Andrew J Saykin
Indiana University Indianapolis, Radiology, Faculty Member
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Research Interests: Engineering, Physics, Chemistry, Biology, Medicine, and 9 moreMultidisciplinary, Linear models, Humans, Female, Male, PLoS one, Aged, Middle Aged, and Alzheimer Disease
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease... more
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p = 2.44×10−5) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10−60, accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10−112. Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10−8). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.
Research Interests: Engineering, Physics, Chemistry, Biology, Medicine, and 9 moreMultidisciplinary, Linear models, Humans, Female, Male, PLoS one, Aged, Middle Aged, and Alzheimer Disease
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Research Interests: Magnetic Resonance Imaging, MRI, Humans, Aggression, Female, and 15 moreSalience Network, Male, Clinical Sciences, Aged, Middle Aged, Questionnaires, Longitudinal Studies, Atrophy, Limbic System, Disease Progression, Alzheimer Disease, Neurosciences, Frontal Lobe, Cognition disorders, and Neuropsychological Tests
Research Interests: Genetics, Neuroscience, Cognitive Science, Auditory Perception, Schizophrenia, and 71 moreCognition, Visual perception, Anterior Cingulate, Magnetic Resonance Imaging, Working Memory, Reading, Writing, China, Treatment Outcome, Japan, Language, Prefrontal Cortex, Executive Function, Information Processing, Cats, Subthalamic Nucleus, Movement disorders, Biological Sciences, Biological Psychiatry, Brain Mapping, Hippocampus, Brain, Gestures, Humans, Thalamus, Cerebral Cortex, Movement, Blood Pressure, PMC, Female, Animals, Neuroimage, Male, Cognitive behavior therapy, Biological, Obsessive Compulsive Disorder, Verbal behavior, Verbal working memory, Heart rate, Urodynamics, Cognitive Behavioral Treatment Method, Clinical Sciences, Dimensional, Middle Aged, Pilot study, Interference, Questionnaires, Urinary Tract, Adult, Parietal Lobe, Nuclear Family, Reflex, Hand, Short Term Memory, Age Factors, Baroreflex, Hypotension, Neural pathways, Pilot Projects, Visual Evoked Potentials, Tower of London, Reference Values, Computers In Human Behavior, D, Neurosciences, Respiratory Mechanics, Verbal Learning, Parkinson Disease, Medial Prefrontal Cortex, Anterior cingulate cortex, and Functional Laterality
Research Interests: Principal Component Analysis, Magnetic Resonance Imaging, Multivariate Analysis, Canada, Brain, and 15 moreHumans, United States, Female, Neuroimage, Male, Multivariate, Epistasis, Aged, Prevalence, Reproducibility of Results, Sensitivity and Specificity, Genotype phenotype, Alzheimer Disease, Cohort Studies, and Pathway
Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for... more
Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer's disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine ...
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BACKGROUND AND PURPOSE: Injected air bubbles are a well-accepted cause of stroke during cerebral angiography. We used an in vitro model to determine the frequency of occur- rence of air emboli during catheter flushing using conventional... more
BACKGROUND AND PURPOSE: Injected air bubbles are a well-accepted cause of stroke during cerebral angiography. We used an in vitro model to determine the frequency of occur- rence of air emboli during catheter flushing using conventional hardware and techniques. METHODS: Two experimental models were used in this study. The first incorporated an in- line bubble trap. Ten members of our
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Alzheimer's disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological... more
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of "missing heritability." We performed a genome-wide association study (GWAS) and a genome-wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from…
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Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to... more
Research increasingly suggests that subjective cognitive decline (SCD) in older adults, in the absence of objective cognitive dysfunction or depression, may be a harbinger of non-normative cognitive decline and eventual progression to dementia. Little is known, however, about the key features of self-report measures currently used to assess SCD. The Subjective Cognitive Decline Initiative (SCD-I) Working Group is an international consortium established to develop a conceptual framework and research criteria for SCD (Jessen et al., 2014, Alzheimers Dement 10, 844-852). In the current study we systematically compared cognitive self-report items used by 19 SCD-I Working Group studies, representing 8 countries and 5 languages. We identified 34 self-report measures comprising 640 cognitive self-report items. There was little overlap among measures- approximately 75% of measures were used by only one study. Wide variation existed in response options and item content. Items pertaining to t...
