Received: 18 August 2021 Revised: 4 February 2022 Accepted: 4 February 2022 DOI: 10.1002/alz.12643 REVIEW ARTICLE New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia Marta del Campo1 Henrik Zetterberg2,3,4,5,6 Sam Gandy7 Chiadi U Onyike8 Fabricio Oliveira9 Chi Udeh-Momoh10,11 Alberto Lleó12 Charlotte E. Teunissen13 Yolande Pijnenburg14 1 Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain 2 Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden 3 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden 4 UK Dementia Research Institute at UCL, London, UK 5 Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK 6 Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China 7 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA 8 Division of Geriatric Psychiatry and Neuropsychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 9 Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo, São Paulo, Brazil 10 Ageing Epidemiology Research Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK 11 Translational Health Sciences, Faculty of Medicine, University of Bristol, Bristol, UK 12 Neurology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain 13 Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands 14 Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands Correspondence Marta del Campo Milan, San Pablo CEU Abstract University, Department of Pharmacy, Urbanización S/N, 28668, Av. de Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders Montepríncipe, Alcorcón, Madrid, Spain. with different phenotypes, genetic backgrounds, and pathological states. Its clinico- E-mail: marta.campomilan@ceu.es pathological diversity challenges the diagnostic process and the execution of clinical [Correction added on 17 March 2022, after trials, calling for specific diagnostic biomarkers of pathologic FTD types. There is also first online publication: The first author’s name a need for biomarkers that facilitate disease staging, quantification of severity, mon- has been corrected from “Martha del Campo” to “Marta del Campo”.] itoring in clinics and observational studies, and for evaluation of target engagement and treatment response in clinical trials. This review discusses current FTD biofluid- Funding information The Swedish Research Council, Grant/Award based biomarker knowledge taking into account the differing applications. The limi- Number: 2018-02532; European Research tations, knowledge gaps, and challenges for the development and implementation of Council, Grant/Award Number: 681712; Swedish State Support for Clinical Research, such markers are also examined. Strategies to overcome these hurdles are proposed, Grant/Award Number: ALFGBG-720931; including the technologies available, patient cohorts, and collaborative research ini- Alzheimer Drug Discovery Foundation tiatives. Access to robust and reliable biomarkers that define the exact underlying This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association 2292 wileyonlinelibrary.com/journal/alz Alzheimer’s Dement. 2022;18:2292–2307. 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License DEL CAMPO ET AL . 2293 (ADDF), USA, Grant/Award Number: 201809-2016862; AD Strategic Fund and the pathophysiological FTD process will meet the needs for specific diagnosis, disease Alzheimer’s Association, Grant/Award Numbers: ADSF-21-831376-C, quantitation, clinical monitoring, and treatment development. ADSF-21-831381-C, ADSF-21-831377-C; Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden, Grant/Award Number: FO2019-0228; European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie, Grant/Award Number: 860197; Attraction talent fellowship of Comunidad de Madrid; San Pablo CEU University; Alzheimer Nederland; Selfridges Group Foundation; bPRIDE - JPND; Marie Curie International Training Network, Grant/Award Number: 860197 (MIRIADE); Health∼Holland, the Dutch Research Council (ZonMW); Alzheimer Drug Discovery Foundation; The Alzheimer’s Association 1 BACKGROUND sions (FTLD‑UPS).14–16 Depending on the immunohistochemical pro- file, that is, density and distribution of the protein aggregates, FTLD- Frontotemporal dementia (FTD) is the second most prevalent neu- TDP, FTLD-tau, and FTLD-FUS can be subclassified into different sub- rodegenerative dementia in young-onset patients (< 65 years old) and types (Figure 1).16–19 has a dramatic effect on life expectancy, with reported survival rates after onset varying from 3 to 14 years.1,2 FTD causes a heavy finan- 1.1.1 FTLD-TDP cial burden with costs per patient estimated at two to three times higher for FTD than those for patients suffering from Alzheimer’s dis- TDP-43 is a nuclear DNA/RNA binding protein that regulates tran- ease (AD) dementia.3,4 FTD is a heterogeneous and complex disor- scription and alternative splicing.20,21 Mislocalization and aggregation der comprising a wide range of subtypes from a clinical, genetic, and of this protein in the cytoplasm leads to the pathological stress gran- pathological perspective (Figure 1). Based on the clinical phenotype, ules observed in FTLD.22 TDP-43 inclusions are also observed in > 95% patients may suffer primarily from behavioral changes and deficits in of ALS,22 supporting the notion that FTLD-TDP and ALS are part of a executive functions (behavioral FTD [bvFTD]) or language disturbances clinicopathological continuum.18,23 The heterogeneity within TDP-43 (primary progressive aphasia [PPA]). PPA encompasses semantic vari- histopathological patterns has prompted the definition of five differ- ant PPA (svPPA) and non-fluent variant PPA (nfvPPA).5,6 A logopenic ent FTLD-TDP subclassifications (FTLD type A, B, C, D, and E; Figure 1), variant of PPA (lvPPA) has also been described, but is usually asso- depending on their shape, distribution, and cellular localization.17,24 ciated with AD pathology.5,6 The phenotypic spectrum also includes FTLD-TDP can present with different clinical phenotypes including cases with concomitant amyotrophic lateral sclerosis (FTD-ALS),7 cor- bvFTD, CBS, or PPA.25 The presence of svPPA and FTD-ALS show a ticobasal syndrome (CBS),8 and progressive supranuclear palsy (PSP; strong correlation with TDP-43 pathology.25,26 Recent research sug- the classic PSP syndrome called Richardson syndrome).9 Furthermore, gests that psychiatric symptoms in FTD patients are associated with the overlap of clinical features in bvFTD or svPPA with those observed underlying TDP pathology.27 in AD or psychiatric disorders represents additional challenges for clin- ical diagnosis.10–13 These diverse clinical phenotypes can share differ- ent pathological and genetic backgrounds (Figure 1), underpinning the 1.1.2 FTLD-tau complexity of this disorder. Misfolded or aggregated tau leads to the formation of pathological 1.1 FTD neuropathology intraneuronal inclusion bodies and destabilization of microtubules. Alternative splicing leads to different tau isoforms with three or FTD is typically associated with focal degeneration of the frontal and four microtubule-binding domains (3-repeat [3R] or 4-repeat [4R] temporal cortices, denoted by the term frontotemporal lobar degen- tauopathies).28 Based on the predominant tau isoform present in such eration (FTLD). Microscopically, ≈50% of FTLD patients are char- aggregates (tau 3R, 4R, or 3/4R) and the morphology of the inclusion acterized by aggregates of TAR DNA‑binding protein 43 (TDP‑43 bodies, FTLD-tau can be classified and subdivided into several neu- [FTLD‑TDP]) and 45% of FTLD patients develop aggregates of the ropathological diagnoses. Thus, FTLD-tau includes Pick’s disease (PiD), microtubule‑associated protein tau (MAPT, i.e., FTLD-tau). Less com- which features 3R tau pathology, and the 4R tauopathies PSP, monly (< 5% of the cases), FTLD features aggregates of RNA‑binding corticobasal degeneration, and globular glial tauopathy (GGT; protein fused in sarcoma (FUS [FTLD‑FUS]) or ubiquitin‑positive inclu- Figure 1).18,19 FTLD-tau can also present across the different clinical 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2294 DEL CAMPO ET AL . phenotypes.18 Almost half of bvFTD have an underlying FTLD-tau pathology, including PiD and to lesser extent CBD and PSP patholo- RESEARCH IN CONTEXT gies. FTLD-tau has also been reported in patients with PPA and CBS 1. Systematic Review: PubMed was used to search, iden- phenotypes. The clinical syndrome of PSP highly correlates with PSP tify, and evaluate the accumulated knowledge in relation tau pathology. In addition, parkinsonism in association with bvFTD or to biofluid-based biomarkers for frontotemporal demen- PPA is a predictor of tau pathology.26 tia (FTD), together with data gathered through meetings, abstract, and presentations. 1.1.3 FTLD-FUS/UPS 2. Interpretation: The findings indicate that FTD clinico- pathological diversity challenges the diagnostic process FUS is also a nuclear DNA/RNA binding protein with diverse functions and the execution of clinical studies and trials, so there including transcription regulation, transport of RNA, and cell growth.16 is a pressing need for reliable biofluid-based biomarkers FUS inclusions are not very common in FTD; still, four different clinico- for different context of use (e.g., prognosis and diagno- pathological subclassifications have been proposed.29,30 Patients with sis, monitoring, target engagement, drug efficacy). Among underlying FTLD-FUS pathology often fulfill the diagnostic criteria of the main limitations and knowledge gaps encountered in bvFTD.30 Clinically, they are characterized by a disease onset before the development and implementation of such markers are 40 years, a negative family history, and caudate atrophy on magnetic (a) the clinicopathological heterogeneity of FTD, (b) the resonance imaging.31 lack of an established definition of the different disease These data highlight that prediction of all these neuropathologi- stages of FTD (e.g., preclinical, prodromal, dementia), (c) cal subtypes on the basis of clinical phenotype is imperfect and varies a better understanding of the similarities and differences across syndromes (Figure 1). Despite some syndromes being highly between sporadic and familial cases or pathological sub- predictive of a specific underlying pathology (e.g., svPPA or FTD-ALS classifications. with TDP or clinical PSP with tau), the most common sporadic bvFTD 3. Future Directions: We propose different strategies to cases can have different neuropathologies that cannot be predicted by overcome the identified challenges covering not only the the clinical syndrome. study design but also the use of new innovative technolo- gies as well as the importance of patients’ cohorts and col- 1.2 FTD genetics laborative research initiatives. FTD is highly heritable with approximately 10% to 20% of FTD cases caused by an autosomal dominant mutation.32,33 Most of these vari- ants have very poor genotype–phenotype correlations, but they are tion or to prevention of translation, which leads to GRN haploinsuffi- highly predictive of the underlying neuropathology (Figure 1).18,34 The ciency in FTD patients.40 GRN mutations likely affect lysosomal func- most common genes linked to familial FTD are MAPT, progranulin tion in a disease-promoting manner.47 GRN carriers often present (GRN), and chromosome 9 open reading frame 72 (C9orf72).35–38 We with FTLD-TDP A pathology and most patients have bvFTD clini- will only focus on these highly penetrant mutations, as exhaustive revi- cal phenotype, though PPA has been also reported in these familial sions outlining the heterogeneity of FTD genes have been previously cases.34 published.34,39,40 1.2.1 C9orf72 1.2.3 MAPT These carriers account for the largest amount of familial cases of FTD, Mutations in the MAPT gene (with ≥ 40 pathogenic mutations) in which abnormal GGGGCC expansions in the non-coding region of lead to abnormal forms of the tau protein, promoting its aggre- the C9orf72 gene produce toxic RNA foci41,42 and dipeptide repeat gation and interfering with the polymerization and stabilization of proteins (DPRs).43,44 The number of expansions is directly corre- microtubules.48 These mutations are often associated with PSP and lated with pathogenicity, with most confirmed cases bearing hundreds CBD pathology.18 Genotype-phenotype correlations showed that of them.40 These carriers mostly present with FTLD-TDP A and B MAPT carriers are associated largely with bvFTD, PPA, and FTD with pathology, although type C has also been reported.45,46 Clinically, FTD parkinsonism.34 C9orf72 carriers can present with bvFTD, and in some cases also with The clinical, pathological, and genetic complexity of FTD requires PPA.34 the development of biomarkers for the molecular subtypes of FTD. Such biomarkers could be used to increase diagnostic accuracy; quan- 1.2.2 GRN titate disease staging; and predict, monitor, and measure disease progression.49 Depending on the context of use, general biomark- More than 70 pathogenic mutations of GRN have been described, ers of FTD or biomarkers for specific FTLD types and subtypes will mostly resulting in loss of function either due to aberrant transcrip- be needed. Pathology-specific biomarkers are especially relevant to 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License DEL CAMPO ET AL . 