Flavonoid intake and risk of Parkinson's disease.

BACKGROUND: Flavonoids have been proposed to reduce the risk of Parkinson's disease (PD). However, results from epidemiological studies have been inconclusive. OBJECTIVE: To prospectively examine the association between the intake of flavonoids and their subclasses and the risk of PD and how pesticides may confound or modify that association. METHODS: The study population comprised 80 701 women (1984-2016) and 48 782 men (1986-2016) from two large US cohorts. Flavonoid intake was ascertained at baseline and every 4 years thereafter using a semiquantitative Food Frequency Questionnaire. We conducted multivariable-adjusted Cox regression models to estimate HRs and 95% CIs of PD according to quintiles of baseline and cumulative average intakes of flavonoids and subclasses. We repeated the analyses, adjusting for intakes of high-pesticide-residue fruits and vegetables (FVs) and stratifying by servings/day of high-pesticide-residue FV intake. RESULTS: We identified 676 incident PD cases in women and 714 in men after 30-32 years of follow-up. Higher total flavonoid intake at baseline was not associated with a lower PD risk, neither in men (HR comparing highest to lowest quintile: 0.89, 95% CI: 0.69 to 1.14) nor in women (HR comparing highest to lowest quintile: 1.27, 95% CI: 0.98 to 1.64). Similar results were observed for cumulative average intakes and flavonoid subclasses. Results remained similar after adjustment for and stratification by high-pesticide-residue FV and when analyses were restricted to younger PD cases. CONCLUSION: These results do not support a protective effect of flavonoid intake on PD risk. Pesticide residues do not confound or modify the association.

Mitochondrial haplogroups and cognitive progression in Parkinson's disease.

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time.

Subjective Cognitive Decline in Women with Features Suggestive of Prodromal Parkinson's Disease.

BACKGROUND: Cognitive deficits can be present in the prodromal phase of Parkinson's disease (PD). Subjective cognitive decline (SCD) may contribute to identifying individuals with prodromal PD. OBJECTIVE: The objective of this study was to examine whether SCD is more likely to be present in women with features suggestive of prodromal PD compared with women without these features. METHODS: The study population comprised 12,427 women from the Nurses' Health Study selected to investigate prodromal PD. Prodromal and risk markers of PD were assessed via self-administered questionnaires. We evaluated the association of hyposmia, constipation, and probable rapid eye movement sleep behavior disorder, three major features of prodromal PD, with SCD, adjusting for age, education, body mass index, physical activity, smoking, alcohol, caffeine intake, and depression. We also explored whether SCD was associated with the probability of prodromal PD and conducted additional analyses using data from neurocognitive tests. RESULTS: Women experiencing the three examined nonmotor features had the worst mean SCD score and the highest odds of poor subjective cognition (odds ratio [OR] = 1.78; 95% confidence interval [CI], 1.29-2.47). This association persisted when women with objective cognitive deficits were excluded from analyses. SCD was also more common in women with a probability of prodromal PD ≥0.80, particularly among those aged younger than 75 years (OR of poor subjective cognition = 6.57 [95% CI, 2.43-17.77]). These observations were consistent with the results from analyses using neurocognitive tests, where a worse global cognitive performance was observed among women with three features. CONCLUSIONS: Our study suggests that self-perceived cognitive decline can be present during the prodromal phase of PD. © 2023 International Parkinson and Movement Disorder Society.

Long-Term Intake of Folate, Vitamin B6, and Vitamin B12 and the Incidence of Parkinson's Disease in a Sample of U.S. Women and Men.

BACKGROUND: Folate and vitamins B6 and B12 have been proposed as protective against the development of Parkinson's disease (PD). Two prior longitudinal studies were inconclusive. OBJECTIVE: The aim was to examine the association of long-term intake of folate, vitamin B6, and vitamin B12 with the incidence of PD. METHODS: The study population comprised 80,965 women (Nurses' Health Study, 1984-2016) and 48,837 men (Health Professionals Follow-up Study, 1986-2016) followed prospectively for the development of PD. Intake of B vitamins was measured at baseline and every 4 years thereafter using food frequency questionnaires. We estimated the hazard ratio (HR) and 95% confidence interval (CI) of PD based on quintiles of cumulative average intake adjusting for potential confounders. Secondary analyses considered different lagged exposure periods as well as baseline and recent intakes. RESULTS: In separate analyses of cumulative average intake, total folate, B6, and B12 were not associated with the risk of PD. Results from 8-, 12-, and 16-year lag analyses were consistent with these findings. Results for baseline intake of folate and B6 also pointed toward a null association. In contrast, a lower PD risk was observed among individuals with higher baseline total intake of B12 (pooled HR top vs. bottom quintile: 0.80; 95% CI: 0.67-0.95; P-trend = 0.01); results from 20-year lag analyses were consistent with this finding. CONCLUSIONS: Our results do not support the hypothesis that a higher intake of folate or vitamin B6 would reduce PD risk in this population. Our results provide moderate support for a possible protective effect of vitamin B12 on the development of PD. © 2023 International Parkinson and Movement Disorder Society.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Attitudes and educational needs of emergency doctors providing palliative and end-of-life care in Hong Kong: a cross-sectional analysis based on a self-report study.

