Neurobiology of Aging 36 (2015) 2024e2033

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The effect of TOMM40 on spatial navigation in amnestic mild cognitive impairment Jan Laczó a, b, *, Ross Andel b, c, Martin Vyhnalek a, b, Vaclav Matoska d, Vojtech Kaplan d, Zuzana Nedelska a, b, Ondrej Lerch a, Ivana Gazova a, b, Scott D. Moffat e, Jakub Hort a, b a Memory Clinic, Department of Neurology, Charles University in Prague, Second Faculty of Medicine and Motol University Hospital, Prague, The Czech Republic b International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, The Czech Republic c School of Aging Studies, University of South Florida, Tampa, FL, USA d Department of Clinical Biochemistry, Hematology and Immunology, Homolka Hospital, Prague, The Czech Republic e School of Psychology, Georgia Institute of Technology, Atlanta, GA, USA

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Article history: Received 11 November 2014 Received in revised form 11 February 2015 Accepted 7 March 2015 Available online 16 March 2015

The very long (VL) poly-T variant at rs10524523 (“523”) of the TOMM40 gene may hasten the onset of late-onset Alzheimer’s disease (LOAD) and induce more profound cognitive impairment compared with the short (S) poly-T variant. We examined the influence of TOMM40 “523” polymorphism on spatial navigation and its brain structural correlates. Participants were apolipoprotein E (APOE) ε3/ε3 homozygotes with amnestic mild cognitive impairment (aMCI). The homozygotes were chosen because APOE ε3/ε3 variant is considered “neutral” with respect to LOAD risk. The participants were stratified according to poly-T length polymorphisms at “523” into homozygous for S (S/S; n ¼ 16), homozygous for VL (VL/VL; n ¼ 15) TOMM40 poly-T variant, and heterozygous (S/VL; n ¼ 28) groups. Neuropsychological examination and testing in real-space human analog of the Morris Water Maze were administered. Both selfcentered (egocentric) and world-centered (allocentric) spatial navigation was assessed. Brain magnetic resonance imaging scans were analyzed using FreeSurfer software. The S/S group, although similar to S/VL and VL/VL groups in demographic and neuropsychological profiles, performed better on allocentric navigation (p  0.004) and allocentric delayed recall (p  0.014), but not on egocentric navigation. Both S/VL and VL/VL groups had thinner right entorhinal cortex (p  0.043) than the S/S group, whereas only the VL/VL group had thinner left entorhinal cortex (p ¼ 0.043) and left posterior cingulate cortex (p ¼ 0.024) than the S/S group. In conclusion, TOMM40 “523” VL variants are related to impairment in allocentric spatial navigation and reduced cortical thickness of specific brain regions among aMCI individuals with (LOAD neutral) APOE ε3/ε3 genotype. This may reflect a specific role of TOMM40 “523” in the pathogenesis of LOAD. Ó 2015 Elsevier Inc. All rights reserved.

Keywords: Alzheimer’s disease Apolipoprotein E Magnetic resonance imaging Morris Water Maze Neuropsychology Memory Hippocampus

1. Introduction Among early cognitive markers of Alzheimer’s disease (AD), increasing attention has been paid recently to spatial navigation impairment (Abbott and Callaway, 2014; Lithfous et al., 2013; Serino et al., 2014; Vl cek and Laczó, 2014). Difficulties with navigation in unfamiliar surroundings is a commonly reported complaint by patients with AD. Impairment of spatial navigation is often present early in the course of ADdin individuals with mild * Corresponding author at: Department of Neurology, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, Praha 5 e Motol 150 06, The Czech Republic. Tel.: þ420 224 436 816; fax: þ420 224 436 875. E-mail address: [email protected] (J. Laczó). 0197-4580/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2015.03.004

cognitive impairment (MCI) (Benke et al., 2014; Cushman et al., 2008; deIpolyi et al., 2007). This is especially so for individuals with amnestic MCI (aMCI) (Hort et al., 2007; Weniger et al., 2011), whose risk of conversion to AD is particularly high (Petersen, 2004), and its subgroups composed of individuals with hippocampal type of memory impairment (Laczó et al., 2009, 2012), hippocampal atrophy (Nedelska et al., 2012), and in apolipoprotein E (APOE) ε4 carriers (Berteau-Pavy et al., 2007; Laczó et al., 2010, 2011). Spatial navigation includes 2 basic navigation strategiesdthe self-centered (egocentric) and the world-centered (allocentric) (Maguire et al., 1998). Allocentric navigation, which uses distal orientation cues (landmarks) for navigation independent of the individual’s position, is closely tied with the function of the hippocampus (Maguire et al., 1998) and its connections with the

