Gain and loss of function of P2X7 receptors: Mechanisms, pharmacology and relevance to diabetic neuropathic pain

Background: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. Results: The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. Conclusions: Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson\u27s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design

Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans

INTRODUCTION: Genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) have been crucial in advancing the understanding of Alzheimer's disease (AD) pathophysiology. Here, we provide an update on sample collection, scientific progress and opportunities, conceptual issues, and future plans. METHODS: Lymphoblastoid cell lines and DNA and RNA samples from blood have been collected and banked, and data and biosamples have been widely disseminated. To date, APOE genotyping, genome-wide association study (GWAS), and whole exome and whole genome sequencing data have been obtained and disseminated. RESULTS: ADNI genetic data have been downloaded thousands of times, and >300 publications have resulted, including reports of large-scale GWAS by consortia to which ADNI contributed. Many of the first applications of quantitative endophenotype association studies used ADNI data, including some of the earliest GWAS and pathway-based studies of biospecimen and imaging biomarkers, as well as memory and other clinical/cognitive variables. Other contributions include some of the first whole exome and whole genome sequencing data sets and reports in healthy controls, mild cognitive impairment, and AD. DISCUSSION: Numerous genetic susceptibility and protective markers for AD and disease biomarkers have been identified and replicated using ADNI data and have heavily implicated immune, mitochondrial, cell cycle/fate, and other biological processes. Early sequencing studies suggest that rare and structural variants are likely to account for significant additional phenotypic variation. Longitudinal analyses of transcriptomic, proteomic, metabolomic, and epigenomic changes will also further elucidate dynamic processes underlying preclinical and prodromal stages of disease. Integration of this unique collection of multiomics data within a systems biology framework will help to separate truly informative markers of early disease mechanisms and potential novel therapeutic targets from the vast background of less relevant biological processes. Fortunately, a broad swath of the scientific community has accepted this grand challenge

Genetic analysis of quantitative phenotypes in AD and MCI: imaging, cognition and biomarkers

The Genetics Core of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), formally established in 2009, aims to provide resources and facilitate research related to genetic predictors of multidimensional Alzheimer’s disease (AD)-related phenotypes. Here, we provide a systematic review of genetic studies published between 2009 and 2012 where either ADNI APOE genotype or genome-wide association study (GWAS) data were used. We review and synthesize ADNI genetic associations with disease status or quantitative disease endophenotypes including structural and functional neuroimaging, fluid biomarker assays, and cognitive performance. We also discuss the diverse analytical strategies used in these studies, including univariate and multivariate analysis, meta-analysis, pathway analysis, and interaction and network analysis. Finally, we perform pathway and network enrichment analyses of these ADNI genetic associations to highlight key mechanisms that may drive disease onset and trajectory. Major ADNI findings included all the top 10 AD genes and several of these (e.g., APOE, BIN1, CLU, CR1, and PICALM) were corroborated by ADNI imaging, fluid and cognitive phenotypes. ADNI imaging genetics studies discovered novel findings (e.g., FRMD6) that were later replicated on different data sets. Several other genes (e.g., APOC1, FTO, GRIN2B, MAGI2, and TOMM40) were associated with multiple ADNI phenotypes, warranting further investigation on other data sets. The broad availability and wide scope of ADNI genetic and phenotypic data has advanced our understanding of the genetic basis of AD and has nominated novel targets for future studies employing next-generation sequencing and convergent multi-omics approaches, and for clinical drug and biomarker development. Electronic supplementary material The online version of this article (doi:10.1007/s11682-013-9262-z) contains supplementary material, which is available to authorized users

Genome-wide association study of rate of cognitive decline in Alzheimer’s Disease patients identifies novel genes and pathways

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD. Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes. Results: Suggestive associations (P < 1.0 × 10-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10-7 ), chromosome 7 (rs60465337,P = 4.06 × 10-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10-7 ) and 4 (rs1304013, P = 7.73 × 10-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified. Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact

Using Clinical Scales and Digital Measures to Explore Falls in Patients with Lewy Body Dementia

Introduction: PRESENCE was a phase 2 clinical trial assessing the efficacy of mevidalen, a D1 receptor positive allosteric modulator, for symptomatic treatment of Lewy body dementia (LBD). Mevidalen demonstrated improvements in motor and non-motor features of LBD, global functioning, and actigraphy-measured activity and daytime sleep. Adverse events (AEs) of fall were numerically increased in mevidalen-treated participants. Methods: A subset of PRESENCE participants wore a wrist actigraphy device for 2-week periods pre-, during, and posttreatment. Actigraphy sleep and activity measures were derived per period and analyzed to assess for their association with participants’ reports of an AE of fall. Prespecified baseline and treatment-emergent clinical characteristics were also included in the retrospective analysis of falls. Independent-samples t test and χ2 test were performed to compare the means and proportions between individuals with/without falls. Results: A trend toward more falls was observed with mevidalen treatment (31/258 mevidalen-treated vs. 4/86 in placebo-treated participants: p = 0.12). Higher body mass index (BMI) (p &lt; 0.05), more severe disease measured by baseline Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part II (p &lt; 0.05), and a trend toward improved Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) (p = 0.06) were associated with individuals with falls. No statistically significant associations with falls and treatment-emergent changes were observed. Conclusion: The association of falls with worse baseline disease severity and higher BMI and overall trend toward improvements on cognitive and motor scales suggest that falls in PRESENCE may be related to increased activity in mevidalen-treated participants at greater risk for falling. Future studies to confirm this hypothesis using fall diaries and digital assessments are necessary

Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia

This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients. Caucasian T/T homozygous patients showed significantly (p ≤ 0.05) greater improvement in Positive and Negative Syndrome Scale (PANSS) total scores during treatment with pomaglumetad methionil 40 mg twice daily compared to A/A homozygous patients. Additionally, T/T homozygous patients receiving pomaglumetad methionil had significantly (p ≤ 0.05) greater improvements in PANSS total scores compared to placebo and similar improvements as T/T homozygous patients receiving standard-of-care (SOC) treatment. The findings reported here in conjunction with prior reports show that in Caucasian patients with schizophrenia, the T/T genotype at rs7330461 is consistently associated with an increased treatment response to pomaglumetad methionil compared to the A/A genotype

Calibrating longitudinal cognition in Alzheimer's disease across diverse test batteries and datasets

Background: We sought to identify optimal approaches by calibrating longitudinal cognitive performance across studies with different neuropsychological batteries. Methods: We examined four approaches to calibrate cognitive performance in nine longitudinal studies of Alzheimer's disease (AD) (n = 10,875): (1) common test, (2) standardize and average available tests, (3) confirmatory factor analysis (CFA) with continuous indicators, and (4) CFA with categorical indicators. To compare precision, we determined the minimum sample sizes needed to detect 25% cognitive decline with 80% power. To compare criterion validity, we correlated cognitive change from each approach with 6-year changes in average cortical thickness and hippocampal volume using available MRI data from the AD Neuroimaging Initiative. Results: CFA with categorical indicators required the smallest sample size to detect 25% cognitive decline with 80% power (n = 232) compared to common test (n = 277), standardize-and-average (n = 291), and CFA with continuous indicators (n = 315) approaches. Associations with changes in biomarkers changes were the strongest for CFA with categorical indicators. Conclusions: CFA with categorical indicators demonstrated greater power to detect change and superior criterion validity compared to other approaches. It has wide applicability to directly compare cognitive performance across studies, making it a good way to obtain operational phenotypes for genetic analyses of cognitive decline among people with AD. i 2014 S. Karger AG, Base