Skip to main content

Advertisement

SpringerLink
Log in

Toward the Validation of Functional Neuroimaging as a Potential Biomarker for Alzheimer’s Disease: Implications for Drug Development

  • Review Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Despite investments carried out in the research since Alzheimer’s disease (AD) was firstly defined as an isolated clinical entity, there is still a lack of appropriate cure and effective therapies to halt or slow the disease progression. While fundamental research has provided a better characterization of AD, much remains to be done for the development of new biological treatment strategies. It is now being debated whether functional neuroimaging (FNI) could help improve diagnostic accuracy and become a possible biomarker of AD. The primary purpose of this review was to determine whether data already published in the literature meet formal technology assessment standards for using regional cerebral blood flow (rCBF) or glucose metabolism (rCMRGlu) as a biomarker for AD. The secondary purpose was to identify any remaining gaps that might need to be systematically addressed before drug developers and regulators accept FNI as a biomarker for AD. The present paper reviews the literature regarding metabolic positron emission tomography (PET) and perfusion single photon emission computed tomography (SPECT) studies in AD. There is evidence that treatment with acetylcholinesterase inhibitors (AChEI) leads to changes in brain physiology within the brain regions critical to AD pathology, i.e. the temporal, parietal and frontal association cortex. However, a thorough analysis combining functional and neuropsychological data has not yet been attempted, and much research is needed to validate the role of FNI as a surrogate endpoint for AD clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. L Fratiglioni D Ronchi ParticleDe H Aguero-Torres (1999) ArticleTitleWorldwide prevalence and incidence of dementia Drugs Aging 15 365–375

    Google Scholar 

  2. http://jin.jcic.or.jp/stat/stats/01CEN2C.html

  3. R Brookmeyer S Gray C Kawas (1998) ArticleTitleProjections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset Am J Public Health 88 1337–1342

    Google Scholar 

  4. G Blessed BE Tomlinson M Roth (1968) ArticleTitleThe association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects Br J Psychiatry 114 797–811 Occurrence Handle1:STN:280:CCeA38bms1U%3D Occurrence Handle5662937

    CAS  PubMed  Google Scholar 

  5. WJ Meerding L Bonneux JJ Polder MA Koopmanschap PJ Maas Particlevan der (1998) ArticleTitleDemographic and epidemiological determinants of healthcare costs in Netherlands: Cost of illness study Br Med J 317 111–115 Occurrence Handle1:STN:280:DyaK1czit1Wqsw%3D%3D

    CAS  Google Scholar 

  6. HM Fillit AW O’Connell WM Brown et al. (2002) ArticleTitleBarriers to drug discovery and development for Alzheimer disease Alzheimer Dis Assoc Disord 16 IssueIDSuppl 1 S1–S8 Occurrence Handle10.1097/00002093-200200001-00001

    Article  Google Scholar 

  7. http://biomed.brown.edu/Courses/BI108/BI108_1999_Groups/Neuroelectrodes_Team/background.html#demographics

  8. NR Cutler JJ Sramek (2001) ArticleTitleReview of the next generation of Alzheimer’s disease therapeutics: Challenges for drug development Prog Neuropsychopharmacol Biol Psychiatry 25 27–57 Occurrence Handle10.1016/S0278-5846(00)00147-0

    Article  Google Scholar 

  9. LD Altstiel (2002) ArticleTitleBarriers to Alzheimer disease drug discovery and development in the biotechnology industry Alzheimer Dis Assoc Disord 16 IssueIDSuppl 1 S29–S32 Occurrence Handle10.1097/00002093-200200001-00005

    Article  Google Scholar 

  10. AJ Atkinson SuffixJr (2001) ArticleTitleBiomarkers and surrogate endpoints: Preferred definitions and conceptual framework Clin Pharmacol Ther 69 89–95 Occurrence Handle10.1067/mcp.2001.113989

    Article  Google Scholar 

  11. TE Golde (2003) ArticleTitleAlzheimer disease therapy: Can the amyloid cascade be halted? J Clin Invest 111 11–18 Occurrence Handle10.1172/JCI200317527

    Article  Google Scholar 

  12. Van Eldik LJ Alzheimer disease. Alzheimer Dis Assoc Disord 16(Suppl 1)

  13. JC Mazziotta ME Phelps (1986) Principles and applications for the brain and heart ME Phelps JC Mazziotta H Schelbert (Eds) Positron emission tomography and autoradiography Raven Press New York 493–579

