Physical Sciences and Mathematics Commons^™

Microrna Expression Patterns In Human Anterior Cingulate And Motor Cortex: A Study Of Dementia With Lewy Bodies Cases And Controls, Peter T. Nelson, Wang-Xia Wang, Sarah A. Janse, Katherine L. Thompson

Sanders-Brown Center on Aging Faculty Publications

Overview

MicroRNAs (miRNAs) have been implicated in neurodegenerative diseases including Parkinson’s disease and Alzheimer’s disease (AD). Here, we evaluated the expression of miRNAs in anterior cingulate (AC; Brodmann area [BA] 24) and primary motor (MO; BA 4) cortical tissue from aged human brains in the University of Kentucky AD Center autopsy cohort, with a focus on dementia with Lewy bodies (DLB).

Methods

RNA was isolated from gray matter of brain samples with pathology-defined DLB, AD, AD+DLB, and low-pathology controls, with n=52 cases initially included (n=23 with DLB), all with low (<4hrs) postmortem intervals. RNA was profiled using Exiqon miRNA microarrays. Quantitative PCR for post-hoc replication was performed on separate cases (n=6 controls) and included RNA isolated from gray matter of MO, AC, primary somatosensory (BA 3), and dorsolateral prefrontal (BA 9) cortical regions.

Results

The miRNA expression patterns differed substantially according to …

Risk Of Incident Clinical Diagnosis Of Alzheimer's Disease-Type Dementia Attributable To Pathology-Confirmed Vascular Disease, Hiroko H. Dodge, Jian Zhu, Randy Woltjer, Peter T. Nelson, David A. Bennett, Nigel J. Cairns, David W. Fardo, Jeffrey A. Kaye, Deniz-Erten Lyons, Nora Mattek, Julie A. Schneider, Lisa C. Silbert, Chengjie Xiong, Lei Yu, Frederick A. Schmitt, Richard J. Kryscio, Erin L. Abner, Smart Data Consortium

Sanders-Brown Center on Aging Faculty Publications

INTRODUCTION: The presence of cerebrovascular pathology may increase the risk of clinical diagnosis of Alzheimer's disease (AD).

METHODS: We examined excess risk of incident clinical diagnosis of AD (probable and possible AD) posed by the presence of lacunes and large infarcts beyond AD pathology using data from the Statistical Modeling of Aging and Risk of Transition study, a consortium of longitudinal cohort studies with more than 2000 autopsies. We created six mutually exclusive pathology patterns combining three levels of AD pathology (low, moderate, or high AD pathology) and two levels of vascular pathology (without lacunes and large infarcts or with …

Outcomes After Diagnosis Of Mild Cognitive Impairment In A Large Autopsy Series, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson

Epidemiology and Environmental Health Faculty Publications

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).

METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.

RESULTS: Mean follow‐up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical …

Genomics And Csf Analyses Implicate Thyroid Hormone In Hippocampal Sclerosis Of Aging, Peter T. Nelson, Yuriko Katsumata, Kwangsik Nho, Sergey C. Artiushin, Gregory A. Jicha, Wang-Xia Wang, Erin L. Abner, Andrew J. Saykin, Walter A. Kukull, Alzheimer’S Disease Neuroimaging Initiative (Adni), David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer’s neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer’s Coordinating Center/Alzheimer’s Disease Genetic Consortium data; n = 2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain …

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

White Matter Diffusion Alterations In Normal Women At Risk Of Alzheimer's Disease, Charles D. Smith, Himachandra Chebrolu, Anders H. Andersen, David A. Powell, Mark A. Lovell, Shuling Xiong, Brian T. Gold

Neurology Faculty Publications

Increased white matter mean diffusivity and decreased fractional anisotropy (FA) has been observed in subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD). We sought to determine whether similar alterations of white matter occur in normal individuals at risk of AD. Diffusion tensor images were acquired in 42 cognitively normal right-handed women with both a family history of dementia and at least one apolipoprotein E4 allele. These were compared with images from 23 normal women without either AD risk factor. Group analyses were performed using tract-based spatial statistics. Reduced FA was observed in the fronto-occipital and inferior temporal …

Focus On Rna Isolation: Obtaining Rna For Microrna (Mirna) Expression Profiling Analyses Of Neural Tissue, Wang-Xia Wang, Bernard R. Wilfred, Donald A. Baldwin, R. Benjamin Isett, Na Ren, Arnold J. Stromberg, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are present in all known plant and animal tissues and appear to be somewhat concentrated in the mammalian nervous system. Many different miRNA expression profiling platforms have been described. However, relatively little research has been published to establish the importance of 'upstream' variables in RNA isolation for neural miRNA expression profiling. We tested whether apparent changes in miRNA expression profiles may be associated with tissue processing, RNA isolation techniques, or different cell types in the sample. RNA isolation was performed on a single brain sample using eight different RNA isolation methods, and results were correlated using a conventional …

The Expression Of Microrna Mir-107 Decreases Early In Alzheimer's Disease And May Accelerate Disease Progression Through Regulation Of Β-Site Amyloid Precursor Protein-Cleaving Enzyme 1, Wang-Xia Wang, Bernard W. Rajeev, Arnold J. Stromberg, Na Ren, Guiliang Tang, Qingwei Huang, Isidore Rigoutsos, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with …