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Biomarkers of Alzheimer’s Disease

  • Living reference work entry
  • First Online:
Mental Health and Illness of the Elderly

Part of the book series: Mental Health and Illness Worldwide ((MHIW))

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a major driver of dementia syndromes around the globe. Despite great advances in neurodegenerative research over the past decade, AD remains a significant diagnostic and treatment challenge, and imposes momentous socioeconomic burden. Much of this overall burden is reflected in low- and middle-income countries, which is projected to increase enormously in the future. In order to meet these challenges locally, nationally and internationally, making an accurate and early clinical diagnosis of AD is crucial. A valid diagnosis at early disease stages will not only help accommodate differential prognostic and disease management approaches, but also allow for the assessment of the efficacy of novel therapeutic drugs in clinical trials. As demonstrated by autopsy-proven population-based studies, the quest for early AD diagnosis is hindered by substantial clinical heterogeneity observed in terms of disease presentation and progression. Imaging and fluid-based biomarkers congruent with AD pathophysiology can raise the certainty of clinical diagnosis, and aid in making early and more informed diagnostic decisions. In this chapter, a concise overview of the well-established and promising biomarkers for imaging and fluid-based modalities will be explored. Imaging biomarkers of AD derived from the following modalities are discussed: structural magnetic resonance imaging, diffusion tensor imaging, positron emission tomography, single photon emission computed tomography, proton magnetic resonance spectroscopy, as well as functional magnetic resonance imaging. Classical fluid-based biomarkers of AD derived from cerebrospinal fluid and blood are surveyed. The utility of these imaging and fluid-based biomarkers for the differential diagnosis and their potential as primary or secondary endpoints in clinical trails are currently intense topics of investigation. A combination of different imaging biomarkers using the “multimodal approach”, or simultaneous quantification of multiple fluid-based biomarkers to identify “biosignatures” are promising applications in AD. Future efforts are needed to standardize research protocols, refine measurement techniques, as well as to replicate controversial findings in autopsyconfirmed samples. Taking advantage of the international multi-centered collaborative efforts and technological refinements that are currently underway, the upcoming decades are sure to bring an exciting era for further advancements in an effort to conquer the “rising tide” of dementia, globally.

Sandra E. Black and Mario Masellis contributed equally as co-senior authors.

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References

  • Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM (2002) Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer’s disease treatment studies. Am J Psychiatry 159:738–745. doi:10.1176/appi.ajp.159.5.738

    Article  PubMed  Google Scholar 

  • Alzheimer’s Disease International – Dementia statistics. n.d.. Available at: https://www.alz.co.uk/research/statistics. Accessed 30 Dec 2016

  • Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B et al (2001) Evaluation of CSF-tau and CSF-A{beta}42 as diagnostic markers for alzheimer disease in clinical practice. Arch Neurol 58:373–379. doi:10.1001/archneur.58.3.373

    Article  CAS  PubMed  Google Scholar 

  • Bakker A, Krauss GL, Albert MS, Speck CL, Jones LR, Stark CE et al (2012) Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74:467–474. doi:10.1016/j.neuron.2012.03.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/S0140-6736(10)61349-9

    Article  PubMed  Google Scholar 

  • Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, O’Brien JT (2000) MRI volumetric correlates of white matter lesions in dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatry 15:911–916. doi:10.1002/1099-1166(200010)15:10<911::AID-GPS217>3.0.CO;2-T

    Article  CAS  PubMed  Google Scholar 

  • Barber R, Mckeith IG, Ballard C, Gholkar A, O’brien JT (2001) A comparison of medial and lateral temporal lobe atrophy in dementia with Lewy bodies and Alzheimer’s disease: magnetic resonance imaging volumetric study. Dement Geriatr Cogn Disord 12:198–205. doi:10.1159/000051258

    Article  CAS  PubMed  Google Scholar 

  • Barber R, Scheltens P, Gholkar A, Ballard C, McKeith I, Ince P et al (1999) White matter lesions on magnetic resonance imaging in dementia with Lewy bodies, Alzheimer’s disease, vascular dementia, and normal aging. J Neurol Neurosurg Psychiatry 67:66–72. doi:10.1136/jnnp.67.1.66

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barnes J, Bartlett JW, van de Pol LA, Loy CT, Scahill RI, Frost C et al (2009) A meta-analysis of hippocampal atrophy rates in Alzheimer’s disease. Neurobiol Aging 30:1711–1723. doi:10.1016/j.neurobiolaging.2008.01.010

    Article  PubMed  Google Scholar 

  • Basso M, Gelernter J, Yang J, MacAvoy MG, Varma P, Bronen RA et al (2006) Apolipoprotein E epsilon4 is associated with atrophy of the amygdala in Alzheimer’s disease. Neurobiol Aging 27:1416–1424. doi:10.1016/j.neurobiolaging.2005.08.002

    Article  CAS  PubMed  Google Scholar 

  • Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95. doi:10.1067/mcp.2001.113989

