Dementia risk prediction in early Parkinson\u27s disease: Validation and genetic integration of the Montreal Parkinson risk of dementia scale (MoPaRDS)

Background: Prediction models for dementia in Parkinson disease (PD) are needed to better identify high-risk patients, but existing risk models often lack validation in early-stage PD, when prognosis is most challenging. Objective: This study aims to validate the Montreal Parkinson Risk of Dementia Scale (MoPaRDS) in six population-based cohorts of newly diagnosed PD and to evaluate if incorporating genetic factors (GBA1 and APOE-ε4) enhances its performance. Methods: We calculated MoPaRDS scores for 1108 newly diagnosed PD patients, and MoPaRDS + GBA1 + APOE for the 941 patients with complete genetic data. We assessed the scores\u27 performance in predicting dementia diagnosed over 10 years using time-dependent receiver operating characteristic (ROC) curves. Results: Of the 1108 patients (mean age 69.5 \ub1 10.0 years; 61.0% men), 350 (31.6%) developed dementia. The area under the time-dependent ROC curve (AUC) was 0.79 for MoPaRDS and 0.80 for MoPaRDS + GBA1 + APOE. Subdividing patients based on their MoPaRDS scores revealed annual observed risks of PDD of 39.4% (n = 8; high risk-), 11.4% (n = 176; intermediate risk-), and 5.0% (n = 942; low risk-group). With the suggested cutoff of ≥4, MoPaRDS had a sensitivity of 21.7% and specificity of 94.9%. Including the genetic items improved the sensitivity to 36.4% while maintaining comparable performance for specificity (91.5%). Conclusions: MoPaRDS demonstrates high specificity but limited sensitivity in early PD, highlighting that a one-size-fits-all approach is inadequate for predicting dementia risk in PD across different disease stages. Integrating genetic items increases sensitivity and identifies more newly diagnosed patients at higher risk of dementia, and may be a useful approach to assist dementia risk assessment in early-stage PD. Many people with Parkinson\u27s disease (PD) are at risk of developing dementia but predicting who will develop dementia early in the disease remains a challenge. Tools like the Montreal Parkinson Risk of Dementia Scale (MoPaRDS) aim to help identify patients at higher risk, but their accuracy in early-stage PD is not well established. This study tested the MoPaRDS tool in six large groups of newly diagnosed PD patients and explored whether adding genetic information (GBA1 and APOE-ε4 genes) could make predictions more accurate. The study included 1108 people with newly diagnosed PD, of whom 350 (31.6%) developed dementia within 10 years. MoPaRDS was highly specific, meaning it could reliably identify people who were unlikely to develop dementia. However, it had limited sensitivity, identifying only 22% of those who later developed dementia. Adding genetic data improved sensitivity to 36%, meaning more at-risk individuals were flagged without losing significant accuracy. Further, the MoPaRDS tool can be used to group patients into low, intermediate, and high-risk categories. Patients in the high-risk group had a 39% annual chance of developing dementia, compared to only 5% in the low-risk group. Adding genetic information improved the tool\u27s ability to identify more high-risk patients. These findings suggest that MoPaRDS is more appropriate for later-stage PD patients, and that incorporating genetic testing could improve existing tools for identifying those at higher risk of dementia, especially in the early stages of PD when intervention may be most beneficial. Such an approach could facilitate more tailored care for PD patients

Beta-adrenoceptor drugs and progression to Parkinson’s disease milestones in a large pooled incident cohort

