A precision medicine initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling

After intense scientific exploration and more than a decade of failed trials, Alzheimer’s disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer’s Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials

Novel variation at chr11p13 associated with cystic fibrosis lung disease severity

Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF subjects, indicating a CFTR genotype-specific mechanism

Expression of genes for estrogen receptors α and β in human articular chondrocytes

AbstractObjective To investigate the gene expression of estrogen receptor (ER) α and ERβ in human articular chondrocytes.Methods 16 articular cartilage specimens were obtained from 15 patients during surgery. Three of the specimens were from men and 13 from women; three from hip joints and 13 from knee joints; four were normal and 12 showed osteoarthritic cartilage. Total RNA was extracted from the articular chondrocytes and the expression of both ERα and ERβ genes was investigated by the reverse transcription-polymerase chain reaction (RT-PCR) method.Results Gene expressions of ERα were detected in all specimens and those of ERβ were found in 15 specimens by the RT-PCR method. There was a significant correlation between the amounts of ERα and ERβ. Expression levels of both genes were significantly higher in men than in women. There were no significant differences in the expression levels of both ER genes between the hip and knee joint sites, nor between normal and osteoarthritic tissues.Conclusion This study is to our knowledge the first to demonstrate the gene expression of both ERα and ERβ in human articular chondrocytes. Since there are some functional differences between the two receptors, the effects of estrogen on cartilage metabolism should be elucidated by two different receptor mechanisms.{copy

Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685

PTX3 genetic variations affect the risk of Pseudomonas aeruginosa airway colonization in cystic fibrosis patients

Cystic fibrosis (CF) is a common life-threatening autosomal recessive disorder in the Caucasian population, and the gene responsible is the CF transmembrane conductance regulator (CFTR). Patients with CF have repeated bacterial infection of the airways caused by Pseudomonas aeruginosa (PA), which is one of the predominant pathogen, and endobronchial chronic infection represents a major cause of morbidity and mortality. Pentraxin 3 (PTX3) is a gene that encodes the antimicrobial protein, PTX3, which is believed to have an important role in innate immunity of lung. To address the role of PTX3 in the risk of PA lung colonization, we investigated five single nucleotide polymorphisms of PTX3 gene in 172 Caucasian CF patients who were homozygous for the F508del mutation. We observed that PTX3 haplotype frequencies were significantly different between patients with PA colonization, as compared with noncolonized patients. Moreover, a protective effect was found in association with a specific haplotype (odds ratio 0.524). Our data suggest that variations within PTX3 affect lung colonization of Pseudomonas in patients with CF

Clustering of Alzheimer's and Parkinson's disease based on genetic burden of shared molecular mechanisms

One of the visions of precision medicine has been to re-define disease taxonomies based on molecular characteristics rather than on phenotypic evidence. However, achieving this goal is highly challenging, specifically in neurology. Our contribution is a machine-learning based joint molecular subtyping of Alzheimer’s (AD) and Parkinson’s Disease (PD), based on the genetic burden of 15 molecular mechanisms comprising 27 proteins (e.g. APOE) that have been described in both diseases. We demonstrate that our joint AD/PD clustering using a combination of sparse autoencoders and sparse non-negative matrix factorization is reproducible and can be associated with significant differences of AD and PD patient subgroups on a clinical, pathophysiological and molecular level. Hence, clusters are disease-associated. To our knowledge this work is the first demonstration of a mechanism based stratification in the field of neurodegenerative diseases. Overall, we thus see this work as an important step towards a molecular mechanism-based taxonomy of neurological disorders, which could help in developing better targeted therapies in the future by going beyond classical phenotype based disease definitions

Glucocorticoid receptor gene polymorphisms associated with progression of lung disease in young patients with cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>The variability in the inflammatory burden of the lung in cystic fibrosis (CF) patients together with the variable effect of glucocorticoid treatment led us to hypothesize that <it>glucocorticoid receptor </it>(<it>GR</it>) gene polymorphisms may affect glucocorticoid sensitivity in CF and, consequently, may contribute to variations in the inflammatory response.</p> <p>Methods</p> <p>We evaluated the association between four <it>GR </it>gene polymorphisms, <it>TthIII</it>, <it>ER22/23EK</it>, <it>N363S </it>and <it>BclI</it>, and disease progression in a cohort of 255 young patients with CF. Genotypes were tested for association with changes in lung function tests, infection with <it>Pseudomonas aeruginosa </it>and nutritional status by multivariable analysis.</p> <p>Results</p> <p>A significant non-corrected for multiple tests association was found between <it>BclI </it>genotypes and decline in lung function measured as the forced expiratory volume in one second (FEV₁) and the forced vital capacity (FVC). Deterioration in FEV₁and FVC was more pronounced in patients with the <it>BclI </it>GG genotype compared to the group of patients with <it>BclI </it>CG and CC genotypes (p = 0.02 and p = 0.04 respectively for the entire cohort and p = 0.01 and p = 0.02 respectively for F508del homozygous patients).</p> <p>Conclusion</p> <p>The <it>BclI </it>polymorphism may modulate the inflammatory burden in the CF lung and in this way influence progression of lung function.</p

Parkinson's disease age at onset genome-wide association study : Defining heritability, genetic loci, and α-synuclein mechanisms

Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder SocietyPeer reviewe