Biomarkers in Frontotemporal Lobar Degenerations - Progress and Challenges

• Type of Material: Article
• Authors: William T. Hu, Emory University; John Q. Trojanowski, University of Pennsylvania; Leslie M. Shaw, University of Pennsylvania
• Language: English
• Date: 2011-12
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.pneurobio.2011.04.012
• Title of Journal or Parent Work: Progress in Neurobiology
• ISSN: 0301-0082
• Volume: 95
• Issue: 4
• Start Page: 636
• End Page: 648
• Grant/Funding Information: This work has been supported by Viretta Brady Discovery Fund at Emory University School of Medicine and AG10124, AG17586, and the Penn-Pfizer Alliance at the University of Pennsylvania.
• Keywords: TDP-43; tauopathy; tau; diagnosis; Biomarker; frontotemporal dementia
• Research Categories: Biology, Neuroscience; Health Sciences, Pathology

Abstract

Neuronal and glial changes associated with tau, TAR DNA binding protein of ~43 kD (TDP-43), and fused in sarcoma (FUS) together constitute the pathologic spectrum of frontotemporal lobar degeneration (FTLD). Most patients with FTLD present with prominent behavior or language changes, sometimes accompanied by extrapyramidal symptoms or motor neuron disease. Identification of FTLD patients with mutations in genes for tau, TDP-43, and FUS lends strong support for their pathogenic roles in FTLD, and elucidation of their dysfunction will pave the way for development of substrate specific therapy. However, there remains no reliable biomarker for early detection of FTLD or prediction of underlying FTLD pathologic change. Clinical syndromes usually reflects the earliest affected brain regions where atrophy can be visualized on structural MRI, but neither clinical nor structural imaging-based biomarkers has been accurately correlated with underlying pathology on the individual patient level. Biochemical markers in the cerebrospinal fluid (CSF) have also been investigated in FTLD and related disorders, including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP). However, their accuracy and pathologic significance need to be confirmed in future multi-center studies. Here we review the progress made in FTLD biomarkers, including clinical phenotype/feature characterization, neuropsychological analysis, CSF and plasma analytes, and patterns of brain atrophy and network dysfunction detectable on brain imaging. Given the pathologic overlap of FTLD with ALS and PSP, collaboration with specialists in those fields will be essential in the translation of promising FTLD biomarkers into clinical practice.