2295 F I G U R E 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.] define FTD biologically. Such biomarkers are urgently needed for made blood-based biomarkers feasible—a revolutionary development recruitment for clinical trials, where homogeneous populations of for AD research.53,54 Compared to developments in the AD field, there patients with specific FTD pathological subtypes are crucial for test- has been significant progress in FTD biofluid biomarker research in the ing candidate drugs that target these specific proteinopathies (e.g., tau last 10 years, but this has also encountered difficulties that relate to or TDP).50 In clinical trials, biomarkers are also needed to assess tar- the relative recency of the key neuropathology discoveries and to the get engagement and evaluate drug response. Such markers are very clinical and pathologic heterogeneity of the syndromes. For instance, important for FTD treatment development, as the heterogeneity of C9orf72 genetic expansions and the resulting pathological hallmarks the clinical presentation prevents the use of clinical or imaging indices were only revealed a decade ago35,41–44 and pathological, genetic, and as outcome measures.51 Biofluid-based biomarkers (e.g., cerebrospinal clinical associations have been expanded.19,24,27,29,30,45–47 Leveraging fluid [CSF] and blood) can be especially helpful in clinical practice and these recent and upcoming discoveries warrants further developments clinical trials.49–51 CSF has been the most widely used source for the within the FTD biomarker field. development of fluid biomarkers for neurological disorders because it Here, we review the key biofluid-based biomarker developments is viewed as reflecting ante mortem biochemical milieu and its changes in FTD (Figure 1 and Table 1) and identify the major opportuni- during the neurodegenerative process, and concentrations of brain ties and obstacles for the development and implementation in prac- pathology-specific proteins are expected to be higher than those mea- tice and research of biofluid-based biomarkers for FTD. We discuss sured in blood.52 In AD, the implementation of CSF biomarkers in clin- potential strategies to overcome the obstacles, taking into account ical practice has shown enormous benefits for early diagnosis and the the contexts of use, the different methods and technologies available, testing of new compounds in AD clinical trials.27 Lately, highly sensitive and the present-day clinical/epidemiological cohorts and collaborative and specific immuno- and mass spectrometry-based approaches have research initiatives. 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2296 DEL CAMPO ET AL . TA B L E 1 Most widely studied biomarkers studies within the FTD field and its context-of-use [Correction added on 17 March 2022, after first online publication: The alignment of table column heads in Table 1 has been corrected.] Context-of-use Sample matrix Remarks Specific FTD diagnosis Clinical/genetic/ Biofluid based vs. vs. vs. pathological Staging and Treatment biomarker CON AD Psych.dis subtypes monitoring Prognosis Response Tau, pTau – ++ ns +a ns ns ns CSF/plasma AD biomarker; (281/217/231), co-pathology Aβ42, Aβ40, dependent and their ratios pTau181/tTau – – + +b ns ns ns CSF AD biomarkers; limited accuracy NfL ++ + ++ + ++ ++ + CSF/plasma/ General serum biomarker of neurodegener- ation sAPPβ + – ns ns ns ns ns CSF Specifically decreased in FTD Progranulin ns ns ns ++c ns ns + CSF/plasma/ Specific genetic serum subtype Poly(GP) ns ns ns ++d – – + CSF Specific genetic subtype Abbreviations; ++, validated biomarker (i.e., changes consistently observed across independent studies); +, promising biomarker; –, not useful; Aβ, amyloid beta; AD, Alzheimer’s disease; CON, controls; CSF, cerebrospinal fluid; FTD, frontotemporal dementia; ns, not studied; Psych.dis., psychiatry disorders. Note: Summary table of the most widely studied biomarkers within the FTD field and their corresponding context-of-use. a Logopenic FTD variant. b For TDP vs. tau. c For GRN mutation carriers. d For C9orf72 mutation carriers. 2 STATE OF THE ART OF BIOFLUID-BASED frontal variant AD.63 Similarly, CSF biomarkers can be useful in the BIOMARKERS FOR FTD evaluation of the logopenic variant of PPA, which is typically associ- ated with AD pathology, rather than FTD.64 In this scenario, the asso- 2.1 Biomarkers to differentiate FTD from other ciation of elevated CSF tau levels and reduced Aβ42/40 ratio, sup- dementias and non-degenerative disorders ports AD pathology as the main etiology of the language syndrome.64 It has also been repeatedly shown that Aβ species including Aβ38, An important challenge for both routine diagnosis and clinical tri- Aβ40, Aβ42, and soluble amyloid precursor protein fragment (sAPPβ) als is to identify cases within the FTD spectrum and differentiate are lower in CSF from FTD patients than in the compared controls.65,66 these from those of related diseases, such as sporadic AD55 or the The reason for this remains unclear, but in AD, cerebral Aβ pathology is non-neurodegenerative primary psychiatric disorders.56 In many AD associated with a relatively selective reduction in Aβ42 in CSF, while studies of tau and amyloid beta (Aβ) fluid biomarkers, FTD has been the reduction in FTD is seen for all measurable Aβ species and the included as a contrast group. It has been shown that elevated CSF decrease correlates with brain atrophy;66 hence, the CSF Aβ42/Aβ40 concentrations of total tau (t-tau) and tau phosphorylated at amino ratio works well to differentiate amyloid pathology in AD (with reduced acids 181 and, more recently, 217 (p-tau181 and p-tau217, respec- Aβ42/40 ratio) from the general reduction of APP-derived peptides tively) are surprisingly AD-specific; tau-associated FTD subtypes do often seen in FTD (with Aβ42/40 ratio in the normal range, area not have elevated CSF t-tau and p-tau concentrations,57–60 at least under the curve [AUC]: 0.85).65 Of note, many biomarker studies in not to the levels present in AD.61 Accordingly, an increased ratio of t- FTD may be confounded by co-occurring secondary AD pathology.67,68 tau or p-tau to the 42 amino acid form of Aβ (Aβ42), i.e., the tau/Aβ42 Therefore, when a patient with an FTD syndrome shows a positive ratio, is an AD-specific finding that separates AD from FTD with high AD CSF biomarker profile it is important to consider all clinical and diagnostic accuracies (70% and 86% specificity when analyzing AD radiological information to evaluate if the AD pathology is the pri- vs. bvFTD or svPPA, respectively).62 Thus, these biomarkers can be mary pathology or a comorbid condition. Besides the classical AD CSF used to identify patients who have frontal lobe dysfunction on the biomarkers, several studies have found much higher CSF neurofilament basis of AD pathology, rather than FTD, a condition sometimes called light (NfL, a general biomarker for neurodegeneration) levels in FTD 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License DEL CAMPO ET AL . 