Scholars@Duke
Michael William Lutz

Michael William Lutz

Professor in Neurology
Neurology, Behavioral Neurology
michael.lutz@duke.edu
Box 2900, Durham, NC 27710
311 Research Drive, Room 201-D, Durham, NC 27710

Selected Publications

Single-nucleus multi-omics of Parkinson's disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks.

Journal Article Acta Neuropathol Commun · July 2, 2024 The genetic architecture of Parkinson's disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression of the disease. Here we aimed to advance our understanding of PD genetic complexity at a cell subtype precisi ... Full text Link to item Cite

Facilitation of motor evoked potentials after tetanic peripheral nerve stimulation.

Journal Article Clin Neurophysiol · June 2024 OBJECTIVE: Tetanic stimulation of a peripheral nerve prior to transcranial electrical stimulation (TES) may enhance motor evoked potential (MEP) amplitudes. The purpose of this study was to investigate the post-tetanic MEP (p-MEP) technique in improving ME ... Full text Link to item Cite

Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease

Journal Article Alzheimer's and Dementia: Translational Research and Clinical Interventions · January 1, 2024 INTRODUCTION: Phase 3 trials using the anti-amyloid antibodies aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease dementia were heterogeneous in respect to statistical significance of effects. However, he ... Full text Cite

Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants.

Journal Article Alzheimers Dement · September 2023 BACKGROUND: Short structural variants (SSVs), including insertions/deletions (indels), are common in the human genome and impact disease risk. The role of SSVs in late-onset Alzheimer's disease (LOAD) has been understudied. In this study, we developed a bi ... Full text Link to item Cite

Exploratory Assessment of Proteomic Network Changes in Cerebrospinal Fluid of Mild Cognitive Impairment Patients: A Pilot Study.

Journal Article Biomolecules · July 8, 2023 (1) Background: Despite the existence of well-established, CSF-based biomarkers such as amyloid-β and phosphorylated-tau, the pathways involved in the pathophysiology of Alzheimer's disease (AD) remain an active area of research. (2) Methods: We measured 3 ... Full text Link to item Cite

Clenbuterol Treatment Is Safe and Associated With Slowed Disease Progression in a Small Open-Label Trial in Patients With Amyotrophic Lateral Sclerosis.

Journal Article J Clin Neuromuscul Dis · June 1, 2023 OBJECTIVE: Clenbuterol, a beta-agonist, has plausible mechanisms for treating amyotrophic lateral sclerosis (ALS). In this highly inclusive open-label trial (NCT04245709), we aimed to study the safety and efficacy of clenbuterol in patients with ALS. METHO ... Full text Link to item Cite

The Duke Myasthenia Gravis Clinic Registry: II. Analysis of outcomes.

Conference Muscle Nerve · April 2023 INTRODUCTION/AIMS: The Duke Myasthenia Gravis (MG) Clinic Registry contains comprehensive physician-derived data on patients with MG seen in the Duke MG Clinic since 1980. The aim of this study was to report outcomes in patients seen in the clinic and trea ... Full text Link to item Cite

Study of "ALS reversals": LifeTime environmental exposures (StARLiTE).

Journal Article Amyotroph Lateral Scler Frontotemporal Degener · February 2023 We previously reported on a series of patients diagnosed with ALS whom had an extraordinary course defined by substantial and sustained improvement in weakness and function. For this study, twenty-five of these "ALS Reversals" completed extensive environme ... Full text Link to item Cite

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

Journal Article Mov Disord · January 2023 BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to th ... Full text Open Access Link to item Cite

Neuromyelitis optica: Clinical course and potential prognostic indicators.

Journal Article Mult Scler Relat Disord · January 2023 BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neurological disorder associated with antibodies to aquaporin-4 (AQP4). NMOSD has been thought to follow a progressive disease course, with step-wise accumulation of disability ... Full text Open Access Link to item Cite

Novel Genetic Variants in TP37, PIK3R1, CALM1, and PLCG2 of the Neurotrophin Signaling Pathway Are Associated with the Progression from Mild Cognitive Impairment to Alzheimer's Disease.

Journal Article J Alzheimers Dis · 2023 BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease and mild cognitive impairment (MCI) is considered as the prodromal stage of AD. Previous studies showed that changes in the neurotrophin signaling pathway could lead to cognitive de ... Full text Open Access Link to item Cite

Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

Journal Article J Prev Alzheimers Dis · 2023 BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APO ... Full text Open Access Link to item Cite

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease: Presentation and outcomes of adults at a single center.

