Explore the vast range of titles available.

Background Alpha‐synuclein (α‐syn), phosphorylated at serine 129 (pS129‐α‐syn), is a potential biomarker for Parkinson's disease (PD) because it is the predominant α‐syn species found in Lewy bodies. Methods We developed an in‐house SIMOA assay, using commercially available components, to quantify pS129‐α‐syn in CSF. The clinical utility of the assay was tested in CSF from 120 patients with PD from the Norwegian ParkWest longitudinal study and 29 normal controls. Prior measurements of CSF total (t)‐α‐syn and the pS129‐α‐syn/t‐α‐syn ratio were included for comparison. Results The lower limit of quantification of the in‐house assay used to analyze CSF samples from participants was 0.57 pg/mL, which was well below the observed concentrations of endogenous pS129‐α‐syn in CSF. Median CSF pS129‐α‐syn levels were slightly lower in PD patients compared to controls (5.7 pg/mL vs. 6.5 pg/mL), but the difference was not significant in the unadjusted (p = 0.404) or adjusted analyses (p = 0.270). There was no difference in the pS129‐α‐syn/t‐α‐syn ratio between patients and controls. Using linear mixed‐effects models, we found no association between baseline pS129‐α‐syn or the pS129‐α‐syn/t‐α‐syn ratio and motor or cognitive decline over a 10‐year period. Conclusion We developed and applied an in‐house SIMOA that reliably quantifies pS129‐α‐syn in CSF samples. This study does not indicate a role for CSF pS129‐α‐syn or the pS129‐α‐syn/t‐α‐syn ratio as clinically useful diagnostic or prognostic biomarkers in PD.

Photoautotrophic microalgae offer a great potential as novel hosts for efficient recombinant protein production. Nannochloropsis oceanica produces an extraordinarily high content of polyunsaturated fatty acids, and its robust growth characteristics, published genome sequence and efficient nuclear transformation make N. oceanica a promising candidate for biotechnological applications. To establish a robust and flexible system for recombinant protein production, we cloned six endogenous, potentially constitutive or inducible promoters from N. oceanica strain CCMP1779 and investigated their strength using monomeric Venus as reporter gene. Microscopic pre-screening of individual transformants revealed that the promoters of elongation factor (EF), tubulin (TUB) and nitrate reductase (NR) enabled high reporter gene expression. Comparative quantitative analyses of transformant populations by flow cytometry and qRT-PCR demonstrated the highest Venus expression from the EF promoter and the NR promoter if extended by an N-terminal 14-amino acid leader sequence. The kinetics of reporter gene expression were analysed during photobioreactor cultivation, achieving Venus yields of 0.3% (for EF) and 4.9% (for NR::LS) of total soluble protein. Since inducible expression systems enable the production of toxic proteins, we developed an auto-induction medium for the NR promoter transformants. By switching the N source from ammonium to nitrate in the presence of low ammonium concentrations, the starting point of Venus induction could be fine-tuned and shifted towards exponential growth phase while maintaining high recombinant protein yields. Taken together, we demonstrate that a model recombinant protein can be produced robustly and at very high levels in N. oceanica not only under constitutive but also under auto-inducible cultivation conditions.Key points• Nannochloropsis oceanica might serve as host for recombinant protein production.• Comparative promoter strength analyses were conducted for twelve different constructs.• Robust high-yield recombinant protein production was achieved under constitutive conditions.• The nitrate reductase promoter enabled protein production under auto-induction conditions.