    Google Scholar 

  14. KJ Friston AP Holmes KJ Worsley J-B Poline CD Frith RSJ Frackowiak (1995) ArticleTitleStatistical parametric maps in functional imaging: A general linear approach Hum Brain Mapping 2 189–210

    Google Scholar 

  15. D Mildvan A Landay V Gruttola ParticleDe SG Machado J Kagan (1997) ArticleTitleAn approach to the validation of markers for use in AIDS clinical trials Clin Infect Dis 24 764–774

    Google Scholar 

  16. RL Heertum ParticleVan RS Tikofsky (2003) ArticleTitlePositron emission tomography and single-photon emission computed tomography brain imaging in the evaluation of dementia Semin Nucl Med 33 77–85 Occurrence Handle10.1053/snuc.2003.127294

    Article  Google Scholar 

  17. S Minoshima NL Foster DE Kuhl (1994) ArticleTitlePosterior cingulate cortex in Alzheimer’s disease Lancet 344 895 Occurrence Handle10.1016/S0140-6736(94)92871-1 Occurrence Handle1:STN:280:ByuA2snlslE%3D

    Article  CAS  Google Scholar 

  18. K Herholz E Salmon D Perani et al. (2002) ArticleTitleDiscrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET NeuroImage 17 302–316 Occurrence Handle10.1006/nimg.2002.1208

    Article  Google Scholar 

  19. DH Silverman GW Small CY Chang et al. (2001) ArticleTitlePositron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome J Am Med Assoc 286 2120–2127 Occurrence Handle10.1001/jama.286.17.2120

    Article  Google Scholar 

  20. K Palmer L Backman B Winblad L Fratiglioni (2003) ArticleTitleDetection of Alzheimer’s disease and dementia in the preclinical phase: Population based cohort study Br Med J 326 245

    Google Scholar 

  21. L Mosconi A Pupi MTR Cristofaro ParticleDe M Fayyaz S Sorbi K Herholz (2004) ArticleTitleFunctional interactions of the entorhinal cortex. An FDG-PET study on normal aging and Alzheimer’s disease J Nucl Med 45 382–392

    Google Scholar 

  22. H Braak E Braak (1991) ArticleTitleNeuropathological staging of Alzheimer-related changes Acta Neuropathol (Berl) 82 239–259 Occurrence Handle10.1007/BF00308809

    Article  Google Scholar 

  23. L Mosconi S Sorbi B Nacmias et al. (2003) ArticleTitleBrain metabolic differences between sporadic and familial Alzheimer’s disease Neurology 61 1138–1141

    Google Scholar 

  24. D Kogure H Matsuda T Ohnishi et al. (2000) ArticleTitleLongitudinal evaluation of early Alzheimer’s disease using brain perfusion SPECT J Nucl Med 41 1155–1162 Occurrence Handle1:STN:280:DC%2BD3czpslemsA%3D%3D Occurrence Handle10914904

    CAS  PubMed  Google Scholar 

  25. P Bartenstein S Minoshima C Hirsch et al. (1997) ArticleTitleQuantitative assessment of cerebral blood flow in patients with Alzheimer’s disease by SPECT J Nucl Med 38 1095–1101 Occurrence Handle1:STN:280:ByiA28bjtV0%3D Occurrence Handle9225797

    CAS  PubMed  Google Scholar 

  26. WJ Jagust MN Haan JL Eberling N Wolfe BR Reed (1996) ArticleTitleFunctional imaging predicts cognitive decline in Alzheimer’s disease J Neuroimaging 6 156–160

    Google Scholar 

  27. K Herholz A Nordberg E Salmon et al. (1999) ArticleTitleImpairment of neocortical metabolism predicts progression in Alzheimer’s disease Dement Geriatr Cogn Disord 10 494–504 Occurrence Handle10.1159/000017196

    Article  Google Scholar 

  28. RC Petersen GE Smith SC Waring RJ Ivnik EG Tangalos E Kokmen (1999) ArticleTitleMild cognitive impairment: Clinical characterization and outcome Arch Neurol 56 303–308 Occurrence Handle10.1001/archneur.56.3.303 Occurrence Handle1:STN:280:DyaK1M3gsFSqtw%3D%3D Occurrence Handle10190820

    Article  CAS  PubMed  Google Scholar 

  29. GW Small PV Rabins PP Barry et al. (1997) ArticleTitleDiagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society J Am Med Assoc 278 1363–1371 Occurrence Handle10.1001/jama.278.16.1363 Occurrence Handle1:STN:280:DyaK1c%2FgtFKgtg%3D%3D

