or Alzheimer's disease. However, the mechanisms linking this alarming association are yet to be fully understood. Recently, there has been a groundswell of evidence implicating the microbiota-gut-brain axis in the pathogenesis of these diseases. Interestingly, survivors of TBI often report gastrointestinal complaints and animal studies have demonstrated gastrointestinal dysfunction and dysbiosis following injury. Autonomic dysregulation and chronic inflammation appear to be the main driver of these pathologies. Consequently, this review will explore the potential role of the microbiota-gut-brain axis in the development of neurodegenerative diseases following TBI.

The gut microbiome and cognition in Parkinson's disease: a systematic review.

BACKGROUND: The pathology underlying cognitive changes in people with Parkinson's disease (PD) is not well understood. In healthy older adults, gut microbiome composition has been associated with cognitive function. In people with PD, preliminary evidence suggests that cortical spreading of abnormal alpha-synuclein aggregates may be associated with cognitive impairment. As changes in the gut have been linked to PD onset and associated Lewy body pathology, an investigation of the gut microbiome and cognition in PD is warranted. OBJECTIVE: To synthesise existing evidence on the relationship between the gut microbiome and cognitive function in PD. METHODS: A systematic review was conducted to search for peer-reviewed articles and grey literature published to July 2021 across seven electronic databases (MEDLINE, EMBASE, PsycINFO, Scopus, Cochrane Library, ProQuest, and ProQuest Dissertations and Theses). English language articles reporting the relationship between cognition and the gut microbiome in human participants with PD were considered for inclusion. Results were qualitatively synthesised and evidence quality was assessed using the QualSyst tool for quantitative studies. RESULTS: Five cross-sectional studies reporting the association between the gut microbiome and cognition in 395 participants with PD were included. Studies provided preliminary evidence of a relationship between cognition and gut microbiota within the Bacteroidetes and Firmicutes phyla, however, associations with specific genera were inconsistent across studies. CONCLUSIONS: Some species of short-chain fatty acid-producing bacteria (e.g. acetate, butyrate, and propionate producers) appear to be reduced in participants with PD with cognitive impairment. More research with larger samples and more consistent methodology is needed to substantiate these findings.

Impact of Gastrointestinal Symptoms on Health-Related Quality of Life in an Australian Parkinson's Disease Cohort.

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.

Genetic Variants within NOGGIN, COL1A1, COL5A1, and IGF2 are Associated with Musculoskeletal Injuries in Elite Male Australian Football League Players: A Preliminary Study.

INTRODUCTION: Australian Football is a dynamic team sport that requires many athletic traits to succeed. Due to this combination of traits, as well as technical skill and physicality, there are many types of injuries that could occur. Injuries are not only a hindrance to the individual player, but to the team as a whole. Many strength and conditioning personnel strive to minimise injuries to players to accomplish team success. PURPOSE: To investigate whether selected polymorphisms have an association with injury occurrence in elite male Australian Football players. METHODS: Using DNA obtained from 46 elite male players, we investigated the associations of injury-related polymorphisms across multiple genes (ACTN3, CCL2, COL1A1, COL5A1, COL12A1, EMILIN1, IGF2, NOGGIN, SMAD6) with injury incidence, severity, type (contact and non-contact), and tissue (muscle, bone, tendon, ligament) over 7 years in one Australian Football League team. RESULTS: A significant association was observed between the rs1372857 variant in NOGGIN (p = 0.023) and the number of total muscle injuries, with carriers of the GG genotype having a higher estimated number of injuries, and moderate, or combined moderate and high severity rated total muscle injuries. The COL5A1 rs12722TT genotype also had a significant association (p = 0.028) with the number of total muscle injuries. The COL5A1 variant also had a significant association with contact bone injuries (p = 0.030), with a significant association being found with moderate rated injuries. The IGF2 rs3213221-CC variant was significantly associated with a higher estimated number of contact tendon injuries per game (p = 0.028), while a higher estimated number of total ligament (p = 0.019) and non-contact ligament (p = 0.002) injuries per game were significantly associated with carriage of the COL1A1 rs1800012-TT genotype. CONCLUSIONS: Our preliminary study is the first to examine associations between genetic variants and injury in Australian Football. NOGGIN rs1372857-GG, COL5A1 rs12722-TT, IGF2 rs3213221-CC, and COL1A1 rs1800012-TT genotypes held various associations with muscle-, bone-, tendon- and ligament-related injuries of differing severities. To further increase our understanding of these, and other, genetic variant associations with injury, competition-wide AFL studies that use more players and a larger array of gene candidates is essential.

Intronic NEFH variant is associated with reduced risk for sporadic ALS and later age of disease onset.

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.

Plasma Lipid Profiles Change with Increasing Numbers of Mild Traumatic Brain Injuries in Rats.

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.

Changes in the rodent gut microbiome following chronic restraint stress and low-intensity rTMS.

