Novel CSF biomarkers for frontotemporal lobar degenerations

Abstract

Objective: To identify antemortem CSF diagnostic biomarkers that can potentially distinguish between the 2 main causes of frontotemporal lobar degeneration (FTLD), i.e., FTLD with TDP-43 pathology (FTLD-TDP) and FTLD with tau pathology (FTLD-tau).Methods: CSF samples were collected antemortem from 23 patients with FTLD with known pathology to form a autopsy cohort as part of a comparative biomarker study that additionally included 33 living cognitively normal subjects and 66 patients with autopsy-confirmed Alzheimer disease (AD). CSF samples were also collected from 80 living patients clinically diagnosed with frontotemporal dementia (FTD). Levels of 151 novel analytes were measured via a targeted multiplex panel enriched in neuropeptides, cytokines, and growth factors, along with levels of CSF biomarkers for AD.Results: CSF levels of multiple analytes differed between FTLD-TDP and FTLD-tau, including Fas, neuropeptides (agouti-related peptide and adrenocorticotropic hormone), and chemokines (IL-23, IL-17). Classification by random forest analysis achieved high sensitivity for FTLD-TDP (86%) with modest specificity (78%) in the autopsy cohort. When the classification algorithm was applied to a living FTD cohort, semantic dementia was the phenotype with the highest predicted proportion of FTLD-TDP. When living patients with behavioral variant FTD were examined in detail, those predicted to have FTLD-TDP demonstrated neuropsychological differences vs those predicted to have FTLD-tau in a pattern consistent with previously reported trends in autopsy-confirmed cases. Conclusions:Clinical cases with FTLD-TDP and FTLD-tau pathology can be potentially identified antemortem by assaying levels of specific analytes that are well-known and readily measurable in CSF. Neurology ® 2010;75:2079-2086 GLOSSARY AD ϭ Alzheimer disease; AgRP ϭ Aguti-related protein; ANG-2 ϭ angiopoietin-2; ACTH ϭ adrenocorticotropic hormone; ALS ϭ amyotrophic lateral sclerosis; ApoB ϭ apolipoprotein B; bv-FTD ϭ behavioral variant FTD; CBS ϭ corticobasal syndrome; FTD ϭ frontotemporal dementia; FTLD ϭ frontotemporal lobar degeneration; FTLD-tau ϭ frontotemporal lobar degeneration with tau pathology; FTLD-TDP ϭ frontotemporal lobar degeneration with TDP-43 pathology; IL ϭ interleukin; MDC ϭ macrophage-derived chemokine; PNFA ϭ progressive nonfluent aphasia; PPA ϭ primary progressive aphasia; PSP ϭ progressive supranuclear palsy; S100b ϭ S100 calcium binding protein b; SemD ϭ semantic dementia; TRAIL-R3 ϭ tumor necrosis factor-related apoptosis-inducing ligand receptor 3.Frontotemporal lobar degeneration (FTLD) includes neurodegenerative disorders which lead to progressive behavioral or language abnormalities.1-3 There are 2 major forms of FTLD: FTLD-TDP with neuronal and glial inclusions immunoreactive to TAR DNA binding protein of ϳ43 kD (TDP-43), and FTLD-tau containing fibrillar and hyperphosphorylated tau inclusions.2,3 The main FTLD lesions likely reflect distinct disease mechanisms, 2 although antemortem diagnosis of the underlying path...

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…We observed that combination of MFG‐E8 together with CSF tTau and A β 42 could discriminate FTLD patients from nondemented controls with 78% sensitivity and 82% specificity, which was validated in a larger independent cohort achieving sensitivity and specificity values >80%. Most of the potential FTLD CSF biomarkers studied to date (e.g., tau, tdp43) did not achieve enough sensitivity or specificity 8, 49, 50, 51, 52. In a subset of cases, we observed that the FTLD vs. CON model achieved similar performance to that observed for NfL alone.…”

White matter imaging contributes to the multimodal diagnosis of frontotemporal lobar degeneration

“…T-tau: A␤ is not, however, sensitive for discriminating between pathologic subtypes of FTLD, and future work is required to identify candidate CSF biomarkers for further discriminating between these subgroups of FTLD. 34 We conclude that individuals with AD and FTLD have significant changes in WM and GM that appear to reflect distinct underlying neuropathologic processes with reasonably high accuracy. This multimodal approach supports noninvasive classification of individual patients with a high degree of sensitivity and specificity in a clinical setting.…”

Eating behavior in frontotemporal dementia

“…In addition to increasing total food intake in rats, AgRP may also lead to a preference for fat-enriched food, 27 and sucrose in the setting of a high-fat diet. 28 One previous study 11 in FTD has suggested that elevated AgRP in CSF may be related to TDP-43 pathology, a finding likely driven by the numbers of patients with svPPA within that cohort; however, this study did not examine the relationship of this peptide to eating behavior or effect on BMI. The current study points toward an important role of AgRP in the eating abnormalities and metabolic changes 4 possibly by promoting hyperphagia, particularly affecting BMI.…”

“…10 An approximately 7-fold increase in CSF AgRP has previously been identified in patients with FTD who have TAR DNAbinding protein 43 (TDP-43) pathology compared to those with tau pathology, an increase associated with the svPPA phenotype. 11 Changes in peripheral eating hormones have not been comprehensively investigated in svPPA, despite the increasing evidence of Figure 1 Peripheral and central pathways and the hypothalamus, controlling appetite and feeding behavior…”