Lysosomal dysfunction is an emerging feature in the pathology of Parkinson’s disease and Dementia with Lewy bodies. Mutations in the GBA gene, encoding the enzyme Glucocerebrosidase (GCase), have been identified as a genetic risk factor for these synucleinopathies. As a result, there has been a growing interest in the involvement of GCase in these diseases. This GCase activity assay is based on the catalytic hydrolysis of 4-methylumbelliferyl β- d -glucopyranoside that releases the highly fluorescent 4-methylumbelliferyl (4-MU). The final assay protocol was tested for the following parameters: Lower limit of quantification (LLOQ), precision, parallelism, linearity, spike recovery, number of freeze–thaw events, and sample handling stability. The GCase activity assay is within acceptable criteria for parallelism, precision and spike recovery. The LLOQ of this assay corresponds to an enzymatic activity of generating 0.26 pmol 4-MU/min/ml. The enzymatic activity was stable when samples were processed and frozen at − 80 °C within 4 h after the lumbar puncture procedure. Repetitive freeze–thaw events significantly decreased enzyme activity. We present the validation of an optimized in vitro GCase activity assay, based on commercially available components, to quantify its enzymatic activity in human cerebrospinal fluid and the assessment of preanalytical factors.

Identification of factors predicting and driving mortality in PD is important for patient information, disease management, and design of future clinical trials. This study included newly diagnosed PD patients and normal controls (NC) from a population-based study with repeated assessments over a 10-year period. We used the Kaplan–Meier method to estimate survival, Cox proportional hazards regression models to identify baseline risk factors of mortality, and Cox regression models with time-dependent covariates to evaluate the impact of four clinical milestones of advanced PD (visual hallucinations, recurrent falls, dementia, and nursing home placement) on mortality risk. During the 10-year study, 65 (34.2%) of 190 patients and 25 (12.3%) of 203 NC died, with an unadjusted hazard ratio (HR) of 2.85 (95% CI 1.80–4.52) and a HR of 2.48 (95% CI 1.55–3.95) when adjusted for confounders, including comorbidities. Higher age, more severe motor impairment, and postural instability-gait difficulty (PIGD) phenotype were independent baseline predictors of mortality. Each clinical milestone alone more than doubled the risk of death and had a cumulative effect on mortality, with a HR of 10.83 (95% CI 4.39–26.73) in those experiencing all four milestones. PD patients have an increased mortality risk that is disease-related and becomes evident early during the course of the disease. While motor severity and PIGD phenotype were early risk factors of mortality, clinical milestones signaled a substantially increased risk of death later during the disease course, highlighting their potential significance in clinical disease staging and prognosis.

N-terminal acetylation (NTA) catalysed by N-terminal acetyltransferases (Nats) is among the most common protein modifications in eukaryotes, but its significance is still enigmatic. Here we characterize the plant NatA complex and reveal evolutionary conservation of NatA biochemical properties in higher eukaryotes and uncover specific and essential functions of NatA for development, biosynthetic pathways and stress responses in plants. We show that NTA decreases significantly after drought stress, and NatA abundance is rapidly downregulated by the phytohormone abscisic acid. Accordingly, transgenic downregulation of NatA induces the drought stress response and results in strikingly drought resistant plants. Thus, we propose that NTA by the NatA complex acts as a cellular surveillance mechanism during stress and that imprinting of the proteome by NatA is an important switch for the control of metabolism, development and cellular stress responses downstream of abscisic acid.

Background: Identifying compounds with neuroprotective properties that target the neurogenic process will have a considerable impact on dementia prevention. Methods: This is a secondary analysis of a 24-week randomised, double-blind, placebo-controlled anthocyanin supplementation trial in 181 participants. Using blood-derived serum collected during this trial, we treated hippocampal progenitor cells and analysed the ensuing cellular changes in the context of the participant’s clinical and blood-based biomarker data. Results: We show that anthocyanin supplementation impacts hippocampal progenitor cells and that this can impact hippocampal-dependent cognition. We also show for the first time that blood-based dementia biomarkers correlate with human in vitro neurogenesis markers. Conclusions: Our data demonstrates moderator effects of BMI and ApoE4 carrier status and supports the need for more individualised trials. Further studies are warranted to explore the mechanism of action of anthocyanins and the use of blood-based biomarkers for clinical trial enrichment, trial individualization, and therapy development. Trial registration: NCT03419039; date first registered: 15/01/2018.

