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Review
. 2022 Nov;18(11):2292-2307.
doi: 10.1002/alz.12643. Epub 2022 Mar 2.

New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia

Marta Del Campo  1 , Henrik Zetterberg  2   3   4   5   6 , Sam Gandy  7 , Chiadi U Onyike  8 , Fabricio Oliveira  9 , Chi Udeh-Momoh  10   11 , Alberto Lleó  12 , Charlotte E Teunissen  13 , Yolande Pijnenburg  14
Affiliations
Review

New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia

Marta Del Campo et al. Alzheimers Dement. 2022 Nov.

Abstract

Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with different phenotypes, genetic backgrounds, and pathological states. Its clinicopathological diversity challenges the diagnostic process and the execution of clinical trials, calling for specific diagnostic biomarkers of pathologic FTD types. There is also a need for biomarkers that facilitate disease staging, quantification of severity, monitoring in clinics and observational studies, and for evaluation of target engagement and treatment response in clinical trials. This review discusses current FTD biofluid-based biomarker knowledge taking into account the differing applications. The limitations, knowledge gaps, and challenges for the development and implementation of such markers are also examined. Strategies to overcome these hurdles are proposed, including the technologies available, patient cohorts, and collaborative research initiatives. Access to robust and reliable biomarkers that define the exact underlying pathophysiological FTD process will meet the needs for specific diagnosis, disease quantitation, clinical monitoring, and treatment development.

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Conflict of interest statement

Support received for the submitted work: None of the authors received support for the present manuscript. MC is supported by the attraction talent fellowship from Comunidad de Madrid and the ‘Europe Research’ 2020 dynamization actions from Research and innovation Spanish government, payment made to institution. SG has a joint appointment at Icahn School of Medicine (1 FTE) and James J. Peters VA Medical Center (5/8th) which constitutes 100% of his total professional responsibilities (TPE). The combined TPE at both institutions does not exceed 12 person months (PM). Dr. Gandy's joint appointment is documented under an MOU between Mount Sinai and the VA. There is no dual compensation for the same work, nor is there an actual or apparent conflict of interest regarding such work. Institution: Icahn School of Medicine at Mount Sinai Type of Appointment: Academic (Professor) Full Time: 1.00 FTE Active support R01AG067312 (MPI: Huffman (contact), Tu) NIH/NIA/Albert Einstein College of Medicine; Co‐I P30AG066514 (PI: Sano) NIH/NIA TC Mount Sinai Alzheimer's Disease Research Center; Associate Director RF1AG062661 (PI: Salton, Ehrlich) NIH/NIA; Co‐I RF1AG058469 (MPI: Ehrlich (contact), Gandy) NIH/NIA; MPI U01AG046170 (MPI: Zhang (contact), Gandy, Ehrlich, Haroutunian NIH/NIA; MPI R01AG061894 (MPI: Gandy, Noggle (contact), Fossati) NIH/NIA/New York; MPI RF1AG059319 (MPI: Gandy (contact), Ehrlich) NIH‐NIA; MPI R03AG070506 (PI: Wang) NIH/NIA; Co‐I R01AG057907 (MPI: Zhang, Haroutunian, Ehrlich) NIH/NIA; Co‐I R21 AG063068 (PI: Readhead) NIH/NIA/Arizona State University; Role: Subaward Co‐I R6AG066431 (MPI: Huffman, Gandy) NIH/NIA/Albert Einstein College of Medicine; MPI (PI: Gandy) Alzheimer Drug Discovery Foundation; PI Pending (JIT Award under consideration) R03AG070710 (PI: Haure‐Mirande) NIH NIA; Co‐I R21 (PI: Vaska) NIH/Stony Brook; Subaward PI Lab Personnel Paid Directly by Third Party Entities: None Overlap: There is no scientific or budgetary overlap Institution: James J. Peters VA Medical Center Type of Appointment: 5/8th appt Active I01RX002333 (Gandy Role PI) Department of Veterans Affairs. Pending: None Lab Personnel Paid Directly by Third Party Entities: None Overlap: There is no scientific or budgetary overlap. CO received research grants from Biogen and Alector; payments were made to the institution. FO received support from FAPESP ‐ The State of São Paulo Research Foundation, grant #2015/10109‐5, payment made to FO. CU has nothing to disclose. AL reports payment to the institution from Health Department of the Government of Catalonia (grant PERIS SLT002/16/00408), Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI17/01896; AC/0013), CIBERNED (COEN), BBVA foundation. CET's research is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE), and for bPRIDE (JPND), Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT is recipient of ABOARD, which is a public‐private partnership receiving funding from ZonMW (#73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP‐allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes‐Strijbisfonds. IV is appointed on a research grant by Alzheimer Nederland (NL‐17004). CET has a collaboration contract with ADx Neurosciences, Quanterix, and Eli Lilly; performed contract research or received grants from AC‐Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. YP has nothing to disclose. All authors are members of the Biofluid Based Biomarkers or Frontotemporal Dementia and Related Disorders Professional Interest Areas (ISTAART). MC has given a lecture at the annual meeting of Spanish Neurology Society, payment made to MC. HZ has served on scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx. HZ has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen. HZ is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. All payments made to HZ. HZ is a chair of the Alzheimer's Association Global Biomarker Standardization Consortium and the AA Biofluid Based Biomarkers Professional Interest Area. No payments made. SG has provided expert testimony to Vernick & Associates, Annapolis, MD, and Post & Schell, Philadelphia, PA. SG has a patent issued method for iPSC derived basal forebrain cholinergic neurons (issued). SG has served as advisor for Ritrova Therapeutics. CO provides technical or medicolegal advice to Alector, Goodell Devries Leech & Dann. Payment made to CO. CO is part of the medical Advisory Council of the Association for Frontotemporal Degeneration and the Scientific Advisory Board of the FTD Disorders Registry. No payments involved. FO has received consulting fees for acting as a healthcare council member for Gerson Lehrman Group, Atheneum Partners, Guidepoint, Health Advances, and Lionbridge. FO received support from the International Parkinson and Movement Disorder Society to attend the 22nd International Congress of Parkinson's Disease and Movement Disorders in Hong Kong, October 2018. From 2018 to 2021, FO was a member of the ISTAART Advisory Council (unpaid). Starting in 2021, FO is a current member of the International Subcommittee of the American Academy of Neurology (unpaid) and of the Awards Committee of the International Parkinson and Movement Disorder Society (unpaid). FO has also been a member of the Community of Experts of the European Science Foundation since 2019 (and receives payments for each review of a grant). CU is an executive Committee member of Biofluid Based Biomarkers Professional Interest Area (ISTAART) (unpaid) and board of Trustees member of the British Society for neuroendocrinology (unpaid). AL has a patent licensed of synaptic markers in neurodegenerative diseases, payments to the institution and to AL. AL received personal fees for serving on scientific advisory boards from Fujirebio‐Europe, Nutricia, Biogen, and Roche Diagnostics. AL received personal fees for lectures from Nutricia and Zambon. CET has given lectures for Roche and serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book from Springer.

