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Search Results: 1 - 10 of 463046 matches for " Kathleen A. Welsh-Bohmer "
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Long-Term Impact of Caregiving and Metabolic Syndrome with Perceived Decline in Cognitive Function 8 Years Later: A Pilot Study Suggesting Important Avenues for Future Research  [PDF]
Beverly H. Brummett, Shirley B. Austin, Kathleen A. Welsh-Bohmer, Redford B. Williams, Ilene C. Siegler
Open Journal of Medical Psychology (OJMP) , 2013, DOI: 10.4236/ojmp.2013.21005
Abstract: The chronic stress of caregiving has been associated with increased risk for cognitive decline and dementia. One theoretical model suggests that a group of risk factors known as the metabolic syndrome MET_SYN (e.g., hypertension, poor glucose regulation, central obesity, and high triglyceride levels) that have demonstrated associations with both stress and cognitive decline, may mediate the association between caregiver stress and cognitive decline. It is also possible that caregiving may moderate the association between MET_SYN and cognitive decline. The present study examined these two potential models. The study sample consisted of 53 caregivers for a relative with dementia and 24 participants who did not have caregiving responsibilities at baseline. We examined associations among caregiving history (yes/no), self-reported decline in cognitive function (the AD8) at follow-up, and a MET_SYN factor comprised of increased systolic blood pressure (SBP), glycosylated hemoglobin concentration (HbA1c), waist circumference, and triglyceride levels at baseline when caregiving was assessed. MET_SYN was associated with AD8 (p = 0.010). Caregiving history was not directly associated with AD8 ratings, however, caregiving did moderate the association between MET_SYN and AD8 (p = 0.043) assessed 8 years later. In caregivers MET_SYN scores reflecting higher risk were associated with scores on the AD8 indicting decline, whereas, in controls MET_SYN was unrelated to AD8 assessment. Thus, it can be concluded that caregiver stress may increase the association between metabolic risk factors and decline in cognitive functioning up to 8 years later.
Metabolomics in Early Alzheimer's Disease: Identification of Altered Plasma Sphingolipidome Using Shotgun Lipidomics
Xianlin Han, Steve Rozen, Stephen H. Boyle, Caroline Hellegers, Hua Cheng, James R. Burke, Kathleen A. Welsh-Bohmer, P. Murali Doraiswamy, Rima Kaddurah-Daouk
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0021643
Abstract: Background The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility. Methods and Findings We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics [1], [2] to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences. Conclusions In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.
Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues
Colton Linnertz,Laura Saucier,Dongliang Ge,Kenneth D. Cronin,James R. Burke,Jeffrey N. Browndyke,Christine M. Hulette,Kathleen A. Welsh-Bohmer,Ornit Chiba-Falek
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007480
Abstract: Genetic variability across the SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson's disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However whether genetic variability in the SNCA gene modulates the risk to develop sporadic PD via regulation of SNCA expression remained elusive. We studied the effect of PD risk-associated variants at SNCA 5′ and 3′regions on SNCA-mRNA levels in vivo in 228 human brain samples from three structures differentially vulnerable to PD pathology (substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD-associated promoter polymorphism, Rep1, had an effect on SNCA-mRNA levels. Homozygous genotype of the ‘protective’, Rep1-259 bp allele, was associated with lower levels of SNCA-mRNA relative to individuals that carried at least one copy of the PD-risk associated alleles, amounting to an average decrease of ~40% and >50% in temporal-cortex and substantia-nigra, respectively. Furthermore, SNPs tagging the SNCA 3′-untranslated-region also showed effects on SNCA-mRNA levels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the ‘decreased-risk’ alleles were correlated with increased SNCA-mRNA levels. Similar to Rep1 findings, no difference in SNCA-mRNA level was seen with different SNCA 3′SNP alleles in the frontal-cortex, indicating there is brain-region specificity of the genetic regulation of SNCA expression. We provide evidence for functional consequences of PD-associated SNCA gene variants in disease relevant brain tissues, suggesting that genetic regulation of SNCA expression plays an important role in the development of the disease.