    Article  Google Scholar 

  • Bird TD (2008) Genetic aspects of Alzheimer disease. Genet Med 10:231–239. doi:10.1097/GIM.0b013e31816b64dc

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Black S, Gao F, Bilbao J (2009) Understanding white matter disease: imaging-pathological correlations in vascular cognitive impairment. Stroke 40. doi:10.1161/STROKEAHA.108.537704

    Google Scholar 

  • Blanc F, Colloby SJ, Philippi N, De Pétigny X, Jung B, Demuynck C et al (2015) Cortical thickness in dementia with Lewy bodies and Alzheimer’s disease: a comparison of prodromal and dementia stages. PLoS One 10. doi:10.1371/journal.pone.0127396

    Google Scholar 

  • Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2:605–613. doi:10.1016/S1474-4422(03)00530-1

    Article  CAS  PubMed  Google Scholar 

  • Bohnen NI, Kaufer DI, Hendrickson R, Ivanco LS, Lopresti BJ, Koeppe RA et al (2005) Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 76:315–319. doi:10.1136/jnnp.2004.038729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bozzali M, Falini A, Franceschi M, Cercignani M, Zuffi M, Scotti G et al (2002) White matter damage in Alzheimer’s disease assessed in vivo using diffusion tensor magnetic resonance imaging. J Neurol Neurosurg Psychiatry 72:742–746. doi:10.1136/jnnp.72.6.742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  CAS  PubMed  Google Scholar 

  • Brown RKJ, Bohnen NI, Wong KK, Minoshima S, Frey K a. Brain PET in suspected dementia: patterns of altered FDG metabolism. Radiographics 2014;34:684–701. doi:10.1148/rg.343135065.

    Google Scholar 

  • Buckner RL, Jessica A-H, Daneil S, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network anatomy, function, and consequence. Ann N Y Acad Sci 1124:1–38. doi:10.1196/annals.1440.011

    Article  PubMed  Google Scholar 

  • Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E et al (2009) Medial temporal lobe atrophy on MRI differentiates Alzheimer’s disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 132:195–203. doi:10.1093/brain/awn298

    Article  CAS  PubMed  Google Scholar 

  • Burton EJ, McKeith IG, Burn DJ, Williams ED, O’Brien JT (2004) Cerebral atrophy in Parkinson’s disease with and without dementia: a comparison with Alzheimer’s disease, dementia with Lewy bodies and controls. Brain 127:791–800. doi:10.1093/brain/awh088

    Article  PubMed  Google Scholar 

  • Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA (2003) Parkinson’s disease is associated with hippocampal atrophy. Mov Disord 18:784–790. doi:10.1002/mds.10444

    Article  PubMed  Google Scholar 

  • Celone KA, Calhoun VD, Dickerson BC, Atri A, Chua EF, Miller SL et al (2006) Alterations in memory networks in mild cognitive impairment and Alzheimer’s disease: an independent component analysis. J Neurosci 26:10222–10231. doi:10.1523/JNEUROSCI.2250-06.2006

    Article  CAS  PubMed  Google Scholar 

  • Ceravolo R, Volterrani D, Gambaccini G, Rossi C, Logi C, Manca G et al (2003) Dopaminergic degeneration and perfusional impairment in Lewy body dementia and Alzheimer’s disease. Neurol Sci 24:162–163. doi:10.1007/s10072-003-0110-6

    Article  CAS  PubMed  Google Scholar 

  • Chao LL, Schuff N, Kramer JH, Du AT, Capizzano AA, O’Neill J et al (2005) Reduced medial temporal lobe N-acetylaspartate in cognitively impaired but nondemented patients. Neurology 64:282–289. doi:10.1212/01.WNL.0000149638.45635.FF

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chien DT, Bahri S, Szardenings AK, Walsh JC, Mu F, Su MY et al (2013) Early clinical PET imaging results with the novel PHF-Tau radioligand [F-18]-T807. J Alzheimer’s Dis 34:457–468. doi:10.3233/JAD-122059

    CAS  Google Scholar 

  • Choo IH, Lee DY, Oh JS, Lee JS, Lee DS, Song IC et al (2010) Posterior cingulate cortex atrophy and regional cingulum disruption in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 31:772–779. doi:10.1016/j.neurobiolaging.2008.06.015

    Article  PubMed  Google Scholar 

  • Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281–7289. doi:10.1523/JNEUROSCI.0490-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Colloby SJ, Fenwick JD, Williams ED, Paling SM, Lobotesis K, Ballard C et al (2002) A comparison of (99m)Tc-HMPAO SPET changes in dementia with Lewy bodies and Alzheimer’s disease using statistical parametric mapping. Eur J Nucl Med Mol Imaging 29:615–622. doi:10.1007/s00259-002-0778-5

    Article  PubMed  Google Scholar 

  • de Leeuw F-EE, de Groot JC, Achten E, Oudkerk M, Ramos LM, Heijboer R et al (2001) Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 70:9–14. doi:10.1136/jnnp.70.1.9

