NEMoE: a nutrition aware regularized mixture of experts model to identify heterogeneous diet-microbiome-host health interactions.

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. Video Abstract.

The Gut Microbiome in Parkinson's Disease: A Longitudinal Study of the Impacts on Disease Progression and the Use of Device-Assisted Therapies.

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.

Nutritional Intake and Gut Microbiome Composition Predict Parkinson's Disease.

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.

Strong Predictive Algorithm of Pathogenesis-Based Biomarkers Improves Parkinson's Disease Diagnosis.

Easily accessible and accurate biomarkers can aid Parkinson's disease diagnosis. We investigated whether combining plasma levels of α-synuclein, anti-α-synuclein, and/or their ratios to amyloid beta-40 correlated with clinical diagnosis. The inclusion of amyloid beta-40 (Aß40) is novel. Plasma levels of biomarkers were quantified with ELISA. Using receiver operating characteristic (ROC) curve analysis, levels of α-synuclein, anti-α-synuclein, and their ratios with Aß40 were analyzed in an initial training set of cases and controls. Promising biomarkers were then used to build a diagnostic algorithm. Verification of the results of biomarkers and the algorithm was performed in an independent set. The training set consisted of 50 cases (age 65.2±9.3, range 44-83, female:male=21:29) with 50 age- and gender-matched controls (67.1±10.0, range 45-96 years; female:male=21:29). ROC curve analysis yielded the following area under the curve results: anti-α-synuclein=0.835, α-synuclein=0.738, anti-α-synuclein/Aß40=0.737, and α-synuclein/Aß40=0.663. A 2-step diagnostic algorithm was built: either α-synuclein or anti-α-synuclein was ≥2 times the means of controls (step-1), resulting in 74% sensitivity; and adding α-synuclein/Aß40 or anti-α-synuclein/Aß40 (step-2) yielded better sensitivity (82%) while using step-2 alone yielded good specificity in controls (98%). The results were verified in an independent sample of 46 cases and 126 controls, with sensitivity reaching 91.3% and specificity 90.5%. The algorithm was equally sensitive in Parkinson's disease of ≤5-year duration with 92.6% correctly identified in the training set and 90% in the verification set. With two independent samples totaling 272 subjects, our study showed that combination of biomarkers of α-synuclein, anti-α-synuclein, and their ratios to Aß40 showed promising sensitivity and specificity.

The impact of device-assisted therapies on the gut microbiome in Parkinson's disease.

BACKGROUND: Microbiome feedbacks are proposed to influence Parkinson's disease (PD) pathophysiology. A number of studies have evaluated the impact of oral medication on the gut microbiome (GM) in PD. However, the influence of PD device-assisted therapies (DATs) on the GM remains to be investigated. OBJECTIVES: To profile acute gut microbial community alterations in response to PD DAT initiation. METHODS: Clinical data and stool samples were collected from 21 PD patients initiating either deep brain stimulation (DBS) or levodopa-carbidopa intestinal gel (LCIG) and ten spousal healthy control (HC) subjects. 16S amplicon sequencing of stool DNA enabled comparison of temporal GM stability between groups and with clinical measures, including disease alterations relative to therapy initiation. RESULTS: We assessed GM response to therapy in the PD group by comparing pre-therapy (- 2 and 0 weeks) with post-therapy initiation timepoints (+ 2 and + 4 weeks) and HCs at baseline (0 weeks). Altered GM compositions were noted between the PD and HC groups at various taxonomic levels, including specific differences for DBS (overrepresentation of Clostridium_XlVa, Bilophila, Parabacteroides, Pseudoflavonifractor and underrepresentation of Dorea) and LCIG therapy (overrepresentation of Pseudoflavonifractor, Escherichia/Shigella, and underrepresentation of Gemmiger). Beta diversity changes were also found over the 4 week post-treatment initiation period. CONCLUSIONS: We report on initial short-term GM changes in response to the initiation of PD DATs. Prior to the introduction of the DAT, a PD-associated GM was observed. Following initiation of DAT, several DAT-specific changes in GM composition were identified, suggesting DATs can influence the GM in PD.

Cognitive Influences in Parkinson's Disease Patients and Their Caregivers: Perspectives From an Australian Cohort.