BACKGROUND: Due to the ageing population in Hong Kong, the importance and need of palliative care and end-of-life (EOL) care are coming under the spotlight. The objectives of this study were to evaluate the attitudes of emergency doctors in providing palliative and EOL care in Hong Kong, and to investigate the educational needs of emergency doctors in these areas. METHODS: A questionnaire was used to study the attitudes of ED doctors of six different hospitals in Hong Kong. The questionnaire recorded the attitudes of the doctors towards the role of palliative and EOL care in EDs, the specific obstacles faced, their comfort level and further educational needs in providing such care. The attitudes of emergency doctors of EDs with EOL care services were compared with those of EDs without such services. RESULTS: In total, 145 emergency doctors completed the questionnaire, of which 60 respondents were from EDs with EOL care services. A significant number of participants recognized that the management of the dying process was essential in ED. Providing palliative and EOL care is also accepted as an important competence and responsibility, but the role and priority of palliative and EOL care in ED are uncertain. Lack of time and access to palliative care specialists/ teams were the major barriers. Doctors from EDs with EOL care services are more comfortable in providing such care and discuss it with patients and their relatives. Further educational needs were identified, including the management of physical complaints, communication skills, and EOL care ethics. CONCLUSIONS: The study identified obstacles in promoting palliative and EOL care in the EDs Hong Kong. With the combination of elements of routine ED practice and a basic palliative medicine skill set, it would promote the development of palliative and EOL care in Emergency Medicine in the future.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Computer mouse use captures ataxia and parkinsonism, enabling accurate measurement and detection.

BACKGROUND: Objective assessments of movement impairment are needed to support clinical trials and facilitate diagnosis. The objective of the current study was to determine if a rapid web-based computer mouse test (Hevelius) could detect and accurately measure ataxia and parkinsonism. METHODS: Ninety-five ataxia, 46 parkinsonism, and 29 control participants and 229,017 online participants completed Hevelius. We trained machine-learning models on age-normalized Hevelius features to (1) measure severity and disease progression and (2) distinguish phenotypes from controls and from each other. RESULTS: Regression model estimates correlated strongly with clinical scores (from r = 0.66 for UPDRS dominant arm total to r = 0.83 for the Brief Ataxia Rating Scale). A disease change model identified ataxia progression with high sensitivity. Classification models distinguished ataxia or parkinsonism from healthy controls with high sensitivity (≥0.91) and specificity (≥0.90). CONCLUSIONS: Hevelius produces a granular and accurate motor assessment in a few minutes of mouse use and may be useful as an outcome measure and screening tool. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

MicroRNA-26b promotes transition from Kit- to Kit+ mouse spermatogonia.

During spermatogenesis, a group of undifferentiated spermatogonia undergoes an essential transition to a differentiating stage, which involves gain of Kit receptor. In the current study, we showed that a small non-coding RNA, miRNA-26b could induce transition from Kit- to Kit+ and inhibit proliferation of spermatogonia. A key transcriptional factor for undifferentiated spermatogonia, Plzf, was proven as a direct target of miR-26b. When undifferentiated spermatogonia were treated with Retinoic acid (RA), miR-26b was increased, further promoting RA-induced differentiation of spermatogonia. In addition, miR-26b could repress 5-hydroxymethylcytosine (5hmC) via repression of Tet3 in spermatogonia. These findings demonstrate that miR-26b might play a role in promoting the transition from Kit- to Kit+ SSCs.

Novel glycylated sugar alcohols protect ESC-specific microRNAs from degradation in iPS cells.

Excessive accumulation of embryonic stem cell (ESC)-specific microRNAs occurs in both ESCs and induced pluripotent stem cells (iPSC); yet, the mechanism involved is unknown. In iPSCs, we for the first time found that novel glycylated sugar alcohols, particularly glycylglycerins, are tightly bound with ESC-specific microRNA precursors (pre-miRNA), such as pre-miR-302. Among these isolated glycylglycerins, we further identified that 1,3-diglycylglycerin and 1,2,3-triglycylglycerin are two major compounds bonded with negatively charged nucleic acids via electro-affinity and subsequently forming sugar-like coats in the hairpin-like double helix structures of pre-miRNAs. As a result, such glycylglycerin-formed coating serves as a protection layer against miRNA degradation. Moreover, we found that the pH value of iPSC cytosol determines the charges of these glycylglycerins. During iPSC differentiation, the cytosol pH is increased and hence neutralizes the charges of glycylglycerins, consequently leading to fast miRNA degradation. Therefore, the current findings not only explain how ESC-specific miRNAs are preserved and accumulated in iPSCs and ESCs but also demonstrate an important function of glycylglycerins in protecting the structural integrity of highly degradable miRNAs, providing a useful means for maintaining miRNA/siRNA function as well as developing the related RNA interference (RNAi) applications.

Compositional mapping of bitumen using local electrostatic force interactions in atomic force microscopy.

