Disease-modifying effects of an structural variant in a predominantly ALS cohort.

Objective: To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 () familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.

Methods: Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (), a gene that is adjacent to , was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.

'Researchers have love for life': opportunities and barriers to engage pregnant women in malaria research in post-Ebola Liberia.

Background: Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials. In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria. Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population.

Characterization of and allele frequencies in the Japanese population.

Introduction: Dementia is one of the major health threats to our aging society, and Alzheimer's disease (AD) is the leading cause. In Japan, ∼15% of the elderly population has dementia. The apolipoprotein E () genotype and a polymorphism (rs10524523) in the translocase of outer mitochondrial membrane 40 () gene have been associated with the age of onset of AD.

Lower limbs venous compression reduces the incidence of maternal hypotension following epidural analgesia during term labor.

Objective(s): Every year in France, 10% to 20% of the 600 000 women given epidural analgesia during labor experience hypotension, which in 15% of cases is associated with fetal heart rate abnormalities. The efficiency of lower limbs venous compression in preventing the occurrence of maternal hypotension after neuraxial anesthesia has already been demonstrated, but only in the context of scheduled cesarean section. We assessed the preventive effect of medical lower limbs venous compression on the incidence of maternal hypotension after epidural analgesia during spontaneous term labor.

The biological foundation of the genetic association of TOMM40 with late-onset Alzheimer's disease.

A variable-length poly-T variant in intron 6 of the TOMM40 gene, rs10524523, is associated with risk and age-of-onset of sporadic (late-onset) Alzheimer's disease. In Caucasians, the three predominant alleles at this locus are Short (S), Long (L) or Very long (VL). On an APOE ε3/3 background, the S/VL and VL/VL genotypes are more protective than S/S.

APOE ε4-TOMM40 '523 haplotypes and the risk of Alzheimer's disease in older Caucasian and African Americans.

Patterns of linkage between the ε4 allele of Apolipoprotein E (APOE) and '523 poly-T alleles in the adjacent gene, TOMM40, differ between Caucasian and African Americans. The extent to which this difference affects the risk of Alzheimer's disease (AD) is unclear. We compared the APOE ε4-TOMM40 '523 haplotypes between older Caucasian and African Americans, and examined their relationship with AD dementia.

Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts.

Introduction: Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly-T length on memory decline.

Methods: For 912 nonapolipoprotein ε4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed.

'523 variant and cognitive decline in older persons with ε3/3 genotype.

Objective: To interrogate a poly-T variant (rs10524523, '523) in , a gene adjacent to the gene on chromosome 19, in older persons with ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).

Methods: Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years. and '523 genotypes were determined from DNA from blood or brain samples.

The effects of PPARγ on the regulation of the TOMM40-APOE-C1 genes cluster.

Chromosome 19q13.32 is a gene rich region, and has been implicated in multiple human phenotypes in adulthood including lipids traits, Alzheimer's disease, and longevity. Peroxisome Proliferator Activated Receptor Gamma (PPARγ) is a ligand-activated nuclear transcription factor that plays a role in human complex traits that are also genetically associated with the chromosome 19q13.

The SSV Evaluation System: A Tool to Prioritize Short Structural Variants for Studies of Possible Regulatory and Causal Variants.

Short structural variants (SSVs) are short genomic variants (<50 bp) other than SNPs. It has been suggested that SSVs contribute to many human complex traits. However, high-throughput analysis of SSVs presents numerous technical challenges.

Blood glucose levels and cortical thinning in cognitively normal, middle-aged adults.

Type II diabetes mellitus (DM) increases risk for cognitive decline and is associated with brain atrophy in older demented and non-demented individuals. We investigated (1) the cross-sectional association between fasting blood glucose level and cortical thickness in a sample of largely middle-aged, cognitively normal adults, and (2) whether these associations were modified by genes associated with both lipid processing and dementia. To explore possible modifications by genetic status, we investigated the interaction between blood glucose levels and the apolipoprotein E (APOE) ε4 allele and the translocase of the outer mitochondrial membrane (TOMM) 40 '523 genotype on cortical thickness.

Understanding the genetics of APOE and TOMM40 and role of mitochondrial structure and function in clinical pharmacology of Alzheimer's disease.

