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BackgroundThe penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.ObjectivesThe objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.MethodsSymptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.ResultsA total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91).ConclusionsRegular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

Parkinson's disease is one of the archetypal and most common neurodegenerative disorders. However, our appreciation of its disease manifestations, its evolution over time and the need for a multidisciplinary approach to assessment and management has grown tremendously over recent decades. It is no longer 'just a movement disorder', but a multisystem condition that requires the attentive and agile collaboration of primary care and neurology. [ABSTRACT FROM AUTHOR]

Genetic testing for persons with Parkinson's disease is becoming increasingly common. Significant gains have been made regarding genetic testing methods, and testing is becoming more readily available in clinical, research, and direct‐to‐consumer settings. Although the potential utility of clinical testing is expanding, there are currently no proven gene‐targeted therapies, but clinical trials are underway. Furthermore, genetic testing practices vary widely, as do knowledge and attitudes of relevant stakeholders. The specter of testing mandates financial, ethical, and physician engagement, and there is a need for guidelines to help navigate the myriad of challenges. However, to develop guidelines, gaps and controversies need to be clearly identified and analyzed. To this end, we first reviewed recent literature and subsequently identified gaps and controversies, some of which were partially addressed in the literature, but many of which are not well delineated or researched. Key gaps and controversies include: (1) Is genetic testing appropriate in symptomatic and asymptomatic individuals without medical actionability? (2) How, if at all, should testing vary based on ethnicity? (3) What are the long‐term outcomes of consumer‐ and research‐based genetic testing in presymptomatic PD? (4) What resources are needed for clinical genetic testing, and how is this impacted by models of care and cost‐benefit considerations? Addressing these issues will help facilitate the development of consensus and guidelines regarding the approach and access to genetic testing and counseling. This is also needed to guide a multidisciplinary approach that accounts for cultural, geographic, and socioeconomic factors in developing testing guidelines. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Unrevealing the interplay between diet, the microbiome, and the health state could enable the design of personalized intervention strategies and improve the health and well-being of individuals. A common approach to this is to divide the study population into smaller cohorts based on dietary preferences in the hope of identifying specific microbial signatures. However, classification of patients based solely on diet is unlikely to reflect the microbiome-host health relationship or the taxonomic microbiome makeup. Results: We present a novel approach, the Nutrition-Ecotype Mixture of Experts (NEMoE) model, for establishing associations between gut microbiota and health state that accounts for diet-specific cohort variability using a regularized mixture of experts model framework with an integrated parameter sharing strategy to ensure data-driven diet-cohort identification consistency across taxonomic levels. The success of our approach was demonstrated through a series of simulation studies, in which NEMoE showed robustness with regard to parameter selection and varying degrees of data heterogeneity. Further application to real-world microbiome data from a Parkinson's disease cohort revealed that NEMoE is capable of not only improving predictive performance for Parkinson's Disease but also for identifying diet-specific microbial signatures of disease. Conclusion: In summary, NEMoE can be used to uncover diet-specific relationships between nutritional-ecotype and patient health and to contextualize precision nutrition for different diseases. 7dNoGdMUXMX1VEgXMiTdDJ Video Abstract [ABSTRACT FROM AUTHOR]

Background: Altered gut microbiome (GM) composition has been established in Parkinson's disease (PD). However, few studies have longitudinally investigated the GM in PD, or the impact of device-assisted therapies. Objectives: To investigate the temporal stability of GM profiles from PD patients on standard therapies and those initiating device-assisted therapies (DAT) and define multivariate models of disease and progression. Methods: We evaluated validated clinical questionnaires and stool samples from 74 PD patients and 74 household controls (HCs) at 0, 6, and 12 months. Faster or slower disease progression was defined from levodopa equivalence dose and motor severity measures. 19 PD patients initiating Deep Brain Stimulation or Levodopa-Carbidopa Intestinal Gel were separately evaluated at 0, 6, and 12 months post-therapy initiation. Results: Persistent underrepresentation of short-chain fatty-acid-producing bacteria, Butyricicoccus, Fusicatenibacter, Lachnospiraceae ND3007 group , and Erysipelotrichaceae UCG-003 , were apparent in PD patients relative to controls. A sustained effect of DAT initiation on GM associations with PD was not observed. PD progression analysis indicated that the genus Barnesiella was underrepresented in faster progressing PD patients at t = 0 and t = 12 months. Two-stage predictive modeling, integrating microbiota abundances and nutritional profiles, improved predictive capacity (change in Area Under the Curve from 0.58 to 0.64) when assessed at Amplicon Sequence Variant taxonomic resolution. Conclusion: We present longitudinal GM studies in PD patients, showing persistently altered GM profiles suggestive of a reduced butyrogenic production potential. DATs exerted variable GM influences across the short and longer-term. We found that specific GM profiles combined with dietary factors improved prediction of disease progression in PD patients. [ABSTRACT FROM AUTHOR]

