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GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.

ABSTRACT: The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3? gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including tau, and has also been associated with risk for neurodegenerative disorders and schizophrenia. We examined the effects of MAPT and two functional promoter polymorphisms in GSK3B (rs3755557 and rs334558) on total grey matter and intracranial volume in three independent cohorts totaling 776 neurologically healthy individuals. In vitro analyses revealed a significant effect of rs3755557 on gene expression, and altered binding of at least two transcription factors, Octamer transcription factor 1 (Oct-1) and Pre-B-cell leukemia transcription factor 1 (Pbx-1), to the GSK3B promoter. Meta-analysis across the three cohorts revealed a significant effect of rs3755557 on total grey matter volume (summary B?=?0.082, 95% confidence interval?=?0.037-0.128) and intracranial volume (summary B?=?0.113, 95% confidence interval?=?0.082-0.144). No significant effect was observed for MAPT H1/H2 diplotype or GSK3B rs334558 on total grey matter or intracranial volume. Our genetic and biochemical analyses have identified a role for GSK3B in brain development, which could have important aetiological implications for neurodegenerative and neurodevelopmental disorders.

SUBMITTER: Dobson-Stone C

PROVIDER: S-EPMC3741177 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.

Dobson-Stone Carol C Polly Patsie P Korgaonkar Mayuresh S MS Williams Leanne M LM Gordon Evian E Schofield Peter R PR Mather Karen K Armstrong Nicola J NJ Wen Wei W Sachdev Perminder S PS Kwok John B J JB

PloS one 20130812 8

The microtubule-associated protein tau gene (MAPT) codes for a protein that plays an integral role in stabilisation of microtubules and axonal transport in neurons. As well as its role in susceptibility to neurodegeneration, previous studies have found an association between the MAPT haplotype and intracranial volume and regional grey matter volumes in healthy adults. The glycogen synthase kinase-3β gene (GSK3B) codes for a serine/threonine kinase that phosphorylates various proteins, including ...[more]

PMID: 23951236

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Project description:Abstract Delirium is associated with long-term cognitive dysfunction and with increased brain atrophy. However, it is unclear whether these problems result from or predisposes to delirium. We aimed to investigate preoperative to postoperative brain changes, as well as the role of delirium in these changes over time. We investigated the effects of surgery and postoperative delirium with brain MRIs made before and 3 months after major elective surgery in 299 elderly patients, and an MRI with a 3 months follow-up MRI in 48 non-surgical control participants. To study the effects of surgery and delirium, we compared brain volumes, white matter hyperintensities and brain infarcts between baseline and follow-up MRIs, using multiple regression analyses adjusting for possible confounders. Within the patients group, 37 persons (12%) developed postoperative delirium. Surgical patients showed a greater decrease in grey matter volume than non-surgical control participants [linear regression: B (95% confidence interval) = −0.65% of intracranial volume (−1.01 to −0.29, P < 0.005)]. Within the surgery group, delirium was associated with a greater decrease in grey matter volume [B (95% confidence interval): −0.44% of intracranial volume (−0.82 to −0.06, P = 0.02)]. Furthermore, within the patients, delirium was associated with a non-significantly increased risk of a new postoperative brain infarct [logistic regression: odds ratio (95% confidence interval): 2.8 (0.7–11.1), P = 0.14]. Our study was the first to investigate the association between delirium and preoperative to postoperative brain volume changes, suggesting that delirium is associated with increased progression of grey matter volume loss. Kant et al. report that patients with postoperative delirium have an increased progression of grey matter loss compared to patients without postoperative delirium. These changes may contribute to impaired long-term cognitive outcomes of postoperative delirium. Graphical Abstract Graphical abstract

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GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.

Publications

GSK3B and MAPT polymorphisms are associated with grey matter and intracranial volume in healthy individuals.

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