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      The effect of white matter hyperintensities on statistical analysis of diffusion tensor imaging in cognitively healthy elderly and prodromal Alzheimer's disease

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          Abstract

          Diffusion tensor imaging (DTI) has been used to study microstructural white matter alterations in a variety of conditions including normal aging and Alzheimer's disease (AD). White matter hyperintensities (WMH) are common in cognitively healthy elderly as well as in AD and exhibit elevated mean diffusivity (MD) and reduced fractional anisotropy (FA). However, the effect of WMH on statistical analysis of DTI estimates has not been thoroughly studied. In the present study we address this in two ways. First, we investigate the effect of WMH on MD and FA in the dorsal and ventral cingulum, the superior longitudinal fasciculus, and the corticospinal tract, by comparing two matched groups of cognitively healthy elderly ( n = 21 + 21) with unequal WMH load. Second, we assess the effects of adjusting for WMH load when comparing MD and FA in prodromal AD subjects ( n = 83) to cognitively healthy elderly ( n = 132) in the abovementioned white matter tracts. Results showed the WMH in cognitively healthy elderly to have a generally large effect on DTI estimates (Cohen’s d = 0.63 to 1.27 for significant differences in MD and −1.06 to −0.69 for FA). These effect sizes were comparable to those of various neurological and psychiatric diseases (Cohen’s d = 0.57 to 2.20 for differences in MD and −1.76 to −0.61 for FA). Adjusting for WMH when comparing DTI estimates in prodromal AD subjects to cognitively healthy elderly improved the explanatory power as well as the outcome of the analysis, indicating that some of the differences in MD and FA were largely driven by unequal WMH load between the groups rather than alterations in normal-appearing white matter (NAWM). Thus, our findings suggest that if the purpose of a study is to compare alterations in NAWM between two groups using DTI it may be necessary to adjust the statistical analysis for WMH.

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          Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study.

          Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people. Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information. Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P < .01) and independently associated with increased grade were greater age, clinically silent stroke on MRI, higher systolic blood pressure, lower forced expiratory volume in 1 second (FEV1), and income less than $50,000 per year. If excluded, FEV1 was replaced in the model by female sex, history of smoking, and history of physician-diagnosed hypertension at the baseline examination. Many clinical features were correlated with the white matter grade, especially those indicating impaired cognitive and lower extremity function. White matter findings were significantly associated with age, silent stroke, hypertension, FEV1, and income. The white matter findings may not be considered benign because they are associated with impaired cognitive and lower extremity function.
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            DTI measures in crossing-fibre areas: increased diffusion anisotropy reveals early white matter alteration in MCI and mild Alzheimer's disease.

            Though mild cognitive impairment is an intermediate clinical state between healthy aging and Alzheimer's disease (AD), there are very few whole-brain voxel-wise diffusion MRI studies directly comparing changes in healthy control, mild cognitive impairment (MCI) and AD subjects. Here we report whole-brain findings from a comprehensive study of diffusion tensor indices and probabilistic tractography obtained in a very large population of healthy controls, MCI and probable AD subjects. As expected from the literature, all diffusion indices converged to show that the cingulum bundle, the uncinate fasciculus, the entire corpus callosum and the superior longitudinal fasciculus are the most affected white matter tracts in AD. Significant differences between MCI and AD were essentially confined to the corpus callosum. More importantly, we introduce for the first time in a degenerative disorder an application of a recently developed tensor index, the "mode" of anisotropy, as well as probabilistic crossing-fibre tractography. The mode of anisotropy specifies the type of anisotropy as a continuous measure reflecting differences in shape of the diffusion tensor ranging from planar (e.g., in regions of crossing fibres from two fibre populations of similar density or regions of "kissing" fibres) to linear (e.g., in regions where one fibre population orientation predominates), while probabilistic crossing-fibre tractography allows to accurately trace pathways from a crossing-fibre region. Remarkably, when looking for whole-brain diffusion differences between MCI patients and healthy subjects, the only region with significant abnormalities was a region of crossing fibres in the centrum semiovale, showing an increased mode of anisotropy. The only white matter region demonstrating a significant difference in correlations between neuropsychological scores and a diffusion measure (mode of anisotropy) across the three groups was the same region of crossing fibres. Further examination using probabilistic tractography established explicitly and quantitatively that this previously unreported increase of mode and co-localised increase of fractional anisotropy was explained by a relative preservation of motor-related projection fibres (at this early stage of the disease) crossing the association fibres of the superior longitudinal fasciculus. These findings emphasise the benefit of looking at the more complex regions in which spared and affected pathways are crossing to detect very early alterations of the white matter that could not be detected in regions consisting of one fibre population only. Finally, the methods used in this study may have general applicability for other degenerative disorders and, beyond the clinical sphere, they could contribute to a better quantification and understanding of subtle effects generated by normal processes such as visuospatial attention or motor learning. Copyright © 2010 Elsevier Inc. All rights reserved.
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              The Malmö Diet and Cancer Study: representativity, cancer incidence and mortality in participants and non-participants.