Background: Models to predict Parkinson's disease (PD) incorporating alterations of gut microbiome (GM) composition have been reported with varying success. Objective: To assess the utility of GM compositional changes combined with macronutrient intake to develop a predictive model of PD. Methods: We performed a cross-sectional analysis of the GM and nutritional intake in 103 PD patients and 81 household controls (HCs). GM composition was determined by 16S amplicon sequencing of the V3-V4 region of bacterial ribosomal DNA isolated from stool. To determine multivariate disease-discriminant associations, we developed two models using Random Forest and support-vector machine (SVM) methodologies. Results: Using updated taxonomic reference, we identified significant compositional differences in the GM profiles of PD patients in association with a variety of clinical PD characteristics. Six genera were overrepresented and eight underrepresented in PD patients relative to HCs, with the largest difference being overrepresentation of Lactobacillaceae at family taxonomic level. Correlation analyses highlighted multiple associations between clinical characteristics and select taxa, whilst constipation severity, physical activity and pharmacological therapies associated with changes in beta diversity. The random forest model of PD, incorporating taxonomic data at the genus level and carbohydrate contribution to total energy demonstrated the best predictive capacity [Area under the ROC Curve (AUC) of 0.74]. Conclusion: The notable differences in GM diversity and composition when combined with clinical measures and nutritional data enabled the development of a predictive model to identify PD. These findings support the combination of GM and nutritional data as a potentially useful biomarker of PD to improve diagnosis and guide clinical management. [ABSTRACT FROM AUTHOR]

Objectives: Cognitive impairment impacts negatively on Parkinson's disease (PD) patient and caregiver quality of life (QoL). We examined cognitive impairment in PD patients and their caregivers to determine if caregiver cognition affected their PD relative. Methods: Validated cognition and clinical outcome measures were assessed in 103 PD patients and 81 caregivers. Results: PD patients showed more cognitive impairment than their carers, with 48.6% having possible Mild Cognitive Impairment (MCI) and 16.5% having PD dementia. Increasing age, male gender, lower education level, various non-motor symptoms and certain therapies, associated with poorer cognition in PD. Eighteen and a half percent of caregivers were found to have MCI, in association with a lower physical and mental QoL. This reflected in lower QoL and mood for the respective PD patients. Conclusion: Impaired cognition and QoL in caregivers was associated with decreased QoL and mood for respective PD patients, suggesting MCI in caregivers is an important consideration for the management of PD. [ABSTRACT FROM AUTHOR]

Recently, there has been a surge in awareness of the gastrointestinal microbiome (GM) and its role in health and disease. Of particular note is an association between the GM and Parkinson's disease (PD) and the realisation that the GM can act via a complex bidirectional communication between the gut and the brain. Compelling evidence suggests that a shift in GM composition may play an important role in the pathogenesis of PD by facilitating the characteristic ascending neurodegenerative spread of α-synuclein aggregates from the enteric nervous system to the brain. Here, we review evidence linking GM changes with PD, highlighting mechanisms supportive of pathological α-synuclein spread and intestinal inflammation in PD. We summarise existing patterns and correlations seen in clinical studies of the GM in PD, together with the impacts of non-motor symptoms, medications, lifestyle, diet and ageing on the GM. Roles of GM modulating therapies including probiotics and faecal microbiota transplantation are discussed. Encouragingly, alterations in the GM have repeatedly been observed in PD, supporting a biological link and highlighting it as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that increased levels of α-synuclein might contribute to the pathogenesis of Parkinson's disease (PD) and therefore, it is crucial to understand the mechanisms underlying α-synuclein expression. Recently, microRNAs (miRNAs) have emerged as key regulators of gene expression involved in several diseases such as PD and other neurodegenerative disorders. A systematic literature search was performed here to identify microRNAs that directly or indirectly impact in α-synuclein expression/accumulation and describe its mechanism of action. A total of 27 studies were incorporated in the review article showing evidences that six microRNAs directly bind and regulate α-synuclein expression while several miRNAs impact on α-synuclein expression indirectly by targeting other genes. In turn, α-synuclein overexpression also impacts miRNAs expression, indicating the complex network between miRNAs and α-synuclein. From the current knowledge on the central role of α-synuclein in PD pathogenesis/progression, miRNAs are likely to play a crucial role at different stages of PD and might potentially be considered as new PD therapeutic approaches. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by the accumulation of a-synuclein (a-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing a-syn inclusions in PD. Recent data has indicated that loss-offunction mutations in the GBAl gene that encodes lysosomal β-gIucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to α-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce α-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological α-syn, regardless of the disease causing mutations. Importantly, the reduction of α-syn was sufficient to reverse downstream cellular pathologies induced by α-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce α-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies. [ABSTRACT FROM AUTHOR]

