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Different Hippocampus Functional Connectivity Patterns in Healthy Young Adults with Mutations of APP/Presenilin-1/2 and APOEε4

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Abstract

This study aims to explore the hippocampus-based functional connectivity patterns in young, healthy APP and/or presenilin-1/2 mutation carriers and APOE ε4 subjects. Seventy-eight healthy young adults (33 male, mean age 24.0 ± 2.2 years; 18 APP and/or presenilin1/2 mutation carriers [APP/presenilin-1/2 group], 30 APOE ε4 subjects [APOE ε4 group], and 30 subjects without the above-mentioned genes [control group]) underwent resting-state functional MR imaging and neuropsychological assessments. Bilateral hippocampus functional connectivity patterns were compared among three groups. The brain regions with statistical differences were then extracted, and correlation analyses were performed between Z values of the brain regions and neuropsychological results. Compared with control group, both APOE ε4 group and APP/presenilin-1/2 group showed increased functional connectivity in medial prefrontal cortex and precuneus for the seeds of bilateral hippocampi. The APOE ε4 group displayed increased functional connectivity from bilateral hippocampi to the left middle temporal gyrus compared with the control group. Moreover, compared with the APP/presenilin-1/2 group, the APOE ε4 group also had markedly increased functional connectivity in right hippocampus-left middle temporal gyrus. The Z values of right hippocampus-left middle temporal gyrus correlated with various neuropsychological results across all the subjects, as well as in APOE ε4 group. Young healthy adults carrying APOE ε4 and APP/presenilin-1/2 displayed different hippocampus functional connectivity patterns, which may underlie the discrepant mechanisms of gene-modulated cognitive dysfunction in Alzheimer’s disease.

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References

  1. Kim DH, Yeo SH, Park J-M, Choi JY, Lee T-H, Park SY, Ock MS, Eo J et al (2014) Genetic markers for diagnosis and pathogenesis of Alzheimer’s disease. Gene 545:185–193

    Article  CAS  PubMed  Google Scholar 

  2. Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG (2004) Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE ɛ4 allele. Neurology 62:1990–1995

    Article  CAS  PubMed  Google Scholar 

  3. Sala-Llonch R, Fortea J, Bartrés-Faz D, Bosch B, Lladó A, Peña-Gómez C, Antonell A, Castellanos-Pinedo F (2013) Evolving brain functional abnormalities in psen1 mutation carriers: a resting and visual encoding FMRI study. J Alzheimers Dis 36:165–175

    CAS  PubMed  Google Scholar 

  4. Kerchner GA, Berdnik D, Shen JC, Bernstein JD, Fenesy MC, Deutsch GK, Wyss-Coray T, Rutt BK (2014) APOE ɛ4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory. Neurology 82:691–697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Godbolt a K, Beck J a, Collinge J, Garrard P, Warren JD, Fox NC, Rossor MN (2004) A presenilin 1 R278I mutation presenting with language impairment. Neurology 63:1702–1704

    Article  CAS  PubMed  Google Scholar 

  6. Guo Q, Wang Z, Li H, Wiese M, Zheng H (2012) APP physiological and pathophysiological functions: insights from animal models. Cell Res Nature Publishing Group 22:78–89

    CAS  Google Scholar 

  7. Zhu L, Zhong M, Elder GA, Sano M, Holtzman DM, Gandy S, Cardozo C, Haroutunian V et al (2015) Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis. Proc Natl Acad Sci U S A 112:11965–11970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Loy CT, Schofield PR, Turner AM, Kwok JBJ (2014) Genetics of dementia. Lancet 383:828–840

    Article  CAS  PubMed  Google Scholar 

  9. Jiang Y, Huang H, Abner E, Broster LS, Jicha GA, Schmitt FA, Kryscio R, Andersen A et al (2016) Alzheimer’s biomarkers are correlated with brain connectivity in older adults differentially during resting and task states. Front Aging Neurosci 8:15

    PubMed  PubMed Central  Google Scholar 

  10. Westlye ET, Lundervold A, Rootwelt H, Lundervold AJ, Westlye LT (2011) Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE ε4 carriers: relationships with memory performance. J Neurosci 31:7775–7783

    Article  CAS  PubMed  Google Scholar 

  11. Mufson EJ, Mahady L, Waters D, Counts SE, Perez SE, DeKosky S, Ginsberg SD, Ikonomovic MD et al (2015) Hippocampal plasticity during the progression of Alzheimer’s disease. Neuroscience IBRO 309:51–67

