White matter pathology isolates the hippocampal formation in Alzheimer's disease
Introduction
Careful histological examination of the brains of individuals with Alzheimer's disease (AD) has uncovered a probable substrate for the memory impairment in this condition. Specifically, layer-preferred degeneration in perirhinal and entorhinal cortices likely impedes the transfer of information from the neocortex to the hippocampus (Ball, 1978, Braak and Braak, 1991, Gomez-Isla et al., 1996, Hyman et al., 1984, Hyman et al., 1986, Van Hoesen et al., 1991), thereby degrading the processing and storage of sensory input. Layer II of the entorhinal cortex shows profound alterations, including substantial loss of neurons even in the early stages of AD (Gomez-Isla et al., 1996). The projection termination zone of these fibers in the dentate gyrus of the hippocampal formation is also marked by degenerative changes, effectively resulting in a ‘disconnection’ between association and limbic cortices (Hyman et al., 1984, Hyman et al., 1986). Given these important pathologic signatures, the majority of studies of mechanisms of AD symptomology have focused on medial temporal lobe (MTL) cortical degeneration. Nevertheless, these prior findings also implicate regional connectivity as a factor contributing to cognitive deterioration. Histological research demonstrates that brain white matter (WM) also degenerates in AD (Brun and Englund, 1986, Englund and Brun, 1990, Englund et al., 1988, Hyman et al., 1986). Brun and Englund (1986) reported a syndrome in 60% of AD patients of demyelination and axonal and oligodendroglial loss with accompanying gliosis in the deep WM that was independent from gray matter lesions. The authors suggested that the degeneration was potentially due to comorbid factors such as hypertension (Brun and Englund, 1986). WM disease, however, has been reported at autopsy in individuals with pure AD with no components of vascular brain disease (Sjobeck et al., 2006). Further, myelin staining is reduced in the perforant pathway, the main input fibers projecting neocortical information from the entorhinal cortex to the granule cells of the dentate gyrus in the hippocampal formation (Hyman et al., 1986). These findings suggest that at least some of the WM changes in AD are not due simply to comorbid factors, but are likely associated with AD pathological processes including MTL cortical pathology. The pathologic signatures spanning the perforant pathway, and the reduction in myelin integrity of this fascicle, underscores the potential influence of regional connectivity in the putative propagation of neurodegenerative events. An open question is whether such changes could be detected in patients in vivo, and whether this principal of degeneration in anatomically connected regions extends beyond the findings in the perforant pathway.
Neuroimaging studies have attempted to understand patterns and mechanisms of WM pathology in AD, and the clinical significance of such changes (de Leeuw et al., 2006), but the regional patterns and potential mechanisms of this WM pathology are still unclear. Moreover, whether WM changes are independent of classically described AD cortical pathology, such as hippocampal atrophy, is completely unknown. Total and regional WM volume is reduced in AD (Fotenos et al., 2005, Jernigan et al., 1991, Salat et al., 1999a, Salat et al., 1999b, Salat et al., 2001, Stout et al., 1996), and WM signal abnormalities are associated with risk for cognitive decline (Au et al., 2006) and dementia (Prins et al., 2004), as well as an enhanced clinical syndrome in specific cognitive domains (Hirono et al., 2000). The use of WM signal abnormalities as a clinically relevant measure of WM pathology remains controversial because a number of studies report little consequence of this marker on clinical status (Mungas et al., 2005, Schmidt et al., 2002). Additionally, WM volume measures are limited because of the need to define regionally identifiable borders using morphometric landmarks, a particularly difficult task given the complex anatomy of WM and the limited information provided about this anatomy from a standard structural MR image.
