Insert slide with concept of networks fluctuating at rest?
Relationships between beta-amyloid andfunctional connectivity in different componentsof the default mode network in agingMormino EC, Smiljic A, Hayenga AO, Onami S, GreiciusMD, Rabinovici GD, Janabi M, Baker SL, Yen I, MadisonCM, Miller BL, Jagust WJCerebral Cortex, 2011
Introduction:• Aβ is common in cognitively normal elderly subjects.• May reflect preclinical AD1.• Initial downstream effects at level of synaptic function2.Overall Aim: Combine PIB-PET imaging with resting state fMRI to examine early effects of Aβ in normals. 1Morris 2009 Arch Neurol; 2Selkoe 2002, Science
The Default Mode Network Buckner et al., 2005; J Neurosci • Highly active ‘at rest’. • Implicated in episodic memory, future planning, mind wandering, considering thoughts of others, self-referential processing… • Overlap with pattern of Aβ deposition.
Subjects & Methods• 44 cognitively normal elderly• PIB-PET imaging – Measure of Aβ• Resting State fMRI – functional connectivity (spontaneous fluctuations) – Decomposed via ICA (FSL MELODIC) – Selected DMN component (template matching procedure)• Higher level Analysis – Global PIB versus voxelwise DMN FC
PIB and DMN Overlap PIB DMN OverlapThresholded at p<0.001, k=100
PIB versus Voxelwise DMN p<0.05, k=50 More PIB, less FC More PIB, more FC RSC: Lower connectivity, worse EM (p=0.08)
FC versus Regional PIB? PIB DMN Overlap Decreased FC Increased FCNo pattern between regional PIB and differences in functional connectivity.
Different subnetworks within DMN, different vulnerabilities to Aβ? Medial temporal system: EM Dorsal medial PFC system: self-referential Midline core: binds subsystemsAndrews-Hanna 2010, Neuron
Summary & Conclusions • Misalignment between regional PIB levels and FC differences. • Elevated A is associated with FC decreases in EM-relevant regions of the DMN. – Impacted in AD – Supports preclinical relevance of A in normals – Consistent with results from other labs (Hedden 2009; Sheline 2010 ) • Elevated A is associated with increases in the dorsal medial PFC subsystem. – Compensation for failing episodic memory regions? – Difficult to interpret resting state connectivity increases
Thank you!Jagust LAβBill JagustGil RabinoviciBeth KuczynskiCindee Madison Research AssistantsSuzanne Baker Michael BrandelSusan Landau Andre SmiljicAudrey Perrotin Irene YenHwamee Oh Susan OnamiShawn Marks Ron LiuAmynta HayengaCandace MarkleyHenry SchwimmerAdi AlkalayNeha AgarwalLinh DangMiranka WirthBénédicte RossiNatalie MarchantRaymond LoTad Haight And the Berkeley Aging Cohort Subjects!Funding: NIH (AG027859, AG032814), Alzheimer’s Association (ZEN-08-87090)