Association of TTR polymorphisms with hippocampal atrophy in Alzheimer disease families

Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Neurobiology of aging (Impact Factor: 5.01). 04/2009; 32(2):249-56. DOI: 10.1016/j.neurobiolaging.2009.02.014
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In vitro and animal model studies suggest that transthyretin (TTR) inhibits the production of the amyloid β protein, a major contributor to Alzheimer disease (AD) pathogenesis. We evaluated the association of 16 TTR single nucleotide polymorphisms (SNPs) with AD risk in 158 African American and 469 Caucasian discordant sibships from the MIRAGE Study. There was no evidence for association of TTR with AD in either population sample. To examine the possibility that TTR SNPs affect specific components of the AD process, we tested association of these SNPs with four measures of neurodegeneration and cerebrovascular disease defined by magnetic resonance imaging (MRI) in a subset of 48 African American and 265 Caucasian sibships. Five of seven common SNPs and several haplotypes were significantly associated with hippocampal atrophy in the Caucasian sample. Two of these SNPs also showed marginal evidence for association in the African American sample. Results for the other MRI traits were unremarkable. This study highlights the potential value of neuroimaging endophenotypes as a tool for finding genes influencing AD pathogenesis.

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    • "In respect to brain function, previous neuroimaging studies of language processing in healthy subjects have demonstrated cerebral activation at the left hemispheric frontotempo-parietal cortices by using functional magnetic resonance imaging (fMRI) (Frost et al., 1999; Springer et al., 1999; Price, 2000; Koeda et al., 2006a, 2007). On the other hand, recent genetic neuroimaging studies have verified the influence of single nucleotide polymorphisms (SNPs) in relation to brain structure and brain function (Camara et al., 2010; Frielingsdorf et al., 2010; Cuenco et al., 2011; Chen et al., 2012; Forbes et al., 2012; Hajek et al., 2012; Blasi et al., 2013; Clemm Von Hohenberg et al., 2013). The contactin-associated protein-like 2 (CNTNAP2) gene is known as a transcriptional factor regulated by forkhead box P2 (FOXP2) gene related to language processing (Grigorenko, 2009; Newbury and Monaco, 2010; Catani et al., 2011; Penagarikano and Geschwind, 2012; Graham and Fisher, 2013; Rodenas- Cuadrado et al., 2014). "
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    ABSTRACT: Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: (1) rs7794745 (A/A or A/T), (2) rs2710102 [G/G or A carrier (A/G and A/A)], and (3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals.
    Frontiers in Behavioral Neuroscience 05/2015; 9(87). DOI:10.3389/fnbeh.2015.00087 · 3.27 Impact Factor
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    • "It has been demonstrated that not only the relatively rare mutations but also common variants of the TTR gene are differentially capable of altering the ability of TTR to carry and transport its ligands [28]. This has been shown in particular for the TTR single nucleotide polymorphisms (SNPs) rs13381522 and rs3764478 (both lie at the 5`end in the promoter region of the TTR gene), rs1800458 (located in exon 2, leads to a non-synonymous amino acid exchange of glycin to serin on position 26 of the TTR nucleotide sequence), rs723744 (localized in intron 3, does not result in amino acid differences), and rs36204272 (is intronic and spliced posttranslationally, should have no effect on the TTR protein) [15], [29]–[31]. As LBD patients obviously show neuronal and neural clearance deficits comparable to AD [16] and TTR seems to be critically involved in these mechanisms, we hypothesized that blood and CSF levels of TTR are altered in LBD patients and may be associated with clinical and demographic data, and that occurrence of the abovementioned SNPs are associated with these TTR levels. "
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    ABSTRACT: Parkinson's disease (PD) without (non-demented, PDND) and with dementia (PDD), and dementia with Lewy bodies (DLB) are subsumed under the umbrella term Lewy body disorders (LBD). The main component of the underlying pathologic substrate, i.e. Lewy bodies and Lewy neurites, is misfolded alpha-synuclein (Asyn), and - in particular in demented LBD patients - co-occurring misfolded amyloid-beta (Abeta). Lowered blood and cerebrospinal fluid (CSF) levels of transthyretin (TTR) - a clearance protein mainly produced in the liver and, autonomously, in the choroid plexus - are associated with Abeta accumulation in Alzheimer's disease. In addition, a recent study suggests that TTR is involved in Asyn clearance. We measured TTR protein levels in serum and cerebrospinal fluid of 131 LBD patients (77 PDND, 26 PDD, and 28 DLB) and 72 controls, and compared TTR levels with demographic and clinical data as well as neurodegenerative markers in the CSF. Five single nucleotide polymorphisms of the TTR gene which are considered to influence the ability of the protein to carry its ligands were also analyzed. CSF TTR levels were significantly higher in LBD patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by PDND patients. In addition, CSF TTR levels correlated negatively with CSF Abeta(1-42), total tau and phospho-tau levels. Serum TTR levels did not significantly differ among the studied groups. There were no relevant associations between TTR levels and genetic, demographic and clinical data, respectively. These results suggest an involvement of the clearance protein TTR in LBD pathophysiology, and should motivate to elucidate TTR-related mechanisms in LBD in more detail.
    PLoS ONE 10/2012; 7(10):e48042. DOI:10.1371/journal.pone.0048042 · 3.23 Impact Factor
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    • "Also plausible is the possibility that patients with AD have a genetic or acquired low CSF TTR level independent of Aβ binding, which conceivably could put them at greater risk for AD. A recent analysis of TTR single nucleotide polymorphisms (SNPs) in the MIRAGE study of AD families has associated 5 TTR SNPs with hippocampal atrophy [186]. A prior single small study did not identify AD in carriers of amyloidogenic TTR mutations, but there is no a priori reason why such mutations would predispose to Aβ deposition [187]. "
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    ABSTRACT: Since the mid-1990's a trickle of publications from scattered independent laboratories have presented data suggesting that the systemic amyloid precursor transthyretin (TTR) could interact with the amyloidogenic β-amyloid (Aβ) peptide of Alzheimer's disease (AD). The notion that one amyloid precursor could actually inhibit amyloid fibril formation by another seemed quite far-fetched. Further it seemed clear that within the CNS, TTR was only produced in choroid plexus epithelial cells, not in neurons. The most enthusiastic of the authors proclaimed that TTR sequestered Aβ in vivo resulting in a lowered TTR level in the cerebrospinal fluid (CSF) of AD patients and that the relationship was salutary. More circumspect investigators merely showed in vitro interaction between the two molecules. A single in vivo study in Caenorhabditis elegans suggested that wild type human TTR could suppress the abnormalities seen when Aβ was expressed in the muscle cells of the worm. Subsequent studies in human Aβ transgenic mice, including those from our laboratory, also suggested that the interaction reduced the Aβ deposition phenotype. We have reviewed the literature analyzing the relationship including recent data examining potential mechanisms that could explain the effect. We have proposed a model which is consistent with most of the published data and current notions of AD pathogenesis and can serve as a hypothesis which can be tested.
    Molecular Neurodegeneration 11/2011; 6(1):79. DOI:10.1186/1750-1326-6-79 · 6.56 Impact Factor
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