Gut microbiome composition is associated with mood-relating behaviours, including those reflecting depression-like phenotypes. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive neuromodulation technique, is an effective treatment for depression, but its effects on the gut microbiome remain largely unknown. This study assessed microbial changes from rat faecal samples longitudinally following chronic restraint stress (CRS) and 10 Hz low-intensity rTMS treatment. CRS increased abundance within the Proteobacteria (Deltaproteobacteria, Desulfovibrionales) and Firmicutes (Anaerostipes, Frinsingococcus), with decreases in Firmicutes family (Acidaminococcaceae) and genera (Roseburia, Phascolarctobacterium and Fusicatenibacter) persisting for up to 4 weeks post CRS. The decrease in Firmicutes was not observed in the handling control and LI-rTMS groups, suggesting that handling alone may have sustained changes in gut microbiome associated with CRS. Nonetheless, LI-rTMS was specifically associated with an increase in Roseburia genus that developed 2 weeks after treatment, and the abundance of both Roseburia and Fusicatenibacter genera was significantly correlated with rTMS behavioural and MRI outcomes. In addition, LI-rTMS treated rats had a reduction in apoptosis pathways and several indicators of reduced inflammatory processes. These findings provide evidence that the brain can influence the gut microbiome in a "top-down" manner, presumably via stimulation of descending pathways, and/or indirectly via behavioural modification.

Short structural variants as informative genetic markers for ALS disease risk and progression.

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.

ACTN3 (R577X) Genotype Is Associated With Australian Football League Players.

ABSTRACT: Jacob, Y, Hart, NH, Cochrane, JL, Spiteri, T, Laws, SM, Jones, A, Rogalski, B, Kenna, J, and Anderton, RS. ACTN3 (R577X) genotype is associated with Australian Football League players. J Strength Cond Res 36(2): 573-576, 2022-Genetic variants in the angiotensin-converting enzyme (ACE) and alpha actinin-3 (ACTN3) genes have been associated with elite sport athletic performance. This study aimed to investigate the frequency of each polymorphism in a cohort of elite Australian football (AF) players. To achieve this, 47 players from an Australian Football League (AFL) club and 59 healthy age matched controls with no history of elite sporting competition were recruited for this study. Each subject provided saliva samples through buccal swab for DNA extraction and genotyping, with group comparisons made using χ2 and odds ratio analysis. There was no significant difference in ACE I/D genotype between healthy control and elite AF players. The ACTN3 XX genotype was significantly underrepresented in AFL players (4.3%) compared with healthy controls (28.8%, p = 0.003). In addition, there was a greater representation of the R allele in elite AF players (70.2%) when compared with healthy controls (50%; χ2 = 8.834, p = 0.002). This is the first study to investigate genetic variants in elite AF players, with results suggesting that the ACTN3 gene may play a significant role explaining aspects of athletic performance in AF.

Changes in the Gut Microbiome and Predicted Functional Metabolic Effects in an Australian Parkinson's Disease Cohort.

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.

TLR2 and TLR4 in Parkinson's disease pathogenesis: the environment takes a toll on the gut.

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.

Syncope in Commercial Pilots and New Regulatory Guidance.

INTRODUCTION: Syncope is both incapacitating and unpredictable, presenting a significant challenge in aircrew assessment. Previous UK Civil Aviation Authority (CAA) guidance lacked transparency and relied heavily on specialist in-house cardiology and neurology opinion. A new algorithm was developed which elaborated and formalized the decision-making process. An analysis of its impact on historic cases was undertaken to ensure it aligned with previous certificatory outcomes.METHODS: The medical literature on syncope and the approaches of other national aviation authorities were reviewed to help inform the development of a new algorithm. Using syncope cases in the CAA database, regulatory outcomes generated using the new algorithm were compared with previous decisions in terms of time off from flying (TOF) and Operational Multi-Crew Limitation (OML) duration.RESULTS: There were 40 historic syncope cases (25 existing certificate holders,15 initial applicants) which were reassessed using the new algorithm. The mean TOF for existing pilots using the new algorithm was 7.1 9.8 (mean SD) vs. 4.2 3.5 mo under the old guidance with an OML duration of 21.4 34.9 vs. 24.5 25.2 mo. One less initial applicant experienced a delay to certification. Four cases with underlying pathology were detected using old and new guidance.DISCUSSION: The reassessment of cases showed no statistically significant difference in TOF and OML duration; this is a positive finding from a regulatory perspective, enabling algorithm-led decision-making with less reliance on in-house expertise. A similar approach may be useful in future updates to other areas of regulatory practice.Anderton RA, Mitchell SJ, ONunain SS. Syncope in commercial pilots and new regulatory guidance. Aerosp Med Hum Perform. 2021; 92(8):642649.

TOMM40 '523' poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson's disease.

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.

Elevated HDL Levels Linked to Poorer Cognitive Ability in Females With Parkinson's Disease.

INTRODUCTION: Cholesterol 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. METHODS: Cognitive 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. RESULTS: Females 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. CONCLUSION: Higher serum HDL associates with poorer cognitive function in females with PD and presents a sex-specific biomarker for cognitive impairment in PD.