    Article  CAS  Google Scholar 

  12. Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L, Wu T, Jiang T et al (2006) Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: evidence from resting state fMRI. NeuroImage 31:496–504

    Article  PubMed  Google Scholar 

  13. Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (2004) Impact of APOE in mild cognitive impairment. Neurology 63:1898–1901

    Article  CAS  PubMed  Google Scholar 

  14. Hostage CA, Choudhury KR, Doraiswamy PM, Petrella JR (2014) Mapping the effect of the apolipoprotein e genotype on 4-year atrophy rates in an Alzheimer disease-related brain. Radiology 271:211–219

    Article  PubMed  Google Scholar 

  15. Honea RA, Vidoni E, Harsha A, Burns JM (2009) Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. J Alzheimers Dis 18:553–564

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wang J, Wang X, He Y, Yu X, Wang H, He Y (2015) Apolipoprotein ɛ4 modulates functional brain connectome in Alzheimer’s disease. Hum Brain Mapp 36:1828–1846

    Article  PubMed  Google Scholar 

  17. Quiroz YT, Budson AE, Celone K, Ruiz A, Newmark R, Castrillõn G, Lopera F, Stern CE (2010) Hippocampal hyperactivation in presymptomatic familial Alzheimer’s disease. Ann Neurol 68:865–875

    Article  PubMed  PubMed Central  Google Scholar 

  18. Filippini N, Ebmeier KP, MacIntosh BJ, Trachtenberg AJ, Frisoni GB, Wilcock GK, Beckmann CF, Smith SM, Matthews PM, Mackay CE (2011) NeuroImage differential effects of the APOE genotype on brain function across the lifespan. Neuroimage. Elsevier Inc; 54: 602–10

  19. Heise V, Filippini N, Trachtenberg AJ, Suri S, Ebmeier KP (2014) Mackay CE. Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults. Neuroimage. Elsevier Inc; 98: 23–30

  20. Filippini N, Rao A, Wetten S, Gibson RA, Borrie M, Guzman D, Kertesz A, Loy-english I, Williams J, Nichols T, Whitcher B, Matthews PM (2009) NeuroImage anatomically-distinct genetic associations of APOE ɛ4 allele load with regional cortical atrophy in Alzheimer’s disease. Neuroimage. Elsevier Inc.; 44: 724–8

  21. Kim J, Kim Y-H, Lee J-H (2013) Hippocampus-precuneus functional connectivity as an early sign of Alzheimer’s disease: a preliminary study using structural and functional magnetic resonance imaging data. Brain Res Elsevier 1495:18–29

    Article  CAS  Google Scholar 

  22. Reiman EM, Quiroz YT, Fleisher AS, Chen K, Velez-Pardo C, Jimenez-Del-Rio M, Fagan AM, Shah AR et al (2007) Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Neuroscience Elsevier Ltd 11:162–184

    Google Scholar 

  23. Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, Matthews PM, Beckmann CF et al (2009) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 106:7209–7214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dennis NA, Browndyke JN, Stokes J, Need A, Burke JR, Welsh-Bohmer KA, Cabeza R (2010) Temporal lobe functional activity and connectivity in young adult APOE-ɛ4 carriers. Alzheimer’s Dement Elsevier Ltd 6:303–311

    Article  Google Scholar 

  25. Mayeux R, Stern Y (2012) Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med 1:2(8)

    Google Scholar 

  26. Galea M, Woodward M (2005) Mini-Mental State Examination (MMSE). Aust J Physiother 51:198

    Article  PubMed  Google Scholar 

  27. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695–699

    Article  PubMed  Google Scholar 

  28. Lehmann M, Ghosh PM, Madison C, Karydas A, Coppola G, O’Neil JP, Huang Y, Miller BL et al (2013) Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J Neurol Neurosurg Psychiatry 85:266–273

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wolk D a, Dickerson BC, Weiner M, Aiello M, Aisen P, Albert MS, Alexander G, Anderson HS et al (2010) Apolipoprotein E (APOE) genotype has dissociable effects on memory and attentional-executive network function in Alzheimer’s disease. Proc Natl Acad Sci 107:10256–10261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Susanto TAK, Pua EPK (2015) Zhou J, Alzheimer’s disease neuroimaging I. Cognition, brain atrophy, and cerebrospinal fluid biomarkers changes from preclinical to dementia stage of Alzheimer’s disease and the influence of apolipoprotein E. J Alzheimers Dis 45:253–268

    CAS  PubMed  Google Scholar 

  31. Shu H, Shi Y, Chen G, Wang Z, Liu D, Yue C, Ward BD, Li W et al (2016) Opposite neural trajectories of apolipoprotein ɛ4 and 2 alleles with aging associated with different risks of Alzheimer’s disease. Cereb Cortex 26(4):1421–1429

