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Cerebral and blood correlates of reduced functional connectivity in mild cognitive impairment

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Abstract

Growing evidence suggests that decreased functional connectivity in cortical networks precedes clinical stages of Alzheimer’s disease (AD), although our knowledge about cerebral and biological correlates of this phenomenon is limited. To shed light on this issue, we have investigated whether resting-state oscillatory connectivity patterns in healthy older (HO) and amnestic mild cognitive impairment (aMCI) subjects are related to anatomical grey matter (GM) and functional (2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET) changes of neuroelectric sources of alpha rhythms, and/or to changes in plasma amyloid-beta (Aβ) and serum lipid levels, blood markers tied to AD pathogenesis and aging-related cognitive decline. We found that aMCI subjects showed decreased levels of cortical connectivity, reduced FDG-PET intake of the precuneus, and GM atrophy of the thalamus, together with higher levels of Aβ and apolipoprotein B (ApoB) compared to HO. Interestingly, levels of high-density lipoprotein (HDL) cholesterol were positively correlated with the strength of neural-phase coupling in aMCI subjects, and increased triglycerides accompanied bilateral GM loss in the precuneus of aMCI subjects. Together, these findings provide peripheral blood correlates of reduced resting-state cortical connectivity in aMCI, supported by anatomo-functional changes in cerebral sources of alpha rhythms. This framework constitutes an integrated approach to assess functional changes in cortical networks through neuroimaging and peripheral blood markers during early stages of neurodegeneration.

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References

  • Amariglio RE, Becker JA, Carmasin J, Wadsworth LP, Lorius N, Sullivan C, Maye JE, Gidicsin C, Pepin LC, Sperling RA, Johnson KA, Rentz DM (2012) Subjective cognitive complaints and amyloid burden in cognitively normal older individuals. Neuropsychologia 50:2880–2886

    Article  PubMed Central  PubMed  Google Scholar 

  • Ancelin ML, Carrière I, Barberger-Gateau P, Auriacombe S, Rouaud O, Fourlanos S, Berr C, Dupuy AM, Ritchie K (2012) Lipid lowering agents, cognitive decline, and dementia: the three-city study. J Alzheimers Dis 30:629–637

    PubMed Central  CAS  PubMed  Google Scholar 

  • Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen GW (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cereb Cortex 1:103–116

    Article  CAS  PubMed  Google Scholar 

  • Ashburner J (2007) A fast diffeomorphic image registration algorithm. Neuroimage 38:95–113

    Article  PubMed  Google Scholar 

  • Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. Neuroimage 11:805–821

    Article  CAS  PubMed  Google Scholar 

  • Babiloni C, Ferri R, Moretti DV, Strambi A, Binetti G, Dal Forno G, Ferreri F, Lanuzza B, Bonato C, Nobili F, Rodriguez G, Salinari S, Passero S, Rocchi R, Stam CJ, Rossini PM (2004) Abnormal fronto-parietal coupling of brain rhythms in mild Alzheimer’s disease: a multicentric EEG study. Eur J Neurosci 19:2583–2590

    Article  PubMed  Google Scholar 

  • Babiloni C, Ferri R, Binetti G, Cassarino A, Dal Forno G, Ercolani M, Ferreri F, Frisoni GB, Lanuzza B, Miniussi C, Nobili F, Rodriguez G, Rundo F, Stam CJ, Musha T, Vecchio F, Rossini PM (2006a) Fronto-parietal coupling of brain rhythms in mild cognitive impairment: a multicentric EEG study. Brain Res Bull 69:63–73

    Article  PubMed  Google Scholar 

  • Babiloni C, Frisoni G, Steriade M, Bresciani L, Binetti G, Del Percio C, Geroldi C, Miniussi C, Nobili F, Rodriguez G, Zappasodi F, Carfagna T, Rossini PM (2006b) Frontal white matter volume and delta EEG sources negatively correlate in awake subjects with mild cognitive impairment and Alzheimer’s disease. Clin Neurophysiol 117:1113–1129

    Article  PubMed  Google Scholar 

  • Babiloni C, Frisoni GB, Vecchio F, Lizio R, Pievani M, Cristina G, Fracassi C, Vernieri F, Rodriguez G, Nobili F, Ferri R, Rossini PM (2011) Stability of clinical condition in mild cognitive impairment is related to cortical sources of alpha rhythms: an electroencephalographic study. Hum Brain Mapp 32:1916–1931