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn2+ homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Mutations in parkin have been associated with autosomal recessive early-onset Parkinson's disease (PD). Here, we report on unusual phenotypic variability within a family with mutations in parkin. Methods: The proband and her parents were clinically assessed. Mutation analysis was performed using genomic DNA and complementary DNA. The protein expression of Parkin and Mitofusin 2 was examined by western blotting. Results: The proband was a compound heterozygote with no detectable Parkin and presented with early-onset PD. The father, a single heterozygote with reduced expression of Parkin, had mild loss of arm swing. The mother, who had only very mild rigidity, was unexpectedly found to be a homozygote with no Parkin expression. The proband, but not the parents, met the Queen Square Brain Bank criteria for PD. Parkin-dependent ubiquitination of Mitofusin 2 was impaired in the mother and the proband. Conclusion: We report the first case of a homozygous mutation carrier in parkin who had no functional protein and only mild signs of parkinsonism in her seventh decade, whereas her daughter developed typical early-onset PD. This family demonstrates phenotypic variability in parkin-related parkinsonism. © 2012 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Gene expression analysis has become a ubiquitous tool for studying a wide range of human diseases. In a typical analysis we compare distinct phenotypic groups and attempt to identify genes that are, on average, significantly different between them. Here we describe an innovative approach to the analysis of gene expression data, one that identifies differences in expression variance between groups as an informative metric of the group phenotype. We find that genes with different expression variance profiles are not randomly distributed across cell signaling networks. Genes with low-expression variance, or higher constraint, are significantly more connected to other network members and tend to function as core members of signal transduction pathways. Genes with higher expression variance have fewer network connections and also tend to sit on the periphery of the cell. Using neural stem cells derived from patients suffering from Schizophrenia (SZ), Parkinson's disease (PD), and a healthy control group, we find marked differences in expression variance in cell signaling pathways that shed new light on potential mechanisms associated with these diverse neurological disorders. In particular, we find that expression variance of core networks in the SZ patient group was considerably constrained, while in contrast the PD patient group demonstrated much greater variance than expected. One hypothesis is that diminished variance in SZ patients corresponds to an increased degree of constraint in these pathways and a corresponding reduction in robustness of the stem cell networks. These results underscore the role that variation plays in biological systems and suggest that analysis of expression variance is far more important in disease than previously recognized. Furthermore, modeling patterns of variability in gene expression could fundamentally alter the way in which we think about how cellular networks are affected by disease processes. [ABSTRACT FROM AUTHOR]

Background: Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy. Methodology/Principal Findings: In this study, we investigated the impact of Parkin mutations on mitochondrial function and morphology in a human cellular model. Fibroblasts were obtained from three members of an Italian PD family with two mutations in Parkin (homozygous c.1072delT, homozygous delEx7, compound-heterozygous c.1072delT/delEx7), as well as from two relatives without mutations. Furthermore, three unrelated compound-heterozygous patients (delEx3-4/duplEx7- 12, delEx4/c.924C>T and delEx1/c.924C>T) and three unrelated age-matched controls were included. Fibroblasts were cultured under basal or paraquat-induced oxidative stress conditions. ATP synthesis rates and cellular levels were detected luminometrically. Activities of complexes I-IV and citrate synthase were measured spectrophotometrically in mitochondrial preparations or cell lysates. The mitochondrial membrane potential was measured with 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolylcarbocyanine iodide. Oxidative stress levels were investigated with the OxyBlot technique. The mitochondrial network was investigated immunocytochemically and the degree of branching was determined with image processing methods. We observed a decrease in the production and overall concentration of ATP coinciding with increased mitochondrial mass in Parkin-mutant fibroblasts. After an oxidative insult, the membrane potential decreased in patient cells but not in controls. We further determined higher levels of oxidized proteins in the mutants both under basal and stress conditions. The degree of mitochondrial network branching was comparable in mutants and controls under basal conditions and decreased to a similar extent under paraquat-induced stress. Conclusions: Our results indicate that Parkin mutations cause abnormal mitochondrial function and morphology in nonneuronal human cells. [ABSTRACT FROM AUTHOR]