In recent years, many researchers have investigated bitumen surface morphology, especially the so-called bee-like structures, in an attempt to relate the chemical composition and molecular conformation to bitumen micromechanics and ultimately performance properties. Even though recent studies related surface morphology and its evolution to stiffness and stress localization, the complex chemical nature of bitumen and its time- and temperature-dependent properties still engender significant questions about the nature and origin of the observed morphological features and how they evolve due to exposure to various environmental and loading conditions. One such question is whether the observed surface features are formed from wax or from the coprecipitation of wax and asphaltene. Our prior work was mainly theoretical; it used density functional theory and showed that the coprecipitation theory may not stand, mainly because wax-asphaltene interactions are not thermodynamically favourable compared to wax-wax interactions. This paper presents a comprehensive approach based on experiments to study surface morphology of bitumen and conduct compositional mapping to shed light on the origin of the bee-like surface morphological features. We used Atomic Force Microscopy (AFM), with the main focus being on single-pass detection and mapping of local electric properties, as a novel approach to enhance existing compositional mapping techniques. This method was found to be highly effective in differentiating various domains with respect to their polarity. The results of our study favour the hypothesis that the bee-like features are mainly composed of wax, including a variety of alkanes.

Movement Disorders in Women.

Movement disorders such as Parkinson's disease (PD), restless legs syndrome (RLS), chorea, essential tremor, and Tourette syndrome, occur in men and women of all ages. Yet, considerable sex differences in epidemiology, clinical features, and treatment exist in these disorders. In this review, we highlight key differences in the evaluation and management of women with movement disorders, addressing sex-specific complications of treatment and unique challenges surrounding the management of movement disorders during pregnancy. We review the complex relationship between estrogen and movement disorders, including the putative neuroprotective effects of estrogen in PD and the modulatory effects on RLS and chorea associated with autoimmune disease. Further understanding of sex-specific and hormonal effects on clinical features will be important to optimize the management of women with movement disorders in the future.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Investigating molecular interactions and surface morphology of wax-doped asphaltenes.

The nature and origin of bee-like microstructures (bees) in asphalt binders and their impact on asphalt oxidation have been the subject of extensive discussions in recent years. While several studies refer to the bees as solely surface features, some others consider them to be bulk microcrystalline components that are formed due to co-precipitation of wax and asphaltene molecules. In this study, we use a rigorous theoretical and experimental approach to investigate the interplay of asphalt components (mainly asphaltene and wax) and their impact on bee formation. In the theoretical section, quantum-mechanical calculations using density functional theory (DFT) are used to evaluate the strength of interactions between asphaltene unit sheets in the presence and absence of a wax component, as well as the mutual interactions between asphaltene molecules (monomers and dimers) and paraffin wax. The results of this section reveal that paraffin waxes not only do not reinforce the interaction between the asphaltene unit sheets, they destabilize asphaltene assembly and dimerization. AIM (Atom in Molecules) analysis shows the destabilizing effect of wax on asphaltene assembly as a reduction in the number of cage and bond critical points between asphaltenes. This destabilization effect among interacting systems (asphaltene-asphaltene and wax-asphaltene) does not support the hypothesis that interaction between paraffin waxes and non-wax components, such as asphaltene, is responsible for their co-precipitation and bee formation. To further examine the effect of wax component on asphalt microstructure experimentally, we used atomic force microscopy (AFM) to study the surface morphology of an asphalt sample doped with 1% to 25% paraffin wax. In agreement with the conclusions drawn from the DFT approach, our experiments indicate that paraffin wax tends to crystallize separately and form lamellar paraffin wax crystal inclusions with 10 nm thickness. Moreover, the addition of 3% wax into asphalt results in a significant increase in surface roughness from 0.5 nm to 4.1 nm and an increase in bee wavelength from 651 nm to 1038 nm.

Hair color, family history of melanoma, and the risk of Parkinson's disease: An analysis update.

BACKGROUND: A shared biological component between melanoma and Parkinson's disease (PD) has been suggested. Yet, epidemiological evidence is scarce. OBJECTIVE: To examine the association of hair color and family history of melanoma, two strong predictors of melanoma risk, with the occurrence of PD. METHODS: We followed 131,342 women and men for ∼30 years for the development of PD. We calculated the cumulative incidence of PD from ages 40 to 90 according to hair color, and estimated the hazard ratio of PD according to hair color and family history of melanoma. RESULTS: Hair color was not strongly associated with the risk of PD, especially at advanced ages. In contrast, individuals with a family history of melanoma had a 1.4-fold higher risk of PD compared to those without a history. CONCLUSIONS: Our results support the hypothesis of a shared biological component between PD and melanoma. Both pigmentary and non-pigmentary pathways may play a role.

Activation of the insulin receptor by insulin-like growth factor 2.

Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.

Switchable nanodumbbell probes for analyte detection.

Nanodumbbell gold nanoparticle (AuNP) dimers connected by DNA show significant change in interparticle distance in the presence of a specific analyte, ATP. The nanodumbbell begins in an extended state, but after the addition of the analyte, the DNA connecting the AuNPs forms a stable hairpin, which causes a large decrease in the interparticle distance.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.

OBJECTIVE: Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility. METHODS: A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls). RESULTS: Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes. INTERPRETATION: We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.