The methodology of Genome-Wide Association Screening (GWAS) has been applied for more than a decade. Translation to clinical utility has been limited, especially in Alzheimer's Disease (AD). It has become standard practice in the analyses of more than two dozen AD GWAS studies to exclude the apolipoprotein E (APOE) region because of its extraordinary statistical support, unique thus far in complex human diseases.

A Genetics-based Biomarker Risk Algorithm for Predicting Risk of Alzheimer's Disease.

Background: A straightforward, reproducible blood-based test that predicts age dependent risk of Alzheimer's disease (AD) could be used as an enrichment tool for clinical development of therapies. This study evaluated the prognostic performance of a genetics-based biomarker risk algorithm (GBRA) established on a combination of Apolipoprotein E (APOE)/Translocase of outer mitochondrial membrane 40 homolog (TOMM40) genotypes and age, then compare it to cerebrospinal fluid (CSF) biomarkers, neuroimaging and neurocognitive tests using data from two independent AD cohorts.

Methods: The GBRA was developed using data from the prospective Bryan-ADRC study (n=407; 86 conversion events (mild cognitive impairment (MCI) or late onset Alzheimer's disease (LOAD)).

New Genetic Approaches to AD: Lessons from APOE-TOMM40 Phylogenetics.

Clinical trials for Alzheimer's disease are now focusing on the earliest stages of the disease with the goal of delaying dementia onset. There is great utility in using genetic variants to identify individuals at high age-dependent risk when the goal is to begin treatment before the development of any cognitive symptoms. Genetic variants identified through large-scale genome-wide association studies have not substantially improved the accuracy provided by APOE genotype to identify people at high risk of late-onset Alzheimer's disease (LOAD).

Structural variants can be more informative for disease diagnostics, prognostics and translation than current SNP mapping and exon sequencing.

Introduction: In this article we discuss several human neurological diseases and their relationship to specific highly polymorphic small structural variants (SVs). Unlike genome-wide association analysis (GWAS), this methodology is not a genome screen to define new possibly associated genes, requiring statistical corrections for a million association tests. SVs provide local mapping information at a specific locus.

Polyallelic structural variants can provide accurate, highly informative genetic markers focused on diagnosis and therapeutic targets: Accuracy vs. Precision.

Structural variants (SVs) include all insertions, deletions, and rearrangements in the genome, with several common types of nucleotide repeats including single sequence repeats, short tandem repeats, and insertion-deletion length variants. Polyallelic SVs provide highly informative markers for association studies with well-phenotyped cohorts. SVs can influence gene regulation by affecting epigenetics, transcription, splicing, and/or translation.

CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

APOE/TOMM40 genetic loci, white matter hyperintensities, and cerebral microbleeds.

Background: Two markers of cerebral small vessel disease are white matter hyperintensities and cerebral microbleeds, which commonly occur in people with Alzheimer's disease.

Aim And/or Hypothesis: To test for independent associations between two Alzheimer's disease-susceptibility gene loci--APOE ε and the TOMM40 '523' poly-T repeat--and white matter hyperintensities/cerebral microbleed burden in community-dwelling older adults.

Methods: Participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε and TOMM40 523, and detailed structural brain magnetic resonance imaging at a mean age of 72·70 years (standard deviation = 0·7; range = 71-74).

A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression.

Introduction: We recently showed that tagging single-nucleotide polymorphisms across the SNCA locus were significantly associated with increased risk for Lewy body (LB) pathology in Alzheimer's disease (AD) cases. However, the actual genetic variant(s) that underlie the observed associations remain elusive.

Methods: We used a bioinformatics algorithm to catalog structural variants in a region of SNCA intron 4, followed by phased sequencing.

The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging.

Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD () is associated with risk and age-of onset of late-onset AD, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondria dysfunction. In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases.

Effects of low doses of pioglitazone on resting-state functional connectivity in conscious rat brain.

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be useful for treating or delaying the onset of Alzheimer's disease (AD), possibly via actions on mitochondria, and that dose strengths lower than those clinically used for T2DM may be efficacious. Our major objective was to determine if low doses of pioglitazone, administered orally, impacted brain activity.