Current Role for Biomarkers in Clinical Diagnosis of Alzheimer Disease and Frontotemporal Dementia
- 1.5k Downloads
Purpose of review Alzheimer’s disease (AD) and frontotemporal dementia can often be diagnosed accurately with careful clinical history, cognitive testing, neurological examination, and structural brain MRI. However, there are certain circumstances wherein detection of specific biomarkers of neurodegeneration or underlying AD pathology will impact the clinical diagnosis or treatment plan. We will review the currently available biomarkers for AD and frontotemporal dementia (FTD) and discuss their clinical importance.
Recent findings With the advent of 18F-labeled tracers that bind amyloid plaques, amyloid PET is now clinically available for the detection of amyloid pathology and to aid in a biomarker-supported diagnosis of AD or mild cognitive impairment (MCI) due to AD. It is not yet possible to test for the specific FTD pathologies (tau or TDP-43); however, a diagnosis of FTD may be “imaging supported” based upon specific MRI or FDG-PET findings. Cerebrospinal fluid measures of amyloid-beta, total-tau, and phospho-tau are clinically available and allow detection of both of the cardinal pathologies of AD: amyloid and tau pathology.
Summary It is appropriate to pursue biomarker testing in cases of MCI and dementia when there remains diagnostic uncertainty and the result will impact diagnosis or treatment. Practically speaking, due to the rising prevalence of amyloid positivity with advancing age, measurement of biomarkers in cases of MCI and dementia is most helpful in early-onset patients, patients with atypical clinical presentations, or when considering referral for AD clinical trials.
KeywordsAlzheimer’s disease Frontotemporal dementia Frontotemporal lobar degeneration Imaging biomarkers Clinical diagnosis
Compliance with Ethical Standards
Conflict of Interest
N.S.-B. and S.A.S. each declare no potential conflicts of interest.
A.L.P. reports contracts from Avid Radiopharmaceuticals, Eli Lilly, Transition Therapeutics (previously Elan), Stemedica, Biogen, Janssen, Axovant, and Roche/Genentech, as well as personal fees from Lundbeck, outside the submitted work.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 3.• Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Cedarbaum J, et al. 2014 update of the Alzheimer’s disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement. 2015;11(6):e1–120. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is one of the most important studies of longitudinal changes in cognition and biomarkers in healthy elderly, MCI, and AD patients in the USA, and has developed numerous standard imaging protocols and analytics for the field. Several studies worldwide have been partially modeled on ADNI, in Europe, Japan, and AustraliaCrossRefPubMedPubMedCentralGoogle Scholar
- 5.McKhann GM, Knopman DS. 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 & dementia : the journal of the Alzheimer's Association. 2011;7(3):263–9.CrossRefGoogle Scholar
- 14.Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the consortium for frontotemporal lobar degeneration. Acta Neuropathol. 2007;114(1):5–22.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.NICE. Dementia: supporting people with dementia and their carers in health and social care | Guidance and guidelines |National Institute for Health and Care Excellence. 2016.Google Scholar
- 17.Soucy JP, Bartha R, Bocti C, Borrie M, Burhan AM, Laforce R, et al. Clinical applications of neuroimaging in patients with Alzheimer’s disease: a review from the fourth Canadian consensus conference on the diagnosis and treatment of dementia 2012. Alzheimers Res Ther. 2013;5(Suppl 1):S3.CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Ossenkoppele R, Cohn-Sheehy BI, La Joie R, Vogel JW, Moller C, Lehmann M, et al. Atrophy patterns in early clinical stages across distinct phenotypes of Alzheimer’s disease. Hum Brain Mapp 2015;36(11):4421–4437.Google Scholar
- 23.Scheltens P, Leys D, Barkhof F. Atrophy of medial temporal lobes on MRI in “probable” Alzheimer’s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol. 1992;8:967–72.Google Scholar