J. Laczó et al. / Neurobiology of Aging 36 (2015) 2024e2033

entorhinal cortex (Ekstrom et al., 2003). Egocentric navigation, which uses own position to set distances and directions to the final destination (is dependent on own position), is reflected in the function of the posterior-inferior parietal cortex (Maguire et al., 1998) and precuneus (Weniger et al., 2009), as well as the caudate nucleus when navigation is relatively simple (Hartley et al., 2003). Finally, the posterior cingulate cortex plays a crucial role for translation between egocentric and allocentric navigation strategies (Byrne et al., 2007). The APOE ε4 is the main known genetic risk factor for the most common form of AD, late-onset AD (LOAD) (Saunders et al., 1996), and it also increases the risk of conversion from MCI to dementia (Xu et al., 2013). Recently, the TOMM40 gene, which encodes the translocase of the outer mitochondrial membrane pore subunit (Humphries et al., 2005) and is adjacent to and in linkage disequilibrium with APOE, has been proposed as another genetic risk factor for LOAD (Roses et al., 2010). Roses et al. (2010) demonstrated that a variable length deoxythymidine homopolymer (poly-T) at rs10524523 (“523”) within intron 6 of the TOMM40 gene modulates risk and onset age of LOAD (Lutz et al., 2010; Roses et al., 2010). The length of the poly-T homopolymer was proposed to be categorized as short (14e20 repeats; i.e., S), long (21e29 repeats, i.e., L), or very long (>29 repeats, i.e., VL). Because of the linkage disequilibrium between APOE and TOMM40 genes, the APOE ε3 allele may be linked to either the S or VL variants of TOMM40 “523”, whereas APOE ε4 is almost exclusively linked to the L variant (Roses et al., 2010). In individuals with APOE ε3, including APOE ε3/ε3 carriers, who were considered to have neutral risk for LOAD, the VL variants were found to be associated with a higher risk for and earlier onset age of LOAD, whereas the S variants were associated with later age of onset (Roses et al., 2010). Researchers have suggested the importance of TOMM40 “523” in early LOAD pathogenesis and proposed that in asymptomatic individuals TOMM40 “523” may induce cognitive and brain changes similar to those found in AD (Caselli et al., 2012; Hayden et al., 2012; Johnson et al., 2011). The VL variants were associated with lower memory performance (Caselli et al., 2012; Hayden et al., 2012; Johnson et al., 2011), reduced gray matter volume in the posterior cingulate cortex, and greater age-related differences in gray matter volume of the right anterior medial temporal lobe (Johnson et al., 2011). We build on previous research demonstrating that spatial navigation impairment is present very early in the course of AD (deIpolyi et al., 2007; Hort et al., 2007; Weniger et al., 2011). It is also known that spatial navigation is highly susceptible to the influence of genetic risk factors, especially to the deleterious effect of APOE ε4 (Berteau-Pavy et al., 2007; Laczó et al., 2011), with the right hippocampal volume particularly affected (Laczó et al., 2014). Here we focused on individuals with aMCI with the APOE ε3/ε3 genotype, considered “neutral” with respect to LOAD risk, thus eliminating variance associated with protective and risk APOE alleles (Roses et al., 2010). We assessed the effects of a new promising genetic risk factor for LOAD, TOMM40 “523”, using data from performance on 2 basic spatial navigation strategies and the relevant structural brain correlates. The aims of this study were to evaluate the associations between the poly-T variants at rs10524523 of TOMM40 gene and (1) 2 basic spatial navigation strategies, allocentric and egocentric, in a realspace human analog of the Morris Water Maze (hMWM) and (2) volumes or cortical thicknesses of the brain regions known to be important for spatial navigation (i.e., hippocampus, caudate nucleus, entorhinal, posterior-inferior parietal, precuneal, and posterior cingulate cortices) among individuals with aMCI with the APOE ε3/ε3 genotype.