Resting-State Multi-Spectrum Functional Connectivity Networks for Identification of MCI Patients
Chong-Yaw Wee, Pew-Thian Yap, Kevin Denny, Jeffrey N. Browndyke, Guy G. Potter, Kathleen A. Welsh-Bohmer, Lihong Wang, Dinggang Shen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037828
Abstract: In this paper, a high-dimensional pattern classification framework, based on functional associations between brain regions during resting-state, is proposed to accurately identify MCI individuals from subjects who experience normal aging. The proposed technique employs multi-spectrum networks to characterize the complex yet subtle blood oxygenation level dependent (BOLD) signal changes caused by pathological attacks. The utilization of multi-spectrum networks in identifying MCI individuals is motivated by the inherent frequency-specific properties of BOLD spectrum. It is believed that frequency specific information extracted from different spectra may delineate the complex yet subtle variations of BOLD signals more effectively. In the proposed technique, regional mean time series of each region-of-interest (ROI) is band-pass filtered ( Hz) before it is decomposed into five frequency sub-bands. Five connectivity networks are constructed, one from each frequency sub-band. Clustering coefficient of each ROI in relation to the other ROIs are extracted as features for classification. Classification accuracy was evaluated via leave-one-out cross-validation to ensure generalization of performance. The classification accuracy obtained by this approach is 86.5%, which is an increase of at least 18.9% from the conventional full-spectrum methods. A cross-validation estimation of the generalization performance shows an area of 0.863 under the receiver operating characteristic (ROC) curve, indicating good diagnostic power. It was also found that, based on the selected features, portions of the prefrontal cortex, orbitofrontal cortex, temporal lobe, and parietal lobe regions provided the most discriminant information for classification, in line with results reported in previous studies. Analysis on individual frequency sub-bands demonstrated that different sub-bands contribute differently to classification, providing extra evidence regarding frequency-specific distribution of BOLD signals. Our MCI classification framework, which allows accurate early detection of functional brain abnormalities, makes an important positive contribution to the treatment management of potential AD patients.
Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish
Jacob L McCauley, Daniel W Hahs, Lan Jiang, William K Scott, Kathleen A Welsh-Bohmer, Charles E Jackson, Jeffery M Vance, Margaret A Pericak-Vance, Jonathan L Haines
BMC Medical Genetics , 2006, DOI: 10.1186/1471-2350-7-19
Abstract: We recently performed a genome scan of dementia in this population that detected several potential loci. However, analyses of these data are complicated by the highly consanguineous nature of these Amish pedigrees. Therefore we applied the Combinatorial Mismatch Scanning (CMS) method that compares identity by state (IBS) (under the presumption of identity by descent (IBD)) sharing in distantly related individuals from such populations where standard linkage and association analyses are difficult to implement. CMS compares allele sharing between individuals in affected and unaffected groups from founder populations. Comparisons between cases and controls were done using two Fisher's exact tests, one testing for excess in IBS allele frequency and the other testing for excess in IBS genotype frequency for 407 microsatellite markers.In all, 13 dementia cases and 14 normal controls were identified who were not related at least through the grandparental generation. The examination of allele frequencies identified 24 markers (6%) nominally (p ≤ 0.05) associated with dementia; the most interesting (empiric p ≤ 0.005) markers were D3S1262, D5S211, and D19S1165. The examination of genotype frequencies identified 21 markers (5%) nominally (p ≤ 0.05) associated with dementia; the most significant markers were both located on chromosome 5 (D5S1480 and D5S211). Notably, one of these markers (D5S211) demonstrated differences (empiric p ≤ 0.005) under both tests.Our results provide the initial groundwork for identifying genes involved in late-onset Alzheimer's disease within the Amish community. Genes identified within this isolated population will likely play a role in a subset of late-onset AD cases across more general populations. Regions highlighted by markers demonstrating suggestive allelic and/or genotypic differences will be the focus of more detailed examination to characterize their involvement in dementia.With over 4 million individuals affected with Alzheimer's disease
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L. Heinzen,Dongliang Ge,Kenneth D. Cronin,Jessica M. Maia,Kevin V. Shianna,Willow N. Gabriel,Kathleen A. Welsh-Bohmer,Christine M. Hulette,Thomas N. Denny,David B. Goldstein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
Alternative ion channel splicing in mesial temporal lobe epilepsy and Alzheimer's disease
Erin L Heinzen, Woohyun Yoon, Michael E Weale, Arjune Sen, Nicholas W Wood, James R Burke, Kathleen A Welsh-Bohmer, Christine M Hulette, Sanjay M Sisodiya, David B Goldstein
Genome Biology , 2007, DOI: 10.1186/gb-2007-8-3-r32