2297 compared to AD;69–72 this finding, particularly in combination with focus on specific pathological processes. Several independent studies negative AD biomarkers, strongly speaks for a non-AD neurodegener- have shown that CSF p-tau/t-tau ratio demarcate FTD-TDP patients ative disease. For instance, combination of AD CSF biomarkers (Aβ42 from FTD-tau cases with sensitivity and specificity values around 82% and p-tau181) with CSF NfL could discriminate FTLD from AD with and 62%, respectively.93–97 Other studies have shown that the value high performance (AUC > 0.90).73 However, FTD should only be con- of CSF tau measurements is limited to pure cases of FTLD (e.g., with- sidered in the presence of a compatible clinical syndrome, as CSF NfL out copathologies).67,61 Lower CSF p-tau could discriminate FTD-TDP levels are increased in multiple related neurodegenerative disorders from FTD-tau in sporadic pure FTD cases after excluding AD.67 As CSF (e.g., ALS, PSP, multiple system).74 For the differentiation between FTD t-tau levels are not strongly associated with underlying FTLD-tau, it and non-neurodegenerative disorders, several CSF studies showed an would be worthwhile to study CSF pathological tau isoforms in more excellent performance of NfL for discriminating FTD from psychiatric detail.98 disorders (AUC > 0.90)56,71,75 and consequent perceived added clini- While it is possible to measure TDP-43 in biofluids, current assays cal use for the physician.76 do not differentiate normal from pathological TDP-43.99 A recent It is to be noted that the studies described above analyze mainly study using real time quaking-induced conversion assay, a test based the performance of classical AD CSF biomarkers and thus are useful on the amplification of misfolded proteins and used for detection of to exclude AD pathology rather than to diagnose FTD; or analyze gen- prion proteins, showed in vitro TDP-43 aggregate formation in CSF.100 eral markers of neurodegeneration (e.g., NfL). These observations high- In a recent proof-of-concept small clinical study this assay discrimi- light the lack of well-established FTD-specific biomarkers. Promising nated FTD and ALS patients from controls with 94% sensitivity and biomarkers have been identified and are being investigated.77,78 For 85% specificity.100 These studies await independent replication. How- example, a study combining CSF NfL, YKL40, and sAPPβ measurements ever, the seed-based testing paradigm may help to develop additional from 159 cases with an FTLD-related syndrome yielded high diagnostic assays for inclusion-specific forms of TDP-43. Biomarkers that reflect accuracies (AUC > 0.90) in discriminating FTD from controls.79 While metabolic changes downstream of TDP-43 pathology might also be YKL40 is also elevated in other neurodegenerative disorders includ- developed. ing AD,80,81 sAPPβ concentrations were specifically lower in FTLD As far as we are aware, there is no biomarker of FUS pathol- syndromes.79 Similar results were observed in an autopsy-confirmed ogy available. Ideally, a combined panel measuring markers of tau, FTLD cohort.82 Other pathways that are currently being examined TDP-43, and FUS would allow for accurate pathologic diagnosis of in the quest for FTD-specific biomarkers include neuroinflammation, FTD, but these have so far posed important challenges. Some stud- lysosomal health, and synaptic health (for a recent review on the topic, ies have analyzed well-established biomarkers that are not directly please see Swift et al.77 ). Combinations of CSF biomarkers (e.g., NfL, related to the specific proteinopathy. For example, higher levels of YKL40, p-/t-tau) do not seem to have added value over NfL alone, both CSF and plasma NfL have been observed in FTD-TDP than in at least not for the discrimination of FTD from primary psychiatric FTD-tau cases, but with high within-group variability.87,101,102 Non- disorders.56 hypothesis driven proteomics studies have identified multiple pro- Regarding blood-based biomarkers, recent AD studies showed that teins that are differentially expressed in FTLD neuropathological plasma concentrations of p-tau181, p-tau217 and p-tau231 are ele- or genetic subtypes.95,103,104 These unbiased approaches have the vated in AD, relative to controls, but not in FTD;83–86 the two dis- potential to facilitate the identification of biomarkers specific for eases can thus be separated with close to 100% accuracy using a the main pathophysiological processes associated with the FTD sub- simple blood test. These promising results were recently confirmed types (e.g., lysosomal degradation, autophagy). Replication and vali- for plasma p-tau181 and p-tau231 in neuropathologically confirmed dation of these findings are of utmost importance to move the field cohorts.84,86 Similar to what was observed in CSF, serum and plasma forward. NfL are elevated in FTD compared to AD, but with limited utility in discriminating FTD from AD.87–89 At present, serum NfL has the highest diagnostic accuracy with AUC of up to 0.94 for differenti- 2.3 Biomarkers for target engagement ating FTD from primary psychiatric disorders.71,90,91 However, nor- and treatment monitoring mal NfL levels still do not rule out FTD. Because NfL levels are also associated with disease progression and survival,85,92 normal NfL Low CSF and blood progranulin levels have been found in GRN muta- levels are probably associated with slowly progressive phenotypes tion carriers with an almost 100% diagnostic accuracy.105–107 It is of FTD. expected that disease-modifying treatments aimed at restoring pro- granulin deficits can be evaluated by these serum GRN measurements. In C9orf72 expansion carriers, poly(GP), one of the DPR proteins pro- 2.2 Biomarkers to define the underlying duced by the C9orf72 expansions, is elevated as early as the presymp- proteinopathies tomatic phase.108–110 Thus, DPR proteins may prove useful as phar- macodynamic biomarkers in gene-silencing studies. While blood NfL Biomarkers for specific FTD-related proteinopathies (TDP-43, tau, or has promise for measuring treatment effects in different neurode- FUS14,15 ) are a pressing need for drug development strategies that generative disorders,51,92,111,112 its utility as an endpoint measure 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2298 DEL CAMPO ET AL . in GRN carriers appears to be limited by the observed longitudinal 3.1 Challenges in the development of biomarkers fluctuations.92 for specific diagnosis of FTD and its pathological subtypes 2.4 Biomarkers for disease staging and prognosis Given the high heterogeneity of FTD, it is not to be expected that a sin- gle FTD-specific biofluid marker will be used to differentiate FTD from As observed in other dementias, accelerated rates of decline have been other neurodegenerative or non-neurodegenerative disorders. Inclu- quantified during the symptomatic phase of both familial and sporadic sion of non-FTD dementias (e.g., AD) in biomarker studies will facili- FTD using clinical and imaging measures113 and thus, markers reflect- tate the distinction of FTD-specific changes from those that are com- ing the disease stage independent of the clinicopathological presen- mon to all neurodegenerative states. The fact that concomitant AD tation would be desirable. Several studies have already indicated that is not uncommon in FTD adds further complexity.68 It will be impor- baseline NfL concentrations in both CSF and blood could reflect the tant, therefore, to evaluate the effects of concomitant AD pathology in aggressiveness of the disease as it can predict rate of disease progres- FTD biomarker studies, using standard AD CSF (and more recently also sion in the different clinicopathological phenotypes in both sporadic