    Article  PubMed  Google Scholar 

  • Babiloni C, Carducci F, Lizio R, Vecchio F, Baglieri A, Bernardini S, Cavedo E, Bozzao A, Buttinelli C, Esposito F, Giubilei F, Guizzaro A, Marino S, Montella P, Quattrocchi CC, Redolfi A, Soricelli A, Tedeschi G, Ferri R, Rossi-Fedele G, Ursini F, Scrascia F, Vernieri F, Pedersen TJ, Hardemark HG, Rossini PM, Frisoni GB (2013) Resting state cortical electroencephalographic rhythms are related to gray matter volume in subjects with mild cognitive impairment and Alzheimer’s disease. Hum Brain Mapp 34:1427–1446

    Article  PubMed  Google Scholar 

  • Babiloni C, Del Percio C, Lizio R, Marzano N, Infarinato F, Soricelli A, Salvatore E, Ferri R, Bonforte C, Tedeschi G, Montella P, Baglieri A, Rodriguez G, Famà F, Nobili F, Vernieri F, Ursini F, Mundi C, Frisoni GB, Rossini PM (2014) Cortical sources of resting state electroencephalographic alpha rhythms deteriorate across time in subjects with amnesic mild cognitive impairment. Neurobiol Aging 35:130–142

    Article  PubMed  Google Scholar 

  • Barter PJ et al (2006) Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med 259:247–258

    Article  CAS  PubMed  Google Scholar 

  • Becker JA, Hedden T, Carmasin J, Maye J, Rentz DM, Putcha D, Fischl B, Greve DN, Marshall GA, Salloway S, Marks D, Buckner RL, Sperling RA, Johnson KA (2011) Amyloid-β associated cortical thinning in clinically normal elderly. Ann Neurol 69:1032–1042

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Benito-Leon J, Louis ED, Vega S, Bermejo-Pareja F (2010) Statins and cognitive functioning in the elderly: a population-based study. J Alzheimers Dis 21:95–102

    CAS  PubMed  Google Scholar 

  • Bishop NA, Lu T, Yankner BA (2010) Neural mechanisms of ageing and cognitive decline. Nature 464:529–535

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Blasko I, Jellinger K, Kemmler G, Krampla W, Jungwirth S, Wichart I, Tragl KH, Fischer P (2008) Conversion from cognitive health to mild cognitive impairment and Alzheimer’s disease: prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine. Neurobiol Aging 29:1–11

    Article  CAS  PubMed  Google Scholar 

  • Blesa R, Pujol M, Aguilar M, Santacruz P, Bertran-Serra I, Hernández G, Sol JM, Peña-Casanova J, NORMACODEM Group (2001) Clinical validity of the ‘mini-mental state’ for Spanish speaking communities. Neuropsychologia 39:1150–1157

    Article  Google Scholar 

  • Bodovitz S, Klein WL (1996) Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem 271:4436–4440

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    Article  CAS  PubMed  Google Scholar 

  • Brier MR, Thomas JB, Snyder AZ, Benzinger TL, Zhang D, Raichle ME, Holtzman DM, Morris JC, Ances BM (2012) Loss of intranetwork and internetwork resting state functional connections with Alzheimer’s disease progression. J Neurosci 32:8890–8899

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burgess BL, McIsaac SA, Naus KE, Chan JY, Tansley GH, Yang J, Miao F, Ross CJ, van Eck M, Hayden MR, van Nostrand W, St George-Hyslop P, Westaway D, Wellington CL (2006) Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer’s disease mouse models with abundant A beta in plasma. Neurobiol Dis 24:114–127

    Article  CAS  PubMed  Google Scholar 

  • Cantero JL, Atienza M, Gomez-Herrero G, Cruz-Vadell A, Gil-Neciga E, Rodriguez-Romero R, Garcia-Solis D (2009a) Functional integrity of thalamocortical circuits differentiates normal aging from mild cognitive impairment. Hum Brain Mapp 30:3944–3957

