Resting metabolic connectivity in Alzheimer’s disease

Clinical and Translational Imaging, Aug 2013

Metabolic connectivity analysis of resting 18F-FDG PET is based on the assumption that brain regions whose metabolism is significantly correlated at rest are functionally associated and that the strength of the association is proportional to the magnitude of the correlation coefficient. Therefore, this method could be used to evaluate connectivity networks independently on the basis of performance in specific tasks. Published studies have provided evidence that metabolic connectivity substantially overlaps underlying anatomical pathways and depends on the location of the analyzed regions, but is not influenced by their size. The present review focuses on the methods and meaning of resting inter-regional correlation analysis of cerebral metabolic rate of glucose consumption in Alzheimer’s disease. Accordingly, we describe the evolution of analytical tools from the correlation with a single region of interest to a voxel-based statistical parametric mapping-based approach. We also discuss the pathophysiological implications of metabolic connectivity studies both for Alzheimer-related disconnection syndrome and for default-mode network impairment and compensation mechanisms.

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Resting metabolic connectivity in Alzheimer’s disease

Silvia Morbelli 0 1 Dario Arnaldi 0 1 Selene Capitanio 0 1 Agnese Picco 0 1 Ambra Buschiazzo 0 1 Flavio Nobili 0 1 0 S. Morbelli (&) D. Arnaldi S. Capitanio A. Picco A. Buschiazzo F. Nobili Clinical Neurophysiology, Department of Neurosciences, Ophthalmology and Genetics , IRCCS AOU San Martino-IST, University of Genoa , Largo R. Benzi 10, 16132 Genoa, Italy 1 S. Morbelli S. Capitanio A. Buschiazzo Nuclear Medicine Unit, Department of Health Sciences , IRCCS AOU San Martino-IST, University of Genoa , Largo R. Benzi 10, 16132 Genoa, Italy Metabolic connectivity analysis of resting 18F-FDG PET is based on the assumption that brain regions whose metabolism is significantly correlated at rest are functionally associated and that the strength of the association is proportional to the magnitude of the correlation coefficient. Therefore, this method could be used to evaluate connectivity networks independently on the basis of performance in specific tasks. Published studies have provided evidence that metabolic connectivity substantially overlaps underlying anatomical pathways and depends on the location of the analyzed regions, but is not influenced by their size. The present review focuses on the methods and meaning of resting inter-regional correlation analysis of cerebral metabolic rate of glucose consumption in Alzheimer's disease. Accordingly, we describe the evolution of analytical tools from the correlation with a single region of interest to a voxel-based statistical parametric mappingbased approach. We also discuss the pathophysiological implications of metabolic connectivity studies both for Alzheimer-related disconnection syndrome and for default-mode network impairment and compensation mechanisms. - Alzheimers disease (AD) is the most prevalent dementing disorder worldwide and is pathologically defined by the presence of amyloid aggregations (neuritic plaques, NP) and tau pathology (neurofibrillary tangles, NFT) [1, 2]. Neuropathological data in AD reveal that NFT are prominent in the medial temporal lobe (MTL) early in the disease and then progress outward [3], while NP have a broader cortical distribution that includes but is not especially prominent in the MTL [4]. Moreover, recent pathological studies have led to the hypothesis that NFT predominate in pyramidal neurons that form corticocortical connections between and within the cerebral hemispheres, whereas NP are prevalent at the end of these tracts and in their collateral branches [5, 6]. Consequently, AD pathophysiology could be the result not only of damage to one or more neuronal systems, but also of a disruption of the brains connectivity due to abnormal interactions between neuronal systems [6]. Consistent with this pathology, magnetic resonance imaging (MRI) in early stage AD demonstrates MTL atrophy [7, 8] while functional imaging with 18F-FDG PET reveals hypometabolism with a characteristic parietotemporal and posterior cingulate pattern [9]. The concept of a corticocortical disconnection syndrome in AD was initially investigated using blood-oxygen-leveldependent (BOLD) fMRI, which can identify functional networks related to the joint activation of brain areas involved in different cognitive functions [10]. Several fMRI studies have shown that patterns of activation are changed in AD patients during the performance of certain tasks [10, 11]. Similarly, PET activation studies with H215O have also been analyzed in terms of functional connectivity and have demonstrated reduced functional interactions implying an anterior-posterior disconnection [12]. Since these approaches focus on the networks that directly underlie specific task performance, they do not evaluate the more general concept of impaired connectivity in AD, nor do they directly address impairment of the default-mode network (DMN). This network, which includes the medial prefrontal cortex, posterior cingulate, and inferior parietal lobule, is thought to be mainly active in resting conditions when individuals are engaged in internally focused tasks including autobiographical memory retrieval, visualizing the future, and conceiving the perspectives of others [13]. Several lines of evidence suggest that in the preclinical stage of AD, beta amyloid deposition is present mainly in DMN regions [14] and that impairment of the DMN may represent a sensitive and specific biomarker of incipient AD. Among the methods proposed for studying the DMN in AD, resting-state fMRI reflects spontaneous neuronal activity and/or the endogenous neurophysiological processes of the human brain in the resting state (see Liu et al. for a review [15]), while H215O PET studies allow analysis of covariance of rest-specific regional cerebral blood flow patterns [16]. Recent combined resting-state fMRI and amyloid PET studies have provided, in vivo, further evidence of the pathophysiological meaning of impaired connectivity in AD. Indeed, two elegant studies, by Drzezga et al. [14] and Sheline et al. [17] (...truncated)


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Silvia Morbelli, Dario Arnaldi, Selene Capitanio, Agnese Picco, Ambra Buschiazzo, Flavio Nobili. Resting metabolic connectivity in Alzheimer’s disease, Clinical and Translational Imaging, 2013, pp. 271-278, Volume 1, Issue 4, DOI: 10.1007/s40336-013-0027-x