\ua9 The Author(s) 2025.Beta-adrenoceptor-blockers and agonists have been associated with an increased and decreased risk of Parkinson’s disease (PD), respectively. We aimed to investigate whether these medications are linked to clinical heterogeneity and progression in PD. Longitudinal data from the Parkinson’s Incident Cohorts Collaboration (n = 1107) were analysed. Baseline clinical status and progression to Hoehn & Yahr stage 3 (H&Y3) or dementia were compared in beta-blocker or beta-agonist users versus non-users of each drug. Baseline motor and cognitive variables were similar in beta-blocker users (n = 195) versus non-users and beta-agonist users (n = 68) versus non-users, following adjustment for relevant confounders. Beta-blocker users (n = 156) progressed faster to H&Y3 (p = 0.002), accounting for relevant confounders (Hazard Ratio (HR) = 1.538; p = 0.011), while beta-agonist users (n = 54) progressed similarly to non-users. Neither drug was associated with progression to dementia. These findings support the possibility that beta-adrenoceptor drugs may have potential in modifying aspects of PD progression. Further investigation is essential to identify any causative component in the relationship

Low linkage disequilibrium in wild Anopheles gambiae s.l. populations

<p>Abstract</p> <p>Background</p> <p>In the malaria vector <it>Anopheles gambiae</it>, understanding diversity in natural populations and genetic components of important phenotypes such as resistance to malaria infection is crucial for developing new malaria transmission blocking strategies. The design and interpretation of many studies here depends critically on Linkage disequilibrium (LD). For example in association studies, LD determines the density of Single Nucleotide Polymorphisms (SNPs) to be genotyped to represent the majority of the genomic information. Here, we aim to determine LD in wild <it>An. gambiae s.l</it>. populations in 4 genes potentially involved in mosquito immune responses against pathogens (<it>Gambicin</it>, <it>NOS</it>, <it>REL2 </it>and <it>FBN9</it>) using previously published and newly generated sequences.</p> <p>Results</p> <p>The level of LD between SNP pairs in cloned sequences of each gene was determined for 7 species (or incipient species) of the <it>An. gambiae </it>complex. In all tested genes and species, LD between SNPs was low: even at short distances (< 200 bp), most SNP pairs gave an r²< 0.3. Mean r²ranged from 0.073 to 0.766. In most genes and species LD decayed very rapidly with increasing inter-marker distance.</p> <p>Conclusions</p> <p>These results are of great interest for the development of large scale polymorphism studies, as LD generally falls below any useful limit. It indicates that very fine scale SNP detection will be required to give an overall view of genome-wide polymorphism. Perhaps a more feasible approach to genome wide association studies is to use targeted approaches using candidate gene selection to detect association to phenotypes of interest.</p

Recombination Drives Vertebrate Genome Contraction

Selective and/or neutral processes may govern variation in DNA content and, ultimately, genome size. The observation in several organisms of a negative correlation between recombination rate and intron size could be compatible with a neutral model in which recombination is mutagenic for length changes. We used whole-genome data on small insertions and deletions within transposable elements from chicken and zebra finch to demonstrate clear links between recombination rate and a number of attributes of reduced DNA content. Recombination rate was negatively correlated with the length of introns, transposable elements, and intergenic spacer and with the rate of short insertions. Importantly, it was positively correlated with gene density, the rate of short deletions, the deletion bias, and the net change in sequence length. All these observations point at a pattern of more condensed genome structure in regions of high recombination. Based on the observed rates of small insertions and deletions and assuming that these rates are representative for the whole genome, we estimate that the genome of the most recent common ancestor of birds and lizards has lost nearly 20% of its DNA content up until the present. Expansion of transposable elements can counteract the effect of deletions in an equilibrium mutation model; however, since the activity of transposable elements has been low in the avian lineage, the deletion bias is likely to have had a significant effect on genome size evolution in dinosaurs and birds, contributing to the maintenance of a small genome. We also demonstrate that most of the observed correlations between recombination rate and genome contraction parameters are seen in the human genome, including for segregating indel polymorphisms. Our data are compatible with a neutral model in which recombination drives vertebrate genome size evolution and gives no direct support for a role of natural selection in this process

Differential diagnosis of perinatal hypophosphatasia: radiologic perspectives

Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies

The hydro-sedimentary system of the Upper-Normandy coast: synthesis

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