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.

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.

The TOMM40 '523' polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson's disease.

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.

Characterization of Gastrointestinal Symptom Type and Severity in Parkinson's Disease: A Case-Control Study in an Australian Cohort.

BACKGROUND: While constipation is a well-known non-motor symptom which may precede the onset of the classical motor symptoms of PD, there have been few comprehensive studies of gastrointestinal (GI) symptoms in people with PD (PwP). OBJECTIVES: To investigate the spectrum of GI symptoms in an Australian PwP cohort and their relationship to use of anti-parkinsonian medications dietary habits and smoking. METHODS: The prevalence and severity of GI symptoms were compared in a group of 163 PwP and 113 healthy control subjects using the Gastrointestinal Symptom Rating Scale (GSRS). Corrected linear regression models were used to determine differences between PwP and controls, and to investigate the influence of different classes of anti-Parkinsonian medications. RESULTS: PwP reported a greater frequency of constipation and GI-associated illnesses when compared to healthy controls. Total GSRS scores (P < 0.0001), upper GI symptoms (P < 0.0001), and hypoactive GI Symptoms (P < 0.0001) were all significantly greater in the PD cohort than controls. Further analyses revealed a positive association between the use of anti-Parkinsonian medications and total GSRS scores (P < 0.001), as well as upper GI symptoms (P < 0.001) and hypoactive GI function (P < 0.001). CONCLUSIONS: This study illustrates the frequency and array of GI symptoms in a large PD cohort. The findings indicate that anti-parkinsonian medications play an important role in the presentation and development of GI symptoms.

Differential effects of sex on longitudinal patterns of cognitive decline in Parkinson's disease.

BACKGROUND: Cognitive impairment is an important and diverse symptom of Parkinson's disease (PD). Sex is a purported risk variable for cognitive decline in PD, but has not been comprehensively investigated. OBJECTIVES: This cross-sectional and longitudinal study examined sex differences in global and domain-specific cognitive performance in a large PD cohort. METHODS: Cognitive function was evaluated using the Addenbrooke's Cognitive Examination in 392 people with PD (PwP) from the Australian Parkinson's Disease Registry. The influence of sex on domain-specific cognitive performance was investigated using covariate-corrected generalised linear models. In a repeated measures longitudinal subset of 127 PwP, linear mixed models were used to assess the impact of sex on cognition over time, while accounting for covariates. RESULTS: Cross-sectional-corrected modelling revealed that sex was significantly predictive of cognitive performance, with males performing worse than females on global cognition, and memory and fluency domains. Longitudinally, sex was significantly predictive of cognitive decline, with males exhibiting a greater reduction in global cognition and language, whereas females showed a greater decline in attention/orientation, memory and visuospatial domains, despite starting with higher baseline scores. At follow-up, a significantly higher proportion of males than females fulfilled criteria for mild cognitive impairment or PD dementia. CONCLUSIONS: Sex was revealed as a significant determinant of overall cognitive performance as well as specific cognitive domains, with a differential pattern of decline in male and female participants. Such sex-specific findings appear to explain some of the heterogeneity observed in PD, warranting further investigation of mechanisms underlying this sexual dimorphism.

Single Nucleotide Polymorphisms Associated With Gut Homeostasis Influence Risk and Age-at-Onset of Parkinson's Disease.

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.

Elevated Serum Ceruloplasmin Levels Are Associated with Higher Impulsivity in People with Parkinson's Disease.

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 < 0.001) and associated with MDS-UPDRS III, Hoehn and Yahr, and ACE-R scores (p < 0.05). When correcting for covariates, higher serum ceruloplasmin concentrations were associated with the 2nd order nonplanning impulsivity and with the 1st order self-control and cognitive complexity impulsivity domains. CONCLUSIONS: Higher serum ceruloplasmin levels are independently associated with heightened nonplanning impulsivity in PwP. Thus, serum ceruloplasmin levels may have clinical utility as a marker for heightened impulsivity in PD.

Trait Impulsivity Is Independent of Mild Cognitive Impairment in a Parkinson's Disease Cohort.

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.

Altered Gut Microbiome in Parkinson's Disease and the Influence of Lipopolysaccharide in a Human α-Synuclein Over-Expressing Mouse Model.

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.

Elevated Serum Homocysteine Levels Have Differential Gender-Specific Associations with Motor and Cognitive States in Parkinson's Disease.

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 < 0.001), but not folate or vitamin B12 levels, when compared to healthy controls. A significant positive correlation between homocysteine and MDS-UPDRS III score was identified in males with Parkinson's disease (r s = 0.319, p < 0.001), but not in females, whereas a significant negative correlation between homocysteine levels and total ACE-R score was observed in females with Parkinson's disease (r s = -0.449, p < 0.001), but not in males. Multivariate general linear models confirmed that homocysteine was significantly predictive of MDS-UPDRS III score in male patients (p=0.004) and predictive of total ACE-R score in female patients (p=0.021). CONCLUSION: Elevated serum homocysteine levels are associated with a greater motor impairment in males with Parkinson's disease and poorer cognitive performance in females with Parkinson's disease. Our gender-specific findings may help to explain previous discrepancies in the literature surrounding the utility of homocysteine as a biomarker in PD.

Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D-enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies.

We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics. Therefore we compared the neuroprotective efficacy of R18 and its D-enantiomer R18D following permanent MCAO in the Wistar rat. Furthermore, as increased peptide stability may also increase peptide toxicity, we examined the effects of R18 and R18D on cultured cortical neurons, astrocytes, brain endothelial cells (bEND.3), and embryonic kidney cells (HEK293) following a 10-minute or 24-hour peptide exposure duration. The in vivo studies demonstrated that R18D resulted in a greater reduction in mean infarct volume compared to R18 (33%, p = 0.004 vs 12%, p = 0.27) after intravenous administration at 300 nmol/kg 30 minutes after MCAO. Both R18D and R18 reduced cerebral hemisphere swelling to a comparable degree (27%, p = 0.03 and 30%, p = 0.02), and improved neurological assessment scores (1.5, p = 0.02 and 2, p = 0.058 vs 3 for vehicle). No abnormal histological findings specific to peptide treatments were observed in hematoxylin and eosin stained sections of kidney, liver, spleen, lung and heart. In vitro studies demonstrated that R18 and R18D were most toxic to neurons, followed by astrocytes, HEK293 and bEND.3 cells, but only at high concentrations and/or following 24-hour exposure. These findings further highlight the neuroprotective properties of poly-arginine peptides, and indicate that R18D at the dose examined is more potent than R18 in Wistar rats, and justify continued investigation of the R18 peptide as a novel neuroprotective agent for stroke.