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We hypothesized that those with VL poly-T variant at rs10524523 of TOMM40 gene would perform worse on spatial navigation than those homozygous for S poly-T variant. We expected differences primarily in the allocentric navigation strategy, which is the first navigation strategy impaired in AD (Hort et al., 2007) and in normal aging (Rodgers et al., 2012) and which depends on the medial temporal lobe structures, an initial site of AD pathological processes (Braak and Braak, 1991) and TOMM40-induced mitochondrial dysfunction and apoptotic processes (Devi et al., 2006). Furthermore, we hypothesized that spatial navigation impairment among those with VL poly-T variant would be accompanied by atrophy of (1) the medial temporal lobe structures, which are affected early in AD and are also susceptible to TOMM40 “523” induced age-dependent gray matter volume reduction (Johnson et al., 2011), and (2) the posterior cingulate cortex, which is one of the earliest regions involved in AD pathogenesis (Rowe et al., 2007), susceptible to TOMM40 “523” induced gray matter volume reduction (Johnson et al., 2011) and a key structure for translation between egocentric and allocentric navigation strategies (Byrne et al., 2007). 2. Methods 2.1. Participants Fifty-nine right-handed APOE ε3 homozygotes with aMCI were recruited from the Czech Brain Aging Study cohort at the Memory Disorders Clinic at Second Faculty of Medicine, Charles University and Motol University Hospital in Prague, Czech Republic between February 2006 and February 2012. They underwent standard neurological, internal and laboratory evaluations, brain magnetic resonance imaging at 1.5 T, neuropsychological examination, and spatial navigation testing in a real-space hMWM within 2 months from the first visit. Participants were referred to the clinic by general practitioners, neurologists, psychiatrists, and geriatricians. Referral to the memory clinic was triggered by memory complaint from the patient or the informant. All participants met clinical criteria for aMCI (Petersen, 2004), including memory complaints reported by a patient or caregiver, evidence of memory dysfunction on neuropsychological testing, generally intact activities of daily living and absence of dementia. All participants had Clinical Dementia Rating global score no greater than 0.5, which commonly designates MCI (Morris, 1993). Memory impairment was established when the patient scored more than 1.5 standard deviations below the mean of age- and education-adjusted norms on any memory test (Laczó et al., 2011). The aMCI patients included both those with isolated memory impairment (single-domain aMCI) and those with memory impairment and additional impairment in any other non-memory domain (multiple-domain aMCI). Participants with depression (6 points on the 15-item Geriatric Depression Scale); (Yesavage, 1988), with a Hachinski Ischemic Scale score 5, and with a history of other primary neurological or psychiatric disorders were not included in this study. The aMCI patients were further stratified into 3 groups based on the TOMM40 poly-T length polymorphisms at rs10524523 using a standard procedure (Roses et al., 2010)dhomozygous for S (S/S; n ¼ 16) poly-T variant, homozygous for VL (VL/VL; n ¼ 15) poly-T variant, and heterozygous (S/VL; n ¼ 28) groups. Group-wise characteristics are listed in Table 1. The study was approved by an institutional ethical committee and the participants have signed written informed consent. 2.2. Neuropsychological battery The neuropsychological assessment comprised the following tests: (1) verbal memory measured with the Rey Auditory

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Table 1 Characteristics of study participants; means (SD) Variables

aMCI S/S (n ¼ 16)

aMCI S/VL (n ¼ 28)

aMCI VL/VL (n ¼ 15)

p-Values

Effect sizes

Women, n (%) Age in years Age in years (range) Education in years MMSE score GDS score RAVLT 1e5 score RAVLT 30 score ECRT free recall score ECRT total recall score TMT A score (in seconds) TMT B score (in seconds) COWAT score Digit span total numbers recalled Reversed digit span total numbers recalled ROCFT-C score ROCFT-IR score BNT error score Allocentric-egocentric navigation distance error value (cm) Egocentric navigation distance error value (cm) Allocentric navigation distance error value (cm) Delayed navigation distance error value (cm) Left hippocampal volume, eTIV adjusted (mm3) Right hippocampal volume, eTIV adjusted (mm3) Left caudate volume, eTIV adjusted (mm3) Right caudate volume, eTIV adjusted (mm3) Left entorhinal cortical thickness (mm) Right entorhinal cortical thickness (mm) Left posterior inferior parietal cortical thickness (mm) Right posterior inferior parietal cortical thickness (mm) Left precuneal cortical thickness (mm) Right precuneal cortical thickness (mm) Left posterior cingulate cortical thickness (mm) Right posterior cingulate cortical thickness (mm)

9 73.9 65e80 14.8 27.6 2.6 36.9 4.7 4.6 12.8 54.8 164.0 41.8 6.0 4.2 28.1 6.6 6.3 49.4 33.6 47.8 53.3 3654.3 3765.7 3313.0 3328.9 3.2 3.5 2.3 2.5 2.2 2.2 2.3 2.2

9 75.4 62e86 15.1 26.2 3.0 32.5 4.5 6.2 13.6 55.4 179.6 33.1 5.4 4.1 26.9 9.6 5.3 63.5 59.1 99.3 120.6 2907.3 3172.0 3451.7 3471.0 2.7 2.8 2.2 2.2 1.9 1.9 2.1 2.1

7 75.4 62e84 13.6 27.6 3.0 35.6 6.6 6.6 14.2 70.1 234.7 32.1 5.4 4.0 29.1 8.8 5.3 71.0 66.4 87.9 106.2 3059.7 3070.4 3143.3 3181.0 2.7 2.8 2.1 2.1 2.0 2.0 1.9 2.0

0.276 0.707 N/A 0.319 0.144 0.922 0.652 0.392 0.521 0.734 0.327 0.388 0.105 0.222 0.876 0.461 0.518 0.895 0.631 0.052