Figures

FIGURE 1
FIGURE 1
Clinicopathological and genetic classification of FTD spectrum. Diagram illustrates the clinicopathological correlations along the FTD spectrum and the corresponding genetic associations. Tau (blue), TDP‐43 (yellow), and FET (gray) pathologies, their corresponding immunohistochemical profiles and associated pathological diagnosis are annotated. Genetic forms of FTD are related to specific pathological aggregates (tau or TDP‐43). Gray arrows indicate specific associations between genetic mutation and immunohistochemical profiles. The biofluid‐based abnormalities indicate biomarkers that are dysregulated either between a specific FTLD subtype (upper panel) or undefined general FTD groups (bottom panel) and controls or between FTLD pathological subtypes (*) in either blood or CSF. Aβ, amyloid beta; bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CSF, cerebrospinal fluid; FET, family of RNA‐binding proteins including FUS, Ewing sarcoma and TAF15; FTD, frontotemporal dementia; FTD‐FUS, frontotemporal dementia fused in sarcoma variant; FTD‐ALS, frontotemporal dementia with concomitant amyotrophic lateral sclerosis; FTLD, frontotemporal lobar degeneration; GFAP, glial fibrillary acidic protein; GGT, globular glial tauopathy; NfL, neurofilament light; nfv, nonfluent variant; PiD, Pick's disease; PPA, primary progressive aphasia; PSP‐RS, progressive supranuclear palsy‐Richardson's syndrome; p‐tau, phosphorylated tau; sv, semantic variant; TDP‐43, TAR DNA‑binding protein 43 [Correction added on 17 March 2022, after first online publication: Figure 1 has been updated. Some text alignment as well as positioning has been corrected.]
See this image and copyright information in PMC

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