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12. Molecular Changes in the Absence of Severe Pathology in the Pulvinar in Dementia With Lewy Bodies

Author

Erskine, Daniel, Ding, Jinhui, Thomas, Alan J., Kaganovich, Alice, Khundakar, Ahmad A., Hanson, Peter S., Taylor, John-Paul, McKeith, Ian G., Attems, Johannes, Cookson, Mark R., and Morris, Christopher M.

Subjects
Dynamins, Lewy Body Disease, Male, Hallucinations, Glutamate Decarboxylase, Synaptophysin, Gene Expression, Syntaxin 1, Pulvinar, Article, Cohort Studies, Gene Ontology, Acetyltransferases, Diagnosis, Glial Fibrillary Acidic Protein, alpha-Synuclein, Humans, Female, HSP70 Heat-Shock Proteins, Chitinase-3-Like Protein 1, RNA, Messenger, N-Ethylmaleimide-Sensitive Proteins
Abstract

Dementia with Lewy bodies is characterized by transient clinical features, including fluctuating cognition and visual hallucinations, implicating dysfunction of cerebral hub regions, such as the pulvinar nuclei of the thalamus. However, the pulvinar is typically only mildly affected by Lewy body pathology in dementia with Lewy bodies, suggesting additional factors may account for its proposed dysfunction.We conducted a comprehensive analysis of postmortem pulvinar tissue using whole-transcriptome RNA sequencing, protein expression analysis, and histological evaluation.We identified 321 transcripts as significantly different between dementia with Lewy bodies cases and neurologically normal controls, with gene ontology pathway analysis suggesting the enrichment of transcripts related to synapses and positive regulation of immune functioning. At the protein level, proteins related to synaptic efficiency were decreased, and general synaptic markers remained intact. Analysis of glial subpopulations revealed astrogliosis without activated microglia, which was associated with synaptic changes but not neurodegenerative pathology.These results indicate that the pulvinar, a region with relatively low Lewy body pathological burden, manifests changes at the molecular level that differ from previous reports in a more severely affected region. We speculate that these alterations result from neurodegenerative changes in regions connected to the pulvinar and likely contribute to a variety of cognitive changes resulting from decreased cortical synchrony in dementia with Lewy bodies. © 2018 International Parkinson and Movement Disorder Society.

Published
2018

14. Additional file 7: Table S7. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Subjects
genetic structures, mental disorders
Abstract

Functional Systems altered in Primary Visual Cortex in Dementia with Lewy Bodies (DOC 42 kb)

Published
2016
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15. Additional file 4: Table S5. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Abstract

Taqman q-RT-PCR Assay Details used in determination of mRNA relative levels in primary visual cortex. Assay ID, specific assay identifier; Gene Name, mRNA target of assay. (DOC 41 kb)

Published
2016
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16. Additional file 2: Table S6. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Abstract

Antibodies, suppliers, and usage. (DOC 47 kb)

Published
2016
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17. Additional file 1: Table S1. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Abstract

Patient Demographics of Neuropathology and Stereology Subjects [2, 3, 41]. (DOC 41 kb)

Published
2016
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18. Additional file 5: Table S3. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Subjects
genetic structures, mental disorders
Abstract

Analysis of pathology related genes in the primary visual cortex in Dementia with Lewy Bodies and Alzheimerâ s disease. (DOC 30 kb)

Published
2016
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19. Additional file 8: Table S4. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Abstract

GAD65/67 Mean (± SD) Cell Counts of GABAergic Neurones in the Primary (BA17) and Secondary (BA18) Visual cortex in Dementia with Lewy Bodies and Alzheimer’s disease. (DOC 30 kb)

Published
2016
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20. Additional file 3: Table S2. of Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad, Hanson, Peter, Erskine, Daniel, Lax, Nichola, Roscamp, Joseph, Karyka, Evangelia, Eliona Tsefou, Singh, Preeti, Cockell, Simon, Gribben, Andrew, Ramsay, Lynne, Blain, Peter, Mosimann, Urs, Lett, Deborah, Elstner, Matthias, Turnbull, Douglass, Xiang, Charles, Brownstein, Michael, O’Brien, John, John-Paul Taylor, Attems, Johannes, Thomas, Alan, McKeith, Ian, and Morris, Christopher

Abstract

Case Details For Microarray, q-PCR and Biochemistry Series [2, 3, 41]. (DOC 41 kb)

Published
2016
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22. [P3-130]: IMMUNE CELL INTERACTIONS IN AMYLOID-BETA PLAQUE PATHOLOGY

Author

Unger, Michael S., primary, Marschallinger, Julia, additional, Klein, Barbara, additional, Johnson, Mary, additional, Khundakar, Ahmad A., additional, Heneka, Michael, additional, Couillard-Despres, Sebastien, additional, Masliah, Eliezer, additional, Attems, Johannes, additional, and Aigner, Ludwig, additional

