Whole cortical and default mode network mean functional connectivity as potential biomarkers for mild Alzheimer's disease Marcio Luiz Figueredo Balthazar a,n , Brunno Machado de Campos a , Alexandre Rosa Franco b , Benito Pereira Damasceno a , Fernando Cendes a a Department of Neurology, University of Campinas (Unicamp), Sao Paulo 13083-970, Brazil b Brain Institute of Rio Grande do Sul, Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil article info Article history: Received 24 April 2013 Received in revised form 6 August 2013 Accepted 31 October 2013 Keywords: Default mode network Biomarker Resting state fMRI Dementia abstract The search for an Alzheimer's disease (AD) biomarker is one of the most relevant contemporary research topics due to the high prevalence and social costs of the disease. Functional connectivity (FC) of the default mode network (DMN) is a plausible candidate for such a biomarker. We evaluated 22 patients with mild AD and 26 age- and gender-matched healthy controls. All subjects underwent resting functional magnetic resonance imaging (fMRI) in a 3.0 T scanner. To identify the DMN, seed-based FC of the posterior cingulate was calculated. We also measured the sensitivity/specificity of the method, and verified a correlation with cognitive performance. We found a significant difference between patients with mild AD and controls in average z-scores: DMN, whole cortical positive (WCP) and absolute values. DMN individual values showed a sensitivity of 77.3% and specificity of 70%. DMN and WCP values were correlated to global cognition and episodic memory performance. We showed that individual measures of DMN connectivity could be considered a promising method to differentiate AD, even at an early phase, from normal aging. Further studies with larger numbers of participants, as well as validation of normal values, are needed for more definitive conclusions. & 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The search for an Alzheimer's disease (AD) biomarker is one of the most relevant research topics of the decade, largely due to the prevalence and social cost of the disease. A number of studies using biological fluids (such as cerebrospinal and plasma) as well as structural, functional, and molecular neuroimaging, are being conducted to improve the accuracy of AD diagnosis. Functional neuroimaging methods, as exemplified by functional magnetic resonance imaging (fMRI), have promise as biomarkers for AD, especially those obtained under resting conditions or with- out a specific task (“resting-state” fMRI, fc-fMRI or intrinsic brain activity). These methods have been helpful in identifying different functional connectivity networks (FC) through interregional corre- lation analysis of spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal. Such studies have shown that synchronous oscillations in the BOLD signal, usually at a low frequency (0.01 to 0.1 Hz), represent functional neural networks that are spatially distinct but functionally connected (Van den Heuvel and Hulshoff Pol, 2010). The main theoretical assumption for investigating FC disrup- tion as a potential biomarker is that neurodegenerative diseases like AD are among those that can damage the neurofunctional organization of mental activity, leading to both cognitive and psychiatric symptoms. Seeley et al. (2009) demonstrated the network degeneration hypothesis across five distinct dementia syndromes, including AD. In typical AD, the progression of symptoms occurs in a stereotyped order, relating to the topo- graphic progression of pathology: episodic memory loss takes place first (hippocampus and medial temporal lobe, along with posterior cingulate cortex), followed by problems with language and semantic memory (lateral temporal cortex) and visuospatial skills (temporal, and parietal neocortex). This orderly progression might be indicative of degeneration throughout interconnected regions within large-scale networks, which will ultimately spread into adjacent regions (Pievani et al., 2011). The default mode network (DMN) is the most studied network in AD. The function of the DMN is not completely understood, but it is accepted that there is increased activity when the patient is not focused on activities directed at the external environment (e.g., when an individual recalls autobiographical facts and events, or plans for the future). Some AD studies have shown a breakdown Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/psychresns Psychiatry Research: Neuroimaging 0925-4927/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.pscychresns.2013.10.010 n Correspondence to: Department of Neurology, FCM, University of Campinas (UNICAMP), Cidade Universitaria, Campinas-SP, Brazil, 13083-970. Tel.: þ55 19 3521 9217. E-mail addresses: mbalth@unicamp.br, mbalth@gmail.com (M.L.F. Balthazar). Please cite this article as: Balthazar, M.L.F., et al., Whole cortical and default mode network mean functional connectivity as potential biomarkers for mild Alzheimer's.... Psychiatry Research: Neuroimaging (2013), http://dx.doi.org/10.1016/j.pscychresns.2013.10.010i Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