Journal Article J Neuroimmunol · December 15, 2022 BACKGROUND/INTRODUCTION: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a chronic demyelinating disorder that has been increasingly recognized since the serum antibody became commercially available in 2017. The most common clini ... Full text Open Access Link to item Cite

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients.

Journal Article Biomolecules · November 12, 2022 Depression is common among late-onset Alzheimer's Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to ... Full text Link to item Cite

A Bayesian perspective on Biogen's aducanumab trial.

Journal Article Alzheimers Dement · November 2022 This perspective is a companion to a recent editorial on the use of Bayesian analysis in clinical research. We aim to introduce and highlight the relevance and advantages that Bayesian inference offers to clinical trials using the data on the amyloid antib ... Full text Link to item Cite

Clinical research in dementia: A perspective on implementing innovation.

Journal Article Alzheimers Dement · November 2022 The increasing global prevalence of dementia demands concrete actions that are aimed strategically at optimizing processes that drive clinical innovation. The first step in this direction requires outlining hurdles in the transition from research to practi ... Full text Link to item Cite

Genetic Association Between Epigenetic Aging-Acceleration and the Progression of Mild Cognitive Impairment to Alzheimer's Disease.

Journal Article J Gerontol A Biol Sci Med Sci · September 1, 2022 Alzheimer's disease (AD) is a progressive neurodegenerative disorder, and previous studies have shown its association with accelerated aging. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) that contributed to aging acceleration ... Full text Open Access Link to item Cite

Motor Evoked Potentials Double Train Stimulation: Optimal Number of Pulses per Train.

Journal Article J Clin Neurophysiol · July 1, 2022 PURPOSE: In neurophysiologic intraoperative monitoring, double train transcranial electrical stimulation (dt-TES) for motor evoked potentials (MEP) consists of an initial, facilitating train of stimuli followed by a second, testing, train. The optimal numb ... Full text Link to item Cite

APOE, TOMM40, and sex interactions on neural network connectivity.

Journal Article Neurobiol Aging · January 2022 The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in AD. TOMM40 rs ... Full text Link to item Cite

Bioinformatics pipeline to guide late-onset Alzheimer's disease (LOAD) post-GWAS studies: Prioritizing transcription regulatory variants within LOAD-associated regions.

Journal Article Alzheimers Dement (N Y) · 2022 INTRODUCTION: As new late-onset Alzheimer's disease (LOAD) genetic risk loci are identified and brain cell-type specific omics data becomes available, there is an unmet need for a bioinformatics framework to prioritize genes and variants for testing in sin ... Full text Link to item Cite

Polygenic Risk Score Effectively Predicts Depression Onset in Alzheimer's Disease Based on Major Depressive Disorder Risk Variants.

Journal Article Front Neurosci · 2022 INTRODUCTION: Depression is a common, though heterogenous, comorbidity in late-onset Alzheimer's Disease (LOAD) patients. In addition, individuals with depression are at greater risk to develop LOAD. In previous work, we demonstrated shared genetic etiolog ... Full text Open Access Link to item Cite

APOE, TOMM40, and Sex Interactions on Neural Network Connectivity.

Journal Article Alzheimers Dement · December 2021 BACKGROUND: The Apolipoprotein E ε4 (APOE ε4) haplotype is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The Translocase of Outer Mitochondrial Membrane-40 (TOMM40) gene maintains cellular bioenergetics, which is disrupted in A ... Full text Link to item Cite

Analysis of pleiotropic genetic effects on cognitive decline and systemic inflammation in the Women's Health Initiative Memory Study

Journal Article Alzheimer's & dementia : the journal of the Alzheimer's Association · December 1, 2021 BACKGROUND: SNPs associated with C-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease (AD) risk SNPs. Previously, we reported pleiotropic effects between SNPs associated with cognitive impairment ... Full text Cite

Bioinformatics pipeline to advance the identification of transcription regulatory variants in LOAD noncoding regions

Journal Article Alzheimer's & dementia : the journal of the Alzheimer's Association · December 1, 2021 BACKGROUND: As new LOAD genetic risk loci are identified and more brain cell-type specific omics data becomes available, there is an unmet need for a bioinformatics framework to prioritize genes and variants for testing in single-cell molecular profiling e ... Full text Cite

Socioeconomic Influence on Emergency Medical Services Utilization for Acute Stroke: Think Nationally, Act Locally.