Published
2017
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23. Analysis of primary visual cortex in dementia with Lewy bodies indicates GABAergic involvement associated with recurrent complex visual hallucinations

Author

Khundakar, Ahmad A., primary, Hanson, Peter S., additional, Erskine, Daniel, additional, Lax, Nichola Z., additional, Roscamp, Joseph, additional, Karyka, Evangelia, additional, Tsefou, Eliona, additional, Singh, Preeti, additional, Cockell, Simon J., additional, Gribben, Andrew, additional, Ramsay, Lynne, additional, Blain, Peter G., additional, Mosimann, Urs P., additional, Lett, Deborah J., additional, Elstner, Matthias, additional, Turnbull, Douglass M., additional, Xiang, Charles C., additional, Brownstein, Michael J., additional, O’Brien, John T., additional, Taylor, John-Paul, additional, Attems, Johannes, additional, Thomas, Alan J., additional, McKeith, Ian G., additional, and Morris, Christopher M., additional

Published
2016
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27. Neuronal Loss and Α-Synuclein Pathology in the Superior Colliculus and Its Relationship to Visual Hallucinations in Dementia with Lewy Bodies.

Author

Attems, Johannes, Khundakar, Ahmad A., Erskine, Daniel, Morris, Christopher M., Thomas, Alan J., Taylor, John-Paul, McKeith, Ian G., and Savage, Michael A.

Abstract

Objective: Patients with dementia with Lewy bodies (DLB) often experience visual hallucinations, which are related to decreased quality of life for patients and increased caregiver distress. The pathologic changes that contribute to visual hallucinations are not known, but several hypotheses implicate deficient attentional processing. The superior colliculus has a role in visual attention and planning eye movements and has been directly implicated in several models of visual hallucinations. Therefore, the present study sought to identify neurodegenerative changes that may contribute to hallucinations in DLB.Methods: Postmortem superior colliculus tissue from 13 comparison, 10 DLB, and 10 Alzheimer disease (AD) cases was evaluated using quantitative neuropathologic methods.Results: α-Synuclein and tau deposition were more severe in deeper layers of the superior colliculus. DLB cases had neuronal density reductions in the stratum griseum intermedium, an important structure in directing attention toward visual targets. In contrast, neuronal density was reduced in all laminae of the superior colliculus in AD.Conclusion: These findings suggest that regions involved in directing attention toward visual targets are subject to neurodegenerative changes in DLB. Considering several hypotheses of visual hallucinations implicating dysfunctional attention toward external stimuli, these findings may provide evidence of pathologic changes that contribute to the manifestation of visual hallucinations in DLB. [ABSTRACT FROM AUTHOR]

Published
2017
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29. Deciphering the potential interplay between matrix metalloproteinase-9 (mmp9) and the mucin 4 (muc4) in glioblastoma molecular mechanisms and diagnostics

Author

Quesnel, Agathe, Islam, Meezanul, Khundakar, Ahmad, and Philippou, Panayiota

Abstract

Despite recent advances, the prognosis of glioblastoma (GBM), the most common brain cancer, remains poor. Evidence suggests that the epidermal growth factor receptor (EGFR)/matrix metalloproteinase-9 (MMP9) axis is implicated in gliomagenesis. Recent studies have shed light on EGFR interaction with the highly-glycosylated transmembrane mucin 4 (MUC4) with implication in carcinogenesis. MUC4 expression in glioma grades and its link with EGFR/MMP9-driven glioma progression have not been studied so far. Changes in the glycosylation pattern through alterations of glycoproteins, such as mucins, in brain cancer represent potential biomarkers in glioma diagnosis and monitoring. In this thesis, EGFR, MUC4, and MMP9 tissue expression was investigated to assess their utility as a panel of biomarkers. Secondly, this thesis aimed to define the molecular mechanisms underlying their role in GBM. Lastly, Raman spectroscopy (RS) with combined bioinformatic analyses were used to monitor changes in glycosylation for glioma diagnosis and monitoring. Immuno-staining techniques and ELISA were used in fixed tissue samples and blood serum samples. MUC4 was overexpressed in glioma grades, and especially in GBM, with MMP9. This expression was found in neoplastic cells and in the microvasculature. The two proteins combined had prognostic value. In-vitro assays using cellular models was employed to define the molecular mechanisms of the pathway and suggested that MUC4 might be involved in cancer cell dissemination and may interact with EGFR in glioma cells. Gene expression analysis supported the involvement of the three proteins in a common pathway. The utility of Raman spectroscopy combined with classification learning was lastly demonstrated on cellular models. This methodology showed a promising high sensitivity potential for the detection of subtle glycoprotein patterns in cell lines. Importantly, this approach was found useful in discriminating glioma grades with high accuracy in tissue and serum samples. Discrimination was possible owing to a significant change in glycosylation.

Published
2023

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