    Article  PubMed  PubMed Central  Google Scholar 

  • Debette S, Markus HS (2010) The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 341:1–9. doi:10.1136/bmj.c3666

    Article  Google Scholar 

  • Dickerson BC, Salat DH, Bates JF, Atiya M, Killiany RJ, Greve DN et al (2004) Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol 56:27–35. doi:10.1002/ana.20163

    Article  PubMed  PubMed Central  Google Scholar 

  • Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam C-PP et al (2012) Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 69:1–8. doi:10.1001/archneurol.2012.1282

    Article  Google Scholar 

  • Drzezga A, Grimmer T, Henriksen G, Mühlau M, Perneczky R, Miederer I et al (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology 72:1487–1494. doi:10.1212/WNL.0b013e3181a2e8d0

    Article  CAS  PubMed  Google Scholar 

  • Engler H, Forsberg A, Almkvist O, Blomquist G, Larsson E, Savitcheva I et al (2006) Two-year follow-up of amyloid deposition in patients with Alzheimer’s disease. Brain 129:2856–2866. doi:10.1093/brain/awl178

    Article  PubMed  Google Scholar 

  • Fellgiebel A, Wille P, Müller MJ, Winterer G, Scheurich A, Vucurevic G et al (2004) Ultrastructural hippocampal and white matter alterations in mild cognitive impairment: a diffusion tensor imaging study. Dement Geriatr Cogn Disord 18:101–108. doi:10.1159/000077817

    Article  PubMed  Google Scholar 

  • Firbank MJ, Blamire AM, Krishnan MS, Teodorczuk A, English P, Gholkar A et al (2007a) Diffusion tensor imaging in dementia with Lewy bodies and Alzheimer’s disease. Psychiatry Res 155:135–145. doi:10.1016/j.pscychresns.2007.01.001

    Article  PubMed  Google Scholar 

  • Firbank MJ, Blamire AM, Krishnan MS, Teodorczuk A, English P, Gholkar A et al (2007b) Atrophy is associated with posterior cingulate white matter disruption in dementia with Lewy bodies and Alzheimer’s disease. Neuroimage 36:1–7. doi:10.1016/j.neuroimage.2007.02.027

    Article  PubMed  Google Scholar 

  • Firbank MJ, Blamire AM, Teodorczuk A, Teper E, Burton EJ, Mitra D et al (2010) High resolution imaging of the medial temporal lobe in Alzheimer’s disease and dementia with Lewy bodies. J Alzheimer’s Dis 21:1129–1140. doi:10.3233/JAD-2010-100138

    Article  Google Scholar 

  • Fodero-Tavoletti MT, Okamura N, Furumoto S, Mulligan RS, Connor AR, McLean CA et al (2011) 18F-THK523: a novel in vivo tau imaging ligand for Alzheimer’s disease. Brain 134:1089–1100. doi:10.1093/brain/awr038

    Article  PubMed  Google Scholar 

  • Fox NC, Cousens S, Scahill R, Harvey RJ, Rossor MN (2000) Using serial registered brain magnetic resonance imaging to measure disease progression in Alzheimer disease – power calculations and estimates of sample size to detect treatment effects. Arch Neurol 57:339–344. doi:10.1001/archneur.57.3.339

    Article  CAS  PubMed  Google Scholar 

  • Frank R, Hargreaves R (2003) Clinical biomarkers in drug discovery and development. Nat Rev Drug Discov 2:566–580. doi:10.1038/nrd1130

    Article  CAS  PubMed  Google Scholar 

  • Friedhoff P, von Bergen M, Mandelkow E-M, Mandelkow E (2000) Structure of tau protein and assembly into paired helical filaments. Biochim Biophys Acta – Mol Basis Dis 1502:122–132. doi:10.1016/S0925-4439(00)00038-7

    Article  CAS  Google Scholar 

  • Gao CM, Yam AY, Wang X, Magdangal E, Salisbury C, Peretz D et al (2010) Aβ40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer’s disease. PLoS One 5. doi:10.1371/journal.pone.0015725

    Google Scholar 

  • Garde E, Lykke Mortensen E, Rostrup E, Paulson OB (2005) Decline in intelligence is associated with progression in white matter hyperintensity volume. J Neurol Neurosurg Psychiatry 76:1289–1291. doi:10.1136/jnnp.2004.055905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilman S, Koeppe RA, Little R, An H, Junck L, Giordani B et al (2005) Differentiation of Alzheimer’s disease from dementia with Lewy bodies utilizing positron emission tomography with [ 18F]fluorodeoxyglucose and neuropsychological testing. Exp Neurol 191. doi:10.1016/j.expneurol.2004.06.017