    Article  PubMed  Google Scholar 

  • Cantero JL, Atienza M, Cruz-Vadell A, Suarez-Gonzalez A, Gil-Neciga E (2009b) Increased synchronization and decreased neural complexity underlie thalamocortical oscillatory dynamics in mild cognitive impairment. Neuroimage 46:938–948

    Article  PubMed  Google Scholar 

  • Cao L, Schrank BR, Rodriguez S, Benz EG, Moulia TW, Rickenbacher GT, Gomez AC, Levites Y, Edwards SR, Golde TE, Hyman BT, Barnea G, Albers MW (2012) Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo. Nat Commun 3:1009

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Caramelli P, Nitrini R, Maranhão R, Lourenço AC, Damasceno MC, Vinagre C, Caramelli B (1999) Increased apolipoprotein B serum concentration in Alzheimer’s disease. Acta Neurol Scand 100:61–63

    Article  CAS  PubMed  Google Scholar 

  • Cheng N, Bai L, Steuer E, Belluscio L (2013) Olfactory functions scale with circuit restoration in a rapidly reversible Alzheimer’s disease model. J Neurosci 33:12208–12217

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • De Jong LW, Van der Hiele K, Veer IM, Houwing JJ, Westendorp RG, Bollen EL, De Bruin PW, Middelkoop HA, Van Buchem MA, Van der Grond J (2008) Strongly reduced volumes of putamen and thalamus in Alzheimer’s disease: an MRI study. Brain 131:3277–3285

    Article  PubMed Central  PubMed  Google Scholar 

  • De Munck JC, Gonçalves SI, Huijboom L, Kuijer JP, Pouwels PJ, Heethaar RM, Lopes da Silva FH (2007) The hemodynamic response of the alpha rhythm: an EEG/fMRI study. Neuroimage 35:1142–1151

    Article  PubMed  Google Scholar 

  • DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464

    Article  CAS  PubMed  Google Scholar 

  • Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Driscoll I, Troncoso JC, Rudow G, Sojkova J, Pletnikova O, Zhou Y, Kraut MA, Ferrucci L, Mathis CA, Klunk WE, O’Brien RJ, Davatzikos C, Wong DF, Resnick SM (2012) Correspondence between in vivo (11)C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques. Acta Neuropathol 124:823–831

    Article  PubMed Central  PubMed  Google Scholar 

  • Drzezga A, Becker JA, Van Dijk KR, Sreenivasan A, Talukdar T, Sullivan C, Schultz AP, Sepulcre J, Putcha D, Greve D, Johnson KA, Sperling RA (2011) Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden. Brain 134:1635–1646

    Article  PubMed Central  PubMed  Google Scholar 

  • Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Roentgenol 149:351–356

    Article  CAS  Google Scholar 

  • Feige B, Scheffler K, Esposito F, Di Salle F, Hennig J, Seifritz E (2005) Cortical and subcortical correlates of electroencephalographic alpha rhythm modulation. J Neurophysiol 93:2864–2872

    Article  PubMed  Google Scholar 

  • Fischl B, Sereno MI, Dale AM (1999a) Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. Neuroimage 9:195–207

    Article  CAS  PubMed  Google Scholar 

  • Fischl B, Sereno MI, Tootell RB, Dale AM (1999b) High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp 8:272–284

    Article  CAS  PubMed  Google Scholar 

  • Ghribi O (2008) Potential mechanisms linking cholesterol to Alzheimer’s disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle. J Alzheimers Dis 15:673–684

    PubMed Central  CAS  PubMed  Google Scholar 

  • Giovacchini G, Lerner A, Toczek MT, Fraser C, Ma K, DeMar JC, Herscovitch P, Eckelman WC, Rapoport SI, Carson RE (2004) Brain incorporation of 11C-arachidonic acid, blood volume, and blood flow in healthy aging: a study with partial-volume correction. J Nucl Med 45:1471–1479

    CAS  PubMed  Google Scholar 

  • Goldman RI, Stern JM, Engel J Jr, Cohen MS (2002) Simultaneous EEG and fMRI of the alpha rhythm. Neuroreport 13:2487–2492

    Article  PubMed Central  PubMed  Google Scholar 

  • Graff-Radford NR, Crook JE, Lucas J, Boeve BF, Knopman DS, Ivnik RJ, Smith GE, Younkin LH, Petersen RC, Younkin SG (2007) Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol 64:354–362