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Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support,... more
Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the follo...
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Biological data mining is a powerful tool that can provide a wealth of information about patterns of genetic and genomic biomarkers of health and disease. A potential disadvantage of data mining is volume and complexity of the results... more
Biological data mining is a powerful tool that can provide a wealth of information about patterns of genetic and genomic biomarkers of health and disease. A potential disadvantage of data mining is volume and complexity of the results that can often be overwhelming. It is our working hypothesis that visualization methods can greatly enhance our ability to make sense of data mining results. More specifically, we propose that 3-D printing has an important role to play as a visualization technology in biological data mining. We provide here a brief review of 3-D printing along with a case study to illustrate how it might be used in a research setting. We present as a case study a genetic interaction network associated with grey matter density, an endophenotype for late onset Alzheimer's disease, as a physical model constructed with a 3-D printer. The synergy or interaction effects of multiple genetic variants were represented through a color gradient of the physical connections bet...
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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... more
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. 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. 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 ot...
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Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization... more
Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. We evaluated individual-level data from the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613 controls), the Health and Retirement Study (HRS: 8403 participants with algorithm-predicted dementia status), and published associations from the Genetic and Environmental Risk for AD consortium (GERAD1: 3177 AD cases and 7277 controls). No evidence from individual single-nucleotide polymorphisms or polygenic scores indicated BMI increased AD risk. Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.9...
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The neurobiological mechanisms that underlie facial affect recognition deficits after traumatic brain injury (TBI) have not yet been identified. Using functional magnetic resonance imaging (fMRI), study aims were to 1) determine if there... more
The neurobiological mechanisms that underlie facial affect recognition deficits after traumatic brain injury (TBI) have not yet been identified. Using functional magnetic resonance imaging (fMRI), study aims were to 1) determine if there are differences in brain activation during facial affect processing in people with TBI who have facial affect recognition impairments (TBI-I) relative to people with TBI and healthy controls who do not have facial affect recognition impairments (TBI-N and HC, respectively); and 2) identify relationships between neural activity and facial affect recognition performance. A facial affect recognition screening task performed outside the scanner was used to determine group classification; TBI patients who performed greater than one standard deviation below normal performance scores were classified as TBI-I, while TBI patients with normal scores were classified as TBI-N. An fMRI facial recognition paradigm was then performed within the 3T environment. Res...
As the most common type of dementia, Alzheimer's disease (AD) is a neurodegenerative disorder initially manifested by impaired memory performances. While the diagnosis information indicates a dichotomous status of a patient, memory... more
As the most common type of dementia, Alzheimer's disease (AD) is a neurodegenerative disorder initially manifested by impaired memory performances. While the diagnosis information indicates a dichotomous status of a patient, memory scores have the potential to capture the continuous nature of the disease progression and may provide more insights into the underlying mechanism. In this work, we performed a targeted genetic study of memory scores on an AD cohort to identify the associations between a set of genes highly expressed in the hippocampal region and seven cognitive scores related to episodic memory. Both main effects and interaction effects of the targeted genetic markers on these correlated memory scores were examined. In addition to well-known AD genetic markers APOE and TOMM40, our analysis identified a new risk gene NAV2 through the gene-level main effect analysis. NAV2 was found to be significantly and consistently associated with all seven episodic memory scores. Ge...