    Google Scholar 

  • Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE et al (2008) Imaging amyloid deposition in Lewy body diseases. Neurology 71:903–910. doi:10.1212/01.wnl.0000326146.60732.d6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffith HR, den Hollander JA, Okonkwo OC, O’Brien T, Watts RL, Marson DC (2008) Brain metabolism differs in Alzheimer’s disease and Parkinson’s disease dementia. Alzheimers Dement 4:421–427. doi:10.1016/j.jalz.2008.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hafkemeijer A, van der Grond J, Rombouts SA (2012) Imaging the default mode network in aging and dementia. Biochim Biophys Acta – Mol Basis Dis 1822:431–441. doi:10.1016/j.bbadis.2011.07.008

    Article  CAS  Google Scholar 

  • Hampel H, Frank R, Broich K, Teipel SJ, Katz RG, Hardy J et al (2010) Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 9:560–574. doi:10.1038/nrd3115

    Article  CAS  PubMed  Google Scholar 

  • Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5:228–234. doi:10.1016/S1474-4422(06)70355-6

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto M, Yasuda M, Tanimukai S, Matsui M, Hirono N, Kazui H et al (2001) Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer’s disease. Neurology 57:1461–1466. doi:ERN-Converted #117; Used to be #1421 and #2126

    Article  CAS  PubMed  Google Scholar 

  • Head D, Buckner RL, Shimony JS, Williams LE, Akbudak E, Conturo TE et al (2004) Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging. Cereb Cortex 14:410–423

    Article  PubMed  Google Scholar 

  • Heiss WD, Hebold I, Klinkhammer P, Ziffling P, Szelies B, Pawlik G et al (1988) Effect of piracetam on cerebral glucose metabolism in Alzheimer’s disease as measured by positron emission tomography. J Cereb Blood Flow Metab 8:613–617. doi:10.1038/jcbfm.1988.104

    Article  CAS  PubMed  Google Scholar 

  • Henneman WJP, Sluimer JD, Barnes J, Van Der Flier WM, Sluimer IC, Fox NC et al (2009) Hippocampal atrophy rates in Alzheimer disease: added value over whole brain volume measures. Neurology 72:999–1007. doi:10.1212/01.wnl.0000344568.09360.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herholz K, Perani D, Salmon E, Franck G, Fazio F, Heiss WD et al (1993) Comparability of FDG PET studies in probable Alzheimer’s disease. J Nucl Med 34:1460–1466

    CAS  PubMed  Google Scholar 

  • Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC et al (2012) National Institute on Aging – Alzheimer ’ s Association guidelines for the neuropathologic assessment of Alzheimer ’ s disease. Alzheimer’s Dement 8:1–13. doi:10.1016/j.jalz.2011.10.007

    Article  Google Scholar 

  • Jack CR, Holtzman DM (2013) Biomarker modeling of Alzheimer’s disease. Neuron 80:1347–1358. doi:10.1016/j.neuron.2013.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jack CRJ, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW et al (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128. doi:10.1016/S1474-4422(09)70299-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jack CR, Petersen RC, Xu YC, O’Brien PC, Waring SC, Tangalos EG et al (1998) Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer’s disease. Ann Neurol 43:303–310. doi:10.1002/ana.410430307

    Article  PubMed  PubMed Central  Google Scholar 

  • Jagust WJ, Thisted R, Devous M (2001) SPECT perfusion imaging in the diagnosis of Alzheimer’s disease: a clinical-pathologic study. Neurology 56:950–956

    Article  CAS  PubMed  Google Scholar 

  • Jessen F, Traeber F, Freymann K, Maier W, Schild HH, Block W (2006) Treatment monitoring and response prediction with proton MR spectroscopy in AD. Neurology 67:528–530. doi:10.1212/01.wnl.0000228218.68451.31

    Article  CAS  PubMed  Google Scholar 

  • Johnson KA, Schultz A, Betensky RA, Becker JA, Sepulcre J, Rentz D et al (2016) Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol 79:110–119. doi:10.1002/ana.24546

    Article  PubMed  Google Scholar 

  • Kaasinen V, Jarvenpaa T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JONK (2002) Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer’s disease. J Clin Psychopharmacol 22:615. doi:10.1097/00004714-200212000-00012

    Article  CAS  PubMed  Google Scholar 

  • Kenny ER, Blamire AM, Firbank MJ, O’Brien JT (2012) Functional connectivity in cortical regions in dementia with Lewy bodies and Alzheimer’s disease. Brain 135:569–581. doi:10.1093/brain/awr327

    Article  PubMed  Google Scholar 

  • Kenny ER, Burton EJ, O’Brien JT (2008) A volumetric magnetic resonance imaging study of entorhinal cortex volume in dementia with Lewy bodies. A comparison with Alzheimer’s disease and Parkinson’s disease with and without dementia. Dement Geriatr Cogn Disord 26:218–225. doi:10.1159/000153432

    Article  PubMed  Google Scholar 

  • Kerchner GA, Hess CP, Hammond-Rosenbluth KE, Xu D, Rabinovici GD, Kelley DAC et al (2010) Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI. Neurology 75:1381–1387. doi:10.1212/WNL.0b013e3181f736a1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KW, MacFall JR, Payne ME (2008) Classification of white matter lesions on magnetic resonance imaging in elderly persons. Biol Psychiatry 64:273–280. doi:10.1016/j.biopsych.2008.03.024