Abstract: This work shows for the first time that two common neurological conditions are associated with extensive changes in gene splicing, with 25% and 12% of the genes considered having significant changes in splicing patterns associated with mesial temporal lobe epilepsy and Alzheimer's disease, respectively. Furthermore, these changes were found to exhibit unique and consistent patterns within the disease groups.This work has identified a set of disease-associated, alternatively spliced gene products that represent high priorities for detailed functional investigations into how these changes impact the pathophysiology of mesial temporal lobe epilepsy and Alzheimer's disease.The complexity of the genome lies not only in the many genes comprising it, but also in the many levels of processing that influence the proteins that are produced and their abundance. One key site of regulation is the splicing of precursor RNAs to their associated mRNA transcripts. This process alone allows a single gene to have multiple different mRNA transcripts, producing proteins that may differ substantially from one another, even to the extent of having opposing effects [1]. Overall, however, little is known about the functional differences amongst the alternative proteins produced from the same gene. Because the functional characterization of proteins can be laborious, it would be useful to be able to prioritize alternative transcripts more likely to have biological significance. One direction for prioritization is on the basis of association with human disease.Alternative splicing of key genes generates alternative proteins that contribute to several prominent human diseases, for example, the spinal motor neuron protein in spinal muscular atrophy [2], cardiac troponin T, insulin receptor, myotubularin-related 1, and other proteins in myotonic dystrophies [3-5], and the tau protein in frontotemporal dementia and Alzheimer's disease [3,4] (other examples are reviewed extensively in [5]). Furthe
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L Heinzen equal contributor,Dongliang Ge equal contributor,Kenneth D Cronin,Jessica M Maia,Kevin V Shianna,Willow N Gabriel,Kathleen A Welsh-Bohmer,Christine M Hulette,Thomas N Denny,David B Goldstein
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
Characterization of the Poly-T Variant in the TOMM40 Gene in Diverse Populations
Colton Linnertz, Ann M. Saunders, Michael W. Lutz, Donna M. Crenshaw, Iris Grossman, Daniel K. Burns, Keith E. Whitfield, Michael A. Hauser, Jeanette J. McCarthy, Megan Ulmer, Rand Allingham, Kathleen A. Welsh-Bohmer, Allen D. Roses, Ornit Chiba-Falek
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030994
Abstract: 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 for rs10524523, hereafter ‘523’, based on the number of ‘T’-residues: ‘Short’ (S, T≤19), ‘Long’ (L, 20≤T≤29) and ‘Very Long’ (VL, T≥30). Homopolymers, particularly long homopolymers like ‘523’, are difficult to genotype because ‘slippage’ occurs during PCR-amplification. We initially genotyped this locus by PCR-amplification followed by Sanger-sequencing. However, we recognized the need to develop a higher-throughput genotyping method that is also accurate and reliable. Here we describe a new ‘523’ genotyping assay that is simple and inexpensive to perform in a standard molecular genetics laboratory. The assay is based on the detection of differences in PCR-fragment length using capillary electrophoresis. We discuss technical problems, solutions, and the steps taken for validation. We employed the novel assay to investigate the ‘523’ allele frequencies in different ethnicities. Whites and Hispanics have similar frequencies of S/L/VL alleles (0.45/0.11/0.44 and 0.43/0.09/0.48, respectively). In African-Americans, the frequency of the L-allele (0.10) is similar to Whites and Hispanics; however, the S-allele is more prevalent (0.65) and the VL-allele is concomitantly less frequent (0.25). The allele frequencies determined using the new methodology are compared to previous reports for Ghanaian, Japanese, Korean and Han Chinese cohorts. Finally, we studied the linkage pattern between TOMM40-‘523’ and APOE alleles. In Whites and Hispanics, consistent with previous reports, the L is primarily linked to ε4, while the majority of the VL and S are linked to ε3. Interestingly, in African-Americans, Ghanaians and Japanese, there is an increased frequency of the ‘523’S-APOEε4 haplotype. These data may be used as references for ‘523’ allele and ‘523’-APOE haplotype frequencies in diverse populations for the design of research studies and clinical trials.
Primate cerebellar granule cells exhibit a tonic GABAAR conductance that is not affected by alcohol: a possible cellular substrate of the low level of response phenotype
Claudia Mohr,Olena Kolotushkina,Joshua S. Kaplan,John Welsh,James B. Daunais,Kathleen A. Grant,David J. Rossi
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2013.00189
Abstract: In many rodent brain regions, alcohol increases vesicular release of GABA, resulting in an increase in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and the magnitude of tonic GABAA receptor (GABAAR) currents. A neglected issue in translating the rodent literature to humans is the possibility that phylogenetic differences alter the actions of alcohol. To address this issue we made voltage-clamp recordings from granule cells (GCs) in cerebellar slices from the non-human primate (NHP), Macaca fascicularis. We found that similar to Sprague Dawley rats (SDRs), NHP GCs exhibit a tonic conductance generated by α6δ subunit containing GABAARs, as evidenced by its blockade by the broad spectrum GABAAR antagonist, GABAzine (10 μM), inhibition by α6 selective antagonist, furosemide (100 μM), and enhancement by THDOC (10–20 nM) and THIP (500 nM). In contrast to SDR GCs, in most NHP GCs (~60%), application of EtOH (25–105 mM) did not increase sIPSC frequency or the tonic GABAAR current. In a minority of cells (~40%), EtOH did increase sIPSC frequency and the tonic current. The relative lack of response to EtOH was associated with reduced expression of neuronal nitric oxide synthase (nNOS), which we recently reported mediates EtOH-induced enhancement of vesicular GABA release in rats. The EtOH-induced increase in tonic GABAAR current was significantly smaller in NHPs than in SDRs, presumably due to less GABA release, because there were no obvious differences in the density of GABAARs or GABA transporters between SDR and NHP GCs. Thus, EtOH does not directly modulate α6δ subunit GABAARs in NHPs. Instead, EtOH enhanced GABAergic transmission is mediated by enhanced GABA release. Further, SDR GC responses to alcohol are only representative of a subpopulation of NHP GCs. This suggests that the impact of EtOH on NHP cerebellar physiology will be reduced compared to SDRs, and will likely have different computational and behavioral consequences.
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