    Article  PubMed  Google Scholar 

  • Greicius MD, Srivastava G, Reiss AL, Menon V (2004) Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 101:4637–4642

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Grimm MO, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C (2008) Independent inhibition of Alzheimer disease beta- and gamma-secretase cleavage by lowered cholesterol levels. J Biol Chem 283:11302–11311

    Article  CAS  PubMed  Google Scholar 

  • Grösgen S, Grimm MO, Friess P, Hartmann T (2010) Role of amyloid beta in lipid homeostasis. Biochim Biophys Acta 1801:966–974

    Article  PubMed  CAS  Google Scholar 

  • Hof PR, Morrison JH (2004) The aging brain: morphomolecular senescence of cortical circuits. Trends Neurosci 27:607–613

    Article  CAS  PubMed  Google Scholar 

  • Hof PR, Cox K, Morrison JH (1990) Quantitative analysis of a vulnerable subset of pyramidal neurons in Alzheimer’s disease: I. SUPERIOR frontal and inferior temporal cortex. J Comp Neurol 301:44–54

    Article  CAS  PubMed  Google Scholar 

  • Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–32233

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hughes SW, Lörincz M, Cope DW, Blethyn KL, Kekesi KA, Parri HR, Juhasz G, Crunelli V (2004) Synchronized oscillations at alpha and theta frequencies in the lateral geniculate nucleus. Neuron 42:253–268

    Article  CAS  PubMed  Google Scholar 

  • Humpel C (2011) Identifying and validating biomarkers for Alzheimer’s disease. Trends Biotechnol 29:26–32

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Iacono D, Markesbery WR, Gross M, Pletnikova O, Rudow G, Zandi P, Troncoso JC (2009) The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life. Neurology 73:665–673

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Karas GB, Scheltens P, Rombouts SA, Visser PJ, van Schijndel RA, Fox NC, Barkhof F (2004) Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 23:708–716

    Article  CAS  PubMed  Google Scholar 

  • Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X, Peck A (1988) Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann Neurol 23:138–144

    Article  CAS  PubMed  Google Scholar 

  • Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F (2012) Plasma amyloid-β as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol 69:824–831

    Article  PubMed Central  PubMed  Google Scholar 

  • Lachaux JP, Rodriguez E, Martinerie J, Varela FJ (1999) Measuring phase synchrony in brain signals. Hum Brain Mapp 8:194–208

    Article  CAS  PubMed  Google Scholar 

  • Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807

    Article  CAS  PubMed  Google Scholar 

  • Lamarche B, Moorjani S, Lupien PJ, Cantin B, Bernard PM, Dagenais GR, Després JP (1996) Apolipoprotein A-I and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Québec cardiovascular study. Circulation 94:273–278

    Article  CAS  PubMed  Google Scholar 

  • Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leritz EC, Salat DH, Williams VJ, Schnyer DM, Rudolph JL, Lipsitz L, Fischl B, McGlinchey RE, Milberg WP (2011) Thickness of the human cerebral cortex is associated with metrics of cerebrovascular health in a normative sample of community dwelling older adults. Neuroimage 54:2659–26571

    Article  PubMed Central  PubMed  Google Scholar 

  • Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440:352–357

    Article  PubMed  CAS  Google Scholar 

  • Lopes da Silva F (1991) Neural mechanisms underlying brain waves: from neural membranes to networks. Electroencephalogr Clin Neurophysiol 79:81–93

    Article  CAS  PubMed  Google Scholar 

  • Lopes da Silva F, Van Rotterdam A (1993) Biophysical aspects of EEG and magnetoencephalogram generation. In: Niedermeyer E, Lopes da Silva FH (eds) Electroencephalography. Basic principles, clinical applications and related fields. Williams and Wilkins, Baltimore, pp 78–91

    Google Scholar 

  • Lopes da Silva FH, van Lierop TH, Schrijer CF, van Leeuwen WS (1973) Organization of thalamic and cortical alpha rhythms: spectra and coherences. Electroencephalogr Clin Neurophysiol 35:627–639

    Article  Google Scholar 

  • Maris E (2004) Randomization tests for ERP topographies and whole spatiotemporal data matrices. Psychophysiology 41:142–151