    Article  PubMed  PubMed Central  Google Scholar 

  • Kolarova M, García-Sierra F, Bartos A, Ricny J, Ripova D (2012) Structure and pathology of tau protein in Alzheimer disease. Int J Alzheimers Dis. doi:10.1155/2012/731526

    PubMed  PubMed Central  Google Scholar 

  • Kovacevic N, Lobaugh NJ, Bronskill MJ, Levine B, Feinstein A, Black SE (2002) A robust method for extraction and automatic segmentation of brain images. Neuroimage 17:1087–1100. doi:10.1006/nimg.2002.1221

    Article  CAS  PubMed  Google Scholar 

  • Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F (2012) Plasma amyloid-beta as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol 69:824–831. doi:10.1001/archneurol.2011.1841

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuhlmann J, Andreasson U, Pannee J, Bjerke M, Portelius E, Leinenbach A et al (2016) CSF Abeta1-42 – an excellent but complicated Alzheimer’s biomarker – a route to standardisation. Clin Chim Acta. doi:10.1016/j.cca.2016.05.014

    PubMed  Google Scholar 

  • Kumar P, Dezso Z, MacKenzie C, Oestreicher J, Agoulnik S, Byrne M et al (2013) Circulating miRNA biomarkers for Alzheimer’s disease. PLoS One 8. doi:10.1371/journal.pone.0069807

    Google Scholar 

  • Laakso MP, Soininen H, Partanen K, Helkala EL, Hartikainen P, Vainio P et al (1995) Volumes of hippocampus, amygdala and frontal lobes in the MRI- based diagnosis of early Alzheimer’s disease: correlation with memory functions. J Neural Transm – Park Dis Dement Sect 9:73–86

    Article  CAS  PubMed  Google Scholar 

  • Lam B, Masellis M, Freedman M, Stuss DT, Black SE (2013) Clinical, imaging, and pathological heterogeneity of the Alzheimer’s disease syndrome. Alzheimers Res Ther 5:1. doi:10.1186/alzrt155

    Article  PubMed  PubMed Central  Google Scholar 

  • Le Bihan D (2003) Looking into the functional architecture of the brain with diffusion MRI. Nat Rev Neurosci 4:469–480

    Article  CAS  PubMed  Google Scholar 

  • Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K et al (2013) A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 14:R78. doi:10.1186/gb-2013-14-7-r78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lobotesis K, Fenwick JD, Phipps A, Ryman A, Swann A, Ballard C et al (2001) Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 56:643–649. doi:10.1212/WNL.56.5.643

    Article  CAS  PubMed  Google Scholar 

  • Logothetis NK, Pauls J, Augath M, Trinath T, Oeltermann A (2001) Neurophysiological investigation of the basis of the fMRI signal. Nature 412:150–157. doi:10.1038/35084005

    Article  CAS  PubMed  Google Scholar 

  • Longstreth WT, Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA et al (1996) Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people the cardiovascular health study. Stroke 27:1274–1282. doi:10.1161/01.STR.27.8.1274

    Article  PubMed  Google Scholar 

  • Mak E, Su L, Williams GB, Watson R, Firbank M, Blamire A et al (2016) Differential atrophy of hippocampal subfields: a comparative study of dementia with Lewy bodies and Alzheimer disease. Am J Geriatr Psychiatry 24:136–143. doi:10.1016/j.jagp.2015.06.006

    Article  PubMed  Google Scholar 

  • Mapstone M, Cheema AK, Fiandaca MS, Zhong X, Mhyre TR, MacArthur LH et al (2014). advance on: 415–418 Plasma phospholipids identify antecedent memory impairment in older adults. Nat Med. doi:10.1038/nm.3466

    PubMed  PubMed Central  Google Scholar 

  • Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E et al (2016) Plasma tau in Alzheimer disease. Neurology 87:1827–1835. doi:10.1212/WNL.0000000000003246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–939. doi:10.1186/alzrt38

    Article  CAS  PubMed  Google Scholar 

  • McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH et al (2011) The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement 7:263–269. doi:10.1016/j.jalz.2011.03.005

    Article  Google Scholar 

  • Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AMA (2007) N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 81:89–131. doi:10.1016/j.pneurobio.2006.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moody DM, Brown WR, Challa VR, Anderson RL (1995) Periventricular venous collagenosis: association with leukoaraiosis. Radiology 194:469–476. (Abstract only). doi:10.1148/radiology.194.2.7824728

    Article  CAS  PubMed  Google Scholar 

  • Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G et al (2008) Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer’s disease, and other dementias. J Nucl Med 49:390–398. doi:10.2967/jnumed.107.045385

    Article  PubMed  PubMed Central  Google Scholar 

  • Mufson EJ, Counts SE, Perez SE, Ginsberg SD (2009) Cholinergic system during the progression of Alzheimer’s disease: therapeutic implications. Expert Rev Neurother 8:1703–1718. doi:10.1586/14737175.8.11.1703.Cholinergic

