Discrimination of normal aging, MCI and AD with multimodal imaging measures on the medial temporal lobe
Introduction
As the possibility of an effective disease modifying treatment against Alzheimer's disease (AD) increases (Cummings et al., 2007), accurate detection and progression monitoring of early stage of AD or its preclinical state, mild cognitive impairment (MCI) (Petersen, 2004), has recently become more important. In this context, various neuroimaging modalities have been increasingly recognized because of their potential to overcome the limitations of clinical and neuropsychological approaches (de Leon et al., 2007).
The neuropathological changes such as neurofibrillary tangle deposition, synaptic damage, and neuronal loss in AD have been known to begin in the medial temporal region encompassing the hippocampus (Braak and Braak, 1991, Ball, 1997). The hippocampus is also known to be a major neural structure related to episodic memory (Deweer et al., 2001), which is the earliest and most severely impaired cognitive function in AD (Soininen and Scheltens, 1998). Therefore, many structural and functional neuroimaging studies for the early discrimination of AD process have focused on the hippocampus and adjacent medical temporal lobe (MTL) structures.
Numerous MRI studies consistently reported hippocampal atrophy in MCI (Pihlajamäki et al., 2009) or AD (De Santi et al., 2001, Kesslak et al., 1991, Jack et al., 1992, Chételat et al., 2008). Several recent studies have also shown hippocampal hypometabolism in mild AD or MCI (De Santi et al., 2001, Nestor et al., 2003, Mevel et al., 2007). In terms of the white matter tracts adjacent to the hippocampus or other medial temporal structures, several recent diffusion tensor imaging (DTI) studies demonstrated significantly decreased fractional anisotropy (FA), a quantitative measure sensitively reflecting the microstructural integrity of white matter fibers (Assaf and Pasternak, 2008), of the parahippocampal cingulum in MCI and AD (Zhang et al., 2007, Choo et al., 2010).
Therefore, each of these imaging measures on medial temporal structures, i.e., hippocampal volume, hippocampal glucose metabolism, and parahippocampal cingulum FA, has a potential for the early detection of preclinical or clinical AD. Several studies compare those modalities for this purpose (De Santi et al., 2001, Walhovd et al., 2009, Wang et al., 2009, Matsunari et al., 2007). However, most of them did not deal with all the three simultaneously for the same subjects. One recent study (Walhovd et al., 2009) investigated the combination effect of MR morphometry, PET metabolism, and DTI FA, and reported that higher diagnostic accuracy was achieved when three methods were combined, but it only focused on the differentiation MCI from normal control (NC) with no consideration of NC vs. AD or MCI vs. AD discrimination.
In this study, we compared the accuracy of hippocampal volume (HC-Vol), parahippocampal cingulum FA (PHC-FA), hippocampal glucose metabolism (HC-Glu), and any combination of the three measurements for NC vs. MCI, NC vs. MCI, and MCI vs. AD discrimination, respectively, in order to find out useful neuroimaging markers for early detection of preclinical and clinical AD. Additionally, we tried to investigate the relationship of the three imaging measures with episodic memory tests to validate these imaging measures as a tool for early AD progression monitoring.
Section snippets
Subjects
17 MCI and 17 AD patients were recruited from a cohort regularly followed at the Dementia & Age-Associated Cognitive Decline Clinic at Seoul National University Hospital. Individuals with MCI met recent criteria for amnestic MCI (9 single amnestic and 8 multi-domain amnestic MCI cases) (Winblad et al., 2004, Petersen, 2004). AD patients met both the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for dementia (American Psychiatric Association, 1994) and the National
Subject characteristics
Subject demographic characteristics and the mean values of HC-Vol, PHC-FA, and HC-Glu are presented in Table 1.
Selection of diagnostic models for between-group discriminations
Before proceeding to model selection process using logistic regression analyses, we checked the intercorrelation matrix derived from the three imaging measures in order to identify any multicollinearity among them. HC-V showed significant, but weak correlation with HC-Glu (Pearson's r = 0.295, P = 0.035), while there was no significant correlation between PHC-FA and HC-Vol or between
NC versus MCI discrimination
When only one candidate models were considered, PHC-FA was the only significant discriminator between NC and MCI, whereas HC-Vol or HC-Glu was not. Such a superior diagnostic ability of PHC-FA for MCI, corresponding to the preclinical state of AD, is probably explained by its direct connection with the entorhinal cortex, in which the earliest neuropathological changes of AD occur (Braak and Braak, 1991). Although the cingulum is known to start from the medial temporal region (Wakana et al., 2004
Conclusions
Our results suggest that, in terms of between-group discrimination by using multimodal imaging measures of MTL structures, stage-specific potential of each imaging measure or their combination as a useful neuroimaging marker for early detection or progression monitoring of MCI and clinical AD. Parahippocampal cingulum FA decline, especially considered with hippocampal atrophy, is probably helpful for MCI discrimination from normal aging, whereas hippocampal hypometabolism is more useful for the
Acknowledgements
This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (Grant No.: A070001) and by a grant from Kangwon National University.
References (45)
- et al.
Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies
Progress in Neurobiology
(2002) - et al.
Altered synaptic function in Alzheimer's disease
European Journal of Pharmacology
(2006) - et al.
Functional compensation in incipient Alzheimer's disease
Neurobiology of Aging
(2010) - et al.
Virtual in vivo interactive dissection of white matter fasciculi in the human brain
NeuroImage
(2002) - et al.