We determined the prevalence of two common leucine-rich repeat kinase 2 (LRRK2) gene mutations in Australian patients with Parkinson's disease (PD). Of 830 affected patients, eight were heterozygous for the G2019S mutation, and two were heterozygous for the R1441H (4,322 G > A) mutation. In addition, one familial patient had a novel A1442P (4,324 G > C) mutation. Haplotype analysis showed that all LRRK2 G2019S-positive individuals carried the common founder haplotype 1 and a putative founder haplotype for the R1441H mutation carriers. Clinically, patients with LRRK2 mutations had typical levodopa responsive Parkinsonism with tremor being the commonest presenting feature. Patients with the G2019S mutation in our series had a similar age of onset of symptoms when compared with patients with other LRRK2 mutations or sporadic PD, although they were more likely to have a family history of PD (2.4% of Australian patients with familial PD and 0.3% of Australian patients with sporadic PD). Our results demonstrate that the G2019S mutation carriers share the same ancestors who migrated to Australia originally from Europe and that other LRRK2 mutations (R1441H and A1442P) can be found in this population. [ABSTRACT FROM AUTHOR]

The gastrointestinal microbiota (GM) have become an increasingly topical area in the quest to better understand the pathogenesis of Parkinson's disease (PD). Studying the GM of PD patients, they showed that the enzyme tyrosine decarboxylase (TDC), predominately found within the GM, decarboxylates l-tyrosine to form tyramine and converts l-dopa to dopamine [[4]]. They did however identify a small molecule inhibitor, -fluoromethyltyrosine (AFMT), that prevented in vitro TDC-dependent l-dopa decarboxylation, as well as within Enterococcus faecalis cultures and GM samples from PD patients [[5]]. [Extracted from the article]

The levodopa carbidopa intestinal gel is a device‐assisted therapy used for the management of fluctuating motor symptoms of Parkinson's disease that are refractory to oral therapy. The approach has demonstrable clinical value, but consideration of the associated need for expert care, access to services, and costs of the treatment impact the method of introduction to optimize uptake and minimize discontinuation across populations examined. Systematic approaches and modifications have been explored by different centers over the years to mitigate these considerations, with the aim of minimizing adverse events and maximizing the quality‐of‐life years gained with the treatment. In this presentation, we aim to outline an approach to managing this treatment while highlighting measures that can be utilized throughout the process to improve patients' experiences. View Supplementary Video 1 [ABSTRACT FROM AUTHOR]

Introduction: Depression is often an under-recognised feature of Parkinson's disease (PD). It is detrimental to physical and interpersonal functioning, negatively impacting a patient's clinical management, quality of life and well-being. We aimed to identify clinical predictors and management implications of depression in Australian PD patients.Methods: 103 PD and 81 Healthy Control (HC) subjects were evaluated using the Beck Depression Inventory (BDI) and other validated PD motor and non-motor symptom (NMS) tools.Results: Nearly twice as many PD patients were depressed, (38.9% vs 20.1%, p = 0.009), with a corresponding increase in depression severity on the BDI (11.9; standard deviation (SD) 8.8 vs 5.2; SD 5.5, p<0.001), and an odds ratio of 2.4 (95% confidence interval 1.2 - 4.7). Employment appeared to be a relative protective factor for depression, whilst patients requiring support services seemed to be more vulnerable to depression. Rapid Eye Movement Sleep Behaviour Disorder, dyskinesias, impulse control disorder, higher daily levodopa equivalent dose, increased motor severity, as well as catechol-O-methyltransferase inhibitor and amantadine use, all showed associations with depression (p<0.05). Chronic pain, decreased physical activity, constipation and upper gastrointestinal dysfunction presented with an apparent increase in risk for developing depression and increased depression severity. Other NMS were also found to be associated with PD-related depression.Limitations: Potential selection bias of self-reporting data collection from specialist PD clinics in a single metropolitan area.Conclusion: Our findings provide novel insight into the prevalence of depression in PD, possible contributory factors and future treatment strategies targeting depression in PD. [ABSTRACT FROM AUTHOR]