    Article  CAS  Google Scholar 

  • Okamura N, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Harada R, Yates P et al (2014) Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain 137:1762–1771. doi:10.1093/brain/awu064

    Article  PubMed  Google Scholar 

  • Okamura N, Furumoto S, Harada R, Tago T, Yoshikawa T, Fodero-Tavoletti M et al (2013) Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J Nucl Med 54:1420–1427. doi:10.2967/jnumed.112.117341

    Article  CAS  PubMed  Google Scholar 

  • Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M et al (2016) CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. doi:10.1016/S1474-4422(16)00070-3

    Google Scholar 

  • Pievani M, Galluzzi S, Thompson PM, Rasser PE, Bonetti M, Frisoni GB (2011) APOE4 is associated with greater atrophy of the hippocampal formation in Alzheimer’s disease. Neuroimage 55:909–919. doi:10.1016/j.neuroimage.2010.12.081

    Article  CAS  PubMed  Google Scholar 

  • Rahimi J, Kovacs GG (2014) Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther 6:82. doi:10.1186/s13195-014-0082-1

    Article  PubMed  PubMed Central  Google Scholar 

  • Ramirez J, Gibson E, Quddus A, Lobaugh NJ, Feinstein A, Levine B et al (2011) Lesion Explorer: a comprehensive segmentation and parcellation package to obtain regional volumetrics for subcortical hyperintensities and intracranial tissue. Neuroimage 54:963–973. doi:10.1016/j.neuroimage.2010.09.013

    Article  CAS  PubMed  Google Scholar 

  • Ramirez J, McNeely AA, Scott CJ, Stuss DT, Black SE (2014) Subcortical hyperintensity volumetrics in Alzheimer’s disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory. Alzheimers Res Ther 6:49. doi:10.1186/alzrt279

    Article  PubMed  PubMed Central  Google Scholar 

  • Rombouts SARB, Barkhof F, Van Meel CS, Scheltens P (2002) Alterations in brain activation during cholinergic enhancement with rivastigmine in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 73:665–671. doi:10.1136/jnnp.73.6.665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rombouts SA, Barkhof F, Veltman DJ, Machielsen WC, Witter MP, Bierlaagh MA et al (2000) Functional MR imaging in Alzheimer’s disease during memory encoding. AJNR Am J Neuroradiol 21:1869–1875. doi:10.3174/ajnr.A1493

    CAS  PubMed  Google Scholar 

  • Rosa-Neto P, Hsiung G-Y, Masellis M (2013) Fluid biomarkers for diagnosing dementia: rationale and the Canadian Consensus on Diagnosis and Treatment of Dementia recommendations for Canadian physicians. Alzheimers Res Ther 5:S8. doi:10.1186/alzrt223

    Article  PubMed  PubMed Central  Google Scholar 

  • Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G et al (2007) Imaging beta-amyloid burden in aging and dementia. Neurology 68:1718–1725. doi:10.1212/01.wnl.0000261919.22630.ea

    Article  CAS  PubMed  Google Scholar 

  • Saeed U, Black SE, Masellis M (2016a) Imaging and cerebrospinal fluid biomarkers in Alzheimer’s disease and Lewy body dementias. In: Gliebus G (ed) Progress. cogn. impair. its neuropathol. correl. Nova Science Publishers, New York, pp 17–50

    Google Scholar 

  • Saeed U, Compagnone J, Black SE, Masellis M (2016b) Apolipoprotein E E4 allele and hippocampal volumetrics in Alzheimer’s disease: a systematic review of cross-sectional and longitudinal studies. Alzheimer’s Dement J Alzheimer’s Assoc 12:P713–P714. doi:10.1016/j.jalz.2016.06.1403

    Article  Google Scholar 

  • Saha GB, MacIntyre WJ, Go RT (1994) Radiopharmaceuticals for brain imaging. Semin Nucl Med 24:324–349. doi:10.1016/S0001-2998(05)80022-4

    Article  CAS  PubMed  Google Scholar 

  • Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR et al (2012) Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. PNAS 109:2895–2903. doi:10.1073/pnas.1121081109

    Article  Google Scholar 

  • Saykin AJ, Wishart HA, Rabin LA, Flashman LA, McHugh TL, Mamourian AC et al (2004) Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain 127:1574–1583. doi:10.1093/brain/awh177

    Article  PubMed  Google Scholar 

  • Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204. doi:10.1212/01.wnl.0000271090.28148.24

    Article  PubMed  Google Scholar 

  • Schwindt GC, Chaudhary S, Crane D, Ganda A, Masellis M, Grady CL et al (2013) Modulation of the default-mode network between rest and task in Alzheimer’s disease. Cereb Cortex 23:1685–1694. doi:10.1093/cercor/bhs160

    Article  PubMed  Google Scholar 

  • Seeman P, Seeman N (2011) Alzheimer’s disease: β-amyloid plaque formation in human brain. Synapse 65:1289–1297. doi:10.1002/syn.20957