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The purpose of this study was to enhance the current understanding and interpretation of longitudinal change on tests of neurocognitive function in individuals with cancer. Scores on standard neuropsychological instruments may be impacted... more
The purpose of this study was to enhance the current understanding and interpretation of longitudinal change on tests of neurocognitive function in individuals with cancer. Scores on standard neuropsychological instruments may be impacted by practice effects and other random forms of error. The current study assessed the test-retest reliability of several tests and overarching cognitive domains comprising a neurocognitive battery typical of those used for research and clinical evaluation using relevant time frames. Practice effect-adjusted reliable change confidence intervals for test-retest difference scores based on a sample of patient-matched healthy controls are provided. By applying reliable change confidence intervals to scores from two samples of breast cancer patients at post-treatment follow-up assessment, meaningful levels of detectable change in cognitive functioning in breast cancer survivors were ascertained and indicate that standardized neuropsychological instruments ...
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Injected air bubbles are a well-accepted cause of stroke during cerebral angiography. We used an in vitro model to determine the frequency of occurrence of air emboli during catheter flushing using conventional hardware and techniques.... more
Injected air bubbles are a well-accepted cause of stroke during cerebral angiography. We used an in vitro model to determine the frequency of occurrence of air emboli during catheter flushing using conventional hardware and techniques. Two experimental models were used in this study. The first incorporated an in-line bubble trap. Ten members of our angiography section flushed this system in their usual fashion and then with two modifications of the hardware. The trap was inspected after each trial of seven injections and any visible bubble was measured with calipers. The second model used a peristaltic pump along with a transcranial Doppler device to look at the relative number of bubble events with modifications of the flush solution or technique. The closed-flush set in common usage in our department caused an increase in the number of visible bubbles in the trap as compared with an open basin. Degassing the solution and delaying injection decreased the number of bubble events not...
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Our goal was to determine whether the size of the lateral ventricle influences asymmetry of the fornix in patients with mesial temporal sclerosis. The cross-sectional area of the lateral ventricle was measured along with the thickness of... more
Our goal was to determine whether the size of the lateral ventricle influences asymmetry of the fornix in patients with mesial temporal sclerosis. The cross-sectional area of the lateral ventricle was measured along with the thickness of the fornix in 18 patients with pathologically proved mesial temporal sclerosis. Two additional patients with ventricular asymmetry and seizures but without mesial sclerosis were also studied. Ten of 18 patients with mesial temporal sclerosis had equally sized ventricular areas or less than a 25% difference between the two sides. In seven of these 10, the left and right fornices were equal; in the other three patients, the fornix was thinner on the side of mesial sclerosis. Among the eight patients with ventricular area differences greater than 25%, the larger ventricle was on the side of mesial sclerosis in five cases. In all of these, the ipsilateral fornix was thinner. In three of eight cases, the contralateral ventricle was larger; in two, the le...
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The purpose of our study was to determine whether proton magnetic resonance spectroscopy (MRS) could detect early brain involvement by human immunodeficiency virus (HIV). We recruited 19 asymptomatic HIV-infected patients, 9 with and 10... more
The purpose of our study was to determine whether proton magnetic resonance spectroscopy (MRS) could detect early brain involvement by human immunodeficiency virus (HIV). We recruited 19 asymptomatic HIV-infected patients, 9 with and 10 without a history of intravenous drug use (IDU), as well as 10 control subjects. All subjects had to have normal MR imaging to be enrolled. We identified the following peaks on proton MRS: n-acetyl aspartate, creatine, choline, and a conglomerate amino acid peak between 2.1 and 2.6 parts per million that we call the marker peaks. Proton MRS was able to demonstrate a statistically significant difference between HIV-infected subjects and controls. The marker/Cr was the best ratio to separate patients from controls, with controls having a mean ratio of 0.50 +/- 0.51 and patients having a mean ratio of 1.8 +/- 0.85 (p = 0.001). There was no difference between HIV-infected subjects with and without a history of IDU. No significant relationship was found b...
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Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular... more
Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer's disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in d...