plasma) biomarkers.67,68,83 and familial FTD.87,96,114–117 Future studies will clarify whether base- The identification of biofluid-based biomarkers that discriminate line CSF NfL levels can be used to stratify FTD severity (e.g., low, inter- FTD pathologies (TDP-43, tau, FUS), has often been hindered by the mediate, high). Longitudinal analysis of CSF NfL shows that the lev- availability of pathologically characterized samples with known under- els of this marker change little during the symptomatic phase of FTD lying pathology—these are usually selected based on autopsy confir- in individual patients.114 However, a recent longitudinal multicenter mation or genetic mutation status (e.g., C9orf72 and GRN for TDP-43 study of familial FTD has shown in symptomatic GRN mutations car- or MAPT for tau18,35,37,22 ). The scarcity of these samples has prompted riers a rise in serum NfL levels as illness duration time and severity efforts to enrich cohorts with FTD syndromes that are highly cor- increased, notable from symptom onset on but with substantial fluctu- related with a specific underlying neuropathology (e.g., FTD-ALS for ations in the individual NfL trajectories.92 Importantly, the study also FTLD-TDP22 or PSP and CBS for FTLD-tau119,120 ) and/or to jointly ana- showed that serum NfL levels increase in presymptomatic carriers 1 lyze data from both combined cohorts of sporadic and familial cases to 2 years before symptom onset. The study was limited by the num- with the same neuropathology background. It must be noted, however, ber of FTD mutation carriers undergoing conversion to symptomatic that recent neuropathological studies have reported TDP-43 copathol- phase (n = 9); nevertheless, it suggests that baseline serum NfL levels ogy in a considerable amount of FTLD-tau–related syndromes such as may discriminate those in the transition from normal to symptomatic CBD, and to lesser extent PSP.121 In addition, it is not clear to what status (i.e., converters) from those that are not in transition (i.e., non- extent the biochemical changes in those cases with FTD mutations converters) with good accuracy,92 indicating a potential utility of serum resemble those of sporadic cases with the same proteinopathy, nor NfL as a prognostic marker and a selection criterion for clinical trials, across the different immunohistochemical profiles within each patho- at least in familial cases. Recent findings observed that higher levels logical subtype (e.g., tau: 3R, 4R, 3R/4R; TDP: A, B, C, D, and E). Patho- of plasma glial fibrillary acidic protein (GFAP), an astrogliosis marker, physiological differences between hereditary and sporadic FTD have was associated with a greater decrease in Mini-Mental State Exami- been reported.122,123 Recent studies have shown that the performance nation score and a poor cognitive outcome in both FTD and AD. Thus, of CSF p-tau181 to discriminate between FTD pathological subtypes in combination with FTD-specific markers, plasma GFAP could also be (i.e., FTLD-tau vs. FTLD-TDP) was considerably reduced when muta- potentially used to track disease severity or predict greater cognitive tion carriers were analyzed separately (AUCs of 0.87 in sporadic pure decline.118 cases vs. 0.58 in genetic cases).67,61 Similarly, the levels of plasma p- tau181 were approximately 2-fold increased in MAPT mutation carri- ers with mixed 3/4R but not in those with 4R tau pathology.83 Recent 3 GAPS AND LIMITATIONS ON THE findings have shown that the levels of plasma GFAP are increased in DEVELOPMENT OF BIOFLUID-BASED symptomatic GRN carriers but not in those with C9orf72 expansions BIOMARKERS FOR FTD or MAPT mutations, and could distinguish these genetic forms with AUCs >0.70.124 Furthermore, findings from molecular studies indi- Taken together, except for NfL, the most robust FTD biofluid- cate that the mechanisms underlying TDP-43 aggregation by C9orf72 based biomarkers developed from the scientific efforts of the last expansions differ from those driven by GRN loss of function.125,126 decade are related to AD pathology rather than that of FTD. The Taken together, these observations indicate a high heterogeneity also high pathologic heterogeneity of FTD is a particular challenge; the within each pathological and genetic subtype, in which different bio- current biomarkers are not specific for any pathologic subtype, logical processes underlying familial and sporadic cases may ultimately and biomarkers may have different utilities depending on the FTD result in similar proteinopathy profiles—but not necessarily in simi- subtype. lar biomarker profiles. In other words, within a proteinopathy class 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License DEL CAMPO ET AL . 2299 different mechanisms may generate different biochemical profiles in accentuates the need to develop markers for different contexts of use body fluids, especially in the early stages of the disease. The biological that account for the clinical and pathologic diversity of FTD.51 complexity of FTLD subtypes needs to be considered in the design and interpretation of FTD biomarker studies. 4 FILLING THE GAPS ON THE DEVELOPMENT OF BIOFLUID-BASED BIOMARKERS FOR FTD 3.2 Challenges in the development of biomarkers for disease stage, prognosis, and drug efficacy 4.1 Emerging technologies and approaches Biofluid-based biomarkers for the different stages of FTD, including The identification of novel biomarkers will be facilitated by leverag- the preclinical and prodromal phases, are still needed. This is espe- ing a variety of technologies. Mass spectrometry (MS) has the advan- cially challenging in FTD as, unlike in AD, there is still not an estab- tage of an unbiased screening, which has facilitated the identification lished definition of the preclinical/prodromal stages (e.g., mild cogni- of novel biomarkers for FTLD subtypes.103,104 Novel proteins identi- tive impairment due to FTD). Diagnosis is typically delayed for up to fied through MS approaches can then be measured as single analytes 6 years.100 Moreover, the first and core symptom of FTD is a deficit in using immunoassays or incorporated into panels of protein arrays for social cognition, which is not readily recognized as such until the illness further validation studies.95,103,104,130,131 Conventional unbiased MS is well established. The construct of social cognition, including emotion methods are, unfortunately, still not optimal for blood proteomic anal- recognition, theory of mind, empathy, and moral reasoning, has been ysis. This limitation is partially overcome by novel and highly sensi- proven difficult to measure in clinical practice.71 Use of newly devel- tive high-throughput protein arrays, such as aptamer-based technolo- oped psychometric measures for characterizing all stages of symptoms gies, immunobased proximity extension assays, or antibody suspension (e.g., FTLD-Clinical Dementia Rating, Multidomain Impairment Rating) beads arrays, which can readily measure large sets of protein libraries in familial FTD