Journal Article Neurohospitalist · October 2021 BACKGROUND AND PURPOSE: Rates of emergency medical services (EMS) utilization for acute stroke remain low nationwide, despite the time-sensitive nature of the disease. Prior research suggests several demographic and social factors are associated with EMS u ... Full text Link to item Cite

Anticoagulation after Spontaneous Intraparenchymal Hemorrhage in Patients with Mechanical Heart Valves and Concomitant Atrial Fibrillation

Journal Article Journal of Neuroanaesthesiology and Critical Care · September 1, 2021 Aim Patients with mechanical heart valves and coexisting atrial fibrillation (AFib-MHV) who suffer an intraparenchymal hemorrhage (IPH, defined as bleeding solely within the brain parenchyma and/or ventricle) are at a high risk of thromboembolism without a ... Full text Cite

TOMM40-APOE haplotypes are associated with cognitive decline in non-demented Blacks.

Journal Article Alzheimers Dement · August 2021 INTRODUCTION: The goal was to investigate effects of APOE-TOMM40-'523 haplotypes on cognitive decline in non-demented non-Hispanic Blacks (NHB), and determine whether effects differ from non-Hispanic Whites (NHW). METHODS: The impact of zero to two copies ... Full text Link to item Cite

Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial.

Journal Article Lancet Neurol · July 2021 BACKGROUND: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify par ... Full text Link to item Cite

Interaction between APOE ε4 and dietary protein intake on cognitive decline: A longitudinal cohort study.

Journal Article Clin Nutr · May 2021 OBJECTIVE: To exam the association of cognitive decline with APOE ε4 allele carriage and dietary protein intake and investigate whether there is a gene-diet (GxD) interaction of APOE ε4 allele carriage and dietary protein intake on cognitive decline in a n ... Full text Link to item Cite

A Triage Model for Interhospital Transfers of Low Risk Intracerebral Hemorrhage Patients.

Journal Article J Stroke Cerebrovasc Dis · April 2021 OBJECTIVES: Intracerebral hemorrhage comprises a large proportion of inter-hospital transfers to comprehensive stroke centers from centers without comprehensive stroke center resources despite lack of mortality benefit and low comprehensive stroke center r ... Full text Link to item Cite

Likelihood ratio statistics for gene set enrichment in Alzheimer's disease pathways.

Journal Article Alzheimers Dement · April 2021 INTRODUCTION: The study of Alzheimer's disease (AD) has revealed biological pathways with implications for disease neuropathology and pathophysiology. These pathway-level effects may also be mediated by individual characteristics or covariates such as age ... Full text Link to item Cite

Characteristics of strokes associated with centrifugal flow left ventricular assist devices.

Journal Article Sci Rep · January 18, 2021 Stroke is a devastating complication of left ventricular assist device (LVAD) therapy. Understanding the characteristics, risk factors and outcomes of strokes associated with the centrifugal flow LVADs is important to devise better strategies for managemen ... Full text Link to item Cite

APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.

Journal Article J Alzheimers Dis · 2021 BACKGROUND: APOE4 has been hypothesized to increase Alzheimer's disease risk by increasing neuroinflammation, though the specific neuroinflammatory pathways involved are unclear. OBJECTIVE: Characterize cerebrospinal fluid (CSF) proteomic changes related t ... Full text Link to item Cite

Leisure Activities, APOE ε4, and Cognitive Decline: A Longitudinal Cohort Study.

Journal Article Front Aging Neurosci · 2021 Background: Both leisure activities and the ε4 allele of the apolipoprotein E (APOE ε4) have been shown to affect cognitive health. We aimed to determine whether engagement in leisure activities protects against APOE ε4-related cognitive decline. Methods: ... Full text Link to item Cite

Association Between Polygenic Risk Score and the Progression from Mild Cognitive Impairment to Alzheimer's Disease.

Journal Article J Alzheimers Dis · 2021 BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer's disease (AD). OBJECTIVE: In this study, we aim to evaluate the associations between polygenic risk ... Full text Open Access Link to item Cite

Genetic and non-genetic factors associated with the phenotype of exceptional longevity & normal cognition.

