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Siamak MahmoudianDehkordi

Bio: Siamak MahmoudianDehkordi is an academic researcher from Duke University. The author has contributed to research in topics: Apolipoprotein E & Citalopram. The author has an hindex of 7, co-authored 21 publications receiving 224 citations.

Papers
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Journal ArticleDOI
03 Jun 2020-Neuron
TL;DR: It is found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes, and these networks and gene expression changes were mostly conserved in human brains.

123 citations

Journal ArticleDOI
03 Jul 2019
TL;DR: In this paper, the authors examined whether liver function markers are associated with cognitive dysfunction and the A/T/N (amyloid, tau, and neurodegeneration) biomarkers for AD.
Abstract: Importance Increasing evidence suggests an important role of liver function in the pathophysiology of Alzheimer disease (AD). The liver is a major metabolic hub; therefore, investigating the association of liver function with AD, cognition, neuroimaging, and CSF biomarkers would improve the understanding of the role of metabolic dysfunction in AD. Objective To examine whether liver function markers are associated with cognitive dysfunction and the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD. Design, Setting, and Participants In this cohort study, serum-based liver function markers were measured from September 1, 2005, to August 31, 2013, in 1581 AD Neuroimaging Initiative participants along with cognitive measures, cerebrospinal fluid (CSF) biomarkers, brain atrophy, brain glucose metabolism, and amyloid-β accumulation. Associations of liver function markers with AD-associated clinical and A/T/N biomarkers were assessed using generalized linear models adjusted for confounding variables and multiple comparisons. Statistical analysis was performed from November 1, 2017, to February 28, 2019. Exposures Five serum-based liver function markers (total bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase) from AD Neuroimaging Initiative participants were used as exposure variables. Main Outcomes and Measures Primary outcomes included diagnosis of AD, composite scores for executive functioning and memory, CSF biomarkers, atrophy measured by magnetic resonance imaging, brain glucose metabolism measured by fludeoxyglucose F 18 (18F) positron emission tomography, and amyloid-β accumulation measured by [18F]florbetapir positron emission tomography. Results Participants in the AD Neuroimaging Initiative (n = 1581; 697 women and 884 men; mean [SD] age, 73.4 [7.2] years) included 407 cognitively normal older adults, 20 with significant memory concern, 298 with early mild cognitive impairment, 544 with late mild cognitive impairment, and 312 with AD. An elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio and lower levels of ALT were associated with AD diagnosis (AST to ALT ratio: odds ratio, 7.932 [95% CI, 1.673-37.617];P = .03; ALT: odds ratio, 0.133 [95% CI, 0.042-0.422];P = .004) and poor cognitive performance (AST to ALT ratio: β [SE], −0.465 [0.180];P = .02 for memory composite score; β [SE], −0.679 [0.215];P = .006 for executive function composite score; ALT: β [SE], 0.397 [0.128];P = .006 for memory composite score; β [SE], 0.637 [0.152];P Conclusions and Relevance Consistent associations of serum-based liver function markers with cognitive performance and A/T/N biomarkers for AD highlight the involvement of metabolic disturbances in the pathophysiology of AD. Further studies are needed to determine if these associations represent a causative or secondary role. Liver enzyme involvement in AD opens avenues for novel diagnostics and therapeutics.

122 citations

Journal ArticleDOI
TL;DR: How sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum is investigated to suggest that females experience greater impairment of mitochondrial energy production than males.
Abstract: Late-onset Alzheimer's disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE e4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE e4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE e4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE e4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

86 citations

Journal ArticleDOI
17 Nov 2020
TL;DR: Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain.
Abstract: Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.

82 citations

Journal ArticleDOI
TL;DR: Electrochemistry-based targeted metabolomics revealed changes in guanosine–homogentisic acid and methionine–tyrosine interactions associated with HRSD17, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
Abstract: Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine–homogentisic acid and methionine–tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.

48 citations


Cited by
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Journal ArticleDOI
TL;DR: Alzheimer’s & Dementia: The Journal of the Alzheimer's Association received acceptance for inclusion n MEDLINE, the bibliographic database of the U.S. National Library of Medicine.
Abstract: i n c y h h i t i a R Last month, Alzheimer’s & Dementia: The Journal of the lzheimer’s Association received acceptance for inclusion n MEDLINE, the bibliographic database of the U.S. Naional Library of Medicine (NLM). Three years since the aunch, this achievement marks an important recognition of he Journal’s scientific merit and contribution to the field of lzheimer’s disease research. The editors, our publishing artners from Elsevier, and our sponsoring colleagues from he Alzheimer’s Association are extremely thankful to the uthors, reviewers, Editorial Board members, and readers or their many valuable contributions. As the official journal of the Alzheimer’s Association, lzheimer’s & Dementia will now be circulated to the active embers of the Association’s new International Society to dvance Alzheimer Research and Treatment (ISTAART) imonthly, as well as other subscribers and libraries. The ournal will continue to cover critical scientific, medical, ocial, and policy issues that investigators and clinicians ace every day, on matters concerning healthy brain aging to ll forms of dementia. Unlike other journals in the field, lzheimer’s & Dementia bridges new thinking across dierse areas of investigation. This interdisciplinary journal rovides the impetus for new scientific initiatives and offers

754 citations

Book ChapterDOI
01 Jan 2009
TL;DR: The GI/BSI/DFKI Protection Profile constitutes after the implementation of the identified improvements as the proposed evaluation methodology for remote electronic voting systems and can now be applied to available systems.
Abstract: The previous part discusses the GI/BSI/DFKI Protection Profile which constitutes after the implementation of the identified improvements as the proposed evaluation methodology for remote electronic voting systems. The result can now be applied to available systems. Currently, there is no system that has been evaluated against the GI/BSI/DFKI Protection Profile or even against the improved version.

332 citations

Journal ArticleDOI
TL;DR: Understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption, and it is important to use this body of knowledge to develop therapies directed at APOE.
Abstract: The APOE e4 allele remains the strongest genetic risk factor for sporadic Alzheimer's disease and the APOE e2 allele the strongest genetic protective factor after multiple large scale genome-wide association studies and genome-wide association meta-analyses. However, no therapies directed at APOE are currently available. Although initial studies causally linked APOE with amyloid-β peptide aggregation and clearance, over the past 5 years our understanding of APOE pathogenesis has expanded beyond amyloid-β peptide-centric mechanisms to tau neurofibrillary degeneration, microglia and astrocyte responses, and blood-brain barrier disruption. Because all these pathological processes can potentially contribute to cognitive impairment, it is important to use this new knowledge to develop therapies directed at APOE. Several therapeutic approaches have been successful in mouse models expressing human APOE alleles, including increasing or reducing APOE levels, enhancing its lipidation, blocking the interactions between APOE and amyloid-β peptide, and genetically switching APOE4 to APOE3 or APOE2 isoforms, but translation to human clinical trials has proven challenging.

293 citations

Journal ArticleDOI
TL;DR: AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation is revealed.
Abstract: Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer’s disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1–42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1–42, or tau and phosphorylated Tau-181. This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.

118 citations