research will facilitate the discovery and validation of in CSF and blood samples.132–138 An additional advantage of such pro- early FTD biomarkers.51,127 As highlighted above, the identification of tein arrays is that the reagents used for biomarker discovery with spe- early diagnostic markers will likely be more effective when accounting cific protein binders (e.g., antibodies) can in principle be also used for for the pathological heterogeneity of the disease. validation, and for translation to the clinical setting in which immunoas- A major challenge in the field of neurodegenerative dementias is to says are a cornerstone of clinical chemistry analyses.52,139 The differ- predict whether and when an individual will develop the specific dis- ent proteome profiling technologies currently available can be useful ease, an important question as early application is expected to increase to cross-validate findings, an essential step toward the development the value and efficacy of treatments aiming to prevent or delay disease of optimal biomarkers. It is, however, expected that these technologies progression. Because disease progression in most neurodegenerative will also complement each other as protein libraries partially differ, and diseases is non-linear, longitudinal studies characterizing the behavior the distinct platforms can detect the proteins in different conforma- of a biomarker over time should include at least three time points.128 tion/states (denatured in MS vs. native in protein arrays). In this respect, blood-based biomarkers are more suitable than CSF It is also conceivable that the search should be continued in alterna- biomarkers. Considering the lack of preclinical/prodromal markers for tive matrices or alternative targets, such as RNA in platelets or extra- sporadic FTD, studies of familial FTD are crucial for such purposes. The cellular vesicles. Blood platelet mRNA analysis has shown potential utility of serum NfL as prognostic marker should be replicated in larger for multiple sclerosis.140 Panels (proteins, nRNA, metabolites) may be cohorts,92 analyzing also the potential influence of the different FTD needed to capture the full complexity of the pathological differences genetic backgrounds. It is also essential to understand whether find- among the FTD subtypes, and within them, and thus multiplex tech- ings from familial FTD research can be generalized to sporadic FTD. nologies and computer assisted algorithms need to be used. These These data also indicate that biochemical changes can be detected in could be extended or incorporated into multimodal approaches that blood before the appearance of clinical symptoms, and it thus boosts include not only biofluid-based biomarkers (e.g., CSF and blood), but the search for additional biomarker candidates. Despite the need for also other types of measures (e.g., imaging results, genetic variation, more studies, it should be noted that the presymptomatic phase of neuropsychological findings, etc.), which can be especially helpful for FTD, at least in familial cases, might be shorter than that observed both clinical practice and trials.49,51 in familial forms of AD; as in the latter, NfL changes were observed already 10 years before symptom onset.129 Considering that serum NfL is also a general marker of neurodegeneration with similar NfL 4.2 Collaborative initiatives changes in presymptomatic familial AD cases,129 the quest for predic- tive biomarkers specific for FTD especially in sporadic cases is war- The identification of biofluid-based biomarkers for FTD pathologies ranted. will require the analysis of data and samples from large and well- To date, there are no established biomarkers to measure target characterized cohorts with longitudinal and autopsy-confirmed cases. engagement or drug efficacy in FTD clinical trials, especially for spo- Study design and analyses should account for the potential influence of radic cases. The increasing number of trials in the industry pipeline specific mutations or pathological subclassifications, especially within 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2300 DEL CAMPO ET AL . the earliest stages of the disease. This would also involve more sys- ture. For vascular and immunological abnormalities, reliable biomark- tematic post mortem research in FTD, together with deep phenotyping. ers are infrequent, imprecise, or lacking altogether. Besides the impre- Considering the limited availability of highly characterized samples, cision that this brings to nosology, the complexity of multiple concur- such studies will only be successful when multiple centers are involved. rent pathologies will certainly hamper the ability to test interventions The extension of existing cohorts and development of new ones will that are aimed at only one component of the concurrent pathologies. In be extremely valuable and, therefore, there is a need to reinforce the other words, the more complex the concurrent pathologies, the greater interest and engagement of the advocacy community, patients and the challenge in designing trials that are sufficiently sensitive to gener- families, and the public in FTD research. ate interpretable clinical or biomarker endpoints. It is also worth noting Several initiatives have facilitated collaborative studies worldwide, that age-, sex-, race-, and ethnicity-based variations; the frequency of including the Genetic Frontotemporal Dementia Initiative (GENFI), comorbidities; and the effects of genetic diversity must always be kept the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degenera- in mind, as observed already in AD and ALS,146–157 but also within the tion (ALLFTD), and their coming together in the worldwide FTD Pre- FTD field.158–160 Indeed, it is far more prudent to assume that these vention Initiative (FPI). These consortia are continuously gathering parameters are more likely to be important than to dismiss them. invaluable information from multiple FTD cohorts worldwide and are The unknown category is illustrated by the proliferation of the reference for many of the FTD biomarker studies performed to newly recognized clinicopathological entities. For example, primary date, especially in familial FTD. The FTD professional interest area aging-related tauopathy (PART), limbic age-related TDP-43 (FTD-PIA) has been recently created within the Alzheimer’s Asso- encephalopathy (LATE), and hippocampal sclerosis may be associ- ciation International Society to Advance Alzheimer’s Research and ated with amnestic syndromes that are only slowly progressive and Treatment (ISTAART), which is collaborating with the biofluid-based may be associated clinically with a “chronic mild cognitive impairment.” biomarkers PIA (BBB-PIA) to facilitate the development and optimiza- Slow progression syndromes have the potential to confound the inter- tion of biomarkers for FTD. pretation of biomarker characterizations and clinical trial outcomes For validation and implementation of the identified markers, the when they