    Article  PubMed  Google Scholar 

  32. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE (2012) Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59:2142–2154

    Article  PubMed  Google Scholar 

  33. Yan C, Cheung B, Colcombe S, Craddock RC, Kelly C, Martino A Di, Li Q, Castellanos FX, Milham M (2012) The motion crisis in functional connectomics: damage assessment and control for resting-state fMRI. 3rd Bienn Conf Resting State Brain Connect. 2012; 15043

  34. Saad ZS, Gotts SJ, Murphy K, Chen G, Jo HJ, Martin A, Cox RW (2012) Trouble at rest: how correlation patterns and group differences become distorted after global signal regression. Brain Connect 2:25–32

    Article  PubMed  PubMed Central  Google Scholar 

  35. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19:1233–1239

    Article  PubMed  Google Scholar 

  36. Yan CG, Wang XD, Zuo XN, Zang YF (2016) DPABI: data processing & analysis for (resting-state) brain imaging. Neuroinformatics 14:339–351

    Article  PubMed  Google Scholar 

  37. Tiraboschi P, Hansen L, Masliah E, Alford M, Thal LJ, Corey-Bloom J (2004) Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease. Neurology 62:1977–1983

    Article  CAS  PubMed  Google Scholar 

  38. Love S, Siew LK, Dawbarn D, Wilcock GK, Ben-Shlomo Y, Allen SJ (2006) Premorbid effects of APOE on synaptic proteins in human temporal neocortex. Neurobiol Aging 27:797–803

    Article  CAS  PubMed  Google Scholar 

  39. Lee GJ, Lu PH, Medina LD, Rodriguez-Agudelo Y, Melchor S, Coppola G, Braskie MN, Hua X et al (2013) Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer’s disease mutations. J Neurol Neurosurg Psychiatry 84(2):154–162

    Article  PubMed  Google Scholar 

  40. Toga AW, Thompson PM (2003) Mapping brain asymmetry. Nat Rev Neurosci 4:37–48

    Article  CAS  PubMed  Google Scholar 

  41. Tang AC, Zou B, Reeb BC, Connor JA (2008) An epigenetic induction of a right-shift in hippocampal asymmetry: selectivity for short- and long-term potentiation but not post-tetanic potentiation. Hippocampus 18:5–10

    Article  PubMed  Google Scholar 

  42. Pedraza O, Bowers D, Gilmore R (2004) Asymmetry of the hippocampus and amygdala in MRI volumetric measurements of normal adults. J Int Neuropsychol Soc 10:664–678

    Article  PubMed  Google Scholar 

  43. Shi F, Liu B, Zhou Y, Yu C, Jiang T (2009) Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer’s disease: meta-analyses of MRI studies. 19(11):1055–64

  44. Tohgi H, Takahashi S, Kato E, Homma A, Niina R (1997) Reduced size of right hippocampus in 39- to 80-year-old normal subjects carrying the apolipoprotein E e 4 allele. 236: 21–4

  45. Geroldi C, Laakso MP, DeCarli C, Beltramello A, Bianchetti A, Soininen H, Trabucchi M, Frisoni GB (2000) Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer’s disease: a volumetric MRI study. J Neurol Neurosurg Psychiatry 68:93–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Eichenbaum H. (2004) Hippocampus: cognitive processes and neural representations that underlie declarative memory the hippocampus serves a critical role in declarative. 44: 109–20

  47. Puthiyedth N, Riveros C, Berretta R, Moscato P (2016) Identification of differentially expressed genes through integrated study of Alzheimer’s disease affected brain regions. PLoS One 11:1–29

    Article  Google Scholar 

  48. Subdivisions M. (2013) The angular gyrus: multiple functions and multiple subdivisions

  49. Ye BS, Seo SW, Lee Y, Kim SY, Choi SH, Lee YM, Kim DH, Han HJ et al (2012) Neuropsychological performance and conversion to Alzheimer’s disease in early- compared to late-onset amnestic mild cognitive impairment: CREDOS study. Dement Geriatr Cogn Disord 34:156–166

    Article  PubMed  Google Scholar 

  50. Sapkota S, Wiebe SA, Small BJ, Dixon RA (2015) Apolipoprotein E and clusterin can magnify effects of personality vulnerability on declarative memory performance in non-demented older adults. Int J Geriatr Psychiatry. 502–9

  51. Sheline YI, Raichle ME, Snyder AZ, Morris JC, Head D, Wang S, Mintun M (2011) Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol Psychiatry 67:584–587

