Progressive Changes in Hippocampal Resting-state Connectivity Across Cognitive Impairment: A Cross-sectional Study From Normal to Alzheimer Disease

We investigate the changes in functional connectivity of the left and right hippocampus by comparing the resting-state low-frequency fluctuations in the blood oxygen level-dependent signal from these regions with relation to Alzheimer disease (AD) progression. AD patients were divided into subgroups based on the clinical dementia rating (CDR) scores. Patients with amnestic mild cognitive impairment (aMCI) were also analyzed as an intermediate stage between normal controls and AD. We found that the total functional connectivity of both the right and left hippocampus was maintained during aMCI and the early stages of AD and that it decreased in the later stages of AD. However, when total functional connectivity was broken down into specific regions of the brain, we observed increased or decreased connectivity to specific regions beginning with aMCI. Direct correlation analysis in seeding the left hippocampus revealed a significant decrease in the functional connectivity with the posterior cingulate cortex region and lateral parietal areas, and an increase in functional connectivity in and the anterior cingulate cortex beginning with aMCI. In this study, we were able to quantify the deterioration of resting-state hippocampal connectivity with disease severity and formation of compensatory recruitment in the early stages of AD.

[1]  S. Black,et al.  Evidence from Functional Neuroimaging of a Compensatory Prefrontal Network in Alzheimer's Disease , 2003, The Journal of Neuroscience.

[2]  M. Greicius,et al.  Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI , 2004, Proc. Natl. Acad. Sci. USA.

[3]  Miranka Wirth,et al.  Semantic memory involvement in the default mode network: A functional neuroimaging study using independent component analysis , 2011, NeuroImage.

[4]  D. Mann,et al.  Patterns of cerebral amyloid angiopathy define histopathological phenotypes in Alzheimer's disease , 2014, Neuropathology and applied neurobiology.

[5]  D. Selkoe.  Alzheimer's disease. , 2011, Cold Spring Harbor perspectives in biology.

[6]  B. Dubois.  'Prodromal Alzheimer's disease': a more useful concept than mild cognitive impairment? , 2000, Current opinion in neurology.

[7]  Maja A. A. Binnewijzend,et al.  Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment , 2012, Neurobiology of Aging.

[8]  J. Morris.  The Clinical Dementia Rating (CDR) , 1993, Neurology.

[9]  P. Tariot,et al.  A 5-month, randomized, placebo-controlled trial of galantamine in AD , 2000, Neurology.

[10]  Marcus E. Raichle,et al.  The Restless Brain , 2011, Brain Connect..

[11]  Dong Young Lee,et al.  Topographic Patterns of Brain Functional Impairment Progression According to Clinical Severity Staging in 116 Alzheimer Disease Patients: FDG-PET Study , 2007, Alzheimer disease and associated disorders.

[12]  Harald Hampel,et al.  Diagnostic power of default mode network resting state fMRI in the detection of Alzheimer's disease , 2012, Neurobiology of Aging.

[13]  Zhi-jun Zhang,et al.  Resting brain connectivity: changes during the progress of Alzheimer disease. , 2010, Radiology.

[14]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[15]  D. Head,et al.  Amyloid Plaques Disrupt Resting State Default Mode Network Connectivity in Cognitively Normal Elderly , 2010, Biological Psychiatry.

[16]  Edgar Erdfelder,et al.  G*Power 3: A flexible statistical power analysis program for the social, behavioral, and biomedical sciences , 2007, Behavior research methods.

[17]  Tianzi Jiang,et al.  Changes in hippocampal connectivity in the early stages of Alzheimer's disease: Evidence from resting state fMRI , 2006, NeuroImage.

[18]  Katherine E. Prater,et al.  Functional connectivity tracks clinical deterioration in Alzheimer's disease , 2012, Neurobiology of Aging.

[19]  R. Buckner.  Memory and Executive Function in Aging and AD Multiple Factors that Cause Decline and Reserve Factors that Compensate , 2004, Neuron.

[20]  J. Callicott,et al.  Age-related alterations in default mode network: Impact on working memory performance , 2010, Neurobiology of Aging.

[21]  R. Mohs,et al.  A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease , 1998, Neurology.

[22]  Zhi-jun Zhang,et al.  Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer’s disease , 2009, Behavioural Brain Research.

[23]  Walter Schneider,et al.  Identifying the brain's most globally connected regions , 2010, NeuroImage.

[24]  James T. Becker,et al.  Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B , 2008, Journal of Neuroscience Methods.

[25]  Florence Rémy,et al.  Verbal episodic memory impairment in Alzheimer's disease: a combined structural and functional MRI study , 2005, NeuroImage.

[26]  Sang Won Seo,et al.  Clinical Characteristics of a Nationwide Hospital-based Registry of Mild-to-Moderate Alzheimer's Disease Patients in Korea: A CREDOS (Clinical Research Center for Dementia of South Korea) Study , 2011, Journal of Korean medical science.