• Mitochondrial DNA abnormalities in the substantia nigra are associated with respiratory chain dysfunction. • There is a reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. • There is strong evidence supporting a role for impaired mitophagy and mitochondrial biogenesis in Parkinson's disease. • Mitochondrial, mtDNA maintenance and lysosomal disease mechanisms may converge at the level of cell-mediated immunity. • Mitochondrial dysfunction is a target for novel drug therapies, although most clinical trials have failed to show benefit. New discoveries providing insights into mitochondrial bioenergetics, their dynamic interactions as well as their role in cellular homeostasis have dramatically advanced our understanding of the neurodegenerative process of Parkinson's disease (PD). Respiratory chain impairment is a key feature in sporadic PD patients and there is growing evidence that links proteins encoded by PD-associated genes to disturbances in mitochondrial function. Against the backdrop of latest advances in the development of PD treatments that target mitochondria, we aim to give an overview of the literature published in the last three decades on the significance of mitochondria in the pathogenesis of PD. We describe the contribution of mitochondrial genome alterations and PD-associated genes to mitochondrial maintenance. We highlight mitophagy as a key mechanism in neurodegeneration. Moreover, we focus on the reciprocal interaction between alpha-synuclein aggregation and mitochondrial dysfunction. We discuss a novel trafficking pathway involving mitochondrial-derived vesicles within the context of PD and provide a synopsis of the most recently emerging topics in PD research with respect to mitochondria. This includes the relationship between mitochondria and cell-mediated immunity, the ER-mitochondria axis, sirtuin-mediated mitochondrial stress response and the role of micro RNAs in the aetiology of PD. In addition, recent studies have challenged the neuro-centric view of PD pathology, moving microglia and astrocytes into the research spotlight. Greater insights into these mechanisms may hold the key for the development of novel targeted therapies, addressing the need for a disease-modifying treatment, which has remained elusive to date. [ABSTRACT FROM AUTHOR]

Background: Kufor-Rakeb syndrome (KRS) is an autosomal recessive, juvenile-onset Parkinson's disease (PD) caused by loss-of-function mutations in ATP13A2 (PARK9). Impaired energy metabolism is considered a pathogenic mechanism in PD and mitochondrial dysfunction resulting from Zn(2+) dyshomeostasis has been found in KRS patient-derived cells. In addition to mitochondrial energy production, glycolysis plays an important role in cellular energy metabolism and glucose hypometabolism has been reported in PD. However, glycolytic status in KRS remains undetermined despite its potential importance.Methods: We assessed glycolytic function in ATP13A2-deficient KRS patient-derived human olfactory neurosphere cells and fibroblasts and determined the effect of pyruvate supplementation on improving cellular energy production.Results: We found impaired extracellular acidification, reduction in pyruvate production and a decrease in the NAD(+)/NADH ratio, indicative of glycolytic dysfunction. In addition, gene expression analysis revealed an altered expression profile for several glycolytic enzymes. Glycolytic dysfunction was aggravated when the intracellular Zn(2+) concentration was increased, while ATP13A2 overexpression and pyruvate supplementation blocked the observed Zn(2+)-mediated toxicity. Moreover, supplementation with pyruvate significantly increased basal mitochondrial ATP production and abolished Zn(2+)-induced cell death.Conclusions: These findings indicate that glycolytic dysfunction contributes to pathogenesis and pyruvate supplementation improves overall cellular bioenergetics in our KRS patient-derived cell model, highlighting a therapeutic potential. [ABSTRACT FROM AUTHOR]

Objective: To determine the prevalence of olfactory impairment and its associations with neurodegenerative and other conditions in older adults. Method: 1,636 participants (≥60 years) enrolled in the Blue Mountains Eye Study (2002-2004) were analyzed. Olfaction was assessed by the San Diego Odor Identification Test and used to classify mild impairment (4 or 5), moderate impairment (≤3), or any impairment (<6). Results: Prevalent olfactory impairment was 27.0%. After multivariate adjustment, the likelihood increased twofold with each decade of life after 60 years and was higher in men than women. Olfactory impairment and body mass index (BMI) were inversely associated. Persons with Parkinson's disease and cognitive impairment had an increased likelihood of mild and moderate olfactory impairment. Discussion: Over one in four older persons had olfactory impairment. The prevalence was higher in men, increased with age and decreasing BMI, and was higher among persons with Parkinson's disease and cognitive impairment. [ABSTRACT FROM AUTHOR]