Journal Article Sci Rep · November 5, 2020 In this study, we split 2156 individuals from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) data into two groups, establishing a phenotype of exceptional longevity & normal cognition versus cognitive impairment. We conducted a genome-wide assoc ... Full text Link to item Cite

The association between neighborhood socioeconomic status, cardiovascular and cerebrovascular risk factors, and cognitive decline in the Health and Retirement Study (HRS).

Journal Article Aging Ment Health · September 2020 Background: A small but growing body of evidence supports a relationship between neighborhood socioeconomic status (NSES) and cognitive decline. Additional work is needed to characterize this relationship controlling for risk factors such as cardiovascular ... Full text Link to item Cite

Shared genetic etiology underlying late-onset Alzheimer's disease and posttraumatic stress syndrome.

Journal Article Alzheimers Dement · September 2020 INTRODUCTION: Late-onset Alzheimer's disease (LOAD) manifests comorbid neuropsychiatric symptoms and posttraumatic stress disorder (PTSD) is associated with an increased risk for dementia in late life, suggesting the two disorders may share genetic etiolog ... Full text Open Access Link to item Cite

Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort.

Journal Article Neurol Genet · August 2020 OBJECTIVE: To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and ... Full text Link to item Cite

Investigating Predictors of Cognitive Decline Using Machine Learning.

Journal Article J Gerontol B Psychol Sci Soc Sci · March 9, 2020 OBJECTIVES: Genetic risks for cognitive decline are not modifiable; however their relative importance compared to modifiable factors is unclear. We used machine learning to evaluate modifiable and genetic risk factors for Alzheimer's disease (AD), to predi ... Full text Link to item Cite

Shared genetic etiology underlying Alzheimer's disease and major depressive disorder.

Journal Article Transl Psychiatry · March 9, 2020 Patients with late-onset Alzheimer's disease (LOAD) frequently manifest comorbid neuropsychiatric symptoms with depression and anxiety being most frequent, and individuals with major depressive disorder (MDD) have an increased prevalence of LOAD. This sugg ... Full text Link to item Cite

Analysis of pleiotropic genetic effects on cognitive impairment, systemic inflammation, and plasma lipids in the Health and Retirement Study.

Journal Article Neurobiol Aging · August 2019 Variants associated with modulation of c-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease risk variants. We examined pleiotropic genetic effects on cognitive impairment conditioned on genetic va ... Full text Link to item Cite

Bioinformatics strategy to advance the interpretation of Alzheimer's disease GWAS discoveries: The roads from association to causation.

Journal Article Alzheimers Dement · August 2019 INTRODUCTION: Genome-wide association studies (GWAS) discovered multiple late-onset Alzheimer's disease (LOAD)-associated SNPs and inferred the genes based on proximity; however, the actual causal genes are yet to be identified. METHODS: We defined LOAD-GW ... Full text Link to item Cite

A systems-based model of Alzheimer's disease.

Journal Article Alzheimers Dement · January 2019 The new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease has been developed to accelerate drug discovery and offer a common structure and language to construct new Alzheimer's disease conceptual models. ... Full text Link to item Cite

The TOMMORROW study: Design of an Alzheimer's disease delay-of-onset clinical trial.

Journal Article Alzheimers Dement (N Y) · 2019 INTRODUCTION: Alzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expres ... Full text Link to item Cite

Sex Differences in Genetic Associations With Longevity.

Journal Article JAMA Netw Open · August 2018 IMPORTANCE: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. OBJECTIVE: To explore sex differences in genetic associations with longevity. DESIGN ... Full text Link to item Cite

The correlation of copy number variations with longevity in a genome-wide association study of Han Chinese.

Journal Article Aging (Albany NY) · June 5, 2018 Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individ ... Full text Link to item Cite

A prognostic model of Alzheimer's disease relying on multiple longitudinal measures and time-to-event data.

Journal Article Alzheimers Dement · May 2018 INTRODUCTION: Characterizing progression in Alzheimer's disease is critically important for early detection and targeted treatment. The objective was to develop a prognostic model, based on multivariate longitudinal markers, for predicting progression-free ... Full text Open Access Link to item Cite

The effects of the TOMM40 poly-T alleles on Alzheimer's disease phenotypes.

Journal Article Alzheimers Dement · May 2018 The TOMM40 poly-T is a polymorphism in intron 6 of the TOMM40 gene, which is adjacent to and in linkage disequilibrium with APOE. Roses et al. identified the association between the length of TOMM40 poly-T with the risk and age of onset of late-onset Alzhe ... Full text Link to item Cite

Neighborhoods, sleep quality, and cognitive decline: Does where you live and how well you sleep matter?