    Article  CAS  Google Scholar 

  30. MJ Leon Particlede A Convit OT Wolf et al. (2001) ArticleTitlePrediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-deoxy-D-glucose/positron-emission tomography (FDG/PET) Proc Natl Acad Sci U S A 98 10966–10971 Occurrence Handle10.1073/pnas.191044198

    Article  Google Scholar 

  31. S Minoshima B Giordani S Berent KA Frey NL Foster DE Kuhl (1997) ArticleTitleMetabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease Ann Neurol 42 85–94 Occurrence Handle1:STN:280:ByiA28bitVU%3D Occurrence Handle9225689

    CAS  PubMed  Google Scholar 

  32. A Drzezga N Lautenschlager H Siebner et al. (2003) ArticleTitleCerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: A PET follow-up study Eur J Nucl Med Mol Imaging 30 1104–1113 Occurrence Handle10.1007/s00259-003-1194-1

    Article  Google Scholar 

  33. KA Johnson K Jones BL Holman et al. (1998) ArticleTitlePreclinical prediction of Alzheimer’s disease using SPECT Neurology 50 1563–1571 Occurrence Handle1:STN:280:DyaK1c3psFCmsA%3D%3D Occurrence Handle9633695

    CAS  PubMed  Google Scholar 

  34. H Hanyu T Shimizu Y Tanaka M Takasaki K Koizumi K Abe (2003) ArticleTitleRegional cerebral blood flow patterns and response to donepezil treatment in patients with Alzheimer’s disease Dement Geriatr Cogn Disord 15 177–182 Occurrence Handle10.1159/000068785

    Article  Google Scholar 

  35. RN Rosenberg (2000) ArticleTitleThe molecular and genetic basis of AD: The end of the beginning. The 2000 Wartenberg lecture Neurology 54 2045–2054

    Google Scholar 

  36. GW Small LM Ercoli DH Silverman et al. (2000) ArticleTitleCerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease Proc Natl Acad Sci U S A 97 6037–6042 Occurrence Handle10.1073/pnas.090106797

    Article  Google Scholar 

  37. EM Reiman RJ Caselli K Chen GE Alexander D Bandy J Frost (2001) ArticleTitleDeclining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer’s disease Proc Natl Acad Sci U S A 98 3334–3339 Occurrence Handle10.1073/pnas.061509598

    Article  Google Scholar 

  38. L Mosconi S Sorbi B Nacmias et al. (2004) ArticleTitleBrain metabolic decreases related to the dose of the APOE E4 allele in Alzheimer’s disease J Neurol Neurosurg Psychiatry 75 370–376 Occurrence Handle10.1136/jnnp.2003.014993

    Article  Google Scholar 

  39. B Reisberg R Doody A Stoffler F Schmitt et al. (2003) ArticleTitleMemantine in moderate-to-severe Alzheimer’s disease N Engl J Med 348 IssueID14 1333–1341 Occurrence Handle10.1056/NEJMoa013128

    Article  Google Scholar 

  40. PN Tariot MR Farlow GT Grossberg et al. (2004) ArticleTitleMemantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: A randomized controlled trial JAMA 291 317–324 Occurrence Handle10.1001/jama.291.3.317

    Article  Google Scholar 

  41. WE Klunk H Engler A Nordberg et al. (2004) ArticleTitleImaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B Ann Neurol 55 306–319 Occurrence Handle10.1002/ana.20009 Occurrence Handle1:CAS:528:DC%2BD2cXisFKntb8%3D Occurrence Handle14991808

    Article  CAS  PubMed  Google Scholar 

  42. MS Mega JL Cummings SM O’Connor et al. (2001) ArticleTitleCognitive and metabolic responses to metrifonate therapy in Alzheimer disease Neuropsych Neuropsychol Behav Neurol 14 38–63

    Google Scholar 

  43. S Nakano T Asada H Matsuda M Uno M Takasaki (2001) ArticleTitleDonepezil hydrochloride preserves regional cerebral blood flow in patients with Alzheimer’s disease J Nucl Med 42 1441–1445

    Google Scholar 

  44. L Tune PJ Tiseo J Ieni et al. (2003) ArticleTitleDonepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: Results of a 24-week, double-blind, placebo-controlled study Am J Geriatr Psychiatry 11 169–177 Occurrence Handle10.1176/appi.ajgp.11.2.169

    Article  Google Scholar 

  45. F Nobili P Vitali M Canfora et al. (2002) ArticleTitleEffects of long-term donepezil therapy on rCBF of Alzheimer’s patients Clin Neurophysiol 113 1241–1248 Occurrence Handle10.1016/S1388-2457(02)00110-4

