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Genes to remember: imaging genetics of hippocampus-based memory functions
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the field of imaging genetics, brain function and structure are used as intermediate phenotypes between genes and cognition/diseases to validate and extend findings from behavioral genetics. In this thesis, three of the strongest candidate genes for episodic memory, KIBRA, BDNF, and APOE, were examined in relation to memory performance and hippocampal/parahippocampal fMRI blood-oxygen level-dependent (BOLD) signal. A common T allele in the KIBRA gene was previously associated with superior memory, and increased hippocampal activation was observed in noncarriers of the T allele which was interpreted as reflecting compensatory recruitment. The results from the first study revealed that both memory performance and hippocampal activation at retrieval was higher in T allele carriers (study I). The BDNF 66Met and APOE ε4 alleles have previously been associated with poorer memory performance, but their relation to brain activation has been inconsistent with reports of both increased and decreased regional brain activation relative to noncarriers. Here, decreased hippocampal/parahippocampal activation was observed in carriers of BDNF 66Met (study II) as well as APOE ε4 (study III) during memory encoding. In addition, there was an additive gene-gene effect of APOE and BDNF on hippocampal and parahippocampal activation (study III). Collectively, the results from these studies on KIBRA, BDNF, and APOE converge on higher medial temporal lobe activation for carriers of a high-memory associated allele, relative to carriers of a low-memory associated allele. In addition, the observed additive effect of APOE and BDNF demonstrate that a larger amount of variance in BOLD signal change can be explained by considering the combined effect of more than one genetic polymorphism. These imaging genetics findings support and extend previous knowledge from behavioral genetics on the role of these memory-related genes.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 84 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1580
Keyword [en]
Imaging genetics, fMRI, Episodic memory, SNP, KIBRA, BDNF, APOE, Hippocampus, Parahippocampus
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-71141ISBN: 978-91-7459-598-7 (print)ISBN: 978-91-7459-597-0 (print)OAI: oai:DiVA.org:umu-71141DiVA: diva2:622176
Public defence
2013-06-14, BiA 201, Biologihuset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2013-05-24 Created: 2013-05-20 Last updated: 2015-04-30Bibliographically approved
List of papers
1. KIBRA polymorphism is related to enhanced memory and elevated hippocampal processing
Open this publication in new window or tab >>KIBRA polymorphism is related to enhanced memory and elevated hippocampal processing
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2011 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, no 40, 14218-14222 p.Article in journal (Refereed) Published
Abstract [en]

Several studies have linked the KIBRA rs17070145 T polymorphism to superior episodic memory in healthy humans. One study investigated the effect of KIBRA on brain activation patterns (Papassotiropoulos et al., 2006) and observed increased hippocampal activation in noncarriers of the T allele during retrieval. Noncarriers were interpreted to need more hippocampal activation to reach the same performance level as T carriers. Using large behavioral (N = 2230) and fMRI (N = 83) samples, we replicated the KIBRA effect on episodic memory performance, but found increased hippocampal activation in T carriers during episodic retrieval. There was no evidence of compensatory brain activation in noncarriers within the hippocampal region. In the main fMRI sample, T carriers performed better than noncarriers during scanning but, importantly, the difference in hippocampus activation remained after post hoc matching according to performance, sex, and age (N = 64). These findings link enhanced memory performance in KIBRA T allele carriers to elevated hippocampal functioning, rather than to neural compensation in noncarriers.

Place, publisher, year, edition, pages
Bethesda, Md.: The Soc., 2011
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-48524 (URN)10.1523/JNEUROSCI.3292-11.2011 (DOI)21976506 (PubMedID)
Available from: 2011-10-20 Created: 2011-10-20 Last updated: 2017-12-08
2. Decreased medial temporal lobe activation in BDNF 66Met allele carriers during memory encoding
Open this publication in new window or tab >>Decreased medial temporal lobe activation in BDNF 66Met allele carriers during memory encoding
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2013 (English)In: Neuropsychologia, ISSN 0028-3932, E-ISSN 1873-3514, Vol. 51, no 12, 2462-2468 p.Article in journal (Refereed) Published
Abstract [en]

The Met allele of the Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism has been associated with impaired activity-dependent secretion of BDNF protein and decreased memory performance. Results from imaging studies relating Val(66)Met to brain activation during memory processing have been inconsistent, with reports of both increased and decreased activation in the Medial Temporal Lobe (MTL) in Met carriers relative to Val homozygotes. Here, we extensively studied BDNF Val(66)Met in relation to brain activation and white matter integrity as well as memory performance in a large imaging (n=194) and behavioral (n=2229) sample, respectively. Functional magnetic resonance imaging (fMRI) was used to investigate MTL activation in healthy participants in the age of 55-75 years during a face-name episodic encoding and retrieval task. White matter integrity was measured using diffusion tensor imaging.

BDNF Met allele carriers had significantly decreased activation in the MTL during encoding processes, but not during retrieval processes. In contrast to previous proposals, the effect was not modulated by age and the polymorphism was not related to white matter integrity. Met carriers had lower memory performance than Val homozygotes, but differences were subtle and not significant. In conclusion, the BDNF Met allele has a negative influence on MTL functioning, preferentially during encoding processes, which might translate into impaired episodic memory function.

Place, publisher, year, edition, pages
Elsevier, 2013
Keyword
imaging, genetics, memory, Val66Met, Parahippocampus
National Category
Neurosciences
Research subject
Physiology
Identifiers
urn:nbn:se:umu:diva-71132 (URN)10.1016/j.neuropsychologia.2012.11.028 (DOI)000328526800014 ()
Available from: 2013-05-20 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
3. Additive genetic effect of APOE and BDNF on hippocampus activity
Open this publication in new window or tab >>Additive genetic effect of APOE and BDNF on hippocampus activity
2014 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 89, no 1, 306-313 p.Article in journal (Refereed) Published
Abstract [en]

Human memory is a highly heritable polygenic trait with complex inheritance patterns. To study the genetics of memory and memory-related diseases, hippocampal functioning has served as an intermediate phenotype. The importance of investigating gene-gene effects on complex phenotypes has been emphasized, but most imaging studies still focus on single polymorphisms. APOE ε4 and BDNF Met, two of the most studied gene variants for variability in memory performance and neuropsychiatric disorders, have both separately been related to poorer episodic memory and altered hippocampal functioning. Here, we investigated the combined effect of APOE and BDNF on hippocampal activation (N=151). No non-additive interaction effects were seen. Instead, the results revealed decreased activation in bilateral hippocampus and parahippocampus as a function of the number of APOE ε4 and BDNF Met alleles present (neither, one, or both). The combined effect was stronger than either of the individual effects, and both gene variables explained significant proportions of variance in BOLD signal change. Thus, there was an additive gene-gene effect of APOE and BDNF on medial temporal lobe (MTL) activation, showing that a larger proportion of variance in brain activation attributed to genetics can be explained by considering more than one gene variant. This effect might be relevant for the understanding of normal variability in memory function as well as memory-related disorders associated with APOE and BDNF.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-86666 (URN)10.1016/j.neuroimage.2013.11.049 (DOI)000332057400029 ()24321557 (PubMedID)2-s2.0-84892892084 (Scopus ID)
Note

Originally included in thesis in manuscript form.

Available from: 2014-03-04 Created: 2014-03-04 Last updated: 2017-12-05Bibliographically approved

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