María R. Sierra

Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease.

Recent genome‐wide association studies of Parkinsons disease have nominated 3 new susceptibility loci (PARK16‐18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single‐nucleotide polymorphisms in each of these genes/loci in 1445 Parkinsons disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinsons disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single‐nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10−4) and SNCA (rs356219; P = 5.5 × 10−4) were significantly associated with Parkinsons disease. However, none of the markers in PARK16‐18 associated with Parkinsons disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinsons disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome‐wide association studies include effects of population structure, power, and population‐specific environmental interactions. Our findings suggest that additional studies of PARK16‐18 are necessary to establish the role of these loci in modifying risk for Parkinsons disease in European‐derived populations.

Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease

Objective: To ascertain in a cross-sectional study whether substantia nigra (SN) echogenicity, olfaction, and dopamine transporter (DaT)-SPECT are reliable premotor biomarkers in a cohort of asymptomatic carriers of the LRRK2 G2019S mutation (AsG2019S+). Methods: These biomarkers were evaluated in 49 AsG2019S+ patients, and we also studied olfaction and SN echogenicity in 29 patients with G2019S-associated Parkinson disease (PD-G2019S), 47 relatives who were noncarriers of the LRRK2 G2019S mutation (AsG2019S−), 50 patients with idiopathic Parkinson disease (iPD), and 50 community controls. Results: Eighty-five percent of unaffected mutation carriers (AsG2019S+) showed pathologic SN hyperechogenicity, with a similar proportion observed among both PD-G2019S and iPD cases, and 41% of AsG2019S− also showing increased SN echogenicity. The proportion of hyposmic individuals was not statistically different in patients with PD-G2019S (50%) and iPD (82%), but hyposmia was significantly less common in both AsG2019S+ (26%) and AsG2019S− (28%). In AsG2019S+ cases, reduced striatal uptake in DaT-SPECT was observed in 43.7%. Conclusions: Independently of age at examination, the most frequently altered premotor biomarker in LRRK2 G2019S-associated PD was SN hyperechogenicity, whereas abnormal DaT-SPECT predominated in older, unaffected mutation carriers.

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson’s Disease

Background Idiopathic Parkinson’s disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. Objective To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. Methods The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. Results University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. Conclusion Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD.

New codification schemas for scheduling with genetic algorithms

Codification is a very important issue when a Genetic Algorithm is designed to dealing with a combinatorial problem. In this paper we introduce new codification schemas for the Job Shop Scheduling problem which are extensions of two schemas of common use, and are worked out from the concept of underlying probabilistic model. Someway the underlying probabilistic model of a codification schema accounts for a tendency of the schema to represent solutions in some region of the search space. We report results from an experimental study showing that in many cases any of the new schemas results to be much more efficient than conventional ones due to the new schema tends to represent more promising solutions than the others. Unfortunately the selection in advance of the best schema for a given problem instance is not an easy problem and remains still open.

High frequency and reduced penetrance of LRRK2 G2019S mutation among Parkinson's disease patients in Cantabria (Spain).

The frequency and penetrance of the LRRK2 G2019S mutation varies considerably in different Parkinson disease (PD) populations. This information is essential both for clinical purposes and genetic counseling. The objective of this study was to estimate the prevalence and penetrance of the G2019S mutation of the LRRK2 gene in a small region in northern Spain (Cantabria). The G2019S mutation was tested in 367 consecutive patients with PD attended as outpatients in a tertiary Hospital in Northern Spain, and 126 at‐risk family members of probands were also investigated for G2019S mutation and disease status. The gene penetrance was estimated in terms of cumulative age‐specific incidence of PD by the Kaplan‐Meier method. Thirty‐two PD patients (8.7%) carried the G2019S mutation. Penetrance estimation of the G2019S mutation was 2% at 50 years, 12% at 60 years, 26% at 70 years, and 47% at 80 years. The frequency of the G2019S mutation of the LRRK2 gene in PD patients from Cantabria is among the highest reported so far after North African Arabs and Ashkenazi Jews. At the age of 80 years only one‐half of G2019S mutation carriers manifest motor symptoms of PD.

Genetic Variability Related to Serum Uric Acid Concentration and Risk of Parkinson's Disease

Low serum uric acid (UA) levels have been associated with increased Parkinsons disease (PD) risk and accelerated disease progression. We analyzed the effect of polymorphisms in 9 genes influencing serum UA concentration on the risk of PD.

Pruning by dominance in best-first search for the job shop Scheduling problem with total flow time

Best-First search is a problem solving paradigm that allows to design exact or admissible algorithms. In this paper, we confront the Job Shop Scheduling problem with total flow time minimization by means of the A* algorithm. We devised a heuristic from a problem relaxation that relies on computing Jackson’s preemptive schedules. In order to reduce the effective search space, we formalized a method for pruning nodes based on dominance relations and established a rule to apply this method efficiently during the search. By means of experimental study, we show that the proposed method is more efficient than a genetic algorithm in solving instances with 10 jobs and 5 machines and that pruning by dominance allows A* to reach optimal schedules, while these instances are not solved by A* otherwise. These experiments have also made it clear that the Job Shop Scheduling problem with total flow time minimization is harder to solve than the same problem with makespan minimization.

Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and GSK3β) on the risk of Parkinson’s disease

Background:  Oxidative stress is a central factor in the pathogenesis of Parkinson’s disease (PD). Heme oxygenase‐1 (HO‐1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase‐3β (GSK3β) activity. Underexpression of HO‐1 in concert with an upregulation of GSK3β would result in a less effective antioxidant response and might increase the risk of PD.

A genetic algorithm for robust berth allocation and quay crane assignment

Scheduling problems usually obtain the optimal solutions assuming that the environment is deterministic. However, actually the environment is dynamic and uncertain. Thus, the initial data could change and the initial schedule obtained might be unfeasible. To overcome this issue, a proactive approach is presented for scheduling problems without any previous knowledge about the incidences that can occur. In this paper, we consider the berth allocation problem and the quay crane assignment problem as a representative example of scheduling problems where a typical objective is to minimize the service time. The robustness is introduced within this problem by means of buffer times that should be maximized to absorb possible incidences or breakdowns. Therefore, this problem becomes a multi-objective optimization problem with two opposite objectives: minimizing the total service time and maximizing the robustness or buffer times.

Intensified iterative deepening A* with application to job shop scheduling

We propose a novel, exact any-time search strategy that combines iterative deepening