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.

Increased Added Sugar Consumption Is Common in Parkinson's Disease.

Objectives: There is limited information about the dietary habits of patients with Parkinson's Disease (PD), or associations of diet with clinical PD features. We report on nutritional intake in an Australian PD cohort. Methods: 103 PD patients and 81 healthy controls (HCs) completed a validated, semi-quantitative food frequency questionnaire. Food and nutrient intake was quantified, with consideration of micronutrients and macronutrients (energy, protein, carbohydrate, fat, fibre, and added sugar). Participants also completed PD-validated non-motor symptom questionnaires to determine any relationships between dietary intake and clinical disease features. Results: Mean daily energy intake did not differ considerably between PD patients and HCs (11,131 kJ/day vs. 10,188 kJ/day, p = 0.241). However, PD patients reported greater total carbohydrate intake (279 g/day vs. 232 g/day, p = 0.034). This was largely attributable to increased daily sugar intake (153 g/day vs. 119 g/day, p = 0.003) and in particular free sugars (61 g/day vs. 41 g/day, p = 0.001). PD patients who (1) experienced chronic pain, (2) were depressed, or (3) reported an impulse control disorder, consumed more total sugars than HCs (all p < 0.05). Increased sugar consumption was associated with an increase in non-motor symptoms, including poorer quality of life, increased constipation severity and greater daily levodopa dose requirement. Conclusions: We provide clinically important insights into the dietary habits of PD patients that may inform simple dietary modifications that could alleviate disease symptoms and severity. The results of this study support clinician led promotion of healthy eating and careful management of patient nutrition as part of routine care.

Health-Related Quality of Life for Parkinson's Disease Patients and Their Caregivers.

OBJECTIVE: Motor and non-motor symptoms (NMS) negatively impact the health-related quality of life (HRQoL) for individuals with Parkinson's disease (PD), as well as their caregivers. NMS can emerge decades prior to the manifestation of motor symptoms but often go unrecognized and therefore untreated. To guide clinical management, we surveyed differences and identified factors that influence HRQoL in a cohort of PD patients and family caregivers. METHODS: A total of 103 PD patients were compared with 81 caregivers. Outcome measures collected from validated questionnaires included generic and disease-specific HRQoL assessments, depression frequency and severity, constipation severity, upper and lower gastrointestinal symptoms, physical activity and motor symptom severity. RESULTS: PD patients reported significantly decreased physical and mental HRQoL compared to their caregivers (both p < 0.001). Unemployment, the need for social support services, rehabilitation use, REM sleep behavior disorder, impulse control disorders and features suggestive of increasing disease severity hallmarked by increasing PD duration, higher MDS UPDRS-III (Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III) scores, higher daily levodopa equivalence dose and motor fluctuations were consistent with a lower HRQoL in our PD cohort. Furthermore, decreased physical activity, chronic pain, depression, constipation and upper gastrointestinal dysfunction (particularly indigestion, excess fullness and bloating) suggested vulnerability to reduced HRQoL. Overall, PD patients perceived their health to decline by 12% more than their caregivers did over a 1-year period. CONCLUSION: PD patients reported decreased HRQoL, with both motor symptoms and NMS negatively impacting HRQoL. Our findings support the routine clinical screening of HRQoL in PD patients to identify and address modifiable factors.

Depression in Parkinson's disease: Perspectives from an Australian cohort.

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.

Gastrointestinal dysfunction in Parkinson's disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD). Symptoms are evident throughout the disease course, affect the length of the GI tract and impact on patient quality of life and management. We clarify real-life differences in the frequency and severity of GI symptoms in a cohort of PD and healthy control (HC) subjects. METHODS: 103 PD patients were compared to 81 HC subjects. Outcome measures collected from validated questionnaires included constipation severity, upper and lower GI symptoms and physical activity. RESULTS: PD patients were three-times more likely to experience constipation than HC subjects, (78.6% vs 28.4%), exhibited a fourfold increase in constipation severity and formed harder stools. PD patients also reported increased symptoms of indigestion, nausea, excessive fullness and bloating, compared to the HCs. A higher mean Leeds Dyspepsia Questionnaire score for PD patients (8.3 (standard deviation (SD) 7.7) vs 4.6 (SD 6.1), p = 0.001)) indicated increased symptom severity. Chronic pain was more frequently reported and correlated with constipation and upper GI dysfunction, being more prevalent and severe in women. Physical activity was notably decreased in the PD cohort (1823.6 (± 1693.6) vs 2942.4 (± 2620.9) metabolic equivalent-minutes/week, p = 0.001) and correlated with constipation severity. PD therapies were associated with increased fullness and bloating and harder stools. CONCLUSIONS: PD patients report more prevalent and severe GI dysfunction, although our cohort comprised of many later-stage participants. Earlier recognition of GI dysfunction in PD provides the opportunity to direct treatment for chronic pain and constipation, promote physical activity and rationalise PD therapies for optimal patient care.