are misclassified in studies as examples of typical cases. It is field can leverage the developments from more advanced fields, such therefore important to acquire the genetic, biofluid, and neuroimaging as the AD field. This especially applies to preanalytical aspects and the panels that will facilitate the characterization and classification of atyp- development of standard operating procedures for sample handling ical proteinopathies and the syndromes with which they are associated. and analysis, such as for AD biomarkers in CSF and blood,141—144 and While biomarker-based diagnosis has made a quantum leap forward in to quality control programs,145 which are a requirement for in vitro the past decade, there remain important caveats as they are translated diagnostic tests. These activities are promoted through different orga- from the research setting into more general application in clinics nizations such as the Society for CSF Analysis and Clinical Neurochem- worldwide. istry or the Global Biomarkers Standardization Consortium (GBSC). Moreover, there is a potential for synergism from initiatives to obtain regulatory approval and reimbursement for, for example, NfL for other 5 CONCLUSIONS AND FUTURE DIRECTIONS diseases. In current clinical practice, the place of CSF analysis is to exclude AD pathology and verify neurodegeneration—it does not have utility for 4.3 Understanding the cautions and caveats in affirmative diagnosis of FTD.5 The blood-based biomarker NfL is now the development of FTD biofluid-based biomarkers being incorporated in clinical practice for FTD, especially to differ- entiate bvFTD from primary psychiatric disorders.71,76 Several novel It is valuable to specify some of the potential pitfalls and shortcom- biomarker candidates reflecting different pathological processes asso- ings when biofluid-based biomarkers are translated from the level of ciated with FTD beyond the classical proteinopathies have been iden- discovery and research to that of clinical dogma. Many of these points tified (lysosomal markers, inflammatory markers, circulating nucleic will be well known to the experts but perhaps less so to others not acids, synaptic markers),77 and are in need of thorough validation in familiar with biomarker-based diagnosis and staging of neurodegener- well characterized independent cohorts of familial and sporadic FTD. ative diseases. Reflection on the state-of-the-art reveals both “known There is a need to identify and validate biomarkers for different pur- unknowns” and “unknown unknowns.” Examples of some of the known poses (differential diagnosis, pathology typing, staging, prognostica- unknowns are the potential contributions of vascular and immune tion, treatment monitoring) using robust approaches that allow their mechanisms as we contemplate the full picture from disease initiation incorporation into clinical diagnostic criteria. It is expected that the to disease progression. Vascular and immunological mechanisms have technical developments of the last years (e.g., ultrasensitive technolo- been proposed for many neurodegenerative diseases and, for some, gies, large high-throughput protein panels) will facilitate such develop- have been demonstrated to play key roles in the development and pro- ments. CSF biomarker research is still essential to support the associ- gression of clinical syndromes. Even when, for example, vascular and/or ation of the different markers with pathophysiological processes, but immune factors have been implicated, there is insufficient knowledge translation into blood-based biomarkers would be ideal for repeated about which biomarkers can be combined to give a more complete pic- measurement in longitudinal studies and broad use, eventually, in 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License DEL CAMPO ET AL . 2301 practice. The high complexity and heterogeneity of FTD discourages Gandy (contact), Ehrlich) NIH-NIA; MPI R03AG070506 (PI: Wang) the use of small sample sizes in biomarker analyses and calls for collab- NIH/NIA; Co-I R01AG057907 (MPI: Zhang, Haroutunian, Ehrlich) orative large multicohort studies with thoroughly characterized sam- NIH/NIA; Co-I R21 AG063068 (PI: Readhead) NIH/NIA/Arizona ples (i.e., with carefully ascertained and measured clinical, genetic, and State University; Role: Subaward Co-I R6AG066431 (MPI: Huffman, pathological indices). A fuller understanding of the molecular factors Gandy) NIH/NIA/Albert Einstein College of Medicine; MPI (PI: Gandy) and biomarkers that underlie FTD pathophysiology at different stages Alzheimer Drug Discovery Foundation; PI Pending (JIT Award under of the disease will optimize clinical and molecular diagnosis and pro- consideration) R03AG070710 (PI: Haure-Mirande) NIH NIA; Co-I R21 vide an invaluable resource for the development and testing of novel (PI: Vaska) NIH/Stony Brook; Subaward PI Lab Personnel Paid Directly therapies. by Third Party Entities: None Overlap: There is no scientific or bud- getary overlap Institution: James J. Peters VA Medical Center Type ACKNOWLEDGMENTS of Appointment: 5/8th appt Active I01RX002333 (Gandy Role PI) This manuscript was facilitated by the Alzheimer’s Association Inter- Department of Veterans Affairs. Pending: None Lab Personnel Paid national Society to Advance Alzheimer’s Research and Treatment Directly by Third Party Entities: None Overlap: There is no scien- (ISTAART), through the Biofluid Based Biomarkers and Frontotempo- tific or budgetary overlap. CO received research grants from Bio- ral Dementia and Related Disorders professional interest areas (PIAs). gen and Alector; payments were made to the institution. FO received The views and opinions expressed by the authors in this publication support from FAPESP - The State of São Paulo Research Founda- represent those of the authors and do not necessarily reflect those of tion, grant #2015/10109-5, payment made to FO. CU has nothing to the PIA membership, ISTAART or the Alzheimer’s Association. HZ is a disclose. AL reports payment to the institution from Health Depart- Wallenberg Scholar supported by grants from the Swedish Research ment of the Government of Catalonia (grant PERIS SLT002/16/00408), Council (#2018-02532), the European Research Council (#681712), Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III Swedish State Support for Clinical Research (#ALFGBG-720931), (PI17/01896; AC/0013), CIBERNED (COEN), BBVA foundation. CET’s the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809- research is supported by the European Commission (Marie Curie Inter- 2016862), the AD Strategic Fund and the Alzheimer’s Association national Training Network, grant agreement No 860197 (MIRIADE), (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377- and for bPRIDE (JPND), Health Holland, the Dutch Research Coun- C), the Olav Thon Foundation, the Erling-Persson Family Foundation, cil (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019- Group Foundation, Alzheimer Netherlands, Alzheimer Association. CT 0228), the European Union’s Horizon 2020 research and innovation is recipient of ABOARD, which is a public-private partnership receiving programme under the Marie Skłodowska-Curie grant agreement No funding from ZonMW (#73305095007) and Health∼Holland, Topsec- 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. tor Life Sciences & Health (PPP-allowance; #LSHM20106). More than CUO is supported by The Robert and Nancy Hall Brain Research Fund. 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes-Strijbisfonds. IV is appointed on CONFLICTS OF INTEREST a research grant by Alzheimer Nederland (NL-17004). CET has a col- Support received for the submitted work: None of the authors received laboration contract with ADx Neurosciences, Quanterix, and Eli Lilly; support for the present manuscript. MC is supported by the attrac- performed contract research or received grants from AC-Immune, tion talent fellowship from Comunidad de Madrid and the ‘Europe Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Research’ 2020 dynamization actions from Research and innovation Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. YP has nothing to Spanish government, payment made to institution. SG has a joint disclose. All authors are members of the Biofluid Based Biomarkers or appointment at Icahn School of Medicine (1 FTE) and James J. Peters Frontotemporal Dementia and Related Disorders Professional Inter- VA Medical Center (5/8th) which constitutes 100% of his total pro- est Areas (ISTAART). MC has given a lecture at the annual meeting fessional responsibilities (TPE). The combined TPE at both institutions of Spanish Neurology Society, payment made to MC. HZ has served does not exceed 12 person months (PM). Dr. Gandy’s joint appoint- on scientific advisory boards for Alector, Eisai, Denali, Roche Diag- ment is documented under an MOU between Mount Sinai and the VA. nostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, There is no dual compensation for the same work, nor is there an actual Nervgen, AZTherapies, and CogRx. HZ has given lectures in symposia or apparent conflict of interest regarding such work. Institution: Icahn sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen. HZ is a co- School of Medicine at Mount Sinai Type of Appointment: Academic founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which (Professor) Full Time: 1.00 FTE Active support R01AG067312 (MPI: is a part of the GU Ventures Incubator Program. All payments made to Huffman (contact), Tu) NIH/NIA/Albert Einstein College of Medicine; HZ. HZ is a chair of the Alzheimer’s Association Global Biomarker Stan- Co-I P30AG066514 (PI: Sano) NIH/NIA TC Mount Sinai Alzheimer’s dardization Consortium and the AA Biofluid Based Biomarkers Pro- Disease Research Center; Associate Director RF1AG062661 (PI: fessional Interest Area. No payments made. SG has provided expert Salton, Ehrlich) NIH/NIA; Co-I RF1AG058469 (MPI: Ehrlich (contact), testimony to Vernick & Associates, Annapolis, MD, and Post & Schell, Gandy) NIH/NIA; MPI U01AG046170 (MPI: Zhang (contact), Gandy, Philadelphia, PA. SG has a patent issued method for iPSC derived basal Ehrlich, Haroutunian NIH/NIA; MPI R01AG061894 (MPI: Gandy, Nog- forebrain cholinergic neurons (issued). SG has served as advisor for gle (contact), Fossati) NIH/NIA/New York; MPI RF1AG059319 (MPI: Ritrova Therapeutics. CO provides technical or medicolegal advice to 15525279, 2022, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12643 by Readcube (Labtiva Inc.), Wiley Online Library on [17/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2302 DEL CAMPO ET AL . Alector, Goodell Devries Leech & Dann. Payment made to CO. CO is syndrome): report of the NINDS-SPSP International Workshop. Neu- part of the medical Advisory Council of the Association for Frontotem- rology. 1996;47:1-9. http://doi.org/10.1212/WNL.47.1.1 10. Harris JM, Gall C, Thompson JC, et al. Sensitivity and specificity poral Degeneration and the Scientific Advisory Board of the FTD Dis- of FTDC criteria for behavioral variant frontotemporal demen- orders Registry. No payments involved. FO has received consulting fees tia. Neurology. 2013;80:1881-1887. http://doi.org/10.1212/WNL. for acting as a healthcare council member for Gerson Lehrman Group, 0b013e318292a342 Atheneum Partners, Guidepoint, Health Advances, and Lionbridge. FO 11. Balasa M, Gelpi E, Martín I, et al. Diagnostic accuracy of behavioral variant frontotemporal dementia consortium criteria (FTDC) in a received support from the International Parkinson and Movement Dis- clinicopathological cohort. Neuropathol Appl Neurobiol. 2015;41:882- order Society to attend the 22nd International Congress of Parkinson’s 892. http://doi.org/10.1111/nan.12194 Disease and Movement Disorders in Hong Kong, October 2018. From 12. Lanata SC, Miller BL. The behavioural variant frontotemporal demen- 2018 to 2021, FO was a member of the ISTAART Advisory Council tia (bvFTD) syndrome in psychiatry. J Neurol Neurosurg Psychiatry. 2016;87:501-511. http://doi.org/10.1136/jnnp-2015-310697 (unpaid). Starting in 2021, FO is a current member of the International 13. Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diag- Subcommittee of the American Academy of Neurology (unpaid) and nostic challenge of psychiatric symptoms in neurodegenerative dis- of the Awards Committee of the International Parkinson and Move- ease. J Clin Psychiatry. 2011;72:126-133. http://doi.org/10.4088/JCP. ment Disorder Society (unpaid). FO has also been a member of the 10m06382oli Community of Experts of the European Science Foundation since 2019 14. Mackenzie IRA, Neumann M, Bigio EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar (and receives payments for each review of a grant). CU is an exec- degeneration: an update. Acta Neuropathol. 2010;119:1-4. http://doi. utive Committee member of Biofluid Based Biomarkers Professional org/10.1007/s00401-009-0612-2 Interest Area (ISTAART) (unpaid) and board of Trustees member of 15. Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnos- the British Society for neuroendocrinology (unpaid). AL has a patent tic and nosologic criteria for frontotemporal lobar degeneration: con- sensus of the consortium for frontotemporal lobar degeneration. licensed of synaptic markers in neurodegenerative diseases, payments Acta Neuropathol. 2007;114:5-22. http://doi.org/10.1007/s00401- to the institution and to AL. AL received personal fees for serving on 007-0237-2 scientific advisory boards from Fujirebio-Europe, Nutricia, Biogen, and 16. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Roche Diagnostics. AL received personal fees for lectures from Nutri- MacKenzie IRA. A new subtype of frontotemporal lobar degenera- tion with FUS pathology. Brain. 2009;132:2922-2931. http://doi.org/ cia and Zambon. CET has given lectures for Roche and serves on edi- 10.1093/BRAIN/AWP214 torial boards of Medidact Neurologie/Springer, Alzheimer Research and 17. Lee EB, Porta S, Michael Baer G, et al. 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