A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes

Abstract

IMPORTANCECerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD copathology. OBJECTIVETo develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP). DESIGN, SETTING, AND PARTICIPANTSA case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n = 143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n = 60); and a living cohort of patients with syndromes highly predictive of FTLD (progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis; n = 62). MAIN OUTCOMES AND MEASURESCerebrospinal fluid values of amyloid β 1-42 (Aβ 1-42 ), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated. RESULTS This autopsy cohort included FTLD-tau (n = 27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n = 13; mean [SD] age at onset, 62.4 [8.5] years), AD (n = 89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n = 14, mean [SD] age at onset, 70.6 [8.5] years).The p-tau/Aβ 1-42 ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to Aβ 1-42 ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers.CONCLUSIONS AND RELEVANCE Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…While our previous proteomics‐based study analyzed mainly FTLD‐Tau cases with MAPT mutations,12 the current study was performed with a more heterogeneous FTLD‐Tau group including also sporadic CBS and PSP cases, which may explain the observed discrepancies. Indeed, recent studies have highlighted that CSF biomarkers (e.g., pTau) can differ between familial and sporadic FTLD cases that develop the same underlying neuropathology 38, 39. Thus, this data also highlights the impact that the heterogeneity within each FTLD subtype can have on the CSF biomarker profile.…”

“…Noteworthy, up to 30% of FTLD cases are misdiagnosed with other disorders, especially AD 55. Several studies have shown that ratios with AD CSF biomarkers (i.e., pTau/A β 42 or tTau/A β 42) can discriminate FTLD from AD with performances over 80% 38, 56. In this study, we identified a model able to discriminate FTLD from a general group of non‐FTLD dementia (AD and DLB) with 91% sensitivity and 84% specificity using pTau, p/tTau ratio and YKL40.…”

The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: A data set for biomarker discovery and validation in neurodegenerative disorders

“…Brain donation not only allows the confirmation of the diagnosis and the presence of comorbid pathologies but is also necessary to correlate pathological data with CSF or imaging biomarkers [24] and to characterize the underlying biological processes of these biomarkers [25]. Moreover, it is known that secondary pathologies can influence the biomarker signatures [26,27], and it is important to capture them for their correct interpretation.…”

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…Otherwise, the FTLD‐TAU group included patients with (1) a pathological diagnosis of primary tauopathy (1 progressive supranuclear palsy, 1 corticobasal degeneration) and (2) a pathogenic mutation in microtubule‐associated protein tau gene (MAPT) ( n = 4). In all FTLD cases, the in vivo evidence of AD pathology was gathered using the AD core CSF biomarkers and in‐house calculated cutoff ratios . Specifically, a phosphorylated (p)‐tau/amyloid‐β (Aβ)42 ratio >0.108 (Bologna) or >0.08 (Ulm) was considered supportive for AD.…”