There is great heterogeneity in both the clinical presentation and rate of disease progression among patients with Parkinson’s disease (PD). This can pose prognostic difficulties in a clinical setting, and a greater understanding of the risk factors that contribute to modify disease course is of clear importance for optimizing patient care and clinical trial design. Genetic variants in SNCA are an established risk factor for PD and are candidates to modify disease presentation and progression. This systematic review aimed to summarize all available primary research reporting the association of SNCA polymorphisms with features of PD. We systematically searched PubMed and Web of Science, from inception to 1 June 2020, for studies evaluating the association of common SNCA variants with age at onset (AAO) or any clinical feature attributed to PD in patients with idiopathic PD. Fifty-eight studies were included in the review that investigated the association between SNCA polymorphisms and a broad range of outcomes, including motor and cognitive impairment, sleep disorders, mental health, hyposmia, or AAO. The most reproducible findings were with the REP1 polymorphism or rs356219 and an earlier AAO, but no clear associations were identified with an SNCA polymorphism and any individual clinical outcome. The results of this comprehensive summary suggest that, while there is evidence that genetic variance in the SNCA region may have a small impact on clinical outcomes in PD, the mechanisms underlying the association of SNCA polymorphisms with PD risk may not be a major factor driving clinical heterogeneity in PD.

Neurofilament light chain (NFL) is elevated in neurodegenerative diseases, including Parkinson’s disease (PD). This study aimed to investigate serum NFL in newly diagnosed PD and its association with cognitive and motor decline over 10 years. Serum NFL levels were measured in PD patients and controls from the ParkWest study at diagnosis (baseline) and after 3 and 5 years. Mixed-effects regression analyzed changes in NFL and the association with annual changes in MMSE and UPDRS-III scores over 10 years. PD patients had elevated serum NFL at all visits and a faster annual increase over 5 years compared to controls (0.09 pg/mL per year; p  = 0.029). Higher baseline NFL predicted faster cognitive decline β −0.77 transformed MMSE; p  = 0.010), and a 40% NFL increase predicted future motor decline (β 0.28 UPDRS-III; p  = 0.004). Elevated serum NFL in early PD is linked to faster cognitive and motor impairment, suggesting its prognostic value in PD biomarker panels.

To define the incidence, predictors and prognosis of the first hospital delirium episode in Parkinson’s disease (PD) and atypical parkinsonism (AP), we identified the first hospital episode of delirium after diagnosis in the Parkinsonism Incidence in North-East Scotland (PINE) study, a prospective community-based incidence cohort of parkinsonism, using chart-based criteria to define delirium. Of 296 patients (189=PD, 107=AP [dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, vascular parkinsonism]), 152 developed delirium (PD = 98, AP = 54). Incidence of first hospital delirium episode per 100 person years was 8.1 (95% confidence interval [CI] 6.6–9.9) in PD and 18.5 (95% CI 13.9–24.7) in AP. Independent predictors of delirium were atypical parkinsonism (Hazard ratio [HR] vs PD = 2.83 [95% CI 1.60–5.03], age in PD but not in AP (HR for 10-year increase 2.29 [95% CI 1.74–3.02]), baseline MMSE (HR = 0.94 [95% CI 0.89–0.99]), APOE ε4 in PD (HR 2.16 [95% CI 1.15–4.08]), and MAPT H1/H1 in PD (HR 2.08 [95% CI 1.08–4.00]). Hazards of dementia and death after delirium vs before delirium were increased (dementia: HR = 6.93 [95% CI 4.18–11.48] in parkinsonism; death: HR = 3.76 [95% CI 2.65–5.35] in PD, 1.59 [95% CI 1.04–2.42] in AP). Delirium is a common non-motor feature of PD and AP and is associated with increased hazards of dementia and mortality. Whether interventions for early identification and treatment improve outcomes requires investigation.

Objective Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid‐beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD. Methods A total of 121 DLB patients from the European‐DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini‐Mental State Examination. Linear mixed‐effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile. Results Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status. Interpretation Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.