Journal Article Alzheimers Dement · April 2018 INTRODUCTION: We evaluated the association between neighborhood socioeconomic status (NSES) and sleep quality on cognitive decline in the Health and Retirement Study. METHODS: Health and Retirement Study participants (n = 8090), aged 65+ with DNA and multi ... Full text Link to item Cite

Neuropathologic features of TOMM40 '523 variant on late-life cognitive decline.

Journal Article Alzheimers Dement · December 2017 INTRODUCTION: The study investigated the role of neuropathologies in the relationship between TOMM40 '523 genotype and late-life cognitive decline. METHODS: Participants were community-dwelling older persons who had annual cognitive assessments and brain a ... Full text Link to item Cite

Genetic analysis of α-synuclein 3' untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies.

Journal Article Alzheimers Dement · November 2017 INTRODUCTION: The α-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: A computational analysis of SNCA 3' untranslated region to identify potential microRNA (miRNA) binding s ... Full text Link to item Cite

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

Journal Article Alzheimers Dement · November 2017 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 non ... Full text Link to item Cite

Characterization of APOE and TOMM40 allele frequencies in the Japanese population.

Journal Article Alzheimers Dement (N Y) · November 2017 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 (APOE) genotype and a polymorphism (rs10524523) i ... Full text Link to item Cite

The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease.

Journal Article Alzheimers Dement · July 2017 It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced a ... Full text Open Access Link to item Cite

TOMM40'523 variant and cognitive decline in older persons with APOE ε3/3 genotype.

Journal Article Neurology · February 14, 2017 OBJECTIVE: To interrogate a poly-T variant (rs10524523, '523) in TOMM40, a gene adjacent to the APOE gene on chromosome 19, in older persons with APOE ε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD) ... Full text Link to item Cite

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

Journal Article PLoS One · 2017 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 u ... Full text Link to item Cite

Towards precision medicine in Alzheimer's disease: deciphering genetic data to establish informative biomarkers.

Journal Article Expert Rev Precis Med Drug Dev · 2017 INTRODUCTION: Developing biomarker tools for identification of individuals at high-risk for late-onset Alzheimer's disease (LOAD) is important for prognosis and early treatment. This review focuses on genetic factors and their potential role for precision ... Full text Link to item Cite

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

Journal Article Hum Mutat · September 2016 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. In order to fac ... Full text Link to item Cite

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

Journal Article J Neurol Sci · June 15, 2016 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 th ... Full text Link to item Cite

Interaction Between the FOXO1A-209 Genotype and Tea Drinking Is Significantly Associated with Reduced Mortality at Advanced Ages.

Journal Article Rejuvenation Res · June 2016 On the basis of the genotypic/phenotypic data from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Cox proportional hazard model, the present study demonstrates that interactions between carrying FOXO1A-209 genotypes and tea drinking are signific ... Full text Open Access Link to item Cite

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

Journal Article Alzheimers Dement · June 2016 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 ... Full text Link to item Cite

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

Journal Article Curr Neurol Neurosci Rep · May 2016 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 ... Full text Link to item Cite

Novel loci and pathways significantly associated with longevity.

Journal Article Sci Rep · February 25, 2016 Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a gen ... Full text Open Access Link to item Cite

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

Journal Article Expert Opin Drug Metab Toxicol · 2016 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 d ... Full text Link to item Cite

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

Journal Article Alzheimers Dement (N Y) · January 1, 2016 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 geneti ... Full text Link to item Cite

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

Journal Article Int J Stroke · December 2015 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' ... Full text Link to item Cite

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.

Journal Article Alzheimers Dement · October 2015 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) tha ... Full text Link to item Cite

Effect of APOE and CD33 on Cognitive Decline.

Journal Article PLoS One · 2015 OBJECTIVE: An Alzheimer's disease (AD) diagnosis is preceded by a long period of cognitive decline. We previously demonstrated increased risk of decline among individuals possessing one or more APOE ε4 alleles together with a family history of AD. The obje ... Full text Link to item Cite

African-American TOMM40'523-APOE haplotypes are admixture of West African and Caucasian alleles.