[27]  F. Schmitt,et al.  Synaptic alterations in CA1 in mild Alzheimer disease and mild cognitive impairment , 2007, Neurology.

[28]  Stephen M. Smith,et al.  A global optimisation method for robust affine registration of brain images , 2001, Medical Image Anal..

[29]  Zhijun Zhang,et al.  Aberrant Hippocampal Subregion Networks Associated with the Classifications of aMCI Subjects: A Longitudinal Resting-State Study , 2011, PloS one.

[30]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[31]  J. Morris,et al.  Loss of Intranetwork and Internetwork Resting State Functional Connections with Alzheimer's Disease Progression , 2012, The Journal of Neuroscience.

[32]  J. Logan,et al.  Under-Recruitment and Nonselective Recruitment Dissociable Neural Mechanisms Associated with Aging , 2002, Neuron.

[33]  R. Petersen,et al.  Aging, Memory, and Mild Cognitive Impairment , 1997, International Psychogeriatrics.

[34]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[35]  S. Rombouts,et al.  Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: An fMRI study , 2005, Human brain mapping.

[36]  Jee Hoon Roh,et al.  Neuronal activity regulates the regional vulnerability to amyloid-β deposition , 2011, Nature Neuroscience.

[37]  L Amaducci,et al.  Magnetic resonance measures in Alzheimer disease: their utility in early diagnosis and evaluating disease progression. , 1999, Alzheimer disease and associated disorders.

[38]  E. Tangalos,et al.  Mild Cognitive Impairment Clinical Characterization and Outcome , 1999 .

[39]  H. Soininen,et al.  Hippocampus and entorhinal cortex in mild cognitive impairment and early AD , 2004, Neurobiology of Aging.

[40]  Scott T. Grafton,et al.  Compensatory recruitment of neural resources during overt rehearsal of word lists in Alzheimer's disease. , 1998, Neuropsychology.

[41]  M. Roth,et al.  Neurofibrillary degeneration and neuronal loss in alzheimer's disease , 1989, Neurobiology of Aging.

[42]  Marco Valenti,et al.  Olfactory Deficit and Hippocampal Volume Loss for Early Diagnosis of Alzheimer Disease: A Pilot Study , 2014, Alzheimer disease and associated disorders.

[43]  Michael D Rugg,et al.  Encoding and the Durability of Episodic Memory: A Functional Magnetic Resonance Imaging Study , 2005, The Journal of Neuroscience.

[44]  Keith A. Johnson,et al.  Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia , 2009, Neuron.

[45]  A. Fleisher,et al.  Altered default mode network connectivity in alzheimer's disease—A resting functional MRI and bayesian network study , 2011, Human brain mapping.

[46]  R. Nagel,et al.  Neural correlates of depth of strategic reasoning in medial prefrontal cortex , 2009, Proceedings of the National Academy of Sciences.

[47]  Benjamin J. Shannon,et al.  Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory , 2005, The Journal of Neuroscience.

[48]  N. Burgess,et al.  The hippocampus and memory: insights from spatial processing , 2008, Nature Reviews Neuroscience.

[49]  Keith A. Johnson,et al.  Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden , 2011, Alzheimer's & Dementia.

[50]  B. Levin,et al.  Predominant left hemisphere metabolic dysfunction in dementia. , 1989, Archives of neurology.

[51]  M. W. Brown,et al.  Episodic memory, amnesia, and the hippocampal–anterior thalamic axis , 1999, Behavioral and Brain Sciences.

[52]  G. E. Alexander,et al.  Activation of brain regions vulnerable to Alzheimer's disease: The effect of mild cognitive impairment , 2006, Neurobiology of Aging.

[53]  R. K. Hutson,et al.  Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer's disease and mild cognitive impairment , 2008, Alzheimer's & Dementia.

[54]  G. V. Prisco,et al.  Theta-rhythmically firing neurons in the anterior thalamus: implications for mnemonic functions of Papez’s circuit , 2001, Neuroscience.

[55]  Sang Won Seo,et al.  Seoul Neuropsychological Screening Battery-Dementia Version (SNSB-D): A Useful Tool for Assessing and Monitoring Cognitive Impairments in Dementia Patients , 2010, Journal of Korean medical science.

[56]  G. Frisoni,et al.  Resting state fMRI in Alzheimer's disease: beyond the default mode network , 2012, Neurobiology of Aging.

[57]  Denise C. Park,et al.  Beta-Amyloid Deposition and the Aging Brain , 2009, Neuropsychology Review.

[58]  R. Mayeux,et al.  Hippocampal and entorhinal atrophy in mild cognitive impairment , 2007, Neurology.

[59]  J. Sepulcre,et al.  Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden , 2011, Alzheimer's & Dementia.