Diffusion tensor imaging (DTI) has been applied extensively to understand the regional basis of tissue degeneration in a variety of clinical conditions including the study of normal aging (Moseley, 2002, Pfefferbaum et al., 2000, Pfefferbaum et al., 2005, Pfefferbaum and Sullivan, 2003, Salat et al., 2005a, Salat et al., 2005b, Sullivan et al., 2001, Sullivan et al., 2006, Sullivan and Pfefferbaum, 2006). Two primary metrics of the diffusion properties within a voxel, termed diffusivity and fractional anisotropy (FA) (Basser, 1995, Basser and Pierpaoli, 1996, Pierpaoli and Basser, 1996), have been commonly employed as indices of tissue pathology. More recently, studies by Song and colleagues utilizing animal models demonstrate that the diffusivity measure can be further subdivided in to axial and radial components, which could provide information on axonal and myelin pathology selectively (Budde et al., 2007, Song et al., 2002, Song et al., 2003). Rose and colleagues (Rose et al., 2000) demonstrated altered diffusion measures in the splenium of the corpus callosum, the superior longitudinal fasciculus, cingulum, and internal capsule in patients with AD, and in parahippocampal, thalamic, and cingulate WM in individuals with mild cognitive impairment (Rose et al., 2006). Diffusion measures were related to indices of disease severity and cognitive ability and the specific association with episodic memory presents a potential clinical role for DTI to index WM degeneration and track AD symptoms. Other studies have found altered diffusion measures in patients with AD in the uncinate and inferior occipital fasciculi (Taoka et al., 2006), and in the corpus callosum and WM of the frontal, temporal, and parietal lobes (Bozzali et al., 2002). Two studies in AD (Head et al., 2004, Medina et al., 2006) demonstrated generalized alterations in diffusion measures of posterior lobar WM that differed from those seen in normal aging. Two recent studies provide preliminary investigation into mechanisms of WM alteration in AD through the examination of axial and radial diffusivity (Choi et al., 2005, Huang et al., 2007). These studies examined selected regions of interest in small participant samples (10 AD in the former, and 6 AD in the latter study), and reached different conclusions with one focusing on compromised myelin (Choi et al., 2005) and the other suggesting loss of axonal processes as a primary pathologic mechanism (Huang et al., 2007). These prior studies provide important information about the regional patterns of AD pathology, yet questions remain about the whole brain patterns of WM change in these various diffusion parameters in AD. Additionally, no prior study has examined how classically described measures of pathology such as white matter signal abnormalities and hippocampal atrophy contribute to the changes measured.
The current study aimed to elucidate regional patterns of alterations in diffusion parameters in AD through a comprehensive, whole brain analysis of commonly and recently described DTI measures of tissue integrity. These analyses included the examination of anisotropy and axial and radial diffusivity components, and whether changes in these diffusion parameters provide information beyond traditional MRI measures of gray and WM degeneration. We used recently developed procedures in the FSL image analysis suite (http://www.fmrib.ox.ac.uk/fsl/) for interparticipant registration, reducing potential confounds in spatial normalization. We additionally utilized tractography procedures to define a path of interest (POI) in the native space of each individual to confirm voxel-based results. We find complex regional patterns of alterations in diffusion parameters with AD, with prominent changes in pathways associated with the hippocampal formation. These changes are beyond what can be explained by classically described AD pathology, and suggest that multiple pathologies may disrupt the transfer of neocortical information to limbic structures important for a range of cognitive processes.
Section snippets
Participants
Images were obtained for 74 participants (Table 1). Twenty patients with probable Alzheimer's disease (mean age 77.8 ± 4.9 years) were recruited through the Massachusetts General Hospital Memory Disorders Unit (MGH-MDU) and 54 non-demented older adults (OA, mean age 75.8 ± 5.6 years) through the Harvard Cooperative Program on Aging (http://www.hebrewrehab.org/home institute.cfm?id=90) and the Nurses’ Health Study (http://www.channing.harvard.edu/nhs/) at Harvard Medical School and Brigham and
Voxel-based group comparisons of DTI measures
Fig. 1 demonstrates a coronal slice showing the mean FA map of each group from the spatially normalized FA volumes using the IRTK nonlinear registration step (Rueckert et al., 1999) of the tract-based spatial statistics (TBSS) (Smith et al., 2006) procedure (top), and a representative individual FA map (bottom) from the OA (left) and the AD (right) groups. Importantly, much of the anatomic detail of the individual participant volumes was retained in this initial processing of the TBSS procedure.
Discussion
These data demonstrate for the first time, the distinct and overlapping anatomy of whole brain changes in anisotropy and diffusivity, as well as the differential patterns of alterations in axial and radial diffusivity. These different diffusion parameters provide unique information, and the results demonstrate the complex anatomical basis of DTI changes in AD. To a certain extent, the most prominent regional tissue changes in overlapping diffusion parameters resembled the anatomic connectivity
Acknowledgements
This work was supported in part by NIH K01AG024898, a Massachusetts Alzheimer's Disease Research Center Pilot Grant 2001/2002 (AG05886), the National Center for Research Resources (P41RR14075), the Mental Illness and Neuroscience Discovery (MIND) Institute, and a grant from the National Alliance for Medical Image Computing (NAMIC U54 EB05149). We thank Dr. Francine Grodstein and the Nurses’ Health Study for a portion of the participant recruitment and imaging.
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