Journal Article Alzheimers Dement · November 2014 BACKGROUND: Several studies have demonstrated a lower apolipoprotein E4 (APOE ε4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40'523 (Translocase of ... Full text Link to item Cite

The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging.

Journal Article J Parkinsons Dis Alzheimers Dis · November 2014 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 k ... Full text Link to item Cite

Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?

Journal Article Transl Psychiatry · September 23, 2014 Genetic polymorphisms in the APOE ɛ and TOMM40 '523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, an ... Full text Link to item Cite

The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.

Journal Article Hum Mol Genet · September 15, 2014 The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's dis ... Full text Link to item Cite

The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes.

Journal Article Alzheimers Dement · September 2014 BACKGROUND: We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) t ... Full text Link to item Cite

The TOMM40 poly-T rs10524523 variant is associated with cognitive performance among non-demented elderly with type 2 diabetes.

Journal Article Eur Neuropsychopharmacol · September 2014 The variable length poly-T, rs10524523 ('523') located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to t ... Full text Link to item Cite

Alzheimer's disease susceptibility genes APOE and TOMM40, and brain white matter integrity in the Lothian Birth Cohort 1936.

Journal Article Neurobiol Aging · June 2014 Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 ("523") variable length poly-T repeat polymor ... Full text Link to item Cite

New applications of disease genetics and pharmacogenetics to drug development.

Journal Article Curr Opin Pharmacol · February 2014 TOMMORROW is a Phase III delay of onset clinical trial to determine whether low doses of pioglitazone, a molecule that induces mitochondrial doubling, delays the onset of MCI-AD in normal subjects treated with low dose compared to placebo. BOLD imaging stu ... Full text Link to item Cite

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Journal Article Mol Psychiatry · January 2014 Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five coho ... Full text Link to item Cite

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms.

Journal Article Neuromuscul Disord · December 2013 A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer's disease an ... Full text Link to item Cite

TOMM40 and APOE: Requirements for replication studies of association with age of disease onset and enrichment of a clinical trial.

Journal Article Alzheimers Dement · March 2013 A number of recent studies have not replicated the association of the translocase of the outer mitochondrial membrane pore subunit (TOMM40) rs10524523 polymorphism, which is in linkage disequilibrium with apolipoprotein E (APOE), with age of onset of Alzhe ... Full text Link to item Cite

Using genetics to enable studies on the prevention of Alzheimer's disease.

Journal Article Clin Pharmacol Ther · February 2013 Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, t ... Full text Link to item Cite

Alzheimer's disease susceptibility genes APOE and TOMM40, and hippocampal volumes in the Lothian birth cohort 1936.

Journal Article PLoS One · 2013 The APOE ε and TOMM40 rs10524523 ('523') variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer's disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly ... Full text Link to item Cite

Clinical Trials of AD Delay of Onset: Enrichment by a Prognostic Genetic Biomarker

Book · January 1, 2013 Modern medicine is shifting its focus to predictive and preventive healthcare utilization. To support this change, early intervention clinical trials that delay the onset of symptomatic disease must be conducted in a safe and cost-effective manner, and wit ... Full text Cite

Longitudinal modeling of cognitive aging and the TOMM40 effect.

Journal Article Alzheimers Dement · November 2012 BACKGROUND: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be a ... Full text Link to item Cite

A homopolymer polymorphism in the TOMM40 gene contributes to cognitive performance in aging.

Journal Article Alzheimers Dement · September 2012 INTRODUCTION: A highly polymorphic T homopolymer was recently found to be associated with late-onset Alzheimer's disease risk and age of onset. OBJECTIVE: To explore the effects of the polymorphic polyT tract (rs10524523, referred as '523') on cognitive pe ... Full text Link to item Cite

Levels of cerebrospinal fluid neurofilament light protein in healthy elderly vary as a function of TOMM40 variants.

Journal Article Exp Gerontol · May 2012 Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to cont ... Full text Link to item Cite

Cerebrospinal fluid cortisol concentrations in healthy elderly are affected by both APOE and TOMM40 variants.

Journal Article Psychoneuroendocrinology · March 2012 Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been reported in subjects with Alzheimer's disease (AD) and may include increased cerebrospinal fluid (CSF) cortisol concentrations. Moreover, presence of the APOE ɛ4 allele, which is an e ... Full text Link to item Cite

Characterization of the poly-T variant in the TOMM40 gene in diverse populations.