    Article  PubMed  Google Scholar 

  • Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN (2009) Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease. J Neurochem 111:1275–1308

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Terry R, Buzsaki G (1989) Thalamic nuclei in Alzheimer disease: evidence against the cholinergic hypothesis of plaque formation. Brain Res 493:241–246

    Article  Google Scholar 

  • Masliah E, Mallory M, Hansen L, DeTeresa R, Terry RD (1993) Quantitative synaptic alterations in the human neocortex during normal aging. Neurology 43:192–197

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel DW Jr, Morris JC (2001) Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56:127–129

    Article  CAS  PubMed  Google Scholar 

  • Michels L, Moazami-Goudarzi M, Jeanmonod D, Sarnthein J (2008) EEG alpha distinguishes between cuneal and precuneal activation in working memory. Neuroimage 40:1296–1310

    Article  PubMed  Google Scholar 

  • Miller S, Dykes D, Polesky H (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Motta M, Bennati E, Cardillo E, Ferlito L, Passamonte M, Malaguarnera M (2009) The significance of apolipoprotein-B (Apo-B) in the elderly as a predictive factor of cardio-cerebrovascular complications. Arch Gerontol Geriatr 49:162–164

    Article  CAS  PubMed  Google Scholar 

  • Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058

    CAS  PubMed  Google Scholar 

  • Nickl-Jockschat T, Kleiman A, Schulz JB, Schneider F, Laird AR, Fox PT, Eickhoff SB, Reetz K (2012) Neuroanatomic changes and their association with cognitive decline in mild cognitive impairment: a meta-analysis. Brain Struct Funct 217:115–125

    Article  PubMed  Google Scholar 

  • Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L (2007) Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 55:697–711

    Article  CAS  PubMed  Google Scholar 

  • Panza F, D’Introno A, Colacicco AM, Capurso C, Pichichero G, Capurso SA, Capurso A, Solfrizzi V (2006) Lipid metabolism in cognitive decline and dementia. Brain Res Rev 51:275–292

    Article  CAS  PubMed  Google Scholar 

  • Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, Cruz-Sanchez FF, Thal LJ, Petanceska SS, Refolo LM (2003) Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology 61:199–205

    Article  CAS  PubMed  Google Scholar 

  • Pereda E, Quian Quiroga R, Bhattacharya J (2005) Nonlinear multivariate analysis of neurophysiological signals. Prog Neurobiol 77:1–37

    Article  PubMed  Google Scholar 

  • Perrotin A, Mormino EC, Madison CM, Hayenga AO, Jagust WJ (2012) Subjective cognition and amyloid deposition imaging: a Pittsburgh Compound B positron emission tomography study in normal elderly individuals. Arch Neurol 69:223–229

    Article  PubMed Central  PubMed  Google Scholar 

  • Pesini P, Pérez-Grijalba V, Monleón I, Boada M, Tárraga L, Martínez-Lage P, San-José I, Sarasa M (2012) Reliable measurements of the β-amyloid pool in blood could help in the early diagnosis of AD. Int J Alzheimers Dis 2012:604141

    PubMed Central  PubMed  Google Scholar 

  • Peters R, Beckett N (2009) Hypertension, dementia, and antihypertensive treatment: implications for the very elderly. Curr Hypertens Rep 11:277–282

    Article  PubMed  Google Scholar 

  • Petersen PR, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment. Clinical characterization and outcome. Arch Neurol 56:303–308

    Article  CAS  PubMed  Google Scholar 

  • Price JL, Morris JC (1999) Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Ann Neurol 45:358–368

    Article  CAS  PubMed  Google Scholar 

  • Price JL, Davis PB, Morris JC, White DL (1991) The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging 12:295–312

    Article  CAS  PubMed  Google Scholar 

  • Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA (2000) Hypercholesterolemia accelerates the Alzheimer’s amyloid pathology in a transgenic mouse model. Neurobiol Dis 7:321–331

    Article  CAS  PubMed  Google Scholar 

  • Richardson K, Schoen M, French B, Umscheid CA, Mitchell MD, Arnold SE, Heidenreich PA, Rader DJ, deGoma EM (2013) Statins and cognitive function: a systematic review. Ann Intern Med 159:688–697