- 25.• Harper L, Barkhof F, Fox NC, Schott JM. Using visual rating to diagnose dementia: a critical evaluation of MRI atrophy scales. J Neurol Neurosurg Psychiatry. 2015;86(11):1225–33. In this systemic review, different cerebral atrophy rating scales for dementia have been examined to highlight the diagnostic potential of these clinically applicable toolsCrossRefPubMedGoogle Scholar
- 27.Wahlund LO, Westman E, van Westen D, Wallin A, Shams S, Cavallin L, et al. Imaging biomarkers of dementia: recommended visual rating scales with teaching cases. Insights Imaging 2017;8(1):79–90.Google Scholar
- 29.•Smailagic N, Vacante M, Hyde C, Martin S, Ukoumunne O, Sachpekidis C. (1)(8)F-FDG PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane database Syst rev. 2015;1:Cd010632. In this Cochrane systemic review, authors searched all the major databases and included and analyzed all the studies that evaluated the diagnostic accuracy of FDG PET to detemine the conversion from MCI to AD or other forms of dementia.Google Scholar
- 46.Vandenberghe R, Van Laere K, Ivanoiu A, Salmon E, Bastin C, Triau E, et al. 18F-Flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: a phase 2 trial. Ann Neurol 2010;68(3):319–329.Google Scholar
- 47.Wong DF, Rosenberg PB, Zhou Y, Kumar A, Raymont V, Ravert HT, et al. In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18). Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2010;51(6):913–20.CrossRefGoogle Scholar
- 51.Klunk WE, Wang Y, Huang GF, Debnath ML, Holt DP, Shao L, et al. The binding of 2-(4′-methylaminophenyl)benzothiazole to postmortem brain homogenates is dominated by the amyloid component. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2003;23(6):2086–92.Google Scholar
- 52.Price JC, Klunk WE, Lopresti BJ, Lu X, Hoge JA, Ziolko SK, et al. Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh compound-B. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2005;25(11):1528–47.CrossRefGoogle Scholar
- 56.Choi SR, Schneider JA, Bennett DA, Beach TG, Bedell BJ, Zehntner SP, et al. Correlation of amyloid PET ligand florbetapir F 18 binding with Abeta aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord. 2012;26(1):8–16.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.•Yeo JM, Waddell B, Khan Z, Pal S. A systematic review and meta-analysis of (18)F-labeled amyloid imaging in Alzheimer’s disease. Alzheimers Dement (Amst). 2015;1(1):5–13. In this systemic review and meta-analysis, the authors have included 19 studies investigating 682 AD patients. They calculated pooled weighted sensitivity, specificity, and odds ratios for each of 18F-labeled amyloid tracer.Google Scholar
- 63.Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid imaging task force of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging. Alzheimers Dement. 2013;9(4):e106–9.CrossRefPubMedGoogle Scholar
- 64.Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Appropriate use criteria for amyloid PET: a report of the amyloid imaging task force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Alzheimers Dement. 2013;(1):9, e-1–e16.Google Scholar
- 67.Rabinovici GD. Impact of amyloid PET on patient management: early results from the IDEAS study. AAIC; London2017.Google Scholar
- 77.•Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15(7):673–84. This tour de force review and meta-analysis of 231 articles containing 15,699 patients with AD and 13,018 controls identified the most consistent AD biomarkers as CSF T-tau, P-tau, Aβ42, and neurofilamentGoogle Scholar
- 78.Molinuevo JL, Blennow K, Dubois B, Engelborghs S, Lewczuk P, Perret-Liaudet A, et al. The clinical use of cerebrospinal fluid biomarker testing for Alzheimer’s disease diagnosis: a consensus paper from the Alzheimer’s biomarkers standardization initiative. Alzheimers Dement. 2014;10(6):808–17.CrossRefPubMedGoogle Scholar
- 79.•Ritchie C, Smailagic N, Noel-Storr AH, Ukoumunne O, Ladds EC, Martin S. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2017;3:Cd010803. This Cochrane Systemic Review urged caution in the use of CSF tau and CSF tau/ABeta ratio in patients with MCI due to risk of misdiagnosis or overdiagnosisGoogle Scholar
- 83.Meeter LH, Kaat LD, Rohrer JD, van Swieten JC. Imaging and fluid biomarkers in frontotemporal dementia. Nat Rev Neurol 2017;13(7):406–419.Google Scholar