Associations between White Matter Hyperintensities and β Amyloid on Integrity of Projection, Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI

and Limbic Fiber Tracts Measured with Diffusion Tensor MRI. PLoS ONE 8(6): e65175. doi:10.1371/journal.pone.0065175 Associations between White Matter Hyperintensities and b Amyloid on Integrity of Projection, Association, and Limbic Fiber Tracts Measured with Diffusion Tensor MRI Linda L. Chao 0 Charles DeCarli 0 Stephen Kriger 0 Diana Truran 0 Yu Zhang 0 Joel Laxamana 0 Sylvia Villeneuve 0 William J. Jagust 0 Nerses Sanossian 0 Wendy J. Mack 0 Helena C. Chui 0 Michael W. Weiner 0 Karl Herholz, University of Manchester, United Kingdom 0 1 Department of Radiology & Biomedical Imaging, University of California San Francisco , San Francisco , California, United States of America, 2 Center for Imaging of Neurodegenerative Diseases, Veterans Affairs Medical Center , San Francisco, San Francisco , California, United States of America, 3 Department of Neurology, University of California Davis, Davis, California, United States of America, 4 Helen Wills Neuroscience Institute, University of California, Berkeley, California, United States of America, 5 School of Public Health, University of California, Berkeley, California, United States of America, 6 Department of Neurology, University of Southern California, Los Angeles, California, United States of America, 7 Department of Preventive Medicine, University of Southern California , Los Angeles, California , United States of America The goal of this study was to assess the relationship between Ab deposition and white matter pathology (i.e., white matter hyperintensities, WMH) on microstructural integrity of the white matter. Fifty-seven participants (mean age: 7867 years) from an ongoing multi-site research program who spanned the spectrum of normal to mild cognitive impairment (Clinical dementia rating 0-0.5) and low to high risk factors for arteriosclerosis and WMH pathology (defined as WMH volume .0.5% total intracranial volume) were assessed with positron emission tomography (PET) with Pittsburg compound B (PiB) and magnetic resonance and diffusion tensor imaging (DTI). Multivariate analysis of covariance were used to investigate the relationship between Ab deposition and WMH pathology on fractional anisotropy (FA) from 9 tracts of interest (i.e., corona radiata, internal capsule, cingulum, parahippocampal white matter, corpus callosum, superior longitudinal, superior and inferior front-occipital fasciculi, and fornix). WMH pathology was associated with reduced FA in projection (i.e., internal capsule and corona radiate) and association (i.e., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts. Ab deposition (i.e., PiB positivity) was associated with reduced FA in the fornix and splenium of the corpus callosum. There were interactions between PiB and WMH pathology in the internal capsule and parahippocampal white matter, where Ab deposition reduced FA more among subjects with WMH pathology than those without. However, accounting for apoE e4 genotype rendered these interactions insignificant. Although this finding suggests that apoE4 may increase amyloid deposition, both in the parenchyma (resulting in PiB positivity) and in blood vessels (resulting in amyloid angiopathy and WMH pathology), and that these two factors together may be associated with compromised white matter microstructural integrity in multiple brain regions, additional studies with a longitudinal design will be necessary to resolve this issue. - Funding: This work was supported by National Institutes of Health (NIH)/National Institute on Aging (NIA) PO1 AG012435, NIH/NIA P30AG010129 and the NIH/ National Center for Research Resources P41RR023953, which were administered by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, California. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: LC is a PLOS ONE Editorial Board member. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: linda.chao @ucsf.edu Focal and diffuse lesions in the white matter, seen as hyperintensities on T2-weighted magnetic resonance images (MRI) (i.e., white matter hyperintensities; WMH) are the most ubiquitous age-related alteration seen in the brain [1]. From an etiological perspective, heterogeneity exists with respect to the presence of WMH. On one hand, they are related to cardiovascular risk factors, such as hypertension and atherosclerosis [24]. On the other hand, they are abundantly present in patients with an underlying amyloid pathology such as cerebral amyloid angiopathy (CAA) [5]. Another common pathological change in the aging brain is cerebral b-amyloid (Ab) deposition. Ab is the major component of amyloid plaques and has been hypothesized to initiate a pathogenic cascade that eventually leads to Alzheimers disease (AD) [6]. Ab deposition and vascular brain injury frequently coexist [7,8]. We recently showed that aggregate coronary disease risk has a moderately strong association with cerebral amyloid deposition [9], consistent with the theory that vascular risk factors (e.g., low high density lipoportein) contribute to AD pathology [10]. The goal of this study was to assess the relationship between Ab deposition and WMH pathology, defined as greater than 0.5% of total intracranial volume (ICV) [11], on microstructural integrity of the white matter. Diffusion tensor imaging (DTI) measures the organization of fibers within specific white matter tracts [12]. An indirect measure of the coordinated directionality and coherence of fibers within a white matter fiber bundle [13], fractional anisotropy (FA) values typically decrease in the presence of pathology such as stroke [14] and WMH [15]. Here we used DTI to determine the regional pattern of FA disruption associated with WMH pathology and Ab deposition. Based on previous DTI studies in patients with AD and mild cognitive impairment (MCI), a prodromal phase of AD, we hypothesized that Ab deposition would be associated with decreased FA in the limbic circuit [1620] (e.g., cingulum, parahippocampal white matter, and fornix) and posterior regions of the corpus callosum [21,22]. Because the anterior internal capsule and supratentorial white matter are common locations for WMH in the human brain [23], we hypothesized that WMH pathology would be associated with lower FA in projection (e.g., internal capsule and corona radiata) and association (e.g., superior longitudinal, superior and inferior fronto-occipital fasciculi) fiber tracts and in the corpus callosum, the major white matter structure involved in intrahemispheric cortico-cortical communication. Recent epidemiologic studies have noted that risk factors for atherosclerosis (e.g., diabetes mellitus, hypertension, and hyperlipidemia) are also associated with increased risk of incident AD [24,25]. More (...truncated)