Posterior cingulate cortex atrophy and regional cingulum distruption in mild cognitive impairment and Alzheimer's disease
Neurobiology of Aging
(2010) - et al.
Hippocampal formation glucose metabolism and volume losses in MCI and AD
Neurobiology of Aging
(2001) - et al.
Is the HM story only a “remote memory”? Some facts about hippocampus and memory in humans
Behavioural Brain Research
(2001) - et al.
Detecting hippocampal hypometabolism in mild cognitive impairment using automatic voxel-based approaches
Neuroimage
(2007) - et al.
Functional implications of hippocampal volume and diffusivity in mild cognitive impairment
NeuroImage
(2005) - et al.
Tractography-guided statistics (TGIS) in diffusion tensor imaging for the detection of gender difference of fiber integrity in the midsagittal and parasagittal corpora callosa
NeuroImage
(2007)
Hippocampus and entorhinal cortex in mild cognitive impairment and early AD
Neurobiology of Aging
Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network
Neuroimage
The commissural connections of the monkey hippocampal formation
The Journal of Comparative Neurology
Diagnostic and Statistical Manual of Mental Disorders
Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review
Journal of Molecular Neuroscience
Neuronal loss, neurofibrillary tangles and granulovacuolar degeneration in the hippocampus with ageing and dementia
Acta Neuropathologica
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathologica
Dissociating atrophy and hypometabolism impact on episodic memory in mild cognitive impairment
Brain
Direct voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer's disease
Brain
Disease-modifying therapies for Alzheimer's disease: challenges to early intervention
Neurology
Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease
Annals of the New York Academy of Sciences
Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment
Annals of Neurology
Cited by (40)
White matter microstructural abnormalities in amnestic mild cognitive impairment: A meta-analysis of whole-brain and ROI-based studies
2017, Neuroscience and Biobehavioral ReviewsSingle time point high-dimensional morphometry in Alzheimer's disease: Group statistics on longitudinally acquired data
2015, Neurobiology of AgingCitation Excerpt :To this end, over the last decade a number of techniques have attempted to characterize mono-or multimodal image information and embed machine learning principles to both characterize and discriminate subject populations (Orru et al., 2012). There is increasing evidence that this family of algorithms allows for better discrimination of AD and prediction of conversion in MCI from a number of reports (Cuingnet et al., 2011; Fan et al., 2008; Jhoo et al., 2010; Kloppel et al., 2008; Koikkalainen et al., 2011; López et al., 2011; Misra et al., 2009; Vemuri et al., 2008; Westman et al., 2011; Zhang et al., 2011). Notable works include Davatzikos et al. (2008) who reported a high degree of accuracy in prediction using a high-dimensional image analysis and pattern classification technique; Fan et al. (2008) who extended this work to combine MRI and positron emission tomography analysis to yield very high predictive accuracy in 30 MCI subjects with area under curve of 0.98; and Hua et al. (2009) who used tensor-based morphometry-derived summary statistics to show that sample sizes can be greatly reduced compared with clinical metrics.
Beta-amyloid associated differential effects of APOE ε4 on brain metabolism in cognitively normal elderly
2014, American Journal of Geriatric PsychiatryCitation Excerpt :Subjects took a supine position with their eyes closed during the scanning in order to minimize the confounding effects of any activity. More specific information for image acquisition procedures was previously described in detail.21 Imaging data were preprocessed using Statistical Parametric Mapping 8 (SPM8) (Institute of Neurology, University College of London, United Kingdom) implemented in Matlab (Mathworks, Inc., Natick, MA).
Hippocampus, caudate nucleus and entorhinal cortex volumetric MRI measurements in discrimination between Alzheimer's disease, mild cognitive impairment, and normal aging
2014, Egyptian Journal of Radiology and Nuclear MedicineCitation Excerpt :This also more accurate than results using caudate nucleus alone as it can be atrophied in other diseases as Huntington’s disease (27). Hippocampal volume was significantly smaller in patients with Mild Cognitive Impairment than in controls in the present study, a finding consistent with other reports (8,9,28). This finding is important in improving the prognosis of the disease and to predict more rapid deterioration to clinical Alzheimer’s disease for early effective treatment.
Meta-analysis of functional network alterations in Alzheimer's disease: Toward a network biomarker
2013, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Therefore, the use of visual rating scales to assess atrophy in the medial temporal regions is nowadays part of the clinical routine (Scheltens et al., 1992). Unfortunately, the sensitivity of medial temporal atrophy for predicting AD in the earliest stages is only modest (Fleisher et al., 2008; Jacobs et al., 2011; Jhoo et al., 2010). Furthermore, medial temporal lobe (MTL) atrophy is not specific for AD, as it is also present in other neurodegenerative diseases such as hippocampal sclerosis, dementia with Lewy-bodies, and argyrophilic grain disease, depression and in healthy aging (Barkhof et al., 2007).
The effect of healthy aging and mild cognitive impairment on semantic ambiguity detection
2013, Journal of NeurolinguisticsCitation Excerpt :Neuroimaging studies suggest similar sites of neuropathology associated with AD and MCI. The degree of hippocampal atrophy has been found to be similar in MCI and AD patients (Du et al., 2001; Jack et al., 1997) and imaging studies that demonstrate neuroanatomical distinct profiles still reveal overlapping areas (Jhoo et al., 2010; Sexton et al., 2010). The early characterization of MCI was episodic memory impairment with other cognitive functions relatively preserved (Morris et al., 2001; Petersen et al., 1999).