Journal of Alzheimer’s Disease 61 (2018) 1477–1483 DOI 10.3233/JAD-170722 IOS Press 1477 Altered Expression of Circulating Cdc42 in Frontotemporal Lobar Degeneration Claudia Saraceno a , Marcella Catania b , Anna Paterlini a , Silvia Fostinelli a , Miriam Ciani a , Roberta Zanardini a , Giuliano Binetti c , Giuseppe Di Fede b , Paola Caroppo b , Luisa Benussi a , Roberta Ghidoni a and Silvia Bolognin a,d,∗ a Molecular Markers Laboratory,IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy b Division of Neurology and Neuropathology, IRCCS Foundation - Carlo Besta Neurological Institute, Milan, Italy c MAC Memory Center,IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy d Developmental and Cellular Biology, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Belvaux, Luxembourg Handling Associate Editor: Michal Novak Accepted 6 November 2017 Abstract. The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer’s disease (AD) patients included in the data-set. On the other hand, the pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant. Keywords: Alzheimer’s disease, biomarkers, Cdc42, frontotemporal dementia, plasma, Rho-GTPases INTRODUCTION Frontotemporal lobar degeneration (FTLD) is the second most common form of early-onset dementia after Alzheimer’s disease (AD), with a prevalence of 15-22/100,00 individuals [1–3]. The term FTLD defines a broad group of disorders all characterized by the degeneration of the frontal and anterior tempo- ral lobes but very heterogeneous in terms of clinical and histological pathology [4]. The major clinical ∗ Correspondence to: Silvia Bolognin, University of Luxem- bourg, Luxembourg Centre for Systems Biomedicine, Campus Belval, House of Biomedicine, 6, avenue du Swing, L-4367 Bel- vaux, Luxembourg. Tel.: +352 466644 5905, +352 466644 35536; E-mail: silvia.bolognin@gmail.com. subtype of FTLD is called behavioral variant of fron- totemporal dementia (bvFTD). It is characterized by progressive behavioral changes, such as apathy, anxiety, disinhibition, compulsive/ritualistic behav- ior, and hyperorality [5]. Another typical subtype of FTLD is the language variant, with the semantic and non-fluent variant of primary progressive aphasia (PPA) [4, 6]. From a histopathological point of view, the autop- tic brain examination of FTLD patients often reveals neuronal inclusions containing TDP-43 and tau [7–10]. However, the correlation between abnormal protein accumulation and presentation of the disease is rather weak. Genetic factors are the only cause of FTLD so far identified and up to 50% of the patients ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved