IntroductionReliable cerebrospinal fluid (CSF) biomarkers enabling identification of frontotemporal dementia (FTD) and its pathologic subtypes are lacking.MethodsUnbiased high-resolution mass spectrometry–based proteomics was applied on CSF of FTD patients with TAR DNA-binding protein 43 (TDP-43, FTD-TDP, n = 12) or tau pathology (FTD-tau, n = 8), and individuals with subjective memory complaints (SMC, n = 10). Validation was performed by applying enzyme-linked immunosorbent assay (ELISA) or enzymatic assays, when available, in a larger cohort (FTLD-TDP, n = 21, FTLD-tau, n = 10, SMC, n = 23) and in Alzheimer's disease (n = 20), dementia with Lewy bodies (DLB, n = 20), and vascular dementia (VaD, n = 18).ResultsOf 1914 identified CSF proteins, 56 proteins were differentially regulated (fold change >1.2, P < .05) between the different patient groups: either between the two pathologic subtypes (10 proteins), or between at least one of these FTD subtypes and SMC (47 proteins). We confirmed the differential expression of YKL-40 by ELISA in a partly independent cohort. Furthermore, enzyme activity of catalase was decreased in FTD subtypes compared with SMC. Further validation in a larger cohort showed that the level of YKL-40 was twofold increased in both FTD pathologic subtypes compared with SMC and that the levels in FTLD-tau were higher compared to Alzheimer's dementia (AD), DLB, and VaD patients. Clinical validation furthermore showed that the catalase enzyme activity was decreased in the FTD subtypes compared to SMC, AD and DLB.DiscussionWe identified promising CSF biomarkers for both FTD differential diagnosis and pathologic subtyping. YKL-40 and catalase enzyme activity should be validated further in similar pathology defined patient cohorts for their use for FTD diagnosis or treatment development.

ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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Background: A biomarker capable of detecting synapse loss, which occurs early in Alzheimer's disease (AD) pathophysiology, would greatly assist in preclinical diagnosis, when treatment would most likely be effective. The objective of this study was to identify and quantify synaptic protein levels in cerebrospinal fluid (CSF) in the search for preclinical biomarkers of synaptic loss. Methods: The CSF proteome database was constructed by non-targeted liquid chromatography mass spectrometry (LS-MS) on CSF samples from 50 cognitively healthy controls (CON) and 10 AD patients. The synaptic proteome database was constructed by literature curation of proteins detected in mouse, rat or human synaptic fractions (according to 16 published proteomic studies) or annotated with a synaptic function in online databases (Gene Ontology, KEGG, SynSysNet). Proteins without a neuropil-specific expression pattern in the cerebral cortex (Human Protein Atlas) were discarded. Array Tomography (AT) microscopy with fluorescent immunostaining for candidate biomarkers and core synaptic markers (synaptophysin and PSD-95) was performed on post-mortem AD and non-AD brains (n¼2). Quantification of up to 3 unlabeled peptides per protein was performed by targeted LC-MS on Phase 2 (15 CON and 15 AD) and Phase 3 (197 CON, 30 Preclinical AD, 56 Prodromal AD, 45 AD) CSF samples. Results: Phase 1) Cross-referencing the CSF (2,704 proteins) and synaptic (709 proteins) proteomes produced a list of 158 synaptic proteins detectable in the CSF (6% of the CSF proteome). Phase 2) A panel of 22 CSF proteins with a core synaptic function (neurotransmission, synaptogenesis or synaptic vesicle recycling) was selected for further evaluation. Co-localisation of the panel proteins with core synaptic markers was assessed by AT microscopy. ATconfirmed synaptic proteins were quantified in the pilot study of AD and CON CSF. Phase 3) Candidate biomarkers were quantified in CSF across the full CON and AD spectrum and evaluated as CSF stage biomarkers for AD. Conclusions:By performing a detailed characterization of the CSF and synaptic proteomes, we have identified a panel of synaptic proteins detectable in the CSF which, if confirmed as biomarkers of synaptic loss, could be invaluable stage biomarkers for AD. We analyzed the levels of YKL40, FABP4, MFGE8 and Catalase enzyme activity using specific assays in CSF cohorts from two different centers: the Emory university and Milan University. These cohorts included patients with FTD with confirmed Tau (n¼20) or TDP43 (n¼30) pathology, Alzheimer's disease (AD, n¼30), dementia with Lewy bodies (DLB, n¼29), vascular dementia (VaD, n¼7) and non-demented controls (n¼29). Results:YKL40 was increased in FTLD-TDP patients not only compared to controls (fold-change -f.c-:1.6, p<0.0001), confirming our previous study, but also compared to FTLD-Tau, DLB and VaD (fc:1.2-1.6; p<0.05). The highest levels of MFGE-8 were found in AD patients and were significantly different from those observed in both FTLD subtypes and DLB (f.c:0.8-1.4; p<...