    Article  Google Scholar 

  46. SG Potkin R Anand K Fleming et al. (2001) ArticleTitleBrain metabolic and clinical effects of rivastigmine in Alzheimer’s disease Int J Neuropsychopharmacol 4 223–230 Occurrence Handle10.1017/S1461145701002528

    Article  Google Scholar 

  47. R Frank R Hargreaves (2003) ArticleTitleClinical biomarkers in drug discovery and development Nat Rev Drug Discov 2 566–580 Occurrence Handle10.1038/nrd1130

    Article  Google Scholar 

  48. F Nobili M Koulibaly P Vitali et al. (2002) ArticleTitleBrain perfusion follow-up in Alzheimer’s patients during treatment with acetylcholinesterase inhibitors J Nucl Med 43 983–990

    Google Scholar 

  49. A Venneri MF Shanks RT Staff et al. (2002) ArticleTitleCerebral blood flow and cognitive responses to rivastigmine treatment in Alzheimer’s disease NeuroReport 13 83–87 Occurrence Handle10.1097/00001756-200201210-00020

    Article  Google Scholar 

  50. http://www.fda.gov/cder/audiences/acspage/peripheralmeetings1.htm

  51. GE Alexander K Chen P Pietrini SI Rapoport EM Reiman (2002) ArticleTitleLongitudinal PET evaluation of cerebral metabolic decline in dementia: A potential outcome measure in Alzheimer’s Disease treatment studies Am J Psychiatry 159 738–745 Occurrence Handle10.1176/appi.ajp.159.5.738 Occurrence Handle11986126

    Article  PubMed  Google Scholar 

  52. DF Moore G Altarescu WC Barker et al. (2003) ArticleTitleWhite matter lesions in Fabry disease occur in ‘prior’ selectively hypometabolic and hyperperfused brain regions Brain Res Bull 62 231–240 Occurrence Handle10.1016/j.brainresbull.2003.09.021

    Article  Google Scholar 

  53. M Bobinski MJ Leon ParticleDe A Convit et al. (1999) ArticleTitleMRI of entorhinal cortex in mild Alzheimer’s Disease Lancet 353 38–40 Occurrence Handle1:STN:280:DyaK1M7ks1Glsg%3D%3D

    CAS  Google Scholar 

  54. X Shao ER Butch MR Kilbourn et al. (2003) ArticleTitleN-[(18)F]Fluoroethylpiperidinyl, N-[(18)F]fluoroethylpiperidinemethyl and N-[(18)F]fluoroethylpyrrolidinyl esters as radiotracers for acetylcholinesterase Nucl Med Biol 30 IssueID5 491–500 Occurrence Handle10.1016/S0969-8051(03)00031-3

    Article  Google Scholar 

  55. K Erlandsson RA Bressan RS Mulligan et al. (2003) ArticleTitleKinetic modelling of [123I]CNS 1261—a potential SPET tracer for the NMDA receptor Nucl Med Biol 30 441–454 Occurrence Handle10.1016/S0969-8051(02)00450-X

    Article  Google Scholar 

  56. A Nordberg (2001) ArticleTitleNicotinic receptor abnormalities of Alzheimer’s disease: Therapeutic implications Biol Psychiatry 49 200–210 Occurrence Handle10.1016/S0006-3223(00)01125-2

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported by European Union grants QLK-6-CT-1999-02178, QLK-6-CT-1999-02112 and by grants from Regione Toscana, Progetto Ministero della Sanità, “Diagnosi Tempestiva e Differenziale della Malattia di Alzheimer”.

Author information

Authors and Affiliations

  1. Department of Clinical Pathophysiology, Nuclear Medicine Unit, University of Florence, Viale Morgagni 85, 50134, Florence, Italy

    Alberto Pupi MD & Lisa Mosconi MD

  2. Clinical Neurophysiology, Department of Internal Medicine, University of Genoa, Genoa, Italy

    Flavio M. Nobili MD

  3. Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy

    Sandro Sorbi MD

Authors
  1. Alberto Pupi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa Mosconi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flavio M. Nobili MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sandro Sorbi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberto Pupi MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pupi, A., Mosconi, L., Nobili, F.M. et al. Toward the Validation of Functional Neuroimaging as a Potential Biomarker for Alzheimer’s Disease: Implications for Drug Development. Mol Imaging Biol 7, 59–68 (2005). https://doi.org/10.1007/s11307-005-0953-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-005-0953-8

Key words

Search

Navigation