Journal Article PLoS One · 2012 We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined f ... Full text Link to item Cite

The effect of TOMM40 poly-T length on gray matter volume and cognition in middle-aged persons with APOE ε3/ε3 genotype.

Journal Article Alzheimers Dement · July 2011 OBJECTIVE: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of th ... Full text Link to item Cite

The importance of being connected.

Journal Article J Alzheimers Dis · 2011 Full text Link to item Cite

A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.

Journal Article Pharmacogenomics J · October 2010 The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T ... Full text Link to item Cite

Alzheimer's disease: diagnostics, prognostics and the road to prevention.

Journal Article EPMA J · June 2010 Alzheimer's disease (AD) presents one of the leading healthcare challenges of the 21st century, with a projected worldwide prevalence of >107 million cases by 2025. While biomarkers have been identified, which may correlate with disease progression or subt ... Full text Link to item Cite

Genetic variation at a single locus and age of onset for Alzheimer's disease.

Journal Article Alzheimers Dement · March 2010 This perspective article provides an opportunity to explain a new genetic finding for late-onset Alzheimer's disease (LOAD). It is specifically written for physicians and scientists who are interested in LOAD, but it may be relevant to those interested in ... Full text Link to item Cite

Peak alignment of urine NMR spectra using fuzzy warping.

Conference J Chem Inf Model · 2006 Proton nuclear magnetic resonance (1H NMR) spectroscopic analysis of mixtures has been used extensively for a variety of applications ranging from the analysis of plant extracts, wine, and food to the evaluation of toxicity in animals. For example, NMR ana ... Full text Link to item Cite

Managing genomic and proteomic knowledge.

Journal Article Drug Discov Today Technol · 2005 Genomic and proteomic platform data constitute a hugely important resource to current efforts in disease understanding, systems biology and drug discovery. We review prerequisites for the adequate management of 'omic' data, the means by which such data are ... Full text Link to item Cite

Interactions of 1263W94 with other antiviral agents in inhibition of human cytomegalovirus replication.

Journal Article Antimicrob Agents Chemother · April 2003 Inhibition of human cytomegalovirus (HCMV) by 1263W94 was additive dosewise in combination with ganciclovir, acyclovir, and foscarnet. None of the commonly used anti-human immunodeficiency virus agents antagonized the inhibition of HCMV by 1263W94. The dat ... Full text Link to item Cite

Assessment of the COBAS Amplicor HBV Monitor Test for quantitation of serum hepatitis B virus DNA levels.

Journal Article J Clin Microbiol · June 2002 Treatment of patients with chronic hepatitis B virus (HBV) infections with potent antiviral therapy often results in dramatic reductions in the levels of viremia to very low levels. Monitoring of serum HBV DNA levels is a consistent method for the assessme ... Full text Link to item Cite

Linking bioinformatics and cheminformatics: From genes to structure-activity relationships

Chapter · January 1, 2000 The terms bioinformatics and cheminformatics refer to the use of computational methods in the study of biology and chemistry. Information derived from DNA or protein sequences, protein structure, and chemical structure is used to build models of biochemica ... Full text Cite

Quantitation of hepatitis B viremia and emergence of YMDD variants in patients with chronic hepatitis B treated with lamivudine.

Journal Article J Infect Dis · December 1999 Hepatitis B viremia and emergence of hepatitis B virus (HBV) YMDD variants with reduced susceptibility to lamivudine were analyzed in patient sera from a phase II study of extended lamivudine therapy. Within 12 weeks, all patients exhibited a marked virolo ... Full text Link to item Cite

Two sensitive PCR-based methods for detection of hepatitis B virus variants associated with reduced susceptibility to lamivudine.

Journal Article J Clin Microbiol · October 1999 Two novel assays, a restriction fragment length polymorphism (RFLP) assay and an assay based on the 5'-nuclease activity of Taq DNA polymerase, were developed for screening viral variants in lamivudine-treated patients' sera containing <1,000 copies of the ... Full text Link to item Cite

Quantitative Molecular Pharmacology and Informatics in Drug Discovery

Book · 1999 Written by two internationally known and well-regarded experts, this book is an essential reference for research and development scientists working in the pharmaceutical and biotechnology industries. ... Cite

A mathematical model for analysis of pharmacologically induced changes in the kinetics of cardiac muscle.

