Effects of aging on default mode network activity in resting state fMRI: Does the method of analysis matter? W. Koch a, ⁎, S. Teipel b , S. Mueller a , K. Buerger c , A.L.W. Bokde c,d , H. Hampel c,d , U. Coates a , M. Reiser a , T. Meindl a a Institute for Clinical Radiology, University of Munich, Marchioninistr. 15, 81377 Munich, Germany b Department of Psychiatry, University of Rostock, Rostock, Germany c Department of Psychiatry & Alzheimer Memorial Center, University of Munich, Munich, Germany d Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging & Biomarker Research, Trinity College Dublin, The Adelaide and Meath Hospital Incorporating the National Children's Hospital (AMiNCH), Dublin, Ireland abstract article info Article history: Received 18 September 2009 Revised 20 November 2009 Accepted 1 December 2009 Keywords: fMRI Default mode network Age dependency Independent component analysis Functional MRI (fMRI) of default mode network (DMN) brain activity during resting state is gaining attention as a potential non-invasive biomarker to diagnose incipient Alzheimer's disease. The aim of this study was to identify effects of normal aging on the DMN using different methods of fMRI processing and evaluation. Methods. fMRI was acquired in 17 young and 21 old healthy subjects and the data were analyzed with (a) volumes of interest (VOI)-based signal time course and (b) independent component analyses (ICA). In the first approach, the strength of DMN region inter-connectivity (as expressed with correlation coefficients) was of primary interest, the second method provided a measure of the magnitude of DMN co-activation. Results. The older subjects exhibited significantly lower DMN activity in the posterior cingulate (PCC, t-test P b .001) as well as a tendency to lower activity in all other DMN regions in comparison to the younger subjects. We found no significant effect of age on DMN inter-connectivity. Conclusion. Effects of normal aging such as loss of PCC co-activity could be detected by ICA, but not by signal time course correlation analyses of DMN inter-connectivity. This either indicates lower sensitivity of inter-connectivity measures to detect subtle DMN changes or indicate that ICA and time course analyses determine different properties of DMN co- activation. Our results, therefore, provide fundamental knowledge for a potential future use of functional MRI as biomarker for neurodegenerative dementias where diminished DMN activity needs to be reliably differentiated from that observed in health aging. © 2009 Elsevier Inc. All rights reserved. Introduction Imaging neuronal activity using functional magnetic resonance imaging (fMRI) has evolved to an important diagnostic tool to evaluate brain function and neuronal connectivity. A range of studies has described brain regions with synchronous, low-frequency blood oxygen level-dependent (BOLD) signal changes during rest compris- ing posterior cingulate/precuneus, medial prefrontal and bilateral lateral parietal cortex. Because this network is typically deactivated during external stimulation, it has been termed the ‘default mode network’ (DMN) (Binder et al., 1999; Shulman et al., 1997). The behavioral function of this network is still unresolved. It has been suggested that the DMN plays a role in attending to environmental stimuli as well as mediating processes such as reviewing past knowledge or preparing future actions. It may also be involved in episodic memory (Greicius et al., 2004). Interestingly, the DMN regions comprise the typical predilection sites of Alzheimer's disease (Mosconi, 2005), the most frequent cause of dementia in the elderly and the most frequent neurodegenerative disorder in humans. Accordingly, resting state fMRI identified significant disruptions in DMN co-activation in patients with AD (Greicius et al., 2004; Rombouts et al., 2009). Hence, attempts have been made to apply resting state fMRI as a non-invasive, readily available and radiation exposure free biomarker of incipient AD (Greicius et al., 2004). One important prerequisite for the employment of resting state fMRI as a biomarker of AD is a clear understanding of the role of normal aging on DMN connectivity. Age effects on DMN co-activation need to be considered in respect to the specificity of the detection of AD-related abnormalities. Additionally, with a range of possible methods of analysis for fMRI data available, the ability of each method to detect slight age-related changes is an indicator for the sensitivity of the respective test. This information may hence help to identify the most appropriate way of data analysis for a potential future clinical routine use of fMRI in the early detection and differential diagnosis of dementias. NeuroImage 51 (2010) 280–287 ⁎ Corresponding author. Fax: +49 89 7095 8832. E-mail address: walter.koch@med.uni-muenchen.de (W. Koch). 1053-8119/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2009.12.008 Contents lists available at ScienceDirect NeuroImage journal homepage: www.elsevier.com/locate/ynimg