Age-related changes in parahippocampal white matter integrity: A diffusion tensor imaging study
Highlights
► Parahippocampal white matter volume is reduced as a consequence of normal aging. ► Age-related microstructural alterations occur in remaining parahippocampal fibers. ► Such changes may lead to partial disconnection of information flow to the hippocampus. ► Parahippocampal changes may contribute to the normal decline in memory seen in aging.
Introduction
The hippocampus, entorhinal cortex (EC), and the parahippocampal region in general have been identified as critical neuroanatomical components of the medial temporal lobe memory system (Squire and Zola-Morgan, 1991, Young et al., 1997). Neurons of the entorhinal cortex receive multimodal sensory information from primary sensory and association cortices (Amaral et al., 1987, Van Hoesen and Pandya, 1975b, Van Hoesen et al., 1975) and relay this information to the hippocampus via the perforant pathway (Hyman et al., 1984, Van Hoesen and Pandya, 1975a). The integrity of this white matter tract is crucial for proper information flow to the hippocampus and, thus, for memory function.
Recent in vivo magnetic resonance imaging (MRI) work from our laboratory demonstrated decreased parahippocampal white matter (PWM) volume, as well as tissue degradation as measured by diffusion tensor imaging (DTI), in the region of the perforant pathway in people with amnestic mild cognitive impairment (aMCI) who are at risk for developing Alzheimer's disease (Rogalski et al., 2009, Stoub et al., 2006) and in those with mild AD (Wang et al., 2010). Similar results have been reported by other laboratories (Kalus et al., 2006, Salat et al., 2010). In addition, these PWM changes were found to be a significant predictor of memory function, suggesting that white matter integrity in the region of the perforant pathway is important for successful memory in humans.
Investigations in animal models of aging have demonstrated that the perforant pathway is altered as a function of the aging process. Although cell numbers remain the same in layer II of the entorhinal cortex, as well as in hippocampal CA3 and dentate gyrus regions (Rasmussen, Schliemann, Sorensen, Zimmer, & West, 1996), there is a reduction in actual synapse numbers in the middle molecular layer of the hippocampal dentate gyrus, especially in rodents with memory dysfunction (Geinisman et al., 1986, Geinisman et al., 1992). Similarly, using synaptophysin immunofluoresence staining as a measure of synaptic loss, Smith, Adams, Gallagher, Morrison and Rapp (2000) also demonstrated alterations in hippocampal connectivity in memory impaired old rodents compared to those without memory dysfunction. In addition, electrophysiological experiments have shown a decrease in the pre-synaptic fiber potential in old rats with age-related memory impairments (Barnes, 1979, Barnes and McNaughton, 1980), suggesting a pruning of axon collaterals from the perforant pathway to the dentate gyrus. If there is a cross-species correspondence in the types of brain changes that occur during aging, then the rodent data predict that humans should also show alterations in the region of the perforant pathway as a function of normal aging. Such changes would be further accentuated by pathological processes predictive of AD.
In fact, a recent investigation from our laboratory has demonstrated that white matter volume changes in the perforant pathway region of the PWM do take place as a function of the aging process in humans (Stoub et al., 2011). It is possible that in addition to age-related volumetric changes, there are micro-structural alterations in remaining fibers in this region that would affect information flow from the entorhinal cortex to the hippocampus. Such micro-structural alterations can be detected in vivo using diffusion tensor imaging (DTI). This technique combines MR diffusion-weighted pulse sequences with tensor mathematics to measure molecular diffusion in three dimensions. Commonly used DTI metrics include mean diffusivity (MD) and fractional anisotropy (FA). MD provides a measure of non-directional diffusion that can be used as a non-invasive proxy measure of the general integrity of tissue. An increase in MD reflects a decrease in the barriers of free diffusion that is thought to be a sign of tissue degradation. In contrast, FA is a scalar metric that describes the directionality of diffusion and offers information about the parallel organization of white matter fibers (Moseley, 2002). In healthy white matter, FA is high because the direction of diffusion is parallel to axon fibers; decreases in FA occur when parallel diffusion is disrupted possibly due to demyelination or axonal damage.
Previous studies that examined age and disease related changes in white matter have reported alterations in FA and MD in multiple white matter regions not only in healthy aging (e.g., Abe et al., 2008, Brickman et al., 2011, Malykhin et al., 2011, Pfefferbaum et al., 2000, Salat et al., 2009, Sasoon et al., 2011, Yassa et al., 2010), but also in people with AD and in those at high risk for developing AD (Huang and Auchus, 2007, Huang et al., 2007, Kalus et al., 2006, Kantarci et al., 2011, Medina et al., 2006, Rogalski et al., 2009, Salat et al., 2010, Wang et al., 2010).
The goal of the present diffusion tensor imaging study was to determine if, in addition to age-related volume loss, there are micro-structural alterations in remaining fibers, specifically in the PWM that includes the perforant pathway, in cognitively healthy older individuals compared to young participants. Such micro-structural alterations in remaining fibers in this region could further degrade information flow from the entorhinal cortex to the hippocampus and affect memory function. In addition to DTI metrics of white matter integrity, we used tractography based on models of coherent directional diffusion across voxels. These models allow the examination of fiber integrity between two regions of interest (ROI) or of fibers passing through a given ROI.
Section snippets
Participants
Participants included 21 young (mean age=25.04 years, range 21–30; 12 male and 9 female) and 21 older, cognitively healthy individuals (mean age=71.5, range 65–86; 8 male and 13 female). We chose these age ranges to clearly separate the younger from the older participants. This specific design allowed us to examine young versus old differences in PWM macro- and micro-structural integrity as opposed to examining the relationship between age as a continuous variable and PWM integrity. Young (YNG)
Results
Yearly clinical examinations indicated that two of the older participants in the study had declined in cognitive status over a two-year follow-up period and had received a diagnosis of MCI. Therefore, the analyses presented below excluded these two individuals.
Demographic data, MMSE scores and episodic memory test scores are presented in Table 1. Examination of outcome variable homogeneity of variance between the young and old groups revealed a significant difference in variance structure only
Discussion
The present study characterized age-related changes in white matter integrity in vivo in the PWM region that includes the perforant pathway using volumetry, DTI and tractography. Our results demonstrate that, in addition to volume changes in the PWM region that includes the perforant pathway as reported by us previously (Stoub et al., 2011), there are micro-structural alterations in remaining fibers that may be occurring as a result of the normal aging process. More specifically, results
Acknowledgments
This work was supported by Grants P01 AG09466 and P30 AG10161 from the National Institute on Aging, National Institutes of Health, the Illinois Department of Public Health and the McKnight Brain Research Foundation. The authors wish to thank Roland Bammer, Ph.D. and Michael E. Moseley, Ph.D. from Stanford University for supplying the pulse sequence used in the diffusion tensor imaging scans.
References (57)
- et al.
Aging in the CNS: Comparison of gray/white matter volume and diffusion tensor data
Neurobiology of Aging
(2008) - et al.
Estimation of the effective self-diffusion tensor from the NMR spin echo
Journal of Magnetic Resonance. Series B
(1994) - et al.
Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI
Journal of Magnetic Resonance. Series B
(1996) - et al.
MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD
Neurobiology of Aging
(2004) - et al.
“Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
Journal of Psychiatric Research
(1975) - et al.
Examining the gateway to the limbic system with diffusion tensor imaging: The perforant pathway in dementia
Neuroimage
(2006) - et al.
White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study
Neurobiology of Aging
(2006) - et al.
Memory impaired aged rats: No loss of principal hippocampal and subicular neurons
Neurobiology of Aging
(1996) - et al.
Age-related alterations in white matter microstructure measured by diffusion tensor imaging
Neurobiology of Aging
(2005) - et al.
Regional white matter volume differences in nondemented aging and Alzheimer's disease
Neuroimage
(2009)
White matter pathology isolates the hippocampal formation in Alzheimer's disease
Neurobiology of Aging
Rate of entorhinal and hippocampal atrophy in incipient and mild AD: Relation to memory function
Neurobiology of Aging
Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis
Neuroimage
Diffusion tensor imaging and aging
Neuroscience and Biobehavioral Reviews
Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: Relations to timed performance
Neurobiology of Aging
Application of Brodmann's area templates for ROI selection in white matter tractography studies
Neuroimage
The relation between global and limbic brain volumes on MRI and cognitive performance in healthy individuals across the age range
Neurobiology of Aging
Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. I. Temporal lobe afferents
Brain Research
Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. III. Efferent connections
Brain Research
Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. II. Frontal lobe afferents
Brain Research
The entorhinal cortex of the monkey: I. Cytoarchitectonic organization
Journal of Comparative Neurology
Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat
Journal of Comparative and Physiological Psychology
Physiological compensation for loss of afferent synapses in rat hippocampal granule cells during senescence
Journal of Physiology
Quantifying age-related myelin breakdown with MRI: Novel therapeutic targets for preventing cognitive decline and Alzheimer's disease
Journal of Alzheimer's Disease: JAD
In vivo fiber tractography using DT-MRI data
Magnetic Resonance in Medicine
Testing the white matter retrogenesis hypothesis of cognitive aging
Neurobiology of Aging
Genuine memory deficits in age-associated memory impairment
Developmental Neuropsychology
Tracking neuronal fiber pathways in the living human brain
Proceedings of the National Academy of Sciences of the United States of America
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