Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Within the Dimensional Spectrum of Neurodegenerative Diseases
The discovery, development, and validation of novel candidate biomarkers in Alzheimer’s disease (AD) and other neurodegenerative diseases (NDs) are increasingly gaining momentum. As a result, evolving diagnostic research criteria of NDs are beginning to integrate biofluid and neuroimaging indicators of pathophysiological mechanisms. More than 10% of people aged over 65 suffer from NDs. There is an urgent need for a refined two-stage diagnostic model to first initiate an early, sensitive, and noninvasive process in primary care settings. Individuals that meet detection criteria will then be channeled to more specific, costly (positron-emission tomography), and invasive (cerebrospinal fluid) assessment methods for confirmatory biological characterization and diagnosis.
A reliable and sensitive blood test for AD and other NDs is not yet established; however, it would provide the golden screening gate for an efficient primary care management. A limitation to the development of a large-scale blood-screening biomarker-based test is the traditional application of clinically descriptive criteria for the categorization of single late-stage ND constructs. These are genetically and biologically heterogeneous, reflected in multiple pathophysiological mechanisms and subsequent pathologies throughout a dimensional continuum. Evidence suggests that a shared, “open-source” integrated multilevel categorization of NDs that clusters individuals based on descriptive clinical phenotypes and pathophysiological biomarker signatures will provide the next incremental step toward an improved diagnostic process of NDs. This intermediate objective toward unbiased biomarker-guided early detection of individuals at risk for NDs is currently carried out by the international pilot Alzheimer Precision Medicine Initiative Cohort Program (APMI-CP).
Key wordsNeurodegenerative diseases Alzheimer’s disease Biomarkers Pathophysiology Alzheimer precision medicine initiative Systems biology Systems neurophysiology Precision medicine Blood Screening
S.E.O. is supported by the National Institute on Aging of the National Institutes of Health under Award Numbers R01AG051848 and R56AG054073. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
H.H. is supported by the AXA Research Fund, the “Fondation Université Pierre et Marie Curie” and the “Fondation pour la Recherche sur Alzheimer,” Paris, France. Ce travail a bénéficié d’une aide de l’Etat “Investissements d’avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d’avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6).
S.L. received lecture honoraria from Roche. H.H. reports no conflict of interest with the content of the present manuscript. He serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia; he has been a scientific consultant and/or speaker and/or attended scientific advisory boards of Axovant, Anavex, Eli Lilly and company, GE Healthcare, Cytox Ltd., Jung Diagnostics GmbH, Roche, Biogen Idec, Takeda-Zinfandel, Oryzon Genomics, and Qynapse; and he receives research support from the Association for Alzheimer Research (Paris), Pierre and Marie Curie University (Paris), and Pfizer & Avid (paid to institution); and he has patents, but receives no royalties. F.B., S.E.O., R.C., and N.T. declare no conflicts of interest.
- 9.O’Bryant SE, Mielke MM, Rissman RA et al (2017) Blood-based biomarkers in Alzheimer disease: current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement J Alzheimers Assoc 13:45–58. https://doi.org/10.1016/j.jalz.2016.09.014 CrossRefGoogle Scholar
- 11.Vellas B, Carrillo MC, Sampaio C et al (2013) Designing drug trials for Alzheimer’s disease: what we have learned from the release of the phase III antibody trials: a report from the EU/US/CTAD Task Force. Alzheimers Dement J Alzheimers Assoc 9:438–444. https://doi.org/10.1016/j.jalz.2013.03.007 CrossRefGoogle Scholar
- 13.Brooks BR (1994) El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 124(Suppl):96–107CrossRefGoogle Scholar
- 18.McKhann GM, Knopman DS, Chertkow H 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. Alzheimers Dement J Alzheimers Assoc 7:263–269. https://doi.org/10.1016/j.jalz.2011.03.005 CrossRefGoogle Scholar
- 19.Albert MS, DeKosky ST, Dickson D et al (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 7:270–279. https://doi.org/10.1016/j.jalz.2011.03.008 CrossRefGoogle Scholar
- 21.Sperling RA, Aisen PS, Beckett LA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc 7:280–292. https://doi.org/10.1016/j.jalz.2011.03.003 CrossRefGoogle Scholar
- 26.McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872. https://doi.org/10.1212/01.wnl.0000187889.17253.b1 CrossRefPubMedGoogle Scholar
- 29.Gilman S, Wenning GK, Low PA et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676. https://doi.org/10.1212/01.wnl.0000324625.00404.15 CrossRefPubMedPubMedCentralGoogle Scholar
- 38.Kovacs GG, Milenkovic I, Wöhrer A et al (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol (Berl) 126:365–384. https://doi.org/10.1007/s00401-013-1157-y CrossRefGoogle Scholar
- 48.Group F-NBW (2016) FDA-NIH Biomarker Working Group. Food and Drug Administration (US)Google Scholar