Impact of Neuroprotection on Incidence of Alzheimer's Disease

Converging evidence suggests that high levels of education and intellectual activity increase the cognitive reserve and reduce the risk of dementia. However, little is known about the impact that different neuroprotective strategies may have on the incidence of Alzheimer's disease. Using a simple mathematical regression model, it is shown here that age-specific counts of basic cognitive units (surrogate of neurons or synapses) in the normal population can be estimated from Alzheimer's incidence rates. Hence, the model can be used to test the effect of neuroprotection on Alzheimer's incidence. It was found that the number of basic cognitive units decreases with age, but levels off in older people. There were no gender differences after correcting for survival. The model shows that even modest neuroprotective effects on basic cognitive units can lead to dramatic reductions in the number of Alzheimer's cases. Most remarkably, a 5% increase in the cognitive reserve would prevent one third of Alzheimer's cases. These results suggest that public health policies aimed at increasing the cognitive reserve in the general population (e.g., implementing higher levels of education) are likely the most effective strategy for preventing Alzheimer's disease

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Understanding Everything NPCs Can Do: Metrics for Action Similarity in Non-Player Characters

Non-Player Characters (NPCs) have actions that allow them to reason about what they can do in a game and how they can do it. The background information about what they can do are the components of the action, and how they can do it is the form or shape of an action, which may be built up from several sub- actions. The components and shape of an action must be fully defined in a game, which can be tedious when several similar actions are needed. Furthermore, as the number of nuanced actions grows, more pressure is placed on an already constrained reasoning system. By discovering the similarities between actions an NPC can do, a given action set can be intelligently organized with similar components being generalized using an action taxonomy. To understand the similarity between actions we have developed measures of action similarity based on their constituent components and form. From this, wediscover a metric to determine the generalization ability of an organization strategy for an NPC action set. We examine the use of our measures on a previously developed action set to show the nuances between those actions. Lastly, we find that intelligently organizing actions has a positive effect on virtual character reasoning abilities.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Comp Graphics & Visualisatio

Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease

Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. clinicaltrials.gov Identifier: NCT00833690

A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p <5x10(-10), PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loc

Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease

Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility

Prediction of cognition in Parkinson's disease with a clinical–genetic score: a longitudinal analysis of nine cohorts

International audienceSummary Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson’s disease. We aimed to develop a clinical-genetic score to predict global cognitive impairment in patients with the disease. Methods A prediction algorithm for global cognitive impairment (defined as Mini Mental State Exam (MMSE) ≤25) was built using data from 1,350 patients with 5,165 longitudinal visits over 12.8 (median, 2.8) years. Age at onset, MMSE, education, motor exam score, gender, depression and GBA mutations, machine selected through stepwise Cox’ hazards analysis and Akaike’s information criterion, were used to compute the multivariable predictor. Independent validation was achieved in another 1,132 patients with 19,127 visits over 8.6 (median, 6.5) years. Findings The cognitive risk score accurately predicted cognitive impairment within ten years of disease onset with an area under the curve (AUC) of >0.85 in both the discovery (95% CI, 0.821–0.902) and validation populations (95% CI, 0.779 – 0.913). 72.6% of patients scoring in the highest quartile were cognitively impaired by ten years vs. 3.7% in the lowest quartile (hazard ratio, 18.4, 95% CI, 9.4 – 36.1). Dementia or disabling cognitive impairment was predicted with an AUC of 0.877 (95% CI 0.788–0.943) and high negative predictive value (0.920, 95% 0.877–0.954) at the predefined cutoff (0.196). Performance was stable in 10,000 randomly resampled subsets. Interpretation Our predictive algorithm provides a potential test for future cognitive health or impairment in patients with Parkinson’s. It could improve trials of cognitive interventions and inform on prognosis