    Article  Google Scholar 

  52. Chhatwal JP, Schultz AP, Johnson K, Benzinger TLS, Jack C, Ances BM, Sullivan CA, Salloway SP et al (2013) Impaired default network functional connectivity in autosomal dominant Alzheimer disease. Neurology 81:736–744

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ryan NS, Biessels G-J, Kim L, Nicholas JM, Barber PA, Walsh P, Gami P, Morris HR et al (2015) Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer’s disease. Neurobiol Aging 36:3140–3145

    Article  CAS  PubMed  Google Scholar 

  54. Ringman JM, Medina LD, Braskie M, Rodriguez-Agudelo Y, Geschwind DH, MacIas-Islas MA, Cummings JL, Bookheimer S (2011) Effects of risk genes on BOLD activation in presymptomatic carriers of familial Alzheimer’s disease mutations during a novelty encoding task. Cereb Cortex 21:877–883

    Article  PubMed  Google Scholar 

  55. Chao OY, Huston JP, Li JS, Wang AL, de Souza Silva MA (2016) The medial prefrontal cortex-lateral entorhinal cortex circuit is essential for episodic-like memory and associative object-recognition. Hippocampus 26(5):633–645

    Article  PubMed  Google Scholar 

  56. Jin J, Maren S (2015) Prefrontal-hippocampal interactions in memory and emotion. Front Syst Neurosci 9:170

    Article  PubMed  PubMed Central  Google Scholar 

  57. de Souza SM (2016) A., Huston JP, Wang a.-L, Petri D, Chao OY-H. Evidence for a specific integrative mechanism for episodic memory mediated by AMPA/kainate receptors in a circuit involving medial prefrontal cortex and hippocampal CA3 region. Cereb Cortex 26(7):3000–3009

    Article  Google Scholar 

  58. Cavanna AE, Trimble MR (2006) The precuneus: a review of its functional anatomy and behavioural correlates. Brain 129(Pt 3):564–583

    Article  PubMed  Google Scholar 

  59. Dean DC, Jerskey BA, Chen K, Protas H, Thiyyagura P, Roontiva A, O’Muircheartaigh J, Dirks H et al (2014) Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol 71:11–22

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tao J, Liu J, Egorova N, Chen X, Sun S, Xue X, Huang J, Zheng G et al (2016) Increased hippocampus–medial prefrontal cortex resting state functional connectivity and memory function after Tai Chi Chuan practice in elder adults. Front Aging Neurosci 8:1–9

    Article  Google Scholar 

  61. Ward B (2011) AlphaSim program documentation for AFNI, simultaneous inference for fMRI data: Medical College of Wisconsin, Milwaukee

  62. Camchong J, Stenger A, Fein G (2013) Resting-state synchrony during early alcohol abstinence can predict subsequent relapse. Cereb Cortex 23:2086–2099

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the altruism of all participants and contributions of this research and gratefully acknowledge the grants from Natural Scientific Foundation of China (81322020, 81230032, and 81171313 to L.J.Z. and Nos. 81671667 and 81471644 to G.Z.) and Program for New Century Excellent Talents in University (NCET-12-0260 to L.J.Z.).

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  1. Li Juan Zheng and Yun Yan Su had equal contribution to this work.

Authors and Affiliations

  1. Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Xuanwu District, Nanjing, Jiangsu, 210002, China

    Li Juan Zheng, Yun Yan Su, Yun Fei Wang, U. Joseph Schoepf, Xue Liang, Gang Zheng, Guang Ming Lu, Gui Fen Yang & Long Jiang Zhang

  2. Division of Cardiovascular Imaging, Department of Radiology and Radiological Science, Medical University of South Carolina, Ashley River Tower, MSC 226, 25 Courtenay Dr, Charleston, SC, 29401, USA

    U. Joseph Schoepf, Akos Varga-Szemes & Jonathan Pannell

  3. College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, China

    Gang Zheng

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  1. Li Juan Zheng
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Correspondence to Gui Fen Yang or Long Jiang Zhang.

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UJS is a consultant for and/or receives research support from Astellas, Bayer, Bracco, GE, Guerbet, Medrad, and Siemens. All other authors have no conflict of interest to disclose.

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Zheng, L.J., Su, Y.Y., Wang, Y.F. et al. Different Hippocampus Functional Connectivity Patterns in Healthy Young Adults with Mutations of APP/Presenilin-1/2 and APOEε4 . Mol Neurobiol 55, 3439–3450 (2018). https://doi.org/10.1007/s12035-017-0540-4

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