    Article  PubMed  Google Scholar 

  • Rogers J, Morrison JH (1985) Quantitative morphology and regional and laminar distribution of senile plaques in Alzheimer’s disease. J Neurosci 5:2801–2808

    CAS  PubMed  Google Scholar 

  • Roher AE, Kuo YM, Kokjohn KM, Emmerling MR, Gracon S (1999) Amyloid and lipids in the pathology of Alzheimer disease. Amyloid 6:136–145

    Article  CAS  PubMed  Google Scholar 

  • Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, Cowie TF, Dickinson KL, Maruff P, Darby D, Smith C, Woodward M, Merory J, Tochon-Danguy H, O’Keefe G, Klunk WE, Mathis CA, Price JC, Masters CL, Villemagne VL (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718–1725

    Article  CAS  PubMed  Google Scholar 

  • Rudelli RD, Ambler MW, Wisniewski HM (1984) Morphology and distribution of Alzheimer neuritic (senile) and amyloid plaques in striatum and diencephalon. Acta Neuropathol 64:273–281

    Article  CAS  PubMed  Google Scholar 

  • Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    Article  CAS  PubMed  Google Scholar 

  • Schiff SJ (2005) Dangerous phase. Neuroinformatics 3:315–318

    Article  PubMed Central  PubMed  Google Scholar 

  • Schreckenberger M, Lange-Asschenfeldt C, Lochmann M, Mann K, Siessmeier T, Buchholz HG, Bartenstein P, Gründer G (2004) The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans. Neuroimage 22:637–644

    Article  PubMed  Google Scholar 

  • Shobab LA, Hsiung GY, Feldman HH (2005) Cholesterol in Alzheimer’s disease. Lancet Neurol 4:841–852

    Article  CAS  PubMed  Google Scholar 

  • Silva LR, Amitai Y, Connors BW (1991) Intrinsic oscillations of neocortex generated by layer 5 pyramidal neurons. Science 251:432–435

    Article  CAS  PubMed  Google Scholar 

  • Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 95:6460–6464

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Snowdon DA, Nun Study (2003) Healthy aging and dementia: findings from the Nun Study. Ann Intern Med 139:450–454

    Article  PubMed  Google Scholar 

  • Sobów T, Flirski M, Kłoszewska I, Liberski PP (2005) Plasma levels of alpha beta peptides are altered in amnestic mild cognitive impairment but not in sporadic Alzheimer’s disease. Acta Neurobiol Exp (Wars) 65:117–124

    Google Scholar 

  • Stam CJ, Jones BF, Manshanden I, van Cappellen van Walsum AM, Montez T, Verbunt JPA, de Munck JC, van Dijk BW, Berendse HW, Scheltens P (2006) Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer’s disease. Neuroimage 32:1335–1344

    Article  CAS  PubMed  Google Scholar 

  • Stam CJ, Nolte G, Daffertshofer A (2007) Phase lag index: assessment of functional connectivity from multi channel EEG and MEG with diminished bias from common sources. Hum Brain Mapp 28:1178–1193

    Article  PubMed  Google Scholar 

  • Storace D, Cammarata S, Borghi R, Sanguineti R, Giliberto L, Piccini A, Pollero V, Novello C, Caltagirone C, Smith MA, Bossù P, Perry G, Odetti P, Tabaton M (2010) Elevation of beta-amyloid 1-42 autoantibodies in the blood of amnestic patients with mild cognitive impairment. Arch Neurol 67:867–872

    Article  PubMed  Google Scholar 

  • Sun X, Bhadelia R, Liebson E, Bergethon P, Folstein M, Zhu JJ, Mwamburi DM, Patz S, Qiu WQ (2011) The relationship between plasma amyloid-β peptides and the medial temporal lobe in the homebound elderly. Int J Geriatr Psychiatry 26:593–601

    Article  PubMed  Google Scholar 

  • Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS (2013) Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc 88:1213–1221

    Article  CAS  PubMed  Google Scholar 

  • Tabet N, Quinn R, Klugman A (2009) Prevalence and cognitive impact of cerebrovascular findings in Alzheimer’s disease: a retrospective, naturalistic study. Int J Clin Pract 63:338–345