    Article  CAS  PubMed  Google Scholar 

  • Small GW, Kepe V, Ercoli LM, Siddarth P, Bookheimer SY, Miller KJ et al (2006) PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med 355:2652–2663. doi:10.1056/NEJMoa054625

    Article  CAS  PubMed  Google Scholar 

  • Soares DP, Law M (2009) Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications. Clin Radiol 64:12–21. doi:10.1016/j.crad.2008.07.002

    Article  CAS  PubMed  Google Scholar 

  • Stebbins GT, Murphy CM (2009) Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol 21:39–49. doi:10.3233/BEN-2009-0234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang MY, Chen TW, Zhang XM, Huang XH (2014) GRE T2∗-weighted MRI: principles and clinical applications. Biomed Res Int 2014:312142. doi:10.1155/2014/312142

    PubMed  PubMed Central  Google Scholar 

  • Teipel SJ, Drzezga A, Bartenstein P, Möller HJ, Schwaiger M, Hampel H (2006) Effects of donepezil on cortical metabolic response to activation during 18FDG-PET in Alzheimer’s disease: a double-blind cross-over trial. Psychopharmacology (Berl) 187:86–94. doi:10.1007/s00213-006-0408-1

    Article  CAS  Google Scholar 

  • Tolboom N, van der Flier WM, Yaqub M, Boellaard R, Verwey NA, Blankenstein MA et al (2009) Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding. J Nucl Med 50:1464–1470. doi:10.2967/jnumed.109.064360

    Article  CAS  PubMed  Google Scholar 

  • Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA et al (2013) APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol 70:223–228. doi:10.1001/jamaneurol.2013.600

    Article  PubMed  PubMed Central  Google Scholar 

  • Villemagne VL, Fodero-Tavoletti MT, Masters CL, Rowe CC (2015) Tau imaging: early progress and future directions. Lancet Neurol 14:114–124. doi:10.1016/S1474-4422(14)70252-2

    Article  PubMed  Google Scholar 

  • Villemagne VL, Furumoto S, Fodero-Tavoletti MT, Mulligan RS, Hodges J, Harada R et al (2014) In vivo evaluation of a novel tau imaging tracer for Alzheimer’s disease. Eur J Nucl Med Mol Imaging 41:816–826. doi:10.1007/s00259-013-2681-7

    Article  CAS  PubMed  Google Scholar 

  • Villemagne VL, Ong K, Mulligan RS, Holl G, Pejoska S, Jones G et al (2011) Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias. J Nucl Med 52:1210–1217. doi:10.2967/jnumed.111.089730

    Article  PubMed  Google Scholar 

  • Wang L, Zang Y, He Y, Liang M, Zhang X, Tian L et al (2006) Changes in hippocampal connectivity in the early stages of Alzheimer ’ s disease: evidence from resting state fMRI. Neuroimage 31:496–504. doi:10.1016/j.neuroimage.2005.12.033

    Article  PubMed  Google Scholar 

  • Weigand SD, Vemuri P, Wiste HJ, Senjem ML, Pankratz VS, Aisen PS et al (2011) Transforming cerebrospinal fluid Aβ42 measures into calculated Pittsburgh compound B units of brain Aβ amyloid. Alzheimer’s Dement 7:133–141. doi:10.1016/j.jalz.2010.08.230

    Article  CAS  Google Scholar 

  • Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Cedarbaum J et al (2015) 2014 update of the Alzheimer’s disease neuroimaging initiative: a review of papers published since its inception. Alzheimer’s Dement 11:e1–120. doi:10.1016/j.jalz.2014.11.001

    Article  Google Scholar 

  • Whitwell JL, Weigand SD, Shiung MM, Boeve BF, Ferman TJ, Smith GE et al (2007a) Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain 130:708–719. doi:10.1093/brain/awl388

    Article  PubMed  PubMed Central  Google Scholar 

  • Whitwell JL, Jack CR, Parisi JE, Knopman DS, Boeve BF, Petersen RC et al (2007b) Rates of cerebral atrophy differ in different degenerative pathologies. Brain 130:1148–1158. doi:10.1093/brain/awm021

    Article  PubMed  PubMed Central  Google Scholar 

  • Whitwell JL, Dickson DW, Murray ME, Weigand SD, Tosakulwong N, Senjem ML et al (2012) Neuroimaging correlates of pathologically defined subtypes of Alzheimer’s disease: a case-control study. Lancet Neurol 11:868–877. doi:10.1016/S1474-4422(12)70200-4

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu X, Li R, Fleisher AS, Reiman EM, Guan X, Zhang Y et al (2011) Altered default mode network connectivity in Alzheimer’s disease. A resting functional MRI and bayesian network study. Hum Brain Mapp 32:1868–1881. doi:10.1002/hbm.21153

    Article  PubMed  PubMed Central  Google Scholar 

  • Xia C-F, Arteaga J, Chen G, Gangadharmath U, Gomez LF, Kasi D et al (2013) [18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimer’s Dement 9:666–676. doi:10.1016/j.jalz.2012.11.008

