CSF Biomarkers of Neurodegeneration in Progressive Non-fluent Aphasia and Other Forms of Frontotemporal Dementia: Clues for Pathomechanisms?

Peter Körtvelyessy,Hans J Heinze,Daniel Bittner,Johannes Prudlo

doi:10.3389/fneur.2018.00504

Abstract

Frontotemporal Dementia (FTD) encompasses distinct pathophysiologically heterogenous disorders with different genetic and cellular disease mechanisms. The objective of this study is to compare the constellation of biomarkers of neurodegeneration in the cerebrospinal fluid (CSF) to the FTD type categorized by clinical symptoms. We investigated the levels of Phospho181-tau, Total-tau, Beta-amyloid1−42, Neurofilament light chain, and Progranulin in the CSF of n = 99 FTD patients regarding to the different subtypes of FTD, including semantic dementia (SD), progressive non-fluent aphasia (PNFA), behavioral variant FTD (bvFTD). We compared these groups to patients without neurodegenerative disorders and another cohort encompassing tauopathies with distinct clinical syndromes (Cortico basal syndrome and progressive supranuclear palsy) and logopenic PNFA (lPPA) as another disorder with predominant speech disturbance. CSF-Progranulin levels were significantly lower in FTD type patients with semantic dementia and behavioral variant FTD mainly attributed to the Tar-DNA-Binding-Protein (TDP) 43 compared to predominantly Tau-mediated PNFA (p < 0.05). Also, neurofilament light chain was significantly higher (p < 0.036) in all FTD patients especially in SD patients (p < 0.01). CSF-Nfl levels also distinguished SD patients from logopenic Alzheimers patients (p < 0.05). In sum, CSF-Neurofilament light chain and CSF-Progranulin seem to be promising biomarkers for FTD, the latter predominantly for assumed TDP43-mediated FTD.

Highlights

Frontotemporal dementia is the second most common form of dementia in patients under the age of 65 [1]
In order to test whether different forms of Frontotemporal Dementia (FTD) are associated with differences in cerebrospinal fluid (CSF) biomarker constellation and in particular with differences in levels of PGRN, we compared these biomarkers in 171 patients, among them 39 control individuals without neurodegenerative disorders, 44 patients with behavioral variant FTD (bvFTD), 33 patients with semantic dementia (SD), 22 patients with PFNA, and 15 logopenic progressive non-fluent aphasia (PNFA) (lPPA) patients
There were no group differences overall concerning basic demographics but age, that was higher in the cortico basal syndrome (CBS)/progressive supranuclear palsy syndrome (PSP) group compared to controls (p < 0.001) and gender in SD with a female preponderance (p = 0.012)

Summary

Introduction

Frontotemporal dementia is the second most common form of dementia in patients under the age of 65 [1]. In a subgroup of patients with semantic dementia (SD) histopathologically, TarDNA-Binding-Protein 43 (TDP-43) aggregates are the main characteristic of a subgroup of patients with semantic dementia (SD) [2], and pathomechanisms associated with dysfunctional TDP-43 or TDP-43 aggregates could play a major role in this form of the disease. CSF Biomarkers Distinguish FTD Forms have been made in most behavioral type (bv)FTD and especially in FTD associated with a concomitant motoneuron disease [3]. CSF measurements of biomarker of neurodegeneration are part of the clinical routine with an excellent sensitivity for Alzheimer pathomechanisms [8]. The diagnosis of a FTD in clinical routine is more challenging than the diagnosis of an Alzheimer’s dementia (AD). CSF-Progranulin (PGRN) and Neurofilament light chain (Nfl) are promising candidates as biomarkers for TDP-43 mediated neurodegeneration in Amyotrophic lateral sclerosis [3, 9] and are interesting candidates in TDP-43 mediated FTD

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Conclusion