    Article  CAS  PubMed  Google Scholar 

  • Terry RD, Peck A, DeTeresa R, Schechter R, Horoupian DS (1981) Some morphometric aspects of the brain in senile dementia of the Alzheimer type. Ann Neurol 10:184–192

    Article  CAS  PubMed  Google Scholar 

  • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580

    Article  CAS  PubMed  Google Scholar 

  • Tomlinson BE, Blessed G, Roth M (1968) Observations on the brains of non-demented old people. J Neurol Sci 7:331–356

    Article  CAS  PubMed  Google Scholar 

  • Toth M, Kiss A, Kosztolanyi P, Kondakor I (2007) Diurnal alterations of brain electrical activity in healthy adults: a LORETA study. Brain Topogr 20:63–76

    Article  PubMed  Google Scholar 

  • Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Jia X, Liang P, Qi Z, Yang Y, Zhou W, Li K (2012) Changes in thalamus connectivity in mild cognitive impairment: evidence from resting state fMRI. Eur J Radiol 81:277–285

    Article  PubMed  Google Scholar 

  • Williams VJ, Leritz EC, Shepel J, McGlinchey RE, Milberg WP, Rudolph JL, Lipsitz LA, Salat DH (2013) Interindividual variation in serum cholesterol is associated with regional white matter tissue integrity in older adults. Hum Brain Mapp 34:1826–1841

    Article  PubMed Central  PubMed  Google Scholar 

  • Wirth M, Oh H, Mormino EC, Markley C, Landau SM, Jagust WJ (2013) The effect of amyloid β on cognitive decline is modulated by neural integrity in cognitively normal elderly. Alzheimers Dement 9:687–698

    Article  PubMed  Google Scholar 

  • Wood WG, Schroeder F, Avdulov NA, Chochina SV, Igbavboa U (1999) Recent advances in brain cholesterol dynamics: transport, domains, and Alzheimer’s disease. Lipids 34:225–234

    Article  CAS  PubMed  Google Scholar 

  • Xiong H, Callaghan D, Jones A, Walker DG, Lue LF, Beach TG, Sue LI, Woulfe J, Xu H, Stanimirovic DB, Zhang W (2008) Cholesterol retention in Alzheimer’s brain is responsible for high beta- and gamma-secretase activities and Abeta production. Neurobiol Dis 29:422–437

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yesavage JA, BrinK TL, Rose TL, Lum O (1983) Development and validation of a geriatric depression scale: a preliminary report. J Psychiat Res 17:37–49

    Article  CAS  Google Scholar 

  • Yotter RA, Doshi J, Clark V, Sojkova J, Zhou Y, Wong DF, Ferrucci L, Resnick SM, Davatzikos C (2013) Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden. Neurobiol Aging 34:2835–2842

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou B, Liu Y, Zhang Z, An N, Yao H, Wang P, Wang L, Zhang X, Jiang T (2013) Impaired functional connectivity of the thalamus in Alzheimer’s disease and mild cognitive impairment: a resting-state FMRI study. Curr Alzheimer Res 10:754–766

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by research grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-25463, PSI2011-24922), the Regional Ministry of Innovation, Science and Enterprise, Junta de Andalucia (P12-CTS-2327), and CIBERNED (CB06/05/1111). The authors declare no competing financial interests.

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Authors and Affiliations

  1. Laboratory of Functional Neuroscience, Spanish Network of Excellence for Research on Neurodegenerative Diseases (CIBERNED), Pablo de Olavide University, Ctra. de Utrera Km 1, 41013, Seville, Spain

    Gabriel Gonzalez-Escamilla, Mercedes Atienza & Jose L. Cantero

  2. Department of Nuclear Medicine, University Hospital Virgen del Rocio, Seville, Spain

    David Garcia-Solis

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  1. Gabriel Gonzalez-Escamilla
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  2. Mercedes Atienza
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  3. David Garcia-Solis
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  4. Jose L. Cantero
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Correspondence to Jose L. Cantero.

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Gonzalez-Escamilla, G., Atienza, M., Garcia-Solis, D. et al. Cerebral and blood correlates of reduced functional connectivity in mild cognitive impairment. Brain Struct Funct 221, 631–645 (2016). https://doi.org/10.1007/s00429-014-0930-6

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  • DOI: https://doi.org/10.1007/s00429-014-0930-6

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