Parkinson's disease and the gastrointestinal microbiome.

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.

Immune-mediated conditions affecting the brain, eye and ear (BEE syndromes).

The triad of central nervous system symptoms, visual disturbance and hearing impairment is an oft-encountered clinical scenario. A number of immune-mediated diseases should be considered among the differential diagnoses including: Susac syndrome, Cogan syndrome or Vogt-Koyanagi-Harada disease; demyelinating conditions such as multiple sclerosis or neuromyelitis optica spectrum disorder; systemic diseases such as systemic lupus erythematosus, Sjögren syndrome or Behcet disease and granulomatous diseases such as sarcoidosis. In this article, we coin the term 'BEE syndromes' to draw attention to the various immune-mediated diseases that affect the brain, eye and ear. We present common disease manifestations and identify key clinical and investigation features.

Rheumatoid leptomeningitis presenting with an acute neuropsychiatric disorder.

Leptomeningitis is a rare central nervous system manifestation of rheumatoid arthritis, generally in patients with established chronic rheumatoid disease. We report a 41-year-old man without previous rheumatoid arthritis or psychiatric disorder who presented with an acute neuropsychiatric disturbance and polyarthralgia. His MR scan of brain showed asymmetric bifrontal leptomeningitis, confirmed on (18F)-fluoro-D-glucose-positron emission tomography. Other investigations showed highly positive serum and cerebrospinal fluid anti-cyclic citrullinated peptide. A leptomeningeal biopsy showed necrotising leptomeningeal inflammation with ill-defined granulomas and lymphoplasmacytic infiltrate without organisms. Prolonged high-dose corticosteroids and then rituximab resulted in recovery. Chronic leptomeningitis can present with an acute neuropsychiatric disorder. We highlight that early rheumatoid disease can, rarely, cause a chronic leptomeningitis, reversible with immunotherapy.

Actinomyces cavernous sinus infection: a case and systematic literature review.

A 63-year-old man presented with a 2-month history of progressive right-sided exophthalmos, painful ophthalmoplegia and fevers. As more features developed, he was diagnosed with giant cell arteritis, then Tolosa-Hunt syndrome, and transiently responded to corticosteroids. A bland cerebrospinal fluid and highly metabolically active brain (18F)-fluoro-D-glucose-positron emission tomography suggested lymphoma. Biopsy of the mass showed sulphur granules with Gram-positive filamentous bacteria with Actinomyces-like colonies. Actinomyces cavernous sinus infections are rare and indolent. They often mimic non-infective causes including other inflammatory and infiltrative conditions, vascular and neoplastic causes, particularly lymphoma. Clinicians should consider infective cavernous sinus syndromes in people with a fluctuating painful ophthalmoplegia that responds poorly to corticosteroids. The term Tolosa-Hunt syndrome is problematic and should be retired or used only with reservation.

An unusual presentation of varicella zoster virus with acute cerebellitis and SIADH without a rash.

We report a case of varicella-zoster virus (VZV) infection with acute cerebellitis and encephalitis with associated Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) in an elderly man presenting with acute cerebellar ataxia without antecedent rash. Cerebrospinal fluid examination (CSF) revealed a mononuclear pleocytosis, high protein, normal glucose, positive for VZV polymerase chain reaction (PCR). Early acyclovir treatment is beneficial for acute VZV cerebellitis. Clinicians should consider infectious Central Nervous System (CNS) causes for presentations of acute cerebellar ataxia in adult patients, particularly if there is an accompanying clouded sensorium.