    Article  Google Scholar 

  • Zhang H-Y, Wang S-J, Liu B, Ma Z-L, Yang M, Zhang Z-J et al (2010) Resting brain connectivity: changes during the progress of Alzheimer disease. Radiology 256:598–606. doi:10.1148/radiol.10091701

    Article  PubMed  Google Scholar 

  • Zhang HY, Wang SJ, Xing J, Liu B, Ma ZL, Yang M et al (2009) Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer’s disease. Behav Brain Res 197:103–108. doi:10.1016/j.bbr.2008.08.012

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank the Brainlab.ca team in the LC Campbell Cognitive Neurology Research Unit (http://brainlab.ca/) for the provision of MRI and PET images for this chapter. MM is supported by the Department of Medicine at Sunnybrook Health Sciences Centre, University of Toronto, and the Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute (SRI). SEB is supported by the Brill Chair in Neurology (Sunnybrook Research Institute, Department of Medicine, University of Toronto) and the Toronto Dementia Research Alliance. US is supported by the Ontario Graduate Scholarship, Margaret and Howard Gamble Research Grant, Scace Graduate Fellowship in Alzheimer’s Research, and Institute of Medical Science Fellowship, University of Toronto.

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Authors and Affiliations

  1. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada

    Usman Saeed, Sandra E. Black & Mario Masellis

  2. LC Campbell Cognitive Neurology Research Unit, Sunnybrook Research Institute, University of Toronto, Toronto, Canada

    Usman Saeed, Walter Swardfager, Sandra E. Black & Mario Masellis

  3. Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Canada

    Walter Swardfager

  4. Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada

    Sandra E. Black & Mario Masellis

  5. Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Health Sciences Centre, Toronto, Canada

    Sandra E. Black

  6. Cognitive and Movement Disorders Clinic, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave., Room A4-55, Toronto, M4N 3M5, Canada

    Mario Masellis

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  1. Usman Saeed
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  2. Walter Swardfager
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Correspondence to Mario Masellis .

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Editors and Affiliations

  1. The Chinese University of Hong Kong, Tai Po, Hong Kong

    Helen Chiu

  2. Sunnybrook Research Institute, Toronto, Ontario, Canada

    Kenneth Shulman

Glossary

11C-PIB

11C-labelled Pittsburgh compound B

11C-PMP

11C-labelled N-methyl-piperidin-4-yl propionate

123I-IMP

123I-labelled N-isopropyl-p-iodoamphetamine

18F-FDG

18F-labelled fluorodeoxyglucose

1H-MRS

Proton magnetic resonance spectroscopy

99mTc-ECD

99mTc-ethyl cysteinate dimer

99mTc-HMPAO

99mTc-hexamethyl propylene amine oxime

AD

Alzheimer’s disease

APOE ε4

Apolipoprotein E ε4 allele

APP

Amyloid precursor protein

Aβ

Amyloid-beta

Aβ40

Amyloid-beta – 40 residue peptide

Aβ42

Amyloid-beta – 42 residue peptide

BOLD

Blood oxygen level dependent

CA1

Cornu ammonis 1

CAA

Cerebral amyloid angiopathy

CERAD

Consortium to Establish a Registry for Alzheimer’s disease

CSF

Cerebrospinal fluid

D

Mean diffusivity

DLB

Dementia with Lewy bodies

DMN

Default mode network

DTI

Diffusion tensor imaging

DWI

Diffusion weighted imaging

FA

Fractional anisotropy

FLAIR

Fluid-attenuated inversion recovery

FTD

Frontotemporal dementia

fMRI

Functional magnetic resonance imaging

GM

Gray matter

GRE

Gradient recalled echo

MCI

Mild cognitive impairment

MP4A

Methyl-N-methyl-piperidyl-4-acetate

MRI

Magnetic resonance imaging

MTL

Medial temporal lobe

NAA

N-acetyl aspartate

NFTs

Neurofibrillary tangles

NIA-AA

National Institute on Aging and the Alzheimer’s Association

NIH

National Institutes of Health

PCC

Posterior cingulate cortex

PD

Proton density-weighted

PDD

Parkinson’s disease dementia

PET

Positron emission tomography

PHF

Paired helical filaments

p-tau

Phosphorylated-tau

ROI

Region of interest

SWI

Susceptibility-weighted imaging

T1

T1 weighted

T2

T2 weighted

TDP-43

Transactive response DNA-binding protein of 43 kDa

t-tau

Total-tau

VBM

Voxel based morphometry

WM

White matter

WMHs

White matter hyperintensities

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Saeed, U., Swardfager, W., Black, S.E., Masellis, M. (2017). Biomarkers of Alzheimer’s Disease. In: Chiu, H., Shulman, K. (eds) Mental Health and Illness of the Elderly. Mental Health and Illness Worldwide. Springer, Singapore. https://doi.org/10.1007/978-981-10-0370-7_8-1

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