              In order to investigate potential selection bias in population-based cohort studies, participants (n = 28098) and non-participants (n = 40807) in the Malmö Diet and Cancer Study (MDCS) were compared with regard to cancer incidence and mortality. MDCS participants were also compared with participants in a mailed health survey with regard to subjective health, socio-demographic characteristics and lifestyle. Cancer incidence prior to recruitment was lower in non-participants, Cox proportional hazards analysis yielded a relative risk (RR) with a 95% confidence interval of 0.95 (0.90-1.00), compared with participants. During recruitment, cancer incidence was higher in non-participants, RR: 1.08 (1.01-1.17). Mortality was higher in non-participants both during, 3.55 (3.13-4.03), and following the recruitment period, 2.21 (2.03-2.41). The proportion reporting good health was higher in the MDCS than in the mailed health survey (where 74.6% participated), but the socio-demographic structure was similar. We conclude that mortality is higher in non-participants than in participants during recruitment and follow-up. It is also suggested that non-participants may have a lower cancer incidence prior to recruitment but a higher incidence during the recruitment period.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: MethodologyRole: SoftwareRole: Supervision
                Role: Data curationRole: Formal analysis
                Role: Data curationRole: Software
                Role: Funding acquisitionRole: Project administrationRole: Resources
                Role: Funding acquisitionRole: Project administrationRole: Resources
                Role: Funding acquisitionRole: Project administrationRole: Resources
                Role: Funding acquisitionRole: Project administrationRole: Resources
                Role: ConceptualizationRole: MethodologyRole: Supervision
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                21 September 2017
                2017
                : 12
                : 9
                : e0185239
                Affiliations
                [1 ] Diagnostic Radiology, Lund University, Lund, Sweden
                [2 ] Medical Imaging and Physiology, Skåne University Hospital, Lund, Sweden
                [3 ] Lund University Bioimaging Center, Lund University, Lund, Sweden
                [4 ] Medical Radiation Physics, Lund University, Lund, Sweden
                [5 ] Clinical Memory Research, Lund University, Malmoö, Sweden
                [6 ] Memory Clinic, Skåne University Hospital, Lund, Sweden
                Brainnetome Center & The National Laboratory of Pattern Recognition, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4487-6229
                Article
                PONE-D-17-12299
                10.1371/journal.pone.0185239
                5608410
                28934374
                dfc3dfd2-f4bd-4f09-9c6b-570da326bbc9
                © 2017 Svärd et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 29 March 2017
                : 9 September 2017
                Page count
                Figures: 2, Tables: 4, Pages: 16
                Funding
                The study was supported by the European Research Council, the Swedish Research Council, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Crafoord Foundation, the Swedish Brain Foundation, the Skåne University Hospital Foundation, the Swedish Alzheimer Association, Stiftelsen för gamla tjänarinnor, and the Swedish Federal Government under the ALF Agreement. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Mental Health and Psychiatry
                Dementia
                Alzheimer's Disease
                Medicine and Health Sciences
                Neurology
                Dementia
                Alzheimer's Disease
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Alzheimer's Disease
                Medicine and Health Sciences
                Geriatrics
                People and Places
                Population Groupings
                Age Groups
                Elderly
                Biology and Life Sciences
                Anatomy
                Nervous System
                Central Nervous System
                Medicine and Health Sciences
                Anatomy
                Nervous System
                Central Nervous System
                Biology and Life Sciences
                Neuroscience
                Brain Mapping
                Brain Morphometry
                Diffusion Tensor Imaging
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Tensor Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Tensor Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Magnetic Resonance Imaging
                Brain Morphometry
                Diffusion Tensor Imaging
                Research and Analysis Methods
                Imaging Techniques
                Neuroimaging
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                Diffusion Tensor Imaging
                Biology and Life Sciences
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                Neuroimaging
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                Cognitive Science
                Cognitive Neuroscience
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                Social Sciences
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                Custom metadata
                Raw image data cannot be made publicly available due to restrictions imposed by Swedish law and the Regionala Etikprövningsnämnden of Lund, Sweden. Requests for data can be sent to the corresponding author, Daniel Svärd ( daniel.svard@ 123456med.lu.se ).

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