Journal Article J Pharmacol Toxicol Methods · November 1996 A mathematical model of the isometric contraction of cardiac muscle is developed and utilized to characterize the inotropic and lusitropic effects of cardioactive compounds in isolated guinea pig left atria. In contrast to metrics that are based on minima ... Full text Link to item Cite

The cubic ternary complex receptor-occupancy model. III. resurrecting efficacy.

Journal Article J Theor Biol · August 21, 1996 Early work in pharmacology characterized the interaction of receptors and ligands in terms of two parameters, affinity and efficacy, an approach we term the bipartite view. A precise formulation of efficacy only exists for very simple pharmacological model ... Full text Link to item Cite

Structure activity relationships of a series of buspirone analogs at alpha-1 adrenoceptors: further evidence that rat aorta alpha-1 adrenoceptors are of the alpha-1D-subtype.

Journal Article J Pharmacol Exp Ther · July 1996 The activity of a series of busprione analogs at recombinant and rat thoracic aorta alpha-1 adrenoceptors was investigated. Compound affinity for recombinant alpha-1A, alpha-1B and alpha-1D adrenoceptors from human and animal sources was determined by radi ... Link to item Cite

The cubic ternary complex receptor-occupancy model II. Understanding apparent affinity

Journal Article Journal of Theoretical Biology · January 21, 1996 In part I of this series of papers, we described the cubic ternary complex (CTC) model. In part II, we examine the pharmacological notion of apparent ligand affinity in the light of this model. The high degree of symmetry that characterizes the CTC model m ... Full text Cite

The cubic ternary complex receptor-occupancy model I. Model description

Journal Article Journal of Theoretical Biology · January 21, 1996 In this paper we propose a new equilibrium model of the interactions between receptors, ligands, and G-proteins--the cubic ternary complex (CTC) model. The CTC model is a generalization of the extended ternary complex model of Samama et al. (1993). It inco ... Full text Cite

Experimental design for high-throughput screening

Journal Article Drug Discovery Today · January 1, 1996 Novel methods in molecular biology and advanced technologies have given pharmaceutical research laboratories the capability to test combinatorial libraries rapidly against large numbers of potential targets. Methods to identify optimal assay conditions eff ... Full text Cite

Use of resampling techniques to estimate the variance of parameters in pharmacological assays when experimental protocols preclude independent replication: an example using Schild regressions.

Journal Article J Pharmacol Toxicol Methods · September 1995 Estimates of variance in pharmacological assays are usually made by repeating the experiment with different tissues. Biological factors, such as the inability to wash a drug from tissue, may preclude the type of replication that is appropriate for the stat ... Full text Link to item Cite

Characterization of alpha-1 adrenoceptor subtypes in human and canine prostate membranes.

Journal Article J Pharmacol Exp Ther · December 1994 Experiments were designed to characterize the predominant subtype of alpha-1 adrenoceptors in human and canine prostate tissue. The chemical (+/-)-beta-([125I]iodo-4-hydroxyphenyl)-ethyl- aminomethyl-tetralone bound in a specific, saturable manner to a sin ... Link to item Cite

A pharmacodynamic model to investigate the structure-activity profile of a series of novel opioid analgesics.

Journal Article J Pharmacol Exp Ther · November 1994 A simple mathematical model of analgesia in the rat is developed and utilized to determine quantitative structure-activity relationships for a series of novel 4-anilidopiperidine opioids. The compounds tested (selected alkyl carboxyethyl esters attached at ... Link to item Cite

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics.

Journal Article J Med Chem · July 1991 In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of ... Full text Link to item Cite

Drug and tissue factors both confound KA measurements.

Journal Article Trends Pharmacol Sci · July 1990 Full text Link to item Cite

AUTOMATIC PROGRAMMING SYSTEM TO CREATE MEDICALLY-ORIENTED REPORT GENERATORS.

Journal Article Proceedings - Annual Symposium on Computer Applications in Medical Care · December 1, 1985 A medical information system must be able to meet the demand for new reports. The authors present the advantages and disadvantages of several techniques which allow the user to write medically oriented reports without programming. The TMR report generator ... Cite

TMR--MEETING THE DEMAND FOR THE VARIETY OF REPORT MODALITIES.

Journal Article Proceedings - Annual Symposium on Computer Applications in Medical Care · December 1, 1984 Five levels of computer-generated reports are discussed. These reports vary from rigid, predefined formats to flexible formats which require some user sophistication but no computer programming experience. It is noted that as reports become more flexible, ... Cite